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9cbe24fead2b97f7d681531145b58b1c1b461b2d	wikidoc	Finasteride	Finasteride # Disclaimer WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here. # Overview Finasteride is a 5α-reductase inhibitor that is FDA approved for the {{{indicationType}}} of symptomatic benign prostatic hyperplasia (BPH). Common adverse reactions include impotence, decreased libido, decreased volume of ejaculate, breast enlargement, breast tenderness and rash. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) - Finasteride tablets USP, are indicated for the treatment of symptomatic benign prostatic hyperplasia (BPH) in men with an enlarged prostate to: - Improve symptoms - Reduce the risk of the need for surgery including transurethral resection of the prostate (TURP) and prostatectomy. - The recommended dose of finasteride tablet USP are one tablet (5 mg) taken once a day - Finasteride tablets USP administered in combination with the alpha-blocker doxazosin is indicated to reduce the risk of symptomatic progression of BPH (a confirmed ≥4 point increase in American Urological Association (AUA) symptom score). - The recommended dose of Finasteride tablets USP is one tablet (5 mg) taken once a day in combination with the alpha-blocker doxazosin - Finasteride tablets USP are not approved for the prevention of prostate cancer. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Finasteride in adult patients. ### Non–Guideline-Supported Use - Dosing Information - Finasteride therapy for 4 years. - Dosing Information - Oral finasteride 5 mg/day or placebo for 7 years - Dosing Information - Finasteride 5 mg daily. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) There is limited information regarding FDA-Labeled Use of Finasteride in pediatric patients. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Finasteride in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Finasteride in pediatric patients. # Contraindications - Finasteride tablets USP are contraindicated in the following: - Hypersensitivity to any component of this medication. - Pregnancy. Finasteride use is contraindicated in women when they are or may potentially be pregnant. Because of the ability of Type II 5α-reductase inhibitors to inhibit the conversion of testosterone to 5α-dihydrotestosterone (DHT), finasteride may cause abnormalities of the external genitalia of a male fetus of a pregnant woman who receives finasteride. If this drug is used during pregnancy, or if pregnancy occurs while taking this drug, the pregnant woman should be apprised of the potential hazard to the male fetus. In female rats, low doses of finasteride administered during pregnancy have produced abnormalities of the external genitalia in male offspring. # Warnings ### Precautions - Effects on Prostate Specific Antigen (PSA) and the Use of PSA in Prostate Cancer Detection - In clinical studies, finasteride tablets USP reduced serum PSA concentration by approximately 50% within six months of treatment. This decrease is predictable over the entire range of PSA values in patients with symptomatic BPH, although it may vary in individuals. - For interpretation of serial PSAs in men taking finasteride tablets USP, a new PSA baseline should be established at least six months after starting treatment and PSA monitored periodically thereafter. Any confirmed increase from the lowest PSA value while on finasteride tablets USP may signal the presence of prostate cancer and should be evaluated, even if PSA levels are still within the normal range for men not taking a 5α-reductase inhibitor. Non-compliance with finasteride tablets USP therapy may also affect PSA test results. To interpret an isolated PSA value in patients treated with finasteride tablets USP for six months or more, PSA values should be doubled for comparison with normal ranges in untreated men. These adjustments preserve the utility of PSA to detect prostate cancer in men treated with finasteride tablets USP. - Finasteride tablets USP may also cause decreases in serum PSA in the presence of prostate cancer. - The ratio of free to total PSA (percent free PSA) remains constant even under the influence of finasteride tablets USP. If clinicians elect to use percent free PSA as an aid in the detection of prostate cancer in men undergoing finasteride therapy, no adjustment to its value appears necessary. - Increased Risk of High-Grade Prostate Cancer - Men aged 55 and over with a normal digital rectal examination and PSA ≤3.0 ng/mL at baseline taking finasteride 5 mg/day in the 7-year Prostate Cancer Prevention Trial (PCPT) had an increased risk of Gleason score 8 to 10 prostate cancer (finasteride 1.8% vs placebo 1.1%). Similar results were observed in a 4-year placebo-controlled clinical trial with another 5α-reductase inhibitor (dutasteride, AVODART) (1% dutasteride vs 0.5% placebo). 5αreductase inhibitors may increase the risk of development of high-grade prostate cancer. Whether the effect of 5α-reductase inhibitors to reduce prostate volume, or study-related factors, impacted the results of these studies has not been established. - Exposure of Women — Risk to Male Fetus - Women should not handle crushed or broken finasteride tablets USP when they are pregnant or may potentially be pregnant because of the possibility of absorption of finasteride and the subsequent potential risk to a male fetus. Finasteride tablets USP are coated and will prevent contact with the active ingredient during normal handling, provided that the tablets have not been broken or crushed. - Pediatric Patients and Women - Finasteride tablets USP is not indicated for use in pediatric patients. - Effect on Semen Characteristics - Treatment with finasteride tablets USP for 24 weeks to evaluate semen parameters in healthy male volunteers revealed no clinically meaningful effects on sperm concentration, mobility, morphology, or pH. A 0.6 mL (22.1%) median decrease in ejaculate volume with a concomitant reduction in total sperm per ejaculate was observed. These parameters remained within the normal range and were reversible upon discontinuation of therapy with an average time to return to baseline of 84 weeks. - Consideration of Other Urological Conditions - Prior to initiating treatment with finasteride tablets USP, consideration should be given to other urological conditions that may cause similar symptoms. In addition, prostate cancer and BPH may coexist. - Patients with large residual urinary volume and/or severely diminished urinary flow should be carefully monitored for obstructive uropathy. These patients may not be candidates for finasteride therapy. # Adverse Reactions ## Clinical Trials Experience - Finasteride tablets USP are generally well tolerated; adverse reactions usually have been mild and transient. - 4-Year Placebo-Controlled Study (A Long-Term Efficacy and Safety Study) - In a long-term efficacy and safety study, 1524 patients treated with finasteride tablets USP and 1516 patients treated with placebo were evaluated for safety over a period of 4 years. The most frequently reported adverse reactions were related to sexual function. 3.7% (57 patients) treated with finasteride tablets USP and 2.1% (32 patients) treated with placebo discontinued therapy as a result of adverse reactions related to sexual function, which are the most frequently reported adverse reactions. Table 1 presents the only clinical adverse reactions considered possibly, probably or definitely drug related by the investigator, for which the incidence on finasteride tablets USP was ≥1% and greater than placebo over the 4 years of the study. In years 2 to 4 of the study, there was no significant difference between treatment groups in the incidences of impotence, decreased libido and ejaculation disorder. - N = 1524 and 1516, finasteride vs placebo, respectively - Phase III Studies and 5-Year Open Extensions - The adverse experience profile in the 1-year, placebo-controlled, Phase III studies, the 5-year open extensions, and a long-term efficacy and safety study were similar. - Medical Therapy of Prostatic Symptoms (MTOPS) Study In the MTOPS study, 3047 men with symptomatic BPH were randomized to receive finasteride tablets USP, 5 mg/day (n=768), doxazosin 4 or 8 mg/day (n=756), the combination of finasteride tablets USP, 5 mg/day and doxazosin 4 or 8 mg/day (n=786), or placebo (n=737) for 4 to 6 years. - The incidence rates of drug-related adverse experiences reported by ≥2% of patients in any treatment group in the MTOPS Study are listed in Table 2. - The individual adverse effects which occurred more frequently in the combination group compared to either drug alone were: asthenia, postural hypotension, peripheral edema, dizziness, decreased libido, rhinitis, abnormal ejaculation, impotence and abnormal sexual function (see Table 2). Of these, the incidence of abnormal ejaculation in patients receiving combination therapy was comparable to the sum of the incidences of this adverse experience reported for the two monotherapies. - Combination therapy with finasteride and doxazosin was associated with no new clinical adverse experience. - Four patients in MTOPS reported the adverse experience breast cancer. Three of these patients were on finasteride only and one was on combination therapy. - The MTOPS Study was not specifically designed to make statistical comparisons between groups for reported adverse experiences. In addition, direct comparisons of safety data between the MTOPS study and previous studies of the single agents may not be appropriate based upon differences in patient population, dosage or dose regimen, and other procedural and study design elements. - Doxazosin dose was achieved by weekly titration (1 to 2 to 4 to 8 mg). The final tolerated dose (4 mg or 8 mg) was administered at end-Week 4. Only those patients tolerating at least 4 mg were kept on doxazosin. The majority of patients received the 8-mg dose over the duration of the study. - Long-Term Data - High-Grade Prostate Cancer The PCPT trial was a 7-year randomized, double-blind, placebo-controlled trial that enrolled 18,882 men ≥55 years of age with a normal digital rectal examination and a PSA ≤ 3.0 ng/mL. Men received either finasteride tablets USP, 5 mg or placebo daily. Patients were evaluated annually with PSA and digital rectal exams. Biopsies were performed for elevated PSA, an abnormal digital rectal exam, or the end of study. The incidence of Gleason score 8 to 10 prostate cancer was higher in men treated with finasteride (1.8%) than in those treated with placebo (1.1%). In a 4-year placebo-controlled clinical trial with another 5α-reductase inhibitor (dutasteride, AVODART), similar results for Gleason score 8 to 10 prostate cancer were observed (1% dutasteride vs 0.5% placebo). - No clinical benefit has been demonstrated in patients with prostate cancer treated with finasteride tablets USP. - Breast Cancer - During the 4- to 6-year placebo- and comparator-controlled MTOPS study that enrolled 3047 men, there were 4 cases of breast cancer in men treated with finasteride but no cases in men not treated with finasteride. During the 7year placebo-controlled Prostate Cancer Prevention Trial (PCPT) that enrolled 18,882 men, there was 1 case of breast cancer in men treated with finasteride, and 1 case of breast cancer in men treated with placebo. The relationship between long-term use of finasteride and male breast neoplasia is currently unknown. - Sexual Function - There is no evidence of increased sexual adverse experiences with increased duration of treatment with finasteride tablets USP. New reports of drug-related sexual adverse experiences decreased with duration of therapy. ## Postmarketing Experience - The following additional adverse effects have been reported in post-marketing experience with finasteride tablets USP and/or finasteride at lower doses. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure: - hypersensitivity reactions, including pruritus, urticaria, and swelling of the lips and face - testicular pain - erectile dysfunction (ED) that continued after discontinuation of treatment, reported rarely in men taking finasteride tablets USP forthe treatment of BPH. Most men were older and were taking concomitant medications and/or had co-morbid conditions with a known association to ED. The independent role of finasteride tablets USP in these events is unknown. - male infertility and/or poor seminal quality have been reported rarely in men taking finasteride tablets USP for the treatment of BPH. The independent role of finasteride tablets USP in these events is unknown. Normalization or improvement of seminal quality has been reported after discontinuation of finasteride. - depression - decreased libido that continued after discontinuation of treatment - male breast cancer. # Drug Interactions - Cytochrome P450-Linked Drug Metabolizing Enzyme System - No drug interactions of clinical importance have been identified. Finasteride does not appear to affect the cytochrome P450-linked drug metabolizing enzyme system. Compounds that have been tested in man have included antipyrine, digoxin, propranolol, theophylline, and warfarin and no clinically meaningful interactions were found. - Other Concomitant Therapy - Although specific interaction studies were not performed, finasteride tablets USP was concomitantly used in clinical studies with acetaminophen, acetylsalicylic acid, α-blockers, angiotensin-converting enzyme (ACE) inhibitors, analgesics, anti-convulsants, beta-adrenergic blocking agents, diuretics, calcium channel blockers, cardiac nitrates, HMG-CoA reductase inhibitors, nonsteroidal anti-inflammatory drugs (NSAIDs), benzodiazepines, H2 antagonists and quinolone anti-infectives without evidence of clinically significant adverse interactions. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): - Pregnancy Category X - Finasteride tablets USP are contraindicated for use in women who are or may become pregnant. Finasteride tablets USP is a Type II 5α-reductase inhibitor that prevents conversion of testosterone to 5α-dihydrotestosterone (DHT), a hormone necessary for normal development of male genitalia. In animal studies, finasteride caused abnormal development of external genitalia in male fetuses. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the male fetus. - Abnormal male genital development is an expected consequence when conversion of testosterone to 5α-dihydrotestosterone (DHT) is inhibited by 5α-reductase inhibitors. These outcomes are similar to those reported in male infants with genetic 5α-reductase deficiency. Women could be exposed to finasteride through contact with crushed or broken finasteride tablets USP or semen from a male partner taking finasteride tablets USP. With regard to finasteride exposure through the skin, finasteride tablets USP are coated and will prevent skin contact with finasteride during normal handling if the tablets have not been crushed or broken. Women who are pregnant or may become pregnant should not handle crushed or broken finasteride tablets USP because of possible exposure of a male fetus. If a pregnant woman comes in contact with crushed or broken finasteride tablets USP, the contact area should be washed immediately with soap and water. With regard to potential finasteride exposure through semen, two studies have been conducted in men receiving finasteride tablets USP, 5 mg/day that measured finasteride concentrations in semen. - In an embryo-fetal development study, pregnant rats received finasteride during the period of major organogenesis (gestation days 6 to 17). At maternal doses of oral finasteride approximately 0.1 to 86 times the maximum recommended human dose (MRHD) of 5 mg/day (based on AUC at animal doses of 0.1 to 100 mg/kg/day) there was a dose-dependent increase in hypospadias that occurred in 3.6 to 100% of male offspring. Exposure multiples were estimated using data from nonpregnant rats. Days 16 to 17 days of gestation is a critical period in male fetal rats for differentiation of the external genitalia. At oral maternal doses approximately 0.03 times the MRHD (based on AUC at animal dose of 0.03 mg/kg/day), male offspring had decreased prostatic and seminal vesicular weights, delayed preputial separation and transient nipple development. Decreased anogenital distance occurred in male offspring of pregnant rats that received approximately 0.003 times the MRHD (based on AUC at animal dose of 0.003 mg/kg/day). No abnormalities were observed in female offspring at any maternal dose of finasteride. - No developmental abnormalities were observed in the offspring of untreated females mated with finasteride treated male rats that received approximately 61 times the MRHD (based on AUC at animal dose of 80 mg/kg/day). Slightly decreased fertility was observed in male offspring after administration of about 3 times the MRHD (based on AUC at animal dose of 3 mg/kg/day) to female rats during late gestation and lactation. No effects on fertility were seen in female offspring under these conditions. - No evidence of male external genital malformations or other abnormalities were observed in rabbit fetuses exposed to finasteride during the period of major organogenesis (gestation days 6 to 18) at maternal oral doses up to 100 mg/kg /day, (finasteride exposure levels were not measured in rabbits). However, this study may not have included the critical period for finasteride effects on development of male external genitalia in the rabbit. - The fetal effects of maternal finasteride exposure during the period of embryonic and fetal development were evaluated in the rhesus monkey (gestation days 20 to 100), in a species and development period more predictive of specific effects in humans than the studies in rats and rabbits. Intravenous administration of finasteride to pregnant monkeys at doses as high as 800 ng/day (estimated maximal blood concentration of 1.86 ng/mL or about 143 times the highest estimated exposure of pregnant women to finasteride from semen of men taking 5 mg/day) resulted in no abnormalities in male fetuses. In confirmation of the relevance of the rhesus model for human fetal development, oral administration of a dose of finasteride (2 mg/kg/day or approximately 18,000 times the highest estimated blood levels of finasteride from semen of men taking 5 mg/day) to pregnant monkeys resulted in external genital abnormalities in male fetuses. No other abnormalities were observed in male fetuses and no finasteride-related abnormalities were observed in female fetuses at any dose. Pregnancy Category (AUS): - Australian Drug Evaluation Committee (ADEC) Pregnancy Category There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Finasteride in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Finasteride during labor and delivery. ### Nursing Mothers - Finasteride tablets USP is not indicated for use in women. - It is not known whether finasteride is excreted in human milk. ### Pediatric Use - Safety and effectiveness in pediatric patients have not been established. ### Geriatic Use - Of the total number of subjects included in a long-term efficacy and safety study, 1480 and 105 subjects were 65 and over and 75 and over, respectively. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients. No dosage adjustment is necessary in the elderly. ### Gender There is no FDA guidance on the use of Finasteride with respect to specific gender populations. ### Race There is no FDA guidance on the use of Finasteride with respect to specific racial populations. ### Renal Impairment - No dosage adjustment is necessary in patients with renal impairment. ### Hepatic Impairment - Caution should be exercised in the administration of finasteride tablets USP in those patients with liver function abnormalities, as finasteride is metabolized extensively in the liver. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Finasteride in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Finasteride in patients who are immunocompromised. # Administration and Monitoring ### Administration - Oral ### Monitoring There is limited information regarding Monitoring of Finasteride in the drug label. # IV Compatibility There is limited information regarding IV Compatibility of Finasteride in the drug label. # Overdosage ## Acute Overdose ### Signs and Symptoms - Patients have received single doses of finasteride tablets USP up to 400 mg and multiple doses of finasteride tablets USP up to 80 mg/day for three months without adverse effects. - Significant lethality was observed in male and female mice at single oral doses of 1500 mg/m2 (500 mg/kg) and in female and male rats at single oral doses of 2360 mg/m2 (400 mg/kg) and 5900 mg/m2 (1000 mg/kg), respectively. ### Management - Until further experience is obtained, no specific treatment for an overdose with finasteride tablets USP can be recommended. ## Chronic Overdose There is limited information regarding Chronic Overdose of Finasteride in the drug label. # Pharmacology There is limited information regarding Finasteride Pharmacology in the drug label. ## Mechanism of Action - The development and enlargement of the prostate gland is dependent on the potent androgen, 5α-dihydrotestosterone (DHT). Type II 5α-reductase metabolizes testosterone to DHT in the prostate gland, liver and skin. DHT induces androgenic effects by binding to androgen receptors in the cell nuclei of these organs. - Finasteride is a competitive and specific inhibitor of Type II 5α-reductase with which it slowly forms a stable enzyme complex. Turnover from this complex is extremely slow (t½ ∼ 30 days). This has been demonstrated both in vivo and in vitro. Finasteride has no affinity for the androgen receptor. In man, the 5α-reduced steroid metabolites in blood and urine are decreased after administration of finasteride. ## Structure - Finasteride USP, a synthetic 4-azasteroid compound, is a specific inhibitor of steroid Type II 5α-reductase, an intracellular enzyme that converts the androgen testosterone into 5α-dihydrotestosterone (DHT). - Finasteride is 4-azaandrost-1-ene-17-carboxamide, N-(1,1-dimethylethyl)-3-oxo-,(5α,17β)-. The empirical formula of finasteride is C23H36N2O2 and its molecular weight is 372.55. Its structural formula is: - Finasteride is a white crystalline powder with a melting point near 250°C. It is freely soluble in chloroform and in lower alcohol solvents, but is practically insoluble in water. - Finasteride tablets USP for oral administration are film-coated tablets that contain 5 mg of finasteride and the following inactive ingredients: lactose monohydrate, microcrystalline cellulose, pregelatinized starch, sodium starch glycolate, docusate sodium, magnesium stearate, opadry blue (FD&C blue #2 aluminium lake, hypromellose, talc, titanium dioxide, yellow iron oxide). ## Pharmacodynamics - In man, a single 5-mg oral dose of finasteride tablets USP produces a rapid reduction in serum DHT concentration, with the maximum effect observed 8 hours after the first dose. The suppression of DHT is maintained throughout the 24-hour dosing interval and with continued treatment. Daily dosing of finasteride tablets USP at 5 mg/day for up to 4 years has been shown to reduce the serum DHT concentration by approximately 70%. The median circulating level of testosterone increased by approximately 10 to 20% but remained within the physiologic range. In a separate study in healthy men treated with finasteride 1 mg per day (n=82) or placebo (n=69), mean circulating levels of testosterone and estradiol were increased by approximately 15% as compared to baseline, but these remained within the physiologic range. - In patients receiving finasteride tablets USP, 5 mg/day, increases of about 10% were observed in luteinizing hormone (LH) and follicle-stimulating hormone (FSH), but levels remained within the normal range. In healthy volunteers, treatment with finasteride tablets USP did not alter the response of LH and FSH to gonadotropin-releasing hormone indicating that the hypothalamic-pituitary-testicular axis was not affected. - In patients with BPH, finasteride tablets USP has no effect on circulating levels of cortisol, prolactin, thyroid-stimulating hormone, or thyroxine. No clinically meaningful effect was observed on the plasma lipid profile (i.e., total cholesterol, low density lipoproteins, high density lipoproteins and triglycerides) or bone mineral density. - Adult males with genetically inherited Type II 5α-reductase deficiency also have decreased levels of DHT. Except for the associated urogenital defects present at birth, no other clinical abnormalities related to Type II 5α-reductase deficiency have been observed in these individuals. These individuals have a small prostate gland throughout life and do not develop BPH. - In patients with BPH treated with finasteride (1 to 100 mg/day) for 7 to 10 days prior to prostatectomy, an approximate 80% lower DHT content was measured in prostatic tissue removed at surgery, compared to placebo; testosterone tissue concentration was increased up to 10 times over pretreatment levels, relative to placebo. Intraprostatic content of PSA was also decreased. - In healthy male volunteers treated with finasteride tablets USP for 14 days, discontinuation of therapy resulted in a return of DHT levels to pretreatment levels in approximately 2 weeks. In patients treated for three months, prostate volume, which declined by approximately 20%, returned to close to baseline value after approximately three months of discontinuation of therapy. ## Pharmacokinetics - Absorption - In a study of 15 healthy young subjects, the mean bioavailability of finasteride 5 mg tablets was 63% (range 34 to 108%), based on the ratio of area under the curve (AUC) relative to an intravenous (IV) reference dose. Maximum finasteride plasma concentration averaged 37 ng/mL (range, 27 to 49 ng/mL) and was reached 1 to 2 hours postdose. Bioavailability of finasteride was not affected by food. - Distribution - Mean steady-state volume of distribution was 76 liters (range, 44 to 96 liters). Approximately 90% of circulating finasteride is bound to plasma proteins. There is a slow accumulation phase for finasteride after multiple dosing. After dosing with 5 mg/day of finasteride for 17 days, plasma concentrations of finasteride were 47 and 54% higher than after the first dose in men 45 to 60 years old (n=12) and ≥70 years old (n=12), respectively. Mean trough concentrations after 17 days of dosing were 6.2 ng/mL (range, 2.4 to 9.8 ng/mL) and 8.1 ng/mL (range, 1.8 to 19.7 ng/mL), respectively, in the two age groups. Although steady state was not reached in this study, mean trough plasma concentration in another study in patients with BPH (mean age, 65 years) receiving 5 mg/day was 9.4 ng/mL (range, 7.1 to 13.3 ng/mL; n=22) after over a year of dosing. Finasteride has been shown to cross the blood brain barrier but does not appear to distribute preferentially to the CSF. - In 2 studies of healthy subjects (n=69) receiving finasteride tablets USP 5 mg/day for 6 to 24 weeks, finasteride concentrations in semen ranged from undetectable (<0.1 ng/mL) to 10.54 ng/mL. In an earlier study using a less sensitive assay, finasteride concentrations in the semen of 16 subjects receiving finasteride tablets USP, 5 mg/day ranged from undetectable (<1.0 ng/mL) to 21 ng/mL. Thus, based on a 5 mL ejaculate volume, the amount of finasteride in semen was estimated to be 50- to 100-fold less than the dose of finasteride (5 mcg) that had no effect on circulating DHT levels in men. - Metabolism - Finasteride is extensively metabolized in the liver, primarily via the cytochrome P450 3A4 enzyme subfamily. Two metabolites, the t-butyl side chain monohydroxylated and monocarboxylic acid metabolites, have been identified that possess no more than 20% of the 5α-reductase inhibitory activity of finasteride. - Excretion - In healthy young subjects (n=15), mean plasma clearance of finasteride was 165 mL/min (range, 70 to 279 mL/min) and mean elimination half-life in plasma was 6 hours (range, 3 to 16 hours). Following an oral dose of 14C-finasteride in man (n=6), a mean of 39% (range, 32 to 46%) of the dose was excreted in the urine in the form of metabolites; 57% (range, 51 to 64%) was excreted in the feces. - The mean terminal half-life of finasteride in subjects ≥70 years of age was approximately 8 hours (range, 6 to 15 hours; n=12), compared with 6 hours (range, 4 to 12 hours; n=12) in subjects 45 to 60 years of age. As a result, mean AUC(0 to 24 hr) after 17 days of dosing was 15% higher in subjects ≥70 years of age than in subjects 45 to 60 years of age (p=0.02). - Pediatric - Finasteride pharmacokinetics have not been investigated in patients <18 years of age. - Finasteride is not indicated for use in pediatric patients. - Gender - Finasteride is not indicated for use in women. - Geriatric - No dosage adjustment is necessary in the elderly. Although the elimination rate of finasteride is decreased in the elderly, these findings are of no clinical significance. - Race - The effect of race on finasteride pharmacokinetics has not been studied. - Hepatic Impairment - The effect of hepatic impairment on finasteride pharmacokinetics has not been studied. Caution should be exercised in the administration of finasteride tablets USP in those patients with liver function abnormalities, as finasteride is metabolized extensively in the liver. - Renal Impairment - No dosage adjustment is necessary in patients with renal impairment. In patients with chronic renal impairment, with creatinine clearances ranging from 9.0 to 55 mL/min, AUC, maximum plasma concentration, half-life, and protein binding after a single dose of 14C-finasteride were similar to values obtained in healthy volunteers. Urinary excretion of metabolites was decreased in patients with renal impairment. This decrease was associated with an increase in fecal excretion of metabolites. Plasma concentrations of metabolites were significantly higher in patients with renal impairment (based on a 60% increase in total radioactivity AUC). However, finasteride has been well tolerated in BPH patients with normal renal function receiving up to 80 mg/day for 12 weeks, where exposure of these patients to metabolites would presumably be much greater. ## Nonclinical Toxicology - No evidence of a tumorigenic effect was observed in a 24-month study in Sprague-Dawley rats receiving doses of finasteride up to 160 mg/kg/day in males and 320 mg/kg/day in females. These doses produced respective systemic exposure in rats of 111 and 274 times those observed in man receiving the recommended human dose of 5 mg/day. All exposure calculations were based on calculated AUC(0 to 24 hr) for animals and mean AUC(0 to 24 hr) for man (0.4 mcghr/mL). - In a 19-month carcinogenicity study in CD-1 mice, a statistically significant (p≤0.05) increase in the incidence of testicular Leydig cell adenomas was observed at 228 times the human exposure (250 mg/kg/day). In mice at 23 times the human exposure, estimated (25 mg/kg/day) and in rats at 39 times the human exposure (40 mg/kg/day) an increase in the incidence of Leydig cell hyperplasia was observed. A positive correlation between the proliferative changes in the Leydig cells and an increase in serum LH levels (2- to 3-fold above control) has been demonstrated in both rodent species treated with high doses of finasteride. No drug-related Leydig cell changes were seen in either rats or dogs treated with finasteride for 1 year at 30 and 350 times (20 mg/kg/day and 45 mg/kg/day, respectively) or in mice treated for 19 months at 2.3 times the human exposure, estimated (2.5 mg/kg/day). - No evidence of mutagenicity was observed in an in vitro bacterial mutagenesis assay, a mammalian cell mutagenesis assay, or in an in vitro alkaline elution assay. In an in vitro chromosome aberration assay, using Chinese hamster ovary cells, there was a slight increase in chromosome aberrations. These concentrations correspond to 4000 to 5000 times the peak plasma levels in man given a total dose of 5 mg. In an in vivo chromosome aberration assay in mice, no treatment-related increase in chromosome aberration was observed with finasteride at the maximum tolerated dose of 250 mg/kg/day (228 times the human exposure) as determined in the carcinogenicity studies. - In sexually mature male rabbits treated with finasteride at 543 times the human exposure (80 mg/kg/day) for up to 12 weeks, no effect on fertility, sperm count, or ejaculate volume was seen. In sexually mature male rats treated with 61 times the human exposure (80 mg/kg/day), there were no significant effects on fertility after 6 or 12 weeks of treatment; however, when treatment was continued for up to 24 or 30 weeks, there was an apparent decrease in fertility, fecundity and an associated significant decrease in the weights of the seminal vesicles and prostate. All these effects were reversible within 6 weeks of discontinuation of treatment. No drug-related effect on testes or on mating performance has been seen in rats or rabbits. This decrease in fertility in finasteride-treated rats is secondary to its effect on accessory sex organs (prostate and seminal vesicles) resulting in failure to form a seminal plug. The seminal plug is essential for normal fertility in rats and is not relevant in man. # Clinical Studies - Finasteride tablets USP, 5 mg/day was initially evaluated in patients with symptoms of BPH and enlarged prostates by digital rectal examination in two 1-year, placebo-controlled, randomized, double-blind studies and their 5-year open extensions. - Finasteride tablets USP was further evaluated in a long-term efficacy and safety study, a double-blind, randomized, placebo-controlled, 4-year, multicenter study. 3040 patients between the ages of 45 and 78, with moderate to severe symptoms of BPH and an enlarged prostate upon digital rectal examination, were randomized into the study (1524 to finasteride, 1516 to placebo) and 3016 patients were evaluable for efficacy. 1883 patients completed the 4-year study (1000 in the finasteride group, 883 in the placebo group). - Effect on Symptom Score - Symptoms were quantified using a score similar to the American Urological Association Symptom Score, which evaluated both obstructive symptoms (impairment of size and force of stream, sensation of incomplete bladder emptying, delayed or interrupted urination) and irritative symptoms (nocturia, daytime frequency, need to strain or push the flow of urine) by rating on a 0 to 5 scale for six symptoms and a 0 to 4 scale for one symptom, for a total possible score of 34. - Patients in a long-term efficacy and safety study had moderate to severe symptoms at baseline (mean of approximately 15 points on a 0 to 34 point scale). Patients randomized to finasteride tablets USP who remained on therapy for 4 years had a mean (± 1 SD) decrease in symptom score of 3.3 (± 5.8) points compared with 1.3 (± 5.6) points in the placebo group. (See Figure 1.) A statistically significant improvement in symptom score was evident at 1 year in patients treated with finasteride tablets USP vs placebo (–2.3 vs –1.6), and this improvement continued through Year 4. - Figure 1 - Results seen in earlier studies were comparable to those seen in a long-term efficacy and safety study. Although an early improvement in urinary symptoms was seen in some patients, a therapeutic trial of at least 6 months was generally necessary to assess whether a beneficial response in symptom relief had been achieved. The improvement in BPH symptoms was seen during the first year and maintained throughout an additional 5 years of open extension studies. - Effect on the Need for Surgery - In a long-term efficacy and safety study, efficacy was also assessed by evaluating treatment failures. Treatment failure was prospectively defined as BPH-related urological events or clinical deterioration, lack of improvement and/or the need for alternative therapy. BPH-related urological events were defined as urological surgical intervention and acute urinary retention requiring catheterization. Complete event information was available for 92% of the patients. The following table summarizes the results. - patients with multiple events may be counted more than once for each type of event - †Hazard ratio based on log rank test - Compared with placebo, finasteride tablets USP was associated with a significantly lower need for BPH-related surgery. Compared with placebo, finasteride tablets USP was associated with a significantly lower risk for surgery ; see Figure 2. - Effect on Maximum Urinary Flow Rate - In the patients in long-term efficacy and safety study who remained on therapy for the duration of the study and had evaluable urinary flow data, finasteride tablets USP increased maximum urinary flow rate by 1.9 mL/sec compared with 0.2 mL/sec in the placebo group. - There was a clear difference between treatment groups in maximum urinary flow rate in favor of finasteride tablets USP by month 4 (1.0 vs 0.3 mL/sec) which was maintained throughout the study. In the earlier 1-year studies, increase in maximum urinary flow rate was comparable to long-term efficacy and safety study and was maintained through the first year and throughout an additional 5 years of open extension studies. - Effect on Prostate Volume - In long-term efficacy and safety study, prostate volume was assessed yearly by magnetic resonance imaging (MRI) in a subset of patients. In patients treated with finasteride tablets USP who remained on therapy, prostate volume was reduced compared with both baseline and placebo throughout the 4-year study. Finasteride tablets USP decreased prostate volume by 17.9% (from 55.9 ml at baseline to 45.8 ml at 4 years) compared with an increase of 14.1% (from 51.3 ml to 58.5 ml) in the placebo group (p<0.001). (See Figure 3.) - Results seen in earlier studies were comparable to those seen in long-term efficacy and safety study. Mean prostate volume at baseline ranged between 40 to 50 ml. The reduction in prostate volume was seen during the first year and maintained throughout an additional five years of open extension studies. - Figure 3 - Prostate Volume as a Predictor of Therapeutic Response - A meta-analysis combining 1-year data from seven double-blind, placebo-controlled studies of similar design, including 4491 patients with symptomatic BPH, demonstrated that, in patients treated with finasteride tablets USP, the magnitude of symptom response and degree of improvement in maximum urinary flow rate were greater in patients with an enlarged prostate at baseline. - The Medical Therapy of Prostatic Symptoms (MTOPS) Trial was a double-blind, randomized, placebo-controlled, multicenter, 4- to 6-year study (average 5 years) in 3047 men with symptomatic BPH, who were randomized to receive finasteride tablets USP, 5 mg/day (n=768), doxazosin 4 or 8 mg/day (n=756), the combination of finasteride tablets USP, 5 mg/day and doxazosin 4 or 8 mg/day (n=786), or placebo (n=737). All participants underwent weekly titration of doxazosin (or its placebo) from 1 to 2 to 4 to 8 mg/day. Only those who tolerated the 4 or 8 mg dose level were kept on doxazosin (or its placebo) in the study. The participant’s final tolerated dose (either 4 mg or 8 mg) was administered beginning at end-Week 4. The final doxazosin dose was administered once per day, at bedtime. - The mean patient age at randomization was 62.6 years (±7.3 years). Patients were Caucasian (82%), African American (9%), Hispanic (7%), Asian (1%) or Native American (<1%). The mean duration of BPH symptoms was 4.7 years (±4.6 years). Patients had moderate to severe BPH symptoms at baseline with a mean AUA symptom score of approximately 17 out of 35 points. Mean maximum urinary flow rate was 10.5 mL/sec (±2.6 mL/sec). The mean prostate volume as measured by transrectal ultrasound was 36.3 mL (±20.1 mL). Prostate volume was ≤20 mL in 16% of patients, ≥50 mL in 18% of patients and between 21 and 49 mL in 66% of patients. - The primary endpoint was a composite measure of the first occurrence of any of the following five outcomes: a ≥4 point confirmed increase from baseline in symptom score, acute urinary retention, BPH-related renal insufficiency (creatinine rise), recurrent urinary tract infections or urosepsis, or incontinence. Compared to placebo, treatment with finasteride tablets USP, doxazosin, or combination therapy resulted in a reduction in the risk of experiencing one of these five outcome events by 34% (p=0.002), 39% (p<0.001), and 67% (p<0.001), respectively. Combination therapy resulted in a significant reduction in the risk of the primary endpoint compared to treatment with finasteride tablets USP alone (49%; p≤0.001) or doxazosin alone (46%; p≤0.001). (See Table 6.) - The majority of the events (274 out of 351; 78%) was a confirmed ≥4 point increase in symptom score, referred to as symptom score progression. The risk of symptom score progression was reduced by 30% (p=0.016), 46% (p<0.001), and 64% (p<0.001) in patients treated with finasteride tablets USP, doxazosin, or the combination, respectively, compared to patients treated with placebo (see Figure 4). Combination therapy significantly reduced the risk of symptom score progression compared to the effect of finasteride tablets USP alone (p<0.001) and compared to doxazosin alone (p=0.037). - Treatment with finasteride tablets USP, doxazosin or the combination of finasteride tablets USP with doxazosin, reduced the mean symptom score from baseline at year 4. Table 7 provides the mean change from baseline for AUA symptom score by treatment group for patients who remained on therapy for four years. - The results of MTOPS are consistent with the findings of the 4-year, placebo-controlled study long-term efficacy and safety study in that treatment with finasteride tablets USP reduces the risk of acute urinary retention and the need for BPH-related surgery. In MTOPS, the risk of developing acute urinary retention was reduced by 67% in patients treated with finasteride tablets USP compared to patients treated with placebo (0.8% for finasteride tablets USP and 2.4% for placebo). Also, the risk of requiring BPH-related invasive therapy was reduced by 64% in patients treated with finasteride tablets USP compared to patients treated with placebo (2.0% for finasteride tablets USP and 5.4% for placebo). - The data from these studies, showing improvement in BPH-related symptoms, reduction in treatment failure (BPH-related urological events), increased maximum urinary flow rates, and decreasing prostate volume, suggest that finasteride tablets USP arrests the disease process of BPH in men with an enlarged prostate. # How Supplied - Finasteride tablets USP, 5 mg are blue color, round film coated tablets, debossed with ‘H’ on one side ‘37’ on other side. They are supplied as follows: - Bottles of 30 NDC 43598-303-30 - Bottles of 90 NDC 43598-303-90 - Storage and Handling - Store at 20° to 25°C (68° to 77°F). Protect from light and keep container tightly closed. - Women should not handle crushed or broken finasteride tablets USP when they are pregnant or may potentially be pregnant because of the possibility of absorption of finasteride and the subsequent potential risk to a male fetus. ## Storage There is limited information regarding Finasteride Storage in the drug label. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information - Patients should be informed that there was an increase in high-grade prostate cancer in men treated with 5α-reductase inhibitors indicated for BPH treatment, including finasteride tablets USP, compared to those treated with placebo in studies looking at the use of these drugs to prevent prostate cancer. - Physicians should inform patients that women who are pregnant or may potentially be pregnant should not handle crushed or broken finasteride tablets USP because of the possibility of absorption of finasteride and the subsequent potential risk to the male fetus. Finasteride tablets USP are coated and will prevent contact with the active ingredient during normal handling, provided that the tablets have not been broken or crushed. If a woman who is pregnant or may potentially be pregnant comes in contact with crushed or broken finasteride tablets USP, the contact area should be washed immediately with soap and water. - Physicians should inform patients that the volume of ejaculate may be decreased in some patients during treatment with finasteride tablets USP. This decrease does not appear to interfere with normal sexual function. However, impotence and decreased libido may occur in patients treated with finasteride tablets USP. - Physicians should instruct their patients to promptly report any changes in their breasts such as lumps, pain or nipple discharge. Breast changes including breast enlargement, tenderness and neoplasm have been reported. - Physicians should instruct their patients to read the patient package insert before starting therapy with finasteride tablets USP and to reread it each time the prescription is renewed so that they are aware of current information for patients regarding finasteride tablets USP. # Precautions with Alcohol - Alcohol-Finasteride interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - FINASTERIDE® # Look-Alike Drug Names - Proscar® — Provera® - Proscar® — PROzac® # Drug Shortage Status # Price	Finasteride Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Vignesh Ponnusamy, M.B.B.S. [2] # Disclaimer WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here. # Overview Finasteride is a 5α-reductase inhibitor that is FDA approved for the {{{indicationType}}} of symptomatic benign prostatic hyperplasia (BPH). Common adverse reactions include impotence, decreased libido, decreased volume of ejaculate, breast enlargement, breast tenderness and rash. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) - Finasteride tablets USP, are indicated for the treatment of symptomatic benign prostatic hyperplasia (BPH) in men with an enlarged prostate to: - Improve symptoms - Reduce the risk of the need for surgery including transurethral resection of the prostate (TURP) and prostatectomy. - The recommended dose of finasteride tablet USP are one tablet (5 mg) taken once a day - Finasteride tablets USP administered in combination with the alpha-blocker doxazosin is indicated to reduce the risk of symptomatic progression of BPH (a confirmed ≥4 point increase in American Urological Association (AUA) symptom score). - The recommended dose of Finasteride tablets USP is one tablet (5 mg) taken once a day in combination with the alpha-blocker doxazosin - Finasteride tablets USP are not approved for the prevention of prostate cancer. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Finasteride in adult patients. ### Non–Guideline-Supported Use - Dosing Information - Finasteride therapy for 4 years. - Dosing Information - Oral finasteride 5 mg/day or placebo for 7 years - Dosing Information - Finasteride 5 mg daily. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) There is limited information regarding FDA-Labeled Use of Finasteride in pediatric patients. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Finasteride in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Finasteride in pediatric patients. # Contraindications - Finasteride tablets USP are contraindicated in the following: - Hypersensitivity to any component of this medication. - Pregnancy. Finasteride use is contraindicated in women when they are or may potentially be pregnant. Because of the ability of Type II 5α-reductase inhibitors to inhibit the conversion of testosterone to 5α-dihydrotestosterone (DHT), finasteride may cause abnormalities of the external genitalia of a male fetus of a pregnant woman who receives finasteride. If this drug is used during pregnancy, or if pregnancy occurs while taking this drug, the pregnant woman should be apprised of the potential hazard to the male fetus. In female rats, low doses of finasteride administered during pregnancy have produced abnormalities of the external genitalia in male offspring. # Warnings ### Precautions - Effects on Prostate Specific Antigen (PSA) and the Use of PSA in Prostate Cancer Detection - In clinical studies, finasteride tablets USP reduced serum PSA concentration by approximately 50% within six months of treatment. This decrease is predictable over the entire range of PSA values in patients with symptomatic BPH, although it may vary in individuals. - For interpretation of serial PSAs in men taking finasteride tablets USP, a new PSA baseline should be established at least six months after starting treatment and PSA monitored periodically thereafter. Any confirmed increase from the lowest PSA value while on finasteride tablets USP may signal the presence of prostate cancer and should be evaluated, even if PSA levels are still within the normal range for men not taking a 5α-reductase inhibitor. Non-compliance with finasteride tablets USP therapy may also affect PSA test results. To interpret an isolated PSA value in patients treated with finasteride tablets USP for six months or more, PSA values should be doubled for comparison with normal ranges in untreated men. These adjustments preserve the utility of PSA to detect prostate cancer in men treated with finasteride tablets USP. - Finasteride tablets USP may also cause decreases in serum PSA in the presence of prostate cancer. - The ratio of free to total PSA (percent free PSA) remains constant even under the influence of finasteride tablets USP. If clinicians elect to use percent free PSA as an aid in the detection of prostate cancer in men undergoing finasteride therapy, no adjustment to its value appears necessary. - Increased Risk of High-Grade Prostate Cancer - Men aged 55 and over with a normal digital rectal examination and PSA ≤3.0 ng/mL at baseline taking finasteride 5 mg/day in the 7-year Prostate Cancer Prevention Trial (PCPT) had an increased risk of Gleason score 8 to 10 prostate cancer (finasteride 1.8% vs placebo 1.1%). Similar results were observed in a 4-year placebo-controlled clinical trial with another 5α-reductase inhibitor (dutasteride, AVODART) (1% dutasteride vs 0.5% placebo). 5αreductase inhibitors may increase the risk of development of high-grade prostate cancer. Whether the effect of 5α-reductase inhibitors to reduce prostate volume, or study-related factors, impacted the results of these studies has not been established. - Exposure of Women — Risk to Male Fetus - Women should not handle crushed or broken finasteride tablets USP when they are pregnant or may potentially be pregnant because of the possibility of absorption of finasteride and the subsequent potential risk to a male fetus. Finasteride tablets USP are coated and will prevent contact with the active ingredient during normal handling, provided that the tablets have not been broken or crushed. - Pediatric Patients and Women - Finasteride tablets USP is not indicated for use in pediatric patients. - Effect on Semen Characteristics - Treatment with finasteride tablets USP for 24 weeks to evaluate semen parameters in healthy male volunteers revealed no clinically meaningful effects on sperm concentration, mobility, morphology, or pH. A 0.6 mL (22.1%) median decrease in ejaculate volume with a concomitant reduction in total sperm per ejaculate was observed. These parameters remained within the normal range and were reversible upon discontinuation of therapy with an average time to return to baseline of 84 weeks. - Consideration of Other Urological Conditions - Prior to initiating treatment with finasteride tablets USP, consideration should be given to other urological conditions that may cause similar symptoms. In addition, prostate cancer and BPH may coexist. - Patients with large residual urinary volume and/or severely diminished urinary flow should be carefully monitored for obstructive uropathy. These patients may not be candidates for finasteride therapy. # Adverse Reactions ## Clinical Trials Experience - Finasteride tablets USP are generally well tolerated; adverse reactions usually have been mild and transient. - 4-Year Placebo-Controlled Study (A Long-Term Efficacy and Safety Study) - In a long-term efficacy and safety study, 1524 patients treated with finasteride tablets USP and 1516 patients treated with placebo were evaluated for safety over a period of 4 years. The most frequently reported adverse reactions were related to sexual function. 3.7% (57 patients) treated with finasteride tablets USP and 2.1% (32 patients) treated with placebo discontinued therapy as a result of adverse reactions related to sexual function, which are the most frequently reported adverse reactions. Table 1 presents the only clinical adverse reactions considered possibly, probably or definitely drug related by the investigator, for which the incidence on finasteride tablets USP was ≥1% and greater than placebo over the 4 years of the study. In years 2 to 4 of the study, there was no significant difference between treatment groups in the incidences of impotence, decreased libido and ejaculation disorder. - N = 1524 and 1516, finasteride vs placebo, respectively - Phase III Studies and 5-Year Open Extensions - The adverse experience profile in the 1-year, placebo-controlled, Phase III studies, the 5-year open extensions, and a long-term efficacy and safety study were similar. - Medical Therapy of Prostatic Symptoms (MTOPS) Study In the MTOPS study, 3047 men with symptomatic BPH were randomized to receive finasteride tablets USP, 5 mg/day (n=768), doxazosin 4 or 8 mg/day (n=756), the combination of finasteride tablets USP, 5 mg/day and doxazosin 4 or 8 mg/day (n=786), or placebo (n=737) for 4 to 6 years. - The incidence rates of drug-related adverse experiences reported by ≥2% of patients in any treatment group in the MTOPS Study are listed in Table 2. - The individual adverse effects which occurred more frequently in the combination group compared to either drug alone were: asthenia, postural hypotension, peripheral edema, dizziness, decreased libido, rhinitis, abnormal ejaculation, impotence and abnormal sexual function (see Table 2). Of these, the incidence of abnormal ejaculation in patients receiving combination therapy was comparable to the sum of the incidences of this adverse experience reported for the two monotherapies. - Combination therapy with finasteride and doxazosin was associated with no new clinical adverse experience. - Four patients in MTOPS reported the adverse experience breast cancer. Three of these patients were on finasteride only and one was on combination therapy. - The MTOPS Study was not specifically designed to make statistical comparisons between groups for reported adverse experiences. In addition, direct comparisons of safety data between the MTOPS study and previous studies of the single agents may not be appropriate based upon differences in patient population, dosage or dose regimen, and other procedural and study design elements. - Doxazosin dose was achieved by weekly titration (1 to 2 to 4 to 8 mg). The final tolerated dose (4 mg or 8 mg) was administered at end-Week 4. Only those patients tolerating at least 4 mg were kept on doxazosin. The majority of patients received the 8-mg dose over the duration of the study. - Long-Term Data - High-Grade Prostate Cancer The PCPT trial was a 7-year randomized, double-blind, placebo-controlled trial that enrolled 18,882 men ≥55 years of age with a normal digital rectal examination and a PSA ≤ 3.0 ng/mL. Men received either finasteride tablets USP, 5 mg or placebo daily. Patients were evaluated annually with PSA and digital rectal exams. Biopsies were performed for elevated PSA, an abnormal digital rectal exam, or the end of study. The incidence of Gleason score 8 to 10 prostate cancer was higher in men treated with finasteride (1.8%) than in those treated with placebo (1.1%). In a 4-year placebo-controlled clinical trial with another 5α-reductase inhibitor (dutasteride, AVODART), similar results for Gleason score 8 to 10 prostate cancer were observed (1% dutasteride vs 0.5% placebo). - No clinical benefit has been demonstrated in patients with prostate cancer treated with finasteride tablets USP. - Breast Cancer - During the 4- to 6-year placebo- and comparator-controlled MTOPS study that enrolled 3047 men, there were 4 cases of breast cancer in men treated with finasteride but no cases in men not treated with finasteride. During the 7year placebo-controlled Prostate Cancer Prevention Trial (PCPT) that enrolled 18,882 men, there was 1 case of breast cancer in men treated with finasteride, and 1 case of breast cancer in men treated with placebo. The relationship between long-term use of finasteride and male breast neoplasia is currently unknown. - Sexual Function - There is no evidence of increased sexual adverse experiences with increased duration of treatment with finasteride tablets USP. New reports of drug-related sexual adverse experiences decreased with duration of therapy. ## Postmarketing Experience - The following additional adverse effects have been reported in post-marketing experience with finasteride tablets USP and/or finasteride at lower doses. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure: - hypersensitivity reactions, including pruritus, urticaria, and swelling of the lips and face - testicular pain - erectile dysfunction (ED) that continued after discontinuation of treatment, reported rarely in men taking finasteride tablets USP forthe treatment of BPH. Most men were older and were taking concomitant medications and/or had co-morbid conditions with a known association to ED. The independent role of finasteride tablets USP in these events is unknown. - male infertility and/or poor seminal quality have been reported rarely in men taking finasteride tablets USP for the treatment of BPH. The independent role of finasteride tablets USP in these events is unknown. Normalization or improvement of seminal quality has been reported after discontinuation of finasteride. - depression - decreased libido that continued after discontinuation of treatment - male breast cancer. # Drug Interactions - Cytochrome P450-Linked Drug Metabolizing Enzyme System - No drug interactions of clinical importance have been identified. Finasteride does not appear to affect the cytochrome P450-linked drug metabolizing enzyme system. Compounds that have been tested in man have included antipyrine, digoxin, propranolol, theophylline, and warfarin and no clinically meaningful interactions were found. - Other Concomitant Therapy - Although specific interaction studies were not performed, finasteride tablets USP was concomitantly used in clinical studies with acetaminophen, acetylsalicylic acid, α-blockers, angiotensin-converting enzyme (ACE) inhibitors, analgesics, anti-convulsants, beta-adrenergic blocking agents, diuretics, calcium channel blockers, cardiac nitrates, HMG-CoA reductase inhibitors, nonsteroidal anti-inflammatory drugs (NSAIDs), benzodiazepines, H2 antagonists and quinolone anti-infectives without evidence of clinically significant adverse interactions. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): - Pregnancy Category X - Finasteride tablets USP are contraindicated for use in women who are or may become pregnant. Finasteride tablets USP is a Type II 5α-reductase inhibitor that prevents conversion of testosterone to 5α-dihydrotestosterone (DHT), a hormone necessary for normal development of male genitalia. In animal studies, finasteride caused abnormal development of external genitalia in male fetuses. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the male fetus. - Abnormal male genital development is an expected consequence when conversion of testosterone to 5α-dihydrotestosterone (DHT) is inhibited by 5α-reductase inhibitors. These outcomes are similar to those reported in male infants with genetic 5α-reductase deficiency. Women could be exposed to finasteride through contact with crushed or broken finasteride tablets USP or semen from a male partner taking finasteride tablets USP. With regard to finasteride exposure through the skin, finasteride tablets USP are coated and will prevent skin contact with finasteride during normal handling if the tablets have not been crushed or broken. Women who are pregnant or may become pregnant should not handle crushed or broken finasteride tablets USP because of possible exposure of a male fetus. If a pregnant woman comes in contact with crushed or broken finasteride tablets USP, the contact area should be washed immediately with soap and water. With regard to potential finasteride exposure through semen, two studies have been conducted in men receiving finasteride tablets USP, 5 mg/day that measured finasteride concentrations in semen. - In an embryo-fetal development study, pregnant rats received finasteride during the period of major organogenesis (gestation days 6 to 17). At maternal doses of oral finasteride approximately 0.1 to 86 times the maximum recommended human dose (MRHD) of 5 mg/day (based on AUC at animal doses of 0.1 to 100 mg/kg/day) there was a dose-dependent increase in hypospadias that occurred in 3.6 to 100% of male offspring. Exposure multiples were estimated using data from nonpregnant rats. Days 16 to 17 days of gestation is a critical period in male fetal rats for differentiation of the external genitalia. At oral maternal doses approximately 0.03 times the MRHD (based on AUC at animal dose of 0.03 mg/kg/day), male offspring had decreased prostatic and seminal vesicular weights, delayed preputial separation and transient nipple development. Decreased anogenital distance occurred in male offspring of pregnant rats that received approximately 0.003 times the MRHD (based on AUC at animal dose of 0.003 mg/kg/day). No abnormalities were observed in female offspring at any maternal dose of finasteride. - No developmental abnormalities were observed in the offspring of untreated females mated with finasteride treated male rats that received approximately 61 times the MRHD (based on AUC at animal dose of 80 mg/kg/day). Slightly decreased fertility was observed in male offspring after administration of about 3 times the MRHD (based on AUC at animal dose of 3 mg/kg/day) to female rats during late gestation and lactation. No effects on fertility were seen in female offspring under these conditions. - No evidence of male external genital malformations or other abnormalities were observed in rabbit fetuses exposed to finasteride during the period of major organogenesis (gestation days 6 to 18) at maternal oral doses up to 100 mg/kg /day, (finasteride exposure levels were not measured in rabbits). However, this study may not have included the critical period for finasteride effects on development of male external genitalia in the rabbit. - The fetal effects of maternal finasteride exposure during the period of embryonic and fetal development were evaluated in the rhesus monkey (gestation days 20 to 100), in a species and development period more predictive of specific effects in humans than the studies in rats and rabbits. Intravenous administration of finasteride to pregnant monkeys at doses as high as 800 ng/day (estimated maximal blood concentration of 1.86 ng/mL or about 143 times the highest estimated exposure of pregnant women to finasteride from semen of men taking 5 mg/day) resulted in no abnormalities in male fetuses. In confirmation of the relevance of the rhesus model for human fetal development, oral administration of a dose of finasteride (2 mg/kg/day or approximately 18,000 times the highest estimated blood levels of finasteride from semen of men taking 5 mg/day) to pregnant monkeys resulted in external genital abnormalities in male fetuses. No other abnormalities were observed in male fetuses and no finasteride-related abnormalities were observed in female fetuses at any dose. Pregnancy Category (AUS): - Australian Drug Evaluation Committee (ADEC) Pregnancy Category There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Finasteride in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Finasteride during labor and delivery. ### Nursing Mothers - Finasteride tablets USP is not indicated for use in women. - It is not known whether finasteride is excreted in human milk. ### Pediatric Use - Safety and effectiveness in pediatric patients have not been established. ### Geriatic Use - Of the total number of subjects included in a long-term efficacy and safety study, 1480 and 105 subjects were 65 and over and 75 and over, respectively. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients. No dosage adjustment is necessary in the elderly. ### Gender There is no FDA guidance on the use of Finasteride with respect to specific gender populations. ### Race There is no FDA guidance on the use of Finasteride with respect to specific racial populations. ### Renal Impairment - No dosage adjustment is necessary in patients with renal impairment. ### Hepatic Impairment - Caution should be exercised in the administration of finasteride tablets USP in those patients with liver function abnormalities, as finasteride is metabolized extensively in the liver. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Finasteride in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Finasteride in patients who are immunocompromised. # Administration and Monitoring ### Administration - Oral ### Monitoring There is limited information regarding Monitoring of Finasteride in the drug label. # IV Compatibility There is limited information regarding IV Compatibility of Finasteride in the drug label. # Overdosage ## Acute Overdose ### Signs and Symptoms - Patients have received single doses of finasteride tablets USP up to 400 mg and multiple doses of finasteride tablets USP up to 80 mg/day for three months without adverse effects. - Significant lethality was observed in male and female mice at single oral doses of 1500 mg/m2 (500 mg/kg) and in female and male rats at single oral doses of 2360 mg/m2 (400 mg/kg) and 5900 mg/m2 (1000 mg/kg), respectively. ### Management - Until further experience is obtained, no specific treatment for an overdose with finasteride tablets USP can be recommended. ## Chronic Overdose There is limited information regarding Chronic Overdose of Finasteride in the drug label. # Pharmacology There is limited information regarding Finasteride Pharmacology in the drug label. ## Mechanism of Action - The development and enlargement of the prostate gland is dependent on the potent androgen, 5α-dihydrotestosterone (DHT). Type II 5α-reductase metabolizes testosterone to DHT in the prostate gland, liver and skin. DHT induces androgenic effects by binding to androgen receptors in the cell nuclei of these organs. - Finasteride is a competitive and specific inhibitor of Type II 5α-reductase with which it slowly forms a stable enzyme complex. Turnover from this complex is extremely slow (t½ ∼ 30 days). This has been demonstrated both in vivo and in vitro. Finasteride has no affinity for the androgen receptor. In man, the 5α-reduced steroid metabolites in blood and urine are decreased after administration of finasteride. ## Structure - Finasteride USP, a synthetic 4-azasteroid compound, is a specific inhibitor of steroid Type II 5α-reductase, an intracellular enzyme that converts the androgen testosterone into 5α-dihydrotestosterone (DHT). - Finasteride is 4-azaandrost-1-ene-17-carboxamide, N-(1,1-dimethylethyl)-3-oxo-,(5α,17β)-. The empirical formula of finasteride is C23H36N2O2 and its molecular weight is 372.55. Its structural formula is: - Finasteride is a white crystalline powder with a melting point near 250°C. It is freely soluble in chloroform and in lower alcohol solvents, but is practically insoluble in water. - Finasteride tablets USP for oral administration are film-coated tablets that contain 5 mg of finasteride and the following inactive ingredients: lactose monohydrate, microcrystalline cellulose, pregelatinized starch, sodium starch glycolate, docusate sodium, magnesium stearate, opadry blue (FD&C blue #2 aluminium lake, hypromellose, talc, titanium dioxide, yellow iron oxide). ## Pharmacodynamics - In man, a single 5-mg oral dose of finasteride tablets USP produces a rapid reduction in serum DHT concentration, with the maximum effect observed 8 hours after the first dose. The suppression of DHT is maintained throughout the 24-hour dosing interval and with continued treatment. Daily dosing of finasteride tablets USP at 5 mg/day for up to 4 years has been shown to reduce the serum DHT concentration by approximately 70%. The median circulating level of testosterone increased by approximately 10 to 20% but remained within the physiologic range. In a separate study in healthy men treated with finasteride 1 mg per day (n=82) or placebo (n=69), mean circulating levels of testosterone and estradiol were increased by approximately 15% as compared to baseline, but these remained within the physiologic range. - In patients receiving finasteride tablets USP, 5 mg/day, increases of about 10% were observed in luteinizing hormone (LH) and follicle-stimulating hormone (FSH), but levels remained within the normal range. In healthy volunteers, treatment with finasteride tablets USP did not alter the response of LH and FSH to gonadotropin-releasing hormone indicating that the hypothalamic-pituitary-testicular axis was not affected. - In patients with BPH, finasteride tablets USP has no effect on circulating levels of cortisol, prolactin, thyroid-stimulating hormone, or thyroxine. No clinically meaningful effect was observed on the plasma lipid profile (i.e., total cholesterol, low density lipoproteins, high density lipoproteins and triglycerides) or bone mineral density. - Adult males with genetically inherited Type II 5α-reductase deficiency also have decreased levels of DHT. Except for the associated urogenital defects present at birth, no other clinical abnormalities related to Type II 5α-reductase deficiency have been observed in these individuals. These individuals have a small prostate gland throughout life and do not develop BPH. - In patients with BPH treated with finasteride (1 to 100 mg/day) for 7 to 10 days prior to prostatectomy, an approximate 80% lower DHT content was measured in prostatic tissue removed at surgery, compared to placebo; testosterone tissue concentration was increased up to 10 times over pretreatment levels, relative to placebo. Intraprostatic content of PSA was also decreased. - In healthy male volunteers treated with finasteride tablets USP for 14 days, discontinuation of therapy resulted in a return of DHT levels to pretreatment levels in approximately 2 weeks. In patients treated for three months, prostate volume, which declined by approximately 20%, returned to close to baseline value after approximately three months of discontinuation of therapy. ## Pharmacokinetics - Absorption - In a study of 15 healthy young subjects, the mean bioavailability of finasteride 5 mg tablets was 63% (range 34 to 108%), based on the ratio of area under the curve (AUC) relative to an intravenous (IV) reference dose. Maximum finasteride plasma concentration averaged 37 ng/mL (range, 27 to 49 ng/mL) and was reached 1 to 2 hours postdose. Bioavailability of finasteride was not affected by food. - Distribution - Mean steady-state volume of distribution was 76 liters (range, 44 to 96 liters). Approximately 90% of circulating finasteride is bound to plasma proteins. There is a slow accumulation phase for finasteride after multiple dosing. After dosing with 5 mg/day of finasteride for 17 days, plasma concentrations of finasteride were 47 and 54% higher than after the first dose in men 45 to 60 years old (n=12) and ≥70 years old (n=12), respectively. Mean trough concentrations after 17 days of dosing were 6.2 ng/mL (range, 2.4 to 9.8 ng/mL) and 8.1 ng/mL (range, 1.8 to 19.7 ng/mL), respectively, in the two age groups. Although steady state was not reached in this study, mean trough plasma concentration in another study in patients with BPH (mean age, 65 years) receiving 5 mg/day was 9.4 ng/mL (range, 7.1 to 13.3 ng/mL; n=22) after over a year of dosing. Finasteride has been shown to cross the blood brain barrier but does not appear to distribute preferentially to the CSF. - In 2 studies of healthy subjects (n=69) receiving finasteride tablets USP 5 mg/day for 6 to 24 weeks, finasteride concentrations in semen ranged from undetectable (<0.1 ng/mL) to 10.54 ng/mL. In an earlier study using a less sensitive assay, finasteride concentrations in the semen of 16 subjects receiving finasteride tablets USP, 5 mg/day ranged from undetectable (<1.0 ng/mL) to 21 ng/mL. Thus, based on a 5 mL ejaculate volume, the amount of finasteride in semen was estimated to be 50- to 100-fold less than the dose of finasteride (5 mcg) that had no effect on circulating DHT levels in men. - Metabolism - Finasteride is extensively metabolized in the liver, primarily via the cytochrome P450 3A4 enzyme subfamily. Two metabolites, the t-butyl side chain monohydroxylated and monocarboxylic acid metabolites, have been identified that possess no more than 20% of the 5α-reductase inhibitory activity of finasteride. - Excretion - In healthy young subjects (n=15), mean plasma clearance of finasteride was 165 mL/min (range, 70 to 279 mL/min) and mean elimination half-life in plasma was 6 hours (range, 3 to 16 hours). Following an oral dose of 14C-finasteride in man (n=6), a mean of 39% (range, 32 to 46%) of the dose was excreted in the urine in the form of metabolites; 57% (range, 51 to 64%) was excreted in the feces. - The mean terminal half-life of finasteride in subjects ≥70 years of age was approximately 8 hours (range, 6 to 15 hours; n=12), compared with 6 hours (range, 4 to 12 hours; n=12) in subjects 45 to 60 years of age. As a result, mean AUC(0 to 24 hr) after 17 days of dosing was 15% higher in subjects ≥70 years of age than in subjects 45 to 60 years of age (p=0.02). - Pediatric - Finasteride pharmacokinetics have not been investigated in patients <18 years of age. - Finasteride is not indicated for use in pediatric patients. - Gender - Finasteride is not indicated for use in women. - Geriatric - No dosage adjustment is necessary in the elderly. Although the elimination rate of finasteride is decreased in the elderly, these findings are of no clinical significance. - Race - The effect of race on finasteride pharmacokinetics has not been studied. - Hepatic Impairment - The effect of hepatic impairment on finasteride pharmacokinetics has not been studied. Caution should be exercised in the administration of finasteride tablets USP in those patients with liver function abnormalities, as finasteride is metabolized extensively in the liver. - Renal Impairment - No dosage adjustment is necessary in patients with renal impairment. In patients with chronic renal impairment, with creatinine clearances ranging from 9.0 to 55 mL/min, AUC, maximum plasma concentration, half-life, and protein binding after a single dose of 14C-finasteride were similar to values obtained in healthy volunteers. Urinary excretion of metabolites was decreased in patients with renal impairment. This decrease was associated with an increase in fecal excretion of metabolites. Plasma concentrations of metabolites were significantly higher in patients with renal impairment (based on a 60% increase in total radioactivity AUC). However, finasteride has been well tolerated in BPH patients with normal renal function receiving up to 80 mg/day for 12 weeks, where exposure of these patients to metabolites would presumably be much greater. ## Nonclinical Toxicology - No evidence of a tumorigenic effect was observed in a 24-month study in Sprague-Dawley rats receiving doses of finasteride up to 160 mg/kg/day in males and 320 mg/kg/day in females. These doses produced respective systemic exposure in rats of 111 and 274 times those observed in man receiving the recommended human dose of 5 mg/day. All exposure calculations were based on calculated AUC(0 to 24 hr) for animals and mean AUC(0 to 24 hr) for man (0.4 mcg•hr/mL). - In a 19-month carcinogenicity study in CD-1 mice, a statistically significant (p≤0.05) increase in the incidence of testicular Leydig cell adenomas was observed at 228 times the human exposure (250 mg/kg/day). In mice at 23 times the human exposure, estimated (25 mg/kg/day) and in rats at 39 times the human exposure (40 mg/kg/day) an increase in the incidence of Leydig cell hyperplasia was observed. A positive correlation between the proliferative changes in the Leydig cells and an increase in serum LH levels (2- to 3-fold above control) has been demonstrated in both rodent species treated with high doses of finasteride. No drug-related Leydig cell changes were seen in either rats or dogs treated with finasteride for 1 year at 30 and 350 times (20 mg/kg/day and 45 mg/kg/day, respectively) or in mice treated for 19 months at 2.3 times the human exposure, estimated (2.5 mg/kg/day). - No evidence of mutagenicity was observed in an in vitro bacterial mutagenesis assay, a mammalian cell mutagenesis assay, or in an in vitro alkaline elution assay. In an in vitro chromosome aberration assay, using Chinese hamster ovary cells, there was a slight increase in chromosome aberrations. These concentrations correspond to 4000 to 5000 times the peak plasma levels in man given a total dose of 5 mg. In an in vivo chromosome aberration assay in mice, no treatment-related increase in chromosome aberration was observed with finasteride at the maximum tolerated dose of 250 mg/kg/day (228 times the human exposure) as determined in the carcinogenicity studies. - In sexually mature male rabbits treated with finasteride at 543 times the human exposure (80 mg/kg/day) for up to 12 weeks, no effect on fertility, sperm count, or ejaculate volume was seen. In sexually mature male rats treated with 61 times the human exposure (80 mg/kg/day), there were no significant effects on fertility after 6 or 12 weeks of treatment; however, when treatment was continued for up to 24 or 30 weeks, there was an apparent decrease in fertility, fecundity and an associated significant decrease in the weights of the seminal vesicles and prostate. All these effects were reversible within 6 weeks of discontinuation of treatment. No drug-related effect on testes or on mating performance has been seen in rats or rabbits. This decrease in fertility in finasteride-treated rats is secondary to its effect on accessory sex organs (prostate and seminal vesicles) resulting in failure to form a seminal plug. The seminal plug is essential for normal fertility in rats and is not relevant in man. # Clinical Studies - Finasteride tablets USP, 5 mg/day was initially evaluated in patients with symptoms of BPH and enlarged prostates by digital rectal examination in two 1-year, placebo-controlled, randomized, double-blind studies and their 5-year open extensions. - Finasteride tablets USP was further evaluated in a long-term efficacy and safety study, a double-blind, randomized, placebo-controlled, 4-year, multicenter study. 3040 patients between the ages of 45 and 78, with moderate to severe symptoms of BPH and an enlarged prostate upon digital rectal examination, were randomized into the study (1524 to finasteride, 1516 to placebo) and 3016 patients were evaluable for efficacy. 1883 patients completed the 4-year study (1000 in the finasteride group, 883 in the placebo group). - Effect on Symptom Score - Symptoms were quantified using a score similar to the American Urological Association Symptom Score, which evaluated both obstructive symptoms (impairment of size and force of stream, sensation of incomplete bladder emptying, delayed or interrupted urination) and irritative symptoms (nocturia, daytime frequency, need to strain or push the flow of urine) by rating on a 0 to 5 scale for six symptoms and a 0 to 4 scale for one symptom, for a total possible score of 34. - Patients in a long-term efficacy and safety study had moderate to severe symptoms at baseline (mean of approximately 15 points on a 0 to 34 point scale). Patients randomized to finasteride tablets USP who remained on therapy for 4 years had a mean (± 1 SD) decrease in symptom score of 3.3 (± 5.8) points compared with 1.3 (± 5.6) points in the placebo group. (See Figure 1.) A statistically significant improvement in symptom score was evident at 1 year in patients treated with finasteride tablets USP vs placebo (–2.3 vs –1.6), and this improvement continued through Year 4. - Figure 1 - Results seen in earlier studies were comparable to those seen in a long-term efficacy and safety study. Although an early improvement in urinary symptoms was seen in some patients, a therapeutic trial of at least 6 months was generally necessary to assess whether a beneficial response in symptom relief had been achieved. The improvement in BPH symptoms was seen during the first year and maintained throughout an additional 5 years of open extension studies. - Effect on the Need for Surgery - In a long-term efficacy and safety study, efficacy was also assessed by evaluating treatment failures. Treatment failure was prospectively defined as BPH-related urological events or clinical deterioration, lack of improvement and/or the need for alternative therapy. BPH-related urological events were defined as urological surgical intervention and acute urinary retention requiring catheterization. Complete event information was available for 92% of the patients. The following table summarizes the results. - patients with multiple events may be counted more than once for each type of event - †Hazard ratio based on log rank test - Compared with placebo, finasteride tablets USP was associated with a significantly lower need for BPH-related surgery. Compared with placebo, finasteride tablets USP was associated with a significantly lower risk for surgery [10.1% for placebo vs 4.6% for finasteride tablets USP; 55% reduction in risk, 95% CI: (37% to 68%)]; see Figure 2. - Effect on Maximum Urinary Flow Rate - In the patients in long-term efficacy and safety study who remained on therapy for the duration of the study and had evaluable urinary flow data, finasteride tablets USP increased maximum urinary flow rate by 1.9 mL/sec compared with 0.2 mL/sec in the placebo group. - There was a clear difference between treatment groups in maximum urinary flow rate in favor of finasteride tablets USP by month 4 (1.0 vs 0.3 mL/sec) which was maintained throughout the study. In the earlier 1-year studies, increase in maximum urinary flow rate was comparable to long-term efficacy and safety study and was maintained through the first year and throughout an additional 5 years of open extension studies. - Effect on Prostate Volume - In long-term efficacy and safety study, prostate volume was assessed yearly by magnetic resonance imaging (MRI) in a subset of patients. In patients treated with finasteride tablets USP who remained on therapy, prostate volume was reduced compared with both baseline and placebo throughout the 4-year study. Finasteride tablets USP decreased prostate volume by 17.9% (from 55.9 ml at baseline to 45.8 ml at 4 years) compared with an increase of 14.1% (from 51.3 ml to 58.5 ml) in the placebo group (p<0.001). (See Figure 3.) - Results seen in earlier studies were comparable to those seen in long-term efficacy and safety study. Mean prostate volume at baseline ranged between 40 to 50 ml. The reduction in prostate volume was seen during the first year and maintained throughout an additional five years of open extension studies. - Figure 3 - Prostate Volume as a Predictor of Therapeutic Response - A meta-analysis combining 1-year data from seven double-blind, placebo-controlled studies of similar design, including 4491 patients with symptomatic BPH, demonstrated that, in patients treated with finasteride tablets USP, the magnitude of symptom response and degree of improvement in maximum urinary flow rate were greater in patients with an enlarged prostate at baseline. - The Medical Therapy of Prostatic Symptoms (MTOPS) Trial was a double-blind, randomized, placebo-controlled, multicenter, 4- to 6-year study (average 5 years) in 3047 men with symptomatic BPH, who were randomized to receive finasteride tablets USP, 5 mg/day (n=768), doxazosin 4 or 8 mg/day (n=756), the combination of finasteride tablets USP, 5 mg/day and doxazosin 4 or 8 mg/day (n=786), or placebo (n=737). All participants underwent weekly titration of doxazosin (or its placebo) from 1 to 2 to 4 to 8 mg/day. Only those who tolerated the 4 or 8 mg dose level were kept on doxazosin (or its placebo) in the study. The participant’s final tolerated dose (either 4 mg or 8 mg) was administered beginning at end-Week 4. The final doxazosin dose was administered once per day, at bedtime. - The mean patient age at randomization was 62.6 years (±7.3 years). Patients were Caucasian (82%), African American (9%), Hispanic (7%), Asian (1%) or Native American (<1%). The mean duration of BPH symptoms was 4.7 years (±4.6 years). Patients had moderate to severe BPH symptoms at baseline with a mean AUA symptom score of approximately 17 out of 35 points. Mean maximum urinary flow rate was 10.5 mL/sec (±2.6 mL/sec). The mean prostate volume as measured by transrectal ultrasound was 36.3 mL (±20.1 mL). Prostate volume was ≤20 mL in 16% of patients, ≥50 mL in 18% of patients and between 21 and 49 mL in 66% of patients. - The primary endpoint was a composite measure of the first occurrence of any of the following five outcomes: a ≥4 point confirmed increase from baseline in symptom score, acute urinary retention, BPH-related renal insufficiency (creatinine rise), recurrent urinary tract infections or urosepsis, or incontinence. Compared to placebo, treatment with finasteride tablets USP, doxazosin, or combination therapy resulted in a reduction in the risk of experiencing one of these five outcome events by 34% (p=0.002), 39% (p<0.001), and 67% (p<0.001), respectively. Combination therapy resulted in a significant reduction in the risk of the primary endpoint compared to treatment with finasteride tablets USP alone (49%; p≤0.001) or doxazosin alone (46%; p≤0.001). (See Table 6.) - The majority of the events (274 out of 351; 78%) was a confirmed ≥4 point increase in symptom score, referred to as symptom score progression. The risk of symptom score progression was reduced by 30% (p=0.016), 46% (p<0.001), and 64% (p<0.001) in patients treated with finasteride tablets USP, doxazosin, or the combination, respectively, compared to patients treated with placebo (see Figure 4). Combination therapy significantly reduced the risk of symptom score progression compared to the effect of finasteride tablets USP alone (p<0.001) and compared to doxazosin alone (p=0.037). - Treatment with finasteride tablets USP, doxazosin or the combination of finasteride tablets USP with doxazosin, reduced the mean symptom score from baseline at year 4. Table 7 provides the mean change from baseline for AUA symptom score by treatment group for patients who remained on therapy for four years. - The results of MTOPS are consistent with the findings of the 4-year, placebo-controlled study long-term efficacy and safety study in that treatment with finasteride tablets USP reduces the risk of acute urinary retention and the need for BPH-related surgery. In MTOPS, the risk of developing acute urinary retention was reduced by 67% in patients treated with finasteride tablets USP compared to patients treated with placebo (0.8% for finasteride tablets USP and 2.4% for placebo). Also, the risk of requiring BPH-related invasive therapy was reduced by 64% in patients treated with finasteride tablets USP compared to patients treated with placebo (2.0% for finasteride tablets USP and 5.4% for placebo). - The data from these studies, showing improvement in BPH-related symptoms, reduction in treatment failure (BPH-related urological events), increased maximum urinary flow rates, and decreasing prostate volume, suggest that finasteride tablets USP arrests the disease process of BPH in men with an enlarged prostate. # How Supplied - Finasteride tablets USP, 5 mg are blue color, round film coated tablets, debossed with ‘H’ on one side ‘37’ on other side. They are supplied as follows: - Bottles of 30 NDC 43598-303-30 - Bottles of 90 NDC 43598-303-90 - Storage and Handling - Store at 20° to 25°C (68° to 77°F). Protect from light and keep container tightly closed. - Women should not handle crushed or broken finasteride tablets USP when they are pregnant or may potentially be pregnant because of the possibility of absorption of finasteride and the subsequent potential risk to a male fetus. ## Storage There is limited information regarding Finasteride Storage in the drug label. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information - Patients should be informed that there was an increase in high-grade prostate cancer in men treated with 5α-reductase inhibitors indicated for BPH treatment, including finasteride tablets USP, compared to those treated with placebo in studies looking at the use of these drugs to prevent prostate cancer. - Physicians should inform patients that women who are pregnant or may potentially be pregnant should not handle crushed or broken finasteride tablets USP because of the possibility of absorption of finasteride and the subsequent potential risk to the male fetus. Finasteride tablets USP are coated and will prevent contact with the active ingredient during normal handling, provided that the tablets have not been broken or crushed. If a woman who is pregnant or may potentially be pregnant comes in contact with crushed or broken finasteride tablets USP, the contact area should be washed immediately with soap and water. - Physicians should inform patients that the volume of ejaculate may be decreased in some patients during treatment with finasteride tablets USP. This decrease does not appear to interfere with normal sexual function. However, impotence and decreased libido may occur in patients treated with finasteride tablets USP. - Physicians should instruct their patients to promptly report any changes in their breasts such as lumps, pain or nipple discharge. Breast changes including breast enlargement, tenderness and neoplasm have been reported. - Physicians should instruct their patients to read the patient package insert before starting therapy with finasteride tablets USP and to reread it each time the prescription is renewed so that they are aware of current information for patients regarding finasteride tablets USP. # Precautions with Alcohol - Alcohol-Finasteride interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - FINASTERIDE®[1] # Look-Alike Drug Names - Proscar® — Provera®[2] - Proscar® — PROzac®[2] # Drug Shortage Status # Price	https://www.wikidoc.org/index.php/Finalo
40164cfe043efada5fcb10c54dc223d17488c666	wikidoc	Fingerprick	Fingerprick In medicine, some blood tests are conducted on venous blood obtained by fingerprick. There are various ways of opening a small wound that produces no more than a few drops of blood. The procedure can be painful, but may be quicker and less distressing than venipuncture. After a droplet has formed, venous blood is sucked up by a capillary (a thin glass tube), usually passively or sometimes by indirect suction. Tests commonly conducted on capillary blood are: - glucose levels - diabetics often have a portable blood meter to check on their blood sugar. - hemoglobin levels - fingerprick testing of hemoglobin is a quick screening procedure to check if a blood donor has a high enough blood count to be allowed to donate blood. Fingerpricks are sometimes done on children and the elderly, when only a small amount of blood (less than 500 μg) is needed for a test. Neonates (newborn babies) are given heelpricks instead, as this is less likely to cause permanent damage (and because babies have very small fingers).	Fingerprick Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] In medicine, some blood tests are conducted on venous blood obtained by fingerprick. There are various ways of opening a small wound that produces no more than a few drops of blood. The procedure can be painful, but may be quicker and less distressing than venipuncture. After a droplet has formed, venous blood is sucked up by a capillary (a thin glass tube), usually passively or sometimes by indirect suction. Tests commonly conducted on capillary blood are: - glucose levels - diabetics often have a portable blood meter to check on their blood sugar. - hemoglobin levels - fingerprick testing of hemoglobin is a quick screening procedure to check if a blood donor has a high enough blood count to be allowed to donate blood. Fingerpricks are sometimes done on children and the elderly, when only a small amount of blood (less than 500 μg) is needed for a test. Neonates (newborn babies) are given heelpricks instead, as this is less likely to cause permanent damage (and because babies have very small fingers). # External links - Details from Euromedix - Heelpricks (see section "Blood collection on babies") Template:WH Template:WikiDoc Sources	https://www.wikidoc.org/index.php/Fingerprick
820e0b6bf0e26312de46485f85c4dfb579a43ecf	wikidoc	Firefighter	Firefighter # Overview Firefighters are rescuers extensively trained primarily to put out hazardous fires that threaten civilian populations and property to rescue people from car accidents, collapsed and burning buildings and other such situations. The increasing complexity of modern industrialized life with an increase in the scale of hazards has stimulated both advances in firefighting technology and a broadening of the firefighter-rescuer's remit. They sometimes provide emergency medical services. The fire service, or fire and rescue service also known in some countries as the fire brigade or fire department, are some of the emergency services. Firefighting and firefighters have become ubiquitous around the world, from urban areas to wildland areas, and on board ships. # Firefighting worldwide Not all firefighters are paid for their services. In some countries, including the United States, Canada, Finland, Australia, and New Zealand, there are often paid, or "career" firefighters working. Additionally, there are volunteer and "retained" (firefighters who are paid for the specific time they are responding to emergencies -Permanent Part time career firefighters) on call 24 hours a day, 7 days a week. In the United Kingdom and Ireland, the use of retained firefighters (who are part-time, but are paid when on duty) rather than volunteers is standard. In Australia volunteer Brigades which are mostly unpaid rural services (although traditionally they are paid by their employers if called out during working hours) In Germany, volunteer fire departments are established in every town: even the biggest German city, Berlin, with more than 3.6 million inhabitants, has volunteer firefighters besides a career fire service. In fact, only 100 German cities (most of them are towns with more than 100,000 inhabitants) have a career fire service, called the "Berufsfeuerwehr" in German, but in every one of these cities a volunteer fire service exists, too. In cities with a career fire service, volunteer fire brigades support the career fire service at big fires, accidents and disasters. Many of the so-called volunteer departments (usually in towns with 35,000 to 150,000 inhabitants), except in very small towns and villages, are in fact a mixed service of a core of career firemen who are supported by true volunteer firefighters should the need arise. However, the official title of those departments is nevertheless "volunteer fire service". The structure in Austria is similar to Germany. There are just 6 career fire services in Vienna, Graz, Innsbruck, Klagenfurt, Salzburg and Linz. There are about 200,000 men and women voluntary firefighters and 4,539 volunteer departments. In Venezuela, there are, beside the types mentioned before, the University Firefighters. They are meant to attend any emergency inside the campus and the zones around; however, their most important job is to develop new technologies in this area, thanks to the high level of education of its members (in the Simón Bolívar University Volunteer Fire Department, around 80% of its members have a university degree or are in the process of obtaining one). # Goals of firefighting Aside from the main task of extinguishing fires, the goals of firefighting are (in order) saving lives, saving property, and protecting the environment. Firefighting is an inherently difficult occupation. As such, the skills required for safe operations are regularly practiced during training evolutions throughout a firefighters career. In the United States, the preeminent fire training and standards organization is the National Fire Protection Association (NFPA). Often initial firefighting skills are taught during a local, regional, or state approved fire academy. Depending on the requirements of a department, additional skills and certifications such as technical rescue and Para-medicine may also be taught at this time. Firefighters work closely with other emergency response agencies, most particularly local and state police departments. As every fire scene is technically a crime scene until deemed otherwise by a qualified investigator, there is often overlap between the responsibilities of responding firefighters and police officers such as evidence and scene protection, initial observations of first respondents, and chain of evidence issues. The increasing role of firefighters in providing emergency medical services also brings firefighters into common overlap with law enforcement. One example of this is a common state law requiring all gunshot wounds to be reported to law enforcement agencies. Most career (full time, paid) firefighters in North America are represented by the International Association of Fire Fighters. Fire fighting has several basic skills: prevention, self preservation, rescue, preservation of property and fire control. Firefighting is further broken down into skills which include size-up, extinguishing, ventilation, and salvage and overhaul. Search and Rescue, which has already been mentioned, is performed early in any fire scenario and many times is in unison with extinguishing and ventilation. ## Prevention Prevention attempts to ensure that no place simultaneously has sufficient heat, fuel and air to allow ignition and combustion. Fernando Cardona, the leading researcher in fire prevention is accredited with much of the advancement and improvement to modern fire fighting technique. Most prevention programs are directed at controlling the energy of activation (heat). Fire suppression systems have a proven record for controlling and extinguishing unwanted fires. Many fire officials recommend that every building, including residences, have fire sprinkler systems. Correctly working sprinklers in a residence greatly reduce the risk of death from a fire. With the small rooms typical of a residence, one or two sprinklers can cover most rooms. In addition, a major duty of fire services is the regular inspection of buildings to ensure they are up to the current building fire codes, which are enforced so that a building can sufficiently resist fire spread, potential hazards are located, and to ensure that occupants can be safely evacuated, commensurate with the risks involved. Other methods of fire prevention are by directing efforts to reduce known hazardous conditions or by preventing dangerous acts before tragedy strikes. This is normally accomplished in many innovative ways such as conducting presentations, distributing safety brochures, providing news articles, writing public safety announcements(PSAs) or establishing meaningful displays in well-visited areas. Ensuring that each household has working smoke alarms, is educated in the proper techniques of fire safety, has an evacuation route and rendezvous point is of top priority in public education for most fire prevention teams in almost all fire department localities. ## Self-preservation Self-preservation is very critical. The basic technique firefighters use is to know where they are, and to avoid hazards. Current standards in the United States recommend that firefighters work in teams, using a "two-in, two-out" rule whenever in an IDLH (Immediately Dangerous to Life or Health) environment. Tools are generally carried at all times and are important for not only forcible entry but also for self rescue. A Self Contained Breathing Apparatus (SCBA) delivers air to the firefighter through a full face mask and is worn to protect against smoke inhalation, toxic fumes, and super heated gasses. A special device called a Personal Alert Safety System (PASS) is commonly worn independently or as a part of the SCBA to alert others when a firefighter stops moving for a specified period of time or manually operates the device. The PASS device sounds an alarm that can assist another firefighter (Firefighter Assist and Search Team), in locating the firefighter in distress. Firefighters often carry personal self rescue ropes. The ropes are generally 30 feet long and can provide a firefighter (that has enough time to deploy the rope) a partially controlled exit out an elevated window. Lack of a personal rescue rope is cited in the deaths of two New York City Firefighters, Lt. John Bellew and Lt. Curtis Meyran, who died after they jumped from a fourth floor of a burning apartment building in the Bronx. Of the four firefighters who jumped and survived only one of them had a self rescue rope. Since the incident the Fire Department of New York City has issued self rescue ropes to their firefighters. In the United States, 25% of fatalities to firefighters are caused by vehicle accidents while responding to or returning from an incident. Many firefighters are also injured or killed by vehicles while working at an incident (Paulison 2005). However, a large percentage of firefighters also succumb to heart disease, in the line of duty. # Occupational health and safety ## Cardiovascular disease Firefighting has long been associated with poor cardiovascular outcomes. In the United States, the most common cause of on-duty fatalities for firefighters is sudden cardiac death. In addition to personal factors that may predispose an individual to coronary artery disease or other cardiovascular diseases, occupational exposures can significantly increase a firefighter's risk. For instance, carbon monoxide, present in nearly all fire environments, and hydrogen cyanide, formed during the combustion of paper, cotton, plastics, and other substances containing carbon and nitrogen, interfere with the transport of oxygen in the body. Hypoxia can then lead to heart injury. In addition, chronic exposure to particulate matter in smoke is associated with atherosclerosis. Noise exposures may contribute to hypertension and possibly ischemic heart disease. Other factors associated with firefighting, such as stress, heat stress, and heavy physical exertion, also increase the risk of cardiovascular events. ## Structural collapses Another leading cause of death during firefighting is structural collapse of part of a burning building (e.g. a wall, floor, ceiling, roof, or truss system). Structural collapse, which often occurs without warning, may crush or trap on-duty firefighters. To avoid loss of life, all on-duty firefighters should maintain two-way communication with the incident commander and be equipped with a Personal Alert Safety System device (PASS). # Rescue Rescue operations consist of searching for and removing trapped occupants of hazardous conditions. Animals may also be recovered, if resources and conditions permit. Generally triage and first aid are performed outside, as removal from the hazardous atmosphere is the primary goal in preserving life. Search patterns include movement against room walls (to prevent rescuers from becoming lost or disoriented) and methodical searches of specific areas by designated teams. Unlike a fire control team, a rescue team typically moves faster, but has no hose to follow out to safety through the smoky darkness. A rescue rope may be needed for tethering a team involved in exceptionally dangerous conditions. Incident commanders also arrange for standby search and rescue teams to assist if firefighters become lost, trapped, or injured. Such teams are commonly, and often interchangeably, known as Rapid Intervention Teams (RIT), or Firefighter Assist and Search Teams (FAST). According to "two-in, two-out", the only time it is permissible for a team of firefighters to enter a burning structure without backup in place outside is when they are operating in what is known as "Rescue Mode". Rescue Mode occurs when firefighters have arrived at the scene, and it is readily apparent that there are occupants trapped inside who need immediate rescue. At such a time, properly equipped firefighters (exercising good judgment tempered by training and experience) may enter the structure and proceed directly to victims in need of rescue, RIT will then be put in place when resources permit. The Worcester Cold Storage Warehouse fire provides a stark example of disoriented rescuers perishing when their air supply was exhausted during a fruitless primary search and subsequent RIT searches. Searches for trapped victims are exhaustively detailed, often including searches of cupboards, closets, and under beds. The search is divided into two stages, the primary and secondary. The primary search is conducted quickly and thoroughly, typically beginning in the area closest to the fire as it is subjected to the highest risk of exposure. The secondary search only begins once the fire is under control, and is always (resources and personnel permitting) performed by a different team from that which did the primary search. Rescue operations may also involve the extrication of victims of motor vehicle crashes (abbreviated MVC). Here firefighters use spreaders, cutters, and hydraulic rams, collectively called hydraulic rescue tools—known better to the public as Jaws of Life—to remove metal from the patient, followed by actually removing the patient, usually on a backboard with collar, and transferring to a waiting ambulance crew in the cold zone. More technical forms of rescue include subsets such as rope rescue, swiftwater rescue, confined space rescue, and trench rescue. These types of rescue are often extremely hazardous and physically demanding. They also require extensive technical training. NFPA regulation 1006 and 1670 state that a "rescuer" must have medical training to perform any technical rescue operation. Accordingly, firefighters involved in rescue operations have some kind of medical training as first responders, emergency medical technicians, paramedics or nurses. # Search procedure These are standard search procedures for most fire departments. These are not actual instructions. Searching a building is normally a two to three man team. The most common way to search a building that is filled with smoke is to crawl on hands and knees with an axe (or any other tool) in the firefighter's left hand. The firefighter will keep one hand on the wall, or a foot in contact at all times with the wall. And scoot himself forward, swinging the handle of the axe back and forth, searching for any objects in his way. If the object moves when touched, it might be a person. Depending on the sound/feel it gives back, he can check what ever the object was. If it's not a person, he will continue down along the wall. Meanwhile his buddy/buddies have their right hand in contact with the lead firefighter's left ankle and scooting with them. This way they cover a far larger spread of ground. Once the person(s) is found, they will drag, carry, push, any way possible really, they will move the victim back the way they came because they know the way they went was safe. It is also important to remember that the Firefighter needs to check the floor before he moves into the room. Once going into the room, he will go right, and follow the right wall. ALWAYS. Next, when in a group of 3, the 2nd in the search line will go into most rooms, check it over, and then return out. (This is when doing a very detailed search because location of the victim is unknown) # Communication and command structure The expedient and accurate handling of fire alarms or calls are significant factors in the successful outcome of any incident. Fire department communications play a critical role in that successful outcome. Fire department communications include the methods by which the public can notify the communications center of an emergency, the methods by which the center can notify the proper fire fighting forces, and the methods by which information is exchanged at the scene. A telecommunicator (often referred to as a dispatcher) has a role different but just as important as other emergency personnel. The telecommunicator must process calls from unknown and unseen individuals, usually calling under stressful conditions. He/she must be able to obtain complete, reliable information from the caller and prioritize requests for assistance. It is the dispatcher's responsibility to bring order to chaos. While some fire departments are large enough to utilize their own telecommunication dispatcher, most rural and small areas rely on a central dispatcher to provide handling of fire, rescue and police services. Firefighters are trained to use communications equipment to receive alarms, give and receive commands, request assistance, and report on conditions. Since firefighters from different agencies routinely provide mutual aid to each other, and routinely operate at incidents where other emergency services are present, it is essential to have structures in place to establish a unified chain of command, and share information between agencies. The U.S. Federal Emergency Management Agency has established a National Incident Management System. One component of this system is the Incident Command System. All radio communication in the United States is under authorization from the Federal Communications Commission (FCC); as such, fire departments that operate radio equipment must hold radio licenses from the FCC. Ten codes were popular in the early days of radio equipment because of poor transmission and reception. Advances in modern radio technology have reduced the need for ten-codes and many departments have converted to simple English (clear text). Most command structures are run in this manner: Rank: Fire Fighter(No insignia) Yellow Helmet: Normal Helmet, No Shield Junior Fire Fighter Yellow Helmet: Black Number Shield Fire Fighter Rank: Lieutenant(One Bugle) Yellow Helmet: Red Number Shield Black Helmet : Senior Fire Fighter Black Helmet : Red Number shield 1st Lieutenant Rank: Captain(Two Bugle) Red Helmet : Black Number shield 2nd Captain Red Helmet : Red Number shield 1st Captain Rank: Chief White Helmet : Deputy Chief (3 Bugle) White Helmet : Black Shield Assistant Chief(4 Bugle) White Helmet : White Shield Gold (5 Bugle) There is no set 'law' to the command structure. This is just a basic idea. # Structure fires Buildings that are made of flammable materials such as wood are different from so called "fire-resistant" buildings such as concrete high-rises. Generally, a "fire-resistant" building is designed to limit fire to a small area or floor. Other floors can be safe simply by preventing smoke inhalation and damage. All buildings suspected of being on fire must be evacuated, regardless of fire rating. While sometimes fires can be limited to small areas of a structure, wider collateral damage due to smoke, water, and burning embers is common. Utility shutoff (such as gas and electricity) is typically an early priority of arriving fire crews. Furthermore, fire prevention can take on a special meaning for property where hazardous materials are being used or stored. Some fire fighting tactics may appear to be destructive, but often serve specific needs. For example, during "ventilation" firefighters are often forced to open holes in the roof or floors of a structure (called "vertical ventilation") or open windows or walls (called "horizontal ventilation") to remove smoke and heated gases from the interior of the structure. Such ventilation methods are also used to locate victims quicker as visibility increases and to help preserve the life of trapped or unconscious individuals due to the poisonous gases inside of the structure. Vertical Ventilation is absolutely vital to firefighter safety in the event of a Flashover or Backdraft scenario. Releasing the flammable gasses through the roof often eliminates the possibility of a backdraft and by the removal of heat the possibility of a flashover is reduced significantly. Flashovers, due to their intense heat (900 - 1200 degrees fahrenheit) and explosive temperaments are almost always fatal to firefighter personnel. Precautionary methods, such as busting a window out, often reveal backdraft situations before the firefighter enters the structure and is met with the circumstance head-on. Firefighter safety is the number one priority. Whenever possible, movable property is moved into the middle of a room and covered with a heavy cloth tarp (a "salvage cover"). Other steps may be taken to divert or remove fire flow runoff (thus salvaging property by avoiding unnecessary damage), retrieving/protecting valuables found during suppression or overhaul, and boarding windows, roofs and doors against the elements and looters. # Fire control Fire control (or fire fighting) consists of depriving a fire of fuel (Reducing Agent), oxygen (Oxidizing Agent), heat and/or the chemical chain reaction that are necessary to sustain itself or re-kindle (also known as the four components of The Fire Tetrahedron). Firefighters are equipped with a wide variety of equipment to accomplish this task. Some of their tools include ladder trucks, pumper trucks, tanker trucks, fire hose, and fire extinguishers. Very frequent training and refresher training is required. Structure fires may be attacked, generally, either by "interior" or "exterior" resources, or both. Interior crews, using the "two-in, two out" rule, may advance hose lines inside the building, find the fire and cool it with water. Exterior crews may direct water into windows or other openings, or against other nearby fuels exposed to the initial fire. A proper command structure will plan and coordinate the various teams and equipment to safely execute each tactic. # Equipment A partial list of some equipment typically used by firefighters: - Hand tools, such as Flat-head and pick-head axe Pike pole Halligan bar Flashlight Spanner wrench Circular ("K-12"), Cutters Edge, and/or chain saws - Flat-head and pick-head axe - Pike pole - Halligan bar - Flashlight - Spanner wrench - Circular ("K-12"), Cutters Edge, and/or chain saws - Personal protective equipment ("PPE") designed to withstand water and high temperatures, such as Bunker gear, including turnout jacket and pants Self-Contained Breathing Apparatus (SCBA) Helmet, face mask and/or visor Boots, gloves, and Nomex and Carbon flash hoods Personal Alert Safety System (PASS) device - Bunker gear, including turnout jacket and pants - Self-Contained Breathing Apparatus (SCBA) - Helmet, face mask and/or visor - Boots, gloves, and Nomex and Carbon flash hoods - Personal Alert Safety System (PASS) device - Handheld radio, pager, or other communication devices - Vehicle extrication tools, such as Hydraulic rescue tools - Thermal Imaging Camera # History of fire brigades The history of organized combating of structural fires dates back at least to Ancient Egypt. Today, fire and rescue remains a mix of paid, call, and volunteer responders. The UK has the retained fire service, whereby fire fighters are on call with pagers from their homes and/or place of work. See article history of fire brigades. # Firefighting worldwide Traditions, protocol, and trends in firefighting vary from country to country. For more information on national firefighting procedures, see article Firefighting worldwide. # Miscellaneous In popular literature, firefighters are usually depicted with Dalmatian dogs. This breed originated in southern Europe to assist with herding livestock and run along with horses, and in the days of horse-drawn fire vehicles, the horses were usually released on arrival at the fire and the Dalmatians would lead the horses through traffic and to a safe place to wait until the fire was out. Dalmatians also filled the role of protecting the horses' feet from other dogs as equipment was being transported to the fire scene. In reality, most fire dogs were mutts pulled from the street (and thus cheaper to acquire). In addition, Dalmatians have a reputation for skittishness and congenital defects, such as deafness due to inbreeding. Many fire companies around the world, especially in the United States, develop annual beefcake calendars. In these calendars, handsome and/or muscular firefighters appear scantily clad and sometimes cavorting. Calendar proceeds function as fund raisers for their fire department and for charities. Other forms of fund-raising may include traditional Firemen's Balls (gala events attended by fire-fighters and supporters from the community), community fairs, and ding-a-ling car washes (where the price is whatever donation one wishes). # Rank A list of various ranks for firefighters around the world: - Auxiliary Firefighter – a volunteer fire fighter, mainly in smaller jurisdictions - Probationary Firefighter – a new firefighter under probation - 1st Class Firefighter – a full time/non-probationary firefighter - Senior Fire Fighter – a senior non-officer firefighter whom provides command and control at fire scene; also refer to as Leading Firefighter in the British Army - Sub Officer - used in British Army	Firefighter # Overview Firefighters are rescuers extensively trained primarily to put out hazardous fires that threaten civilian populations and property to rescue people from car accidents, collapsed and burning buildings and other such situations. The increasing complexity of modern industrialized life with an increase in the scale of hazards has stimulated both advances in firefighting technology and a broadening of the firefighter-rescuer's remit. They sometimes provide emergency medical services. The fire service, or fire and rescue service also known in some countries as the fire brigade or fire department, are some of the emergency services. Firefighting and firefighters have become ubiquitous around the world, from urban areas to wildland areas, and on board ships. # Firefighting worldwide Not all firefighters are paid for their services. In some countries, including the United States, Canada, Finland, Australia, and New Zealand, there are often paid, or "career" firefighters working. Additionally, there are volunteer and "retained" (firefighters who are paid for the specific time they are responding to emergencies -Permanent Part time career firefighters) on call 24 hours a day, 7 days a week. In the United Kingdom and Ireland, the use of retained firefighters (who are part-time, but are paid when on duty) rather than volunteers is standard. In Australia volunteer Brigades which are mostly unpaid rural services (although traditionally they are paid by their employers if called out during working hours) In Germany, volunteer fire departments are established in every town: even the biggest German city, Berlin, with more than 3.6 million inhabitants, has volunteer firefighters besides a career fire service. In fact, only 100 German cities (most of them are towns with more than 100,000 inhabitants) have a career fire service, called the "Berufsfeuerwehr" in German, but in every one of these cities a volunteer fire service exists, too. In cities with a career fire service, volunteer fire brigades support the career fire service at big fires, accidents and disasters. Many of the so-called volunteer departments (usually in towns with 35,000 to 150,000 inhabitants), except in very small towns and villages, are in fact a mixed service of a core of career firemen who are supported by true volunteer firefighters should the need arise. However, the official title of those departments is nevertheless "volunteer fire service". The structure in Austria is similar to Germany. There are just 6 career fire services in Vienna, Graz, Innsbruck, Klagenfurt, Salzburg and Linz. There are about 200,000 men and women voluntary firefighters and 4,539 volunteer departments. In Venezuela, there are, beside the types mentioned before, the University Firefighters. They are meant to attend any emergency inside the campus and the zones around; however, their most important job is to develop new technologies in this area, thanks to the high level of education of its members (in the Simón Bolívar University Volunteer Fire Department, around 80% of its members have a university degree or are in the process of obtaining one). # Goals of firefighting Aside from the main task of extinguishing fires, the goals of firefighting are (in order) saving lives, saving property, and protecting the environment. Firefighting is an inherently difficult occupation. As such, the skills required for safe operations are regularly practiced during training evolutions throughout a firefighters career. In the United States, the preeminent fire training and standards organization is the National Fire Protection Association (NFPA). Often initial firefighting skills are taught during a local, regional, or state approved fire academy. Depending on the requirements of a department, additional skills and certifications such as technical rescue and Para-medicine may also be taught at this time. Firefighters work closely with other emergency response agencies, most particularly local and state police departments. As every fire scene is technically a crime scene until deemed otherwise by a qualified investigator, there is often overlap between the responsibilities of responding firefighters and police officers such as evidence and scene protection, initial observations of first respondents, and chain of evidence issues.[citation needed] The increasing role of firefighters in providing emergency medical services also brings firefighters into common overlap with law enforcement. One example of this is a common state law requiring all gunshot wounds to be reported to law enforcement agencies. Most career (full time, paid) firefighters in North America are represented by the International Association of Fire Fighters. Fire fighting has several basic skills: prevention, self preservation, rescue, preservation of property and fire control. Firefighting is further broken down into skills which include size-up, extinguishing, ventilation, and salvage and overhaul. Search and Rescue, which has already been mentioned, is performed early in any fire scenario and many times is in unison with extinguishing and ventilation. ## Prevention Prevention attempts to ensure that no place simultaneously has sufficient heat, fuel and air to allow ignition and combustion. Fernando Cardona, the leading researcher in fire prevention is accredited with much of the advancement and improvement to modern fire fighting technique. Most prevention programs are directed at controlling the energy of activation (heat). Fire suppression systems have a proven record for controlling and extinguishing unwanted fires. Many fire officials recommend that every building, including residences, have fire sprinkler systems. Correctly working sprinklers in a residence greatly reduce the risk of death from a fire. With the small rooms typical of a residence, one or two sprinklers can cover most rooms. In addition, a major duty of fire services is the regular inspection of buildings to ensure they are up to the current building fire codes, which are enforced so that a building can sufficiently resist fire spread, potential hazards are located, and to ensure that occupants can be safely evacuated, commensurate with the risks involved. Other methods of fire prevention are by directing efforts to reduce known hazardous conditions or by preventing dangerous acts before tragedy strikes. This is normally accomplished in many innovative ways such as conducting presentations, distributing safety brochures, providing news articles, writing public safety announcements(PSAs) or establishing meaningful displays in well-visited areas. Ensuring that each household has working smoke alarms, is educated in the proper techniques of fire safety, has an evacuation route and rendezvous point is of top priority in public education for most fire prevention teams in almost all fire department localities. ## Self-preservation Self-preservation is very critical. The basic technique firefighters use is to know where they are, and to avoid hazards. Current standards in the United States recommend that firefighters work in teams, using a "two-in, two-out" rule whenever in an IDLH (Immediately Dangerous to Life or Health) environment. Tools are generally carried at all times and are important for not only forcible entry but also for self rescue. A Self Contained Breathing Apparatus (SCBA) delivers air to the firefighter through a full face mask and is worn to protect against smoke inhalation, toxic fumes, and super heated gasses. A special device called a Personal Alert Safety System (PASS) is commonly worn independently or as a part of the SCBA to alert others when a firefighter stops moving for a specified period of time or manually operates the device. The PASS device sounds an alarm that can assist another firefighter (Firefighter Assist and Search Team), in locating the firefighter in distress. Firefighters often carry personal self rescue ropes. The ropes are generally 30 feet long and can provide a firefighter (that has enough time to deploy the rope) a partially controlled exit out an elevated window. Lack of a personal rescue rope is cited in the deaths of two New York City Firefighters, Lt. John Bellew and Lt. Curtis Meyran, who died after they jumped from a fourth floor of a burning apartment building in the Bronx. Of the four firefighters who jumped and survived only one of them had a self rescue rope. Since the incident the Fire Department of New York City has issued self rescue ropes to their firefighters. In the United States, 25% of fatalities to firefighters are caused by vehicle accidents while responding to or returning from an incident. Many firefighters are also injured or killed by vehicles while working at an incident (Paulison 2005). However, a large percentage of firefighters also succumb to heart disease, in the line of duty. # Occupational health and safety ## Cardiovascular disease Firefighting has long been associated with poor cardiovascular outcomes. In the United States, the most common cause of on-duty fatalities for firefighters is sudden cardiac death. In addition to personal factors that may predispose an individual to coronary artery disease or other cardiovascular diseases, occupational exposures can significantly increase a firefighter's risk. For instance, carbon monoxide, present in nearly all fire environments, and hydrogen cyanide, formed during the combustion of paper, cotton, plastics, and other substances containing carbon and nitrogen, interfere with the transport of oxygen in the body. Hypoxia can then lead to heart injury. In addition, chronic exposure to particulate matter in smoke is associated with atherosclerosis. Noise exposures may contribute to hypertension and possibly ischemic heart disease. Other factors associated with firefighting, such as stress, heat stress, and heavy physical exertion, also increase the risk of cardiovascular events.[1] ## Structural collapses Another leading cause of death during firefighting is structural collapse of part of a burning building (e.g. a wall, floor, ceiling, roof, or truss system). Structural collapse, which often occurs without warning, may crush or trap on-duty firefighters. To avoid loss of life, all on-duty firefighters should maintain two-way communication with the incident commander and be equipped with a Personal Alert Safety System device (PASS).[2][3] # Rescue Rescue operations consist of searching for and removing trapped occupants of hazardous conditions. Animals may also be recovered, if resources and conditions permit. Generally triage and first aid are performed outside, as removal from the hazardous atmosphere is the primary goal in preserving life. Search patterns include movement against room walls (to prevent rescuers from becoming lost or disoriented) and methodical searches of specific areas by designated teams. Unlike a fire control team, a rescue team typically moves faster, but has no hose to follow out to safety through the smoky darkness. A rescue rope may be needed for tethering a team involved in exceptionally dangerous conditions. Incident commanders also arrange for standby search and rescue teams to assist if firefighters become lost, trapped, or injured. Such teams are commonly, and often interchangeably, known as Rapid Intervention Teams (RIT), or Firefighter Assist and Search Teams (FAST). According to "two-in, two-out", the only time it is permissible for a team of firefighters to enter a burning structure without backup in place outside is when they are operating in what is known as "Rescue Mode". Rescue Mode occurs when firefighters have arrived at the scene, and it is readily apparent that there are occupants trapped inside who need immediate rescue. At such a time, properly equipped firefighters (exercising good judgment tempered by training and experience) may enter the structure and proceed directly to victims in need of rescue, RIT will then be put in place when resources permit. The Worcester Cold Storage Warehouse fire provides a stark example of disoriented rescuers perishing when their air supply was exhausted during a fruitless primary search and subsequent RIT searches. Searches for trapped victims are exhaustively detailed, often including searches of cupboards, closets, and under beds. The search is divided into two stages, the primary and secondary. The primary search is conducted quickly and thoroughly, typically beginning in the area closest to the fire as it is subjected to the highest risk of exposure. The secondary search only begins once the fire is under control, and is always (resources and personnel permitting) performed by a different team from that which did the primary search. Rescue operations may also involve the extrication of victims of motor vehicle crashes (abbreviated MVC). Here firefighters use spreaders, cutters, and hydraulic rams, collectively called hydraulic rescue tools—known better to the public as Jaws of Life—to remove metal from the patient, followed by actually removing the patient, usually on a backboard with collar, and transferring to a waiting ambulance crew in the cold zone. More technical forms of rescue include subsets such as rope rescue, swiftwater rescue, confined space rescue, and trench rescue. These types of rescue are often extremely hazardous and physically demanding. They also require extensive technical training. NFPA regulation 1006 and 1670 state that a "rescuer" must have medical training to perform any technical rescue operation. Accordingly, firefighters involved in rescue operations have some kind of medical training as first responders, emergency medical technicians, paramedics or nurses. # Search procedure These are standard search procedures for most fire departments. These are not actual instructions. Searching a building is normally a two to three man team. The most common way to search a building that is filled with smoke is to crawl on hands and knees with an axe (or any other tool) in the firefighter's left hand. The firefighter will keep one hand on the wall, or a foot in contact at all times with the wall. And scoot himself forward, swinging the handle of the axe back and forth, searching for any objects in his way. If the object moves when touched, it might be a person. Depending on the sound/feel it gives back, he can check what ever the object was. If it's not a person, he will continue down along the wall. Meanwhile his buddy/buddies have their right hand in contact with the lead firefighter's left ankle and scooting with them. This way they cover a far larger spread of ground. Once the person(s) is found, they will drag, carry, push, any way possible really, they will move the victim back the way they came because they know the way they went was safe. It is also important to remember that the Firefighter needs to check the floor before he moves into the room. Once going into the room, he will go right, and follow the right wall. ALWAYS. Next, when in a group of 3, the 2nd in the search line will go into most rooms, check it over, and then return out. (This is when doing a very detailed search because location of the victim is unknown) # Communication and command structure The expedient and accurate handling of fire alarms or calls are significant factors in the successful outcome of any incident. Fire department communications play a critical role in that successful outcome. Fire department communications include the methods by which the public can notify the communications center of an emergency, the methods by which the center can notify the proper fire fighting forces, and the methods by which information is exchanged at the scene. A telecommunicator (often referred to as a dispatcher)[citation needed] has a role different but just as important as other emergency personnel. The telecommunicator must process calls from unknown and unseen individuals, usually calling under stressful conditions. He/she must be able to obtain complete, reliable information from the caller and prioritize requests for assistance. It is the dispatcher's responsibility to bring order to chaos. While some fire departments are large enough to utilize their own telecommunication dispatcher, most rural and small areas rely on a central dispatcher to provide handling of fire, rescue and police services. Firefighters are trained to use communications equipment to receive alarms, give and receive commands, request assistance, and report on conditions. Since firefighters from different agencies routinely provide mutual aid to each other, and routinely operate at incidents where other emergency services are present, it is essential to have structures in place to establish a unified chain of command, and share information between agencies. The U.S. Federal Emergency Management Agency has established a National Incident Management System. One component of this system is the Incident Command System. All radio communication in the United States is under authorization from the Federal Communications Commission (FCC); as such, fire departments that operate radio equipment must hold radio licenses from the FCC. Ten codes were popular in the early days of radio equipment because of poor transmission and reception. Advances in modern radio technology have reduced the need for ten-codes and many departments have converted to simple English (clear text). Most[citation needed] command structures are run in this manner: Rank: Fire Fighter(No insignia) Yellow Helmet: Normal Helmet, No Shield Junior Fire Fighter Yellow Helmet: Black Number Shield Fire Fighter Rank: Lieutenant(One Bugle) Yellow Helmet: Red Number Shield Black Helmet : Senior Fire Fighter Black Helmet : Red Number shield 1st Lieutenant Rank: Captain(Two Bugle) Red Helmet : Black Number shield 2nd Captain Red Helmet : Red Number shield 1st Captain Rank: Chief White Helmet : Deputy Chief (3 Bugle) White Helmet : Black Shield Assistant Chief(4 Bugle) White Helmet : White Shield Gold (5 Bugle) There is no set 'law' to the command structure. This is just a basic idea. # Structure fires Buildings that are made of flammable materials such as wood are different from so called "fire-resistant" buildings such as concrete high-rises. Generally, a "fire-resistant" building is designed to limit fire to a small area or floor. Other floors can be safe simply by preventing smoke inhalation and damage. All buildings suspected of being on fire must be evacuated, regardless of fire rating. While sometimes fires can be limited to small areas of a structure, wider collateral damage due to smoke, water, and burning embers is common. Utility shutoff (such as gas and electricity) is typically an early priority of arriving fire crews. Furthermore, fire prevention can take on a special meaning for property where hazardous materials are being used or stored. Some fire fighting tactics may appear to be destructive, but often serve specific needs. For example, during "ventilation" firefighters are often forced to open holes in the roof or floors of a structure (called "vertical ventilation") or open windows or walls (called "horizontal ventilation") to remove smoke and heated gases from the interior of the structure. Such ventilation methods are also used to locate victims quicker as visibility increases and to help preserve the life of trapped or unconscious individuals due to the poisonous gases inside of the structure. Vertical Ventilation is absolutely vital to firefighter safety in the event of a Flashover or Backdraft scenario. Releasing the flammable gasses through the roof often eliminates the possibility of a backdraft and by the removal of heat the possibility of a flashover is reduced significantly. Flashovers, due to their intense heat (900 - 1200 degrees fahrenheit) and explosive temperaments are almost always fatal to firefighter personnel. Precautionary methods, such as busting a window out, often reveal backdraft situations before the firefighter enters the structure and is met with the circumstance head-on. Firefighter safety is the number one priority. Whenever possible, movable property is moved into the middle of a room and covered with a heavy cloth tarp (a "salvage cover"). Other steps may be taken to divert or remove fire flow runoff (thus salvaging property by avoiding unnecessary damage), retrieving/protecting valuables found during suppression or overhaul, and boarding windows, roofs and doors against the elements and looters. # Fire control Fire control (or fire fighting) consists of depriving a fire of fuel (Reducing Agent), oxygen (Oxidizing Agent), heat and/or the chemical chain reaction that are necessary to sustain itself or re-kindle (also known as the four components of The Fire Tetrahedron). Firefighters are equipped with a wide variety of equipment to accomplish this task. Some of their tools include ladder trucks, pumper trucks, tanker trucks, fire hose, and fire extinguishers. Very frequent training and refresher training is required. Structure fires may be attacked, generally, either by "interior" or "exterior" resources, or both. Interior crews, using the "two-in, two out" rule, may advance hose lines inside the building, find the fire and cool it with water. Exterior crews may direct water into windows or other openings, or against other nearby fuels exposed to the initial fire. A proper command structure will plan and coordinate the various teams and equipment to safely execute each tactic. # Equipment A partial list of some equipment typically used by firefighters: - Hand tools, such as Flat-head and pick-head axe Pike pole Halligan bar Flashlight Spanner wrench Circular ("K-12"), Cutters Edge, and/or chain saws - Flat-head and pick-head axe - Pike pole - Halligan bar - Flashlight - Spanner wrench - Circular ("K-12"), Cutters Edge, and/or chain saws - Personal protective equipment ("PPE") designed to withstand water and high temperatures, such as Bunker gear, including turnout jacket and pants Self-Contained Breathing Apparatus (SCBA) Helmet, face mask and/or visor Boots, gloves, and Nomex and Carbon flash hoods Personal Alert Safety System (PASS) device - Bunker gear, including turnout jacket and pants - Self-Contained Breathing Apparatus (SCBA) - Helmet, face mask and/or visor - Boots, gloves, and Nomex and Carbon flash hoods - Personal Alert Safety System (PASS) device - Handheld radio, pager, or other communication devices - Vehicle extrication tools, such as Hydraulic rescue tools - Thermal Imaging Camera # History of fire brigades The history of organized combating of structural fires dates back at least to Ancient Egypt. Today, fire and rescue remains a mix of paid, call, and volunteer responders. The UK has the retained fire service, whereby fire fighters are on call with pagers from their homes and/or place of work. See article history of fire brigades. # Firefighting worldwide Traditions, protocol, and trends in firefighting vary from country to country. For more information on national firefighting procedures, see article Firefighting worldwide. # Miscellaneous In popular literature, firefighters are usually depicted with Dalmatian dogs. This breed originated in southern Europe to assist with herding livestock and run along with horses, and in the days of horse-drawn fire vehicles, the horses were usually released on arrival at the fire and the Dalmatians would lead the horses through traffic and to a safe place to wait until the fire was out. Dalmatians also filled the role of protecting the horses' feet from other dogs as equipment was being transported to the fire scene. In reality, most fire dogs were mutts pulled from the street (and thus cheaper to acquire). In addition, Dalmatians have a reputation for skittishness and congenital defects, such as deafness due to inbreeding. Many fire companies around the world, especially in the United States, develop annual beefcake calendars. In these calendars, handsome and/or muscular firefighters appear scantily clad and sometimes cavorting. Calendar proceeds function as fund raisers for their fire department and for charities.[4] Other forms of fund-raising may include traditional Firemen's Balls (gala events attended by fire-fighters and supporters from the community), community fairs, and ding-a-ling car washes (where the price is whatever donation one wishes). # Rank A list of various ranks for firefighters around the world: - Auxiliary Firefighter – a volunteer fire fighter, mainly in smaller jurisdictions - Probationary Firefighter – a new firefighter under probation - 1st Class Firefighter – a full time/non-probationary firefighter - Senior Fire Fighter – a senior non-officer firefighter whom provides command and control at fire scene; also refer to as Leading Firefighter in the British Army - Sub Officer - used in British Army	https://www.wikidoc.org/index.php/Fire_department
d9bb4539ae7bd3229134d3c33388848f326fbafe	wikidoc	Flibanserin	Flibanserin CONTRAINDICATED WITH ALCOHOL: The use of Flibanserin tablets and alcohol increases the risk of severe hypotension and syncope. Therefore, alcohol use is contraindicated in patients taking Flibanserin. Before prescribing Flibanserin, assess the likelihood of the patient abstaining from alcohol, taking into account the patient’s current and past drinking behavior, and other pertinent social and medical history. Counsel patients who are prescribed Flibanserin about the importance of abstaining from alcohol use. Because of the increased risk of hypotension and syncope due to an interaction with alcohol, Flibanserin is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the Flibanserin REMS Program. CONTRAINDICATED WITH STRONG OR MODERATE CYP3A4 INHIBITORS: The concomitant use of Flibanserin and moderate or strong CYP3A4 inhibitors increases Flibanserin concentrations, which can cause severe hypotension and syncope. Therefore, the use of moderate or strong CYP3A4 inhibitors is contraindicated in patients taking Flibanserin. CONTRAINDICATED IN PATIENTS WITH HEPATIC IMPAIRMENT: The use of Flibanserin in patients with hepatic impairment increases Flibanserin concentrations, which can cause severe hypotension and syncope. Therefore, Flibanserin is contraindicated in patients with hepatic impairment. Flibanserin tablets are indicated for the treatment of premenopausal women with acquired, generalized hypoactive sexual desire disorder (HSDD), as characterized by low sexual desire that causes marked distress or interpersonal difficulty and is NOT due to: - A co-existing medical or psychiatric condition, - Problems within the relationship, or - The effects of a medication or other drug substance. Acquired HSDD refers to HSDD that develops in a patient who previously had no problems with sexual desire. Generalized HSDD refers to HSDD that occurs regardless of the type of stimulation, situation or partner. Limitations of Use - Flibanserin is not indicated for the treatment of HSDD in postmenopausal women or in men. - Flibanserin is not indicated to enhance sexual performance. The recommended dosage of Flibanserin is 100 mg administered orally once per day at bedtime. - With use of alcohol. - With concomitant use with moderate or strong CYP3A4 inhibitors. - In patients with hepatic impairment. Alcohol use is contraindicated in patients taking Flibanserin. Before prescribing Flibanserin, the healthcare provider must assess the likelihood of the patient abstaining from alcohol use, taking into account the patient’s current and past drinking behavior, and other pertinent social and medical history. Counsel patients who are prescribed Flibanserin about the importance of abstaining from alcohol use. The use of Flibanserin and alcohol increases the risk of severe hypotension and syncope. In a dedicated alcohol interaction study conducted in 25 subjects (23 men and 2 premenopausal women), hypotension or syncope requiring therapeutic intervention (ammonia salts and/or placement in supine or Trendelenburg position) occurred in 4 (17%) of the 23 subjects co-administered Flibanserin 100 mg and 0.4 g/kg alcohol (equivalent of two 12 ounce cans of beer containing 5% alcohol content, two 5 ounce glasses of wine containing 12% alcohol content, or two 1.5 ounce shots of 80-proof spirit in a 70 kg person, consumed over 10 minutes in the morning). In these four subjects, all of whom were men, the magnitude of the systolic blood pressure reductions ranged from about 28 to 54 mmHg and the magnitude of the diastolic blood pressure reductions ranged from about 24 to 46 mmHg. In addition, 6 (25%) of the 24 subjects co-administered Flibanserin 100 mg and 0.8 g/kg alcohol experienced orthostatic hypotension when standing from a sitting position. The magnitude of the systolic blood pressure reductions in these 6 subjects ranged from 22 to 48 mmHg, and the diastolic blood pressure reductions ranged from 0 to 27 mmHg. One of these subjects required therapeutic intervention (ammonia salts and placement supine with the foot of the bed elevated). There were no events requiring therapeutic interventions when Flibanserin or alcohol were administered alone. Flibanserin is available only through a restricted program under a REMS. Flibanserin is available only through a restricted program under a REMS called the Flibanserin REMS Program, because of the increased risk of severe hypotension and syncope due to an interaction between Flibanserin and alcohol. Notable requirements of the Flibanserin REMS Program include the following: - Prescribers must be certified with the program by enrolling and completing training. - Pharmacies must be certified with the program and must only dispense to patients pursuant to a prescription from a certified prescriber. Further information, including a list of qualified pharmacies, is available at www.AddyiREMS.com or 844-746-5745. - Moderate or Strong CYP3A4 Inhibitors The concomitant use of Flibanserin with moderate or strong CYP3A4 inhibitors significantly increases Flibanserin concentrations, which can lead to hypotension and syncope. The concomitant use of Flibanserin with a moderate or strong CYP3A4 inhibitor is contraindicated. If the patient requires a moderate or strong CYP3A4 inhibitor, discontinue Flibanserin at least 2 days prior to starting the moderate or strong CYP3A4 inhibitor. In cases where the benefit of initiating a moderate or strong CYP3A4 inhibitor within 2 days of stopping Flibanserin clearly outweighs the risk of Flibanserin exposure related hypotension and syncope, monitor the patient for signs of hypotension and syncope. Discontinue the moderate or strong CYP3A4 inhibitor for 2 weeks before restarting Flibanserin. - Multiple Concomitant Weak CYP3A4 Inhibitors Concomitant use of multiple weak CYP3A4 inhibitors that may include herbal supplements (e.g., ginkgo, resveratrol) or non-prescription drugs (e.g., cimetidine) could also lead to clinically relevant increases in Flibanserin concentrations that may increase the risk of hypotension and syncope. Flibanserin can cause CNS depression (e.g., somnolence, sedation). In five 24-week, randomized, placebo-controlled, double-blind trials of premenopausal women with HSDD, the incidence of somnolence, sedation or fatigue was 21% and 8% in patients treated with 100 mg Flibanserin once daily at bedtime and placebo, respectively. The risk of CNS depression is increased if Flibanserin is taken during waking hours, or if Flibanserin is taken with alcohol or other CNS depressants, or with medications that increase Flibanserin concentrations, such as CYP3A4 inhibitors. Patients should not drive or engage in other activities requiring full alertness until at least 6 hours after taking Flibanserin and until they know how Flibanserin affects them. The use of Flibanserin − without other concomitant medications known to cause hypotension or syncope − can cause hypotension and syncope. In five 24-week, randomized, placebo-controlled, double-blind trials of premenopausal women with HSDD, hypotension was reported in 0.2% and <0.1% of Flibanserin -treated patients and placebo-treated patients, respectively; syncope was reported in 0.4% and 0.2% of Flibanserin - treated patients and placebo-treated patients, respectively. The risk of hypotension and syncope is increased if Flibanserin is taken during waking hours or if higher than the recommended dose is taken. Consider the benefits of Flibanserin and the risks of hypotension and syncope in patients with pre- existing conditions that predispose to hypotension. Patients who experience pre-syncope should immediately lie supine and promptly seek medical help if the symptoms do not resolve. Prompt medical attention should also be obtained for patients who experience syncope. The use of Flibanserin in patients with any degree of hepatic impairment significantly increases Flibanserin concentrations, which can lead to hypotension and syncope. Therefore, the use of Flibanserin is contraindicated in patients with hepatic impairment. In a 2-year carcinogenicity study in mice, there was a statistically significant and dose-related increase in the incidence of malignant mammary tumors in female mice at exposures 3 and 10 times the recommended clinical dose. No such increases were seen in male mice or in male or female rats. The clinical significance of these findings is unknown. The approved 100 mg Flibanserin dosage at bedtime was administered to 2,997 premenopausal women with acquired, generalized HSDD in clinical trials, of whom 1672 received treatment for at least 6 months, 850 received treatment for at least 12 months, and 88 received treatment for at least 18 months. The data presented below are derived from five 24-week randomized, double-blind, placebo-controlled trials in premenopausal women with acquired, generalized HSDD. In these five trials, the frequency and quantity of alcohol use was not recorded. Three of these trials (Studies 1 through 3) also provided efficacy data. One of these trials (Study 5) did not evaluate the 100 mg bedtime dose. In four trials, 100 mg Flibanserin at bedtime was administered to 1543 premenopausal women with HSDD, of whom 1060 completed 24 weeks of treatment. The clinical trial population was generally healthy without significant comorbid medical conditions or concomitant medications. The age range was 18-56 years old with a mean age of 36 years old, and 88% were Caucasian and 9% were Black. Serious adverse reactions were reported in 0.9% and 0.5% of Flibanserin-treated patients and placebo-treated patients, respectively. - Adverse Reactions Leading to Discontinuation The discontinuation rate due to adverse reactions was 13% among patients treated with 100 mg Flibanserin at bedtime and 6% among patients treated with placebo. TABLE 1 displays the most common adverse reactions leading to discontinuation in four trials of premenopausal women with HSDD. - Table 1. Adverse Reactions- Leading to Discontinuation in Randomized, Double-blind, Placebo-controlled Trials in Premenopausal Women with HSDD ADDYI: Flibanserin's Brand name - Most Common Adverse Reactions TABLE 2 summarizes the most common adverse reactions reported in four trials of premenopausal women with HSDD. This table shows adverse reactions reported in at least 2% of patients treated with Flibanserin and at a higher incidence than with placebo. The majority of these adverse reactions began within the first 14 days of treatment. - Table 2. Common Adverse Reactions- in Randomized, Double-blind, Placebo-controlled Trials in Premenopausal Women with HSDD ADDYI: Flibanserin's Brand name - Less Common Adverse Reactions In four trials in premenopausal women with HSDD treated with 100 mg Flibanserin at bedtime, less common adverse reactions (reported in ≥1% but <2% of Flibanserin-treated patients and at a higher incidence than with placebo) included: - Anxiety (Flibanserin 1.8%; placebo 1.0%), - Constipation (Flibanserin 1.6%; placebo 0.4%), - Abdominal pain (Flibanserin 1.5%; placebo 0.9%), - Metrorrhagia (Flibanserin 1.4%; placebo 1.4%), - Rash (Flibanserin 1.3%; placebo 0.8%), - Sedation (Flibanserin 1.3%; placebo 0.2%), and - Vertigo (Flibanserin 1%; placebo 0.3%). - Appendicitis In the five trials of premenopausal women with HSDD, appendicitis was reported in 6/3973 (0.2%) Flibanserin-treated patients, while there were no reports of appendicitis in the 1905 placebo-treated patients. - Accidental Injury In five trials of premenopausal women with HSDD, accidental injury was reported in 42/1543 (2.7%) Flibanserin-treated patients and 47/1905 (2.5%) placebo-treated patients. Among these 89 patients who experienced injuries, 9/42 (21%) Flibanserin-treated patients and 3/47 (6%) placebo-treated patients reported adverse reactions consistent with CNS depression (e.g., somnolence, fatigue, or sedation) within the preceding 24 hours. - Adverse Reactions in Patients Who Reported Hormonal Contraceptive Use In four trials of premenopausal women with HSDD, 1466 patients (43%) reported concomitant use of hormonal contraceptives (HC) at study enrollment. These trials were not prospectively designed to assess an interaction between Flibanserin and HC. Flibanserin-treated patients who reported HC use had a greater incidence of dizziness, somnolence, and fatigue compared to Flibanserin-treated patients who did not report HC use (dizziness 9.9% in HC non-users, 13.4% in HC users; somnolence 10.6% in HC non-users, 12.3% in HC users; fatigue 7.5% in HC non-users, 11.4% in HC users). There were no meaningful differences in the incidence of these adverse reactions in placebo-treated patients who reported or did not report HC use. One death occurred in a 54 year-old postmenopausal woman treated with 100 mg Flibanserin taken at bedtime (Flibanserin is not approved for the treatment of postmenopausal women with HSDD). This patient had a history of hypertension and hypercholesterolemia and baseline alcohol consumption of 1-3 drinks daily. She died of acute alcohol intoxication 14 days after starting Flibanserin. Blood alcohol concentration on autopsy was 0.289 g/dL. The autopsy report also noted coronary artery disease. A relationship between this patient’s death and use of Flibanserinis unknown. - Hypotension, Syncope, and CNS Depression in Studies of Healthy Subjects - Hypotension, Syncope, and CNS Depression with Alcohol In a cross-over alcohol interaction study of 100 mg Flibanserin and alcohol in 25 healthy subjects dosed in the morning, somnolence was reported in 67%, 74%, and 92% of subjects who received Flibanserin alone, Flibanserin in combination with 0.4 g/kg ethanol, and Flibanserin in combination with 0.8 g/kg ethanol, respectively. In the group receiving Flibanserin in combination with 0.4 g/kg ethanol, 4/23 (17%) subjects had substantial reductions in blood pressure, resulting in hypotension and/or syncope requiring medical intervention. In the group receiving Flibanserin in combination with 0.8 g/kg ethanol, 6/24 (25%) subjects experienced orthostatic hypotension. - Hypotension and Syncope with Fluconazole In a pharmacokinetic drug interaction study of 100 mg Flibanserin and 200 mg fluconazole (a moderate CYP3A4 inhibitor, moderate CYP2C9 inhibitor, and a strong CYP2C19 inhibitor) in healthy subjects, hypotension or syncope requiring placement supine with legs elevated occurred in 3/15 (20%) subjects treated with concomitant Flibanserin and fluconazole compared to no such adverse reactions in subjects treated with Flibanserin alone or fluconazole alone. One of these 3 subjects became unresponsive with a blood pressure of 64/41 mm Hg and required transportation to the hospital emergency department where she required intravenous saline. Due to these adverse reactions, the study was stopped. In this study, the concomitant use of Flibanserin and fluconazole increased Flibanserin exposure 7-fold. - Syncope with Ketoconazole In a pharmacokinetic drug interaction study of 50 mg Flibanserin and 400 mg ketoconazole, a strong CYP3A4 inhibitor, syncope occurred in 1/24 (4%) healthy subjects treated with concomitant Flibanserin and ketoconazole, 1/24 (4%) receiving Flibanserin alone, and no subjects receiving ketoconazole alone. In this study, the concomitant use of Flibanserin and ketoconazole increased Flibanserin exposure 4.5-fold. - Syncope in Poor CYP2C19 Metabolizers In a pharmacogenomic study of 100 mg Flibanserin in subjects who were poor or extensive CYP2C19 metabolizers, syncope occurred in 1/9 (11%) subjects who were CYP2C19 poor metabolizers (this subject had a 3.2 fold higher Flibanserin exposure compared to CYP2C19 extensive metabolizers) compared to no such adverse reactions in subjects who were CYP2C19 extensive metabolizers. - Table 3: Clinically Significant Drug Interactions with Flibanserin ADDYI: Flibanserin's Brand name There are no studies of Flibanserin in pregnant women to inform whether there is a drug-associated risk in humans. In animals, fetal toxicity only occurred in the presence of significant maternal toxicity including reductions in weight gain and sedation. Adverse reproductive and developmental effects consisted of decreased fetal weight, structural anomalies and increases in fetal loss at exposures greater than 15 times exposures achieved with the recommended human dosage. Animal studies cannot rule out the potential for fetal harm. In the general population (not taking Flibanserin), the estimated background risk of major birth defects is 2% to 4% of live births, and the estimated background risk of miscarriage of clinically recognized pregnancies is 15% to 20%. - Data - Animal Data Pregnant rats were administered Flibanserin at doses of 0, 20, 80 and 400 mg/kg/day (3, 15 and 41 times clinical exposures at the recommended human dose based on AUC) during organogenesis. The highest dose was associated with significant maternal toxicity as evidenced by severe clinical signs and marked reductions in weight gain during dosing. In the litters of high-dose dams, there were decreased fetal weights, decreased ossification of the forelimbs and increased number of lumbar ribs, and two fetuses with anophthalmia secondary to severe maternal toxicity. The no adverse effect level for embryofetal toxicity was 80 mg/kg/day (15 times clinical exposure based on AUC). Pregnant rabbits were administered Flibanserin at doses of 0, 20, 40 and 80 mg/kg/day (4, 8 and 16 times the clinical exposure at the recommended human dose) during organogenesis. Marked decreases in maternal body weight gain (>75%), abortion and complete litter resorption were observed at 40 and 80 mg/kg/day indicating significant maternal toxicity at these doses. Increases in resorptions and decreased fetal weights were observed at ≥ 40 mg/kg/day. No treatment-related teratogenic effects were observed in fetuses at any dose level. The no adverse effect level for maternal and embryofetal effects was 20 mg/kg/day (3-4 times clinical exposure based on AUC). Pregnant rats were administered Flibanserin at doses of 0, 20, 80 and 200 mg/kg/day (3, 15 and ~ 20 times clinical exposures at the recommended human dose) from day 6 of pregnancy until day 21 of lactation to assess for effects on peri- and postnatal development. The highest dose was associated with clinical signs of toxicity in pregnant and lactating rats. All doses resulted in sedation and decreases in body weight gain during pregnancy. Flibanserin prolonged gestation in some dams in all dose groups and decreased implantations, number of fetuses and fetal weights at 200 mg/kg/day. Dosing dams with 200 mg/kg also decreased pup weight gain and viability during the lactation period and delayed opening of the vagina and auditory canals. Flibanserin had no effects on learning, reflexes, fertility or reproductive capacity of the F1 generation. The no adverse effect level for maternal toxicity and peri/postnatal effects was 20 mg/kg/day. The recommended dosage of Flibanserin is 100 mg administered orally once per day at bedtime. Flibanserin is dosed at bedtime because administration during waking hours increases the risks of hypotension, syncope, accidental injury, and central nervous system (CNS) depression (such as somnolence and sedation). - Missed Dose If a dose of Flibanserin is missed at bedtime, instruct the patient to take the next dose at bedtime on the next day. Instruct the patient to not double the next dose. - Discontinuation of Flibanserin Discontinue Flibanserin after 8 weeks if the patient does not report an improvement in her symptoms. - Initiation of Flibanserin Following Moderate or Strong CYP3A4 Inhibitor Use If initiating Flibanserin following moderate or strong CYP3A4 inhibitor use, start Flibanserin 2 weeks after the last dose of the CYP3A4 inhibitor. If initiating a moderate or strong CYP3A4 inhibitor following Flibanserin use, start the moderate or strong CYP3A4 inhibitor 2 days after the last dose of Flibanserin. In vitro, Flibanserin demonstrated high affinity for the following serotonin (5-hydroxytryptamine or 5-HT) receptors: agonist activity at 5-HT1A and antagonist activity at 5-HT2A. Flibanserin also has moderate antagonist activities at the 5-HT2B, 5-HT2C, and dopamine D4 receptors. - Alcohol Interaction A randomized, double-blind, single-dose, cross-over, dedicated alcohol interaction study was conducted in 25 healthy subjects (23 men and 2 premenopausal women). In this study, 68%, 16%, 8% and 8% subjects reported a history of drinking 5-6, 7-10, 11-15 and 16-21 drinks per week, respectively. Subjects received one of the following five treatments : - 100 mg of Flibanserin alone - 0.4 g/kg 95% ethanol (equivalent to two 12-ounce cans of beer containing 5% alcohol content, two 5- ounce glasses of wine containing 12% alcohol, or two 1.5-ounce shots of 80 proof spirit in a 70 kg person) - 0.8 g/kg 95% ethanol (equivalent to four 12-ounce cans of beer containing 5% alcohol content, four 5-ounce glasses of wine containing 12% alcohol, or four 1.5-ounce shots of 80 proof spirit in a 70 kg person) - 100 mg of Flibanserin in combination with 0.4 g/kg 95% ethanol - 100 mg of Flibanserin in combination with 0.8 g/kg 95% ethanol Patients who received Flibanserin with alcohol had a higher incidence of somnolence than patients who received Flibanserin alone or alcohol alone. There were no significant changes in the pharmacokinetics of Flibanserin when administered with or without alcohol. - Cardiac Electrophysiology The effect of Flibanserin on the QT interval was evaluated in a randomized, double-blind, placebo- and active- (single dose moxifloxacin) controlled crossover study in 56 healthy men and women. Subjects in the Flibanserin groups received either 50 mg twice a day (equivalent to the daily recommended dosage) or 100 mg three times a day (3 times the daily recommended dosage) administered for 5 days. The time frame for electrocardiogram (ECG) measurements covered maximum plasma concentrations of Flibanserin and relevant metabolites. In this study, Flibanserin did not prolong the QT interval to any clinically relevant extent. The mean increase in heart rate associated with the 100 mg three times a day dose of Flibanserin compared to placebo ranged from 1.7 to 3.2 beats per minute. - Absorption Following oral administration of a single 100 mg dose of Flibanserin in healthy premenopausal women (N=8), mean (SD) Cmax was 419 (206) ng/mL and mean (SD) AUC(0-inf) was 1543 (511) nghr/mL. Median (range) time to reach Cmax was 0.75 (0.75 to 4.0) hours. Absolute bioavailability of Flibanserin following oral dosing is 33%. - Effect of Food Food increased the extent of absorption and slowed the rate of absorption of a 50 mg dose of Flibanserin (one half the recommended dosage). Low-, moderate-, and high-fat meals increased Flibanserin AUC(0-inf) by 1.18-, 1.43-, and 1.56-fold; increased Cmax by 1.02-, 1.13-, and 1.15-fold; and prolonged median Tmax to 1.5, 0.9, 1.8 hours from 0.8 hours under fasted conditions, respectively. - Distribution Approximately 98% of Flibanserin is bound to human serum proteins, mainly to albumin. - Elimination - Metabolism Flibanserin is primarily metabolized by CYP3A4 and, to a lesser extent, by CYP2C19. Based on in vitro and/or in vivo data, CYP1A2, CYP2B6, CYP2C8, CYP2C9, and CYP2D6 contribute minimally to the metabolism of Flibanserin. After a single oral solution dose of 50 mg 14C-radiolabeled Flibanserin, 44% of the total 14C-Flibanserin related radioactivity was recovered in urine, and 51% was recovered in feces. Flibanserin is extensively metabolized to at least 35 metabolites, most of them occurring in low concentrations in plasma. Two metabolites could be characterized that showed plasma concentrations similar to that achieved with Flibanserin: 6,21-dihydroxy-flibanserin-6,21-disulfate and 6-hydroxy-flibanserin-6-sulfate. These two metabolites are inactive. - Excretion Flibanserin has a mean terminal half-life of approximately 11 hours. - Specific Populations - Hepatic Impairment Single 50 mg oral doses of Flibanserin were administered to 10 patients with mild hepatic impairment (Child-Pugh score of 6 points), 4 patients with moderate hepatic impairment (Child-Pugh score of 8-9 points), and 14 healthy subjects matched by age, weight, and gender. Systemic Flibanserin exposure (AUC(0-inf)) increased 4.5-fold in patients with mild hepatic impairment, compared to subjects with normal hepatic function, and t1/2 was longer (26 hours compared to 10 hours in matching healthy controls). Due to the small number of patients (n=4) with moderate hepatic impairment enrolled in the study, it is not possible to make conclusions about the quantitative effect of moderate hepatic impairment on Flibanserin exposure. Flibanserin is contraindicated in patients with hepatic impairment. - Renal Impairment Single 50 mg oral doses of Flibanserin were administered to 7 patients with mild to moderate renal impairment (GFR 30 to 80 mL/min), 9 patients with severe renal impairment (GFR <30 mL/min, not on dialysis), and 16 healthy subjects matched by age, weight, and gender. Flibanserin exposure (AUC(0-inf)) increased 1.1-fold in patients with mild to moderate renal impairment and 1.2-fold in patients with severe renal impairment, compared to the healthy control subjects. - Race/Ethnicity A cross-study comparison between healthy Japanese women and Caucasian women with HSDD showed that Flibanserin exposure was approximately 1.4-fold higher in Japanese women. When the mean Flibanserin exposure in Japanese women was adjusted for weight, the AUC(tau,ss) in Japanese women was 2246 nghr/mL, which is comparable to 2080 ng*hr/mL in Caucasian women. The similarity in weight-adjusted AUC(tau,ss) suggests that weight, not race, is the factor contributing to the observed difference in Flibanserin exposure between Japanese and Caucasian women. - Age No formal study has been conducted to study the effect of age on Flibanserin exposures. - Drug Interaction Studies - Drugs that Increase Flibanserin Exposure The effects of other drugs on the pharmacokinetics of Flibanserin are presented in TABLE 4 as change relative to Flibanserin administered alone (test/reference). - Moderate CYP3A4/Moderate CYP2C9/Strong CYP2C19 Inhibitor (Fluconazole) In a study of 15 healthy female subjects, a fluconazole 400 mg loading dose followed by 200 mg administered once daily for 5 days increased Flibanserin 100 mg single dose exposure (AUC(0-inf)) 7-fold and Cmax 2.2-fold compared to Flibanserin 100 mg alone. Three of 15 subjects (20%) experienced hypotension or syncope from concomitant use of fluconazole and Flibanserin; therefore, the study was stopped early. - Strong CYP3A4 Inhibitor (Ketoconazole) In a study of 24 healthy female subjects, ketoconazole 400 mg administered once daily for 5 days following a light breakfast increased Flibanserin 50 mg single-dose exposure (AUC(0-inf)) 4.5-fold and Cmax 1.8-fold compared to Flibanserin 50 mg alone. - Strong CYP3A4 Inhibitor (Itraconazole) In a study of 12 healthy male and female subjects, itraconazole 200 mg administered once daily for 4 days following a loading dose of 400 mg increased Flibanserin 50 mg single dose exposure (AUC(0-inf)) 2.6-fold and Cmax 1.7-fold when Flibanserin was given 2 hours after itraconazole on Day 5, compared to exposures with Flibanserin 50 mg alone. The 200 mg itraconazole dose does not maximally inhibit the CYP3A4 enzyme. - Moderate CYP3A4 Inhibitor (Grapefruit Juice) In a study of 26 healthy female subjects, grapefruit juice (240 mL) increased Flibanserin 100 mg single dose exposure (AUC(0-inf)) by 1.4-fold and Cmax 1.1-fold compared to Flibanserin 100 mg alone. - Weak CYP3A4 Inhibitor (Oral Contraceptives) In a meta-analysis of 17 oral contraceptive users and 91 non-users in Phase 1 studies, the oral contraceptive users had a 1.4-fold higher Flibanserin AUC and 1.3‑fold higher Cmax compared to the non-users. - Strong CYP2D6 Inhibitor (Paroxetine) Paroxetine is a strong CYP2D6 inhibitor. In a study of 19 healthy male and female subjects, Flibanserin exposure decreased by approximately 4% when Flibanserin 50 mg twice daily was given with paroxetine compared to Flibanserin alone. Paroxetine was dosed at 20 mg once daily for 3 days followed by 40 mg once daily for 7 days. - Drugs that Decrease Flibanserin Exposure - Strong CYP3A4 Inducer (Rifampin) In a study of 24 healthy female subjects, rifampin 600 mg given once daily for 7 days prior to administration of 100 mg Flibanserin significantly decreased Flibanserin exposure by 95%. - Moderate CYP3A4 Inducer (Etravirine) Steady state etravirine, a moderate CYP3A4 inducer, decreased Flibanserin exposures by approximately 21%. - Table 4 Drugs That Increase Flibanserin Exposure ADDYI: Flibanserin's Brand name - Effects of Flibanserin on Other Drugs The effects of Flibanserin on the pharmacokinetics of other drugs are presented in Table 5 as change relative to the other drug administered alone (test/reference). - Digoxin and P-glycoprotein Substrates A single center, open-label, randomized, two-way crossover study in 24 healthy men and women evaluated the effect of Flibanserin on the pharmacokinetics of digoxin. Flibanserin 100 mg was administered once daily over 5 days followed by a single dose of 0.5 mg digoxin, a P-gp substrate. Flibanserin increased digoxin AUC(0-inf) by 2.0-fold and Cmax by 1.5-fold, compared to digoxin alone. - Drugs Metabolized by CYP3A4 (Simvastatin) An open-label, randomized, crossover study in 12 healthy men and women evaluated the effect of Flibanserin 50 mg twice daily for 4 days on the pharmacokinetics of simvastatin 40 mg once daily. Flibanserin increased the AUC(0-inf) of simvastatin, a substrate of CYP3A4, 1.3‑fold and Cmax by 1.2-fold. Flibanserin co-administered with simvastatin increased simvastatin acid AUC(0-inf) by 1.5-fold and Cmax by 1.4-fold. - Oral Contraceptives A study in 24 healthy women evaluated the effect of 100 mg Flibanserin once daily for 2 weeks on the pharmacokinetics of a single-dose of ethinyl estradiol (EE) 30 mcg/levonorgestrel (LNG) 150 mcg. Flibanserin increased the EE AUC(0-inf) by 1.09-fold and the EE Cmax by 1.1-fold. Flibanserin decreased the LNG AUC(0-inf) by 1.06-fold and did not change the LNG Cmax. - Drugs Metabolized by CYP2B6 (Bupropion) An open-label, randomized, two-period crossover study in 28 healthy women evaluated the effect of Flibanserin on the pharmacokinetics of bupropion. Flibanserin 50 mg twice daily was administered for 2 days followed by 100 mg once daily for 13 days. Bupropion 150 mg twice daily was given for 8 days beginning on Day 6 of Flibanserin treatment. Flibanserin did not change bupropion AUC(t,ss) (1.0-fold change) and Cmax (1.0-fold change) but hydroxybupropion AUC(t,ss) decreased by 9% and Cmax by 11%. - Table 5 Effects of Flibanserin on Exposure of Other Drugs ADDYI: Flibanserin's Brand name Patients who are poor metabolizers of CYP2D6, CYP2C9 or CYP2C19 are deficient in CYP2D6, CYP2C9 or CYP2C19 enzyme activity, respectively. Extensive metabolizers have normal functioning CYP enzymes. - CYP2C19 Poor Metabolizers A study comparing Flibanserin exposure in CYP2C19 poor metabolizers to CYP2C19 extensive metabolizers was conducted in lieu of a drug interaction study with Flibanserin and a strong CYP2C19 inhibitor. In 9 women who were poor metabolizers of CYP2C19, Cmax and AUC(0-inf) of Flibanserin 100 mg once daily increased 1.5-fold (1.1-2.1) and 1.3-fold (0.9-2.1), compared to exposures among 8 extensive metabolizers of CYP2C19. Flibanserin half-life was increased from 11.1 hours in the extensive metabolizers of CYP2C19 to 13.5 hours in the poor metabolizers of CYP2C19. The frequencies of poor metabolizers of CYP2C19 are approximately 2–5% among Caucasians and Africans and approximately 2–15% among Asians. - CYP2D6 Poor Metabolizers A study comparing Flibanserin exposure in CYP2D6 poor metabolizers to CYP2D6 extensive metabolizers was conducted in addition to a drug interaction study with paroxetine, a strong CYP2D6 inhibitor. In 12 poor metabolizers of CYP2D6, steady state Cmax and AUC of Flibanserin 50 mg twice daily was decreased by 4% and increased by 18%, respectively, compared to exposures among 19 extensive metabolizers, intermediate metabolizers and ultra rapid metabolizers of CYP2D6. - CYP2C9 Poor Metabolizers A study comparing Flibanserin exposure in CYP2C9 poor metabolizers to CYP2C9 extensive metabolizers was conducted in lieu of a drug interaction study with Flibanserin and a strong CYP2C9 inhibitor. In 8 women who were poor metabolizers of CYP2C9, Cmax and AUC(0-inf) of Flibanserin 100 mg once daily decreased 23% and 18%, compared to exposures among 8 extensive metabolizers of CYP2C9. A two-year carcinogenicity study was conducted in CD-1 mice with dietary administration of 0, 10, 80, 200 and 1000/1200 mg/kg/day of Flibanserin. Statistically significant increases in combined mammary tumors (adenoacanthoma and adenocarcinomas) were observed in female mice administered Flibanserin at doses of 200 and 1200 mg/kg/day (exposures, based on AUC, were 3 and 10 times the clinical exposures at the recommended clinical dose). No increases in mammary tumors were observed in male mice. Statistically significant increases were also seen for combined hepatocellular adenomas/carcinomas in female mice treated with Flibanserin 1200 mg/kg/day and for hepatocellular carcinomas in male mice treated with Flibanserin 1000 mg/kg/day (exposures, based on AUC, were 8 times the clinical exposure at the recommended clinical dose). There were no significant increases in tumor incidence in a two year carcinogenicity study conducted in Wistar rats with dietary administration of 0, 10, 30 and 100 mg/kg/day Flibanserin (up to 5-8 times human exposure at the recommended clinical dose). - Mutagenesis Flibanserin was negative for mutagenesis in vitro in Salmonella typhimurium (Ames test) and in Chinese hamster ovary cells. Flibanserin was positive for chromosomal aberrations in cultured human lymphocytes but negative for chromosomal aberrations in vivo in the rat bone marrow micronucleus assay and negative for DNA damage in rat liver in the Comet assay. - Impairment of Fertility Female and male rats were administered Flibanserin 14 and 28 days before mating, respectively, to assess for potential effects on fertility and early reproductive performance. Flibanserin slightly increased the duration of the estrus cycle but had no adverse effects on fertility or early embryonic development at doses up to 200 mg/kg/day (~20 times human exposure at the recommended clinical dose). The efficacy of Flibanserin for the treatment of HSDD in premenopausal women was established in three 24-week, randomized, double-blind, placebo-controlled trials (Studies 1, 2, and 3). The three trials included premenopausal women with acquired, generalized HSDD of at least 6 months duration. In the clinical trials, acquired HSDD was defined as HSDD that developed in patients who previously had no problems with sexual desire. Generalized HSDD was defined as HSDD that was not limited to certain types of stimulation, situations or partners. The patients were treated with Flibanserin 100 mg once daily at bedtime (n = 1187) or placebo (n = 1188). Most of the trial participants were Caucasian (88.6%); the remainder were Black (9.6%) and Asian (1.5%). The mean age of study participants was 36 years old (range 19 to 55 years old); the mean duration in the monogamous, heterosexual relationship was 11 years, and the mean duration of HSDD was approximately 5 years. The completion rate across these three trials was 69% and 78% for the Flibanserin and placebo groups, respectively. These trials each had two co-primary efficacy endpoints, one for satisfying sexual events (SSEs) and the other for sexual desire: - The change from baseline to Week 24 in the number of monthly SSEs (i.e., sexual intercourse, oral sex, masturbation, or genital stimulation by the partner). The SSEs were based on patient responses to the following questions: “Did you have a sexual event?” and “Was the sex satisfying for you?” - Studies 1 and 2 had a different sexual desire endpoint than Study 3: - In Studies 1 and 2, the sexual desire co-primary endpoint was the change from baseline to Week 24 in the calculated monthly sexual desire score and was based on patient responses to the question: “Indicate your most intense level of sexual desire.” Every day, patients rated their sexual desire level from 0 (no desire) to 3 (strong desire) and recorded their response in an electronic Diary (eDiary). These responses were summed over a 28-day period to yield the calculated monthly sexual desire score, which ranged from 0 to 84. - In Study 3, the desire domain of the Female Sexual Function Index (FSFI Desire) was the sexual desire co-primary endpoint. The desire domain of the FSFI has two questions. The first question asks patients “Over the past 4 weeks, how often did you feel sexual desire or interest?”, with responses ranging from 1 (almost never or never) to 5 (almost always or always). The second question asks patients “Over the past 4 weeks, how would you rate your level (degree) of sexual desire or interest?”, with responses ranging from 1 (very low or none at all) to 5 (very high). The FSFI Desire score was calculated by adding the patient’s responses to these two questions then multiplying that sum by 0.6. The FSFI Desire domain score ranged from 1.2 to 6. The desire domain of the Female Sexual Function Index (FSFI Desire) was also used as a secondary endpoint in Studies 1 and 2. The three trials had a secondary endpoint that measured bother (a component of distress) related to sexual desire using Question 13 of the Female Sexual Distress Scale-Revised (FSDS-R). This question asks “How often did you feel: Bothered by low sexual desire?” Patients assessed their sexual distress over a 7-day recall period and responded on a scale of 0 (never) to 4 (always). The efficacy results from Studies 1, 2, and 3 are summarized in Table 6. In all three trials, Flibanserin resulted in statistically significant improvement compared to placebo in the change from baseline in monthly SSEs at Week 24. In Study 1 and 2, there were no statistically significant differences between Flibanserin and placebo for the eDiary sexual desire endpoint (change in baseline to Week 24). In contrast, in Study 3 there was statistically significant improvement in the change from baseline to Week 24 in sexual desire (using the FSFI Desire Domain) with Flibanserin compared to placebo. The FSFI Desire Domain findings were consistent across all three trials as were the findings for the secondary endpoint that assessed distress using Question 13 of the FSDS-R. - Table 6 Efficacy Results in Premenopausal HSDD Patients in Studies 1, 2, and 3 ADDYI: Flibanserin's Brand name Exploratory analyses were conducted to assess whether the treatment effects varied depending on baseline number of SSEs, FSFI Desire score, and FSDS-R Question 13 distress score. No notable differences were identified among these subgroups. Supportive analyses were conducted to help interpret the clinical meaningfulness of the observed treatment effects. These analyses defined responders for each efficacy endpoint by anchoring change from baseline to end of treatment with the Patient's Global Impression of Improvement (PGI‑I). The first analysis considered responders to be those who reported being “much improved” or “very much improved.” In this analysis, the absolute difference in the percentage of responders with Flibanserin and the percentage of responders with placebo across the three trials was 8-9% for SSEs (29-39% for Flibanserin; 21-31% for placebo), 10-13% for FSFI desire domain (43-48% for Flibanserin; 31-38% for placebo), and 7-13% for FSDS-R Question 13 (21-34% for Flibanserin; 14-25% for placebo). The second analysis considered responders to be those who reported being at least minimally improved. The absolute difference in the percentage of responders with Flibanserin and the percentage of responders with placebo across the three trials was 10-15% for SSEs (44-48% for Flibanserin; 33-36% for placebo), 12-13% for FSFI desire domain (43-51% for Flibanserin; 31-39% for placebo), and 9-12% for FSDS-R Question 13 (50-60% for Flibanserin; 41-48% for placebo). In a randomized, placebo-controlled, 4-way crossover study in 83 healthy premenopausal female subjects, no adverse effect was detected on measures of driving performance itself or psychomotor performance thought to be important for driving performance when assessed 9 hours following single and multiple doses of Flibanserin 100 mg once daily at bedtime or single doses of Flibanserin 200 mg at bedtime (two times the maximum recommended dosage). Flibanserin is available as a 100 mg oval, pink, film-coated tablet debossed on one side with “f100” and blank on the other side. Available in bottles of 30 tablets. (NDC 58604-214-30) - Hypotension and Syncope Inform patients that Flibanserin can cause severe hypotension and syncope, particularly with alcohol or with moderate or strong CYP3A4 inhibitors. Inform patients that alcohol use and moderate or strong CYP3A4 inhibitors are contraindicated. Counsel patients about the importance of abstaining from alcohol and to ask about drug interactions before starting a new prescription or non-prescription medication or using other products that contain CYP3A4 inhibitors (e.g., grapefruit juice or St. John’s Wort). Advise patients who experience pre-syncope or lightheadedness to lie down and to call for help if symptoms persist. Flibanserin is available only through a restricted program called the Flibanserin REMS Program. Patients can only obtain Flibanserin from certified pharmacies participating in the program. Therefore, provide patients with the telephone number and website for information on how to obtain Flibanserin. - CNS Depression Advise patients that Flibanserin can cause CNS depression, such as somnolence and sedation, and that the risk is increased with other CNS depressants and with certain drug interactions (e.g., hypnotics, benzodiazepines, opioids). The risk is also increased if Flibanserin is taken during waking hours. Advise patients to avoid engaging in activities requiring full alertness (e.g., operating machinery or driving) until at least 6 hours after the Flibanserin dose and until they know how Flibanserin affects them. - Nursing Mothers Advise patients not to breastfeed if they are taking Flibanserin. - Bedtime Dosing Advise patients to take only one tablet at bedtime and not to take Flibanserin at any other time of day. - ↑ "Addyi™ (flibanserin) Tablets, for Oral Use. Full Prescribing Information" (PDF). Addyi REMS (Risk Evaluation and Mitigation Strategy). Sprout Pharmaceuticals, Inc. Raleigh, NC 27609 USA. Retrieved 21 October 2015..mw-parser-output cite.citation{font-style:inherit}.mw-parser-output q{quotes:"\"""\"""'""'"}.mw-parser-output code.cs1-code{color:inherit;background:inherit;border:inherit;padding:inherit}.mw-parser-output .cs1-lock-free a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-limited a,.mw-parser-output .cs1-lock-registration a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-subscription a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration{color:#555}.mw-parser-output .cs1-subscription span,.mw-parser-output .cs1-registration span{border-bottom:1px dotted;cursor:help}.mw-parser-output .cs1-hidden-error{display:none;font-size:100%}.mw-parser-output .cs1-visible-error{display:none;font-size:100%}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration,.mw-parser-output .cs1-format{font-size:95%}.mw-parser-output .cs1-kern-left,.mw-parser-output .cs1-kern-wl-left{padding-left:0.2em}.mw-parser-output .cs1-kern-right,.mw-parser-output .cs1-kern-wl-right{padding-right:0.2em}	Flibanserin CONTRAINDICATED WITH ALCOHOL: The use of Flibanserin tablets and alcohol increases the risk of severe hypotension and syncope. Therefore, alcohol use is contraindicated in patients taking Flibanserin. Before prescribing Flibanserin, assess the likelihood of the patient abstaining from alcohol, taking into account the patient’s current and past drinking behavior, and other pertinent social and medical history. Counsel patients who are prescribed Flibanserin about the importance of abstaining from alcohol use. Because of the increased risk of hypotension and syncope due to an interaction with alcohol, Flibanserin is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the Flibanserin REMS Program. CONTRAINDICATED WITH STRONG OR MODERATE CYP3A4 INHIBITORS: The concomitant use of Flibanserin and moderate or strong CYP3A4 inhibitors increases Flibanserin concentrations, which can cause severe hypotension and syncope. Therefore, the use of moderate or strong CYP3A4 inhibitors is contraindicated in patients taking Flibanserin. CONTRAINDICATED IN PATIENTS WITH HEPATIC IMPAIRMENT: The use of Flibanserin in patients with hepatic impairment increases Flibanserin concentrations, which can cause severe hypotension and syncope. Therefore, Flibanserin is contraindicated in patients with hepatic impairment. Flibanserin tablets are indicated for the treatment of premenopausal women with acquired, generalized hypoactive sexual desire disorder (HSDD), as characterized by low sexual desire that causes marked distress or interpersonal difficulty and is NOT due to: - A co-existing medical or psychiatric condition, - Problems within the relationship, or - The effects of a medication or other drug substance. Acquired HSDD refers to HSDD that develops in a patient who previously had no problems with sexual desire. Generalized HSDD refers to HSDD that occurs regardless of the type of stimulation, situation or partner. Limitations of Use - Flibanserin is not indicated for the treatment of HSDD in postmenopausal women or in men. - Flibanserin is not indicated to enhance sexual performance. The recommended dosage of Flibanserin is 100 mg administered orally once per day at bedtime. - With use of alcohol. - With concomitant use with moderate or strong CYP3A4 inhibitors. - In patients with hepatic impairment. Alcohol use is contraindicated in patients taking Flibanserin. Before prescribing Flibanserin, the healthcare provider must assess the likelihood of the patient abstaining from alcohol use, taking into account the patient’s current and past drinking behavior, and other pertinent social and medical history. Counsel patients who are prescribed Flibanserin about the importance of abstaining from alcohol use. The use of Flibanserin and alcohol increases the risk of severe hypotension and syncope. In a dedicated alcohol interaction study conducted in 25 subjects (23 men and 2 premenopausal women), hypotension or syncope requiring therapeutic intervention (ammonia salts and/or placement in supine or Trendelenburg position) occurred in 4 (17%) of the 23 subjects co-administered Flibanserin 100 mg and 0.4 g/kg alcohol (equivalent of two 12 ounce cans of beer containing 5% alcohol content, two 5 ounce glasses of wine containing 12% alcohol content, or two 1.5 ounce shots of 80-proof spirit in a 70 kg person, consumed over 10 minutes in the morning). In these four subjects, all of whom were men, the magnitude of the systolic blood pressure reductions ranged from about 28 to 54 mmHg and the magnitude of the diastolic blood pressure reductions ranged from about 24 to 46 mmHg. In addition, 6 (25%) of the 24 subjects co-administered Flibanserin 100 mg and 0.8 g/kg alcohol experienced orthostatic hypotension when standing from a sitting position. The magnitude of the systolic blood pressure reductions in these 6 subjects ranged from 22 to 48 mmHg, and the diastolic blood pressure reductions ranged from 0 to 27 mmHg. One of these subjects required therapeutic intervention (ammonia salts and placement supine with the foot of the bed elevated). There were no events requiring therapeutic interventions when Flibanserin or alcohol were administered alone. Flibanserin is available only through a restricted program under a REMS. Flibanserin is available only through a restricted program under a REMS called the Flibanserin REMS Program, because of the increased risk of severe hypotension and syncope due to an interaction between Flibanserin and alcohol. Notable requirements of the Flibanserin REMS Program include the following: - Prescribers must be certified with the program by enrolling and completing training. - Pharmacies must be certified with the program and must only dispense to patients pursuant to a prescription from a certified prescriber. Further information, including a list of qualified pharmacies, is available at www.AddyiREMS.com or 844-746-5745. - Moderate or Strong CYP3A4 Inhibitors The concomitant use of Flibanserin with moderate or strong CYP3A4 inhibitors significantly increases Flibanserin concentrations, which can lead to hypotension and syncope. The concomitant use of Flibanserin with a moderate or strong CYP3A4 inhibitor is contraindicated. If the patient requires a moderate or strong CYP3A4 inhibitor, discontinue Flibanserin at least 2 days prior to starting the moderate or strong CYP3A4 inhibitor. In cases where the benefit of initiating a moderate or strong CYP3A4 inhibitor within 2 days of stopping Flibanserin clearly outweighs the risk of Flibanserin exposure related hypotension and syncope, monitor the patient for signs of hypotension and syncope. Discontinue the moderate or strong CYP3A4 inhibitor for 2 weeks before restarting Flibanserin. - Multiple Concomitant Weak CYP3A4 Inhibitors Concomitant use of multiple weak CYP3A4 inhibitors that may include herbal supplements (e.g., ginkgo, resveratrol) or non-prescription drugs (e.g., cimetidine) could also lead to clinically relevant increases in Flibanserin concentrations that may increase the risk of hypotension and syncope. Flibanserin can cause CNS depression (e.g., somnolence, sedation). In five 24-week, randomized, placebo-controlled, double-blind trials of premenopausal women with HSDD, the incidence of somnolence, sedation or fatigue was 21% and 8% in patients treated with 100 mg Flibanserin once daily at bedtime and placebo, respectively. The risk of CNS depression is increased if Flibanserin is taken during waking hours, or if Flibanserin is taken with alcohol or other CNS depressants, or with medications that increase Flibanserin concentrations, such as CYP3A4 inhibitors. Patients should not drive or engage in other activities requiring full alertness until at least 6 hours after taking Flibanserin and until they know how Flibanserin affects them. The use of Flibanserin − without other concomitant medications known to cause hypotension or syncope − can cause hypotension and syncope. In five 24-week, randomized, placebo-controlled, double-blind trials of premenopausal women with HSDD, hypotension was reported in 0.2% and <0.1% of Flibanserin -treated patients and placebo-treated patients, respectively; syncope was reported in 0.4% and 0.2% of Flibanserin - treated patients and placebo-treated patients, respectively. The risk of hypotension and syncope is increased if Flibanserin is taken during waking hours or if higher than the recommended dose is taken. Consider the benefits of Flibanserin and the risks of hypotension and syncope in patients with pre- existing conditions that predispose to hypotension. Patients who experience pre-syncope should immediately lie supine and promptly seek medical help if the symptoms do not resolve. Prompt medical attention should also be obtained for patients who experience syncope. The use of Flibanserin in patients with any degree of hepatic impairment significantly increases Flibanserin concentrations, which can lead to hypotension and syncope. Therefore, the use of Flibanserin is contraindicated in patients with hepatic impairment. In a 2-year carcinogenicity study in mice, there was a statistically significant and dose-related increase in the incidence of malignant mammary tumors in female mice at exposures 3 and 10 times the recommended clinical dose. No such increases were seen in male mice or in male or female rats. The clinical significance of these findings is unknown. The approved 100 mg Flibanserin dosage at bedtime was administered to 2,997 premenopausal women with acquired, generalized HSDD in clinical trials, of whom 1672 received treatment for at least 6 months, 850 received treatment for at least 12 months, and 88 received treatment for at least 18 months. The data presented below are derived from five 24-week randomized, double-blind, placebo-controlled trials in premenopausal women with acquired, generalized HSDD. In these five trials, the frequency and quantity of alcohol use was not recorded. Three of these trials (Studies 1 through 3) also provided efficacy data. One of these trials (Study 5) did not evaluate the 100 mg bedtime dose. In four trials, 100 mg Flibanserin at bedtime was administered to 1543 premenopausal women with HSDD, of whom 1060 completed 24 weeks of treatment. The clinical trial population was generally healthy without significant comorbid medical conditions or concomitant medications. The age range was 18-56 years old with a mean age of 36 years old, and 88% were Caucasian and 9% were Black. Serious adverse reactions were reported in 0.9% and 0.5% of Flibanserin-treated patients and placebo-treated patients, respectively. - Adverse Reactions Leading to Discontinuation The discontinuation rate due to adverse reactions was 13% among patients treated with 100 mg Flibanserin at bedtime and 6% among patients treated with placebo. TABLE 1 displays the most common adverse reactions leading to discontinuation in four trials of premenopausal women with HSDD. - Table 1. Adverse Reactions* Leading to Discontinuation in Randomized, Double-blind, Placebo-controlled Trials in Premenopausal Women with HSDD ADDYI: Flibanserin's Brand name - Most Common Adverse Reactions TABLE 2 summarizes the most common adverse reactions reported in four trials of premenopausal women with HSDD. This table shows adverse reactions reported in at least 2% of patients treated with Flibanserin and at a higher incidence than with placebo. The majority of these adverse reactions began within the first 14 days of treatment. - Table 2. Common Adverse Reactions* in Randomized, Double-blind, Placebo-controlled Trials in Premenopausal Women with HSDD ADDYI: Flibanserin's Brand name - Less Common Adverse Reactions In four trials in premenopausal women with HSDD treated with 100 mg Flibanserin at bedtime, less common adverse reactions (reported in ≥1% but <2% of Flibanserin-treated patients and at a higher incidence than with placebo) included: - Anxiety (Flibanserin 1.8%; placebo 1.0%), - Constipation (Flibanserin 1.6%; placebo 0.4%), - Abdominal pain (Flibanserin 1.5%; placebo 0.9%), - Metrorrhagia (Flibanserin 1.4%; placebo 1.4%), - Rash (Flibanserin 1.3%; placebo 0.8%), - Sedation (Flibanserin 1.3%; placebo 0.2%), and - Vertigo (Flibanserin 1%; placebo 0.3%). - Appendicitis In the five trials of premenopausal women with HSDD, appendicitis was reported in 6/3973 (0.2%) Flibanserin-treated patients, while there were no reports of appendicitis in the 1905 placebo-treated patients. - Accidental Injury In five trials of premenopausal women with HSDD, accidental injury was reported in 42/1543 (2.7%) Flibanserin-treated patients and 47/1905 (2.5%) placebo-treated patients. Among these 89 patients who experienced injuries, 9/42 (21%) Flibanserin-treated patients and 3/47 (6%) placebo-treated patients reported adverse reactions consistent with CNS depression (e.g., somnolence, fatigue, or sedation) within the preceding 24 hours. - Adverse Reactions in Patients Who Reported Hormonal Contraceptive Use In four trials of premenopausal women with HSDD, 1466 patients (43%) reported concomitant use of hormonal contraceptives (HC) at study enrollment. These trials were not prospectively designed to assess an interaction between Flibanserin and HC. Flibanserin-treated patients who reported HC use had a greater incidence of dizziness, somnolence, and fatigue compared to Flibanserin-treated patients who did not report HC use (dizziness 9.9% in HC non-users, 13.4% in HC users; somnolence 10.6% in HC non-users, 12.3% in HC users; fatigue 7.5% in HC non-users, 11.4% in HC users). There were no meaningful differences in the incidence of these adverse reactions in placebo-treated patients who reported or did not report HC use. One death occurred in a 54 year-old postmenopausal woman treated with 100 mg Flibanserin taken at bedtime (Flibanserin is not approved for the treatment of postmenopausal women with HSDD). This patient had a history of hypertension and hypercholesterolemia and baseline alcohol consumption of 1-3 drinks daily. She died of acute alcohol intoxication 14 days after starting Flibanserin. Blood alcohol concentration on autopsy was 0.289 g/dL. The autopsy report also noted coronary artery disease. A relationship between this patient’s death and use of Flibanserinis unknown. - Hypotension, Syncope, and CNS Depression in Studies of Healthy Subjects - Hypotension, Syncope, and CNS Depression with Alcohol In a cross-over alcohol interaction study of 100 mg Flibanserin and alcohol in 25 healthy subjects dosed in the morning, somnolence was reported in 67%, 74%, and 92% of subjects who received Flibanserin alone, Flibanserin in combination with 0.4 g/kg ethanol, and Flibanserin in combination with 0.8 g/kg ethanol, respectively. In the group receiving Flibanserin in combination with 0.4 g/kg ethanol, 4/23 (17%) subjects had substantial reductions in blood pressure, resulting in hypotension and/or syncope requiring medical intervention. In the group receiving Flibanserin in combination with 0.8 g/kg ethanol, 6/24 (25%) subjects experienced orthostatic hypotension. - Hypotension and Syncope with Fluconazole In a pharmacokinetic drug interaction study of 100 mg Flibanserin and 200 mg fluconazole (a moderate CYP3A4 inhibitor, moderate CYP2C9 inhibitor, and a strong CYP2C19 inhibitor) in healthy subjects, hypotension or syncope requiring placement supine with legs elevated occurred in 3/15 (20%) subjects treated with concomitant Flibanserin and fluconazole compared to no such adverse reactions in subjects treated with Flibanserin alone or fluconazole alone. One of these 3 subjects became unresponsive with a blood pressure of 64/41 mm Hg and required transportation to the hospital emergency department where she required intravenous saline. Due to these adverse reactions, the study was stopped. In this study, the concomitant use of Flibanserin and fluconazole increased Flibanserin exposure 7-fold. - Syncope with Ketoconazole In a pharmacokinetic drug interaction study of 50 mg Flibanserin and 400 mg ketoconazole, a strong CYP3A4 inhibitor, syncope occurred in 1/24 (4%) healthy subjects treated with concomitant Flibanserin and ketoconazole, 1/24 (4%) receiving Flibanserin alone, and no subjects receiving ketoconazole alone. In this study, the concomitant use of Flibanserin and ketoconazole increased Flibanserin exposure 4.5-fold. - Syncope in Poor CYP2C19 Metabolizers In a pharmacogenomic study of 100 mg Flibanserin in subjects who were poor or extensive CYP2C19 metabolizers, syncope occurred in 1/9 (11%) subjects who were CYP2C19 poor metabolizers (this subject had a 3.2 fold higher Flibanserin exposure compared to CYP2C19 extensive metabolizers) compared to no such adverse reactions in subjects who were CYP2C19 extensive metabolizers. - Table 3: Clinically Significant Drug Interactions with Flibanserin ADDYI: Flibanserin's Brand name There are no studies of Flibanserin in pregnant women to inform whether there is a drug-associated risk in humans. In animals, fetal toxicity only occurred in the presence of significant maternal toxicity including reductions in weight gain and sedation. Adverse reproductive and developmental effects consisted of decreased fetal weight, structural anomalies and increases in fetal loss at exposures greater than 15 times exposures achieved with the recommended human dosage. Animal studies cannot rule out the potential for fetal harm. In the general population (not taking Flibanserin), the estimated background risk of major birth defects is 2% to 4% of live births, and the estimated background risk of miscarriage of clinically recognized pregnancies is 15% to 20%. - Data - Animal Data Pregnant rats were administered Flibanserin at doses of 0, 20, 80 and 400 mg/kg/day (3, 15 and 41 times clinical exposures at the recommended human dose based on AUC) during organogenesis. The highest dose was associated with significant maternal toxicity as evidenced by severe clinical signs and marked reductions in weight gain during dosing. In the litters of high-dose dams, there were decreased fetal weights, decreased ossification of the forelimbs and increased number of lumbar ribs, and two fetuses with anophthalmia secondary to severe maternal toxicity. The no adverse effect level for embryofetal toxicity was 80 mg/kg/day (15 times clinical exposure based on AUC). Pregnant rabbits were administered Flibanserin at doses of 0, 20, 40 and 80 mg/kg/day (4, 8 and 16 times the clinical exposure at the recommended human dose) during organogenesis. Marked decreases in maternal body weight gain (>75%), abortion and complete litter resorption were observed at 40 and 80 mg/kg/day indicating significant maternal toxicity at these doses. Increases in resorptions and decreased fetal weights were observed at ≥ 40 mg/kg/day. No treatment-related teratogenic effects were observed in fetuses at any dose level. The no adverse effect level for maternal and embryofetal effects was 20 mg/kg/day (3-4 times clinical exposure based on AUC). Pregnant rats were administered Flibanserin at doses of 0, 20, 80 and 200 mg/kg/day (3, 15 and ~ 20 times clinical exposures at the recommended human dose) from day 6 of pregnancy until day 21 of lactation to assess for effects on peri- and postnatal development. The highest dose was associated with clinical signs of toxicity in pregnant and lactating rats. All doses resulted in sedation and decreases in body weight gain during pregnancy. Flibanserin prolonged gestation in some dams in all dose groups and decreased implantations, number of fetuses and fetal weights at 200 mg/kg/day. Dosing dams with 200 mg/kg also decreased pup weight gain and viability during the lactation period and delayed opening of the vagina and auditory canals. Flibanserin had no effects on learning, reflexes, fertility or reproductive capacity of the F1 generation. The no adverse effect level for maternal toxicity and peri/postnatal effects was 20 mg/kg/day. The recommended dosage of Flibanserin is 100 mg administered orally once per day at bedtime. Flibanserin is dosed at bedtime because administration during waking hours increases the risks of hypotension, syncope, accidental injury, and central nervous system (CNS) depression (such as somnolence and sedation). - Missed Dose If a dose of Flibanserin is missed at bedtime, instruct the patient to take the next dose at bedtime on the next day. Instruct the patient to not double the next dose. - Discontinuation of Flibanserin Discontinue Flibanserin after 8 weeks if the patient does not report an improvement in her symptoms. - Initiation of Flibanserin Following Moderate or Strong CYP3A4 Inhibitor Use If initiating Flibanserin following moderate or strong CYP3A4 inhibitor use, start Flibanserin 2 weeks after the last dose of the CYP3A4 inhibitor. If initiating a moderate or strong CYP3A4 inhibitor following Flibanserin use, start the moderate or strong CYP3A4 inhibitor 2 days after the last dose of Flibanserin. In vitro, Flibanserin demonstrated high affinity for the following serotonin (5-hydroxytryptamine or 5-HT) receptors: agonist activity at 5-HT1A and antagonist activity at 5-HT2A. Flibanserin also has moderate antagonist activities at the 5-HT2B, 5-HT2C, and dopamine D4 receptors. - Alcohol Interaction A randomized, double-blind, single-dose, cross-over, dedicated alcohol interaction study was conducted in 25 healthy subjects (23 men and 2 premenopausal women). In this study, 68%, 16%, 8% and 8% subjects reported a history of drinking 5-6, 7-10, 11-15 and 16-21 drinks per week, respectively. Subjects received one of the following five treatments [Flibanserin and alcohol were administered in the morning and the alcohol was consumed in 10 minutes. Flibanserin is to be only administered at bedtime]: - 100 mg of Flibanserin alone - 0.4 g/kg 95% ethanol (equivalent to two 12-ounce cans of beer containing 5% alcohol content, two 5- ounce glasses of wine containing 12% alcohol, or two 1.5-ounce shots of 80 proof spirit in a 70 kg person) - 0.8 g/kg 95% ethanol (equivalent to four 12-ounce cans of beer containing 5% alcohol content, four 5-ounce glasses of wine containing 12% alcohol, or four 1.5-ounce shots of 80 proof spirit in a 70 kg person) - 100 mg of Flibanserin in combination with 0.4 g/kg 95% ethanol - 100 mg of Flibanserin in combination with 0.8 g/kg 95% ethanol Patients who received Flibanserin with alcohol had a higher incidence of somnolence than patients who received Flibanserin alone or alcohol alone. There were no significant changes in the pharmacokinetics of Flibanserin when administered with or without alcohol. - Cardiac Electrophysiology The effect of Flibanserin on the QT interval was evaluated in a randomized, double-blind, placebo- and active- (single dose moxifloxacin) controlled crossover study in 56 healthy men and women. Subjects in the Flibanserin groups received either 50 mg twice a day (equivalent to the daily recommended dosage) or 100 mg three times a day (3 times the daily recommended dosage) administered for 5 days. The time frame for electrocardiogram (ECG) measurements covered maximum plasma concentrations of Flibanserin and relevant metabolites. In this study, Flibanserin did not prolong the QT interval to any clinically relevant extent. The mean increase in heart rate associated with the 100 mg three times a day dose of Flibanserin compared to placebo ranged from 1.7 to 3.2 beats per minute. - Absorption Following oral administration of a single 100 mg dose of Flibanserin in healthy premenopausal women (N=8), mean (SD) Cmax was 419 (206) ng/mL and mean (SD) AUC(0-inf) was 1543 (511) nghr/mL. Median (range) time to reach Cmax was 0.75 (0.75 to 4.0) hours. Absolute bioavailability of Flibanserin following oral dosing is 33%. - Effect of Food Food increased the extent of absorption and slowed the rate of absorption of a 50 mg dose of Flibanserin (one half the recommended dosage). Low-, moderate-, and high-fat meals increased Flibanserin AUC(0-inf) by 1.18-, 1.43-, and 1.56-fold; increased Cmax by 1.02-, 1.13-, and 1.15-fold; and prolonged median Tmax to 1.5, 0.9, 1.8 hours from 0.8 hours under fasted conditions, respectively. - Distribution Approximately 98% of Flibanserin is bound to human serum proteins, mainly to albumin. - Elimination - Metabolism Flibanserin is primarily metabolized by CYP3A4 and, to a lesser extent, by CYP2C19. Based on in vitro and/or in vivo data, CYP1A2, CYP2B6, CYP2C8, CYP2C9, and CYP2D6 contribute minimally to the metabolism of Flibanserin. After a single oral solution dose of 50 mg 14C-radiolabeled Flibanserin, 44% of the total 14C-Flibanserin related radioactivity was recovered in urine, and 51% was recovered in feces. Flibanserin is extensively metabolized to at least 35 metabolites, most of them occurring in low concentrations in plasma. Two metabolites could be characterized that showed plasma concentrations similar to that achieved with Flibanserin: 6,21-dihydroxy-flibanserin-6,21-disulfate and 6-hydroxy-flibanserin-6-sulfate. These two metabolites are inactive. - Excretion Flibanserin has a mean terminal half-life of approximately 11 hours. - Specific Populations - Hepatic Impairment Single 50 mg oral doses of Flibanserin were administered to 10 patients with mild hepatic impairment (Child-Pugh score of 6 points), 4 patients with moderate hepatic impairment (Child-Pugh score of 8-9 points), and 14 healthy subjects matched by age, weight, and gender. Systemic Flibanserin exposure (AUC(0-inf)) increased 4.5-fold in patients with mild hepatic impairment, compared to subjects with normal hepatic function, and t1/2 was longer (26 hours compared to 10 hours in matching healthy controls). Due to the small number of patients (n=4) with moderate hepatic impairment enrolled in the study, it is not possible to make conclusions about the quantitative effect of moderate hepatic impairment on Flibanserin exposure. Flibanserin is contraindicated in patients with hepatic impairment. - Renal Impairment Single 50 mg oral doses of Flibanserin were administered to 7 patients with mild to moderate renal impairment (GFR 30 to 80 mL/min), 9 patients with severe renal impairment (GFR <30 mL/min, not on dialysis), and 16 healthy subjects matched by age, weight, and gender. Flibanserin exposure (AUC(0-inf)) increased 1.1-fold in patients with mild to moderate renal impairment and 1.2-fold in patients with severe renal impairment, compared to the healthy control subjects. - Race/Ethnicity A cross-study comparison between healthy Japanese women and Caucasian women with HSDD showed that Flibanserin exposure was approximately 1.4-fold higher in Japanese women. When the mean Flibanserin exposure in Japanese women was adjusted for weight, the AUC(tau,ss) in Japanese women was 2246 nghr/mL, which is comparable to 2080 ng*hr/mL in Caucasian women. The similarity in weight-adjusted AUC(tau,ss) suggests that weight, not race, is the factor contributing to the observed difference in Flibanserin exposure between Japanese and Caucasian women. - Age No formal study has been conducted to study the effect of age on Flibanserin exposures. - Drug Interaction Studies - Drugs that Increase Flibanserin Exposure The effects of other drugs on the pharmacokinetics of Flibanserin are presented in TABLE 4 as change relative to Flibanserin administered alone (test/reference). - Moderate CYP3A4/Moderate CYP2C9/Strong CYP2C19 Inhibitor (Fluconazole) In a study of 15 healthy female subjects, a fluconazole 400 mg loading dose followed by 200 mg administered once daily for 5 days increased Flibanserin 100 mg single dose exposure (AUC(0-inf)) 7-fold and Cmax 2.2-fold compared to Flibanserin 100 mg alone. Three of 15 subjects (20%) experienced hypotension or syncope from concomitant use of fluconazole and Flibanserin; therefore, the study was stopped early. - Strong CYP3A4 Inhibitor (Ketoconazole) In a study of 24 healthy female subjects, ketoconazole 400 mg administered once daily for 5 days following a light breakfast increased Flibanserin 50 mg single-dose exposure (AUC(0-inf)) 4.5-fold and Cmax 1.8-fold compared to Flibanserin 50 mg alone. - Strong CYP3A4 Inhibitor (Itraconazole) In a study of 12 healthy male and female subjects, itraconazole 200 mg administered once daily for 4 days following a loading dose of 400 mg increased Flibanserin 50 mg single dose exposure (AUC(0-inf)) 2.6-fold and Cmax 1.7-fold when Flibanserin was given 2 hours after itraconazole on Day 5, compared to exposures with Flibanserin 50 mg alone. The 200 mg itraconazole dose does not maximally inhibit the CYP3A4 enzyme. - Moderate CYP3A4 Inhibitor (Grapefruit Juice) In a study of 26 healthy female subjects, grapefruit juice (240 mL) increased Flibanserin 100 mg single dose exposure (AUC(0-inf)) by 1.4-fold and Cmax 1.1-fold compared to Flibanserin 100 mg alone. - Weak CYP3A4 Inhibitor (Oral Contraceptives) In a meta-analysis of 17 oral contraceptive users and 91 non-users in Phase 1 studies, the oral contraceptive users had a 1.4-fold higher Flibanserin AUC and 1.3‑fold higher Cmax compared to the non-users. - Strong CYP2D6 Inhibitor (Paroxetine) Paroxetine is a strong CYP2D6 inhibitor. In a study of 19 healthy male and female subjects, Flibanserin exposure decreased by approximately 4% when Flibanserin 50 mg twice daily was given with paroxetine compared to Flibanserin alone. Paroxetine was dosed at 20 mg once daily for 3 days followed by 40 mg once daily for 7 days. - Drugs that Decrease Flibanserin Exposure - Strong CYP3A4 Inducer (Rifampin) In a study of 24 healthy female subjects, rifampin 600 mg given once daily for 7 days prior to administration of 100 mg Flibanserin significantly decreased Flibanserin exposure by 95%. - Moderate CYP3A4 Inducer (Etravirine) Steady state etravirine, a moderate CYP3A4 inducer, decreased Flibanserin exposures by approximately 21%. - Table 4 Drugs That Increase Flibanserin Exposure ADDYI: Flibanserin's Brand name - Effects of Flibanserin on Other Drugs The effects of Flibanserin on the pharmacokinetics of other drugs are presented in Table 5 as change relative to the other drug administered alone (test/reference). - Digoxin and P-glycoprotein Substrates A single center, open-label, randomized, two-way crossover study in 24 healthy men and women evaluated the effect of Flibanserin on the pharmacokinetics of digoxin. Flibanserin 100 mg was administered once daily over 5 days followed by a single dose of 0.5 mg digoxin, a P-gp substrate. Flibanserin increased digoxin AUC(0-inf) by 2.0-fold and Cmax by 1.5-fold, compared to digoxin alone. - Drugs Metabolized by CYP3A4 (Simvastatin) An open-label, randomized, crossover study in 12 healthy men and women evaluated the effect of Flibanserin 50 mg twice daily for 4 days on the pharmacokinetics of simvastatin 40 mg once daily. Flibanserin increased the AUC(0-inf) of simvastatin, a substrate of CYP3A4, 1.3‑fold and Cmax by 1.2-fold. Flibanserin co-administered with simvastatin increased simvastatin acid AUC(0-inf) by 1.5-fold and Cmax by 1.4-fold. - Oral Contraceptives A study in 24 healthy women evaluated the effect of 100 mg Flibanserin once daily for 2 weeks on the pharmacokinetics of a single-dose of ethinyl estradiol (EE) 30 mcg/levonorgestrel (LNG) 150 mcg. Flibanserin increased the EE AUC(0-inf) by 1.09-fold and the EE Cmax by 1.1-fold. Flibanserin decreased the LNG AUC(0-inf) by 1.06-fold and did not change the LNG Cmax. - Drugs Metabolized by CYP2B6 (Bupropion) An open-label, randomized, two-period crossover study in 28 healthy women evaluated the effect of Flibanserin on the pharmacokinetics of bupropion. Flibanserin 50 mg twice daily was administered for 2 days followed by 100 mg once daily for 13 days. Bupropion 150 mg twice daily was given for 8 days beginning on Day 6 of Flibanserin treatment. Flibanserin did not change bupropion AUC(t,ss) (1.0-fold change) and Cmax (1.0-fold change) but hydroxybupropion AUC(t,ss) decreased by 9% and Cmax by 11%. - Table 5 Effects of Flibanserin on Exposure of Other Drugs ADDYI: Flibanserin's Brand name Patients who are poor metabolizers of CYP2D6, CYP2C9 or CYP2C19 are deficient in CYP2D6, CYP2C9 or CYP2C19 enzyme activity, respectively. Extensive metabolizers have normal functioning CYP enzymes. - CYP2C19 Poor Metabolizers A study comparing Flibanserin exposure in CYP2C19 poor metabolizers to CYP2C19 extensive metabolizers was conducted in lieu of a drug interaction study with Flibanserin and a strong CYP2C19 inhibitor. In 9 women who were poor metabolizers of CYP2C19, Cmax and AUC(0-inf) of Flibanserin 100 mg once daily increased 1.5-fold (1.1-2.1) and 1.3-fold (0.9-2.1), compared to exposures among 8 extensive metabolizers of CYP2C19. Flibanserin half-life was increased from 11.1 hours in the extensive metabolizers of CYP2C19 to 13.5 hours in the poor metabolizers of CYP2C19. The frequencies of poor metabolizers of CYP2C19 are approximately 2–5% among Caucasians and Africans and approximately 2–15% among Asians. - CYP2D6 Poor Metabolizers A study comparing Flibanserin exposure in CYP2D6 poor metabolizers to CYP2D6 extensive metabolizers was conducted in addition to a drug interaction study with paroxetine, a strong CYP2D6 inhibitor. In 12 poor metabolizers of CYP2D6, steady state Cmax and AUC of Flibanserin 50 mg twice daily was decreased by 4% and increased by 18%, respectively, compared to exposures among 19 extensive metabolizers, intermediate metabolizers and ultra rapid metabolizers of CYP2D6. - CYP2C9 Poor Metabolizers A study comparing Flibanserin exposure in CYP2C9 poor metabolizers to CYP2C9 extensive metabolizers was conducted in lieu of a drug interaction study with Flibanserin and a strong CYP2C9 inhibitor. In 8 women who were poor metabolizers of CYP2C9, Cmax and AUC(0-inf) of Flibanserin 100 mg once daily decreased 23% and 18%, compared to exposures among 8 extensive metabolizers of CYP2C9. A two-year carcinogenicity study was conducted in CD-1 mice with dietary administration of 0, 10, 80, 200 and 1000/1200 mg/kg/day of Flibanserin. Statistically significant increases in combined mammary tumors (adenoacanthoma and adenocarcinomas) were observed in female mice administered Flibanserin at doses of 200 and 1200 mg/kg/day (exposures, based on AUC, were 3 and 10 times the clinical exposures at the recommended clinical dose). No increases in mammary tumors were observed in male mice. Statistically significant increases were also seen for combined hepatocellular adenomas/carcinomas in female mice treated with Flibanserin 1200 mg/kg/day and for hepatocellular carcinomas in male mice treated with Flibanserin 1000 mg/kg/day (exposures, based on AUC, were 8 times the clinical exposure at the recommended clinical dose). There were no significant increases in tumor incidence in a two year carcinogenicity study conducted in Wistar rats with dietary administration of 0, 10, 30 and 100 mg/kg/day Flibanserin (up to 5-8 times human exposure at the recommended clinical dose). - Mutagenesis Flibanserin was negative for mutagenesis in vitro in Salmonella typhimurium (Ames test) and in Chinese hamster ovary cells. Flibanserin was positive for chromosomal aberrations in cultured human lymphocytes but negative for chromosomal aberrations in vivo in the rat bone marrow micronucleus assay and negative for DNA damage in rat liver in the Comet assay. - Impairment of Fertility Female and male rats were administered Flibanserin 14 and 28 days before mating, respectively, to assess for potential effects on fertility and early reproductive performance. Flibanserin slightly increased the duration of the estrus cycle but had no adverse effects on fertility or early embryonic development at doses up to 200 mg/kg/day (~20 times human exposure at the recommended clinical dose). The efficacy of Flibanserin for the treatment of HSDD in premenopausal women was established in three 24-week, randomized, double-blind, placebo-controlled trials (Studies 1, 2, and 3). The three trials included premenopausal women with acquired, generalized HSDD of at least 6 months duration. In the clinical trials, acquired HSDD was defined as HSDD that developed in patients who previously had no problems with sexual desire. Generalized HSDD was defined as HSDD that was not limited to certain types of stimulation, situations or partners. The patients were treated with Flibanserin 100 mg once daily at bedtime (n = 1187) or placebo (n = 1188). Most of the trial participants were Caucasian (88.6%); the remainder were Black (9.6%) and Asian (1.5%). The mean age of study participants was 36 years old (range 19 to 55 years old); the mean duration in the monogamous, heterosexual relationship was 11 years, and the mean duration of HSDD was approximately 5 years. The completion rate across these three trials was 69% and 78% for the Flibanserin and placebo groups, respectively. These trials each had two co-primary efficacy endpoints, one for satisfying sexual events (SSEs) and the other for sexual desire: - The change from baseline to Week 24 in the number of monthly SSEs (i.e., sexual intercourse, oral sex, masturbation, or genital stimulation by the partner). The SSEs were based on patient responses to the following questions: “Did you have a sexual event?” and “Was the sex satisfying for you?” - Studies 1 and 2 had a different sexual desire endpoint than Study 3: - In Studies 1 and 2, the sexual desire co-primary endpoint was the change from baseline to Week 24 in the calculated monthly sexual desire score and was based on patient responses to the question: “Indicate your most intense level of sexual desire.” Every day, patients rated their sexual desire level from 0 (no desire) to 3 (strong desire) and recorded their response in an electronic Diary (eDiary). These responses were summed over a 28-day period to yield the calculated monthly sexual desire score, which ranged from 0 to 84. - In Study 3, the desire domain of the Female Sexual Function Index (FSFI Desire) was the sexual desire co-primary endpoint. The desire domain of the FSFI has two questions. The first question asks patients “Over the past 4 weeks, how often did you feel sexual desire or interest?”, with responses ranging from 1 (almost never or never) to 5 (almost always or always). The second question asks patients “Over the past 4 weeks, how would you rate your level (degree) of sexual desire or interest?”, with responses ranging from 1 (very low or none at all) to 5 (very high). The FSFI Desire score was calculated by adding the patient’s responses to these two questions then multiplying that sum by 0.6. The FSFI Desire domain score ranged from 1.2 to 6. The desire domain of the Female Sexual Function Index (FSFI Desire) was also used as a secondary endpoint in Studies 1 and 2. The three trials had a secondary endpoint that measured bother (a component of distress) related to sexual desire using Question 13 of the Female Sexual Distress Scale-Revised (FSDS-R). This question asks “How often did you feel: Bothered by low sexual desire?” Patients assessed their sexual distress over a 7-day recall period and responded on a scale of 0 (never) to 4 (always). The efficacy results from Studies 1, 2, and 3 are summarized in Table 6. In all three trials, Flibanserin resulted in statistically significant improvement compared to placebo in the change from baseline in monthly SSEs at Week 24. In Study 1 and 2, there were no statistically significant differences between Flibanserin and placebo for the eDiary sexual desire endpoint (change in baseline to Week 24). In contrast, in Study 3 there was statistically significant improvement in the change from baseline to Week 24 in sexual desire (using the FSFI Desire Domain) with Flibanserin compared to placebo. The FSFI Desire Domain findings were consistent across all three trials as were the findings for the secondary endpoint that assessed distress using Question 13 of the FSDS-R. - Table 6 Efficacy Results in Premenopausal HSDD Patients in Studies 1, 2, and 3 ADDYI: Flibanserin's Brand name Exploratory analyses were conducted to assess whether the treatment effects varied depending on baseline number of SSEs, FSFI Desire score, and FSDS-R Question 13 distress score. No notable differences were identified among these subgroups. Supportive analyses were conducted to help interpret the clinical meaningfulness of the observed treatment effects. These analyses defined responders for each efficacy endpoint by anchoring change from baseline to end of treatment with the Patient's Global Impression of Improvement (PGI‑I). The first analysis considered responders to be those who reported being “much improved” or “very much improved.” In this analysis, the absolute difference in the percentage of responders with Flibanserin and the percentage of responders with placebo across the three trials was 8-9% for SSEs (29-39% for Flibanserin; 21-31% for placebo), 10-13% for FSFI desire domain (43-48% for Flibanserin; 31-38% for placebo), and 7-13% for FSDS-R Question 13 (21-34% for Flibanserin; 14-25% for placebo). The second analysis considered responders to be those who reported being at least minimally improved. The absolute difference in the percentage of responders with Flibanserin and the percentage of responders with placebo across the three trials was 10-15% for SSEs (44-48% for Flibanserin; 33-36% for placebo), 12-13% for FSFI desire domain (43-51% for Flibanserin; 31-39% for placebo), and 9-12% for FSDS-R Question 13 (50-60% for Flibanserin; 41-48% for placebo). In a randomized, placebo-controlled, 4-way crossover study in 83 healthy premenopausal female subjects, no adverse effect was detected on measures of driving performance itself or psychomotor performance thought to be important for driving performance when assessed 9 hours following single and multiple doses of Flibanserin 100 mg once daily at bedtime or single doses of Flibanserin 200 mg at bedtime (two times the maximum recommended dosage). Flibanserin is available as a 100 mg oval, pink, film-coated tablet debossed on one side with “f100” and blank on the other side. Available in bottles of 30 tablets. (NDC 58604-214-30) - Hypotension and Syncope Inform patients that Flibanserin can cause severe hypotension and syncope, particularly with alcohol or with moderate or strong CYP3A4 inhibitors. Inform patients that alcohol use and moderate or strong CYP3A4 inhibitors are contraindicated. Counsel patients about the importance of abstaining from alcohol and to ask about drug interactions before starting a new prescription or non-prescription medication or using other products that contain CYP3A4 inhibitors (e.g., grapefruit juice or St. John’s Wort). Advise patients who experience pre-syncope or lightheadedness to lie down and to call for help if symptoms persist. Flibanserin is available only through a restricted program called the Flibanserin REMS Program. Patients can only obtain Flibanserin from certified pharmacies participating in the program. Therefore, provide patients with the telephone number and website for information on how to obtain Flibanserin. - CNS Depression Advise patients that Flibanserin can cause CNS depression, such as somnolence and sedation, and that the risk is increased with other CNS depressants and with certain drug interactions (e.g., hypnotics, benzodiazepines, opioids). The risk is also increased if Flibanserin is taken during waking hours. Advise patients to avoid engaging in activities requiring full alertness (e.g., operating machinery or driving) until at least 6 hours after the Flibanserin dose and until they know how Flibanserin affects them. - Nursing Mothers Advise patients not to breastfeed if they are taking Flibanserin. - Bedtime Dosing Advise patients to take only one tablet at bedtime and not to take Flibanserin at any other time of day. - ↑ "Addyi™ (flibanserin) Tablets, for Oral Use. Full Prescribing Information" (PDF). Addyi REMS (Risk Evaluation and Mitigation Strategy). Sprout Pharmaceuticals, Inc. Raleigh, NC 27609 USA. Retrieved 21 October 2015..mw-parser-output cite.citation{font-style:inherit}.mw-parser-output q{quotes:"\"""\"""'""'"}.mw-parser-output code.cs1-code{color:inherit;background:inherit;border:inherit;padding:inherit}.mw-parser-output .cs1-lock-free a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/6/65/Lock-green.svg/9px-Lock-green.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-limited a,.mw-parser-output .cs1-lock-registration a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/d/d6/Lock-gray-alt-2.svg/9px-Lock-gray-alt-2.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-subscription a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/a/aa/Lock-red-alt-2.svg/9px-Lock-red-alt-2.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration{color:#555}.mw-parser-output .cs1-subscription span,.mw-parser-output .cs1-registration span{border-bottom:1px dotted;cursor:help}.mw-parser-output .cs1-hidden-error{display:none;font-size:100%}.mw-parser-output .cs1-visible-error{display:none;font-size:100%}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration,.mw-parser-output .cs1-format{font-size:95%}.mw-parser-output .cs1-kern-left,.mw-parser-output .cs1-kern-wl-left{padding-left:0.2em}.mw-parser-output .cs1-kern-right,.mw-parser-output .cs1-kern-wl-right{padding-right:0.2em}	https://www.wikidoc.org/index.php/Flibanserin
0fb82a8bac573421806281111b7d535941ddc141	wikidoc	Florfenicol	Florfenicol # Overview Florfenicol (marketed by Schering-Plough Animal Health under the trade name Nuflor) is a fluorinated synthetic analog of thiamphenicol. In the United States, florfenicol is currently indicated for the treatment of bovine respiratory disease (BRD) associated with Mannheimia (Pasteurella) haemolytica, Pasteurella multocida, and Haemophilus somnus, for treatment of bovine interdigital phlegmon (foot rot, acute interdigital necrobacillosis, infectious pododermatitis) associated with Fusobacterium necrophorum and Bacteroides melaninogenicus. Florfenicol is also used in aquaculture, and is licensed for use in the United States for the control of enteric septicemia in catfish. The use of florfenicol in horses, and likely in other equids, typically causes diarrhea. This has been anecdotally reported to progress to lethal cases of acute colitis. Therefore, use of this antimicrobial in the equine patient should be limited to cases in which other, safer, options are not available. # Contamination Florfenicol was among the drug contaminants in a brand of supermarket eggs in Taiwan and Iran.	Florfenicol Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview Florfenicol (marketed by Schering-Plough Animal Health under the trade name Nuflor) is a fluorinated synthetic analog of thiamphenicol.[1] In the United States, florfenicol is currently indicated for the treatment of bovine respiratory disease (BRD) associated with Mannheimia (Pasteurella) haemolytica, Pasteurella multocida, and Haemophilus somnus, for treatment of bovine interdigital phlegmon (foot rot, acute interdigital necrobacillosis, infectious pododermatitis) associated with Fusobacterium necrophorum and Bacteroides melaninogenicus. Florfenicol is also used in aquaculture, and is licensed for use in the United States for the control of enteric septicemia in catfish.[2] The use of florfenicol in horses, and likely in other equids, typically causes diarrhea. This has been anecdotally reported to progress to lethal cases of acute colitis. Therefore, use of this antimicrobial in the equine patient should be limited to cases in which other, safer, options are not available. [3] # Contamination Florfenicol was among the drug contaminants in a brand of supermarket eggs in Taiwan and Iran.[4] # External links - Nuflor website	https://www.wikidoc.org/index.php/Florfenicol
1716088e5580ad4a192200de1e7e4a1c8eace0d4	wikidoc	Flosequinan	Flosequinan # Overview Flosequinan is a quinolone vasodilator. It has direct relaxing effects on peripheral arteries and veins. It is administered orally in cases of congestive heart failure in patients who are not responsive to digitalis or ACE inhibitors. It was sold under the trade name Manoplax. It was withdrawn from the US market in October 1993 due to an increased risk of hospitalization or death. # Synthesis Both methods for forming the heterocyclic ring in quinolones involved cyclization into the carbocyclic ring. A closely related quinolone that displays cardiovascular rather than antibiotic activity is constructed by a condensation that closes the bond at the 2,3 position in the heterocyclic ring. The starting material (2) is obtained by reaction of the aminoacetophenone derivative (1) with ethyl formate. Heating the product in ethylene glycol methyl ether leads to an aldol-like cyclization and the formation of a quinolone ring. The product, flosequinan (3), displays vasodilator and cardiotonic activities.	Flosequinan Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview Flosequinan is a quinolone vasodilator. It has direct relaxing effects on peripheral arteries and veins. It is administered orally in cases of congestive heart failure in patients who are not responsive to digitalis or ACE inhibitors. It was sold under the trade name Manoplax. It was withdrawn from the US market in October 1993 due to an increased risk of hospitalization or death.[1] # Synthesis Both methods for forming the heterocyclic ring in quinolones involved cyclization into the carbocyclic ring. A closely related quinolone that displays cardiovascular rather than antibiotic activity is constructed by a condensation that closes the bond at the 2,3 position in the heterocyclic ring. The starting material (2) is obtained by reaction of the aminoacetophenone derivative (1) with ethyl formate. Heating the product in ethylene glycol methyl ether leads to an aldol-like cyclization and the formation of a quinolone ring. The product, flosequinan (3), displays vasodilator and cardiotonic activities.	https://www.wikidoc.org/index.php/Flosequinan
72ea29fad187efebb9fe13fe45f094ba6428254e	wikidoc	Fluticasone	Fluticasone # Disclaimer WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here. # Overview Fluticasone is a corticosteroid that is FDA approved for the treatment of asthma, management of the nasal symptoms of seasonal and perennial allergic rhinitis and nonallergic rhinitis, inflammatory and pruritic manifestations of atopic dermatitis. Common adverse reactions include candidiasis of mouth and esophagus, nausea and vomiting, osteoporosis, headache, cough, epistaxis, pharyngitis, sinusitis, throat irritation, upper respiratory infection. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) - Fluticasone should be administered by the orally inhaled route only in patients aged 4 years and older. Individual patients will experience a variable time to onset and degree of symptom relief. Maximum benefit may not be achieved for 1 to 2 weeks or longer after starting treatment. - After asthma stability has been achieved, it is always desirable to titrate to the lowest effective dosage to reduce the possibility of side effects. For patients who do not respond adequately to the starting dosage after 2 weeks of therapy, higher dosages may provide additional asthma control. The safety and efficacy of fluticasone when administered in excess of recommended dosages have not been established. - The recommended starting dosage and the highest recommended dosage of fluticasone, based on prior asthma therapy, are listed below: - Bronchodilators alone: Initial dose of 88 mcg twice daily to a maximum of 440 mcg twice daily. - Inhaled corticosteroids: Initial dose of 88-220 mcg twice dailya, to a maximum of 440 mcg twice daily. - Oral corticosteroidsb: Initial dose of 440 mcg twice daily, to a maximum of 880 mcg twice daily. a Starting dosages above 88 mcg twice daily may be considered for patients with poorer asthma control or those who have previously required doses of inhaled corticosteroids that are in the higher range for the specific agent. b For patients currently receiving chronic oral corticosteroid therapy, prednisone should be reduced no faster than 2.5 to 5 mg/day on a weekly basis beginning after at least 1 week of therapy with fluticasone. Patients should be carefully monitored for signs of asthma instability, including serial objective measures of airflow, and for signs of adrenal insufficiency. Once prednisone reduction is complete, the dosage of fluticasone should be reduced to the lowest effective dosage. Fluticasone should be primed before using for the first time by releasing 4 test sprays into the air away from the face, shaking well for 5 seconds before each spray. In cases where the inhaler has not been used for more than 7 days or when it has been dropped, prime the inhaler again by shaking well for 5 seconds and releasing 1 test spray into the air away from the face. - Dosing Information - The recommended starting dosage in adults is 2 sprays (50 mcg of fluticasone propionate each) in each nostril once daily (total daily dose, 200 mcg). The same dosage divided into 100 mcg given twice daily (e.g., 8 a.m. and 8 p.m.) is also effective. After the first few days, patients may be able to reduce their dosage to 100 mcg (1 spray in each nostril) once daily for maintenance therapy. Some patients (12 years of age and older) with seasonal allergic rhinitis may find as-needed use of 200 mcg once daily effective for symptom control. Greater symptom control may be achieved with scheduled regular use. - Dosing information - Apply a thin film of fluticasone to the affected skin areas once daily. Rub in gently. - As with other corticosteroids, therapy should be discontinued when control is achieved. If no improvement is seen within 2 weeks, reassessment of diagnosis may be necessary. The safety and efficacy of drug use for longer than 4 weeks have not been established. - Fluticasone should not be used with occlusive dressings or applied in the diaper area unless directed by a physician. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Fluticasone in adult patients. ### Non–Guideline-Supported Use - Dosing Information - 200 mcg twice daily. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) - Dosing Information: Pediatric patients (aged 4-11 years)c - The recommended starting dosage and the highest recommended dosage of fluticasone, based on prior asthma therapy: Initial dose of 88 mcg twice daily to a maximum of 88 mcg twice daily. c Recommended pediatric dosage is 88 mcg twice daily regardless of prior therapy. A valved holding chamber and mask may be used to deliver fluticasone to young patients. Fluticasone should be primed before using for the first time by releasing 4 test sprays into the air away from the face, shaking well for 5 seconds before each spray. In cases where the inhaler has not been used for more than 7 days or when it has been dropped, prime the inhaler again by shaking well for 5 seconds and releasing 1 test spray into the air away from the face. - Dosing Information - Patients should be started with 100 mcg (1 spray in each nostril once daily). Patients not adequately responding to 100 mcg may use 200 mcg (2 sprays in each nostril). Once adequate control is achieved, the dosage should be decreased to 100 mcg (1 spray in each nostril) daily. - The maximum total daily dosage should not exceed 2 sprays in each nostril (200 mcg/day). - Fluticasone nasal spray is not recommended for children under 4 years of age. - Dosing information - Apply a thin film of fluticasone to the affected skin areas once daily. Rub in gently. - As with other corticosteroids, therapy should be discontinued when control is achieved. If no improvement is seen within 2 weeks, reassessment of diagnosis may be necessary. The safety and efficacy of drug use for longer than 4 weeks have not been established. - Fluticasone should not be used with occlusive dressings or applied in the diaper area unless directed by a physician. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Fluticasone in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Fluticasone in pediatric patients. # Contraindications The use of fluticasone is contraindicated in the following conditions: - Primary treatment of status asthmaticus or other acute episodes of asthma where intensive measures are required. - Hypersensitivity to any of the ingredients in the formulation. # Warnings ### Aerosol In clinical studies, the development of localized infections of the mouth and pharynx with Candida albicans has occurred in patients treated with fluticasone. When such an infection develops, it should be treated with appropriate local or systemic (i.e., oral antifungal) therapy while treatment with fluticasone continues, but at times therapy with fluticasone may need to be interrupted. Patients should rinse the mouth after inhalation of fluticasone. Fluticasone is not to be regarded as a bronchodilator and is not indicated for rapid relief of bronchospasm. Patients should be instructed to contact their physicians immediately when episodes of asthma that are not responsive to bronchodilators occur during the course of treatment with fluticasone. During such episodes, patients may require therapy with oral corticosteroids. Persons who are using drugs that suppress the immune system are more susceptible to infections than healthy individuals. Chickenpox and measles, for example, can have a more serious or even fatal course in susceptible children or adults using corticosteroids. In such children or adults who have not had these diseases or been properly immunized, particular care should be taken to avoid exposure. How the dose, route, and duration of corticosteroid administration affect the risk of developing a disseminated infection is not known. The contribution of the underlying disease and/or prior corticosteroid treatment to the risk is also not known. If a patient is exposed to chickenpox, prophylaxis with varicella zoster immune globulin (VZIG) may be indicated. If a patient is exposed to measles, prophylaxis with pooled intramuscular immunoglobulin (IG) may be indicated. If chickenpox develops, treatment with antiviral agents may be considered. Because of the potential for worsening infections, inhaled corticosteroids should be used with caution, if at all, in patients with active or quiescent tuberculosis infection of the respiratory tract; untreated systemic fungal, bacterial, viral, or parasitic infections; or ocular herpes simplex. Particular care is needed for patients who have been transferred from systemically active corticosteroids to inhaled corticosteroids because deaths due to adrenal insufficiency have occurred in patients with asthma during and after transfer from systemic corticosteroids to less systemically available inhaled corticosteroids. After withdrawal from systemic corticosteroids, a number of months are required for recovery of hypothalamic-pituitary-adrenal (HPA) function. Patients requiring oral corticosteroids should be weaned slowly from systemic corticosteroid use after transferring to fluticasone. In a clinical trial of 168 patients, prednisone reduction was successfully accomplished by reducing the daily prednisone dose on a weekly basis following initiation of treatment with fluticasone. Successive reduction of prednisone dose was allowed only when lung function, symptoms, and as-needed short-acting beta-agonist use were better than or comparable to that seen before initiation of prednisone dose reduction. Lung function (forced expiratory volume in 1 second or morning peak expiratory flow ), beta-agonist use, and asthma symptoms should be carefully monitored during withdrawal of oral corticosteroids. In addition to monitoring asthma signs and symptoms, patients should be observed for signs and symptoms of adrenal insufficiency such as fatigue, lassitude, weakness, nausea and vomiting, and hypotension. Patients who have been previously maintained on 20 mg or more per day of prednisone (or its equivalent) may be most susceptible, particularly when their systemic corticosteroids have been almost completely withdrawn. During this period of HPA suppression, patients may exhibit signs and symptoms of adrenal insufficiency when exposed to trauma, surgery, or infection (particularly gastroenteritis) or other conditions associated with severe electrolyte loss. Although inhaled corticosteroids may provide control of asthma symptoms during these episodes, in recommended doses they supply less than normal physiological amounts of glucocorticoid (cortisol) systemically and do not provide the mineralocorticoid activity that is necessary for coping with these emergencies. During periods of stress or a severe asthma attack, patients who have been withdrawn from systemic corticosteroids should be instructed to resume oral corticosteroids immediately and to contact their physicians for further instruction. These patients should also be instructed to carry a warning card indicating that they may need supplementary systemic corticosteroids during periods of stress or a severe asthma attack. Transfer of patients from systemic corticosteroid therapy to fluticasone may unmask conditions previously suppressed by the systemic corticosteroid therapy (e.g., rhinitis, conjunctivitis, eczema, arthritis, eosinophilic conditions). Some patients may experience symptoms of systemically active corticosteroid withdrawal (e.g., joint and/or muscular pain, lassitude, and depression, despite maintenance or even improvement of respiratory function). Fluticasone propionate will often help control asthma symptoms with less suppression of HPA function than therapeutically equivalent oral doses of prednisone. Since fluticasone propionate is absorbed into the circulation and can be systemically active at higher doses, the beneficial effects of fluticasone in minimizing HPA dysfunction may be expected only when recommended dosages are not exceeded and individual patients are titrated to the lowest effective dose. A relationship between plasma levels of fluticasone propionate and inhibitory effects on stimulated cortisol production has been shown after 4 weeks of treatment with fluticasone propionate. Since individual sensitivity to effects on cortisol production exists, physicians should consider this information when prescribing fluticasone. Because of the possibility of systemic absorption of inhaled corticosteroids, patients treated with fluticasone should be observed carefully for any evidence of systemic corticosteroid effects. Particular care should be taken in observing patients postoperatively or during periods of stress for evidence of inadequate adrenal response. It is possible that systemic corticosteroid effects such as hypercorticism and adrenal suppression (including adrenal crisis) may appear in a small number of patients, particularly when fluticasone is administered at higher than recommended doses over prolonged periods of time. If such effects occur, the dosage of fluticasone should be reduced slowly, consistent with accepted procedures for reducing systemic corticosteroids and for management of asthma. Hypersensitivity reactions, including anaphylaxis, angioedema, urticaria, and bronchospasm, may occur after administration of fluticasone. Decreases in bone mineral density (BMD) have been observed with long-term administration of products containing inhaled corticosteroids. The clinical significance of small changes in BMD with regard to long-term outcomes is unknown. Patients with major risk factors for decreased bone mineral content, such as prolonged immobilization, family history of osteoporosis, postmenopausal status, tobacco use, advanced age, poor nutrition, or chronic use of drugs that can reduce bone mass (e.g., anticonvulsants, oral corticosteroids), should be monitored and treated with established standards of care. Orally inhaled corticosteroids may cause a reduction in growth velocity when administered to pediatric patients. Monitor the growth of pediatric patients receiving fluticasone routinely (e.g., via stadiometry). To minimize the systemic effects of orally inhaled corticosteroids, including fluticasone, titrate each patient’s dosage to the lowest dosage that effectively controls his/her symptoms. Glaucoma, increased intraocular pressure, and cataracts have been reported in patients following the long-term administration of inhaled corticosteroids, including fluticasone propionate. Therefore, close monitoring is warranted in patients with a change in vision or with a history of increased intraocular pressure, glaucoma, and/or cataracts. As with other inhaled medications, bronchospasm may occur with an immediate increase in wheezing after dosing. If bronchospasm occurs following dosing with fluticasone, it should be treated immediately with a fast-acting inhaled bronchodilator. Treatment with fluticasone should be discontinued immediately and alternative therapy instituted. The use of strong cytochrome P450 3A4 (CYP3A4) inhibitors (e.g., ritonavir, atazanavir, clarithromycin, indinavir, itraconazole, nefazodone, nelfinavir, saquinavir, ketoconazole, telithromycin) with fluticasone is not recommended because increased systemic corticosteroid adverse effects may occur. In rare cases, patients on inhaled fluticasone propionate may present with systemic eosinophilic conditions. Some of these patients have clinical features of vasculitis consistent with Churg-Strauss syndrome, a condition that is often treated with systemic corticosteroid therapy. These events usually, but not always, have been associated with the reduction and/or withdrawal of oral corticosteroid therapy following the introduction of fluticasone propionate. Cases of serious eosinophilic conditions have also been reported with other inhaled corticosteroid in this clinical setting. Physicians should be alert to eosinophilia, vasculitic rash, worsening pulmonary symptoms, cardiac complications, and/or neuropathy presenting in their patients. A causal relationship between fluticasone propionate and these underlying conditions has not been established. ### Spray - The replacement of a systemic corticosteroids with a topical corticosteroids can be accompanied by signs of adrenal insufficiency, and in addition some patients may experience symptoms of withdrawal, e.g., joint and/or muscular pain, lassitude, and depression. Patients previously treated for prolonged periods with systemic corticosteroids and transferred to topical corticosteroids should be carefully monitored for acute adrenal insufficiency in response to stress. In those patients who have asthma or other clinical conditions requiring long-term systemic corticosteroids treatment, too rapid a decrease in systemic corticosteroids may cause a severe exacerbation of their symptoms. - The concomitant use of intranasal corticosteroids with other inhaled corticosteroids could increase the risk of signs or symptoms of hypercorticism and/or suppression of the HPA axis. - A drug interaction study in healthy subjects has shown that ritonavir (a highly potent cytochrome P450 3A4 inhibitor) can significantly increase plasma fluticasone propionate exposure, resulting in significantly reduced serum cortisol concentrations. - Persons who are using drugs that suppress the immune system are more susceptible to infections than healthy individuals. Chickenpox and measles, for example, can have a more serious or even fatal course in susceptible children or adults using corticosteroids. In children or adults who have not had these diseases or been properly immunized, particular care should be taken to avoid exposure. How the dose, route, and duration of corticosteroid administration affect the risk of developing a disseminated infection is not known. The contribution of the underlying disease and/or prior corticosteroid treatment to the risk is also not known. If exposed to chickenpox, prophylaxis with varicella zoster immune globulin (VZIG) may be indicated. If exposed to measles, prophylaxis with pooled intramuscular immunoglobulin (IG) may be indicated. (See the respective package inserts for complete VZIG and IG prescribing information.) If chickenpox develops, treatment with antiviral agents may be considered. - Avoid spraying in eyes. ## Precautions ### Spray - Intranasal corticosteroids may cause a reduction in growth velocity when administered to pediatric patients. - Rarely, immediate hypersensitivity reactions or contact dermatitis may occur after the administration of fluticasone nasal spray. Rare instances of wheezing, nasal septum perforation, cataracts, glaucoma, and increased intraocular pressure have been reported following the intranasal application of corticosteroids, including fluticasone propionate. - Use of excessive doses of corticosteroids may lead to signs or symptoms of hypercorticism and/or suppression of HPA function. - Although systemic effects have been minimal with recommended doses of fluticasone nasal spray, potential risk increases with larger doses. Therefore, larger than recommended doses of fluticasone nasal spray should be avoided. - When used at higher than recommended doses or in rare individuals at recommended doses, systemic corticosteroid effects such as hypercorticism and adrenal suppression may appear. If such changes occur, the dosage of fluticasone nasal spray should be discontinued slowly consistent with accepted procedures for discontinuing oral corticosteroid therapy. - In clinical studies with fluticasone propionate administered intranasally, the development of localized infections of the nose and pharynx with Candida albicans has occurred only rarely. When such an infection develops, it may require treatment with appropriate local therapy and discontinuation of treatment with fluticasone nasal spray. Patients using fluticasone nasal spray over several months or longer should be examined periodically for evidence of Candida infection or other signs of adverse effects on the nasal mucosa. - Intranasal corticosteroids should be used with caution, if at all, in patients with active or quiescent tuberculous infections of the respiratory tract; untreated local or systemic fungal or bacterial infections; systemic viral or parasitic infections; or ocular herpes simplex. - Because of the inhibitory effect of corticosteroids on wound healing, patients who have experienced recent nasal septal ulcers, nasal surgery, or nasal trauma should not use a nasal corticosteroid until healing has occurred. ### Lotion/Cream - Fluticasone contains the excipient imidurea which releases formaldehyde as a breakdown product. Formaldehyde may cause allergic sensitization or irritation upon contact with the skin. Fluticasone should not be used in individuals with hypersensitivity to formaldehyde as it may prevent healing or worsen dermatitis. - Systemic absorption of topical corticosteroids can produce reversible hypothalamic-pituitary-adrenal axis (HPA) suppression with the potential for glucocorticosteroid insufficiency after withdrawal from treatment. Manifestations of Cushing's syndrome, hyperglycemia, and glucosuria can also be produced in some patients by systemic absorption of topical corticosteroids while on treatment. - Patients applying a potent topical steroid to a large surface area or to areas under occlusion should be evaluated periodically for evidence of HPA axis suppression. This may be done by using cosyntropin (ACTH1·24) stimulation testing. - Forty-two pediatric patients (4 months to < 6 years of age) with moderate to severe atopic eczema who were treated with fluticasone for at least 3-4 weeks were assessed for HPA axis suppression and 40 of these subjects applied at least 90% of applications. None of the 40 evaluable patients suppressed, where the sole criterion for HPA axis suppression is a plasma cortisol level of less than or equal to 18 micrograms per deciliter after cosyntropin stimulation. Although HPA axis suppression was observed in 0 of 40 pediatric patients (upper 95% confidence bound is 7.2%), the occurrence of HPA axis suppression in any patient and especially with longer use cannot be ruled out. In other studies with fluticasone propionate topical formulations, adrenal suppression has been observed. - If HPA axis suppression is noted, an attempt should be made to withdraw the drug, to reduce the frequency of application, or to substitute a less potent steroid. Recovery of HPA axis function is generally prompt upon discontinuation of topical corticosteroids. Infrequently, signs and symptoms of glucocorticosteroid insufficiency may occur requiring supplemental systemic corticosteroids. For information on systemic supplementation, see prescribing information for those products. - Pediatric patients may be more susceptible to systemic toxicity from equivalent doses due to their larger skin surface to body mass ratios. - The following local adverse reactions have been reported with topical corticosteroids, and they may occur more frequently with the use of occlusive dressings and higher potency corticosteroids. These reactions are listed in an approximately decreasing order of occurrence: irritation, folliculitis, acneiform eruptions, hypopigmentation, perioral dermatitis, allergic contact dermatitis, secondary infection, skin atrophy, striae, hypertrichosis, and miliaria. - Fluticasone, 0.05% may cause local cutaneous adverse reactions. - If irritation develops, fluticasone should be discontinued and appropriate therapy instituted. Allergic contact dermatitis with corticosteroids is usually diagnosed by observing failure to heal rather than noting a clinical exacerbation as with most topical products not containing corticosteroids. Such an observation should be corroborated with appropriate diagnostic patch testing. - If concomitant skin infections are present or develop, an appropriate antifungal or antibacterial agent should be used. If a favorable response does not occur promptly, use of fluticasone should be discontinued until the infection has been adequately controlled. - Fluticasone should not be used in the presence of preexisting skin atrophy and should not be used where infection is present at the treatment site. Fluticasone should not be used in the treatment of rosacea and perioral dermatitis. - Patients that apply fluticasone to exposed portions of the body should avoid excessive exposure to either natural or artificial sunlight (including tanning booths, sun lamps, etc.). # Adverse Reactions ## Clinical Trials Experience ### Aerosol Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in practice. The incidence of common adverse reactions in the table below is based upon 2 placebo-controlled US clinical trials in which 812 adult and adolescent patients (457 females and 355 males) previously treated with as-needed bronchodilators and/or inhaled corticosteroids were treated twice daily for up to 12 weeks with 2 inhalations of fluticasone 44 mcg Inhalation Aerosol,fluticasone 110 mcg Inhalation Aerosol,fluticasone 220 mcg Inhalation Aerosol (dosages of 88, 220, or 440 mcg twice daily), or placebo. The table above includes all events (whether considered drug-related or nondrug-related by the investigator) that occurred at a rate of over 3% in any of the groups treated with fluticasone and were more common than in the placebo group. Less than 2% of patients discontinued from the studies because of adverse reactions. The average duration of exposure was 73 to 76 days in the active treatment groups compared with 60 days in the placebo group. Additional Adverse Reactions: Other adverse reactions not previously listed, whether considered drug-related or not by the investigators, that were reported more frequently by patients with asthma treated with fluticasone compared with patients treated with placebo include the following: rhinitis, rhinorrhea/post-nasal drip, nasal sinus disorders, laryngitis, diarrhea, viral gastrointestinal infections, dyspeptic symptoms, gastrointestinal discomfort and pain, hyposalivation, musculoskeletal pain, muscle pain, muscle stiffness/tightness/rigidity, dizziness, migraines, fever, viral infections, pain, chest symptoms, viral skin infections, muscle injuries, soft tissue injuries, urinary infections. Fluticasone propionate inhalation aerosol (440 or 880 mcg twice daily) was administered for 16 weeks to 168 patients with asthma requiring oral corticosteroids (Study 3). Adverse reactions not included above, but reported by more than 3 patients in either group treated with fluticasone and more commonly than in the placebo group included nausea and vomiting, arthralgia and articular rheumatism, and malaise and fatigue. In 2 long-term studies (26 and 52 weeks), the pattern of adverse reactions in patients treated with fluticasone at dosages up to 440 mcg twice daily was similar to that observed in the 12-week studies. There were no new and/or unexpected adverse reactions with long-term treatment. Pediatric Patients Aged 4 to 11 Years: fluticasone has been evaluated for safety in 56 pediatric patients who received 88 mcg twice daily for 4 weeks. Types of adverse reactions in these pediatric patients were generally similar to those observed in adults and adolescents. ### Spray In controlled US studies, more than 3,300 patients with seasonal allergic, perennial allergic, or perennial nonallergic rhinitis received treatment with intranasal fluticasone propionate. In general, adverse reactions in clinical studies have been primarily associated with irritation of the nasal mucous membranes, and the adverse reactions were reported with approximately the same frequency by patients treated with the vehicle itself. The complaints did not usually interfere with treatment. Less than 2% of patients in clinical trials discontinued because of adverse events; this rate was similar for vehicle placebo and active comparators. Systemic corticosteroid side effects were not reported during controlled clinical studies up to 6 months’ duration with fluticasone nasal spray. If recommended doses are exceeded, however, or if individuals are particularly sensitive or taking fluticasone nasal spray in conjunction with administration of other corticosteroids, symptoms of hypercorticism, e.g., Cushing syndrome, could occur. The following incidence of common adverse reactions (>3%, where incidence in fluticasone propionate-treated subjects exceeded placebo) is based upon 7 controlled clinical trials in which 536 patients (57 girls and 108 boys aged 4 to 11 years, 137 female and 234 male adolescents and adults) were treated with fluticasone nasal spray 200 mcg once daily over 2 to 4 weeks and 2 controlled clinical trials in which 246 patients (119 female and 127 male adolescents and adults) were treated with fluticasone nasal spray 200 mcg once daily over 6 months. Also included in the table are adverse events from 2 studies in which 167 children (45 girls and 122 boys aged 4 to 11 years) were treated with fluticasone nasal spray 100 mcg once daily for 2 to 4 weeks. Overall Adverse Experiences With >3% Incidence on Fluticasone Propionate in Controlled Clinical Trials With fluticasone nasal spray in Patients ≥4 Years With Seasonal or Perennial Allergic Rhinitis. Other adverse events that occurred in ≤3% but ≥1% of patients and that were more common with fluticasone propionate (with uncertain relationship to treatment) included: blood in nasal mucus, runny nose, abdominal pain, diarrhea, fever, flu-like symptoms, aches and pains, dizziness, bronchitis. In addition to adverse events reported from clinical trials, the following events have been identified during postapproval use of intranasal fluticasone propionate in clinical practice. Because they are reported voluntarily from a population of unknown size, estimates of frequency cannot be made. These events have been chosen for inclusion due to either their seriousness, frequency of reporting, or causal connection to fluticasone propionate or a combination of these factors. - General: Hypersensitivity reactions, including angioedema, skin rash, edema of the face and tongue, pruritus, urticaria, bronchospasm, wheezing, dyspnea, and anaphylaxis/anaphylactoid reactions, which in rare instances were severe. - Ear, Nose, and Throat: Alteration or loss of sense of taste and/or smell and, rarely, nasal septal perforation, nasal ulcer, sore throat, throat irritation and dryness, cough, hoarseness, and voice changes. - Eye: Dryness and irritation, conjunctivitis, blurred vision, glaucoma, increased intraocular pressure, and cataracts. - Cases of growth suppression have been reported for intranasal corticosteroids, including fluticasone. ### Cream/Lotion In 2 multicenter vehicle-controlled clinical trials of once-daily application of fluticasone by 196 adult and 242 pediatric patients, the total incidence of adverse reactions considered drug related by investigators was approximately 4%. Events were local cutaneous events, usually mild and self-limiting, and consisted primarily of burning/stinging (2%). All other drug-related events occurred with an incidence of less than 1%, and inclusively were contact dermatitis, exacerbation of atopic dermatitis, folliculitis of legs, pruritus, pustules on arm, rash, and skin infection. The incidence of drug-related events on drug compared to vehicle (4% and 5%, respectively) was similar. The incidence of drug-related events between study populations of 242 pediatric patients (age 3 months to < 17 years) and 196 adult patients (17 years or older) (4% and 5%, respectively) was also similar. In an open-label study of 44 pediatric patients applying fluticasone to at least 35% of body surface area twice daily for 3 or 4 weeks, the overall incidence of drug-related adverse events was 14%. Events were local, cutaneous, and inclusively were dry skin (7%), stinging at application site (5%), and excoriation (2%). The table below summarizes all adverse events by body system that occurred in at least 1% of patients in either the drug or vehicle group in controlled clinical trials. During the clinical trials, eczema herpeticum occurred in a 33-year-old male patient treated with fluticasone. Additionally, a 4-month-old patient treated with fluticasone in the open-label trial had marked elevations of the hepatic enzymes AST and ALT. ## Postmarketing Experience ### Aerosol In addition to adverse reactions reported from clinical trials, the following adverse reactions have been identified during postmarketing use of fluticasone propionate. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. These events have been chosen for inclusion due to either their seriousness, frequency of reporting, or causal connection to fluticasone propionate or a combination of these factors. - Ear, Nose, and Throat: Aphonia, facial and oropharyngeal edema, and throat soreness and irritation. - Endocrine and Metabolic: Cushingoid features, growth velocity reduction in children/adolescents, hyperglycemia, osteoporosis, and weight gain. - Eye: Cataracts. - Gastrointestinal Disorders: Dental caries and tooth discoloration. - Immune System Disorders: Immediate and delayed hypersensitivity reactions, including urticaria, anaphylaxis, rash, and angioedema and bronchospasm, have been reported. - Infections and Infestations: Esophageal candidiasis. - Psychiatry: Agitation, aggression, anxiety, depression, and restlessness. Behavioral changes, including hyperactivity and irritability, have been reported very rarely and primarily in children. - Respiratory: Asthma exacerbation, chest tightness, cough, dyspnea, immediate and delayed bronchospasm, paradoxical bronchospasm, pneumonia, and wheeze. - Skin: Contusions, cutaneous hypersensitivity reactions, ecchymoses, and pruritus. - Eosinophilic Conditions: In rare cases, patients on inhaled fluticasone propionate may present with systemic eosinophilic conditions, with some patients presenting with clinical features of vasculitis consistent with Churg-Strauss syndrome, a condition that is often treated with systemic corticosteroid therapy. These events usually, but not always, have been associated with the reduction and/or withdrawal of oral corticosteroid therapy following the introduction of fluticasone propionate ### Spray During postmarketing use, there have been reports of clinically significant drug interactions in patients receiving fluticasone propionate and ritonavir, resulting in systemic corticosteroid effects including Cushing syndrome and adrenal suppression. Therefore, coadministration of fluticasone propionate and ritonavir is not recommended unless the potential benefit to the patient outweighs the risk of systemic corticosteroid side effects. ### Lotion/Cream Systemic adverse events with fluticasone cream and fluticasone ointment have included: - Immunosuppression/Pneumocystis carinii pneumonia/leukopenia/thrombocytopenia - Hyperglycemia/ glycosuria - Cushing syndrome - Generalized body edema/blurred vision - Acute urticarial reaction (edema, urticaria, pruritus, and throat swelling) The following localized adverse reactions have been reported during post approval use of fluticasone: - Erythema - Edema/swelling - Bleeding - Lack of efficacy Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. # Drug Interactions - Fluticasone propionate is a substrate of CYP3A4. The use of strong CYP3A4 inhibitors (e.g., ritonavir, atazanavir, clarithromycin, indinavir, itraconazole, nefazodone, nelfinavir, saquinavir, ketoconazole, telithromycin) with fluticasone is not recommended because increased systemic corticosteroid adverse effects may occur. - A drug interaction study with fluticasone propionate aqueous nasal spray in healthy subjects has shown that ritonavir (a strong CYP3A4 inhibitor) can significantly increase plasma fluticasone propionate concentration, resulting in significantly reduced serum cortisol concentrations. During postmarketing use, there have been reports of clinically significant drug interactions in patients receiving fluticasone propionate and ritonavir, resulting in systemic corticosteroid effects including Cushing’s syndrome and adrenal suppression. Therefore, coadministration of fluticasone propionate and ritonavir is not recommended unless the potential benefit to the patient outweighs the risk of systemic corticosteroid side effects. - Coadministration of orally inhaled fluticasone propionate (1,000 mcg) and ketoconazole (200 mg once daily) resulted in a 1.9-fold increase in plasma fluticasone propionate exposure and a 45% decrease in plasma cortisol area under the curve (AUC), but had no effect on urinary excretion of cortisol. Coadministration of fluticasone propionate and ketoconazole is not recommended unless the potential benefit to the patient outweighs the risk of systemic corticosteroid side effects. - In a multiple-dose drug interaction study, coadministration of orally inhaled fluticasone propionate (500 mcg twice daily) and erythromycin (333 mg 3 times daily) did not affect fluticasone propionate pharmacokinetics. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): C ### Aerosol There are no adequate and well-controlled studies with fluticasone in pregnant women. Fluticasone should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Subcutaneous studies in mice at a dose approximately 0.1 times the maximum recommended human daily inhalation dose (MRHD) for adults on a mg/m2 basis and in the rat at a dose approximately 0.5 times the MRHD in adults on a mg/m2 basis revealed fetal toxicity characteristic of potent corticosteroid compounds, including embryonic growth retardation, omphalocele, cleft palate, and retarded cranial ossification. In rabbits, fetal weight reduction and cleft palate were observed at a subcutaneous dose approximately 0.04 times the MRHD for adults on a mg/m2 basis. However, no teratogenic effects were reported at oral doses up to approximately 3 times the MRHD for adults on a mg/m2 basis. No fluticasone propionate was detected in the plasma in this study, consistent with the established low bioavailability following oral administration. Experience with oral corticosteroids since their introduction in pharmacologic, as opposed to physiologic, doses suggests that rodents are more prone to teratogenic effects from corticosteroids than humans. In addition, because there is a natural increase in corticosteroid production during pregnancy, most women will require a lower exogenous corticosteroid dose and many will not need corticosteroid treatment during pregnancy. ### Spray Subcutaneous studies in the mouse and rat at 45 and 100 mcg/kg, respectively (approximately equivalent to and 4 times, respectively, the maximum recommended daily intranasal dose in adults on a mcg/m2 basis), revealed fetal toxicity characteristic of potent corticosteroid compounds, including embryonic growth retardation, omphalocele, cleft palate, and retarded cranial ossification. In the rabbit, fetal weight reduction and cleft palate were observed at a subcutaneous dose of 4 mcg/kg (less than the maximum recommended daily intranasal dose in adults on a mcg/m2 basis). However, no teratogenic effects were reported at oral doses up to 300 mcg/kg (approximately 25 times the maximum recommended daily intranasal dose in adults on a mcg/m2 basis) of fluticasone propionate to the rabbit. No fluticasone propionate was detected in the plasma in this study, consistent with the established low bioavailability following oral administration. Fluticasone propionate crossed the placenta following oral administration of 100 mcg/kg to rats and 300 mcg/kg to rabbits (approximately 4 and 25 times, respectively, the maximum recommended daily intranasal dose in adults on a mcg/m2 basis). There are no adequate and well-controlled studies in pregnant women. Fluticasone propionate should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Experience with oral corticosteroids since their introduction in pharmacologic, as opposed to physiologic, doses suggests that rodents are more prone to teratogenic effects from corticosteroids than humans. In addition, because there is a natural increase in corticosteroid production during pregnancy, most women will require a lower exogenous corticosteroid dose and many will not need corticosteroid treatment during pregnancy. ### Lotion/Cream Corticosteroids have been shown to be teratogenic in laboratory animals when administered systemically at relatively low dosage levels. Some corticosteroids have been shown to be teratogenic after dermal application in laboratory animals. Systemic embryofetal development studies were conducted in mice, rats and rabbits. Subcutaneous doses of 15, 45 and 150 μg/kg/day of fluticasone propionate were administered to pregnant female mice from gestation days 6 – 15. A teratogenic effect characteristic of corticosteroids (cleft palate) was noted after administration of 45 and 150 μg/kg/day (less than the MRHD in adults based on body surface area comparisons) in this study. No treatment related effects on embryofetal toxicity or teratogenicity were noted at 15 μg/kg/day (less than the MRHD in adults based on body surface area comparisons). Subcutaneous doses of 10, 30 and 100 μg/kg/day of fluticasone propionate were administered to pregnant female rats in two embryofetal development studies (one study administered fluticasone propionate from gestation days 6 – 15 and the other study from gestation days 7 – 17). In the presence of maternal toxicity, fetal effects noted at 100 μg/kg/day (less than the MRHD in adults based on body surface area comparisons) included decreased fetal weights, omphalocele, cleft palate, and retarded skeletal ossification. No treatment related effects on embryofetal toxicity or teratogenicity were noted at 10 μg/kg/day (less than the MRHD in adults based on body surface area comparisons). Subcutaneous doses of 0.08, 0.57 and 4 μg/kg/day of fluticasone propionate were administered to pregnant female rabbits from gestation days 6 – 18. Fetal effects noted at 4 μg/kg/day (less than the MRHD in adults based on body surface area comparisons) included decreased fetal weights, cleft palate and retarded skeletal ossification. No treatment related effects on embryofetal toxicity or teratogenicity were noted at 0.57 μg/kg/day (less than the MRHD in adults based on body surface area comparisons). Oral doses of 3, 30 and 300 μg/kg/day fluticasone propionate were administered to pregnant female rabbits from gestation days 8 – 20. No fetal or teratogenic effects were noted at oral doses up to 300 μg/kg/day (less than the MRHD in adults based on body surface area comparisons) in this study. However, no fluticasone propionate was detected in the plasma in this study, consistent with the established low bioavailability following oral administration. Fluticasone propionate crossed the placenta following administration of a subcutaneous or an oral dose of 100 μg/kg tritiated fluticasone propionate to pregnant rats. There are no adequate and well-controlled studies in pregnant women. During clinical trials of fluticasone, women of childbearing potential were required to use contraception to avoid pregnancy. Therefore, fluticasone should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Fluticasone in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Fluticasone during labor and delivery. ### Nursing Mothers ### Aerosol It is not known whether fluticasone propionate is excreted in human breast milk. However, other corticosteroids have been detected in human milk. Subcutaneous administration to lactating rats of tritiated fluticasone propionate (approximately 0.05 times the MRHD in adults on a mg/m2 basis) resulted in measurable radioactivity in milk. Since there are no data from controlled trials on the use of fluticasone by nursing mothers, caution should be exercised when fluticasone is administered to a nursing woman. ### Spray Subcutaneous administration to lactating rats of 10 mcg/kg of tritiated fluticasone propionate (less than the maximum recommended daily intranasal dose in adults on a mcg/m2 basis) resulted in measurable radioactivity in the milk. Since there are no data from controlled trials on the use of intranasal fluticasone propionate by nursing mothers, caution should be exercised when fluticasone nasal spray is administered to a nursing woman. ### Lotion/Cream It is not known whether topical administration of corticosteroids could result in sufficient systemic absorption to produce detectable quantities in human milk. Because many drugs are excreted in human milk, caution should be exercised when fluticasone is administered to a nursing woman. ### Pediatric Use ### Aerosol The safety and effectiveness of fluticasone in children aged 4 years and older have been established. The safety and effectiveness of fluticasone in children younger than 4 years have not been established. Use of fluticasone in patients aged 4 to 11 years is supported by evidence from adequate and well-controlled studies in adults and adolescents aged 12 years and older, pharmacokinetic studies in patients aged 4 to 11 years, established efficacy of fluticasone propionate formulated as fluticasone inhalation powder and fluticasone inhalation powder in patients aged 4 to 11 years, and supportive findings with fluticasone in a study conducted in patients aged 4 to 11 years. Orally inhaled corticosteroids may cause a reduction in growth velocity when administered to pediatric patients. A reduction of growth velocity in children or teenagers may occur as a result of poorly controlled asthma or from use of corticosteroids including inhaled corticosteroids. The effects of long-term treatment of children and adolescents with inhaled corticosteroids, including fluticasone propionate, on final adult height are not known. Controlled clinical studies have shown that inhaled corticosteroids may cause a reduction in growth in pediatric patients. In these studies, the mean reduction in growth velocity was approximately 1 cm/year (range: 0.3 to 1.8 cm/year) and appeared to depend upon dose and duration of exposure. This effect was observed in the absence of laboratory evidence of HPA axis suppression, suggesting that growth velocity is a more sensitive indicator of systemic corticosteroid exposure in pediatric patients than some commonly used tests of HPA axis function. The long-term effects of this reduction in growth velocity associated with orally inhaled corticosteroids, including the impact on final adult height, are unknown. The potential for “catch-up” growth following discontinuation of treatment with orally inhaled corticosteroids has not been adequately studied. The effects on growth velocity of treatment with orally inhaled corticosteroids for over 1 year, including the impact on final adult height, are unknown. The growth of children and adolescents receiving orally inhaled corticosteroids, including fluticasone, should be monitored routinely (e.g., via stadiometry). The potential growth effects of prolonged treatment should be weighed against the clinical benefits obtained and the risks associated with alternative therapies. To minimize the systemic effects of orally inhaled corticosteroids, including fluticasone, each patient should be titrated to the lowest dose that effectively controls his/her symptoms. Since a cross study comparison in adult and adolescent patients (aged 12 years and older) indicated that systemic exposure of inhaled fluticasone would be higher than exposure from fluticasone propionate inhalation powder, results from a study to assess the potential growth effects of fluticasone propionate inhalation powder in pediatric patients (aged 4 to 11 years) are provided. A 52-week placebo-controlled study to assess the potential growth effects of fluticasone propionate inhalation powder at 50 and 100 mcg twice daily was conducted in the US in 325 prepubescent children (244 males and 81 females) aged 4 to 11 years. The mean growth velocities at 52 weeks observed in the intent-to-treat population were 6.32 cm/year in the placebo group (n = 76), 6.07 cm/year in the 50-mcg group (n = 98), and 5.66 cm/year in the 100-mcg group (n = 89). An imbalance in the proportion of children entering puberty between groups and a higher dropout rate in the placebo group due to poorly controlled asthma may be confounding factors in interpreting these data. A separate subset analysis of children who remained prepubertal during the study revealed growth rates at 52 weeks of 6.10 cm/year in the placebo group (n = 57), 5.91 cm/year in the 50-mcg group (n = 74), and 5.67 cm/year in the 100-mcg group (n = 79). In children aged 8.5 years, the mean age of children in this study, the range for expected growth velocity is: boys – 3rd percentile = 3.8 cm/year, 50th percentile = 5.4 cm/year, and 97th percentile = 7.0 cm/year; girls – 3rd percentile = 4.2 cm/year, 50th percentile = 5.7 cm/year, and 97th percentile = 7.3 cm/year. The clinical significance of these growth data is not certain. Physicians should closely follow the growth of children and adolescents taking corticosteroids by any route, and weigh the benefits of corticosteroid therapy against the possibility of growth suppression if growth appears slowed. Patients should be maintained on the lowest dose of inhaled corticosteroid that effectively controls their asthma. Children Younger Than 4 Years:Pharmacokinetics: Pharmacodynamics: A 12-week, double-blind, placebo-controlled, parallel-group study was conducted in children with asthma aged 1 to younger than 4 years. Twelve-hour overnight urinary cortisol excretion after a 12-week treatment period with 88 mcg of fluticasone twice daily (n = 73) and with placebo (n = 42) were calculated. The mean and median change from baseline in urine cortisol over 12 hours were -0.7 and 0.0 mcg for fluticasone and 0.3 and -0.2 mcg for placebo, respectively. In a 1-way crossover study in children aged 6 to younger than 12 months with reactive airways disease (N = 21), serum cortisol was measured over a 12-hour dosing period. Patients received placebo treatment for a 2-week period followed by a 4-week treatment period with 88 mcg of fluticasone twice daily with a valved holding Chamber (VHC) with mask. The geometric mean ratio of serum cortisol over 12 hours (AUC0-12 h) following fluticasone (n = 16) versus placebo (n = 18) was 0.95 (95% CI: 0.72, 1.27). Safety: Fluticasone administered as 88 mcg twice daily has been evaluated for safety in 239 pediatric patients aged 1 to younger than 4 years in a 12-week, double-blind, placebo-controlled study. Treatments were administered with an valved holding Chamber (VHC) with mask. In pediatric patients aged 1 to younger than 4 years receiving fluticasone, the following events occurred with a frequency greater than 3% and more frequently than in pediatric patients who received placebo, regardless of causality assessment: pyrexia, nasopharyngitis, upper respiratory tract infection, vomiting, otitis media, diarrhea, bronchitis, pharyngitis, and viral infection. Fluticasone administered as 88 mcg twice daily has also been evaluated for safety in 23 pediatric patients aged 6 to 12 months in an open-label placebo-controlled study. Treatments were administered with an valved holding Chamber (VHC) with mask for 2 weeks with placebo followed by 4 weeks with active drug. There was no discernable difference in the types of adverse events reported between patients receiving placebo compared to the active drug. In Vitro Testing of Dose Delivery With Holding Chambers: In vitro dose characterization studies were performed to evaluate the delivery of fluticasone via holding chambers with attached masks. The studies were conducted with 2 different holding chambers (valved holding Chamber (VHC) and AeroChamber Z-STAT Plus™ VHC) with masks (small and medium size) at inspiratory flow rates of 4.9, 8.0, and 12.0 L/min in combination with holding times of 0, 2, 5, and 10 seconds. The flow rates were selected to be representative of inspiratory flow rates of children aged 6 to 12 months, 2 to 5 years, and over 5 years, respectively. The mean delivered dose of fluticasone propionate through the holding chambers with masks was lower than the 44 mcg of fluticasone propionate delivered directly from the actuator mouthpiece. The results were similar through both holding chambers. The fine particle fraction (approximately 1 to 5 μm) across the flow rates used in these studies was 70% to 84% of the delivered dose, consistent with the removal of the coarser fraction by the holding chamber. In contrast, the fine particle fraction for fluticasone delivered without a holding chamber typically represents 42% to 55% of the delivered dose measured at the standard flow rate of 28.3 L/min. These data suggest that, on a per kilogram basis, young children receive a comparable dose of fluticasone propionate when delivered via a holding chamber and mask as adults do without their use. aCenters for Disease Control growth charts, developed by the National Center for Health Statistics in collaboration with the National Center for Chronic Disease Prevention and Health Promotion (2000). Ranges correspond to the average of the 50th percentile weight for boys and girls at the ages indicated. bA single inhalation of fluticasone in a 70-kg adult without use of a valved holding chamber and mask delivers approximately 44 mcg, or 0.6 mcg/kg. ### Spray Six hundred fifty (650) patients aged 4 to 11 years and 440 patients aged 12 to 17 years were studied in US clinical trials with fluticasone propionate nasal spray. The safety and effectiveness of fluticasone nasal spray in children below 4 years of age have not been established. Controlled clinical studies have shown that intranasal corticosteroids may cause a reduction in growth velocity in pediatric patients. This effect has been observed in the absence of laboratory evidence of HPA axis suppression, suggesting that growth velocity is a more sensitive indicator of systemic corticosteroid exposure in pediatric patients than some commonly used tests of HPA axis function. The long-term effects of this reduction in growth velocity associated with intranasal corticosteroids, including the impact on final adult height, are unknown. The potential for “catch-up” growth following discontinuation of treatment with intranasal corticosteroids has not been adequately studied. The growth of pediatric patients receiving intranasal corticosteroids, including fluticasone nasal spray, should be monitored routinely (e.g., via stadiometry). The potential growth effects of prolonged treatment should be weighed against the clinical benefits obtained and the risks/benefits of treatment alternatives. To minimize the systemic effects of intranasal corticosteroids, including fluticasone nasal spray, each patient should be titrated to the lowest dose that effectively controls his/her symptoms. A 1-year placebo-controlled clinical growth study was conducted in 150 pediatric patients (ages 3 to 9 years) to assess the effect of fluticasone nasal spray (single daily dose of 200 mcg, the maximum approved dose) on growth velocity. From the primary population of 56 patients receiving fluticasone nasal spray and 52 receiving placebo, the point estimate for growth velocity with fluticasone nasal spray was 0.14 cm/year lower than that noted with placebo (95% confidence interval ranging from 0.54 cm/year lower than placebo to 0.27 cm/year higher than placebo). Thus, no statistically significant effect on growth was noted compared to placebo. No evidence of clinically relevant changes in HPA axis function or bone mineral density was observed as assessed by 12-hour urinary cortisol excretion and dual-energy x-ray absorptiometry, respectively. The potential for fluticasone nasal spray to cause growth suppression in susceptible patients or when given at higher doses cannot be ruled out. ### Lotion/Cream Fluticasone contains the excipient imidurea which releases formaldehyde as a breakdown product. Formaldehyde may cause allergic sensitization or irritation upon contact with the skin. Fluticasone should not be used in individuals with hypersensitivity to formaldehyde as it may prevent healing or worsen dermatitis. Fluticasone should be discontinued if control is achieved before 4 weeks. If no improvement is seen within 2 weeks, contact a physician. The safety of the use of fluticasone for longer than 4 weeks has not been established. The safety and efficacy of fluticasone in pediatric patients below 1 year of age have not been established. Parents of pediatric patients should be advised not to use this medication in the treatment of diaper dermatitis unless directed by the physician. Fluticasone should not be applied in the diaper areas as diapers or plastic pants may constitute occlusive dressing. Forty-two pediatric patients (4 months to < 6 years of age) with moderate to severe atopic eczema who were treated with Fluticasone for at least 3-4 weeks were assessed for HPA axis suppression and 40 of these subjects applied at least 90% of applications. None of the 40 evaluable patients suppressed, where the sole criterion for HPA axis suppression is a plasma cortisol level of less than or equal to 18 micrograms per deciliter after cosyntropin stimulation. Although HPA axis suppression was observed in 0 of 40 pediatric patients (upper 95% confidence bound is 7.2%), the occurrence of HPA axis suppression in any patient and especially with longer use cannot be ruled out. In other studies with fluticasone propionate topical formulations, adrenal suppression has been observed. Fluticasone cream, 0.05% caused HPA axis suppression in 2 of 43 pediatric patients, ages 2 and 5 years old, who were treated for 4 weeks covering at least 35% of the body surface area. Follow-up testing 12 days after treatment discontinuation, available for 1 of the 2 patients, demonstrated a normally responsive HPA axis. HPA axis suppression, Cushing's syndrome, linear growth retardation, delayed weight gain, and intracranial hypertension have been reported in pediatric patients receiving topical corticosteroids. Manifestations of adrenal suppression in pediatric patients include low plasma cortisol levels to an absence of response to ACTH stimulation. Manifestations of intracranial hypertension include bulging fontanelles, headaches, and bilateral papilledema. Administration of topical corticosteroids to children should be limited to the least amount compatible with an effective therapeutic regimen. Chronic corticosteroid therapy may interfere with the growth and development of children. In addition, local adverse events including cutaneous atrophy, striae, telangiectasia, and pigmentation change have been reported with topical use of corticosteroids in pediatric patients. ### Geriatic Use ### Aerosol Of the total number of patients treated with fluticasone in US and non-US clinical trials, 173 were aged 65 years or older, 19 of which were 75 years or older. No overall differences in safety or effectiveness were observed between these patients and younger patients, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. ### Spray A limited number of patients 65 years of age and older (n = 129) or 75 years of age and older (n = 11) have been treated with fluticasone nasal spray in US and non-US clinical trials. While the number of patients is too small to permit separate analysis of efficacy and safety, the adverse reactions reported in this population were similar to those reported by younger patients. ### Lotion/Cream A limited number of patients above 65 years of age have been treated with fluticasone in US and non-US clinical trials. Specifically only 8 patients above 65 years of age were treated with fluticasone in controlled clinical trials. The number of patients is too small to permit separate analyses of efficacy and safety. ### Gender No significant difference in clearance (CL/F) of fluticasone propionate was observed. ### Race There is no FDA guidance on the use of Fluticasone with respect to specific racial populations. ### Renal Impairment Formal pharmacokinetic studies using fluticasone have not been conducted in patients with renal impairment. ### Hepatic Impairment Formal pharmacokinetic studies using fluticasone have not been conducted in patients with hepatic impairment. Since fluticasone propionate is predominantly cleared by hepatic metabolism, impairment of liver function may lead to accumulation of fluticasone propionate in plasma. Therefore, patients with hepatic disease should be closely monitored. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Fluticasone in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Fluticasone in patients who are immunocompromised. # Administration and Monitoring ### Administration - Inhaled - Spray - Cutaneous application ### Monitoring Patients previously treated for prolonged periods with systemic corticosteroids and transferred to topical corticosteroids should be carefully monitored for acute adrenal insufficiency in response to stress. Lung function (forced expiratory volume in 1 second or morning peak expiratory flow ), beta-agonist use, and asthma symptoms should be carefully monitored during withdrawal of oral corticosteroids. # IV Compatibility There is limited information regarding the compatibility of Fluticasone and IV administrations. # Overdosage - Chronic overdosage may result in signs/symptoms of hypercorticism. - Inhalation by healthy volunteers of a single dose of 1,760 or 3,520 mcg of fluticasone was well tolerated. Doses of 1,320 mcg administered to healthy human volunteers twice daily for 7 to 15 days were also well tolerated. - Intranasal administration of 2 mg (10 times the recommended dose) of fluticasone propionate twice daily for 7 days to healthy human volunteers was well tolerated. Single oral doses up to 16 mg have been studied in human volunteers with no acute toxic effects reported. - Repeat oral doses up to 80 mg daily for 10 days in healthy volunteers and repeat oral doses up to 20 mg daily for 42 days in patients were well tolerated. Adverse reactions were of mild or moderate severity, and incidences were similar in active and placebo treatment groups. - No deaths were seen in mice given an oral dose of 1,000 mg/kg (approximately 2,300 and 11,000 times the MRHD for adults and children aged 4 to 11 years, respectively, on a mg/m2 basis). No deaths were seen in rats given an oral dose of 1,000 mg/kg (approximately 4,600 and 22,000 times the MRHD in adults and children aged 4 to 11 years, respectively, on a mg/m2 basis). - The oral and subcutaneous median lethal doses in mice and rats were >1,000 mg/kg (>20,000 and >41,000 times, respectively, the maximum recommended daily intranasal dose in adults and >10,000 and >20,000 times, respectively, the maximum recommended daily intranasal dose in children on a mg/m2 basis). - Topically applied fluticasone can be absorbed in sufficient amounts to produce systemic effects. # Pharmacology ## Mechanism of Action ### Aerosol Fluticasone propionate is a synthetic trifluorinated corticosteroid with potent anti-inflammatory activity. In vitro assays using human lung cytosol preparations have established fluticasone propionate as a human glucocorticoid receptor agonist with an affinity 18 times greater than dexamethasone, almost twice that of beclomethasone‑17‑monopropionate (BMP), the active metabolite of beclomethasone dipropionate, and over 3 times that of budesonide. Data from the McKenzie vasoconstrictor assay in man are consistent with these results. The clinical significance of these findings is unknown. Inflammation is an important component in the pathogenesis of asthma. Corticosteroids have been shown to inhibit multiple cell types (e.g., mast cells, eosinophils, basophils, lymphocytes, macrophages, neutrophils) and mediator production or secretion (e.g., histamine, eicosanoids, leukotrienes, cytokines) involved in the asthmatic response. These anti-inflammatory actions of corticosteroids contribute to their efficacy in asthma. Though effective for the treatment of asthma, corticosteroids do not affect asthma symptoms immediately. Individual patients will experience a variable time to onset and degree of symptom relief. Maximum benefit may not be achieved for 1 to 2 weeks or longer after starting treatment. When corticosteroids are discontinued, asthma stability may persist for several days or longer. Studies in patients with asthma have shown a favorable ratio between topical anti-inflammatory activity and systemic corticosteroid effects with recommended doses of orally inhaled fluticasone propionate. This is explained by a combination of a relatively high local anti-inflammatory effect, negligible oral systemic bioavailability (less than 1%), and the minimal pharmacological activity of the only metabolite detected in man. ### Nasal Spray Fluticasone propionate is a synthetic trifluorinated corticosteroid with anti-inflammatory activity. In vitro dose response studies on a cloned human glucocorticoid receptor system involving binding and gene expression afforded 50% responses at 1.25 and 0.17 nM concentrations, respectively. Fluticasone propionate was 3-fold to 5-fold more potent than dexamethasone in these assays. Data from the McKenzie vasoconstrictor assay in man also support its potent glucocorticoid activity. In preclinical studies, fluticasone propionate revealed progesterone-like activity similar to the natural hormone. However, the clinical significance of these findings in relation to the low plasma levels (see Pharmacokinetics) is not known. The precise mechanism through which fluticasone propionate affects allergic rhinitis symptoms is not known. Corticosteroids have been shown to have a wide range of effects on multiple cell types (e.g., mast cells, eosinophils, neutrophils, macrophages, and lymphocytes) and mediators (e.g., histamine, eicosanoids, leukotrienes, and cytokines) involved in inflammation. In 7 trials in adults, fluticasone nasal spray has decreased nasal mucosal eosinophils in 66% (35% for placebo) of patients and basophils in 39% (28% for placebo) of patients. The direct relationship of these findings to long-term symptom relief is not known. Fluticasone nasal spray, like other corticosteroids, is an agent that does not have an immediate effect on allergic symptoms. A decrease in nasal symptoms has been noted in some patients 12 hours after initial treatment with fluticasone nasal spray. Maximum benefit may not be reached for several days. Similarly, when corticosteroids are discontinued, symptoms may not return for several days. ### Lotion/Spray The mechanism of the anti-inflammatory activity of the topical steroids, in general, is unclear. However, corticosteroids are thought to act by the induction of phospholipase A2 inhibitory proteins, collectively called lipocortins. It is postulated that these proteins control the biosynthesis of potent mediators of inflammation such as prostaglandins and leukotrienes by inhibiting the release of their common precursor, arachidonic acid. Arachidonic acid is released from membrane phospholipids by phospholipase A2. ## Structure The active component of fluticaasone 44 mcg inhalation aerosol, fluticasone 110 mcg inhalation aerosol, and fluticasone 220 mcg inhalation aerosol is fluticasone propionate, a corticosteroid having the chemical name S-(fluoromethyl) 6α,9-difluoro-11β,17-dihydroxy-16α-methyl-3-oxoandrosta-1,4-diene-17β-carbothioate, 17-propionate and the following chemical structure: ### Aerosol - Fluticasone propionate is a white powder with a molecular weight of 500.6, and the empirical formula is C25H31F3O5S. It is practically insoluble in water, freely soluble in dimethyl sulfoxide and dimethylformamide, and slightly soluble in methanol and 95% ethanol. - Fluticasone 44 mcg Inhalation Aerosol, fluticasone 110 mcg Inhalation Aerosol, and fluticasone 220 mcg inhalation aerosol are pressurized metered-dose aerosol units fitted with a counter. Fluticasone is intended for oral inhalation only. Each unit contains a microcrystalline suspension of fluticasone propionate (micronized) in propellant HFA-134a (1,1,1,2-tetrafluoroethane). It contains no other excipients. - After priming, each actuation of the inhaler delivers 50, 125, or 250 mcg of fluticasone propionate in 60 mg of suspension (for the 44-mcg product) or in 75 mg of suspension (for the 110- and 220-mcg products) from the valve. Each actuation delivers 44, 110, or 220 mcg of fluticasone propionate from the actuator. The actual amount of drug delivered to the lung may depend on patient factors, such as the coordination between the actuation of the device and inspiration through the delivery system. - Each 10.6-g canister (44 mcg) and each 12-g canister (110 and 220 mcg) provides 120 inhalations. - Fluticasone should be primed before using for the first time by releasing 4 test sprays into the air away from the face, shaking well for 5 seconds before each spray. In cases where the inhaler has not been used for more than 7 days or when it has been dropped, prime the inhaler again by shaking well for 5 seconds and releasing 1 test spray into the air away from the face. - This product does not contain any chlorofluorocarbon (CFC) as the propellant. ### Nasal Spray - Fluticasone propionate is a white powder with a molecular weight of 500.6, and the empirical formula is C25H31F3O5S. It is practically insoluble in water, freely soluble in dimethyl sulfoxide and dimethylformamide, and slightly soluble in methanol and 95% ethanol. - Fluticasone nasal spray, 50 mcg is an aqueous suspension of microfine fluticasone propionate for topical administration to the nasal mucosa by means of a metering, atomizing spray pump. Fluticasone nasal spray also contains microcrystalline cellulose and carboxymethylcellulose sodium, dextrose, 0.02% w/w benzalkonium chloride, polysorbate 80, and 0.25% w/w phenylethyl alcohol, and has a pH between 5 and 7. - It is necessary to prime the pump before first use or after a period of non-use (1 week or more). After initial priming (6 actuations), each actuation delivers 50 mcg of fluticasone propionate in 100 mg of formulation through the nasal adapter. Each 16-g bottle of fluticasone nasal spray provides 120 metered sprays. After 120 metered sprays, the amount of fluticasone propionate delivered per actuation may not be consistent and the unit should be discarded. ### Lotion/Spray - Fluticasone propionate is a white to off-white powder with a molecular weight of 500.6. It is practically insoluble in water, freely soluble in dimethyl sulfoxide and dimethylformamide, and slightly soluble in methanol and 95% ethanol. - Each gram of fluticasone contains 0.5mg fluticasone propionate in a base of cetostearyl alcohol, isopropyl myristate, propylene glycol, cetomacrogol 1000, dimethicone 350, citric acid, sodium citrate, and purified water, with imidurea, methylparaben, and propylparaben as preservatives. ## Pharmacodynamics ### Aerosol - Serum cortisol concentrations, urinary excretion of cortisol, and urine 6-β-hydroxycortisol excretion collected over 24 hours in 24 healthy subjects following 8 inhalations of fluticasone propionate HFA 44, 110, and 220 mcg decreased with increasing dose. However, in patients with asthma treated with 2 inhalations of fluticasone propionate HFA 44, 110, and 220 mcg twice daily for at least 4 weeks, differences in serum cortisol AUC(0-12 h) (n = 65) and 24-hour urinary excretion of cortisol (n = 47) compared with placebo were not related to dose and generally not significant. In the study with healthy volunteers, the effect of propellant was also evaluated by comparing results following the 220-mcg strength inhaler containing HFA 134a propellant with the same strength of inhaler containing CFC 11/12 propellant. A lesser effect on the HPA axis with the HFA formulation was observed for serum cortisol, but not urine cortisol and 6-betahydroxy cortisol excretion. In addition, in a crossover study of children with asthma aged 4 to 11 years (N = 40), 24-hour urinary excretion of cortisol was not affected after a 4-week treatment period with 88 mcg of fluticasone propionate HFA twice daily compared with urinary excretion after the 2-week placebo period. The ratio (95% CI) of urinary excretion of cortisol over 24 hours following fluticasone propionate HFA versus placebo was 0.987 (0.796, 1.223). - The potential systemic effects of fluticasone propionate HFA on the HPA axis were also studied in patients with asthma. Fluticasone propionate given by inhalation aerosol at dosages of 440 or 880 mcg twice daily was compared with placebo in oral corticosteroid-dependent patients with asthma (range of mean dose of prednisone at baseline: 13 to 14 mg/day) in a 16-week study. Consistent with maintenance treatment with oral corticosteroids, abnormal plasma cortisol responses to short cosyntropin stimulation (peak plasma cortisol less than 18 mcg/dL) were present at baseline in the majority of patients participating in this study (69% of patients later randomized to placebo and 72% to 78% of patients later randomized to fluticasone propionate HFA). At week 16, 8 patients (73%) on placebo compared with 14 (54%) and 13 (68%) patients receiving fluticasone propionate HFA (440 and 880 mcg twice daily, respectively) had post-stimulation cortisol levels of less than 18 mcg/dL. ### Nasal Spray - In a trial to evaluate the potential systemic and topical effects of fluticasone nasal spray on allergic rhinitis symptoms, the benefits of comparable drug blood levels produced by fluticasone nasal spray and oral fluticasone propionate were compared. The dosages used were 200 mcg of Fluticasone nasal spray, the nasal spray vehicle (plus oral placebo), and 5 and 10 mg of oral fluticasone propionate (plus nasal spray vehicle) per day for 14 days. Plasma levels were undetectable in the majority of patients after intranasal dosing, but present at low levels in the majority after oral dosing. Fluticasone nasal spray was significantly more effective in reducing symptoms of allergic rhinitis than either the oral fluticasone propionate or the nasal vehicle. This trial demonstrated that the therapeutic effect of fluticasone nasal spray can be attributed to the topical effects of fluticasone propionate. - In another trial, the potential systemic effects of fluticasone nasal spray on the hypothalamic-pituitary-adrenal (HPA) axis were also studied in allergic patients. Fluticasone nasal spray given as 200 mcg once daily or 400 mcg twice daily was compared with placebo or oral prednisone 7.5 or 15 mg given in the morning. Fluticasone nasal spray at either dosage for 4 weeks did not affect the adrenal response to 6-hour cosyntropin stimulation, while both dosages of oral prednisone significantly reduced the response to cosyntropin. ### Lotion/Spray - Like other topical corticosteroids, fluticasone propionate has anti-inflammatory, antipruritic, and vasoconstrictive properties. - Although fluticasone propionate has a weak affinity for the progesterone receptor and virtually no affinity for the mineralocorticoid, estrogen or androgen receptors, the clinical relevance as related to safety is unknown. Fluticasone propionate is lipophilic and has strong affinity for the glucocorticoid receptor. The therapeutic potency of glucocorticoids is related to the half-life of the glucocorticoid receptor complex. The half-life of the fluticasone propionate-glucocorticoid receptor complex is approximately 10 hours. ## Pharmacokinetics ### Aerosol - Absorption: Fluticasone propionate acts locally in the lung; therefore, plasma levels do not predict therapeutic effect. Studies using oral dosing of labeled and unlabeled drug have demonstrated that the oral systemic bioavailability of fluticasone propionate is negligible (less than 1%), primarily due to incomplete absorption and presystemic metabolism in the gut and liver. In contrast, the majority of the fluticasone propionate delivered to the lung is systemically absorbed. - Distribution: Following intravenous administration, the initial disposition phase for fluticasone propionate was rapid and consistent with its high lipid solubility and tissue binding. The volume of distribution averaged 4.2 L/kg. - Metabolism: The total clearance of fluticasone propionate is high (average, 1,093 mL/min), with renal clearance accounting for less than 0.02% of the total. The only circulating metabolite detected in man is the 17β-carboxylic acid derivative of fluticasone propionate, which is formed through the CYP 3A4 pathway. This metabolite had less affinity (approximately 1/2,000) than the parent drug for the corticosteroid receptor of human lung cytosol in vitro and negligible pharmacological activity in animal studies. Other metabolites detected in vitro using cultured human hepatoma cells have not been detected in man. - Elimination: Following intravenous dosing, fluticasone propionate showed polyexponential kinetics and had a terminal elimination half-life of approximately 7.8 hours. Less than 5% of a radiolabeled oral dose was excreted in the urine as metabolites, with the remainder excreted in the feces as parent drug and metabolites. ### =Pediatrics - A population pharmacokinetic analysis was performed for fluticasone using steady-state data from 4 controlled clinical trials and single-dose data from 1 controlled clinical trial. The combined cohort for analysis included 269 patients (161 males and 108 females) with asthma aged 6 months to 66 years who received treatment with fluticasone. Most of these subjects (n = 215) were treated with fluticasone 44 mcg given as 88 mcg twice daily. Fluticasone was delivered using an AeroChamber Plus VHC with a mask to patients aged younger than 4 years. Data from adult patients with asthma following fluticasone 110 mcg given as 220 mcg twice daily (n = 15) and following fluticasone 220 mcg given as 440 mcg twice daily (n = 17) at steady state were also included. Data for 22 patients came from a single-dose crossover study of 264 mcg (6 doses of fluticasone 44 mcg) with and without AeroChamber Plus VHC in children with asthma aged 4 to 11 years. - Stratification of exposure data following fluticasone 88 mcg by age and study indicated that systemic exposure to fluticasone propionate at steady state was similar in children aged 6 to younger than 12 months, children aged 1 to younger than 4 years, and adults and adolescents aged 12 years and older. Exposure was lower in children aged 4 to 11 years, who did not use a VHC, as shown in Table 4. - The lower exposure to fluticasone propionate in children aged 4 to 11 years who did not use a VHC may reflect the inability to coordinate actuation and inhalation of the metered-dose inhaler. The impact of the use of a VHC on exposure to fluticasone propionate in patients aged 4 to 11 years was evaluated in a single-dose crossover study with fluticasone 44 mcg given as 264 mcg. In this study, use of a VHC increased systemic exposure to fluticasone propionate (table below), possibly correcting for the inability to coordinate actuation and inhalation. - There was a dose-related increase in systemic exposure in patients aged 12 years and older receiving higher doses of fluticasone propionate (220 and 440 mcg twice daily). The AUC0-τ in pgh/mL was 358 (95% CI: 272, 473) and 640 (95% CI: 477, 858), and Cmax in pg/mL was 47.3 (95% CI: 37, 61) and 87 (95% CI: 68, 112) following fluticasone propionate 220 and 440 mcg, respectively. ### Nasal Spray - Absorption: The activity of fluticasone nasal spray is due to the parent drug, fluticasone propionate. Indirect calculations indicate that fluticasone propionate delivered by the intranasal route has an absolute bioavailability averaging less than 2%. After intranasal treatment of patients with allergic rhinitis for 3 weeks, fluticasone propionate plasma concentrations were above the level of detection (50 pg/mL) only when recommended doses were exceeded and then only in occasional samples at low plasma levels. Due to the low bioavailability by the intranasal route, the majority of the pharmacokinetic data was obtained via other routes of administration. Studies using oral dosing of radiolabeled drug have demonstrated that fluticasone propionate is highly extracted from plasma and absorption is low. Oral bioavailability is negligible, and the majority of the circulating radioactivity is due to an inactive metabolite. - Distribution: Following intravenous administration, the initial disposition phase for fluticasone propionate was rapid and consistent with its high lipid solubility and tissue binding. The volume of distribution averaged 4.2 L/kg. - Metabolism: The total blood clearance of fluticasone propionate is high (average, 1,093 mL/min), with renal clearance accounting for less than 0.02% of the total. The only circulating metabolite detected in man is the 17β-carboxylic acid derivative of fluticasone propionate, which is formed through the cytochrome P450 3A4 pathway. This inactive metabolite had less affinity (approximately 1/2,000) than the parent drug for the glucocorticoid receptor of human lung cytosol in vitro and negligible pharmacological activity in animal studies. Other metabolites detected in vitro using cultured human hepatoma cells have not been detected in man. - Elimination: Following intravenous dosing, fluticasone propionate showed polyexponential kinetics and had a terminal elimination half-life of approximately 7.8 hours. Less than 5% of a radiolabeled oral dose was excreted in the urine as metabolites, with the remainder excreted in the feces as parent drug and metabolites. ### Lotion/Spray - Absorption: The extent of percutaneous absorption of topical corticosteroids is determined by many factors, including the vehicle and the integrity of the epidermal barrier. Occlusive dressing enhances penetration. Topical corticosteroids can be absorbed from normal intact skin. Inflammation and/or other disease processes in the skin increase percutaneous absorption. - Distribution: Following intravenous administration of 1 mg of fluticasone propionate in healthy volunteers, the initial disposition phase for fluticasone propionate was rapid and consistent with its high lipid solubility and tissue binding. The apparent volume of distribution averaged 4.2 L/kg (range, 2.3 to 16.7 L/kg). The percentage of fluticasone propionate bound to human plasma proteins averaged 91%. Fluticasone propionate is weakly and reversibly bound to erythrocytes. Fluticasone propionate is not significantly bound to human transcortin. - Metabolism: No metabolites of fluticasone propionate were detected in an in vitro study of radiolabeled fluticasone propionate incubated in a human skin homogenate. The total blood clearance of systemically absorbed fluticasone propionate averages 1093 mL/min (range, 618 to 1702 mL/min) after a 1-mg intravenous dose, with renal clearance accounting for less than 0.02% of the total. - Excretion: Following an intravenous dose of 1 mg in healthy volunteers, fluticasone propionate showed polyexponential kinetics and had an average terminal half-life of 7.2 hours (range, 3.2 to 11.2 hours). Plasma fluticasone levels were measured in patients 2 years - 6 years of age in an HPA axis suppression study. A total of 13 (62%) of 21 patients tested had measurable fluticasone at the end of 3 - 4 weeks of treatment. The mean ± SD fluticasone plasma values for patients aged under 3 years was 47.7 ± 31.7 pg/mL and 175.5 ± 243.6 pg/mL. Three patients had fluticasone levels over 300 pg/mL, with one of these having a level of 819.81 pg/mL. No data was obtained for patients < 2 years of age. ## Nonclinical Toxicology ### Aerosol - Fluticasone propionate demonstrated no tumorigenic potential in mice at oral doses up to 1,000 mcg/kg (approximately 2 and 10 times the MRHD for adults and children aged 4 to 11 years, respectively, on a mg/m2 basis) for 78 weeks or in rats at inhalation doses up to 57 mcg/kg (approximately 0.3 times and approximately equivalent to the MRHD for adults and children aged 4 to 11 years, respectively, on a mg/m2 basis) for 104 weeks. - Fluticasone propionate did not induce gene mutation in prokaryotic or eukaryotic cells in vitro. No significant clastogenic effect was seen in cultured human peripheral lymphocytes in vitro or in the in vivo mouse micronucleus test. - No evidence of impairment of fertility was observed in reproductive studies conducted in male and female rats at subcutaneous doses up to 50 mcg/kg (approximately 0.2 times the MRHD for adults on a mg/m2 basis). Prostate weight was significantly reduced at a subcutaneous dose of 50 mcg/kg. - Reproductive Toxicology: Subcutaneous studies in mice and rats at 45 and 100 mcg/kg (approximately 0.1 and 0.5 times the MRHD for adults on a mg/m2 basis, respectively) revealed fetal toxicity characteristic of potent corticosteroid compounds, including embryonic growth retardation, omphalocele, cleft palate, and retarded cranial ossification. - In rabbits, fetal weight reduction and cleft palate were observed at a subcutaneous dose of 4 mcg/kg (approximately 0.04 times the MRHD for adults on a mg/m2 basis). However, no teratogenic effects were reported at oral doses up to 300 mcg/kg (approximately 3 times the MRHD for adults on a mg/m2 basis) of fluticasone propionate. No fluticasone propionate was detected in the plasma in this study, consistent with the established low bioavailability following oral administration. - Fluticasone propionate crossed the placenta following subcutaneous administration to mice and rats and oral administration to rabbits. - In animals and humans, propellant HFA-134a was found to be rapidly absorbed and rapidly eliminated, with an elimination half-life of 3 to 27 minutes in animals and 5 to 7 minutes in humans. Time to maximum plasma concentration (Tmax) and mean residence time are both extremely short, leading to a transient appearance of HFA-134a in the blood with no evidence of accumulation. - Propellant HFA-134a is devoid of pharmacological activity except at very high doses in animals (i.e., 380 to 1,300 times the maximum human exposure based on comparisons of AUC values), primarily producing ataxia, tremors, dyspnea, or salivation. These events are similar to effects produced by the structurally related CFCs, which have been used extensively in metered-dose inhalers. - Fluticasone propionate demonstrated no tumorigenic potential in mice at oral doses up to 1,000 mcg/kg (approximately 20 times the maximum recommended daily intranasal dose in adults and approximately 10 times the maximum recommended daily intranasal dose in children on a mcg/m2 basis) for 78 weeks or in rats at inhalation doses up to 57 mcg/kg (approximately 2 times the maximum recommended daily intranasal dose in adults and approximately equivalent to the maximum recommended daily intranasal dose in children on a mcg/m2 basis) for 104 weeks. - Fluticasone propionate did not induce gene mutation in prokaryotic or eukaryotic cells in vitro. No significant clastogenic effect was seen in cultured human peripheral lymphocytes in vitro or in the mouse micronucleus test. - No evidence of impairment of fertility was observed in reproductive studies conducted in male and female rats at subcutaneous doses up to 50 mcg/kg (approximately 2 times the maximum recommended daily intranasal dose in adults on a mcg/m2 basis). Prostate weight was significantly reduced at a subcutaneous dose of 50 mcg/kg. - In an oral (gavage) mouse carcinogenicity study, doses of 0.1, 0.3 and 1 mg/kg/day fluticasone propionate were administered to mice for 18 months. Fluticasone propionate demonstrated no tumorigenic potential at oral doses up to 1 mg/kg/day (less than the MRHD in adults based on body surface area comparisons) in this study. - In a dermal mouse carcinogenicity study, 0.05% fluticasone propionate ointment (40 μl) was topically administered for 1, 3 or 7 days/week for 80 weeks. Fluticasone propionate demonstrated no tumorigenic potential at dermal doses up to 6.7 μg/kg/day (less than the MRHD in adults based on body surface area comparisons) in this study. - In a 52 week dermal photo-carcinogenicity study conducted in hairless albino mice with concurrent exposure to low level ultraviolet radiation (40 weeks of treatment followed by 12 weeks of observation), topically treated lotion vehicle animals and 0.05% fluticasone propionate lotion animals demonstrated shorter time to benign skin tumor formation compared to untreated control animals. Lotion vehicle treated animals developed benign skin tumors in a shorter time than 0.05% fluticasone propionate lotion treated animals. Although applicability of results to clinical use of fluticasone in humans is unknown, and enhanced tumor growth in patients treated with fluticasone has not been reported, patients should exercise general precautions in minimizing UV light exposure by avoiding excessive or unnecessary exposure to either natural or artificial sunlight (including sunbathing, tanning booths, sun lamps, etc.) - Fluticasone propionate revealed no evidence of mutagenic or clastogenic potential based on the results of five in vitro genotoxicity tests (Ames assay, E. coli fluctuation test, S. cerevisiae gene conversion test, Chinese hamster ovary cell chromosome aberration assay and human lymphocyte chromosome aberration assay) and one in vivo genotoxicity test (mouse micronucleus assay). - No evidence of impairment of fertility or effect on mating performance was observed in a fertility and general reproductive performance study conducted in male and female rats at subcutaneous doses up to 50 μg/kg/day (less than the MRHD in adults based on body surface area comparisons). # Clinical Studies ### Aerosol Three randomized, double-blind, parallel-group, placebo-controlled, US clinical trials were conducted in 980 adult and adolescent patients (aged 12 years and older) with asthma to assess the efficacy and safety of fluticasone in the treatment of asthma. Fixed dosages of 88, 220, and 440 mcg twice daily (each dose administered as 2 inhalations of the 44-, 110-, and 220-mcg strengths, respectively) and 880 mcg twice daily (administered as 4 inhalations of the 220-mcg strength) were compared with placebo to provide information about appropriate dosing to cover a range of asthma severity. Patients in these studies included those inadequately controlled with bronchodilators alone (Study 1), those already receiving inhaled corticosteroids (Study 2), and those requiring oral corticosteroid therapy (Study 3). In all 3 studies, patients (including placebo-treated patients) were allowed to use albuterol inhalation aerosol as needed for relief of acute asthma symptoms. In Studies 1 and 2, other maintenance asthma therapies were discontinued. - Study 1 enrolled 397 patients with asthma inadequately controlled on bronchodilators alone. Fluticasone was evaluated at dosages of 88, 220, and 440 mcg twice daily for 12 weeks. Baseline FEV1 values were similar across groups (mean 67% of predicted normal). All 3 dosages of Fluticasone demonstrated a statistically significant improvement in lung function as measured by improvement in AM pre-dose FEV1 compared with placebo. This improvement was observed after the first week of treatment, and was maintained over the 12-week treatment period. - At Endpoint (last observation), mean change from baseline in AM pre-dose percent predicted FEV1 was greater in all 3 groups treated with fluticasone (9.0% to 11.2%) compared with the placebo group (3.4%). The mean differences between the groups treated with fluticasone 88, 220, and 440 mcg and the placebo group were statistically significant, and the corresponding 95% confidence intervals were (2.2%, 9.2%), (2.8%, 9.9%), and (4.3%, 11.3%), respectively. - The figure below displays results of pulmonary function tests (mean percent change from baseline in FEV1 prior to AM dose) for the recommended starting dosage of fluticasone (88 mcg twice daily) and placebo from Study 1. This trial used predetermined criteria for lack of efficacy (indicators of worsening asthma), resulting in withdrawal of more patients in the placebo group. Therefore, pulmonary function results at Endpoint (the last evaluable FEV1 result, including most patients’ lung function data) are also displayed. Figure: A 12-Week Clinical Trial in Patients Aged 12 Years and Older Inadequately Controlled on Bronchodilators Alone: Mean Percent Change From Baseline in FEV1 Prior to AM Dose (Study 1) - In Study 2, fluticasone at dosages of 88, 220, and 440 mcg twice daily was evaluated over 12 weeks of treatment in 415 patients with asthma who were already receiving an inhaled corticosteroid at a daily dose within its recommended dose range in addition to as-needed albuterol. Baseline FEV1 values were similar across groups (mean 65% to 66% of predicted normal). All 3 dosages of fluticasone demonstrated a statistically significant improvement in lung function, as measured by improvement in FEV1, compared with placebo. This improvement was observed after the first week of treatment and was maintained over the 12-week treatment period. Discontinuations from the study for lack of efficacy (defined by a pre-specified decrease in FEV1 or PEF, or an increase in use of albuterol or nighttime awakenings requiring treatment with albuterol) were lower in the groups treated with fluticasone (6% to 11%) compared with placebo (50%). - At Endpoint (last observation), mean change from baseline in AM pre-dose percent predicted FEV1 was greater in all 3 groups treated with fluticasone (2.2% to 4.6%) compared with the placebo group (-8.3%). The mean differences between the groups treated with fluticasone 88, 220, and 440 mcg and the placebo group were statistically significant, and the corresponding 95% confidence intervals were (7.1%, 13.8%), (8.2%, 14.9%), and (9.6%, 16.4%), respectively. - Figure 2 displays the mean percent change from baseline in FEV1 from Week 1 through Week 12. This study also used predetermined criteria for lack of efficacy, resulting in withdrawal of more patients in the placebo group; therefore, pulmonary function results at Endpoint are also displayed. Figure: A 12-Week Clinical Trial in Patients Aged 12 Years and Older Already Receiving Daily Inhaled Corticosteroids: Mean Percent Change From Baseline in FEV1 Prior to AM Dose (Study 2) In both studies, use of albuterol, AM and PM PEF, and asthma symptom scores showed numerical improvement with fluticasone compared with placebo. - Study 3 enrolled 168 patients with asthma requiring oral prednisone therapy (average baseline daily prednisone dose ranged from 13 to 14 mg). Fluticasone at dosages of 440 and 880 mcg twice daily was evaluated over a 16-week treatment period. Baseline FEV1 values were similar across groups (mean 59% to 62% of predicted normal). Over the course of the study, patients treated with either dosage of fluticasone required a statistically significantly lower mean daily oral prednisone dose (6 mg) compared with placebo-treated patients (15 mg). Both dosages of fluticasone enabled a larger percentage of patients (59% and 56% in the groups treated with fluticasone 440 and 880 mcg, respectively, twice daily) to eliminate oral prednisone as compared with placebo (13%). There was no efficacy advantage of fluticasone 880 mcg twice daily compared with 440 mcg twice daily. Accompanying the reduction in oral corticosteroid use, patients treated with either dosage of fluticasone had statistically significantly improved lung function, fewer asthma symptoms, and less use of albuterol inhalation aerosol compared with the placebo-treated patients. Figure: A 16-Week Clinical Trial in Patients Aged 12 Years and Older Requiring Chronic Oral Prednisone Therapy: Change in Maintenance Prednisone Dose - Two long-term safety studies (Study 4 and Study 5) of ≥6 months’ duration were conducted in 507 adult and adolescent patients with asthma. Study 4 was designed to monitor the safety of 2 doses of fluticasone, while Study 5 compared fluticasone propionate HFA with fluticasone propionate CFC. Study 4 enrolled 182 patients who were treated daily with low to high doses of inhaled corticosteroids, beta-agonists (short-acting or long-acting), theophylline, inhaled cromolyn or nedocromil sodium, leukotriene receptor antagonists, or 5-lipoxygenase inhibitors at baseline. Fluticasone at dosages of 220 and 440 mcg twice daily was evaluated over a 26-week treatment period in 89 and 93 patients, respectively. - Study 5 enrolled 325 patients who were treated daily with moderate to high doses of inhaled corticosteroids, with or without concurrent use of salmeterol or albuterol, at baseline. Fluticasone propionate HFA at a dosage of 440 mcg twice daily and fluticasone propionate CFC at a dosage of 440 mcg twice daily were evaluated over a 52-week treatment period in 163 and 162 patients, respectively. Baseline FEV1 values were similar across groups (mean 81% to 84% of predicted normal). Throughout the 52-week treatment period, asthma control was maintained with both formulations of fluticasone propionate compared with baseline. In both studies, none of the patients were withdrawn due to lack of efficacy. ### Pediatric Patients Aged 4 to 11 Years A 12-week clinical trial conducted in 241 pediatric patients with asthma was supportive of efficacy but inconclusive due to measurable levels of fluticasone propionate in 6/48 (13%) of the plasma samples from patients randomized to placebo. Efficacy in patients aged 4 to 11 years is extrapolated from adult data with fluticasone and other supporting data ### Nasal Spray - A total of 13 randomized, double-blind, parallel-group, multicenter, vehicle placebo-controlled clinical trials were conducted in the United States in adults and pediatric patients (4 years of age and older) to investigate regular use of fluticasone nasal spray in patients with seasonal or perennial allergic rhinitis. The trials included 2,633 adults (1,439 men and 1,194 women) with a mean age of 37 (range, 18 to 79 years). A total of 440 adolescents (405 boys and 35 girls), mean age of 14 (range, 12 to 17 years), and 500 children (325 boys and 175 girls), mean age of 9 (range, 4 to 11 years) were also studied. The overall racial distribution was 89% white, 4% black, and 7% other. These trials evaluated the total nasal symptom scores (TNSS) that included rhinorrhea, nasal obstruction, sneezing, and nasal itching in known allergic patients who were treated for 2 to 24 weeks. Subjects treated with fluticasone nasal spray exhibited significantly greater decreases in TNSS than vehicle placebo-treated patients. Nasal mucosal basophils and eosinophils were also reduced at the end of treatment in adult studies; however, the clinical significance of this decrease is not known. - There were no significant differences between fluticasone propionate regimens whether administered as a single daily dose of 200 mcg (two 50-mcg sprays in each nostril) or as 100 mcg (one 50-mcg spray in each nostril) twice daily in 6 clinical trials. A clear dose response could not be identified in clinical trials. In 1 trial, 200 mcg/day was slightly more effective than 50 mcg/day during the first few days of treatment; thereafter, no difference was seen. - Two randomized, double-blind, parallel-group, multicenter, vehicle placebo-controlled 28-day trials were conducted in the United States in 732 patients (243 given fluticasone nasal spray) 12 years of age and older to investigate “as-needed” use of fluticasone nasal spray (200 mcg) in patients with seasonal allergic rhinitis. Patients were instructed to take the study medication only on days when they thought they needed the medication for symptom control, not to exceed 2 sprays per nostril on any day, and not more than once daily. “As-needed” use was prospectively defined as average use of study medication no more than 75% of study days. Average use of study medications was 57% to 70% of days for all treatment arms. The studies demonstrated significantly greater reduction in TNSS (sum of nasal congestion, rhinorrhea, sneezing, and nasal itching) with fluticasone nasal spray 200 mcg compared to placebo. The relative difference in efficacy with as-needed use as compared to regularly administered doses was not studied. - Three randomized, double-blind, parallel-group, vehicle placebo-controlled trials were conducted in 1,191 patients to investigate regular use of fluticasone nasal spray in patients with perennial nonallergic rhinitis. These trials evaluated the patient-rated TNSS (nasal obstruction, postnasal drip, rhinorrhea) in patients treated for 28 days of double-blind therapy and in 1 of the 3 trials for 6 months of open-label treatment. Two of these trials demonstrated that patients treated with fluticasone nasal spray at a dosage of 100 mcg twice daily exhibited statistically significant decreases in TNSS compared with patients treated with vehicle. - Patients should use fluticasone nasal spray at regular intervals for optimal effect. - Adult patients may be started on a 200-mcg once-daily regimen (two 50-mcg sprays in each nostril once daily). An alternative 200-mcg/day dosage regimen can be given as 100 mcg twice daily (one 50-mcg spray in each nostril twice daily). - Individual patients will experience a variable time to onset and different degree of symptom relief. In 4 randomized, double-blind, vehicle placebo-controlled, parallel-group allergic rhinitis studies and 2 studies of patients in an outdoor “park” setting (park studies), a decrease in nasal symptoms in treated subjects compared to placebo was shown to occur as soon as 12 hours after treatment with a 200-mcg dose of fluticasone nasal spray. Maximum effect may take several days. Regular-use patients who have responded may be able to be maintained (after 4 to 7 days) on 100 mcg/day (1 spray in each nostril once daily). - Some patients (12 years of age and older) with seasonal allergic rhinitis may find as-needed use of fluticasone nasal spray (not to exceed 200 mcg daily) effective for symptom control. Greater symptom control may be achieved with scheduled regular use. Efficacy of as-needed use of fluticasone nasal spray has not been studied in pediatric patients under 12 years of age with seasonal allergic rhinitis, or patients with perennial allergic or nonallergic rhinitis. - Pediatric patients (4 years of age and older) should be started with 100 mcg (1 spray in each nostril once daily). Treatment with 200 mcg (2 sprays in each nostril once daily or 1 spray in each nostril twice daily) should be reserved for pediatric patients not adequately responding to 100 mcg daily. Once adequate control is achieved, the dosage should be decreased to 100 mcg (1 spray in each nostril) daily. - Maximum total daily doses should not exceed 2 sprays in each nostril (total dose, 200 mcg/day). There is no evidence that exceeding the recommended dose is more effective. ### Lotion/Cream Fluticasone applied once daily was superior to vehicle in the treatment of atopic dermatitis in two studies. The two studies enrolled 438 patients with atopic dermatitis aged 3 months and older, of which 169 patients were selected as having clinically significant- signs of erythema, infiltration/papulation and erosion/oozing/crusting at baseline. Table 1 presents the percentage of patients who completely cleared of erythema, infiltration/papulation and erosion/oozing/crusting at Week 4 out of those patients with clinically significant baseline signs. # How Supplied - Flovent HFA 44 mcg Inhalation Aerosol is supplied in 10.6-g pressurized aluminum canisters containing 120 metered inhalations in boxes of 1 with patient instructions (NDC 0173-0718-20). - Flovent HFA 110 mcg Inhalation Aerosol is supplied in 12-g pressurized aluminum canisters containing 120 metered inhalations in boxes of 1 with patient instructions (NDC 0173-0719-20). - Flovent HFA 220 mcg Inhalation Aerosol is supplied in 12-g pressurized aluminum canisters containing 120 metered inhalations in boxes of 1 with patient instructions (NDC 0173-0720-20). - Each canister is fitted with a counter and a dark orange oral actuator with a peach strapcap. The dark orange actuator supplied with FLOVENT HFA should not be used with any other product canisters, and actuators from other products should not be used with a FLOVENT HFA canister. - The correct amount of medication in each inhalation cannot be assured after the counter reads 000, even though the canister is not completely empty and will continue to operate. The inhaler should be discarded when the counter reads 000. - Keep out of reach of children. Avoid spraying in eyes. - Contents Under Pressure: Do not puncture. Do not use or store near heat or open flame. Exposure to temperatures above 120°F may cause bursting. Never throw into fire or incinerator. - Fluticasone nasal Spray, 50 mcg is supplied in an amber glass bottle fitted with a white metering atomizing pump, white nasal adapter, and green dust cover in a box of 1 (NDC 0173-0453-01) with patient’s instructions for use. - Each bottle contains a net fill weight of 16 g and will provide 120 actuations. - Each actuation delivers 50 mcg of fluticasone propionate in 100 mg of formulation through the nasal adapter. - The correct amount of medication in each spray cannot be assured after 120 sprays even though the bottle is not completely empty. - The bottle should be discarded when the labeled number of actuations has been used. Fluticasone is supplied in: - 60 mL bottle NDC 10337-434-60 - 120 mL bottle NDC 10337-434-04 ## Storage - Store at 25°C (77°F); excursions permitted from 15° to 30°C (59° to 86°F). - Store the inhaler with the mouthpiece down. - For best results, the inhaler should be at room temperature before use. - Store between 4° and 30°C (39° and 86°F). - Store between 15° and 30°C (59° and 86°F). Do not refrigerate. - Keep container tightly sealed. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information ### Aerosol Patients should be advised that localized infections with Candida albicans have occurred in the mouth and pharynx in some patients. If oropharyngeal candidiasis develops, it should be treated with appropriate local or systemic (i.e., oral antifungal) therapy while still continuing therapy with fluticasone, but at times therapy with fluticasone may need to be temporarily interrupted under close medical supervision. Rinsing the mouth after inhalation is advised. Patients should be advised that fluticasone is not a bronchodilator and is not intended for use as rescue medication for acute asthma exacerbations. Acute asthma symptoms should be treated with an inhaled, short-acting beta2-agonist such as albuterol. Patients should be instructed to contact their physicians immediately if there is deterioration of their asthma. Patients who are on immunosuppressant doses of corticosteroids should be warned to avoid exposure to chickenpox or measles and if they are exposed to consult their physicians without delay. Patients should be informed of potential worsening of existing tuberculosis, fungal, bacterial, viral, or parasitic infections, or ocular herpes simplex. Patients should be advised that fluticasone may cause systemic corticosteroid effects of hypercorticism and adrenal suppression. Additionally, patients should be instructed that deaths due to adrenal insufficiency have occurred during and after transfer from systemic corticosteroids. Patients should taper slowly from systemic corticosteroids if transferring to fluticasone. Patients should be advised that hypersensitivity reactions including anaphylaxis, angioedema, urticaria, and bronchospasm may occur after administration of fluticasone. Patients should discontinue fluticasone if such reactions occur. Patients who are at an increased risk for decreased BMD should be advised that the use of corticosteroids may pose an additional risk. Patients should be informed that orally inhaled corticosteroids, including fluticasone, may cause a reduction in growth velocity when administered to pediatric patients. Physicians should closely follow the growth of children and adolescents taking corticosteroids by any route. Long-term use of inhaled corticosteroids may increase the risk of some eye problems (cataracts or glaucoma); regular eye examinations should be considered. Patients should use fluticasone at regular intervals as directed. Individual patients will experience a variable time to onset and degree of symptom relief and the full benefit may not be achieved until treatment has been administered for 1 to 2 weeks or longer. Patients should not increase the prescribed dosage but should contact their physicians if symptoms do not improve or if the condition worsens. Patients should be instructed not to stop use of fluticasone abruptly. Patients should contact their physicians immediately if they discontinue use of fluticasone. ### Nasal Spray - Patients being treated with fluticasone nasal spray should receive the following information and instructions. This information is intended to aid them in the safe and effective use of this medication. It is not a disclosure of all possible adverse or intended effects. - Patients should be warned to avoid exposure to chickenpox or measles and, if exposed, to consult their physician without delay. - Patients should use fluticasone nasal spray at regular intervals for optimal effect. Some patients (12 years of age and older) with seasonal allergic rhinitis may find as-needed use of 200 mcg once daily effective for symptom control. - A decrease in nasal symptoms may occur as soon as 12 hours after starting therapy with fluticasone nasal spray. Results in several clinical trials indicate statistically significant improvement within the first day or two of treatment; however, the full benefit of fluticasone nasal spray may not be achieved until treatment has been administered for several days. The patient should not increase the prescribed dosage but should contact the physician if symptoms do not improve or if the condition worsens. - For the proper use of fluticasone nasal spray and to attain maximum improvement, the patient should read and follow carefully the patient’s instructions accompanying the product. ### Lotion/Cream Patients using fluticasone should receive the following information and instructions: - Fluticasone is to be used as directed by the physician. It is for external use only. Avoid contact with the eyes. - Fluticasone should not be used for any disorder other than that for which it was prescribed. - The treated skin area should not be bandaged or otherwise covered or wrapped so as to be occlusive unless directed by the physician. - Patients should report to their physician any signs of local adverse reactions as well as non-healing or worsening of skin condition. - Parents of pediatric patients should be advised not to use this medication in the treatment of diaper dermatitis unless directed by the physician. Fluticasone should not be applied in the diaper areas as diapers or plastic pants may constitute occlusive dressing. - Fluticasone should not be used on the face, underarms, or groin areas unless directed by a physician. - Fluticasone therapy should be discontinued if control is achieved before 4 weeks. If no improvement is seen within 2 weeks, contact a physician. The safety of the use of fluticasone for longer than 4 weeks has not been established. - Patients should report to their physician if they are allergic to formaldehyde. - Patients that apply fluticasone to exposed portions of the body should follow physician advice and routine precautions to avoid excessive or unnecessary exposure to either natural or artificial sunlight (such as sunbathing, tanning booths, sun lamps, etc.). # Precautions with Alcohol Alcohol-Fluticasone interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - Cutivate - Flonase - Flovent - Flovent Rotadisk - Flovent HFA - Flovent Diskus # Look-Alike Drug Names - Flonase - Flovent # Drug Shortage Status Drug Shortage # Price	Fluticasone Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Alonso Alvarado, M.D. [2] # Disclaimer WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here. # Overview Fluticasone is a corticosteroid that is FDA approved for the treatment of asthma, management of the nasal symptoms of seasonal and perennial allergic rhinitis and nonallergic rhinitis, inflammatory and pruritic manifestations of atopic dermatitis. Common adverse reactions include candidiasis of mouth and esophagus, nausea and vomiting, osteoporosis, headache, cough, epistaxis, pharyngitis, sinusitis, throat irritation, upper respiratory infection. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) - Fluticasone should be administered by the orally inhaled route only in patients aged 4 years and older. Individual patients will experience a variable time to onset and degree of symptom relief. Maximum benefit may not be achieved for 1 to 2 weeks or longer after starting treatment. - After asthma stability has been achieved, it is always desirable to titrate to the lowest effective dosage to reduce the possibility of side effects. For patients who do not respond adequately to the starting dosage after 2 weeks of therapy, higher dosages may provide additional asthma control. The safety and efficacy of fluticasone when administered in excess of recommended dosages have not been established. - The recommended starting dosage and the highest recommended dosage of fluticasone, based on prior asthma therapy, are listed below: - Bronchodilators alone: Initial dose of 88 mcg twice daily to a maximum of 440 mcg twice daily. - Inhaled corticosteroids: Initial dose of 88-220 mcg twice dailya, to a maximum of 440 mcg twice daily. - Oral corticosteroidsb: Initial dose of 440 mcg twice daily, to a maximum of 880 mcg twice daily. a Starting dosages above 88 mcg twice daily may be considered for patients with poorer asthma control or those who have previously required doses of inhaled corticosteroids that are in the higher range for the specific agent. b For patients currently receiving chronic oral corticosteroid therapy, prednisone should be reduced no faster than 2.5 to 5 mg/day on a weekly basis beginning after at least 1 week of therapy with fluticasone. Patients should be carefully monitored for signs of asthma instability, including serial objective measures of airflow, and for signs of adrenal insufficiency. Once prednisone reduction is complete, the dosage of fluticasone should be reduced to the lowest effective dosage. Fluticasone should be primed before using for the first time by releasing 4 test sprays into the air away from the face, shaking well for 5 seconds before each spray. In cases where the inhaler has not been used for more than 7 days or when it has been dropped, prime the inhaler again by shaking well for 5 seconds and releasing 1 test spray into the air away from the face. - Dosing Information - The recommended starting dosage in adults is 2 sprays (50 mcg of fluticasone propionate each) in each nostril once daily (total daily dose, 200 mcg). The same dosage divided into 100 mcg given twice daily (e.g., 8 a.m. and 8 p.m.) is also effective. After the first few days, patients may be able to reduce their dosage to 100 mcg (1 spray in each nostril) once daily for maintenance therapy. Some patients (12 years of age and older) with seasonal allergic rhinitis may find as-needed use of 200 mcg once daily effective for symptom control. Greater symptom control may be achieved with scheduled regular use. - Dosing information - Apply a thin film of fluticasone to the affected skin areas once daily. Rub in gently. - As with other corticosteroids, therapy should be discontinued when control is achieved. If no improvement is seen within 2 weeks, reassessment of diagnosis may be necessary. The safety and efficacy of drug use for longer than 4 weeks have not been established. - Fluticasone should not be used with occlusive dressings or applied in the diaper area unless directed by a physician. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Fluticasone in adult patients. ### Non–Guideline-Supported Use - Dosing Information - 200 mcg twice daily.[1] # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) - Dosing Information: Pediatric patients (aged 4-11 years)c - The recommended starting dosage and the highest recommended dosage of fluticasone, based on prior asthma therapy: Initial dose of 88 mcg twice daily to a maximum of 88 mcg twice daily. c Recommended pediatric dosage is 88 mcg twice daily regardless of prior therapy. A valved holding chamber and mask may be used to deliver fluticasone to young patients. Fluticasone should be primed before using for the first time by releasing 4 test sprays into the air away from the face, shaking well for 5 seconds before each spray. In cases where the inhaler has not been used for more than 7 days or when it has been dropped, prime the inhaler again by shaking well for 5 seconds and releasing 1 test spray into the air away from the face. - Dosing Information - Patients should be started with 100 mcg (1 spray in each nostril once daily). Patients not adequately responding to 100 mcg may use 200 mcg (2 sprays in each nostril). Once adequate control is achieved, the dosage should be decreased to 100 mcg (1 spray in each nostril) daily. - The maximum total daily dosage should not exceed 2 sprays in each nostril (200 mcg/day). - Fluticasone nasal spray is not recommended for children under 4 years of age. - Dosing information - Apply a thin film of fluticasone to the affected skin areas once daily. Rub in gently. - As with other corticosteroids, therapy should be discontinued when control is achieved. If no improvement is seen within 2 weeks, reassessment of diagnosis may be necessary. The safety and efficacy of drug use for longer than 4 weeks have not been established. - Fluticasone should not be used with occlusive dressings or applied in the diaper area unless directed by a physician. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Fluticasone in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Fluticasone in pediatric patients. # Contraindications The use of fluticasone is contraindicated in the following conditions: - Primary treatment of status asthmaticus or other acute episodes of asthma where intensive measures are required. - Hypersensitivity to any of the ingredients in the formulation. # Warnings ### Aerosol In clinical studies, the development of localized infections of the mouth and pharynx with Candida albicans has occurred in patients treated with fluticasone. When such an infection develops, it should be treated with appropriate local or systemic (i.e., oral antifungal) therapy while treatment with fluticasone continues, but at times therapy with fluticasone may need to be interrupted. Patients should rinse the mouth after inhalation of fluticasone. Fluticasone is not to be regarded as a bronchodilator and is not indicated for rapid relief of bronchospasm. Patients should be instructed to contact their physicians immediately when episodes of asthma that are not responsive to bronchodilators occur during the course of treatment with fluticasone. During such episodes, patients may require therapy with oral corticosteroids. Persons who are using drugs that suppress the immune system are more susceptible to infections than healthy individuals. Chickenpox and measles, for example, can have a more serious or even fatal course in susceptible children or adults using corticosteroids. In such children or adults who have not had these diseases or been properly immunized, particular care should be taken to avoid exposure. How the dose, route, and duration of corticosteroid administration affect the risk of developing a disseminated infection is not known. The contribution of the underlying disease and/or prior corticosteroid treatment to the risk is also not known. If a patient is exposed to chickenpox, prophylaxis with varicella zoster immune globulin (VZIG) may be indicated. If a patient is exposed to measles, prophylaxis with pooled intramuscular immunoglobulin (IG) may be indicated. If chickenpox develops, treatment with antiviral agents may be considered. Because of the potential for worsening infections, inhaled corticosteroids should be used with caution, if at all, in patients with active or quiescent tuberculosis infection of the respiratory tract; untreated systemic fungal, bacterial, viral, or parasitic infections; or ocular herpes simplex. Particular care is needed for patients who have been transferred from systemically active corticosteroids to inhaled corticosteroids because deaths due to adrenal insufficiency have occurred in patients with asthma during and after transfer from systemic corticosteroids to less systemically available inhaled corticosteroids. After withdrawal from systemic corticosteroids, a number of months are required for recovery of hypothalamic-pituitary-adrenal (HPA) function. Patients requiring oral corticosteroids should be weaned slowly from systemic corticosteroid use after transferring to fluticasone. In a clinical trial of 168 patients, prednisone reduction was successfully accomplished by reducing the daily prednisone dose on a weekly basis following initiation of treatment with fluticasone. Successive reduction of prednisone dose was allowed only when lung function, symptoms, and as-needed short-acting beta-agonist use were better than or comparable to that seen before initiation of prednisone dose reduction. Lung function (forced expiratory volume in 1 second [FEV1] or morning peak expiratory flow [AM PEF]), beta-agonist use, and asthma symptoms should be carefully monitored during withdrawal of oral corticosteroids. In addition to monitoring asthma signs and symptoms, patients should be observed for signs and symptoms of adrenal insufficiency such as fatigue, lassitude, weakness, nausea and vomiting, and hypotension. Patients who have been previously maintained on 20 mg or more per day of prednisone (or its equivalent) may be most susceptible, particularly when their systemic corticosteroids have been almost completely withdrawn. During this period of HPA suppression, patients may exhibit signs and symptoms of adrenal insufficiency when exposed to trauma, surgery, or infection (particularly gastroenteritis) or other conditions associated with severe electrolyte loss. Although inhaled corticosteroids may provide control of asthma symptoms during these episodes, in recommended doses they supply less than normal physiological amounts of glucocorticoid (cortisol) systemically and do not provide the mineralocorticoid activity that is necessary for coping with these emergencies. During periods of stress or a severe asthma attack, patients who have been withdrawn from systemic corticosteroids should be instructed to resume oral corticosteroids immediately and to contact their physicians for further instruction. These patients should also be instructed to carry a warning card indicating that they may need supplementary systemic corticosteroids during periods of stress or a severe asthma attack. Transfer of patients from systemic corticosteroid therapy to fluticasone may unmask conditions previously suppressed by the systemic corticosteroid therapy (e.g., rhinitis, conjunctivitis, eczema, arthritis, eosinophilic conditions). Some patients may experience symptoms of systemically active corticosteroid withdrawal (e.g., joint and/or muscular pain, lassitude, and depression, despite maintenance or even improvement of respiratory function). Fluticasone propionate will often help control asthma symptoms with less suppression of HPA function than therapeutically equivalent oral doses of prednisone. Since fluticasone propionate is absorbed into the circulation and can be systemically active at higher doses, the beneficial effects of fluticasone in minimizing HPA dysfunction may be expected only when recommended dosages are not exceeded and individual patients are titrated to the lowest effective dose. A relationship between plasma levels of fluticasone propionate and inhibitory effects on stimulated cortisol production has been shown after 4 weeks of treatment with fluticasone propionate. Since individual sensitivity to effects on cortisol production exists, physicians should consider this information when prescribing fluticasone. Because of the possibility of systemic absorption of inhaled corticosteroids, patients treated with fluticasone should be observed carefully for any evidence of systemic corticosteroid effects. Particular care should be taken in observing patients postoperatively or during periods of stress for evidence of inadequate adrenal response. It is possible that systemic corticosteroid effects such as hypercorticism and adrenal suppression (including adrenal crisis) may appear in a small number of patients, particularly when fluticasone is administered at higher than recommended doses over prolonged periods of time. If such effects occur, the dosage of fluticasone should be reduced slowly, consistent with accepted procedures for reducing systemic corticosteroids and for management of asthma. Hypersensitivity reactions, including anaphylaxis, angioedema, urticaria, and bronchospasm, may occur after administration of fluticasone. Decreases in bone mineral density (BMD) have been observed with long-term administration of products containing inhaled corticosteroids. The clinical significance of small changes in BMD with regard to long-term outcomes is unknown. Patients with major risk factors for decreased bone mineral content, such as prolonged immobilization, family history of osteoporosis, postmenopausal status, tobacco use, advanced age, poor nutrition, or chronic use of drugs that can reduce bone mass (e.g., anticonvulsants, oral corticosteroids), should be monitored and treated with established standards of care. Orally inhaled corticosteroids may cause a reduction in growth velocity when administered to pediatric patients. Monitor the growth of pediatric patients receiving fluticasone routinely (e.g., via stadiometry). To minimize the systemic effects of orally inhaled corticosteroids, including fluticasone, titrate each patient’s dosage to the lowest dosage that effectively controls his/her symptoms. Glaucoma, increased intraocular pressure, and cataracts have been reported in patients following the long-term administration of inhaled corticosteroids, including fluticasone propionate. Therefore, close monitoring is warranted in patients with a change in vision or with a history of increased intraocular pressure, glaucoma, and/or cataracts. As with other inhaled medications, bronchospasm may occur with an immediate increase in wheezing after dosing. If bronchospasm occurs following dosing with fluticasone, it should be treated immediately with a fast-acting inhaled bronchodilator. Treatment with fluticasone should be discontinued immediately and alternative therapy instituted. The use of strong cytochrome P450 3A4 (CYP3A4) inhibitors (e.g., ritonavir, atazanavir, clarithromycin, indinavir, itraconazole, nefazodone, nelfinavir, saquinavir, ketoconazole, telithromycin) with fluticasone is not recommended because increased systemic corticosteroid adverse effects may occur. In rare cases, patients on inhaled fluticasone propionate may present with systemic eosinophilic conditions. Some of these patients have clinical features of vasculitis consistent with Churg-Strauss syndrome, a condition that is often treated with systemic corticosteroid therapy. These events usually, but not always, have been associated with the reduction and/or withdrawal of oral corticosteroid therapy following the introduction of fluticasone propionate. Cases of serious eosinophilic conditions have also been reported with other inhaled corticosteroid in this clinical setting. Physicians should be alert to eosinophilia, vasculitic rash, worsening pulmonary symptoms, cardiac complications, and/or neuropathy presenting in their patients. A causal relationship between fluticasone propionate and these underlying conditions has not been established. ### Spray - The replacement of a systemic corticosteroids with a topical corticosteroids can be accompanied by signs of adrenal insufficiency, and in addition some patients may experience symptoms of withdrawal, e.g., joint and/or muscular pain, lassitude, and depression. Patients previously treated for prolonged periods with systemic corticosteroids and transferred to topical corticosteroids should be carefully monitored for acute adrenal insufficiency in response to stress. In those patients who have asthma or other clinical conditions requiring long-term systemic corticosteroids treatment, too rapid a decrease in systemic corticosteroids may cause a severe exacerbation of their symptoms. - The concomitant use of intranasal corticosteroids with other inhaled corticosteroids could increase the risk of signs or symptoms of hypercorticism and/or suppression of the HPA axis. - A drug interaction study in healthy subjects has shown that ritonavir (a highly potent cytochrome P450 3A4 inhibitor) can significantly increase plasma fluticasone propionate exposure, resulting in significantly reduced serum cortisol concentrations. - Persons who are using drugs that suppress the immune system are more susceptible to infections than healthy individuals. Chickenpox and measles, for example, can have a more serious or even fatal course in susceptible children or adults using corticosteroids. In children or adults who have not had these diseases or been properly immunized, particular care should be taken to avoid exposure. How the dose, route, and duration of corticosteroid administration affect the risk of developing a disseminated infection is not known. The contribution of the underlying disease and/or prior corticosteroid treatment to the risk is also not known. If exposed to chickenpox, prophylaxis with varicella zoster immune globulin (VZIG) may be indicated. If exposed to measles, prophylaxis with pooled intramuscular immunoglobulin (IG) may be indicated. (See the respective package inserts for complete VZIG and IG prescribing information.) If chickenpox develops, treatment with antiviral agents may be considered. - Avoid spraying in eyes. ## Precautions ### Spray - Intranasal corticosteroids may cause a reduction in growth velocity when administered to pediatric patients. - Rarely, immediate hypersensitivity reactions or contact dermatitis may occur after the administration of fluticasone nasal spray. Rare instances of wheezing, nasal septum perforation, cataracts, glaucoma, and increased intraocular pressure have been reported following the intranasal application of corticosteroids, including fluticasone propionate. - Use of excessive doses of corticosteroids may lead to signs or symptoms of hypercorticism and/or suppression of HPA function. - Although systemic effects have been minimal with recommended doses of fluticasone nasal spray, potential risk increases with larger doses. Therefore, larger than recommended doses of fluticasone nasal spray should be avoided. - When used at higher than recommended doses or in rare individuals at recommended doses, systemic corticosteroid effects such as hypercorticism and adrenal suppression may appear. If such changes occur, the dosage of fluticasone nasal spray should be discontinued slowly consistent with accepted procedures for discontinuing oral corticosteroid therapy. - In clinical studies with fluticasone propionate administered intranasally, the development of localized infections of the nose and pharynx with Candida albicans has occurred only rarely. When such an infection develops, it may require treatment with appropriate local therapy and discontinuation of treatment with fluticasone nasal spray. Patients using fluticasone nasal spray over several months or longer should be examined periodically for evidence of Candida infection or other signs of adverse effects on the nasal mucosa. - Intranasal corticosteroids should be used with caution, if at all, in patients with active or quiescent tuberculous infections of the respiratory tract; untreated local or systemic fungal or bacterial infections; systemic viral or parasitic infections; or ocular herpes simplex. - Because of the inhibitory effect of corticosteroids on wound healing, patients who have experienced recent nasal septal ulcers, nasal surgery, or nasal trauma should not use a nasal corticosteroid until healing has occurred. ### Lotion/Cream - Fluticasone contains the excipient imidurea which releases formaldehyde as a breakdown product. Formaldehyde may cause allergic sensitization or irritation upon contact with the skin. Fluticasone should not be used in individuals with hypersensitivity to formaldehyde as it may prevent healing or worsen dermatitis. - Systemic absorption of topical corticosteroids can produce reversible hypothalamic-pituitary-adrenal axis (HPA) suppression with the potential for glucocorticosteroid insufficiency after withdrawal from treatment. Manifestations of Cushing's syndrome, hyperglycemia, and glucosuria can also be produced in some patients by systemic absorption of topical corticosteroids while on treatment. - Patients applying a potent topical steroid to a large surface area or to areas under occlusion should be evaluated periodically for evidence of HPA axis suppression. This may be done by using cosyntropin (ACTH1·24) stimulation testing. - Forty-two pediatric patients (4 months to < 6 years of age) with moderate to severe atopic eczema who were treated with fluticasone for at least 3-4 weeks were assessed for HPA axis suppression and 40 of these subjects applied at least 90% of applications. None of the 40 evaluable patients suppressed, where the sole criterion for HPA axis suppression is a plasma cortisol level of less than or equal to 18 micrograms per deciliter after cosyntropin stimulation. Although HPA axis suppression was observed in 0 of 40 pediatric patients (upper 95% confidence bound is 7.2%), the occurrence of HPA axis suppression in any patient and especially with longer use cannot be ruled out. In other studies with fluticasone propionate topical formulations, adrenal suppression has been observed. - If HPA axis suppression is noted, an attempt should be made to withdraw the drug, to reduce the frequency of application, or to substitute a less potent steroid. Recovery of HPA axis function is generally prompt upon discontinuation of topical corticosteroids. Infrequently, signs and symptoms of glucocorticosteroid insufficiency may occur requiring supplemental systemic corticosteroids. For information on systemic supplementation, see prescribing information for those products. - Pediatric patients may be more susceptible to systemic toxicity from equivalent doses due to their larger skin surface to body mass ratios. - The following local adverse reactions have been reported with topical corticosteroids, and they may occur more frequently with the use of occlusive dressings and higher potency corticosteroids. These reactions are listed in an approximately decreasing order of occurrence: irritation, folliculitis, acneiform eruptions, hypopigmentation, perioral dermatitis, allergic contact dermatitis, secondary infection, skin atrophy, striae, hypertrichosis, and miliaria. - Fluticasone, 0.05% may cause local cutaneous adverse reactions. - If irritation develops, fluticasone should be discontinued and appropriate therapy instituted. Allergic contact dermatitis with corticosteroids is usually diagnosed by observing failure to heal rather than noting a clinical exacerbation as with most topical products not containing corticosteroids. Such an observation should be corroborated with appropriate diagnostic patch testing. - If concomitant skin infections are present or develop, an appropriate antifungal or antibacterial agent should be used. If a favorable response does not occur promptly, use of fluticasone should be discontinued until the infection has been adequately controlled. - Fluticasone should not be used in the presence of preexisting skin atrophy and should not be used where infection is present at the treatment site. Fluticasone should not be used in the treatment of rosacea and perioral dermatitis. - Patients that apply fluticasone to exposed portions of the body should avoid excessive exposure to either natural or artificial sunlight (including tanning booths, sun lamps, etc.). # Adverse Reactions ## Clinical Trials Experience ### Aerosol Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in practice. The incidence of common adverse reactions in the table below is based upon 2 placebo-controlled US clinical trials in which 812 adult and adolescent patients (457 females and 355 males) previously treated with as-needed bronchodilators and/or inhaled corticosteroids were treated twice daily for up to 12 weeks with 2 inhalations of fluticasone 44 mcg Inhalation Aerosol,fluticasone 110 mcg Inhalation Aerosol,fluticasone 220 mcg Inhalation Aerosol (dosages of 88, 220, or 440 mcg twice daily), or placebo. The table above includes all events (whether considered drug-related or nondrug-related by the investigator) that occurred at a rate of over 3% in any of the groups treated with fluticasone and were more common than in the placebo group. Less than 2% of patients discontinued from the studies because of adverse reactions. The average duration of exposure was 73 to 76 days in the active treatment groups compared with 60 days in the placebo group. Additional Adverse Reactions: Other adverse reactions not previously listed, whether considered drug-related or not by the investigators, that were reported more frequently by patients with asthma treated with fluticasone compared with patients treated with placebo include the following: rhinitis, rhinorrhea/post-nasal drip, nasal sinus disorders, laryngitis, diarrhea, viral gastrointestinal infections, dyspeptic symptoms, gastrointestinal discomfort and pain, hyposalivation, musculoskeletal pain, muscle pain, muscle stiffness/tightness/rigidity, dizziness, migraines, fever, viral infections, pain, chest symptoms, viral skin infections, muscle injuries, soft tissue injuries, urinary infections. Fluticasone propionate inhalation aerosol (440 or 880 mcg twice daily) was administered for 16 weeks to 168 patients with asthma requiring oral corticosteroids (Study 3). Adverse reactions not included above, but reported by more than 3 patients in either group treated with fluticasone and more commonly than in the placebo group included nausea and vomiting, arthralgia and articular rheumatism, and malaise and fatigue. In 2 long-term studies (26 and 52 weeks), the pattern of adverse reactions in patients treated with fluticasone at dosages up to 440 mcg twice daily was similar to that observed in the 12-week studies. There were no new and/or unexpected adverse reactions with long-term treatment. Pediatric Patients Aged 4 to 11 Years: fluticasone has been evaluated for safety in 56 pediatric patients who received 88 mcg twice daily for 4 weeks. Types of adverse reactions in these pediatric patients were generally similar to those observed in adults and adolescents. ### Spray In controlled US studies, more than 3,300 patients with seasonal allergic, perennial allergic, or perennial nonallergic rhinitis received treatment with intranasal fluticasone propionate. In general, adverse reactions in clinical studies have been primarily associated with irritation of the nasal mucous membranes, and the adverse reactions were reported with approximately the same frequency by patients treated with the vehicle itself. The complaints did not usually interfere with treatment. Less than 2% of patients in clinical trials discontinued because of adverse events; this rate was similar for vehicle placebo and active comparators. Systemic corticosteroid side effects were not reported during controlled clinical studies up to 6 months’ duration with fluticasone nasal spray. If recommended doses are exceeded, however, or if individuals are particularly sensitive or taking fluticasone nasal spray in conjunction with administration of other corticosteroids, symptoms of hypercorticism, e.g., Cushing syndrome, could occur. The following incidence of common adverse reactions (>3%, where incidence in fluticasone propionate-treated subjects exceeded placebo) is based upon 7 controlled clinical trials in which 536 patients (57 girls and 108 boys aged 4 to 11 years, 137 female and 234 male adolescents and adults) were treated with fluticasone nasal spray 200 mcg once daily over 2 to 4 weeks and 2 controlled clinical trials in which 246 patients (119 female and 127 male adolescents and adults) were treated with fluticasone nasal spray 200 mcg once daily over 6 months. Also included in the table are adverse events from 2 studies in which 167 children (45 girls and 122 boys aged 4 to 11 years) were treated with fluticasone nasal spray 100 mcg once daily for 2 to 4 weeks. Overall Adverse Experiences With >3% Incidence on Fluticasone Propionate in Controlled Clinical Trials With fluticasone nasal spray in Patients ≥4 Years With Seasonal or Perennial Allergic Rhinitis. Other adverse events that occurred in ≤3% but ≥1% of patients and that were more common with fluticasone propionate (with uncertain relationship to treatment) included: blood in nasal mucus, runny nose, abdominal pain, diarrhea, fever, flu-like symptoms, aches and pains, dizziness, bronchitis. In addition to adverse events reported from clinical trials, the following events have been identified during postapproval use of intranasal fluticasone propionate in clinical practice. Because they are reported voluntarily from a population of unknown size, estimates of frequency cannot be made. These events have been chosen for inclusion due to either their seriousness, frequency of reporting, or causal connection to fluticasone propionate or a combination of these factors. - General: Hypersensitivity reactions, including angioedema, skin rash, edema of the face and tongue, pruritus, urticaria, bronchospasm, wheezing, dyspnea, and anaphylaxis/anaphylactoid reactions, which in rare instances were severe. - Ear, Nose, and Throat: Alteration or loss of sense of taste and/or smell and, rarely, nasal septal perforation, nasal ulcer, sore throat, throat irritation and dryness, cough, hoarseness, and voice changes. - Eye: Dryness and irritation, conjunctivitis, blurred vision, glaucoma, increased intraocular pressure, and cataracts. - Cases of growth suppression have been reported for intranasal corticosteroids, including fluticasone. ### Cream/Lotion In 2 multicenter vehicle-controlled clinical trials of once-daily application of fluticasone by 196 adult and 242 pediatric patients, the total incidence of adverse reactions considered drug related by investigators was approximately 4%. Events were local cutaneous events, usually mild and self-limiting, and consisted primarily of burning/stinging (2%). All other drug-related events occurred with an incidence of less than 1%, and inclusively were contact dermatitis, exacerbation of atopic dermatitis, folliculitis of legs, pruritus, pustules on arm, rash, and skin infection. The incidence of drug-related events on drug compared to vehicle (4% and 5%, respectively) was similar. The incidence of drug-related events between study populations of 242 pediatric patients (age 3 months to < 17 years) and 196 adult patients (17 years or older) (4% and 5%, respectively) was also similar. In an open-label study of 44 pediatric patients applying fluticasone to at least 35% of body surface area twice daily for 3 or 4 weeks, the overall incidence of drug-related adverse events was 14%. Events were local, cutaneous, and inclusively were dry skin (7%), stinging at application site (5%), and excoriation (2%). The table below summarizes all adverse events by body system that occurred in at least 1% of patients in either the drug or vehicle group in controlled clinical trials. During the clinical trials, eczema herpeticum occurred in a 33-year-old male patient treated with fluticasone. Additionally, a 4-month-old patient treated with fluticasone in the open-label trial had marked elevations of the hepatic enzymes AST and ALT. ## Postmarketing Experience ### Aerosol In addition to adverse reactions reported from clinical trials, the following adverse reactions have been identified during postmarketing use of fluticasone propionate. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. These events have been chosen for inclusion due to either their seriousness, frequency of reporting, or causal connection to fluticasone propionate or a combination of these factors. - Ear, Nose, and Throat: Aphonia, facial and oropharyngeal edema, and throat soreness and irritation. - Endocrine and Metabolic: Cushingoid features, growth velocity reduction in children/adolescents, hyperglycemia, osteoporosis, and weight gain. - Eye: Cataracts. - Gastrointestinal Disorders: Dental caries and tooth discoloration. - Immune System Disorders: Immediate and delayed hypersensitivity reactions, including urticaria, anaphylaxis, rash, and angioedema and bronchospasm, have been reported. - Infections and Infestations: Esophageal candidiasis. - Psychiatry: Agitation, aggression, anxiety, depression, and restlessness. Behavioral changes, including hyperactivity and irritability, have been reported very rarely and primarily in children. - Respiratory: Asthma exacerbation, chest tightness, cough, dyspnea, immediate and delayed bronchospasm, paradoxical bronchospasm, pneumonia, and wheeze. - Skin: Contusions, cutaneous hypersensitivity reactions, ecchymoses, and pruritus. - Eosinophilic Conditions: In rare cases, patients on inhaled fluticasone propionate may present with systemic eosinophilic conditions, with some patients presenting with clinical features of vasculitis consistent with Churg-Strauss syndrome, a condition that is often treated with systemic corticosteroid therapy. These events usually, but not always, have been associated with the reduction and/or withdrawal of oral corticosteroid therapy following the introduction of fluticasone propionate ### Spray During postmarketing use, there have been reports of clinically significant drug interactions in patients receiving fluticasone propionate and ritonavir, resulting in systemic corticosteroid effects including Cushing syndrome and adrenal suppression. Therefore, coadministration of fluticasone propionate and ritonavir is not recommended unless the potential benefit to the patient outweighs the risk of systemic corticosteroid side effects. ### Lotion/Cream Systemic adverse events with fluticasone cream and fluticasone ointment have included: - Immunosuppression/Pneumocystis carinii pneumonia/leukopenia/thrombocytopenia - Hyperglycemia/ glycosuria - Cushing syndrome - Generalized body edema/blurred vision - Acute urticarial reaction (edema, urticaria, pruritus, and throat swelling) The following localized adverse reactions have been reported during post approval use of fluticasone: - Erythema - Edema/swelling - Bleeding - Lack of efficacy Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. # Drug Interactions - Fluticasone propionate is a substrate of CYP3A4. The use of strong CYP3A4 inhibitors (e.g., ritonavir, atazanavir, clarithromycin, indinavir, itraconazole, nefazodone, nelfinavir, saquinavir, ketoconazole, telithromycin) with fluticasone is not recommended because increased systemic corticosteroid adverse effects may occur. - A drug interaction study with fluticasone propionate aqueous nasal spray in healthy subjects has shown that ritonavir (a strong CYP3A4 inhibitor) can significantly increase plasma fluticasone propionate concentration, resulting in significantly reduced serum cortisol concentrations. During postmarketing use, there have been reports of clinically significant drug interactions in patients receiving fluticasone propionate and ritonavir, resulting in systemic corticosteroid effects including Cushing’s syndrome and adrenal suppression. Therefore, coadministration of fluticasone propionate and ritonavir is not recommended unless the potential benefit to the patient outweighs the risk of systemic corticosteroid side effects. - Coadministration of orally inhaled fluticasone propionate (1,000 mcg) and ketoconazole (200 mg once daily) resulted in a 1.9-fold increase in plasma fluticasone propionate exposure and a 45% decrease in plasma cortisol area under the curve (AUC), but had no effect on urinary excretion of cortisol. Coadministration of fluticasone propionate and ketoconazole is not recommended unless the potential benefit to the patient outweighs the risk of systemic corticosteroid side effects. - In a multiple-dose drug interaction study, coadministration of orally inhaled fluticasone propionate (500 mcg twice daily) and erythromycin (333 mg 3 times daily) did not affect fluticasone propionate pharmacokinetics. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): C ### Aerosol There are no adequate and well-controlled studies with fluticasone in pregnant women. Fluticasone should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Subcutaneous studies in mice at a dose approximately 0.1 times the maximum recommended human daily inhalation dose (MRHD) for adults on a mg/m2 basis and in the rat at a dose approximately 0.5 times the MRHD in adults on a mg/m2 basis revealed fetal toxicity characteristic of potent corticosteroid compounds, including embryonic growth retardation, omphalocele, cleft palate, and retarded cranial ossification. In rabbits, fetal weight reduction and cleft palate were observed at a subcutaneous dose approximately 0.04 times the MRHD for adults on a mg/m2 basis. However, no teratogenic effects were reported at oral doses up to approximately 3 times the MRHD for adults on a mg/m2 basis. No fluticasone propionate was detected in the plasma in this study, consistent with the established low bioavailability following oral administration. Experience with oral corticosteroids since their introduction in pharmacologic, as opposed to physiologic, doses suggests that rodents are more prone to teratogenic effects from corticosteroids than humans. In addition, because there is a natural increase in corticosteroid production during pregnancy, most women will require a lower exogenous corticosteroid dose and many will not need corticosteroid treatment during pregnancy. ### Spray Subcutaneous studies in the mouse and rat at 45 and 100 mcg/kg, respectively (approximately equivalent to and 4 times, respectively, the maximum recommended daily intranasal dose in adults on a mcg/m2 basis), revealed fetal toxicity characteristic of potent corticosteroid compounds, including embryonic growth retardation, omphalocele, cleft palate, and retarded cranial ossification. In the rabbit, fetal weight reduction and cleft palate were observed at a subcutaneous dose of 4 mcg/kg (less than the maximum recommended daily intranasal dose in adults on a mcg/m2 basis). However, no teratogenic effects were reported at oral doses up to 300 mcg/kg (approximately 25 times the maximum recommended daily intranasal dose in adults on a mcg/m2 basis) of fluticasone propionate to the rabbit. No fluticasone propionate was detected in the plasma in this study, consistent with the established low bioavailability following oral administration. Fluticasone propionate crossed the placenta following oral administration of 100 mcg/kg to rats and 300 mcg/kg to rabbits (approximately 4 and 25 times, respectively, the maximum recommended daily intranasal dose in adults on a mcg/m2 basis). There are no adequate and well-controlled studies in pregnant women. Fluticasone propionate should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Experience with oral corticosteroids since their introduction in pharmacologic, as opposed to physiologic, doses suggests that rodents are more prone to teratogenic effects from corticosteroids than humans. In addition, because there is a natural increase in corticosteroid production during pregnancy, most women will require a lower exogenous corticosteroid dose and many will not need corticosteroid treatment during pregnancy. ### Lotion/Cream Corticosteroids have been shown to be teratogenic in laboratory animals when administered systemically at relatively low dosage levels. Some corticosteroids have been shown to be teratogenic after dermal application in laboratory animals. Systemic embryofetal development studies were conducted in mice, rats and rabbits. Subcutaneous doses of 15, 45 and 150 μg/kg/day of fluticasone propionate were administered to pregnant female mice from gestation days 6 – 15. A teratogenic effect characteristic of corticosteroids (cleft palate) was noted after administration of 45 and 150 μg/kg/day (less than the MRHD in adults based on body surface area comparisons) in this study. No treatment related effects on embryofetal toxicity or teratogenicity were noted at 15 μg/kg/day (less than the MRHD in adults based on body surface area comparisons). Subcutaneous doses of 10, 30 and 100 μg/kg/day of fluticasone propionate were administered to pregnant female rats in two embryofetal development studies (one study administered fluticasone propionate from gestation days 6 – 15 and the other study from gestation days 7 – 17). In the presence of maternal toxicity, fetal effects noted at 100 μg/kg/day (less than the MRHD in adults based on body surface area comparisons) included decreased fetal weights, omphalocele, cleft palate, and retarded skeletal ossification. No treatment related effects on embryofetal toxicity or teratogenicity were noted at 10 μg/kg/day (less than the MRHD in adults based on body surface area comparisons). Subcutaneous doses of 0.08, 0.57 and 4 μg/kg/day of fluticasone propionate were administered to pregnant female rabbits from gestation days 6 – 18. Fetal effects noted at 4 μg/kg/day (less than the MRHD in adults based on body surface area comparisons) included decreased fetal weights, cleft palate and retarded skeletal ossification. No treatment related effects on embryofetal toxicity or teratogenicity were noted at 0.57 μg/kg/day (less than the MRHD in adults based on body surface area comparisons). Oral doses of 3, 30 and 300 μg/kg/day fluticasone propionate were administered to pregnant female rabbits from gestation days 8 – 20. No fetal or teratogenic effects were noted at oral doses up to 300 μg/kg/day (less than the MRHD in adults based on body surface area comparisons) in this study. However, no fluticasone propionate was detected in the plasma in this study, consistent with the established low bioavailability following oral administration. Fluticasone propionate crossed the placenta following administration of a subcutaneous or an oral dose of 100 μg/kg tritiated fluticasone propionate to pregnant rats. There are no adequate and well-controlled studies in pregnant women. During clinical trials of fluticasone, women of childbearing potential were required to use contraception to avoid pregnancy. Therefore, fluticasone should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Fluticasone in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Fluticasone during labor and delivery. ### Nursing Mothers ### Aerosol It is not known whether fluticasone propionate is excreted in human breast milk. However, other corticosteroids have been detected in human milk. Subcutaneous administration to lactating rats of tritiated fluticasone propionate (approximately 0.05 times the MRHD in adults on a mg/m2 basis) resulted in measurable radioactivity in milk. Since there are no data from controlled trials on the use of fluticasone by nursing mothers, caution should be exercised when fluticasone is administered to a nursing woman. ### Spray Subcutaneous administration to lactating rats of 10 mcg/kg of tritiated fluticasone propionate (less than the maximum recommended daily intranasal dose in adults on a mcg/m2 basis) resulted in measurable radioactivity in the milk. Since there are no data from controlled trials on the use of intranasal fluticasone propionate by nursing mothers, caution should be exercised when fluticasone nasal spray is administered to a nursing woman. ### Lotion/Cream It is not known whether topical administration of corticosteroids could result in sufficient systemic absorption to produce detectable quantities in human milk. Because many drugs are excreted in human milk, caution should be exercised when fluticasone is administered to a nursing woman. ### Pediatric Use ### Aerosol The safety and effectiveness of fluticasone in children aged 4 years and older have been established. The safety and effectiveness of fluticasone in children younger than 4 years have not been established. Use of fluticasone in patients aged 4 to 11 years is supported by evidence from adequate and well-controlled studies in adults and adolescents aged 12 years and older, pharmacokinetic studies in patients aged 4 to 11 years, established efficacy of fluticasone propionate formulated as fluticasone inhalation powder and fluticasone inhalation powder in patients aged 4 to 11 years, and supportive findings with fluticasone in a study conducted in patients aged 4 to 11 years. Orally inhaled corticosteroids may cause a reduction in growth velocity when administered to pediatric patients. A reduction of growth velocity in children or teenagers may occur as a result of poorly controlled asthma or from use of corticosteroids including inhaled corticosteroids. The effects of long-term treatment of children and adolescents with inhaled corticosteroids, including fluticasone propionate, on final adult height are not known. Controlled clinical studies have shown that inhaled corticosteroids may cause a reduction in growth in pediatric patients. In these studies, the mean reduction in growth velocity was approximately 1 cm/year (range: 0.3 to 1.8 cm/year) and appeared to depend upon dose and duration of exposure. This effect was observed in the absence of laboratory evidence of HPA axis suppression, suggesting that growth velocity is a more sensitive indicator of systemic corticosteroid exposure in pediatric patients than some commonly used tests of HPA axis function. The long-term effects of this reduction in growth velocity associated with orally inhaled corticosteroids, including the impact on final adult height, are unknown. The potential for “catch-up” growth following discontinuation of treatment with orally inhaled corticosteroids has not been adequately studied. The effects on growth velocity of treatment with orally inhaled corticosteroids for over 1 year, including the impact on final adult height, are unknown. The growth of children and adolescents receiving orally inhaled corticosteroids, including fluticasone, should be monitored routinely (e.g., via stadiometry). The potential growth effects of prolonged treatment should be weighed against the clinical benefits obtained and the risks associated with alternative therapies. To minimize the systemic effects of orally inhaled corticosteroids, including fluticasone, each patient should be titrated to the lowest dose that effectively controls his/her symptoms. Since a cross study comparison in adult and adolescent patients (aged 12 years and older) indicated that systemic exposure of inhaled fluticasone would be higher than exposure from fluticasone propionate inhalation powder, results from a study to assess the potential growth effects of fluticasone propionate inhalation powder in pediatric patients (aged 4 to 11 years) are provided. A 52-week placebo-controlled study to assess the potential growth effects of fluticasone propionate inhalation powder at 50 and 100 mcg twice daily was conducted in the US in 325 prepubescent children (244 males and 81 females) aged 4 to 11 years. The mean growth velocities at 52 weeks observed in the intent-to-treat population were 6.32 cm/year in the placebo group (n = 76), 6.07 cm/year in the 50-mcg group (n = 98), and 5.66 cm/year in the 100-mcg group (n = 89). An imbalance in the proportion of children entering puberty between groups and a higher dropout rate in the placebo group due to poorly controlled asthma may be confounding factors in interpreting these data. A separate subset analysis of children who remained prepubertal during the study revealed growth rates at 52 weeks of 6.10 cm/year in the placebo group (n = 57), 5.91 cm/year in the 50-mcg group (n = 74), and 5.67 cm/year in the 100-mcg group (n = 79). In children aged 8.5 years, the mean age of children in this study, the range for expected growth velocity is: boys – 3rd percentile = 3.8 cm/year, 50th percentile = 5.4 cm/year, and 97th percentile = 7.0 cm/year; girls – 3rd percentile = 4.2 cm/year, 50th percentile = 5.7 cm/year, and 97th percentile = 7.3 cm/year. The clinical significance of these growth data is not certain. Physicians should closely follow the growth of children and adolescents taking corticosteroids by any route, and weigh the benefits of corticosteroid therapy against the possibility of growth suppression if growth appears slowed. Patients should be maintained on the lowest dose of inhaled corticosteroid that effectively controls their asthma. Children Younger Than 4 Years:Pharmacokinetics: Pharmacodynamics: A 12-week, double-blind, placebo-controlled, parallel-group study was conducted in children with asthma aged 1 to younger than 4 years. Twelve-hour overnight urinary cortisol excretion after a 12-week treatment period with 88 mcg of fluticasone twice daily (n = 73) and with placebo (n = 42) were calculated. The mean and median change from baseline in urine cortisol over 12 hours were -0.7 and 0.0 mcg for fluticasone and 0.3 and -0.2 mcg for placebo, respectively. In a 1-way crossover study in children aged 6 to younger than 12 months with reactive airways disease (N = 21), serum cortisol was measured over a 12-hour dosing period. Patients received placebo treatment for a 2-week period followed by a 4-week treatment period with 88 mcg of fluticasone twice daily with a valved holding Chamber (VHC) with mask. The geometric mean ratio of serum cortisol over 12 hours (AUC0-12 h) following fluticasone (n = 16) versus placebo (n = 18) was 0.95 (95% CI: 0.72, 1.27). Safety: Fluticasone administered as 88 mcg twice daily has been evaluated for safety in 239 pediatric patients aged 1 to younger than 4 years in a 12-week, double-blind, placebo-controlled study. Treatments were administered with an valved holding Chamber (VHC) with mask. In pediatric patients aged 1 to younger than 4 years receiving fluticasone, the following events occurred with a frequency greater than 3% and more frequently than in pediatric patients who received placebo, regardless of causality assessment: pyrexia, nasopharyngitis, upper respiratory tract infection, vomiting, otitis media, diarrhea, bronchitis, pharyngitis, and viral infection. Fluticasone administered as 88 mcg twice daily has also been evaluated for safety in 23 pediatric patients aged 6 to 12 months in an open-label placebo-controlled study. Treatments were administered with an valved holding Chamber (VHC) with mask for 2 weeks with placebo followed by 4 weeks with active drug. There was no discernable difference in the types of adverse events reported between patients receiving placebo compared to the active drug. In Vitro Testing of Dose Delivery With Holding Chambers: In vitro dose characterization studies were performed to evaluate the delivery of fluticasone via holding chambers with attached masks. The studies were conducted with 2 different holding chambers (valved holding Chamber (VHC) and AeroChamber Z-STAT Plus™ VHC) with masks (small and medium size) at inspiratory flow rates of 4.9, 8.0, and 12.0 L/min in combination with holding times of 0, 2, 5, and 10 seconds. The flow rates were selected to be representative of inspiratory flow rates of children aged 6 to 12 months, 2 to 5 years, and over 5 years, respectively. The mean delivered dose of fluticasone propionate through the holding chambers with masks was lower than the 44 mcg of fluticasone propionate delivered directly from the actuator mouthpiece. The results were similar through both holding chambers. The fine particle fraction (approximately 1 to 5 μm) across the flow rates used in these studies was 70% to 84% of the delivered dose, consistent with the removal of the coarser fraction by the holding chamber. In contrast, the fine particle fraction for fluticasone delivered without a holding chamber typically represents 42% to 55% of the delivered dose measured at the standard flow rate of 28.3 L/min. These data suggest that, on a per kilogram basis, young children receive a comparable dose of fluticasone propionate when delivered via a holding chamber and mask as adults do without their use. aCenters for Disease Control growth charts, developed by the National Center for Health Statistics in collaboration with the National Center for Chronic Disease Prevention and Health Promotion (2000). Ranges correspond to the average of the 50th percentile weight for boys and girls at the ages indicated. bA single inhalation of fluticasone in a 70-kg adult without use of a valved holding chamber and mask delivers approximately 44 mcg, or 0.6 mcg/kg. ### Spray Six hundred fifty (650) patients aged 4 to 11 years and 440 patients aged 12 to 17 years were studied in US clinical trials with fluticasone propionate nasal spray. The safety and effectiveness of fluticasone nasal spray in children below 4 years of age have not been established. Controlled clinical studies have shown that intranasal corticosteroids may cause a reduction in growth velocity in pediatric patients. This effect has been observed in the absence of laboratory evidence of HPA axis suppression, suggesting that growth velocity is a more sensitive indicator of systemic corticosteroid exposure in pediatric patients than some commonly used tests of HPA axis function. The long-term effects of this reduction in growth velocity associated with intranasal corticosteroids, including the impact on final adult height, are unknown. The potential for “catch-up” growth following discontinuation of treatment with intranasal corticosteroids has not been adequately studied. The growth of pediatric patients receiving intranasal corticosteroids, including fluticasone nasal spray, should be monitored routinely (e.g., via stadiometry). The potential growth effects of prolonged treatment should be weighed against the clinical benefits obtained and the risks/benefits of treatment alternatives. To minimize the systemic effects of intranasal corticosteroids, including fluticasone nasal spray, each patient should be titrated to the lowest dose that effectively controls his/her symptoms. A 1-year placebo-controlled clinical growth study was conducted in 150 pediatric patients (ages 3 to 9 years) to assess the effect of fluticasone nasal spray (single daily dose of 200 mcg, the maximum approved dose) on growth velocity. From the primary population of 56 patients receiving fluticasone nasal spray and 52 receiving placebo, the point estimate for growth velocity with fluticasone nasal spray was 0.14 cm/year lower than that noted with placebo (95% confidence interval ranging from 0.54 cm/year lower than placebo to 0.27 cm/year higher than placebo). Thus, no statistically significant effect on growth was noted compared to placebo. No evidence of clinically relevant changes in HPA axis function or bone mineral density was observed as assessed by 12-hour urinary cortisol excretion and dual-energy x-ray absorptiometry, respectively. The potential for fluticasone nasal spray to cause growth suppression in susceptible patients or when given at higher doses cannot be ruled out. ### Lotion/Cream Fluticasone contains the excipient imidurea which releases formaldehyde as a breakdown product. Formaldehyde may cause allergic sensitization or irritation upon contact with the skin. Fluticasone should not be used in individuals with hypersensitivity to formaldehyde as it may prevent healing or worsen dermatitis. Fluticasone should be discontinued if control is achieved before 4 weeks. If no improvement is seen within 2 weeks, contact a physician. The safety of the use of fluticasone for longer than 4 weeks has not been established. The safety and efficacy of fluticasone in pediatric patients below 1 year of age have not been established. Parents of pediatric patients should be advised not to use this medication in the treatment of diaper dermatitis unless directed by the physician. Fluticasone should not be applied in the diaper areas as diapers or plastic pants may constitute occlusive dressing. Forty-two pediatric patients (4 months to < 6 years of age) with moderate to severe atopic eczema who were treated with Fluticasone for at least 3-4 weeks were assessed for HPA axis suppression and 40 of these subjects applied at least 90% of applications. None of the 40 evaluable patients suppressed, where the sole criterion for HPA axis suppression is a plasma cortisol level of less than or equal to 18 micrograms per deciliter after cosyntropin stimulation. Although HPA axis suppression was observed in 0 of 40 pediatric patients (upper 95% confidence bound is 7.2%), the occurrence of HPA axis suppression in any patient and especially with longer use cannot be ruled out. In other studies with fluticasone propionate topical formulations, adrenal suppression has been observed. Fluticasone cream, 0.05% caused HPA axis suppression in 2 of 43 pediatric patients, ages 2 and 5 years old, who were treated for 4 weeks covering at least 35% of the body surface area. Follow-up testing 12 days after treatment discontinuation, available for 1 of the 2 patients, demonstrated a normally responsive HPA axis. HPA axis suppression, Cushing's syndrome, linear growth retardation, delayed weight gain, and intracranial hypertension have been reported in pediatric patients receiving topical corticosteroids. Manifestations of adrenal suppression in pediatric patients include low plasma cortisol levels to an absence of response to ACTH stimulation. Manifestations of intracranial hypertension include bulging fontanelles, headaches, and bilateral papilledema. Administration of topical corticosteroids to children should be limited to the least amount compatible with an effective therapeutic regimen. Chronic corticosteroid therapy may interfere with the growth and development of children. In addition, local adverse events including cutaneous atrophy, striae, telangiectasia, and pigmentation change have been reported with topical use of corticosteroids in pediatric patients. ### Geriatic Use ### Aerosol Of the total number of patients treated with fluticasone in US and non-US clinical trials, 173 were aged 65 years or older, 19 of which were 75 years or older. No overall differences in safety or effectiveness were observed between these patients and younger patients, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. ### Spray A limited number of patients 65 years of age and older (n = 129) or 75 years of age and older (n = 11) have been treated with fluticasone nasal spray in US and non-US clinical trials. While the number of patients is too small to permit separate analysis of efficacy and safety, the adverse reactions reported in this population were similar to those reported by younger patients. ### Lotion/Cream A limited number of patients above 65 years of age have been treated with fluticasone in US and non-US clinical trials. Specifically only 8 patients above 65 years of age were treated with fluticasone in controlled clinical trials. The number of patients is too small to permit separate analyses of efficacy and safety. ### Gender No significant difference in clearance (CL/F) of fluticasone propionate was observed. ### Race There is no FDA guidance on the use of Fluticasone with respect to specific racial populations. ### Renal Impairment Formal pharmacokinetic studies using fluticasone have not been conducted in patients with renal impairment. ### Hepatic Impairment Formal pharmacokinetic studies using fluticasone have not been conducted in patients with hepatic impairment. Since fluticasone propionate is predominantly cleared by hepatic metabolism, impairment of liver function may lead to accumulation of fluticasone propionate in plasma. Therefore, patients with hepatic disease should be closely monitored. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Fluticasone in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Fluticasone in patients who are immunocompromised. # Administration and Monitoring ### Administration - Inhaled - Spray - Cutaneous application ### Monitoring Patients previously treated for prolonged periods with systemic corticosteroids and transferred to topical corticosteroids should be carefully monitored for acute adrenal insufficiency in response to stress. Lung function (forced expiratory volume in 1 second [FEV1] or morning peak expiratory flow [AM PEF]), beta-agonist use, and asthma symptoms should be carefully monitored during withdrawal of oral corticosteroids. # IV Compatibility There is limited information regarding the compatibility of Fluticasone and IV administrations. # Overdosage - Chronic overdosage may result in signs/symptoms of hypercorticism. - Inhalation by healthy volunteers of a single dose of 1,760 or 3,520 mcg of fluticasone was well tolerated. Doses of 1,320 mcg administered to healthy human volunteers twice daily for 7 to 15 days were also well tolerated. - Intranasal administration of 2 mg (10 times the recommended dose) of fluticasone propionate twice daily for 7 days to healthy human volunteers was well tolerated. Single oral doses up to 16 mg have been studied in human volunteers with no acute toxic effects reported. - Repeat oral doses up to 80 mg daily for 10 days in healthy volunteers and repeat oral doses up to 20 mg daily for 42 days in patients were well tolerated. Adverse reactions were of mild or moderate severity, and incidences were similar in active and placebo treatment groups. - No deaths were seen in mice given an oral dose of 1,000 mg/kg (approximately 2,300 and 11,000 times the MRHD for adults and children aged 4 to 11 years, respectively, on a mg/m2 basis). No deaths were seen in rats given an oral dose of 1,000 mg/kg (approximately 4,600 and 22,000 times the MRHD in adults and children aged 4 to 11 years, respectively, on a mg/m2 basis). - The oral and subcutaneous median lethal doses in mice and rats were >1,000 mg/kg (>20,000 and >41,000 times, respectively, the maximum recommended daily intranasal dose in adults and >10,000 and >20,000 times, respectively, the maximum recommended daily intranasal dose in children on a mg/m2 basis). - Topically applied fluticasone can be absorbed in sufficient amounts to produce systemic effects. # Pharmacology ## Mechanism of Action ### Aerosol Fluticasone propionate is a synthetic trifluorinated corticosteroid with potent anti-inflammatory activity. In vitro assays using human lung cytosol preparations have established fluticasone propionate as a human glucocorticoid receptor agonist with an affinity 18 times greater than dexamethasone, almost twice that of beclomethasone‑17‑monopropionate (BMP), the active metabolite of beclomethasone dipropionate, and over 3 times that of budesonide. Data from the McKenzie vasoconstrictor assay in man are consistent with these results. The clinical significance of these findings is unknown. Inflammation is an important component in the pathogenesis of asthma. Corticosteroids have been shown to inhibit multiple cell types (e.g., mast cells, eosinophils, basophils, lymphocytes, macrophages, neutrophils) and mediator production or secretion (e.g., histamine, eicosanoids, leukotrienes, cytokines) involved in the asthmatic response. These anti-inflammatory actions of corticosteroids contribute to their efficacy in asthma. Though effective for the treatment of asthma, corticosteroids do not affect asthma symptoms immediately. Individual patients will experience a variable time to onset and degree of symptom relief. Maximum benefit may not be achieved for 1 to 2 weeks or longer after starting treatment. When corticosteroids are discontinued, asthma stability may persist for several days or longer. Studies in patients with asthma have shown a favorable ratio between topical anti-inflammatory activity and systemic corticosteroid effects with recommended doses of orally inhaled fluticasone propionate. This is explained by a combination of a relatively high local anti-inflammatory effect, negligible oral systemic bioavailability (less than 1%), and the minimal pharmacological activity of the only metabolite detected in man. ### Nasal Spray Fluticasone propionate is a synthetic trifluorinated corticosteroid with anti-inflammatory activity. In vitro dose response studies on a cloned human glucocorticoid receptor system involving binding and gene expression afforded 50% responses at 1.25 and 0.17 nM concentrations, respectively. Fluticasone propionate was 3-fold to 5-fold more potent than dexamethasone in these assays. Data from the McKenzie vasoconstrictor assay in man also support its potent glucocorticoid activity. In preclinical studies, fluticasone propionate revealed progesterone-like activity similar to the natural hormone. However, the clinical significance of these findings in relation to the low plasma levels (see Pharmacokinetics) is not known. The precise mechanism through which fluticasone propionate affects allergic rhinitis symptoms is not known. Corticosteroids have been shown to have a wide range of effects on multiple cell types (e.g., mast cells, eosinophils, neutrophils, macrophages, and lymphocytes) and mediators (e.g., histamine, eicosanoids, leukotrienes, and cytokines) involved in inflammation. In 7 trials in adults, fluticasone nasal spray has decreased nasal mucosal eosinophils in 66% (35% for placebo) of patients and basophils in 39% (28% for placebo) of patients. The direct relationship of these findings to long-term symptom relief is not known. Fluticasone nasal spray, like other corticosteroids, is an agent that does not have an immediate effect on allergic symptoms. A decrease in nasal symptoms has been noted in some patients 12 hours after initial treatment with fluticasone nasal spray. Maximum benefit may not be reached for several days. Similarly, when corticosteroids are discontinued, symptoms may not return for several days. ### Lotion/Spray The mechanism of the anti-inflammatory activity of the topical steroids, in general, is unclear. However, corticosteroids are thought to act by the induction of phospholipase A2 inhibitory proteins, collectively called lipocortins. It is postulated that these proteins control the biosynthesis of potent mediators of inflammation such as prostaglandins and leukotrienes by inhibiting the release of their common precursor, arachidonic acid. Arachidonic acid is released from membrane phospholipids by phospholipase A2. ## Structure The active component of fluticaasone 44 mcg inhalation aerosol, fluticasone 110 mcg inhalation aerosol, and fluticasone 220 mcg inhalation aerosol is fluticasone propionate, a corticosteroid having the chemical name S-(fluoromethyl) 6α,9-difluoro-11β,17-dihydroxy-16α-methyl-3-oxoandrosta-1,4-diene-17β-carbothioate, 17-propionate and the following chemical structure: ### Aerosol - Fluticasone propionate is a white powder with a molecular weight of 500.6, and the empirical formula is C25H31F3O5S. It is practically insoluble in water, freely soluble in dimethyl sulfoxide and dimethylformamide, and slightly soluble in methanol and 95% ethanol. - Fluticasone 44 mcg Inhalation Aerosol, fluticasone 110 mcg Inhalation Aerosol, and fluticasone 220 mcg inhalation aerosol are pressurized metered-dose aerosol units fitted with a counter. Fluticasone is intended for oral inhalation only. Each unit contains a microcrystalline suspension of fluticasone propionate (micronized) in propellant HFA-134a (1,1,1,2-tetrafluoroethane). It contains no other excipients. - After priming, each actuation of the inhaler delivers 50, 125, or 250 mcg of fluticasone propionate in 60 mg of suspension (for the 44-mcg product) or in 75 mg of suspension (for the 110- and 220-mcg products) from the valve. Each actuation delivers 44, 110, or 220 mcg of fluticasone propionate from the actuator. The actual amount of drug delivered to the lung may depend on patient factors, such as the coordination between the actuation of the device and inspiration through the delivery system. - Each 10.6-g canister (44 mcg) and each 12-g canister (110 and 220 mcg) provides 120 inhalations. - Fluticasone should be primed before using for the first time by releasing 4 test sprays into the air away from the face, shaking well for 5 seconds before each spray. In cases where the inhaler has not been used for more than 7 days or when it has been dropped, prime the inhaler again by shaking well for 5 seconds and releasing 1 test spray into the air away from the face. - This product does not contain any chlorofluorocarbon (CFC) as the propellant. ### Nasal Spray - Fluticasone propionate is a white powder with a molecular weight of 500.6, and the empirical formula is C25H31F3O5S. It is practically insoluble in water, freely soluble in dimethyl sulfoxide and dimethylformamide, and slightly soluble in methanol and 95% ethanol. - Fluticasone nasal spray, 50 mcg is an aqueous suspension of microfine fluticasone propionate for topical administration to the nasal mucosa by means of a metering, atomizing spray pump. Fluticasone nasal spray also contains microcrystalline cellulose and carboxymethylcellulose sodium, dextrose, 0.02% w/w benzalkonium chloride, polysorbate 80, and 0.25% w/w phenylethyl alcohol, and has a pH between 5 and 7. - It is necessary to prime the pump before first use or after a period of non-use (1 week or more). After initial priming (6 actuations), each actuation delivers 50 mcg of fluticasone propionate in 100 mg of formulation through the nasal adapter. Each 16-g bottle of fluticasone nasal spray provides 120 metered sprays. After 120 metered sprays, the amount of fluticasone propionate delivered per actuation may not be consistent and the unit should be discarded. ### Lotion/Spray - Fluticasone propionate is a white to off-white powder with a molecular weight of 500.6. It is practically insoluble in water, freely soluble in dimethyl sulfoxide and dimethylformamide, and slightly soluble in methanol and 95% ethanol. - Each gram of fluticasone contains 0.5mg fluticasone propionate in a base of cetostearyl alcohol, isopropyl myristate, propylene glycol, cetomacrogol 1000, dimethicone 350, citric acid, sodium citrate, and purified water, with imidurea, methylparaben, and propylparaben as preservatives. ## Pharmacodynamics ### Aerosol - Serum cortisol concentrations, urinary excretion of cortisol, and urine 6-β-hydroxycortisol excretion collected over 24 hours in 24 healthy subjects following 8 inhalations of fluticasone propionate HFA 44, 110, and 220 mcg decreased with increasing dose. However, in patients with asthma treated with 2 inhalations of fluticasone propionate HFA 44, 110, and 220 mcg twice daily for at least 4 weeks, differences in serum cortisol AUC(0-12 h) (n = 65) and 24-hour urinary excretion of cortisol (n = 47) compared with placebo were not related to dose and generally not significant. In the study with healthy volunteers, the effect of propellant was also evaluated by comparing results following the 220-mcg strength inhaler containing HFA 134a propellant with the same strength of inhaler containing CFC 11/12 propellant. A lesser effect on the HPA axis with the HFA formulation was observed for serum cortisol, but not urine cortisol and 6-betahydroxy cortisol excretion. In addition, in a crossover study of children with asthma aged 4 to 11 years (N = 40), 24-hour urinary excretion of cortisol was not affected after a 4-week treatment period with 88 mcg of fluticasone propionate HFA twice daily compared with urinary excretion after the 2-week placebo period. The ratio (95% CI) of urinary excretion of cortisol over 24 hours following fluticasone propionate HFA versus placebo was 0.987 (0.796, 1.223). - The potential systemic effects of fluticasone propionate HFA on the HPA axis were also studied in patients with asthma. Fluticasone propionate given by inhalation aerosol at dosages of 440 or 880 mcg twice daily was compared with placebo in oral corticosteroid-dependent patients with asthma (range of mean dose of prednisone at baseline: 13 to 14 mg/day) in a 16-week study. Consistent with maintenance treatment with oral corticosteroids, abnormal plasma cortisol responses to short cosyntropin stimulation (peak plasma cortisol less than 18 mcg/dL) were present at baseline in the majority of patients participating in this study (69% of patients later randomized to placebo and 72% to 78% of patients later randomized to fluticasone propionate HFA). At week 16, 8 patients (73%) on placebo compared with 14 (54%) and 13 (68%) patients receiving fluticasone propionate HFA (440 and 880 mcg twice daily, respectively) had post-stimulation cortisol levels of less than 18 mcg/dL. ### Nasal Spray - In a trial to evaluate the potential systemic and topical effects of fluticasone nasal spray on allergic rhinitis symptoms, the benefits of comparable drug blood levels produced by fluticasone nasal spray and oral fluticasone propionate were compared. The dosages used were 200 mcg of Fluticasone nasal spray, the nasal spray vehicle (plus oral placebo), and 5 and 10 mg of oral fluticasone propionate (plus nasal spray vehicle) per day for 14 days. Plasma levels were undetectable in the majority of patients after intranasal dosing, but present at low levels in the majority after oral dosing. Fluticasone nasal spray was significantly more effective in reducing symptoms of allergic rhinitis than either the oral fluticasone propionate or the nasal vehicle. This trial demonstrated that the therapeutic effect of fluticasone nasal spray can be attributed to the topical effects of fluticasone propionate. - In another trial, the potential systemic effects of fluticasone nasal spray on the hypothalamic-pituitary-adrenal (HPA) axis were also studied in allergic patients. Fluticasone nasal spray given as 200 mcg once daily or 400 mcg twice daily was compared with placebo or oral prednisone 7.5 or 15 mg given in the morning. Fluticasone nasal spray at either dosage for 4 weeks did not affect the adrenal response to 6-hour cosyntropin stimulation, while both dosages of oral prednisone significantly reduced the response to cosyntropin. ### Lotion/Spray - Like other topical corticosteroids, fluticasone propionate has anti-inflammatory, antipruritic, and vasoconstrictive properties. - Although fluticasone propionate has a weak affinity for the progesterone receptor and virtually no affinity for the mineralocorticoid, estrogen or androgen receptors, the clinical relevance as related to safety is unknown. Fluticasone propionate is lipophilic and has strong affinity for the glucocorticoid receptor. The therapeutic potency of glucocorticoids is related to the half-life of the glucocorticoid receptor complex. The half-life of the fluticasone propionate-glucocorticoid receptor complex is approximately 10 hours. ## Pharmacokinetics ### Aerosol - Absorption: Fluticasone propionate acts locally in the lung; therefore, plasma levels do not predict therapeutic effect. Studies using oral dosing of labeled and unlabeled drug have demonstrated that the oral systemic bioavailability of fluticasone propionate is negligible (less than 1%), primarily due to incomplete absorption and presystemic metabolism in the gut and liver. In contrast, the majority of the fluticasone propionate delivered to the lung is systemically absorbed. - Distribution: Following intravenous administration, the initial disposition phase for fluticasone propionate was rapid and consistent with its high lipid solubility and tissue binding. The volume of distribution averaged 4.2 L/kg. - Metabolism: The total clearance of fluticasone propionate is high (average, 1,093 mL/min), with renal clearance accounting for less than 0.02% of the total. The only circulating metabolite detected in man is the 17β-carboxylic acid derivative of fluticasone propionate, which is formed through the CYP 3A4 pathway. This metabolite had less affinity (approximately 1/2,000) than the parent drug for the corticosteroid receptor of human lung cytosol in vitro and negligible pharmacological activity in animal studies. Other metabolites detected in vitro using cultured human hepatoma cells have not been detected in man. - Elimination: Following intravenous dosing, fluticasone propionate showed polyexponential kinetics and had a terminal elimination half-life of approximately 7.8 hours. Less than 5% of a radiolabeled oral dose was excreted in the urine as metabolites, with the remainder excreted in the feces as parent drug and metabolites. ### =Pediatrics - A population pharmacokinetic analysis was performed for fluticasone using steady-state data from 4 controlled clinical trials and single-dose data from 1 controlled clinical trial. The combined cohort for analysis included 269 patients (161 males and 108 females) with asthma aged 6 months to 66 years who received treatment with fluticasone. Most of these subjects (n = 215) were treated with fluticasone 44 mcg given as 88 mcg twice daily. Fluticasone was delivered using an AeroChamber Plus VHC with a mask to patients aged younger than 4 years. Data from adult patients with asthma following fluticasone 110 mcg given as 220 mcg twice daily (n = 15) and following fluticasone 220 mcg given as 440 mcg twice daily (n = 17) at steady state were also included. Data for 22 patients came from a single-dose crossover study of 264 mcg (6 doses of fluticasone 44 mcg) with and without AeroChamber Plus VHC in children with asthma aged 4 to 11 years. - Stratification of exposure data following fluticasone 88 mcg by age and study indicated that systemic exposure to fluticasone propionate at steady state was similar in children aged 6 to younger than 12 months, children aged 1 to younger than 4 years, and adults and adolescents aged 12 years and older. Exposure was lower in children aged 4 to 11 years, who did not use a VHC, as shown in Table 4. - The lower exposure to fluticasone propionate in children aged 4 to 11 years who did not use a VHC may reflect the inability to coordinate actuation and inhalation of the metered-dose inhaler. The impact of the use of a VHC on exposure to fluticasone propionate in patients aged 4 to 11 years was evaluated in a single-dose crossover study with fluticasone 44 mcg given as 264 mcg. In this study, use of a VHC increased systemic exposure to fluticasone propionate (table below), possibly correcting for the inability to coordinate actuation and inhalation. - There was a dose-related increase in systemic exposure in patients aged 12 years and older receiving higher doses of fluticasone propionate (220 and 440 mcg twice daily). The AUC0-τ in pg•h/mL was 358 (95% CI: 272, 473) and 640 (95% CI: 477, 858), and Cmax in pg/mL was 47.3 (95% CI: 37, 61) and 87 (95% CI: 68, 112) following fluticasone propionate 220 and 440 mcg, respectively. ### Nasal Spray - Absorption: The activity of fluticasone nasal spray is due to the parent drug, fluticasone propionate. Indirect calculations indicate that fluticasone propionate delivered by the intranasal route has an absolute bioavailability averaging less than 2%. After intranasal treatment of patients with allergic rhinitis for 3 weeks, fluticasone propionate plasma concentrations were above the level of detection (50 pg/mL) only when recommended doses were exceeded and then only in occasional samples at low plasma levels. Due to the low bioavailability by the intranasal route, the majority of the pharmacokinetic data was obtained via other routes of administration. Studies using oral dosing of radiolabeled drug have demonstrated that fluticasone propionate is highly extracted from plasma and absorption is low. Oral bioavailability is negligible, and the majority of the circulating radioactivity is due to an inactive metabolite. - Distribution: Following intravenous administration, the initial disposition phase for fluticasone propionate was rapid and consistent with its high lipid solubility and tissue binding. The volume of distribution averaged 4.2 L/kg. - Metabolism: The total blood clearance of fluticasone propionate is high (average, 1,093 mL/min), with renal clearance accounting for less than 0.02% of the total. The only circulating metabolite detected in man is the 17β-carboxylic acid derivative of fluticasone propionate, which is formed through the cytochrome P450 3A4 pathway. This inactive metabolite had less affinity (approximately 1/2,000) than the parent drug for the glucocorticoid receptor of human lung cytosol in vitro and negligible pharmacological activity in animal studies. Other metabolites detected in vitro using cultured human hepatoma cells have not been detected in man. - Elimination: Following intravenous dosing, fluticasone propionate showed polyexponential kinetics and had a terminal elimination half-life of approximately 7.8 hours. Less than 5% of a radiolabeled oral dose was excreted in the urine as metabolites, with the remainder excreted in the feces as parent drug and metabolites. ### Lotion/Spray - Absorption: The extent of percutaneous absorption of topical corticosteroids is determined by many factors, including the vehicle and the integrity of the epidermal barrier. Occlusive dressing enhances penetration. Topical corticosteroids can be absorbed from normal intact skin. Inflammation and/or other disease processes in the skin increase percutaneous absorption. - Distribution: Following intravenous administration of 1 mg of fluticasone propionate in healthy volunteers, the initial disposition phase for fluticasone propionate was rapid and consistent with its high lipid solubility and tissue binding. The apparent volume of distribution averaged 4.2 L/kg (range, 2.3 to 16.7 L/kg). The percentage of fluticasone propionate bound to human plasma proteins averaged 91%. Fluticasone propionate is weakly and reversibly bound to erythrocytes. Fluticasone propionate is not significantly bound to human transcortin. - Metabolism: No metabolites of fluticasone propionate were detected in an in vitro study of radiolabeled fluticasone propionate incubated in a human skin homogenate. The total blood clearance of systemically absorbed fluticasone propionate averages 1093 mL/min (range, 618 to 1702 mL/min) after a 1-mg intravenous dose, with renal clearance accounting for less than 0.02% of the total. - Excretion: Following an intravenous dose of 1 mg in healthy volunteers, fluticasone propionate showed polyexponential kinetics and had an average terminal half-life of 7.2 hours (range, 3.2 to 11.2 hours). Plasma fluticasone levels were measured in patients 2 years - 6 years of age in an HPA axis suppression study. A total of 13 (62%) of 21 patients tested had measurable fluticasone at the end of 3 - 4 weeks of treatment. The mean ± SD fluticasone plasma values for patients aged under 3 years was 47.7 ± 31.7 pg/mL and 175.5 ± 243.6 pg/mL. Three patients had fluticasone levels over 300 pg/mL, with one of these having a level of 819.81 pg/mL. No data was obtained for patients < 2 years of age. ## Nonclinical Toxicology ### Aerosol - Fluticasone propionate demonstrated no tumorigenic potential in mice at oral doses up to 1,000 mcg/kg (approximately 2 and 10 times the MRHD for adults and children aged 4 to 11 years, respectively, on a mg/m2 basis) for 78 weeks or in rats at inhalation doses up to 57 mcg/kg (approximately 0.3 times and approximately equivalent to the MRHD for adults and children aged 4 to 11 years, respectively, on a mg/m2 basis) for 104 weeks. - Fluticasone propionate did not induce gene mutation in prokaryotic or eukaryotic cells in vitro. No significant clastogenic effect was seen in cultured human peripheral lymphocytes in vitro or in the in vivo mouse micronucleus test. - No evidence of impairment of fertility was observed in reproductive studies conducted in male and female rats at subcutaneous doses up to 50 mcg/kg (approximately 0.2 times the MRHD for adults on a mg/m2 basis). Prostate weight was significantly reduced at a subcutaneous dose of 50 mcg/kg. - Reproductive Toxicology: Subcutaneous studies in mice and rats at 45 and 100 mcg/kg (approximately 0.1 and 0.5 times the MRHD for adults on a mg/m2 basis, respectively) revealed fetal toxicity characteristic of potent corticosteroid compounds, including embryonic growth retardation, omphalocele, cleft palate, and retarded cranial ossification. - In rabbits, fetal weight reduction and cleft palate were observed at a subcutaneous dose of 4 mcg/kg (approximately 0.04 times the MRHD for adults on a mg/m2 basis). However, no teratogenic effects were reported at oral doses up to 300 mcg/kg (approximately 3 times the MRHD for adults on a mg/m2 basis) of fluticasone propionate. No fluticasone propionate was detected in the plasma in this study, consistent with the established low bioavailability following oral administration. - Fluticasone propionate crossed the placenta following subcutaneous administration to mice and rats and oral administration to rabbits. - In animals and humans, propellant HFA-134a was found to be rapidly absorbed and rapidly eliminated, with an elimination half-life of 3 to 27 minutes in animals and 5 to 7 minutes in humans. Time to maximum plasma concentration (Tmax) and mean residence time are both extremely short, leading to a transient appearance of HFA-134a in the blood with no evidence of accumulation. - Propellant HFA-134a is devoid of pharmacological activity except at very high doses in animals (i.e., 380 to 1,300 times the maximum human exposure based on comparisons of AUC values), primarily producing ataxia, tremors, dyspnea, or salivation. These events are similar to effects produced by the structurally related CFCs, which have been used extensively in metered-dose inhalers. - Fluticasone propionate demonstrated no tumorigenic potential in mice at oral doses up to 1,000 mcg/kg (approximately 20 times the maximum recommended daily intranasal dose in adults and approximately 10 times the maximum recommended daily intranasal dose in children on a mcg/m2 basis) for 78 weeks or in rats at inhalation doses up to 57 mcg/kg (approximately 2 times the maximum recommended daily intranasal dose in adults and approximately equivalent to the maximum recommended daily intranasal dose in children on a mcg/m2 basis) for 104 weeks. - Fluticasone propionate did not induce gene mutation in prokaryotic or eukaryotic cells in vitro. No significant clastogenic effect was seen in cultured human peripheral lymphocytes in vitro or in the mouse micronucleus test. - No evidence of impairment of fertility was observed in reproductive studies conducted in male and female rats at subcutaneous doses up to 50 mcg/kg (approximately 2 times the maximum recommended daily intranasal dose in adults on a mcg/m2 basis). Prostate weight was significantly reduced at a subcutaneous dose of 50 mcg/kg. - In an oral (gavage) mouse carcinogenicity study, doses of 0.1, 0.3 and 1 mg/kg/day fluticasone propionate were administered to mice for 18 months. Fluticasone propionate demonstrated no tumorigenic potential at oral doses up to 1 mg/kg/day (less than the MRHD in adults based on body surface area comparisons) in this study. - In a dermal mouse carcinogenicity study, 0.05% fluticasone propionate ointment (40 μl) was topically administered for 1, 3 or 7 days/week for 80 weeks. Fluticasone propionate demonstrated no tumorigenic potential at dermal doses up to 6.7 μg/kg/day (less than the MRHD in adults based on body surface area comparisons) in this study. - In a 52 week dermal photo-carcinogenicity study conducted in hairless albino mice with concurrent exposure to low level ultraviolet radiation (40 weeks of treatment followed by 12 weeks of observation), topically treated lotion vehicle animals and 0.05% fluticasone propionate lotion animals demonstrated shorter time to benign skin tumor formation compared to untreated control animals. Lotion vehicle treated animals developed benign skin tumors in a shorter time than 0.05% fluticasone propionate lotion treated animals. Although applicability of results to clinical use of fluticasone in humans is unknown, and enhanced tumor growth in patients treated with fluticasone has not been reported, patients should exercise general precautions in minimizing UV light exposure by avoiding excessive or unnecessary exposure to either natural or artificial sunlight (including sunbathing, tanning booths, sun lamps, etc.) - Fluticasone propionate revealed no evidence of mutagenic or clastogenic potential based on the results of five in vitro genotoxicity tests (Ames assay, E. coli fluctuation test, S. cerevisiae gene conversion test, Chinese hamster ovary cell chromosome aberration assay and human lymphocyte chromosome aberration assay) and one in vivo genotoxicity test (mouse micronucleus assay). - No evidence of impairment of fertility or effect on mating performance was observed in a fertility and general reproductive performance study conducted in male and female rats at subcutaneous doses up to 50 μg/kg/day (less than the MRHD in adults based on body surface area comparisons). # Clinical Studies ### Aerosol Three randomized, double-blind, parallel-group, placebo-controlled, US clinical trials were conducted in 980 adult and adolescent patients (aged 12 years and older) with asthma to assess the efficacy and safety of fluticasone in the treatment of asthma. Fixed dosages of 88, 220, and 440 mcg twice daily (each dose administered as 2 inhalations of the 44-, 110-, and 220-mcg strengths, respectively) and 880 mcg twice daily (administered as 4 inhalations of the 220-mcg strength) were compared with placebo to provide information about appropriate dosing to cover a range of asthma severity. Patients in these studies included those inadequately controlled with bronchodilators alone (Study 1), those already receiving inhaled corticosteroids (Study 2), and those requiring oral corticosteroid therapy (Study 3). In all 3 studies, patients (including placebo-treated patients) were allowed to use albuterol inhalation aerosol as needed for relief of acute asthma symptoms. In Studies 1 and 2, other maintenance asthma therapies were discontinued. - Study 1 enrolled 397 patients with asthma inadequately controlled on bronchodilators alone. Fluticasone was evaluated at dosages of 88, 220, and 440 mcg twice daily for 12 weeks. Baseline FEV1 values were similar across groups (mean 67% of predicted normal). All 3 dosages of Fluticasone demonstrated a statistically significant improvement in lung function as measured by improvement in AM pre-dose FEV1 compared with placebo. This improvement was observed after the first week of treatment, and was maintained over the 12-week treatment period. - At Endpoint (last observation), mean change from baseline in AM pre-dose percent predicted FEV1 was greater in all 3 groups treated with fluticasone (9.0% to 11.2%) compared with the placebo group (3.4%). The mean differences between the groups treated with fluticasone 88, 220, and 440 mcg and the placebo group were statistically significant, and the corresponding 95% confidence intervals were (2.2%, 9.2%), (2.8%, 9.9%), and (4.3%, 11.3%), respectively. - The figure below displays results of pulmonary function tests (mean percent change from baseline in FEV1 prior to AM dose) for the recommended starting dosage of fluticasone (88 mcg twice daily) and placebo from Study 1. This trial used predetermined criteria for lack of efficacy (indicators of worsening asthma), resulting in withdrawal of more patients in the placebo group. Therefore, pulmonary function results at Endpoint (the last evaluable FEV1 result, including most patients’ lung function data) are also displayed. Figure: A 12-Week Clinical Trial in Patients Aged 12 Years and Older Inadequately Controlled on Bronchodilators Alone: Mean Percent Change From Baseline in FEV1 Prior to AM Dose (Study 1) - In Study 2, fluticasone at dosages of 88, 220, and 440 mcg twice daily was evaluated over 12 weeks of treatment in 415 patients with asthma who were already receiving an inhaled corticosteroid at a daily dose within its recommended dose range in addition to as-needed albuterol. Baseline FEV1 values were similar across groups (mean 65% to 66% of predicted normal). All 3 dosages of fluticasone demonstrated a statistically significant improvement in lung function, as measured by improvement in FEV1, compared with placebo. This improvement was observed after the first week of treatment and was maintained over the 12-week treatment period. Discontinuations from the study for lack of efficacy (defined by a pre-specified decrease in FEV1 or PEF, or an increase in use of albuterol or nighttime awakenings requiring treatment with albuterol) were lower in the groups treated with fluticasone (6% to 11%) compared with placebo (50%). - At Endpoint (last observation), mean change from baseline in AM pre-dose percent predicted FEV1 was greater in all 3 groups treated with fluticasone (2.2% to 4.6%) compared with the placebo group (-8.3%). The mean differences between the groups treated with fluticasone 88, 220, and 440 mcg and the placebo group were statistically significant, and the corresponding 95% confidence intervals were (7.1%, 13.8%), (8.2%, 14.9%), and (9.6%, 16.4%), respectively. - Figure 2 displays the mean percent change from baseline in FEV1 from Week 1 through Week 12. This study also used predetermined criteria for lack of efficacy, resulting in withdrawal of more patients in the placebo group; therefore, pulmonary function results at Endpoint are also displayed. Figure: A 12-Week Clinical Trial in Patients Aged 12 Years and Older Already Receiving Daily Inhaled Corticosteroids: Mean Percent Change From Baseline in FEV1 Prior to AM Dose (Study 2) In both studies, use of albuterol, AM and PM PEF, and asthma symptom scores showed numerical improvement with fluticasone compared with placebo. - Study 3 enrolled 168 patients with asthma requiring oral prednisone therapy (average baseline daily prednisone dose ranged from 13 to 14 mg). Fluticasone at dosages of 440 and 880 mcg twice daily was evaluated over a 16-week treatment period. Baseline FEV1 values were similar across groups (mean 59% to 62% of predicted normal). Over the course of the study, patients treated with either dosage of fluticasone required a statistically significantly lower mean daily oral prednisone dose (6 mg) compared with placebo-treated patients (15 mg). Both dosages of fluticasone enabled a larger percentage of patients (59% and 56% in the groups treated with fluticasone 440 and 880 mcg, respectively, twice daily) to eliminate oral prednisone as compared with placebo (13%). There was no efficacy advantage of fluticasone 880 mcg twice daily compared with 440 mcg twice daily. Accompanying the reduction in oral corticosteroid use, patients treated with either dosage of fluticasone had statistically significantly improved lung function, fewer asthma symptoms, and less use of albuterol inhalation aerosol compared with the placebo-treated patients. Figure: A 16-Week Clinical Trial in Patients Aged 12 Years and Older Requiring Chronic Oral Prednisone Therapy: Change in Maintenance Prednisone Dose - Two long-term safety studies (Study 4 and Study 5) of ≥6 months’ duration were conducted in 507 adult and adolescent patients with asthma. Study 4 was designed to monitor the safety of 2 doses of fluticasone, while Study 5 compared fluticasone propionate HFA with fluticasone propionate CFC. Study 4 enrolled 182 patients who were treated daily with low to high doses of inhaled corticosteroids, beta-agonists (short-acting [as needed or regularly scheduled] or long-acting), theophylline, inhaled cromolyn or nedocromil sodium, leukotriene receptor antagonists, or 5-lipoxygenase inhibitors at baseline. Fluticasone at dosages of 220 and 440 mcg twice daily was evaluated over a 26-week treatment period in 89 and 93 patients, respectively. - Study 5 enrolled 325 patients who were treated daily with moderate to high doses of inhaled corticosteroids, with or without concurrent use of salmeterol or albuterol, at baseline. Fluticasone propionate HFA at a dosage of 440 mcg twice daily and fluticasone propionate CFC at a dosage of 440 mcg twice daily were evaluated over a 52-week treatment period in 163 and 162 patients, respectively. Baseline FEV1 values were similar across groups (mean 81% to 84% of predicted normal). Throughout the 52-week treatment period, asthma control was maintained with both formulations of fluticasone propionate compared with baseline. In both studies, none of the patients were withdrawn due to lack of efficacy. ### Pediatric Patients Aged 4 to 11 Years A 12-week clinical trial conducted in 241 pediatric patients with asthma was supportive of efficacy but inconclusive due to measurable levels of fluticasone propionate in 6/48 (13%) of the plasma samples from patients randomized to placebo. Efficacy in patients aged 4 to 11 years is extrapolated from adult data with fluticasone and other supporting data ### Nasal Spray - A total of 13 randomized, double-blind, parallel-group, multicenter, vehicle placebo-controlled clinical trials were conducted in the United States in adults and pediatric patients (4 years of age and older) to investigate regular use of fluticasone nasal spray in patients with seasonal or perennial allergic rhinitis. The trials included 2,633 adults (1,439 men and 1,194 women) with a mean age of 37 (range, 18 to 79 years). A total of 440 adolescents (405 boys and 35 girls), mean age of 14 (range, 12 to 17 years), and 500 children (325 boys and 175 girls), mean age of 9 (range, 4 to 11 years) were also studied. The overall racial distribution was 89% white, 4% black, and 7% other. These trials evaluated the total nasal symptom scores (TNSS) that included rhinorrhea, nasal obstruction, sneezing, and nasal itching in known allergic patients who were treated for 2 to 24 weeks. Subjects treated with fluticasone nasal spray exhibited significantly greater decreases in TNSS than vehicle placebo-treated patients. Nasal mucosal basophils and eosinophils were also reduced at the end of treatment in adult studies; however, the clinical significance of this decrease is not known. - There were no significant differences between fluticasone propionate regimens whether administered as a single daily dose of 200 mcg (two 50-mcg sprays in each nostril) or as 100 mcg (one 50-mcg spray in each nostril) twice daily in 6 clinical trials. A clear dose response could not be identified in clinical trials. In 1 trial, 200 mcg/day was slightly more effective than 50 mcg/day during the first few days of treatment; thereafter, no difference was seen. - Two randomized, double-blind, parallel-group, multicenter, vehicle placebo-controlled 28-day trials were conducted in the United States in 732 patients (243 given fluticasone nasal spray) 12 years of age and older to investigate “as-needed” use of fluticasone nasal spray (200 mcg) in patients with seasonal allergic rhinitis. Patients were instructed to take the study medication only on days when they thought they needed the medication for symptom control, not to exceed 2 sprays per nostril on any day, and not more than once daily. “As-needed” use was prospectively defined as average use of study medication no more than 75% of study days. Average use of study medications was 57% to 70% of days for all treatment arms. The studies demonstrated significantly greater reduction in TNSS (sum of nasal congestion, rhinorrhea, sneezing, and nasal itching) with fluticasone nasal spray 200 mcg compared to placebo. The relative difference in efficacy with as-needed use as compared to regularly administered doses was not studied. - Three randomized, double-blind, parallel-group, vehicle placebo-controlled trials were conducted in 1,191 patients to investigate regular use of fluticasone nasal spray in patients with perennial nonallergic rhinitis. These trials evaluated the patient-rated TNSS (nasal obstruction, postnasal drip, rhinorrhea) in patients treated for 28 days of double-blind therapy and in 1 of the 3 trials for 6 months of open-label treatment. Two of these trials demonstrated that patients treated with fluticasone nasal spray at a dosage of 100 mcg twice daily exhibited statistically significant decreases in TNSS compared with patients treated with vehicle. - Patients should use fluticasone nasal spray at regular intervals for optimal effect. - Adult patients may be started on a 200-mcg once-daily regimen (two 50-mcg sprays in each nostril once daily). An alternative 200-mcg/day dosage regimen can be given as 100 mcg twice daily (one 50-mcg spray in each nostril twice daily). - Individual patients will experience a variable time to onset and different degree of symptom relief. In 4 randomized, double-blind, vehicle placebo-controlled, parallel-group allergic rhinitis studies and 2 studies of patients in an outdoor “park” setting (park studies), a decrease in nasal symptoms in treated subjects compared to placebo was shown to occur as soon as 12 hours after treatment with a 200-mcg dose of fluticasone nasal spray. Maximum effect may take several days. Regular-use patients who have responded may be able to be maintained (after 4 to 7 days) on 100 mcg/day (1 spray in each nostril once daily). - Some patients (12 years of age and older) with seasonal allergic rhinitis may find as-needed use of fluticasone nasal spray (not to exceed 200 mcg daily) effective for symptom control. Greater symptom control may be achieved with scheduled regular use. Efficacy of as-needed use of fluticasone nasal spray has not been studied in pediatric patients under 12 years of age with seasonal allergic rhinitis, or patients with perennial allergic or nonallergic rhinitis. - Pediatric patients (4 years of age and older) should be started with 100 mcg (1 spray in each nostril once daily). Treatment with 200 mcg (2 sprays in each nostril once daily or 1 spray in each nostril twice daily) should be reserved for pediatric patients not adequately responding to 100 mcg daily. Once adequate control is achieved, the dosage should be decreased to 100 mcg (1 spray in each nostril) daily. - Maximum total daily doses should not exceed 2 sprays in each nostril (total dose, 200 mcg/day). There is no evidence that exceeding the recommended dose is more effective. ### Lotion/Cream Fluticasone applied once daily was superior to vehicle in the treatment of atopic dermatitis in two studies. The two studies enrolled 438 patients with atopic dermatitis aged 3 months and older, of which 169 patients were selected as having clinically significant* signs of erythema, infiltration/papulation and erosion/oozing/crusting at baseline. Table 1 presents the percentage of patients who completely cleared of erythema, infiltration/papulation and erosion/oozing/crusting at Week 4 out of those patients with clinically significant baseline signs. # How Supplied - Flovent HFA 44 mcg Inhalation Aerosol is supplied in 10.6-g pressurized aluminum canisters containing 120 metered inhalations in boxes of 1 with patient instructions (NDC 0173-0718-20). - Flovent HFA 110 mcg Inhalation Aerosol is supplied in 12-g pressurized aluminum canisters containing 120 metered inhalations in boxes of 1 with patient instructions (NDC 0173-0719-20). - Flovent HFA 220 mcg Inhalation Aerosol is supplied in 12-g pressurized aluminum canisters containing 120 metered inhalations in boxes of 1 with patient instructions (NDC 0173-0720-20). - Each canister is fitted with a counter and a dark orange oral actuator with a peach strapcap. The dark orange actuator supplied with FLOVENT HFA should not be used with any other product canisters, and actuators from other products should not be used with a FLOVENT HFA canister. - The correct amount of medication in each inhalation cannot be assured after the counter reads 000, even though the canister is not completely empty and will continue to operate. The inhaler should be discarded when the counter reads 000. - Keep out of reach of children. Avoid spraying in eyes. - Contents Under Pressure: Do not puncture. Do not use or store near heat or open flame. Exposure to temperatures above 120°F may cause bursting. Never throw into fire or incinerator. - Fluticasone nasal Spray, 50 mcg is supplied in an amber glass bottle fitted with a white metering atomizing pump, white nasal adapter, and green dust cover in a box of 1 (NDC 0173-0453-01) with patient’s instructions for use. - Each bottle contains a net fill weight of 16 g and will provide 120 actuations. - Each actuation delivers 50 mcg of fluticasone propionate in 100 mg of formulation through the nasal adapter. - The correct amount of medication in each spray cannot be assured after 120 sprays even though the bottle is not completely empty. - The bottle should be discarded when the labeled number of actuations has been used. Fluticasone is supplied in: - 60 mL bottle NDC 10337-434-60 - 120 mL bottle NDC 10337-434-04 ## Storage - Store at 25°C (77°F); excursions permitted from 15° to 30°C (59° to 86°F). - Store the inhaler with the mouthpiece down. - For best results, the inhaler should be at room temperature before use. - Store between 4° and 30°C (39° and 86°F). - Store between 15° and 30°C (59° and 86°F). Do not refrigerate. - Keep container tightly sealed. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information ### Aerosol Patients should be advised that localized infections with Candida albicans have occurred in the mouth and pharynx in some patients. If oropharyngeal candidiasis develops, it should be treated with appropriate local or systemic (i.e., oral antifungal) therapy while still continuing therapy with fluticasone, but at times therapy with fluticasone may need to be temporarily interrupted under close medical supervision. Rinsing the mouth after inhalation is advised. Patients should be advised that fluticasone is not a bronchodilator and is not intended for use as rescue medication for acute asthma exacerbations. Acute asthma symptoms should be treated with an inhaled, short-acting beta2-agonist such as albuterol. Patients should be instructed to contact their physicians immediately if there is deterioration of their asthma. Patients who are on immunosuppressant doses of corticosteroids should be warned to avoid exposure to chickenpox or measles and if they are exposed to consult their physicians without delay. Patients should be informed of potential worsening of existing tuberculosis, fungal, bacterial, viral, or parasitic infections, or ocular herpes simplex. Patients should be advised that fluticasone may cause systemic corticosteroid effects of hypercorticism and adrenal suppression. Additionally, patients should be instructed that deaths due to adrenal insufficiency have occurred during and after transfer from systemic corticosteroids. Patients should taper slowly from systemic corticosteroids if transferring to fluticasone. Patients should be advised that hypersensitivity reactions including anaphylaxis, angioedema, urticaria, and bronchospasm may occur after administration of fluticasone. Patients should discontinue fluticasone if such reactions occur. Patients who are at an increased risk for decreased BMD should be advised that the use of corticosteroids may pose an additional risk. Patients should be informed that orally inhaled corticosteroids, including fluticasone, may cause a reduction in growth velocity when administered to pediatric patients. Physicians should closely follow the growth of children and adolescents taking corticosteroids by any route. Long-term use of inhaled corticosteroids may increase the risk of some eye problems (cataracts or glaucoma); regular eye examinations should be considered. Patients should use fluticasone at regular intervals as directed. Individual patients will experience a variable time to onset and degree of symptom relief and the full benefit may not be achieved until treatment has been administered for 1 to 2 weeks or longer. Patients should not increase the prescribed dosage but should contact their physicians if symptoms do not improve or if the condition worsens. Patients should be instructed not to stop use of fluticasone abruptly. Patients should contact their physicians immediately if they discontinue use of fluticasone. ### Nasal Spray - Patients being treated with fluticasone nasal spray should receive the following information and instructions. This information is intended to aid them in the safe and effective use of this medication. It is not a disclosure of all possible adverse or intended effects. - Patients should be warned to avoid exposure to chickenpox or measles and, if exposed, to consult their physician without delay. - Patients should use fluticasone nasal spray at regular intervals for optimal effect. Some patients (12 years of age and older) with seasonal allergic rhinitis may find as-needed use of 200 mcg once daily effective for symptom control. - A decrease in nasal symptoms may occur as soon as 12 hours after starting therapy with fluticasone nasal spray. Results in several clinical trials indicate statistically significant improvement within the first day or two of treatment; however, the full benefit of fluticasone nasal spray may not be achieved until treatment has been administered for several days. The patient should not increase the prescribed dosage but should contact the physician if symptoms do not improve or if the condition worsens. - For the proper use of fluticasone nasal spray and to attain maximum improvement, the patient should read and follow carefully the patient’s instructions accompanying the product. ### Lotion/Cream Patients using fluticasone should receive the following information and instructions: - Fluticasone is to be used as directed by the physician. It is for external use only. Avoid contact with the eyes. - Fluticasone should not be used for any disorder other than that for which it was prescribed. - The treated skin area should not be bandaged or otherwise covered or wrapped so as to be occlusive unless directed by the physician. - Patients should report to their physician any signs of local adverse reactions as well as non-healing or worsening of skin condition. - Parents of pediatric patients should be advised not to use this medication in the treatment of diaper dermatitis unless directed by the physician. Fluticasone should not be applied in the diaper areas as diapers or plastic pants may constitute occlusive dressing. - Fluticasone should not be used on the face, underarms, or groin areas unless directed by a physician. - Fluticasone therapy should be discontinued if control is achieved before 4 weeks. If no improvement is seen within 2 weeks, contact a physician. The safety of the use of fluticasone for longer than 4 weeks has not been established. - Patients should report to their physician if they are allergic to formaldehyde. - Patients that apply fluticasone to exposed portions of the body should follow physician advice and routine precautions to avoid excessive or unnecessary exposure to either natural or artificial sunlight (such as sunbathing, tanning booths, sun lamps, etc.). # Precautions with Alcohol Alcohol-Fluticasone interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - Cutivate - Flonase - Flovent - Flovent Rotadisk - Flovent HFA - Flovent Diskus # Look-Alike Drug Names - Flonase - Flovent # Drug Shortage Status Drug Shortage # Price	https://www.wikidoc.org/index.php/Flovent_Diskus
8851f2320cae03f31c00e20380e0edeae20b11f4	wikidoc	Floxuridine	Floxuridine # Disclaimer WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here. # Overview Floxuridine is an antineoplastic agent that is FDA approved for the treatment of palliative management of gastrointestinal adenocarcinoma metastatic to the liver. Common adverse reactions include nausea, vomiting, diarrhea, enteritis, stomatitis and localized erythema. The more common laboratory abnormalities are anemia, leukopenia, thrombocytopenia and elevations of alkaline phosphatase, serum transaminase, serum bilirubin and lactic dehydrogenase.. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) - Floxuridine for Injection, USP is effective in the palliative management of gastrointestinal adenocarcinoma metastatic to the liver, when given by continuous regional intra-arterial infusion in carefully selected patients who are considered incurable by surgery or other means. Patients with known disease extending beyond an area capable of infusion via a single artery should, except in unusual circumstances, be considered for systemic therapy with other chemotherapeutic agents. - Each vial must be reconstituted with 5 mL of sterile water for injection to yield a solution containing approximately 100 mg of floxuridine/mL. The calculated daily dose(s) of the drug is then diluted with 5% dextrose or 0.9% sodium chloride injection to a volume appropriate for the infusion apparatus to be used. The administration of floxuridine is best achieved with the use of an appropriate pump to overcome pressure in large arteries and to ensure a uniform rate of infusion. - Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. - The recommended therapeutic dosage schedule of floxuridine by continuous arterial infusion is 0.1 to 0.6 mg/kg/day. The higher dosage ranges (0.4 to 0.6 mg) are usually employed for hepatic artery infusion because the liver metabolizes the drug, thus reducing the potential for systemic toxicity. Therapy can be given until adverse reactions appear. When these side effects have subsided, therapy may be resumed. The patients should be maintained on therapy as long as response to floxuridine continues. - Procedures for proper handling and disposal of anticancer drugs should be considered. Several guidelines on this subject have been published.1-7 There is no general agreement that all of the procedures recommended in the guidelines are necessary or appropriate. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Floxuridine in adult patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Floxuridine in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) There is limited information regarding FDA-Labeled Use of Floxuridine in pediatric patients. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Floxuridine in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Floxuridine in pediatric patients. # Contraindications - Floxuridine therapy is contraindicated for patients in a poor nutritional state, those with depressed bone marrow function or those with potentially serious infections. # Warnings - Floxuridine should be used with extreme caution in poor risk patients with impaired hepatic or renal function or a history of high-dose pelvic irradiation or previous use of alkylating agents. The drug is not intended as an adjuvant to surgery. - Floxuridine may cause fetal harm when administered to a pregnant woman. It has been shown to be teratogenic in the chick embryo, mouse (at doses of 2.5 to 100 mg/kg) and rat (at doses of 75 to 150 mg/kg). Malformations included cleft palates; skeletal defects; and deformed appendages, paws and tails. The dosages which were teratogenic in animals are 4.2 to 125 times the recommended human therapeutic dose. - There are no adequate and well-controlled studies with floxuridine in pregnant women. If this drug is used during pregnancy or if the patient becomes pregnant while taking (receiving) this drug, the patient should be apprised of the potential hazard to the fetus. Women of childbearing potential should be advised to avoid becoming pregnant. - Any form of therapy which adds to the stress of the patient, interferes with nutrition or depresses bone marrow function will increase the toxicity of floxuridine. ### Precautions - Floxuridine is a highly toxic drug with a narrow margin of safety. Therefore, patients should be carefully supervised since therapeutic response is unlikely to occur without some evidence of toxicity. Severe hematological toxicity, gastrointestinal hemorrhage and even death may result from the use of floxuridine despite meticulous selection of patients and careful adjustment of dosage. Although severe toxicity is more likely in poor risk patients, fatalities may be encountered occasionally even in patients in relatively good condition. - Therapy is to be discontinued promptly whenever one of the following signs of toxicity appears: - Myocardial ischemia - Stomatitis or esophagopharyngitis, at the first visible sign - Leukopenia (WBC under 3500) or a rapidly falling white blood count - Vomiting, intractable - Diarrhea, frequent bowel movements or watery stools - Gastrointestinal ulceration and bleeding - Thrombocytopenia (platelets under 100,000) - Hemorrhage from any site # Adverse Reactions ## Clinical Trials Experience - Adverse reactions to the arterial infusion of floxuridine are generally related to the procedural complications of regional arterial infusion. - The more common adverse reactions to the drug are nausea, vomiting, diarrhea, enteritis, stomatitis and localized erythema. The more common laboratory abnormalities are anemia, leukopenia, thrombocytopenia and elevations of alkaline phosphatase, serum transaminase, serum bilirubin and lactic dehydrogenase. - Other adverse reactions are: - Gastrointestinal: duodenal ulcer, duodenitis, gastritis, bleeding, gastroenteritis, glossitis, pharyngitis, anorexia, cramps, abdominal pain; possible intra- and extrahepatic biliary sclerosis, as well as acalculous cholecystitis. - Dermatologic: alopecia, dermatitis, nonspecific skin toxicity, rash. - Cardiovascular: myocardial ischemia. - Miscellaneous Clinical Reactions: fever, lethargy, malaise, weakness. - Laboratory Abnormalities: BSP, prothrombin, total proteins, sedimentation rate and thrombopenia. - Procedural Complications of Regional Arterial Infusion: arterial aneurysm; arterial ischemia; arterial thrombosis; embolism; fibromyositis; thrombophlebitis; hepatic necrosis; abscesses; infection at catheter site; bleeding at catheter site; catheter blocked, displaced or leaking. - The following adverse reactions have not been reported with floxuridine but have been noted following the administration of 5-fluorouracil. While the possibility of these occurring following floxuridine therapy is remote because of its regional administration, one should be alert for these reactions following the administration of floxuridine because of the pharmacological similarity of these two drugs: pancytopenia, agranulocytosis, myocardial ischemia, angina, anaphylaxis, generalized allergic reactions, acute cerebellar syndrome, nystagmus, headache, dry skin, fissuring, photosensitivity, pruritic maculopapular rash, increased pigmentation of the skin, vein pigmentation, lacrimal duct stenosis, visual changes, lacrimation, photophobia, disorientation, confusion, euphoria, epistaxis and nail changes, including loss of nails. ## Postmarketing Experience There is limited information regarding Postmarketing Experience of Floxuridine in the drug label. # Drug Interactions There is limited information regarding Floxuridine Drug Interactions in the drug label. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): D - Floxuridine has been shown to be teratogenic in the chick embryo, mouse (at doses of 2.5 to 100 mg/kg) and rat (at doses of 75 to 150 mg/kg). Malformations included cleft palates, skeletal defects and deformed appendages, paws and tails. The dosages which were teratogenic in animals are 3.2 to 125 times the recommended human therapeutic dose. - There are no adequate and well-controlled studies with floxuridine in pregnant women. While there is no evidence of teratogenicity in humans due to floxuridine, it should be kept in mind that other drugs which inhibit DNA synthesis (eg, methotrexate and aminopterin) have been reported to be teratogenic in humans. Floxuridine should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. - Floxuridine has not been studied in animals for its effects on peri- and postnatal development. However, compounds which inhibit DNA, RNA and protein synthesis might be expected to have adverse effects on peri- and postnatal development. Pregnancy Category (AUS): - There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Floxuridine in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Floxuridine during labor and delivery. ### Nursing Mothers - It is not known whether floxuridine is excreted in human milk. Because floxuridine inhibits DNA and RNA synthesis, mothers should not nurse while receiving this drug. ### Pediatric Use Safety and effectiveness in pediatric patients have not been established. ### Geriatic Use There is no FDA guidance on the use of Floxuridine with respect to geriatric patients. ### Gender There is no FDA guidance on the use of Floxuridine with respect to specific gender populations. ### Race There is no FDA guidance on the use of Floxuridine with respect to specific racial populations. ### Renal Impairment There is no FDA guidance on the use of Floxuridine in patients with renal impairment. ### Hepatic Impairment There is no FDA guidance on the use of Floxuridine in patients with hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Floxuridine in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Floxuridine in patients who are immunocompromised. # Administration and Monitoring ### Administration - Intra arterial ### Monitoring There is limited information regarding Monitoring of Floxuridine in the drug label. # IV Compatibility There is limited information regarding IV Compatibility of Floxuridine in the drug label. # Overdosage - The possibility of overdosage with floxuridine is unlikely in view of the mode of administration. Nevertheless, the anticipated manifestations would be nausea, vomiting, diarrhea, gastrointestinal ulceration and bleeding, bone marrow depression (including thrombocytopenia, leukopenia and agranulocytosis). No specific antidotal therapy exists. Patients who have been exposed to an overdosage of floxuridine should be monitored hematologically for at least 4 weeks. Should abnormalities appear, appropriate therapy should be utilized. The acute intravenous toxicity of floxuridine is as follows: # Pharmacology ## Mechanism of Action - When floxuridine is given by rapid intra-arterial injection it is apparently rapidly catabolized to 5-fluorouracil. Thus, rapid injection of floxuridine produces the same toxic and antimetabolic effects as does 5-fluorouracil. The primary effect is to interfere with the synthesis of deoxyribonucleic acid (DNA) and to a lesser extent inhibit the formation of ribonucleic acid (RNA). However, when floxuridine is given by continuous intra-arterial infusion its direct anabolism to floxuridine-monophosphate is enhanced, thus increasing the inhibition of DNA. ## Structure - Floxuridine for Injection, USP, an antineoplastic antimetabolite, is available as a sterile, nonpyrogenic, lyophilized powder for reconstitution. Each vial contains 500 mg of floxuridine which is to be reconstituted with 5 mL of sterile water for injection. An appropriate amount of reconstituted solution is then diluted with a parenteral solution for intra-arterial infusion. - Floxuridine is a fluorinated pyrimidine. Chemically, floxuridine is 2’-deoxy-5-fluorouridine. It is a white to off-white odorless solid which is freely soluble in water. The 2% aqueous solution has a pH of between 4.0 and 5.5. The structural formula is: ## Pharmacodynamics There is limited information regarding Pharmacodynamics of Floxuridine in the drug label. ## Pharmacokinetics - Floxuridine is metabolized in the liver. The drug is excreted intact and as urea, fluorouracil, α-fluoro-β-ureidopropionic acid, dihydrofluorouracil, α-fluoro-β-guanidopropionic acid and α-fluoro-β-alanine in the urine; it is also expired as respiratory carbon dioxide. Pharmacokinetic data on intra-arterial infusion of floxuridine are not available. ## Nonclinical Toxicology - Long-term studies in animals to evaluate the carcinogenic potential of floxuridine have not been conducted. On the basis of the available data, no evaluation can be made of the carcinogenic risk of floxuridine to humans. - Oncogenic transformation of fibroblasts from mouse embryo has been induced in vitro by floxuridine, but the relationship between oncogenicity and mutagenicity is not clear. Floxuridine has also been shown to be mutagenic in human leukocytes in vitro and in the Drosophila test system. In addition, 5-fluorouracil, to which floxuridine is catabolized when given by intraarterial injection, has been shown to be mutagenic in in vitro tests. - The effects of floxuridine on fertility and general reproductive performance have not been studied in animals. However, because floxuridine is catabolized to 5-fluorouracil, it should be noted that 5-fluorouracil has been shown to induce chromosomal aberrations and changes in chromosome organization of spermatogonia in rats at doses of 125 or 250 mg/kg, administered intraperitoneally. - Spermatogonial differentiation was also inhibited by fluorouracil, resulting in transient infertility. In female rats, fluorouracil, administered intraperitoneally at doses of 25 or 50 mg/kg during the preovulatory phase of oogenesis, significantly reduced the incidence of fertile matings, delayed the development of pre- and post-implantation embryos, increased the incidence of preimplantation lethality and induced chromosomal anomalies in these embryos. Compounds such as floxuridine, which interfere with DNA, RNA and protein synthesis, might be expected to have adverse effects on gametogenesis. # Clinical Studies There is limited information regarding Clinical Studies of Floxuridine in the drug label. # How Supplied - Vial stoppers do not contain natural rubber latex. The sterile powder should be stored at 20° to 25°C (68° to 77°F) . Reconstituted vials should be stored under refrigeration 2° to 8°C (36° to 46°F) for not more than 2 weeks. ## Storage There is limited information regarding Floxuridine Storage in the drug label. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information There is limited information regarding Patient Counseling Information of Floxuridine in the drug label. # Precautions with Alcohol - Alcohol-Floxuridine interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names There is limited information regarding Floxuridine Brand Names in the drug label. # Look-Alike Drug Names There is limited information regarding Floxuridine Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	Floxuridine Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Aparna Vuppala, M.B.B.S. [2] # Disclaimer WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here. # Overview Floxuridine is an antineoplastic agent that is FDA approved for the treatment of palliative management of gastrointestinal adenocarcinoma metastatic to the liver. Common adverse reactions include nausea, vomiting, diarrhea, enteritis, stomatitis and localized erythema. The more common laboratory abnormalities are anemia, leukopenia, thrombocytopenia and elevations of alkaline phosphatase, serum transaminase, serum bilirubin and lactic dehydrogenase.. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) - Floxuridine for Injection, USP is effective in the palliative management of gastrointestinal adenocarcinoma metastatic to the liver, when given by continuous regional intra-arterial infusion in carefully selected patients who are considered incurable by surgery or other means. Patients with known disease extending beyond an area capable of infusion via a single artery should, except in unusual circumstances, be considered for systemic therapy with other chemotherapeutic agents. - Each vial must be reconstituted with 5 mL of sterile water for injection to yield a solution containing approximately 100 mg of floxuridine/mL. The calculated daily dose(s) of the drug is then diluted with 5% dextrose or 0.9% sodium chloride injection to a volume appropriate for the infusion apparatus to be used. The administration of floxuridine is best achieved with the use of an appropriate pump to overcome pressure in large arteries and to ensure a uniform rate of infusion. - Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. - The recommended therapeutic dosage schedule of floxuridine by continuous arterial infusion is 0.1 to 0.6 mg/kg/day. The higher dosage ranges (0.4 to 0.6 mg) are usually employed for hepatic artery infusion because the liver metabolizes the drug, thus reducing the potential for systemic toxicity. Therapy can be given until adverse reactions appear. When these side effects have subsided, therapy may be resumed. The patients should be maintained on therapy as long as response to floxuridine continues. - Procedures for proper handling and disposal of anticancer drugs should be considered. Several guidelines on this subject have been published.1-7 There is no general agreement that all of the procedures recommended in the guidelines are necessary or appropriate. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Floxuridine in adult patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Floxuridine in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) There is limited information regarding FDA-Labeled Use of Floxuridine in pediatric patients. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Floxuridine in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Floxuridine in pediatric patients. # Contraindications - Floxuridine therapy is contraindicated for patients in a poor nutritional state, those with depressed bone marrow function or those with potentially serious infections. # Warnings - Floxuridine should be used with extreme caution in poor risk patients with impaired hepatic or renal function or a history of high-dose pelvic irradiation or previous use of alkylating agents. The drug is not intended as an adjuvant to surgery. - Floxuridine may cause fetal harm when administered to a pregnant woman. It has been shown to be teratogenic in the chick embryo, mouse (at doses of 2.5 to 100 mg/kg) and rat (at doses of 75 to 150 mg/kg). Malformations included cleft palates; skeletal defects; and deformed appendages, paws and tails. The dosages which were teratogenic in animals are 4.2 to 125 times the recommended human therapeutic dose. - There are no adequate and well-controlled studies with floxuridine in pregnant women. If this drug is used during pregnancy or if the patient becomes pregnant while taking (receiving) this drug, the patient should be apprised of the potential hazard to the fetus. Women of childbearing potential should be advised to avoid becoming pregnant. - Any form of therapy which adds to the stress of the patient, interferes with nutrition or depresses bone marrow function will increase the toxicity of floxuridine. ### Precautions - Floxuridine is a highly toxic drug with a narrow margin of safety. Therefore, patients should be carefully supervised since therapeutic response is unlikely to occur without some evidence of toxicity. Severe hematological toxicity, gastrointestinal hemorrhage and even death may result from the use of floxuridine despite meticulous selection of patients and careful adjustment of dosage. Although severe toxicity is more likely in poor risk patients, fatalities may be encountered occasionally even in patients in relatively good condition. - Therapy is to be discontinued promptly whenever one of the following signs of toxicity appears: - Myocardial ischemia - Stomatitis or esophagopharyngitis, at the first visible sign - Leukopenia (WBC under 3500) or a rapidly falling white blood count - Vomiting, intractable - Diarrhea, frequent bowel movements or watery stools - Gastrointestinal ulceration and bleeding - Thrombocytopenia (platelets under 100,000) - Hemorrhage from any site # Adverse Reactions ## Clinical Trials Experience - Adverse reactions to the arterial infusion of floxuridine are generally related to the procedural complications of regional arterial infusion. - The more common adverse reactions to the drug are nausea, vomiting, diarrhea, enteritis, stomatitis and localized erythema. The more common laboratory abnormalities are anemia, leukopenia, thrombocytopenia and elevations of alkaline phosphatase, serum transaminase, serum bilirubin and lactic dehydrogenase. - Other adverse reactions are: - Gastrointestinal: duodenal ulcer, duodenitis, gastritis, bleeding, gastroenteritis, glossitis, pharyngitis, anorexia, cramps, abdominal pain; possible intra- and extrahepatic biliary sclerosis, as well as acalculous cholecystitis. - Dermatologic: alopecia, dermatitis, nonspecific skin toxicity, rash. - Cardiovascular: myocardial ischemia. - Miscellaneous Clinical Reactions: fever, lethargy, malaise, weakness. - Laboratory Abnormalities: BSP, prothrombin, total proteins, sedimentation rate and thrombopenia. - Procedural Complications of Regional Arterial Infusion: arterial aneurysm; arterial ischemia; arterial thrombosis; embolism; fibromyositis; thrombophlebitis; hepatic necrosis; abscesses; infection at catheter site; bleeding at catheter site; catheter blocked, displaced or leaking. - The following adverse reactions have not been reported with floxuridine but have been noted following the administration of 5-fluorouracil. While the possibility of these occurring following floxuridine therapy is remote because of its regional administration, one should be alert for these reactions following the administration of floxuridine because of the pharmacological similarity of these two drugs: pancytopenia, agranulocytosis, myocardial ischemia, angina, anaphylaxis, generalized allergic reactions, acute cerebellar syndrome, nystagmus, headache, dry skin, fissuring, photosensitivity, pruritic maculopapular rash, increased pigmentation of the skin, vein pigmentation, lacrimal duct stenosis, visual changes, lacrimation, photophobia, disorientation, confusion, euphoria, epistaxis and nail changes, including loss of nails. ## Postmarketing Experience There is limited information regarding Postmarketing Experience of Floxuridine in the drug label. # Drug Interactions There is limited information regarding Floxuridine Drug Interactions in the drug label. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): D - Floxuridine has been shown to be teratogenic in the chick embryo, mouse (at doses of 2.5 to 100 mg/kg) and rat (at doses of 75 to 150 mg/kg). Malformations included cleft palates, skeletal defects and deformed appendages, paws and tails. The dosages which were teratogenic in animals are 3.2 to 125 times the recommended human therapeutic dose. - There are no adequate and well-controlled studies with floxuridine in pregnant women. While there is no evidence of teratogenicity in humans due to floxuridine, it should be kept in mind that other drugs which inhibit DNA synthesis (eg, methotrexate and aminopterin) have been reported to be teratogenic in humans. Floxuridine should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. - Floxuridine has not been studied in animals for its effects on peri- and postnatal development. However, compounds which inhibit DNA, RNA and protein synthesis might be expected to have adverse effects on peri- and postnatal development. Pregnancy Category (AUS): - There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Floxuridine in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Floxuridine during labor and delivery. ### Nursing Mothers - It is not known whether floxuridine is excreted in human milk. Because floxuridine inhibits DNA and RNA synthesis, mothers should not nurse while receiving this drug. ### Pediatric Use Safety and effectiveness in pediatric patients have not been established. ### Geriatic Use There is no FDA guidance on the use of Floxuridine with respect to geriatric patients. ### Gender There is no FDA guidance on the use of Floxuridine with respect to specific gender populations. ### Race There is no FDA guidance on the use of Floxuridine with respect to specific racial populations. ### Renal Impairment There is no FDA guidance on the use of Floxuridine in patients with renal impairment. ### Hepatic Impairment There is no FDA guidance on the use of Floxuridine in patients with hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Floxuridine in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Floxuridine in patients who are immunocompromised. # Administration and Monitoring ### Administration - Intra arterial ### Monitoring There is limited information regarding Monitoring of Floxuridine in the drug label. # IV Compatibility There is limited information regarding IV Compatibility of Floxuridine in the drug label. # Overdosage - The possibility of overdosage with floxuridine is unlikely in view of the mode of administration. Nevertheless, the anticipated manifestations would be nausea, vomiting, diarrhea, gastrointestinal ulceration and bleeding, bone marrow depression (including thrombocytopenia, leukopenia and agranulocytosis). No specific antidotal therapy exists. Patients who have been exposed to an overdosage of floxuridine should be monitored hematologically for at least 4 weeks. Should abnormalities appear, appropriate therapy should be utilized. The acute intravenous toxicity of floxuridine is as follows: # Pharmacology ## Mechanism of Action - When floxuridine is given by rapid intra-arterial injection it is apparently rapidly catabolized to 5-fluorouracil. Thus, rapid injection of floxuridine produces the same toxic and antimetabolic effects as does 5-fluorouracil. The primary effect is to interfere with the synthesis of deoxyribonucleic acid (DNA) and to a lesser extent inhibit the formation of ribonucleic acid (RNA). However, when floxuridine is given by continuous intra-arterial infusion its direct anabolism to floxuridine-monophosphate is enhanced, thus increasing the inhibition of DNA. ## Structure - Floxuridine for Injection, USP, an antineoplastic antimetabolite, is available as a sterile, nonpyrogenic, lyophilized powder for reconstitution. Each vial contains 500 mg of floxuridine which is to be reconstituted with 5 mL of sterile water for injection. An appropriate amount of reconstituted solution is then diluted with a parenteral solution for intra-arterial infusion. - Floxuridine is a fluorinated pyrimidine. Chemically, floxuridine is 2’-deoxy-5-fluorouridine. It is a white to off-white odorless solid which is freely soluble in water. The 2% aqueous solution has a pH of between 4.0 and 5.5. The structural formula is: ## Pharmacodynamics There is limited information regarding Pharmacodynamics of Floxuridine in the drug label. ## Pharmacokinetics - Floxuridine is metabolized in the liver. The drug is excreted intact and as urea, fluorouracil, α-fluoro-β-ureidopropionic acid, dihydrofluorouracil, α-fluoro-β-guanidopropionic acid and α-fluoro-β-alanine in the urine; it is also expired as respiratory carbon dioxide. Pharmacokinetic data on intra-arterial infusion of floxuridine are not available. ## Nonclinical Toxicology - Long-term studies in animals to evaluate the carcinogenic potential of floxuridine have not been conducted. On the basis of the available data, no evaluation can be made of the carcinogenic risk of floxuridine to humans. - Oncogenic transformation of fibroblasts from mouse embryo has been induced in vitro by floxuridine, but the relationship between oncogenicity and mutagenicity is not clear. Floxuridine has also been shown to be mutagenic in human leukocytes in vitro and in the Drosophila test system. In addition, 5-fluorouracil, to which floxuridine is catabolized when given by intraarterial injection, has been shown to be mutagenic in in vitro tests. - The effects of floxuridine on fertility and general reproductive performance have not been studied in animals. However, because floxuridine is catabolized to 5-fluorouracil, it should be noted that 5-fluorouracil has been shown to induce chromosomal aberrations and changes in chromosome organization of spermatogonia in rats at doses of 125 or 250 mg/kg, administered intraperitoneally. - Spermatogonial differentiation was also inhibited by fluorouracil, resulting in transient infertility. In female rats, fluorouracil, administered intraperitoneally at doses of 25 or 50 mg/kg during the preovulatory phase of oogenesis, significantly reduced the incidence of fertile matings, delayed the development of pre- and post-implantation embryos, increased the incidence of preimplantation lethality and induced chromosomal anomalies in these embryos. Compounds such as floxuridine, which interfere with DNA, RNA and protein synthesis, might be expected to have adverse effects on gametogenesis. # Clinical Studies There is limited information regarding Clinical Studies of Floxuridine in the drug label. # How Supplied - Vial stoppers do not contain natural rubber latex. The sterile powder should be stored at 20° to 25°C (68° to 77°F) [see USP Controlled Room Temperature]. Reconstituted vials should be stored under refrigeration 2° to 8°C (36° to 46°F) for not more than 2 weeks. ## Storage There is limited information regarding Floxuridine Storage in the drug label. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information There is limited information regarding Patient Counseling Information of Floxuridine in the drug label. # Precautions with Alcohol - Alcohol-Floxuridine interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names There is limited information regarding Floxuridine Brand Names in the drug label. # Look-Alike Drug Names There is limited information regarding Floxuridine Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	https://www.wikidoc.org/index.php/Floxuridine
8b8ab5738650542b3b23679721a6910955129d11	wikidoc	Flu vaccine	Flu vaccine The influenza vaccine or flu shot is a vaccine to protect against the highly variable influenza virus. The annual flu kills an estimated 36,000 people in the United States. The annually updated trivalent flu vaccine for the 2007–2008 season consists of hemagglutinin (HA) surface glycoprotein components from influenza H3N2, H1N1, and B influenza viruses. Each year the influenza virus changes and different strains become dominant. Due to the high mutability of the virus a particular vaccine formulation usually only works for about a year. The World Health Organization coordinates the contents of the vaccine each year to contain the most likely strains of the virus to attack the next year. The flu vaccine is usually recommended for anyone in a high-risk group who would be likely to suffer complications from influenza. # History of the flu vaccine Vaccines are used in both humans and nonhumans. Human vaccine is meant unless specifically identified as a veterinary or poultry or livestock vaccine. ## Influenza Influenza, commonly known as the flu, is an infectious disease that infects birds and mammals (primarily of the upper airways and lungs in mammals) and is caused by an RNA virus of the Orthomyxoviridae family (the influenza viruses). The most common and characteristic symptoms of influenza in humans are fever, pharyngitis (sore throat), myalgia (muscle pains), severe headache, coughing, and malaise (weakness and fatigue). Hippocrates first described the symptoms of influenza in 412 B.C. Since then, the virus has undergone mutations and shifts and has caused numerous pandemics. The first influenza pandemic was recorded in 1580, since this time, various methods have been employed to eradicate its cause. The etiological cause of influenza, the orthomyxoviridae was finally discovered by the Medical Research Council (MRC) of the United Kingdom in 1933. Known flu pandemics: - 1889–90 - Asiatic (Russian) Flu, mortality rate said to be 0.75-1 death per 1000 possibly H2N2 - 1900 - possibly H3N8 - 1918–20 – Spanish Flu, 500 million ill, at least 20-40 million died of H1N1 - 1957–58 – Asian Flu, 1 to 1.5 million died of H2N2 - 1968–69 – Hong Kong Flu, 3/4 to 1 million died of H3N2 ## Flu vaccine origins In the world wide Spanish flu pandemic of 1918, "Physicians tried everything they knew, everything they had ever heard of, from the ancient art of bleeding patients, to administering oxygen, to developing new vaccines and sera (chiefly against what we now call Hemophilus influenzae—a name derived from the fact that it was originally considered the etiological agent—and several types of pneumococci). Only one therapeutic measure, transfusing blood from recovered patients to new victims, showed any hint of success." "In 1931, viral growth in embryonated hens' eggs was discovered, and in the 1940s, the U.S. military developed the first approved inactivated vaccines for influenza, which were used in the Second World War". ## Flu vaccine acceptance The current egg-based technology for producing influenza vaccine was created in the 1950s. "The WHO Global Influenza Surveillance Network was established in 1952. The network comprises 4 WHO Collaborating Centres (WHO CCs) and 112 institutions in 83 countries, which are recognized by WHO as WHO National Influenza Centres (NICs). These NICs collect specimens in their country, perform primary virus isolation and preliminary antigenic characterization. They ship newly isolated strains to WHO CCs for high level antigenic and genetic analysis, the result of which forms the basis for WHO recommendations on the composition of influenza vaccine for the Northern and Southern Hemisphere each year." In the U.S. swine flu scare of 1976 President Gerald Ford was confronted with a potential swine flu pandemic. The vaccination program was plagued by delays and public relations problems, but about 24% of the population was vaccinated by the time the program was canceled with much concern and doubt about flu vaccination. According to the CDC: "Influenza vaccination is the primary method for preventing influenza and its severe complications. Vaccination is associated with reductions in influenza-related respiratory illness and physician visits among all age groups, hospitalization and death among persons at high risk, otitis media among children, and work absenteeism among adults. Although influenza vaccination levels increased substantially during the 1990s, further improvements in vaccine coverage levels are needed". ## Current status Flu research includes molecular virology, molecular evolution, pathogenesis, host immune responses, genomics, and epidemiology. These help in developing influenza countermeasures such as vaccines, therapies and diagnostic tools. Improved influenza countermeasures require basic research on how viruses enter cells, replicate, mutate, evolve into new strains and induce an immune response. The Influenza Genome Sequencing Project is creating a library of influenza sequences that will help us understand what makes one strain more lethal than another, what genetic determinants most affect immunogenicity, and how the virus evolves over time. Solutions to limitations in current vaccine methods are being researched. "Today, we have the capability to produce 300 million doses of trivalent vaccine per year - enough for current epidemics in the Western world, but insufficient for coping with a pandemic." # Clinical trials of vaccines A vaccine is assessed in terms of the reduction of the risk of disease produced by vaccination, its efficacy. In contrast, in the field, the effectiveness of a vaccine is the practical reduction in risk for an individual when they are vaccinated under real-world conditions. Measuring efficacy of influenza vaccines is relatively simple, as the immune response produced by the vaccine can be assessed in animal models, or the amount of antibody produced in vaccinated people can be measured, or most rigorously, by immunising adult volunteers and then challenging with virulent influenza virus. In studies such as these, influenza vaccines showed high efficacy and produced a protective immune response. For ethical reasons, such challenge studies cannot be performed in the population most at risk from influenza - the elderly and young children. However, studies on the effectiveness of flu vaccines in the real world are uniquely difficult. The vaccine may not be matched to the virus in circulation; virus prevalence varies widely between years, and influenza is often confused with other flu-like illnesses. Nevertheless, multiple clinical trials of both live and inactivated influenza vaccines have been performed and their results pooled and analyzed in several recent meta-analyses. Studies on live vaccines have very limited data, but these preparations may be more effective than inactivated vaccines. The meta-analyses examined the efficacy and effectiveness of inactivated vaccines in adults, children, and the elderly. In adults, vaccines show high efficacy against the targeted strains, but low effectiveness overall, so the benefits of vaccination are small, with a one-quarter reduction in risk of contracting influenza but no effect on the rate of hospitalization. In children, vaccines again showed high efficacy, but low effectiveness in preventing "flu-like illness", in children under two the data are extremely limited, but vaccination appeared to confer no measurable benefit. In the elderly, vaccination does not reduce the frequency of influenza, but may reduce pneumonia, hospital admission and deaths from influenza or pneumonia. The measured effectiveness of the vaccine in the elderly varies depending on whether the population studied is in residential care homes, or in the community, with the vaccine appearing more effective in an institutional environment. This apparent effect may be due to selection bias or differences in diagnosis and surveillance. Overall, the benefit of influenza vaccination is clearest in the elderly, with vaccination in children of questionable benefit. Vaccination of adults is not predicted to produce significant improvements in public health. The apparent contradiction between vaccines with high efficacy, but low effectiveness, may reflect the difficulty in diagnosing influenza under clinical conditions and the large number of strains circulating in the population. # Who should get it Yearly influenza vaccination should be routinely offered to patients at risk of complications of influenza: - the elderly (UK recommendation is those aged 65 or above) - patients with chronic lung diseases (asthma, COPD, etc.) - patients with chronic heart diseases (congenital heart disease, chronic heart failure, ischaemic heart disease) - patients with chronic liver diseases (including liver cirrhosis) - patients who are immunosuppressed (those with HIV or who are receiving drugs to suppress the immune system such as chemotherapy and long-term steroids) and their household contacts - all people who are institutionalized in an environment where influenza can spread rapidly, such as in prisons or nursing homes - healthcare workers (both to prevent sickness and to prevent spread to patients) The only contraindication is known anaphylaxis to the vaccine or its component. In the United States a person aged 50–64 is nearly ten times more likely to die an influenza-associated death than a younger person, and a person over age 65 is over ten times more likely to die an influenza-associated death than the 50–64 age group. Vaccination of those over age 65 reduces influenza-associated death by about 50%. However, it is unlikely that the vaccine completely explains the results since elderly people who get vaccinated are probably more healthy and health-conscious than those who do not. As mortality is high among infants who contract influenza, the household contacts and caregivers of infants should be vaccinated to reduce the risk of passing an influenza infection to the infant. Data from the years when Japan required annual flu vaccinations for school-aged children indicate that vaccinating children—the group most likely to catch and spread the disease—has a strikingly positive effect on reducing mortality among older people: one life saved for every 420 children who received the flu vaccine. This may be due to herd immunity or to direct causes, such as individual older people not being exposed to influenza. For example, retired grandparents often risk infection by caring for their sick grandchildren in households where the parents can't take time off work or are sick themselves. # Flu vaccine virus selection Selecting viruses for the vaccine manufacturing process is very difficult. At the U.S.'s Food and Drug Administration's (FDA) Center for Biologics Evaluation and Research's Vaccines and Related Biological Products Advisory Committee's 101st meeting of February 16 2005, an extensive discussion and vote was held concerning the following year's flu vaccine virus selection, but began with a summary of the previous year: ## Influenza B ## New viruses ## Manufacturing issues ## Strains selected ## Unexpected difficulties ## Response to unexpected difficulties # Flu vaccine manufacturing Flu vaccines are available both as an injection of killed virus and as nasal spray of live attenuated influenza virus (LAIV) (sold as FluMist). Clinical trials suggest that the live virus may be more effective at preventing infection. FluMist previously was not approved in the United States for use in children younger than 5. Starting in 2006 it is available to healthy children aged 2 and older. Flu vaccine is usually grown in fertilized chicken eggs. Both types of flu vaccines are contraindicated for those with severe allergies to egg proteins and people with a history of Guillain-Barré syndrome. On October 5 2004, Chiron Corporation, a corporation contracted to deliver half of the expected flu vaccine for the United States and a significant portion to the UK, issued a press release that stated it was unable to dispense its stock for the 2004-2005 season, due to suspension of the corporation's license to produce the vaccine by the Medicines and Healthcare Products Regulatory Agency. However, the Centers for Disease Control and Prevention took swift action to enlist the help of other companies such as MedImmune and Sanofi pasteur to supply vaccine in high-risk populations in the United States. Most flu vaccines intended for adults in the United States still contain Thiomersal, despite having been banned in many countries. # H5N1 There are several H5N1 vaccines for several of the avian H5N1 varieties, some for use in humans and some for use in poultry. H5N1 continually mutates, meaning vaccines based on current samples of avian H5N1 cannot be depended upon to work in the case of a future pandemic of H5N1. While there can be some cross-protection against related flu strains, the best protection would be from a vaccine specifically produced for any future pandemic flu virus strain. Dr. Daniel Lucey, co-director of the Biohazardous Threats and Emerging Diseases graduate program at Georgetown University has made this point, "There is no H5N1 pandemic so there can be no pandemic vaccine." However, "pre-pandemic vaccines" have been created; are being refined and tested; and do have some promise both in furthering research and preparedness for the next pandemic. Vaccine manufacturing companies are being encouraged to increase capacity so that if a pandemic vaccine is needed, facilities will be available for rapid production of large amounts of a vaccine specific to a new pandemic strain. Problems with H5N1 vaccine production include: - lack of overall production capacity - lack of surge production capacity (it is impractical to develop a system that depends on hundreds of millions of 11-day old specialized eggs on a standby basis) - the pandemic H5N1 might be lethal to chickens Cell culture (cell-based) manufacturing technology can be applied to influenza vaccines as they are with most viral vaccines and thereby solve the problems associated with creating flu vaccines using chicken eggs as is currently done. The US government has purchased from Sanofi Pasteur and Chiron Corporation several million doses of vaccine meant to be used in case of an influenza pandemic of H5N1 avian influenza and is conducting clinical trials with these vaccines. Researchers at the University of Pittsburgh have had success with a genetically engineered vaccine that took only a month to make and completely protected chickens from the highly pathogenic H5N1 virus. According to the United States Department of Health & Human Services: Chiron Corporation is now recertified and under contract with the National Institutes of Health to produce 8,000-10,000 investigational doses of Avian Flu (H5N1) vaccine. MedImmune and Aventis Pasteur are under similar contracts. The United States government hopes to obtain enough vaccine in 2006 to treat 4 million people. However, it is unclear whether this vaccine would be effective against a hypothetical mutated strain that would be easily transmitted through human populations, and the shelflife of stockpiled doses has yet to be determined. The New England Journal of Medicine reported on March 30, 2006 on one of dozens of vaccine studies currently being conducted. The Treanor et al. study was on vaccine produced from the human isolate (A/Vietnam/1203/2004 H5N1) of a virulent clade 1 influenza A (H5N1) virus with the use of a plasmid rescue system, with only the hemagglutinin and neuraminidase genes expressed and administered without adjuvant. "The rest of the genes were derived from an avirulent egg-adapted influenza A/PR/8/34 strain. The hemagglutinin gene was further modified to replace six basic amino acids associated with high pathogenicity in birds at the cleavage site between hemagglutinin 1 and hemagglutinin 2. Immunogenicity was assessed by microneutralization and hemagglutination-inhibition assays with the use of the vaccine virus, although a subgroup of samples were tested with the use of the wild-type influenza A/Vietnam/1203/2004 (H5N1) virus." The results of this study combined with others scheduled to be completed by Spring 2007 is hoped will provide a highly immunogenic vaccine that is cross-protective against heterologous influenza strains. On August 18, 2006. the World Health Organization changed the H5N1 strains recommended for candidate vaccines for the first time since 2004. "The WHO's new prototype strains, prepared by reverse genetics, include three new H5N1 subclades. The hemagglutinin sequences of most of the H5N1 avian influenza viruses circulating in the past few years fall into two genetic groups, or clades. Clade 1 includes human and bird isolates from Vietnam, Thailand, and Cambodia and bird isolates from Laos and Malaysia. Clade 2 viruses were first identified in bird isolates from China, Indonesia, Japan, and South Korea before spreading westward to the Middle East, Europe, and Africa. The clade 2 viruses have been primarily responsible for human H5N1 infections that have occurred during late 2005 and 2006, according to WHO. Genetic analysis has identified six subclades of clade 2, three of which have a distinct geographic distribution and have been implicated in human infections: - Subclade 1, Indonesia - Subclade 2, Middle East, Europe, and Africa - Subclade 3, China On the basis of the three subclades, the WHO is offering companies and other groups that are interested in pandemic vaccine development these three new prototype strains: - An A/Indonesia/2/2005-like virus - An A/Bar headed goose/Quinghai/1A/2005-like virus - An A/Anhui/1/2005-like virus Until now, researchers have been working on prepandemic vaccines for H5N1 viruses in clade 1. In March, the first clinical trial of a U.S. vaccine for H5N1 showed modest results. In May, French researchers showed somewhat better results in a clinical trial of an H5N1 vaccine that included an adjuvant. Vaccine experts aren't sure if a vaccine effective against known H5N1 viral strains would be effective against future strains. Although the new viruses will now be available for vaccine research, WHO said clinical trials using the clade 1 viruses should continue as an essential step in pandemic preparedness, because the trials yield useful information on priming, cross-reactivity, and cross-protection by vaccine viruses from different clades and subclades." As of November 2006, the United States Department of Health and Human Services still had enough H5N1 pre-pandemic vaccine to treat about 3 million people (5.9 million full-potency doses) in spite of 0.2 million doses used for research and 1.4 million doses that have begun to lose potency (from the original 7.5 million full-potency doses purchased from Sanofi Pasteur and Chiron Corp.). The expected shelf life of seasonal flu vaccine is about a year so the fact that most of the H5N1 pre-pandemic stockpile is still good after about 2 years is considered encouraging. # Flu seasons ## 2003–2004 season (Northern Hemisphere) The production of flu vaccine requires a lead time of about six months before the season. It is possible that by flu season a strain becomes common for which the vaccine does not provide protection. In the 2003–2004 season the vaccine was produced to protect against A/Panama, A/New Caledonia, and B/Hong Kong. A new strain, A/Fujian, was discovered after production of the vaccine started and vaccination gave only partial protection against this strain. Nature magazine reported that the Influenza Genome Sequencing Project, using phylogenetic analysis of 156 H3N2 genomes, "explains the appearance, during the 2003–2004 season, of the 'Fujian/411/2002'-like strain, for which the existing vaccine had limited effectiveness" as due to an epidemiologically significant reassortment. "Through a reassortment event, a minor clade provided the haemagglutinin gene that later became part of the dominant strain after the 2002–2003 season. Two of our samples, A/New York/269/2003 (H3N2) and A/New York/32/2003 (H3N2), show that this minor clade continued to circulate in the 2003–2004 season, when most other isolates were reassortants." According to the CDC: During September 28, 2003–May 22, 2004, WHO and NREVSS collaborating laboratories in the United States tested 130,577 respiratory specimens for influenza viruses; 24,649 (18.9%) were positive. Of these, 24,393 (99.0%) were influenza A viruses, and 249 (1.0%) were influenza B viruses. Among the influenza A viruses, 7,191 (29.5%) were subtyped; 7,189 (99.9%) were influenza A (H3N2) viruses, and two (0.1%) were influenza A (H1) viruses. The proportion of specimens testing positive for influenza first increased to >10% during the week ending October 25, 2003 (week 43), peaked at 35.2% during the week ending November 29 (week 48), and declined to <10% during the week ending January 17, 2004 (week 2). The peak percentage of specimens testing positive for influenza during the previous four seasons had ranged from 23% to 31% and peaked during late December to late February. As of June 15, 2004, CDC had antigenically characterized 1,024 influenza viruses collected by U.S. laboratories since October 1, 2003: 949 influenza A (H3N2) viruses, three influenza A (H1) viruses, one influenza A (H7N2) virus, and 71 influenza B viruses. Of the 949 influenza A (H3N2) isolates characterized, 106 (11.2%) were similar antigenically to the vaccine strain A/Panama/2007/99 (H3N2), and 843 (88.8%) were similar to the drift variant, A/Fujian/411/2002 (H3N2). Of the three A (H1) isolates that were characterized, two were H1N1 viruses, and one was an H1N2 virus. The hemagglutinin proteins of the influenza A (H1) viruses were similar antigenically to the hemagglutinin of the vaccine strain A/New Caledonia/20/99. Of the 71 influenza B isolates that were characterized, 66 (93%) belonged to the B/Yamagata/16/88 lineage and were similar antigenically to B/Sichuan/379/99, and five (7%) belonged to the B/Victoria/2/87 lineage and were similar antigenically to the corresponding vaccine strain B/Hong Kong/330/2001. In December 2003, one confirmed case of avian influenza A (H9N2) virus infection was reported in a child aged 5 years in Hong Kong. The child had fever, cough, and nasal discharge in late November, was hospitalized for 2 days, and fully recovered. The source of this child's H9N2 infection is unknown. During January–March 2004, a total of 34 confirmed human cases of avian influenza A (H5N1) virus infection were reported in Vietnam and Thailand. The cases were associated with severe respiratory illness requiring hospitalization and a case-fatality proportion of 68% (Vietnam: 22 cases, 15 deaths; Thailand: 12 cases, eight deaths). A substantial proportion of the cases were among children and young adults (i.e., persons aged 5–24 years). These cases were associated with widespread outbreaks of highly pathogenic H5N1 influenza among domestic poultry. During March 2004, health authorities in Canada reported two confirmed cases of avian influenza A (H7N3) virus infection in poultry workers who were involved in culling of poultry during outbreaks of highly pathogenic H7N3 on farms in the Fraser River Valley, British Columbia. One patient had unilateral conjunctivitis and nasal discharge, and the other had unilateral conjunctivitis and headache. Both illnesses resolved without hospitalization. During the 2003–2004 influenza season, a case of avian influenza A (H7N2) virus infection was detected in an adult male from New York, who was hospitalized for upper and lower respiratory tract illness in November 2003. Influenza A (H7N2) virus was isolated from a respiratory specimen from the patient, whose acute symptoms resolved. The source of this person's infection is unknown. ## 2004 season (Southern Hemisphere) The composition of influenza virus vaccines for use in the 2004 Southern Hemisphere influenza season recommended by the World Health Organization was: - an A/New Caledonia/20/99(H1N1)-like virus - an A/Fujian/411/2002(H3N2)-like virus (A/Kumamoto/102/2002 and A/Wyoming/3/2003 were egg-grown A/Fujian/411/2002-like viruses) - a B/Hong Kong/330/2001-like virus (B/Shandong/7/97, B/Hong Kong/330/2001 and B/Hong Kong/1434/2002 were among those used at the time. B/Brisbane/32/2002 was also available.) ## 2004–2005 season (Northern Hemisphere) According to the CDC: ## 2005 season (Southern Hemisphere) The composition of influenza virus vaccines for use in the 2005 Southern Hemisphere influenza season recommended by the World Health Organization was: - an A/New Caledonia/20/99(H1N1)-like virus; - an A/Wellington/1/2004(H3N2)-like virus; - a B/Shanghai/361/2002-like virus (B/Shanghai/361/2002, B/Jilin/20/2003 and B/Jiangsu/10/2003 were used at the time) ## 2005–2006 season (Northern Hemisphere) The vaccines produced for the 2005–2006 season use: - an A/New Caledonia/20/1999-like(H1N1); - an A/California/7/2004-like(H3N2) (or the antigenically equivalent strain A/New York/55/2004); - a B/Jiangsu/10/2003-like viruses. In people in the U.S., overall flu and pneumonia deaths were below those of a typical flu season with 84% Influenzavirus A and the rest Influenzavirus B. Of the patients who had Type A viruses, 80% had viruses identical or similar to the A bugs in the vaccine. 70% of the people testing positive for a B virus had Type B Victoria, a version not found in the vaccine. "During the 2005–06 season, influenza A (H3N2) viruses predominated overall, but late in the season influenza B viruses were more frequently isolated than influenza A viruses. Influenza A (H1N1) viruses circulated at low levels throughout the season. Nationally, activity was low from October through early January, increased during February, and peaked in early March. Peak activity was less intense, but activity remained elevated for a longer period of time this season compared to the previous three seasons. The longer period of elevated activity may be due in part to regional differences in the timing of peak activity and intensity of influenza B activity later in the season." ## 2006 season (Southern Hemisphere) The composition of influenza virus vaccines for use in the 2006 Southern Hemisphere influenza season recommended by the World Health Organization was: - an A/New Caledonia/20/99(H1N1)-like virus; - an A/California/7/2004(H3N2)-like virus (A/New York/55/2004 was used at the time); - a B/Malaysia/2506/2004-like virus ## 2006–2007 season (Northern Hemisphere) The 2006–2007 influenza vaccine composition recommended by the World Health Organization on February 15, 2006 and the U.S. FDA's Vaccines and Related Biological Products Advisory Committee (VRBPAC) on February 17, 2006 use: - an A/New Caledonia/20/99 (H1N1)-like virus; - an A/Wisconsin/67/2005 (H3N2)-like virus (A/Wisconsin/67/2005 and A/Hiroshima/52/2005 strains); - a B/Malaysia/2506/2004-like virus from B/Malaysia/2506/2004 and B/Ohio/1/2005 strains which are of B/Victoria/2/87 lineage. ## 2007 season (Southern Hemisphere) The composition of influenza virus vaccines for use in the 2006 Southern Hemisphere influenza season recommended by the World Health Organization on September 20, 2006 was: - an A/New Caledonia/20/99(H1N1)-like virus, - an A/Wisconsin/67/2005(H3N2)-like virus (A/Wisconsin/67/2005 and A/Hiroshima/52/2005 were used at the time), - a B/Malaysia/2506/2004-like virus ## 2007-2008 season (Northern Hemisphere) The composition of influenza virus vaccines for use in the 2007–2008 Northern Hemisphere influenza season recommended by the World Health Organization on February 14, 2007 was: - an A/Solomon Islands/3/2006 (H1N1)-like virus; - an A/Wisconsin/67/2005 (H3N2)-like virus (A/Wisconsin/67/2005 (H3N2) and A/Hiroshima/52/2005 were used at the time); - a B/Malaysia/2506/2004-like virus ## 2008 season (Southern Hemisphere) The composition of virus vaccines for use in the 2006 Southern Hemisphere influenza season recommended by the World Health Organization on September 17-19, 2007 was: - an A/Solomon Islands/3/2006 (H1N1)-like virus; - an A/Brisbane/10/2007 (H3N2)-like virus; - a B/Florida/4/2006-like virus # Flu vaccine for nonhumans "Vaccination in the veterinary world pursues four goals: (i) protection from clinical disease, (ii) protection from infection with virulent virus, (iii) protection from virus excretion, and (iv) serological differentiation of infected from vaccinated animals (so-called DIVA principle). In the field of influenza vaccination, neither commercially available nor experimentally tested vaccines have been shown so far to fulfil all of these requirements." ## Horses Horses with horse flu can run a fever, have a dry hacking cough, have a runny nose, and become depressed and reluctant to eat or drink for several days but usually recover in 2 to 3 weeks. "Vaccination schedules generally require a primary course of 2 doses, 3–6 weeks apart, followed by boosters at 6–12 month intervals. It is generally recognised that in many cases such schedules may not maintain protective levels of antibody and more frequent administration is advised in high-risk situations." ## Poultry Poultry vaccines for bird flu are made on the cheap and are not filtered and purified like human vaccines to remove bits of bacteria or other viruses. They usually contain whole virus, not just hemagglutin as in most human flu vaccines. Purification to standards needed for humans is far more expensive than the original creation of the unpurified vaccine from eggs. There is no market for veterinary vaccines that are that expensive. Another difference between human and poultry vaccines is that poultry vaccines are adjuvated with mineral oil, which induces a strong immune reaction but can cause inflammation and abscesses. "Chicken vaccinators who have accidentally jabbed themselves have developed painful swollen fingers or even lost thumbs, doctors said. Effectiveness may also be limited. Chicken vaccines are often only vaguely similar to circulating flu strains — some contain an H5N2 strain isolated in Mexico years ago. 'With a chicken, if you use a vaccine that's only 85 percent related, you'll get protection,' Dr. Cardona said. 'In humans, you can get a single point mutation, and a vaccine that's 99.99 percent related won't protect you.' And they are weaker . 'Chickens are smaller and you only need to protect them for six weeks, because that's how long they live till you eat them,' said Dr. John J. Treanor, a vaccine expert at the University of Rochester. Human seasonal flu vaccines contain about 45 micrograms of antigen, while an experimental A(H5N1) vaccine contains 180. Chicken vaccines may contain less than 1 microgram. 'You have to be careful about extrapolating data from poultry to humans,' warned Dr. David E. Swayne, director of the agriculture department's Southeast Poultry Research Laboratory. 'Birds are more closely related to dinosaurs.'" Researchers, led by Nicholas Savill of the University of Edinburgh in Scotland, used mathematical models to simulate the spread of H5N1 and concluded that "at least 95 per cent of birds need to be protected to prevent the virus spreading silently. In practice, it is difficult to protect more than 90 per cent of a flock; protection levels achieved by a vaccine are usually much lower than this." ## Pigs Swine influenza virus (SIV) vaccines are extensively used in the swine industry in Europe and North America. Most swine flu vaccine manufacturers include an H1N1 and an H3N2 SIV strains. Swine influenza has become a greater problem in recent decades. Evolution of the virus has resulted in inconsistent responses to traditional vaccines. Standard commercial swine flu vaccines are effective in controlling the problem when the virus strains match enough to have significant cross-protection and custom (autogenous) vaccines made from the specific viruses isolated are created and used in the more difficult cases. SIV vaccine manufacture Novartis paints this picture: "A strain of swine influenza virus (SIV) called H3N2, first identified in the US in 1998, has brought exasperating production losses to swine producers. Abortion storms are a common sign. Sows go off feed for two or three days and run a fever up to 106° F. Mortality in a naïve herd can run as high as 15%."	Flu vaccine Template:Flu The influenza vaccine or flu shot is a vaccine to protect against the highly variable influenza virus. The annual flu kills an estimated 36,000 people in the United States. The annually updated trivalent flu vaccine for the 2007–2008 season consists of hemagglutinin (HA) surface glycoprotein components from influenza H3N2, H1N1, and B influenza viruses.[1] Each year the influenza virus changes and different strains become dominant. Due to the high mutability of the virus a particular vaccine formulation usually only works for about a year. The World Health Organization coordinates the contents of the vaccine each year to contain the most likely strains of the virus to attack the next year. The flu vaccine is usually recommended for anyone in a high-risk group who would be likely to suffer complications from influenza. # History of the flu vaccine Template:Seealso Vaccines are used in both humans and nonhumans. Human vaccine is meant unless specifically identified as a veterinary or poultry or livestock vaccine. ## Influenza Influenza, commonly known as the flu, is an infectious disease that infects birds and mammals (primarily of the upper airways and lungs in mammals) and is caused by an RNA virus of the Orthomyxoviridae family (the influenza viruses). The most common and characteristic symptoms of influenza in humans are fever, pharyngitis (sore throat), myalgia (muscle pains), severe headache, coughing, and malaise (weakness and fatigue).[2] Hippocrates first described the symptoms of influenza in 412 B.C. Since then, the virus has undergone mutations and shifts and has caused numerous pandemics. The first influenza pandemic was recorded in 1580, since this time, various methods have been employed to eradicate its cause.[3] The etiological cause of influenza, the orthomyxoviridae was finally discovered by the Medical Research Council (MRC) of the United Kingdom in 1933.[4] Known flu pandemics:[5] - 1889–90 - Asiatic (Russian) Flu, mortality rate said to be 0.75-1 death per 1000 possibly H2N2 - 1900 - possibly H3N8 - 1918–20 – Spanish Flu, 500 million ill, at least 20-40 million died of H1N1 - 1957–58 – Asian Flu, 1 to 1.5 million died of H2N2 - 1968–69 – Hong Kong Flu, 3/4 to 1 million died of H3N2 ## Flu vaccine origins In the world wide Spanish flu pandemic of 1918, "Physicians tried everything they knew, everything they had ever heard of, from the ancient art of bleeding patients, to administering oxygen, to developing new vaccines and sera (chiefly against what we now call Hemophilus influenzae—a name derived from the fact that it was originally considered the etiological agent—and several types of pneumococci). Only one therapeutic measure, transfusing blood from recovered patients to new victims, showed any hint of success."[6] "In 1931, viral growth in embryonated hens' eggs was discovered, and in the 1940s, the U.S. military developed the first approved inactivated vaccines for influenza, which were used in the Second World War".[7] ## Flu vaccine acceptance The current egg-based technology for producing influenza vaccine was created in the 1950s.[8] "The WHO Global Influenza Surveillance Network was established in 1952. The network comprises 4 WHO Collaborating Centres (WHO CCs) and 112 institutions in 83 countries, which are recognized by WHO as WHO National Influenza Centres (NICs). These NICs collect specimens in their country, perform primary virus isolation and preliminary antigenic characterization. They ship newly isolated strains to WHO CCs for high level antigenic and genetic analysis, the result of which forms the basis for WHO recommendations on the composition of influenza vaccine for the Northern and Southern Hemisphere each year."[9] In the U.S. swine flu scare of 1976 President Gerald Ford was confronted with a potential swine flu pandemic. The vaccination program was plagued by delays and public relations problems, but about 24% of the population was vaccinated by the time the program was canceled with much concern and doubt about flu vaccination.[10] According to the CDC: "Influenza vaccination is the primary method for preventing influenza and its severe complications. [...] Vaccination is associated with reductions in influenza-related respiratory illness and physician visits among all age groups, hospitalization and death among persons at high risk, otitis media among children, and work absenteeism among adults. Although influenza vaccination levels increased substantially during the 1990s, further improvements in vaccine coverage levels are needed".[11] ## Current status Flu research includes molecular virology, molecular evolution, pathogenesis, host immune responses, genomics, and epidemiology. These help in developing influenza countermeasures such as vaccines, therapies and diagnostic tools. Improved influenza countermeasures require basic research on how viruses enter cells, replicate, mutate, evolve into new strains and induce an immune response. The Influenza Genome Sequencing Project is creating a library of influenza sequences that will help us understand what makes one strain more lethal than another, what genetic determinants most affect immunogenicity, and how the virus evolves over time. Solutions to limitations in current vaccine methods are being researched. "Today, we have the capability to produce 300 million doses of trivalent vaccine per year - enough for current epidemics in the Western world, but insufficient for coping with a pandemic."[7][12] # Clinical trials of vaccines A vaccine is assessed in terms of the reduction of the risk of disease produced by vaccination, its efficacy. In contrast, in the field, the effectiveness of a vaccine is the practical reduction in risk for an individual when they are vaccinated under real-world conditions.[13] Measuring efficacy of influenza vaccines is relatively simple, as the immune response produced by the vaccine can be assessed in animal models, or the amount of antibody produced in vaccinated people can be measured,[14] or most rigorously, by immunising adult volunteers and then challenging with virulent influenza virus.[15] In studies such as these, influenza vaccines showed high efficacy and produced a protective immune response. For ethical reasons, such challenge studies cannot be performed in the population most at risk from influenza - the elderly and young children. However, studies on the effectiveness of flu vaccines in the real world are uniquely difficult. The vaccine may not be matched to the virus in circulation; virus prevalence varies widely between years, and influenza is often confused with other flu-like illnesses.[16] Nevertheless, multiple clinical trials of both live and inactivated influenza vaccines have been performed and their results pooled and analyzed in several recent meta-analyses. Studies on live vaccines have very limited data, but these preparations may be more effective than inactivated vaccines.[15] The meta-analyses examined the efficacy and effectiveness of inactivated vaccines in adults,[17] children,[18] and the elderly.[19][20] In adults, vaccines show high efficacy against the targeted strains, but low effectiveness overall, so the benefits of vaccination are small, with a one-quarter reduction in risk of contracting influenza but no effect on the rate of hospitalization.[17] In children, vaccines again showed high efficacy, but low effectiveness in preventing "flu-like illness", in children under two the data are extremely limited, but vaccination appeared to confer no measurable benefit.[18] In the elderly, vaccination does not reduce the frequency of influenza, but may reduce pneumonia, hospital admission and deaths from influenza or pneumonia.[19][20] The measured effectiveness of the vaccine in the elderly varies depending on whether the population studied is in residential care homes, or in the community, with the vaccine appearing more effective in an institutional environment. This apparent effect may be due to selection bias or differences in diagnosis and surveillance. Overall, the benefit of influenza vaccination is clearest in the elderly, with vaccination in children of questionable benefit. Vaccination of adults is not predicted to produce significant improvements in public health. The apparent contradiction between vaccines with high efficacy, but low effectiveness, may reflect the difficulty in diagnosing influenza under clinical conditions and the large number of strains circulating in the population.[16] # Who should get it Yearly influenza vaccination should be routinely offered to patients at risk of complications of influenza: - the elderly (UK recommendation is those aged 65 or above) - patients with chronic lung diseases (asthma, COPD, etc.) - patients with chronic heart diseases (congenital heart disease, chronic heart failure, ischaemic heart disease) - patients with chronic liver diseases (including liver cirrhosis) - patients who are immunosuppressed (those with HIV or who are receiving drugs to suppress the immune system such as chemotherapy and long-term steroids) and their household contacts - all people who are institutionalized in an environment where influenza can spread rapidly, such as in prisons or nursing homes - healthcare workers (both to prevent sickness and to prevent spread to patients)[21] The only contraindication is known anaphylaxis to the vaccine or its component. In the United States a person aged 50–64 is nearly ten times more likely to die an influenza-associated death than a younger person, and a person over age 65 is over ten times more likely to die an influenza-associated death than the 50–64 age group.[22] Vaccination of those over age 65 reduces influenza-associated death by about 50%.[23][24] However, it is unlikely that the vaccine completely explains the results since elderly people who get vaccinated are probably more healthy and health-conscious than those who do not.[25] As mortality is high among infants who contract influenza, the household contacts and caregivers of infants should be vaccinated to reduce the risk of passing an influenza infection to the infant. Data from the years when Japan required annual flu vaccinations for school-aged children indicate that vaccinating children—the group most likely to catch and spread the disease—has a strikingly positive effect on reducing mortality among older people: one life saved for every 420 children who received the flu vaccine.[26] This may be due to herd immunity or to direct causes, such as individual older people not being exposed to influenza. For example, retired grandparents often risk infection by caring for their sick grandchildren in households where the parents can't take time off work or are sick themselves. # Flu vaccine virus selection Selecting viruses for the vaccine manufacturing process is very difficult. At the U.S.'s Food and Drug Administration's (FDA) Center for Biologics Evaluation and Research's Vaccines and Related Biological Products Advisory Committee's 101st meeting of February 16 2005, an extensive discussion and vote was held concerning the following year's flu vaccine virus selection, but began with a summary of the previous year: ## Influenza B ## New viruses ## Manufacturing issues ## Strains selected ## Unexpected difficulties ## Response to unexpected difficulties # Flu vaccine manufacturing Flu vaccines are available both as an injection of killed virus and as nasal spray of live attenuated influenza virus (LAIV) (sold as FluMist). Clinical trials suggest that the live virus may be more effective at preventing infection. FluMist previously was not approved in the United States for use in children younger than 5[28]. Starting in 2006 it is available to healthy children aged 2 and older. Flu vaccine is usually grown in fertilized chicken eggs. Both types of flu vaccines are contraindicated for those with severe allergies to egg proteins and people with a history of Guillain-Barré syndrome.[29] On October 5 2004, Chiron Corporation, a corporation contracted to deliver half of the expected flu vaccine for the United States and a significant portion to the UK, issued a press release[30] that stated it was unable to dispense its stock for the 2004-2005 season, due to suspension of the corporation's license to produce the vaccine by the Medicines and Healthcare Products Regulatory Agency. However, the Centers for Disease Control and Prevention took swift action to enlist the help of other companies such as MedImmune and Sanofi pasteur to supply vaccine in high-risk populations in the United States. Most flu vaccines intended for adults in the United States still contain Thiomersal, despite having been banned in many countries. # H5N1 Template:H5N1 There are several H5N1 vaccines for several of the avian H5N1 varieties, some for use in humans and some for use in poultry. H5N1 continually mutates, meaning vaccines based on current samples of avian H5N1 cannot be depended upon to work in the case of a future pandemic of H5N1. While there can be some cross-protection against related flu strains, the best protection would be from a vaccine specifically produced for any future pandemic flu virus strain. Dr. Daniel Lucey, co-director of the Biohazardous Threats and Emerging Diseases graduate program at Georgetown University has made this point, "There is no H5N1 pandemic so there can be no pandemic vaccine." However, "pre-pandemic vaccines" have been created; are being refined and tested; and do have some promise both in furthering research and preparedness for the next pandemic. Vaccine manufacturing companies are being encouraged to increase capacity so that if a pandemic vaccine is needed, facilities will be available for rapid production of large amounts of a vaccine specific to a new pandemic strain. Problems with H5N1 vaccine production include: - lack of overall production capacity - lack of surge production capacity (it is impractical to develop a system that depends on hundreds of millions of 11-day old specialized eggs on a standby basis) - the pandemic H5N1 might be lethal to chickens Cell culture (cell-based) manufacturing technology can be applied to influenza vaccines as they are with most viral vaccines and thereby solve the problems associated with creating flu vaccines using chicken eggs as is currently done.[31][32] The US government has purchased from Sanofi Pasteur and Chiron Corporation several million doses of vaccine meant to be used in case of an influenza pandemic of H5N1 avian influenza and is conducting clinical trials with these vaccines.[33] Researchers at the University of Pittsburgh have had success with a genetically engineered vaccine that took only a month to make and completely protected chickens from the highly pathogenic H5N1 virus.[34] According to the United States Department of Health & Human Services: Chiron Corporation is now recertified and under contract with the National Institutes of Health to produce 8,000-10,000 investigational doses of Avian Flu (H5N1) vaccine. MedImmune and Aventis Pasteur are under similar contracts.[36] The United States government hopes to obtain enough vaccine in 2006 to treat 4 million people. However, it is unclear whether this vaccine would be effective against a hypothetical mutated strain that would be easily transmitted through human populations, and the shelflife of stockpiled doses has yet to be determined.[37] The New England Journal of Medicine reported on March 30, 2006 on one of dozens of vaccine studies currently being conducted. The Treanor et al. study was on vaccine produced from the human isolate (A/Vietnam/1203/2004 H5N1) of a virulent clade 1 influenza A (H5N1) virus with the use of a plasmid rescue system, with only the hemagglutinin and neuraminidase genes expressed and administered without adjuvant. "The rest of the genes were derived from an avirulent egg-adapted influenza A/PR/8/34 strain. The hemagglutinin gene was further modified to replace six basic amino acids associated with high pathogenicity in birds at the cleavage site between hemagglutinin 1 and hemagglutinin 2. Immunogenicity was assessed by microneutralization and hemagglutination-inhibition assays with the use of the vaccine virus, although a subgroup of samples were tested with the use of the wild-type influenza A/Vietnam/1203/2004 (H5N1) virus." The results of this study combined with others scheduled to be completed by Spring 2007 is hoped will provide a highly immunogenic vaccine that is cross-protective against heterologous influenza strains.[38] On August 18, 2006. the World Health Organization changed the H5N1 strains recommended for candidate vaccines for the first time since 2004. "The WHO's new prototype strains, prepared by reverse genetics, include three new H5N1 subclades. The hemagglutinin sequences of most of the H5N1 avian influenza viruses circulating in the past few years fall into two genetic groups, or clades. Clade 1 includes human and bird isolates from Vietnam, Thailand, and Cambodia and bird isolates from Laos and Malaysia. Clade 2 viruses were first identified in bird isolates from China, Indonesia, Japan, and South Korea before spreading westward to the Middle East, Europe, and Africa. The clade 2 viruses have been primarily responsible for human H5N1 infections that have occurred during late 2005 and 2006, according to WHO. Genetic analysis has identified six subclades of clade 2, three of which have a distinct geographic distribution and have been implicated in human infections: - Subclade 1, Indonesia - Subclade 2, Middle East, Europe, and Africa - Subclade 3, China On the basis of the three subclades, the WHO is offering companies and other groups that are interested in pandemic vaccine development these three new prototype strains: - An A/Indonesia/2/2005-like virus - An A/Bar headed goose/Quinghai/1A/2005-like virus - An A/Anhui/1/2005-like virus [...] Until now, researchers have been working on prepandemic vaccines for H5N1 viruses in clade 1. In March, the first clinical trial of a U.S. vaccine for H5N1 showed modest results. In May, French researchers showed somewhat better results in a clinical trial of an H5N1 vaccine that included an adjuvant. Vaccine experts aren't sure if a vaccine effective against known H5N1 viral strains would be effective against future strains. Although the new viruses will now be available for vaccine research, WHO said clinical trials using the clade 1 viruses should continue as an essential step in pandemic preparedness, because the trials yield useful information on priming, cross-reactivity, and cross-protection by vaccine viruses from different clades and subclades."[39][40] As of November 2006, the United States Department of Health and Human Services still had enough H5N1 pre-pandemic vaccine to treat about 3 million people (5.9 million full-potency doses) in spite of 0.2 million doses used for research and 1.4 million doses that have begun to lose potency (from the original 7.5 million full-potency doses purchased from Sanofi Pasteur and Chiron Corp.). The expected shelf life of seasonal flu vaccine is about a year so the fact that most of the H5N1 pre-pandemic stockpile is still good after about 2 years is considered encouraging.[41] # Flu seasons ## 2003–2004 season (Northern Hemisphere) The production of flu vaccine requires a lead time of about six months before the season. It is possible that by flu season a strain becomes common for which the vaccine does not provide protection. In the 2003–2004 season the vaccine was produced to protect against A/Panama, A/New Caledonia, and B/Hong Kong. A new strain, A/Fujian, was discovered after production of the vaccine started and vaccination gave only partial protection against this strain. Nature magazine reported that the Influenza Genome Sequencing Project, using phylogenetic analysis of 156 H3N2 genomes, "explains the appearance, during the 2003–2004 season, of the 'Fujian/411/2002'-like strain, for which the existing vaccine had limited effectiveness" as due to an epidemiologically significant reassortment. "Through a reassortment event, a minor clade provided the haemagglutinin gene that later became part of the dominant strain after the 2002–2003 season. Two of our samples, A/New York/269/2003 (H3N2) and A/New York/32/2003 (H3N2), show that this minor clade continued to circulate in the 2003–2004 season, when most other isolates were reassortants." [42] According to the CDC: During September 28, 2003–May 22, 2004, WHO and NREVSS collaborating laboratories in the United States tested 130,577 respiratory specimens for influenza viruses; 24,649 (18.9%) were positive. Of these, 24,393 (99.0%) were influenza A viruses, and 249 (1.0%) were influenza B viruses. Among the influenza A viruses, 7,191 (29.5%) were subtyped; 7,189 (99.9%) were influenza A (H3N2) viruses, and two (0.1%) were influenza A (H1) viruses. The proportion of specimens testing positive for influenza first increased to >10% during the week ending October 25, 2003 (week 43), peaked at 35.2% during the week ending November 29 (week 48), and declined to <10% during the week ending January 17, 2004 (week 2). The peak percentage of specimens testing positive for influenza during the previous four seasons had ranged from 23% to 31% and peaked during late December to late February.[43] As of June 15, 2004, CDC had antigenically characterized 1,024 influenza viruses collected by U.S. laboratories since October 1, 2003: 949 influenza A (H3N2) viruses, three influenza A (H1) viruses, one influenza A (H7N2) virus, and 71 influenza B viruses. Of the 949 influenza A (H3N2) isolates characterized, 106 (11.2%) were similar antigenically to the vaccine strain A/Panama/2007/99 (H3N2), and 843 (88.8%) were similar to the drift variant, A/Fujian/411/2002 (H3N2). Of the three A (H1) isolates that were characterized, two were H1N1 viruses, and one was an H1N2 virus. The hemagglutinin proteins of the influenza A (H1) viruses were similar antigenically to the hemagglutinin of the vaccine strain A/New Caledonia/20/99. Of the 71 influenza B isolates that were characterized, 66 (93%) belonged to the B/Yamagata/16/88 lineage and were similar antigenically to B/Sichuan/379/99, and five (7%) belonged to the B/Victoria/2/87 lineage and were similar antigenically to the corresponding vaccine strain B/Hong Kong/330/2001.[43] In December 2003, one confirmed case of avian influenza A (H9N2) virus infection was reported in a child aged 5 years in Hong Kong. The child had fever, cough, and nasal discharge in late November, was hospitalized for 2 days, and fully recovered. The source of this child's H9N2 infection is unknown.[43] During January–March 2004, a total of 34 confirmed human cases of avian influenza A (H5N1) virus infection were reported in Vietnam and Thailand. The cases were associated with severe respiratory illness requiring hospitalization and a case-fatality proportion of 68% (Vietnam: 22 cases, 15 deaths; Thailand: 12 cases, eight deaths). A substantial proportion of the cases were among children and young adults (i.e., persons aged 5–24 years). These cases were associated with widespread outbreaks of highly pathogenic H5N1 influenza among domestic poultry.[43] During March 2004, health authorities in Canada reported two confirmed cases of avian influenza A (H7N3) virus infection in poultry workers who were involved in culling of poultry during outbreaks of highly pathogenic H7N3 on farms in the Fraser River Valley, British Columbia. One patient had unilateral conjunctivitis and nasal discharge, and the other had unilateral conjunctivitis and headache. Both illnesses resolved without hospitalization.[43] During the 2003–2004 influenza season, a case of avian influenza A (H7N2) virus infection was detected in an adult male from New York, who was hospitalized for upper and lower respiratory tract illness in November 2003. Influenza A (H7N2) virus was isolated from a respiratory specimen from the patient, whose acute symptoms resolved. The source of this person's infection is unknown.[43] ## 2004 season (Southern Hemisphere) The composition of influenza virus vaccines for use in the 2004 Southern Hemisphere influenza season recommended by the World Health Organization was: - an A/New Caledonia/20/99(H1N1)-like virus - an A/Fujian/411/2002(H3N2)-like virus (A/Kumamoto/102/2002 and A/Wyoming/3/2003 were egg-grown A/Fujian/411/2002-like viruses) - a B/Hong Kong/330/2001-like virus (B/Shandong/7/97, B/Hong Kong/330/2001 and B/Hong Kong/1434/2002 were among those used at the time. B/Brisbane/32/2002 was also available.) [44] [45] ## 2004–2005 season (Northern Hemisphere) According to the CDC: ## 2005 season (Southern Hemisphere) The composition of influenza virus vaccines for use in the 2005 Southern Hemisphere influenza season recommended by the World Health Organization was: - an A/New Caledonia/20/99(H1N1)-like virus; - an A/Wellington/1/2004(H3N2)-like virus; - a B/Shanghai/361/2002-like virus (B/Shanghai/361/2002, B/Jilin/20/2003 and B/Jiangsu/10/2003 were used at the time) [46] [47] ## 2005–2006 season (Northern Hemisphere) The vaccines produced for the 2005–2006 season use: - an A/New Caledonia/20/1999-like(H1N1); - an A/California/7/2004-like(H3N2) (or the antigenically equivalent strain A/New York/55/2004); - a B/Jiangsu/10/2003-like viruses. In people in the U.S., overall flu and pneumonia deaths were below those of a typical flu season with 84% Influenzavirus A and the rest Influenzavirus B. Of the patients who had Type A viruses, 80% had viruses identical or similar to the A bugs in the vaccine. 70% of the people testing positive for a B virus had Type B Victoria, a version not found in the vaccine.[48] "During the 2005–06 season, influenza A (H3N2) viruses predominated overall, but late in the season influenza B viruses were more frequently isolated than influenza A viruses. Influenza A (H1N1) viruses circulated at low levels throughout the season. Nationally, activity was low from October through early January, increased during February, and peaked in early March. Peak activity was less intense, but activity remained elevated for a longer period of time this season compared to the previous three seasons. The longer period of elevated activity may be due in part to regional differences in the timing of peak activity and intensity of influenza B activity later in the season."[49] ## 2006 season (Southern Hemisphere) The composition of influenza virus vaccines for use in the 2006 Southern Hemisphere influenza season recommended by the World Health Organization was: - an A/New Caledonia/20/99(H1N1)-like virus; - an A/California/7/2004(H3N2)-like virus (A/New York/55/2004 was used at the time); - a B/Malaysia/2506/2004-like virus [50] [51] ## 2006–2007 season (Northern Hemisphere) The 2006–2007 influenza vaccine composition recommended by the World Health Organization on February 15, 2006 and the U.S. FDA's Vaccines and Related Biological Products Advisory Committee (VRBPAC) on February 17, 2006 use: - an A/New Caledonia/20/99 (H1N1)-like virus; - an A/Wisconsin/67/2005 (H3N2)-like virus (A/Wisconsin/67/2005 and A/Hiroshima/52/2005 strains); - a B/Malaysia/2506/2004-like virus from B/Malaysia/2506/2004 and B/Ohio/1/2005 strains which are of B/Victoria/2/87 lineage. [52] ## 2007 season (Southern Hemisphere) The composition of influenza virus vaccines for use in the 2006 Southern Hemisphere influenza season recommended by the World Health Organization on September 20, 2006 [53] was: - an A/New Caledonia/20/99(H1N1)-like virus, - an A/Wisconsin/67/2005(H3N2)-like virus (A/Wisconsin/67/2005 and A/Hiroshima/52/2005 were used at the time), - a B/Malaysia/2506/2004-like virus [54] [55] ## 2007-2008 season (Northern Hemisphere) The composition of influenza virus vaccines for use in the 2007–2008 Northern Hemisphere influenza season recommended by the World Health Organization on February 14, 2007 [56] was: - an A/Solomon Islands/3/2006 (H1N1)-like virus; - an A/Wisconsin/67/2005 (H3N2)-like virus (A/Wisconsin/67/2005 (H3N2) and A/Hiroshima/52/2005 were used at the time); - a B/Malaysia/2506/2004-like virus [57] [58] ## 2008 season (Southern Hemisphere) The composition of virus vaccines for use in the 2006 Southern Hemisphere influenza season recommended by the World Health Organization on September 17-19, 2007 was: - an A/Solomon Islands/3/2006 (H1N1)-like virus; - an A/Brisbane/10/2007 (H3N2)-like virus; - a B/Florida/4/2006-like virus [59][60] # Flu vaccine for nonhumans "Vaccination in the veterinary world pursues four goals: (i) protection from clinical disease, (ii) protection from infection with virulent virus, (iii) protection from virus excretion, and (iv) serological differentiation of infected from vaccinated animals (so-called DIVA principle). In the field of influenza vaccination, neither commercially available nor experimentally tested vaccines have been shown so far to fulfil all of these requirements."[61] ## Horses Horses with horse flu can run a fever, have a dry hacking cough, have a runny nose, and become depressed and reluctant to eat or drink for several days but usually recover in 2 to 3 weeks. "Vaccination schedules generally require a primary course of 2 doses, 3–6 weeks apart, followed by boosters at 6–12 month intervals. It is generally recognised that in many cases such schedules may not maintain protective levels of antibody and more frequent administration is advised in high-risk situations."[62] ## Poultry Poultry vaccines for bird flu are made on the cheap and are not filtered and purified like human vaccines to remove bits of bacteria or other viruses. They usually contain whole virus, not just hemagglutin as in most human flu vaccines. Purification to standards needed for humans is far more expensive than the original creation of the unpurified vaccine from eggs. There is no market for veterinary vaccines that are that expensive. Another difference between human and poultry vaccines is that poultry vaccines are adjuvated with mineral oil, which induces a strong immune reaction but can cause inflammation and abscesses. "Chicken vaccinators who have accidentally jabbed themselves have developed painful swollen fingers or even lost thumbs, doctors said. Effectiveness may also be limited. Chicken vaccines are often only vaguely similar to circulating flu strains — some contain an H5N2 strain isolated in Mexico years ago. 'With a chicken, if you use a vaccine that's only 85 percent related, you'll get protection,' Dr. Cardona said. 'In humans, you can get a single point mutation, and a vaccine that's 99.99 percent related won't protect you.' And they are weaker [than human vaccines]. 'Chickens are smaller and you only need to protect them for six weeks, because that's how long they live till you eat them,' said Dr. John J. Treanor, a vaccine expert at the University of Rochester. Human seasonal flu vaccines contain about 45 micrograms of antigen, while an experimental A(H5N1) vaccine contains 180. Chicken vaccines may contain less than 1 microgram. 'You have to be careful about extrapolating data from poultry to humans,' warned Dr. David E. Swayne, director of the agriculture department's Southeast Poultry Research Laboratory. 'Birds are more closely related to dinosaurs.'"[63] Researchers, led by Nicholas Savill of the University of Edinburgh in Scotland, used mathematical models to simulate the spread of H5N1 and concluded that "at least 95 per cent of birds need to be protected to prevent the virus spreading silently. In practice, it is difficult to protect more than 90 per cent of a flock; protection levels achieved by a vaccine are usually much lower than this."[64] ## Pigs Swine influenza virus (SIV) vaccines are extensively used in the swine industry in Europe and North America. Most swine flu vaccine manufacturers include an H1N1 and an H3N2 SIV strains. Swine influenza has become a greater problem in recent decades. Evolution of the virus has resulted in inconsistent responses to traditional vaccines. Standard commercial swine flu vaccines are effective in controlling the problem when the virus strains match enough to have significant cross-protection and custom (autogenous) vaccines made from the specific viruses isolated are created and used in the more difficult cases.[65] SIV vaccine manufacture Novartis paints this picture: "A strain of swine influenza virus (SIV) called H3N2, first identified in the US in 1998, has brought exasperating production losses to swine producers. Abortion storms are a common sign. Sows go off feed for two or three days and run a fever up to 106° F. Mortality in a naïve herd can run as high as 15%."[66]	https://www.wikidoc.org/index.php/Flu_vaccine
52a151443ebc1e29f3519f71ebab757d4c52a33c	wikidoc	Fluid ounce	Fluid ounce A fluid ounce (abbreviated fl oz, fl. oz. or oz. fl.) is a unit of volume in both the imperial and the US customary systems. It is common to refer to the unit simply as an ounce, especially in cases where no confusion with the unit of mass is likely to occur. # Definitions Given the definitions above, we can calculate how many US fluid ounces are in one liter: There are thus about 34 fluid ounces in one liter. # References and notes - ↑ The imperial gallon was originally defined as the volume occupied by ten avoirdupois pounds at 62 °F (16.7 °C), weighed in air with brass weights. - ↑ Jump up to: 2.0 2.1 "The Units of Measurement Regulations 1995". 2000-09-20. Retrieved 2006-04-18..mw-parser-output cite.citation{font-style:inherit}.mw-parser-output q{quotes:"\"""\"""'""'"}.mw-parser-output code.cs1-code{color:inherit;background:inherit;border:inherit;padding:inherit}.mw-parser-output .cs1-lock-free a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-limited a,.mw-parser-output .cs1-lock-registration a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-subscription a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration{color:#555}.mw-parser-output .cs1-subscription span,.mw-parser-output .cs1-registration span{border-bottom:1px dotted;cursor:help}.mw-parser-output .cs1-hidden-error{display:none;font-size:100%}.mw-parser-output .cs1-visible-error{display:none;font-size:100%}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration,.mw-parser-output .cs1-format{font-size:95%}.mw-parser-output .cs1-kern-left,.mw-parser-output .cs1-kern-wl-left{padding-left:0.2em}.mw-parser-output .cs1-kern-right,.mw-parser-output .cs1-kern-wl-right{padding-right:0.2em} - ↑ Jump up to: 3.0 3.1 One U.S. gallon is defined as 231 cubic inches. - ↑ Jump up to: 4.0 4.1 4.2 This assumes the international inch of exactly 25.4 millimetres. - ↑ "Food and Drug Administration, HHS" (PDF). Retrieved 2006-04-18. de:Fluid ounce ko:플루이드 온스 it:Oncia liquida nl:Fluid ounce simple:Fluid ounce	Fluid ounce Template:Wiktionarypar A fluid ounce (abbreviated fl oz, fl. oz. or oz. fl.) is a unit of volume in both the imperial and the US customary systems. It is common to refer to the unit simply as an ounce, especially in cases where no confusion with the unit of mass is likely to occur. # Definitions Given the definitions above, we can calculate how many US fluid ounces are in one liter: 1/29.5735295625 * 1000 = 33.8140 There are thus about 34 fluid ounces in one liter. # References and notes - ↑ The imperial gallon was originally defined as the volume occupied by ten avoirdupois pounds at 62 °F (16.7 °C), weighed in air with brass weights. - ↑ Jump up to: 2.0 2.1 "The Units of Measurement Regulations 1995". 2000-09-20. Retrieved 2006-04-18..mw-parser-output cite.citation{font-style:inherit}.mw-parser-output q{quotes:"\"""\"""'""'"}.mw-parser-output code.cs1-code{color:inherit;background:inherit;border:inherit;padding:inherit}.mw-parser-output .cs1-lock-free a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/6/65/Lock-green.svg/9px-Lock-green.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-limited a,.mw-parser-output .cs1-lock-registration a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/d/d6/Lock-gray-alt-2.svg/9px-Lock-gray-alt-2.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-subscription a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/a/aa/Lock-red-alt-2.svg/9px-Lock-red-alt-2.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration{color:#555}.mw-parser-output .cs1-subscription span,.mw-parser-output .cs1-registration span{border-bottom:1px dotted;cursor:help}.mw-parser-output .cs1-hidden-error{display:none;font-size:100%}.mw-parser-output .cs1-visible-error{display:none;font-size:100%}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration,.mw-parser-output .cs1-format{font-size:95%}.mw-parser-output .cs1-kern-left,.mw-parser-output .cs1-kern-wl-left{padding-left:0.2em}.mw-parser-output .cs1-kern-right,.mw-parser-output .cs1-kern-wl-right{padding-right:0.2em} - ↑ Jump up to: 3.0 3.1 One U.S. gallon is defined as 231 cubic inches. - ↑ Jump up to: 4.0 4.1 4.2 This assumes the international inch of exactly 25.4 millimetres. - ↑ "Food and Drug Administration, HHS" (PDF). Retrieved 2006-04-18. de:Fluid ounce ko:플루이드 온스 it:Oncia liquida nl:Fluid ounce simple:Fluid ounce Template:WikiDoc Sources	https://www.wikidoc.org/index.php/Fluid_ounce
d72ea00ebbb91d4136991073679f9000397a40f4	wikidoc	Rimantadine	Rimantadine # Disclaimer WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here. # Overview Rimantadine is a adamantane, anti-infective agent , antiviral that is FDA approved for the treatment of and for the prophylaxis of illness caused by various strains of influenza A virus in adults (17 years and older) and for prophylaxis against influenza A virus in children (1 year to 16 years of age).. Common adverse reactions include abdominal pain, loss of appetite, nausea, vomiting, xerostomia, asthenia dizziness, nervousness, headache, insomnia, fatigue. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) - Flumadine is indicated for the prophylaxis and treatment of illness caused by various strains of influenza A virus in adults (17 years and older). ### PROPHYLAXIS: - In controlled studies of children (1 year to 16 years of age), healthy adults (17 years and older), and elderly patients (65 yeas of age and older), Flumadine has been shown to be safe and effective in preventing signs and symptoms of infection caused by various strains of influenza A virus. Since Flumadine does not completely prevent the host immune response to influenza A infection, individuals who take this drug may still develop immune responses to natural disease or vaccination and may be protected when later exposed to antigenically-related viruses. Following vaccination during an influenza outbreak, Flumadine prophylaxis should be considered for the 2 to 4 week time period required to develop an antibody response. However, the safety and effectiveness of Flumadine prophylaxis have not been demonstrated for longer than 6 weeks. ### TREATMENT: - Flumadine therapy should be considered for adults (17 years and older) who develop an influenza-like illness during known or suspected influenza A infection in the community. When administered within 48 hours after onset of signs and symptoms of infection caused by influenza A virus strains, Flumadine has been shown to reduce the duration of fever and systemic symptoms. - The following points should be considered before initiating treatment or prophylaxis with FLUMADINE: - FLUMADINE is not a substitute for early vaccination on an annual basis as recommended by the :- Centers for Disease Control and Prevention Advisory Committee on Immunization Practices. - Influenza viruses change over time. Emergence of resistance mutations could decrease drug effectiveness. Other factors (for example, changes in viral virulence) might also diminish clinical benefit of antiviral drugs. Prescribers should consider available information on influenza drug susceptibility patterns and treatment effects when deciding whether to use FLUMADINE. ### Dosing Information - Adults( 17 years and older): - The recommended adult dose of Flumadine is 100 mg twice a day. Study durations ranged from 11 days to 6 weeks in adult and elderly patients. In patients with severe hepatic dysfunction, severe renal impairment (CrCl 5 to 29 mL/min) or renal failure (CrCI ≤ 10 mL/min) and elderly nursing home patients, a dose reduction to 100 mg daily is recommended. Because of the potential for accumulation of rimantadine metabolites during multiple dosing, patients with hepatic or renal impairment should be monitored for adverse effects. - Adults(17 years and older): - The recommended adult dose of Flumadine is 100 mg twice a day for 7 days. In patients with severe hepatic dysfunction, severe renal impairment (CrCl 5 to 29 mL/min) or renal failure (CrCI ≤ 10 mL/ min) and elderly nursing home patients, a dose reduction to 100 mg daily is recommended. Because of the potential for accumulation of rimantadine metabolites during multiple dosing, patients with hepatic or renal impairment should be monitored for adverse effects. Flumadine therapy should be initiated as soon as possible, preferably within 48 hours after onset of signs and symptoms of influenza A infection. Therapy should be continued for approximately seven days from the initial onset of symptoms. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Rimantadine in adult patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Rimantadine in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) - Flumadine is indicated for prophylaxis against influenza A virus in children (1 year to 16 years of age). ### Dosing Information - Children (1 year to 16 years of age): - Study durations ranged from 5 weeks to 6 weeks in pediatric patients. - In children 1 year to 9 years of age, Flumadine should be administered once a day, at a dose of 5 mg/kg but not exceeding 150 mg. - For children 10 to 16 years of age, use the adult dose. (see DIRECTIONS FOR COMPOUNDING OF AN ORAL SUSPENSION FROM FLUMADINE TABLETS to prepare an oral suspension for administration to children and patients with difficulty swallowing tablets). - Children(Birth to 11 months): - The safety and efficacy of Flumadine for prophylaxis of influenza in pediatric patients younger than 1 year of age have not been established. - Children (16 years of age and younger): - Flumadine is not indicated for treatment of influenza in pediatric patients 16 years or younger. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Rimantadine in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Rimantadine in pediatric patients. # Contraindications - Flumadine is contraindicated in patients with known hypersensitivity to drugs of the adamantane class, including rimantadine and amantadine. # Warnings ### PRECAUTIONS - An increased incidence of seizures has been reported in patients with a history of epilepsy who received the related drug amantadine. In clinical trials of Flumadine, the occurrence of seizure-like activity was observed in a small number of patients with a history of seizures who were not receiving anticonvulsant medication while taking Flumadine. If seizures develop, Flumadine should be discontinued. - The safety and pharmacokinetics of rimantadine in hepatic insufficiency have only been evaluated after single dose administration. In a study of 14 persons with chronic liver disease (mostly stabilized cirrhotics), no alterations in the pharmacokinetics were observed after the administration of a single dose of rimantadine. However, the apparent clearance of rimantadine following a single dose to 10 patients with severe liver dysfunction was 50% lower than reported for healthy subjects. Because of the potential for accumulation of rimantadine and its metabolites in plasma, caution should be exercised when patients with hepatic insufficiency are treated with rimantadine. - Following multiple-dose administration of rimantadine, there were no clinically relevant differences in rimantadine systemic exposure between subjects with mild or moderate renal impairment compared to healthy subjects. In subjects with severe renal impairment, rimantadine systemic exposure increased by 81%, compared with healthy subjects. Because of the potential for increased accumulation of rimantadine metabolites in renally impaired subjects, caution should be exercised when these patients are treated with rimantadine. - Transmission of rimantadine resistant virus should be considered when treating patients whose contacts are at high risk for influenza A illness. Influenza A virus strains resistant to rimantadine can emerge during treatment and such resistant strains have been shown to be transmissible and to cause typical influenza illness (Ref. 3). Although the frequency, rapidity, and clinical significance of the emergence of drug-resistant virus are not yet established, several small studies have demonstrated that 10% to 30% of patients with initially sensitive virus, upon treatment with rimantadine, shed rimantadine resistant virus. (Ref. 3, 4, 5, 6) - Clinical response to rimantadine, although slower in those patients who subsequently shed resistant virus, was not significantly different from those who did not shed resistant virus. (Ref. 3) No data are available in humans that address the activity or effectiveness of rimantadine therapy in subjects infected with resistant virus. - Serious bacterial infections may begin with influenza-like symptoms or may coexist with or occur as complications during the course of influenza. FLUMADINE has not been shown to prevent such complications. # Adverse Reactions ## Clinical Trials Experience - In 1,027 patients treated with Flumadine in controlled clinical trials at the recommended dose of 200 mg daily, the most frequently reported adverse events involved the gastrointestinal and nervous systems. - Incidence >1 %: Adverse events reported most frequently (1-3%) at the recommended dose in controlled clinical trials are shown in the table below. table - Less frequent adverse events (0.3 to 1%) at the recommended dose in controlled clinical trials were: - Gastrointestinal System: Diarrhea, dyspepsia; Nervous System: impairment of concentration, ataxia, somnolence, agitation, depression; Skin and Appendages: rash; Hearing and Vestibular: tinnitus;Respiratory: dyspnea. - Additional adverse events (less than 0.3%) reported at recommended doses in controlled clinical trials were: Nervous System: gait abnormality, euphoria, hyperkinesia, tremor, hallucination, confusion, convulsions; Respiratory: bronchospasm, cough; Cardiovascular: pallor, palpitation, hypertension, cerebrovascular disorder, cardiac failure, pedal edema, heart block, tachycardia, syncope; Reproduction: non-puerperal lactation; Special Senses: taste loss/change, parosmia. Rates of adverse events, particularly those involving the gastrointestinal and nervous systems, increased significantly in controlled studies using higher than recommended doses of Flumadine. In most cases, symptoms resolved rapidly with discontinuation of treatment. In addition to the adverse events reported above, the following were also reported at higher than recommended doses: increased lacrimation, increased micturition frequency, fever, rigors, agitation, constipation, diaphoresis, dysphagia, stomatitis, hypesthesia and eye pain. - Adverse Reactions in Trials of Rimantadine and Amantadine: In a six-week prophylaxis study of 436 healthy adults comparing rimantadine with amantadine and placebo, the following adverse reactions were reported with an incidence >1 %. TABLE ## Postmarketing Experience There is limited information regarding Postmarketing Experience of Rimantadine in the drug label. # Drug Interactions - Acetaminophen: Flumadine, 100 mg, was given twice daily for 13 days to 12 healthy volunteers. On day 11, acetaminophen (650 mg four times daily) was started and continued for 8 days. The pharmacokinetics of rimantadine were assessed on days 11 and 13. Coadministration with acetaminophen reduced the peak concentration and AUC values for rimantadine by approximately 11%. - Flumadine, 100 mg, was given twice daily for 13 days to 12 healthy volunteers. On day 11, aspirin (650 mg, four times daily) was started and continued for 8 days. The pharmacokinetics of rimantadine were assessed on days 11 and 13. Peak plasma concentrations and AUC of rimantadine were reduced approximately 10% in the presence of aspirin. - When a single 100 mg dose of Flumadine was administered with steady-state cimetidine (300 mg four times a day), there were no statistically significant differences in rimantadine Cmax or AUC between Flumadine alone and Flumadine in the presence of cimetidine. - The concurrent use of Flumadine® with live attenuated intranasal influenza vaccine has not been evaluated. However, because of potential interference between these products, the live attenuated intranasal influenza vaccine should not be administered until 48 hours after cessation of Flumadine® and Flumadine® should not be administered until two weeks after the administration of live attenuated intranasal influenza vaccine unless medically indicated. The concern about potential interference arises principally from the potential for antiviral drugs to inhibit replication of live vaccine virus. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): C - There are no adequate and well-controlled studies in pregnant women. Rimantadine is reported to cross the placenta in mice. Rimantadine has been shown to be embryotoxic in rats when given at a dose of 200 mg/kg/d (11 times the MRHD based on mg/m2). At this dose the embryotoxic effect consisted of increased fetal resorption in rats; this dose also produced a variety of maternal effects including ataxia, tremors, convulsions and significantly reduced weight gain. No embryotoxicity was observed when rabbits were given doses up to 50 mg/kg/d (approximately 0.1 times the MRHD based on AUC), but evidence of a developmental abnormality in the form of a change in the ratio of fetuses with 12 or 13 ribs was noted. This ratio is normally about 50:50 in a litter but was 80:20 after rimantadine treatment. However, in a repeat embryofetal toxicity study in rabbits at doses up to 50 mg/kg/d (approximately 0.1 times the MRHD based on AUC), this abnormality was not observed. - Rimantadine was administered to pregnant rats in a peri- and postnatal reproduction toxicity study at doses of 30, 60 and 120 mg/kg/d(1.7, 3.4 and 6.8 times the MRHD based on mg/m2). Maternal toxicity during gestation was noted at the two higher doses of rimantadine, and at the highest dose, 120 mg/kg/day, there was an increase in pup mortality during the first 2 to 4 days postpartum. Decreased fertility of the F1 generation was also noted for the two higher doses. - For these reasons, Flumadine should be used during pregnancy only if the potential benefit justifies the risk to the fetus. Pregnancy Category (AUS): - Australian Drug Evaluation Committee (ADEC) Pregnancy Category There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Rimantadine in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Rimantadine during labor and delivery. ### Nursing Mothers - Flumadine should not be administered to nursing mothers because of the adverse effects noted in offspring of rats treated with rimantadine during the nursing period. Rimantadine is concentrated in rat milk in a dose-related manner: 2 to 3 hours following administration of rimantadine, rat breast milk levels were approximately twice those observed in the serum. ### Pediatric Use - In children (1 year to 16 years of age), Flumadine is recommended for the prophylaxis of influenza A. The safety and effectiveness of Flumadine in the treatment of symptomatic influenza infection in children (1 year to 16 years of age) have not been established. Prophylaxis studies with Flumadine have not been performed in children below the age of 1 year. ### Geriatic Use - Approximately 200 patients over the age of 64 were evaluated for safety in controlled clinical trials with Flumadine® (rimantadine hydrochloride). Geriatric subjects who received either 200 mg or 400 mg of rimantadine daily for 1 to 50 days experienced considerably more central nervous system and gastrointestinal adverse events than comparable geriatric subjects receiving placebo. Central nervous system events including dizziness, headache, anxiety, asthenia, and fatigue, occurred up to two times more often in subjects treated with rimantadine than in those treated with placebo. Gastrointestinal symptoms, particularly nausea, vomiting, and abdominal pain occurred at least twice as frequently in subjects receiving rimantadine than in those receiving placebo. The gastrointestinal symptoms appeared to be dose related. In patients over 64, the recommended dose is 100 mg, daily. ### Gender There is no FDA guidance on the use of Rimantadine with respect to specific gender populations. ### Race There is no FDA guidance on the use of Rimantadine with respect to specific racial populations. ### Renal Impairment There is no FDA guidance on the use of Rimantadine in patients with renal impairment. ### Hepatic Impairment There is no FDA guidance on the use of Rimantadine in patients with hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Rimantadine in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Rimantadine in patients who are immunocompromised. # Administration and Monitoring ### Administration - Oral ### Monitoring There is limited information regarding Monitoring of Rimantadine in the drug label. - Description # IV Compatibility There is limited information regarding IV Compatibility of Rimantadine in the drug label. # Overdosage - As with any overdose, supportive therapy should be administered as indicated. Overdoses of a related drug, amantadine, have been reported with adverse reactions consisting of agitation, hallucinations, cardiac arrhythmia and death. The administration of intravenous physostigmine (a cholinergic agent) at doses of 1 to 2 mg in adults (Ref. 7) and 0.5 mg in children (Ref. 8) repeated as needed as long as the dose did not exceed 2 mg/hour has been reported anecdotally to be beneficial in patients with central nervous system effects from overdoses of amantadine. # Pharmacology There is limited information regarding Rimantadine Pharmacology in the drug label. ## Mechanism of Action - The mechanism of action of rimantadine is not fully understood. Rimantadine appears to exert its inhibitory effect early in the viral replicative cycle, possibly inhibiting the uncoating of the virus. Genetic studies suggest that a virus protein specified by the virion M2 gene plays an important role in the susceptibility of influenza A virus to inhibition by rimantadine. ## Structure - Flumadine® (rimantadine hydrochloride) is a synthetic antiviral drug available as a 100 mg film-coated tablet. Each film-coated tablet contains 100 mg of rimantadine hydrochloride plus hypromellose, magnesium stearate, microcrystalline cellulose, sodium starch glycolate, FD&C Yellow No. 6 Lake and FD&C Yellow No. 6. The film coat contains hypromellose and polyethylene glycol. - Rimantadine hydrochloride is a white to off-white crystalline powder which is freely soluble in water (50 mg/mL at 20°C). Chemically, rimantadine hydrochloride is alpha-methyltricyclo-decane-1-methanamine hydrochloride, with an empirical formula of C12H21NHCI, a molecular weight of 215.77 and the following structural formula: ## Pharmacodynamics ### MICROBIOLOGY: - Rimantadine inhibits the replication in cell culture of influenza A virus isolates from each of the three antigenic subtypes, i.e., H1N1, H2N2 and H3N2, that have been isolated from man. Rimantadine has little or no activity against influenza B virus (Ref. 1,2). Rimantadine does not appear to interfere with the immunogenicity of inactivated influenza A vaccine. - A quantitative relationship between the susceptibility in cell culture of influenza A virus to rimantadine and clinical response to therapy has not been established. - Susceptibility test results, expressed as the concentration of the drug required to inhibit virus replication by 50% or more in a cell culture system, vary greatly (from 18 nM to 93 μgM) depending upon the assay protocol used, size of the virus inoculum, isolates of the influenza A virus strains tested, and the cell types used (Ref. 2). - Influenza A virus isolates resistant to rimantadine have been selected in cell culture and in vivo as a result of treatment. Rimantadine-resistant strains of influenza A virus have emerged among freshly isolated strains in closed settings where rimantadine has been used. Resistant viruses have been shown to be transmissible and to cause typical influenza illness. (Ref. 3,9). Substitutions at any one of 5 amino acid positions in the transmembrane domain of M2 confer resistance to rimantadine. The most common substitution causing resistance among influenza A (H1N1) and A (H3N2) is S31N. Other less common substitutions that cause resistance include substitutions A30F, V27A, V30A, and L26F. - Rimantadine resistance has been observed in circulating seasonal influenza and pandemic isolates from individuals who have not received rimantadine. Swine-origin influenza A (H1N1) (S-OIV) viruses that were resistant to rimantadine have been shown to contain the S31N substitution. Existing primers used for detection of adamantine resistance in seasonal viruses do not work with all tested S-OIVs (Ref. 11). The CDC should be consulted for questions regarding resistance to rimantadine in circulating influenza strains. - Cross-resistance among the adamantanes rimantadine and amantadine has been observed. Resistance to rimantadine confers cross-resistance to amantadine and vice-versa. Substitutions that confer resistance to rimantadine include (most frequently) M2 S31N, as well as the less common changes V27A, V30A, L26F and A30T (Ref. 10). ## Pharmacokinetics - Although the pharmacokinetic profile of Flumadine has been described, no pharmacodynamic data establishing a correlation between plasma concentration and its antiviral effect are available. - Flumadine is absorbed after oral administration. The mean ± SD peak plasma concentration after a single 100 mg dose of Flumadine was 74 ± 22 ng/mL (range: 45 to 138 ng/mL). The time to peak concentration was 6 ± 1 hours in healthy adults (age 20 to 44 years). The single dose elimination half-life in this population was 25.4 ± 6.3 hours (range: 13 to 65 hours). The single dose elimination half-life in a group of healthy 71 to 79 year-old subjects was 32 ± 16 hours (range: 20 to 65 hours). - After the administration of rimantadine 100 mg twice daily to healthy volunteers (age 18 to 70 years) for 10 days, area under the curve (AUC) values were approximately 30% greater than predicted from a single dose. Plasma trough levels at steady state ranged between 118 and 468 ng/mL. In these patients no age-related differences in pharmacokinetics were detected. However, in a comparison of three groups of healthy older subjects (age 50-60, 61-70 and 71-79 years), the 71 to 79 year-old group had average AUC values, peak concentrations and elimination half-life values at steady state that were 20 to 30% higher than the other two groups. Steady-state concentrations in elderly nursing home patients (age 68 to 102 years) were 2- to 4-fold higher than those seen in healthy young and elderly adults. - The pharmacokinetic profile of rimantadine in children has not been established. - Following oral administration, rimantadine is extensively metabolized in the liver with less than 25% of the dose excreted in the urine as unchanged drug. Three hydroxylated metabolites have been found in plasma. These metabolites, an additional conjugated metabolite and parent drug account for 74 ± 10% (n=4) of a single 200 mg dose of rimantadine excreted in urine over 72 hours. - In a group (n=14) of patients with chronic liver disease, the majority of whom were stabilized cirrhotics, the pharmacokinetics of rimantadine were not appreciably altered following a single 200 mg oral dose compared to 6 healthy subjects who were sex, age and weight matched to 6 of the patients with liver disease. After administration of a single 200 mg dose to patients (n=10) with severe hepatic dysfunction, AUC was approximately 3-fold larger, elimination half-life was approximately 2-fold longer and apparent clearance was about 50% lower when compared to historic data from healthy subjects. - Rimantadine pharmacokinetics were evaluated following administration of 100 mg Flumadine twice daily for 14 days to subjects with mild (creatinine clearance 50-80 mL/min), moderate (CrCL 30-49 mL/min), and severe (CrCl 5-29 mL/min) renal impairment and to healthy subjects (CrCl > 80 mL/min). There were no clinically relevant differences in rimantadine Cmax, Cmin, and AUC0-τ between subjects with mild or moderate renal impairment compared to healthy subjects. In subjects with severe renal impairment, rimantadine Cmax, Cmin, and AUC0-τ on Day 14 increased by 75%, 82%, and 81%, respectively, compared with healthy subjects. The rimantadine elimination half-life was slightly prolonged (increase of 18% or less) in subjects with mild and moderate renal impairment but increased by 49% in subjects with severe renal impairment compared to healthy subjects. - After a single 200 mg oral dose of rimantadine was given to 8 hemodialysis patients (CrCl 0-10 mL/min), there was a 1.6-fold increase in the elimination half-life and a 40% decrease in apparent clearance compared to age-matched healthy subjects. Hemodialysis did not contribute to the clearance of rimantadine. - The in vitro human plasma protein binding of rimantadine is about 40% over typical plasma concentrations. Albumin is the major binding protein. ## Nonclinical Toxicology ### Carcinogenesis, Mutagenesis and Impairment of Fertility - Oral administration of rimantadine to rats for 2 years at doses up to 100 mg/kg/d showed no evidence of increased tumor incidence. - No mutagenic effects were seen when rimantadine was evaluated in several standard assays for mutagenicity. - A reproduction study in male and female rats did not show detectable impairment of fertility at dosages up to 60 mg/kg/d (3 times the MRHD based on mg/m2). # Clinical Studies There is limited information regarding Clinical Studies of Rimantadine in the drug label. # How Supplied - Flumadine® tablets (rimantadine hydrochloride tablets) are supplied as 100 mg tablets (orange, oval-shaped, film-coated) in bottles of 100 (NDC 49708- 521-88). Imprint on tablets: (Front) FLUMADINE 100; (Back) FOREST. ## Storage - Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F) # Images ## Drug Images ## Package and Label Display Panel NDC 49708-521-88 Flumadine® Tablets (rimantadine hydrochloride tablets) Each tablet contains 100 mg rimantadine hydrochloride Rx only 100 Tablets Distributed by: Caraco Pharmaceutical Laboratories, Ltd. Detroit, MI 48202 # Patient Counseling Information There is limited information regarding Patient Counseling Information of Rimantadine in the drug label. # Precautions with Alcohol - Alcohol-Rimantadine interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - Flumadine® # Look-Alike Drug Names There is limited information regarding Rimantadine Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	Rimantadine Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Adeel Jamil, M.D. [2] # Disclaimer WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here. # Overview Rimantadine is a adamantane, anti-infective agent , antiviral that is FDA approved for the treatment of and for the prophylaxis of illness caused by various strains of influenza A virus in adults (17 years and older) and for prophylaxis against influenza A virus in children (1 year to 16 years of age).. Common adverse reactions include abdominal pain, loss of appetite, nausea, vomiting, xerostomia, asthenia dizziness, nervousness, headache, insomnia, fatigue. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) - Flumadine is indicated for the prophylaxis and treatment of illness caused by various strains of influenza A virus in adults (17 years and older). ### PROPHYLAXIS: - In controlled studies of children (1 year to 16 years of age), healthy adults (17 years and older), and elderly patients (65 yeas of age and older), Flumadine has been shown to be safe and effective in preventing signs and symptoms of infection caused by various strains of influenza A virus. Since Flumadine does not completely prevent the host immune response to influenza A infection, individuals who take this drug may still develop immune responses to natural disease or vaccination and may be protected when later exposed to antigenically-related viruses. Following vaccination during an influenza outbreak, Flumadine prophylaxis should be considered for the 2 to 4 week time period required to develop an antibody response. However, the safety and effectiveness of Flumadine prophylaxis have not been demonstrated for longer than 6 weeks. ### TREATMENT: - Flumadine therapy should be considered for adults (17 years and older) who develop an influenza-like illness during known or suspected influenza A infection in the community. When administered within 48 hours after onset of signs and symptoms of infection caused by influenza A virus strains, Flumadine has been shown to reduce the duration of fever and systemic symptoms. - The following points should be considered before initiating treatment or prophylaxis with FLUMADINE: - FLUMADINE is not a substitute for early vaccination on an annual basis as recommended by the :* Centers for Disease Control and Prevention Advisory Committee on Immunization Practices. - Influenza viruses change over time. Emergence of resistance mutations could decrease drug effectiveness. Other factors (for example, changes in viral virulence) might also diminish clinical benefit of antiviral drugs. Prescribers should consider available information on influenza drug susceptibility patterns and treatment effects when deciding whether to use FLUMADINE. ### Dosing Information - Adults( 17 years and older): - The recommended adult dose of Flumadine is 100 mg twice a day. Study durations ranged from 11 days to 6 weeks in adult and elderly patients. In patients with severe hepatic dysfunction, severe renal impairment (CrCl 5 to 29 mL/min) or renal failure (CrCI ≤ 10 mL/min) and elderly nursing home patients, a dose reduction to 100 mg daily is recommended. Because of the potential for accumulation of rimantadine metabolites during multiple dosing, patients with hepatic or renal impairment should be monitored for adverse effects. - Adults(17 years and older): - The recommended adult dose of Flumadine is 100 mg twice a day for 7 days. In patients with severe hepatic dysfunction, severe renal impairment (CrCl 5 to 29 mL/min) or renal failure (CrCI ≤ 10 mL/ min) and elderly nursing home patients, a dose reduction to 100 mg daily is recommended. Because of the potential for accumulation of rimantadine metabolites during multiple dosing, patients with hepatic or renal impairment should be monitored for adverse effects. Flumadine therapy should be initiated as soon as possible, preferably within 48 hours after onset of signs and symptoms of influenza A infection. Therapy should be continued for approximately seven days from the initial onset of symptoms. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Rimantadine in adult patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Rimantadine in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) - Flumadine is indicated for prophylaxis against influenza A virus in children (1 year to 16 years of age). ### Dosing Information - Children (1 year to 16 years of age): - Study durations ranged from 5 weeks to 6 weeks in pediatric patients. - In children 1 year to 9 years of age, Flumadine should be administered once a day, at a dose of 5 mg/kg but not exceeding 150 mg. - For children 10 to 16 years of age, use the adult dose. (see DIRECTIONS FOR COMPOUNDING OF AN ORAL SUSPENSION FROM FLUMADINE TABLETS to prepare an oral suspension for administration to children and patients with difficulty swallowing tablets). - Children(Birth to 11 months): - The safety and efficacy of Flumadine for prophylaxis of influenza in pediatric patients younger than 1 year of age have not been established. - Children (16 years of age and younger): - Flumadine is not indicated for treatment of influenza in pediatric patients 16 years or younger. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Rimantadine in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Rimantadine in pediatric patients. # Contraindications - Flumadine is contraindicated in patients with known hypersensitivity to drugs of the adamantane class, including rimantadine and amantadine. # Warnings ### PRECAUTIONS - An increased incidence of seizures has been reported in patients with a history of epilepsy who received the related drug amantadine. In clinical trials of Flumadine, the occurrence of seizure-like activity was observed in a small number of patients with a history of seizures who were not receiving anticonvulsant medication while taking Flumadine. If seizures develop, Flumadine should be discontinued. - The safety and pharmacokinetics of rimantadine in hepatic insufficiency have only been evaluated after single dose administration. In a study of 14 persons with chronic liver disease (mostly stabilized cirrhotics), no alterations in the pharmacokinetics were observed after the administration of a single dose of rimantadine. However, the apparent clearance of rimantadine following a single dose to 10 patients with severe liver dysfunction was 50% lower than reported for healthy subjects. Because of the potential for accumulation of rimantadine and its metabolites in plasma, caution should be exercised when patients with hepatic insufficiency are treated with rimantadine. - Following multiple-dose administration of rimantadine, there were no clinically relevant differences in rimantadine systemic exposure between subjects with mild or moderate renal impairment compared to healthy subjects. In subjects with severe renal impairment, rimantadine systemic exposure increased by 81%, compared with healthy subjects. Because of the potential for increased accumulation of rimantadine metabolites in renally impaired subjects, caution should be exercised when these patients are treated with rimantadine. - Transmission of rimantadine resistant virus should be considered when treating patients whose contacts are at high risk for influenza A illness. Influenza A virus strains resistant to rimantadine can emerge during treatment and such resistant strains have been shown to be transmissible and to cause typical influenza illness (Ref. 3). Although the frequency, rapidity, and clinical significance of the emergence of drug-resistant virus are not yet established, several small studies have demonstrated that 10% to 30% of patients with initially sensitive virus, upon treatment with rimantadine, shed rimantadine resistant virus. (Ref. 3, 4, 5, 6) - Clinical response to rimantadine, although slower in those patients who subsequently shed resistant virus, was not significantly different from those who did not shed resistant virus. (Ref. 3) No data are available in humans that address the activity or effectiveness of rimantadine therapy in subjects infected with resistant virus. - Serious bacterial infections may begin with influenza-like symptoms or may coexist with or occur as complications during the course of influenza. FLUMADINE has not been shown to prevent such complications. # Adverse Reactions ## Clinical Trials Experience - In 1,027 patients treated with Flumadine in controlled clinical trials at the recommended dose of 200 mg daily, the most frequently reported adverse events involved the gastrointestinal and nervous systems. - Incidence >1 %: Adverse events reported most frequently (1-3%) at the recommended dose in controlled clinical trials are shown in the table below. table - Less frequent adverse events (0.3 to 1%) at the recommended dose in controlled clinical trials were: - Gastrointestinal System: Diarrhea, dyspepsia; Nervous System: impairment of concentration, ataxia, somnolence, agitation, depression; Skin and Appendages: rash; Hearing and Vestibular: tinnitus;Respiratory: dyspnea. - Additional adverse events (less than 0.3%) reported at recommended doses in controlled clinical trials were: Nervous System: gait abnormality, euphoria, hyperkinesia, tremor, hallucination, confusion, convulsions; Respiratory: bronchospasm, cough; Cardiovascular: pallor, palpitation, hypertension, cerebrovascular disorder, cardiac failure, pedal edema, heart block, tachycardia, syncope; Reproduction: non-puerperal lactation; Special Senses: taste loss/change, parosmia. Rates of adverse events, particularly those involving the gastrointestinal and nervous systems, increased significantly in controlled studies using higher than recommended doses of Flumadine. In most cases, symptoms resolved rapidly with discontinuation of treatment. In addition to the adverse events reported above, the following were also reported at higher than recommended doses: increased lacrimation, increased micturition frequency, fever, rigors, agitation, constipation, diaphoresis, dysphagia, stomatitis, hypesthesia and eye pain. - Adverse Reactions in Trials of Rimantadine and Amantadine: In a six-week prophylaxis study of 436 healthy adults comparing rimantadine with amantadine and placebo, the following adverse reactions were reported with an incidence >1 %. TABLE ## Postmarketing Experience There is limited information regarding Postmarketing Experience of Rimantadine in the drug label. # Drug Interactions - Acetaminophen: Flumadine, 100 mg, was given twice daily for 13 days to 12 healthy volunteers. On day 11, acetaminophen (650 mg four times daily) was started and continued for 8 days. The pharmacokinetics of rimantadine were assessed on days 11 and 13. Coadministration with acetaminophen reduced the peak concentration and AUC values for rimantadine by approximately 11%. - Flumadine, 100 mg, was given twice daily for 13 days to 12 healthy volunteers. On day 11, aspirin (650 mg, four times daily) was started and continued for 8 days. The pharmacokinetics of rimantadine were assessed on days 11 and 13. Peak plasma concentrations and AUC of rimantadine were reduced approximately 10% in the presence of aspirin. - When a single 100 mg dose of Flumadine was administered with steady-state cimetidine (300 mg four times a day), there were no statistically significant differences in rimantadine Cmax or AUC between Flumadine alone and Flumadine in the presence of cimetidine. - The concurrent use of Flumadine® with live attenuated intranasal influenza vaccine has not been evaluated. However, because of potential interference between these products, the live attenuated intranasal influenza vaccine should not be administered until 48 hours after cessation of Flumadine® and Flumadine® should not be administered until two weeks after the administration of live attenuated intranasal influenza vaccine unless medically indicated. The concern about potential interference arises principally from the potential for antiviral drugs to inhibit replication of live vaccine virus. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): C - There are no adequate and well-controlled studies in pregnant women. Rimantadine is reported to cross the placenta in mice. Rimantadine has been shown to be embryotoxic in rats when given at a dose of 200 mg/kg/d (11 times the MRHD based on mg/m2). At this dose the embryotoxic effect consisted of increased fetal resorption in rats; this dose also produced a variety of maternal effects including ataxia, tremors, convulsions and significantly reduced weight gain. No embryotoxicity was observed when rabbits were given doses up to 50 mg/kg/d (approximately 0.1 times the MRHD based on AUC), but evidence of a developmental abnormality in the form of a change in the ratio of fetuses with 12 or 13 ribs was noted. This ratio is normally about 50:50 in a litter but was 80:20 after rimantadine treatment. However, in a repeat embryofetal toxicity study in rabbits at doses up to 50 mg/kg/d (approximately 0.1 times the MRHD based on AUC), this abnormality was not observed. - Rimantadine was administered to pregnant rats in a peri- and postnatal reproduction toxicity study at doses of 30, 60 and 120 mg/kg/d(1.7, 3.4 and 6.8 times the MRHD based on mg/m2). Maternal toxicity during gestation was noted at the two higher doses of rimantadine, and at the highest dose, 120 mg/kg/day, there was an increase in pup mortality during the first 2 to 4 days postpartum. Decreased fertility of the F1 generation was also noted for the two higher doses. - For these reasons, Flumadine should be used during pregnancy only if the potential benefit justifies the risk to the fetus. Pregnancy Category (AUS): - Australian Drug Evaluation Committee (ADEC) Pregnancy Category There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Rimantadine in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Rimantadine during labor and delivery. ### Nursing Mothers - Flumadine should not be administered to nursing mothers because of the adverse effects noted in offspring of rats treated with rimantadine during the nursing period. Rimantadine is concentrated in rat milk in a dose-related manner: 2 to 3 hours following administration of rimantadine, rat breast milk levels were approximately twice those observed in the serum. ### Pediatric Use - In children (1 year to 16 years of age), Flumadine is recommended for the prophylaxis of influenza A. The safety and effectiveness of Flumadine in the treatment of symptomatic influenza infection in children (1 year to 16 years of age) have not been established. Prophylaxis studies with Flumadine have not been performed in children below the age of 1 year. ### Geriatic Use - Approximately 200 patients over the age of 64 were evaluated for safety in controlled clinical trials with Flumadine® (rimantadine hydrochloride). Geriatric subjects who received either 200 mg or 400 mg of rimantadine daily for 1 to 50 days experienced considerably more central nervous system and gastrointestinal adverse events than comparable geriatric subjects receiving placebo. Central nervous system events including dizziness, headache, anxiety, asthenia, and fatigue, occurred up to two times more often in subjects treated with rimantadine than in those treated with placebo. Gastrointestinal symptoms, particularly nausea, vomiting, and abdominal pain occurred at least twice as frequently in subjects receiving rimantadine than in those receiving placebo. The gastrointestinal symptoms appeared to be dose related. In patients over 64, the recommended dose is 100 mg, daily. ### Gender There is no FDA guidance on the use of Rimantadine with respect to specific gender populations. ### Race There is no FDA guidance on the use of Rimantadine with respect to specific racial populations. ### Renal Impairment There is no FDA guidance on the use of Rimantadine in patients with renal impairment. ### Hepatic Impairment There is no FDA guidance on the use of Rimantadine in patients with hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Rimantadine in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Rimantadine in patients who are immunocompromised. # Administration and Monitoring ### Administration - Oral ### Monitoring There is limited information regarding Monitoring of Rimantadine in the drug label. - Description # IV Compatibility There is limited information regarding IV Compatibility of Rimantadine in the drug label. # Overdosage - As with any overdose, supportive therapy should be administered as indicated. Overdoses of a related drug, amantadine, have been reported with adverse reactions consisting of agitation, hallucinations, cardiac arrhythmia and death. The administration of intravenous physostigmine (a cholinergic agent) at doses of 1 to 2 mg in adults (Ref. 7) and 0.5 mg in children (Ref. 8) repeated as needed as long as the dose did not exceed 2 mg/hour has been reported anecdotally to be beneficial in patients with central nervous system effects from overdoses of amantadine. # Pharmacology There is limited information regarding Rimantadine Pharmacology in the drug label. ## Mechanism of Action - The mechanism of action of rimantadine is not fully understood. Rimantadine appears to exert its inhibitory effect early in the viral replicative cycle, possibly inhibiting the uncoating of the virus. Genetic studies suggest that a virus protein specified by the virion M2 gene plays an important role in the susceptibility of influenza A virus to inhibition by rimantadine. ## Structure - Flumadine® (rimantadine hydrochloride) is a synthetic antiviral drug available as a 100 mg film-coated tablet. Each film-coated tablet contains 100 mg of rimantadine hydrochloride plus hypromellose, magnesium stearate, microcrystalline cellulose, sodium starch glycolate, FD&C Yellow No. 6 Lake and FD&C Yellow No. 6. The film coat contains hypromellose and polyethylene glycol. - Rimantadine hydrochloride is a white to off-white crystalline powder which is freely soluble in water (50 mg/mL at 20°C). Chemically, rimantadine hydrochloride is alpha-methyltricyclo-[3.3.1.1/3.7]decane-1-methanamine hydrochloride, with an empirical formula of C12H21N•HCI, a molecular weight of 215.77 and the following structural formula: ## Pharmacodynamics ### MICROBIOLOGY: - Rimantadine inhibits the replication in cell culture of influenza A virus isolates from each of the three antigenic subtypes, i.e., H1N1, H2N2 and H3N2, that have been isolated from man. Rimantadine has little or no activity against influenza B virus (Ref. 1,2). Rimantadine does not appear to interfere with the immunogenicity of inactivated influenza A vaccine. - A quantitative relationship between the susceptibility in cell culture of influenza A virus to rimantadine and clinical response to therapy has not been established. - Susceptibility test results, expressed as the concentration of the drug required to inhibit virus replication by 50% or more in a cell culture system, vary greatly (from 18 nM to 93 μgM) depending upon the assay protocol used, size of the virus inoculum, isolates of the influenza A virus strains tested, and the cell types used (Ref. 2). - Influenza A virus isolates resistant to rimantadine have been selected in cell culture and in vivo as a result of treatment. Rimantadine-resistant strains of influenza A virus have emerged among freshly isolated strains in closed settings where rimantadine has been used. Resistant viruses have been shown to be transmissible and to cause typical influenza illness. (Ref. 3,9). Substitutions at any one of 5 amino acid positions in the transmembrane domain of M2 confer resistance to rimantadine. The most common substitution causing resistance among influenza A (H1N1) and A (H3N2) is S31N. Other less common substitutions that cause resistance include substitutions A30F, V27A, V30A, and L26F. - Rimantadine resistance has been observed in circulating seasonal influenza and pandemic isolates from individuals who have not received rimantadine. Swine-origin influenza A (H1N1) (S-OIV) viruses that were resistant to rimantadine have been shown to contain the S31N substitution. Existing primers used for detection of adamantine resistance in seasonal viruses do not work with all tested S-OIVs (Ref. 11). The CDC should be consulted for questions regarding resistance to rimantadine in circulating influenza strains. - Cross-resistance among the adamantanes rimantadine and amantadine has been observed. Resistance to rimantadine confers cross-resistance to amantadine and vice-versa. Substitutions that confer resistance to rimantadine include (most frequently) M2 S31N, as well as the less common changes V27A, V30A, L26F and A30T (Ref. 10). ## Pharmacokinetics - Although the pharmacokinetic profile of Flumadine has been described, no pharmacodynamic data establishing a correlation between plasma concentration and its antiviral effect are available. - Flumadine is absorbed after oral administration. The mean ± SD peak plasma concentration after a single 100 mg dose of Flumadine was 74 ± 22 ng/mL (range: 45 to 138 ng/mL). The time to peak concentration was 6 ± 1 hours in healthy adults (age 20 to 44 years). The single dose elimination half-life in this population was 25.4 ± 6.3 hours (range: 13 to 65 hours). The single dose elimination half-life in a group of healthy 71 to 79 year-old subjects was 32 ± 16 hours (range: 20 to 65 hours). - After the administration of rimantadine 100 mg twice daily to healthy volunteers (age 18 to 70 years) for 10 days, area under the curve (AUC) values were approximately 30% greater than predicted from a single dose. Plasma trough levels at steady state ranged between 118 and 468 ng/mL. In these patients no age-related differences in pharmacokinetics were detected. However, in a comparison of three groups of healthy older subjects (age 50-60, 61-70 and 71-79 years), the 71 to 79 year-old group had average AUC values, peak concentrations and elimination half-life values at steady state that were 20 to 30% higher than the other two groups. Steady-state concentrations in elderly nursing home patients (age 68 to 102 years) were 2- to 4-fold higher than those seen in healthy young and elderly adults. - The pharmacokinetic profile of rimantadine in children has not been established. - Following oral administration, rimantadine is extensively metabolized in the liver with less than 25% of the dose excreted in the urine as unchanged drug. Three hydroxylated metabolites have been found in plasma. These metabolites, an additional conjugated metabolite and parent drug account for 74 ± 10% (n=4) of a single 200 mg dose of rimantadine excreted in urine over 72 hours. - In a group (n=14) of patients with chronic liver disease, the majority of whom were stabilized cirrhotics, the pharmacokinetics of rimantadine were not appreciably altered following a single 200 mg oral dose compared to 6 healthy subjects who were sex, age and weight matched to 6 of the patients with liver disease. After administration of a single 200 mg dose to patients (n=10) with severe hepatic dysfunction, AUC was approximately 3-fold larger, elimination half-life was approximately 2-fold longer and apparent clearance was about 50% lower when compared to historic data from healthy subjects. - Rimantadine pharmacokinetics were evaluated following administration of 100 mg Flumadine twice daily for 14 days to subjects with mild (creatinine clearance [CrCL] 50-80 mL/min), moderate (CrCL 30-49 mL/min), and severe (CrCl 5-29 mL/min) renal impairment and to healthy subjects (CrCl > 80 mL/min). There were no clinically relevant differences in rimantadine Cmax, Cmin, and AUC0-τ between subjects with mild or moderate renal impairment compared to healthy subjects. In subjects with severe renal impairment, rimantadine Cmax, Cmin, and AUC0-τ on Day 14 increased by 75%, 82%, and 81%, respectively, compared with healthy subjects. The rimantadine elimination half-life was slightly prolonged (increase of 18% or less) in subjects with mild and moderate renal impairment but increased by 49% in subjects with severe renal impairment compared to healthy subjects. - After a single 200 mg oral dose of rimantadine was given to 8 hemodialysis patients (CrCl 0-10 mL/min), there was a 1.6-fold increase in the elimination half-life and a 40% decrease in apparent clearance compared to age-matched healthy subjects. Hemodialysis did not contribute to the clearance of rimantadine. - The in vitro human plasma protein binding of rimantadine is about 40% over typical plasma concentrations. Albumin is the major binding protein. ## Nonclinical Toxicology ### Carcinogenesis, Mutagenesis and Impairment of Fertility - Oral administration of rimantadine to rats for 2 years at doses up to 100 mg/kg/d [approximately 11-14 times the maximum recommended human dose (MRHD) based on AUC] showed no evidence of increased tumor incidence. - No mutagenic effects were seen when rimantadine was evaluated in several standard assays for mutagenicity. - A reproduction study in male and female rats did not show detectable impairment of fertility at dosages up to 60 mg/kg/d (3 times the MRHD based on mg/m2). # Clinical Studies There is limited information regarding Clinical Studies of Rimantadine in the drug label. # How Supplied - Flumadine® tablets (rimantadine hydrochloride tablets) are supplied as 100 mg tablets (orange, oval-shaped, film-coated) in bottles of 100 (NDC 49708- 521-88). Imprint on tablets: (Front) FLUMADINE 100; (Back) FOREST. ## Storage - Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F) # Images ## Drug Images ## Package and Label Display Panel NDC 49708-521-88 Flumadine® Tablets (rimantadine hydrochloride tablets) Each tablet contains 100 mg rimantadine hydrochloride Rx only 100 Tablets Distributed by: Caraco Pharmaceutical Laboratories, Ltd. Detroit, MI 48202 # Patient Counseling Information There is limited information regarding Patient Counseling Information of Rimantadine in the drug label. # Precautions with Alcohol - Alcohol-Rimantadine interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - Flumadine® # Look-Alike Drug Names There is limited information regarding Rimantadine Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	https://www.wikidoc.org/index.php/Flumadine
420d9847f865f58726e1f8e3322a2684ebc71f04	wikidoc	Flunarizine	Flunarizine Flunarizine is a drug classified as a calcium channel blocker. Flunarizine is a non-selective calcium entry blocker with other actions including histamine H1 receptor blocking activity. It is effective in the prophylaxis of migraine, occlusive peripheral vascular disease, vertigo of central and peripheral origin, and as an adjuvant in the therapy of epilepsy. It may help to reduce the severity and duration of attacks of paralysis associated with the more serious form of alternating hemiplegia, as well as being effective in rapid onset dystonia-parkinsonism (RDP). Both these conditions share a mutation in the ATP13A gene; flunarizine is not available by prescription in the U.S. or Japan. Flunarizine has been shown to significantly reduce headache frequency and severity in both adults and children. Flunarizine was discovered at Janssen Pharmaceutica in 1968. # Side effects and contraindications Flunarizine has some side effects including weight gain, extrapyramidal effects, drowsiness and depression, it is contraindicated in hypotension, heart failure and arrhythmia. Flunarizine use is avoided in patients with depression, severe constipation or those with extrapyramidal disorders.	Flunarizine Flunarizine is a drug classified as a calcium channel blocker.[1] Flunarizine is a non-selective calcium entry blocker with other actions including histamine H1 receptor blocking activity. It is effective in the prophylaxis of migraine,[2] occlusive peripheral vascular disease, vertigo of central and peripheral origin, and as an adjuvant in the therapy of epilepsy. It may help to reduce the severity and duration of attacks of paralysis associated with the more serious form of alternating hemiplegia, as well as being effective in rapid onset dystonia-parkinsonism (RDP). Both these conditions share a mutation in the ATP13A gene; flunarizine is not available by prescription in the U.S. or Japan.[3] Flunarizine has been shown to significantly reduce headache frequency and severity in both adults and children. Flunarizine was discovered at Janssen Pharmaceutica in 1968. # Side effects and contraindications Flunarizine has some side effects including weight gain, extrapyramidal effects, drowsiness and depression, it is contraindicated in hypotension, heart failure and arrhythmia. Flunarizine use is avoided in patients with depression, severe constipation or those with extrapyramidal disorders.	https://www.wikidoc.org/index.php/Flunarizine
3664b03574be72084a4cbd543fad856051ca5492	wikidoc	Fluoroscopy	Fluoroscopy Assistant Editor-In-Chief: Anand Patel, MD Fluoroscopy is an imaging technique commonly used by physicians to obtain real-time images of the internal structures of a patient through the use of a fluoroscope. In its simplest form, a fluoroscope consists of an x-ray source and fluorescent screen between which a patient is placed. However, modern fluoroscopes couple the screen to an x-ray image intensifier and CCD video camera allowing the images to be played and recorded on a monitor. The use of x-rays, a form of ionizing radiation, requires that the potential risks from a procedure be carefully balanced with the benefits of the procedure to the patient. While physicians always try to use low dose rates during fluoroscopy procedures, the length of a typical procedure often results in a relatively high absorbed dose to the patient. Recent advances include the digitization of the images captured and flat-panel detector systems which reduce the radiation dose to the patient still further. # History The beginning of fluoroscopy can be traced back to 8 November 1895 when Wilhelm Röntgen noticed a barium platinocyanide screen fluorescing as a result of being exposed to what he would later call x-rays. Within months of this discovery, the first fluoroscopes were created. Early fluoroscopes were simply cardboard funnels, open at narrow end for the eyes of the observer, while the wide end was closed with a thin cardboard piece that had been coated on the inside with a layer of fluorescent metal salt. The fluoroscopic image obtained in this way is rather faint. Thomas Edison quickly discovered that calcium tungstate screens produced brighter images and is credited with designing and producing the first commercially available fluoroscope. In its infancy, many incorrectly predicted that the moving images from fluoroscopy would completely replace the still x-ray radiographs, but the superior diagnostic quality of the earlier radiographs prevented this from occurring. Ignorance of the harmful effects of x-rays resulted in the absence of standard radiation safety procedures which are employed today. Scientists and physicians would often place their hands directly in the x-ray beam resulting in radiation burns. Trivial uses for the technology also resulted, including the shoe-fitting fluoroscope used by shoe stores in the 1930s-1950s. Due to the limited light produced from the fluorescent screens, early radiologists were required to sit in a darkened room, in which the procedure was to be performed, accustomizing their eyes to the dark and thereby increasing their sensitivity to the light. The placement of the radiologist behind the screen resulted in significant radiation doses to the radiologist. Red adaptation goggles were developed by Wilhelm Trendelenburg in 1916 to address the problem of dark adaptation of the eyes, previously studied by Antoine Beclere. The resulting red light from the goggles' filtration correctly sensitized the physician's eyes prior to the procedure while still allowing him to receive enough light to function normally. The development of the X-ray image intensifier and the television camera in the 1950s revolutionized fluoroscopy. The red adaptation goggles became obsolete as image intensifiers allowed the light produced by the fluorescent screen to be amplified, allowing it to be seen even in a lighted room. The addition of the camera enabled viewing of the image on a monitor, allowing a radiologist to view the images in a separate room away from the risk of radiation exposure. More modern improvements in screen phosphors, image intensifiers and even flat panel detectors have allowed for increased image quality while minimizing the radiation dose to the patient. Modern fluoroscopes use CsI screens and produce noise-limited images, ensuring that the minimal radiation dose results while still obtaining images of acceptable quality. # Risks Because fluoroscopy involves the use of x rays, a form of ionizing radiation, all fluoroscopic procedures pose a potential health risk to the patient. Radiation doses to the patient depend greatly on the size of the patient as well as length of the procedure, with typical skin dose rates quoted as 20-50 mGy/min. Exposure times vary depending on the procedure being performed, but procedure times up to 75 minutes have been documented. Because of the long length of some procedures, in addition to standard cancer-inducing stochastic radiation effects, deterministic radiation effects have also been observed ranging from mild erythema, equivalent of a sun burn, to more serious burns. A study has been performed by the Food and Drug Administration (FDA) entitled Radiation-induced Skin Injuries from Fluoroscopy with an additional publication to minimize further fluoroscopy-induced injuries, Public Health Advisory on Avoidance of Serious X-Ray-Induced skin Injuries to Patients During Fluoroscopically-Guided Procedures. While deterministic radiation effects are a possibility, radiation burns are not typical of standard fluoroscopic procedures. Most procedures sufficiently long in length to produce radiation burns are part of necessary life-saving operations. # Fluoroscopy Equipment The first fluoroscopes consisted of an x-ray source and fluorescent screen between which the patient would be placed. As the x rays pass through the patient, they are attenuated by varying amounts as they interact with the different internal structures of the body, casting a shadow of the structures on the fluorescent screen. Images on the screen are produced as the unattenuated x rays interact with atoms in the screen through the photoelectric effect, giving their energy to the electrons. While much of the energy given to the electrons is dissipated as heat, a fraction of it is given off as visible light, producing the images. Early radiologists would adapt their eyes to view the dim fluoroscopic images by sitting in darkened rooms, or by wearing red adaptation goggles. ## X-ray Image Intensifiers The invention of X-ray image intensifiers in the 1950s allowed the image on the screen to be visible under normal lighting conditions, as well as providing the option of recording the images with a conventional camera. Subsequent improvements included the coupling of, at first, video cameras and, later, CCD cameras to permit recording of moving images and electronic storage of still images. Modern image intensifiers no longer use a separate fluorescent screen. Instead, a caesium iodide phosphor is deposited directly on the photocathode of the intensifier tube. On a typical general purpose system, the output image is approximately 105 times brighter than the input image. This brightness gain comprises a flux gain (amplification of photon number) and minification gain (concentration of photons from a large input screen onto a small output screen) each of approximately 100. This level of gain is sufficient that quantum noise, due to the limited number of x-ray photons, is a significant factor limiting image quality. Image intensifiers are available with input diameters of up to 45 cm, and a resolution of approximately 2-3 line pairs mm-1. ## Flat-panel detectors The introduction of flat-panel detectors allows for the replacement of the image intensifier in fluoroscope design. Flat panel detectors offer increased sensitivity to X-rays, and therefore have the potential to reduce patient radiation dose. Temporal resolution is also improved over image intensifiers, reducing motion blurring. Contrast ratio is also improved over image intensifiers: flat-panel detectors are linear over a very wide latitude, whereas image intensifiers have a maximum contrast ratio of about 35:1. Spatial resolution is approximately equal, although an image intensifier operating in 'magnification' mode may be slightly better than a flat panel. Flat panel detectors are considerably more expensive to purchase and repair than image intensifiers, so their uptake is primarily in specialties that require high-speed imaging, e.g., vascular imaging and cardiac catheterization. # Imaging concerns In addition to spatial blurring factors that plague all x-ray imaging devices, caused by such things as Lubberts effect, K-fluorescence reabsorption and electron range, fluoroscopic systems also experience temporal blurring due to system lag. This temporal blurring has the effect of averaging frames together. While this helps reduce noise in images with stationary objects, it creates motion blurring for moving objects. Temporal blurring also complicates measurements of system performance for fluoroscopic systems. # Common procedures using fluoroscopy - Investigations of the gastrointestinal tract, including barium enemas, barium meals and barium swallows, and enteroclysis. - Orthopaedic surgery to guide fracture reduction and the placement of metalwork. - Angiography of the leg, heart and cerebral vessels. - Placement of a PICC (peripherally inserted central catheter) - Placement of a weighted feeding tube (e.g. Dobhoff) into the duodenum after previous attempts without fluoroscopy have failed. - Urological surgery – particularly in retrograde pyelography. - Implantation of cardiac rhythm management devices (pacemakers, implantable cardioverter defibrillators and cardiac resynchronization devices) Another common procedure is the modified barium swallow study during which barium-impregnated liquids and solids are ingested by the patient. A radiologist records and, with a speech pathologist, interprets the resulting images to diagnose oral and pharyngeal swallowing dysfunction. Modified barium swallow studies are also used in studying normal swallow function.	Fluoroscopy Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Assistant Editor-In-Chief: Anand Patel, MD [2] Fluoroscopy is an imaging technique commonly used by physicians to obtain real-time images of the internal structures of a patient through the use of a fluoroscope. In its simplest form, a fluoroscope consists of an x-ray source and fluorescent screen between which a patient is placed. However, modern fluoroscopes couple the screen to an x-ray image intensifier and CCD video camera allowing the images to be played and recorded on a monitor. The use of x-rays, a form of ionizing radiation, requires that the potential risks from a procedure be carefully balanced with the benefits of the procedure to the patient. While physicians always try to use low dose rates during fluoroscopy procedures, the length of a typical procedure often results in a relatively high absorbed dose to the patient. Recent advances include the digitization of the images captured and flat-panel detector systems which reduce the radiation dose to the patient still further. # History The beginning of fluoroscopy can be traced back to 8 November 1895 when Wilhelm Röntgen noticed a barium platinocyanide screen fluorescing as a result of being exposed to what he would later call x-rays. Within months of this discovery, the first fluoroscopes were created. Early fluoroscopes were simply cardboard funnels, open at narrow end for the eyes of the observer, while the wide end was closed with a thin cardboard piece that had been coated on the inside with a layer of fluorescent metal salt. The fluoroscopic image obtained in this way is rather faint. Thomas Edison quickly discovered that calcium tungstate screens produced brighter images and is credited with designing and producing the first commercially available fluoroscope. In its infancy, many incorrectly predicted that the moving images from fluoroscopy would completely replace the still x-ray radiographs, but the superior diagnostic quality of the earlier radiographs prevented this from occurring. Ignorance of the harmful effects of x-rays resulted in the absence of standard radiation safety procedures which are employed today. Scientists and physicians would often place their hands directly in the x-ray beam resulting in radiation burns. Trivial uses for the technology also resulted, including the shoe-fitting fluoroscope used by shoe stores in the 1930s-1950s.[3] Due to the limited light produced from the fluorescent screens, early radiologists were required to sit in a darkened room, in which the procedure was to be performed, accustomizing their eyes to the dark and thereby increasing their sensitivity to the light. The placement of the radiologist behind the screen resulted in significant radiation doses to the radiologist. Red adaptation goggles were developed by Wilhelm Trendelenburg in 1916 to address the problem of dark adaptation of the eyes, previously studied by Antoine Beclere. The resulting red light from the goggles' filtration correctly sensitized the physician's eyes prior to the procedure while still allowing him to receive enough light to function normally. The development of the X-ray image intensifier and the television camera in the 1950s revolutionized fluoroscopy. The red adaptation goggles became obsolete as image intensifiers allowed the light produced by the fluorescent screen to be amplified, allowing it to be seen even in a lighted room. The addition of the camera enabled viewing of the image on a monitor, allowing a radiologist to view the images in a separate room away from the risk of radiation exposure. More modern improvements in screen phosphors, image intensifiers and even flat panel detectors have allowed for increased image quality while minimizing the radiation dose to the patient. Modern fluoroscopes use CsI screens and produce noise-limited images, ensuring that the minimal radiation dose results while still obtaining images of acceptable quality. # Risks Because fluoroscopy involves the use of x rays, a form of ionizing radiation, all fluoroscopic procedures pose a potential health risk to the patient. Radiation doses to the patient depend greatly on the size of the patient as well as length of the procedure, with typical skin dose rates quoted as 20-50 mGy/min. Exposure times vary depending on the procedure being performed, but procedure times up to 75 minutes have been documented. Because of the long length of some procedures, in addition to standard cancer-inducing stochastic radiation effects, deterministic radiation effects have also been observed ranging from mild erythema, equivalent of a sun burn, to more serious burns. A study has been performed by the Food and Drug Administration (FDA) entitled Radiation-induced Skin Injuries from Fluoroscopy[4] with an additional publication to minimize further fluoroscopy-induced injuries, Public Health Advisory on Avoidance of Serious X-Ray-Induced skin Injuries to Patients During Fluoroscopically-Guided Procedures[5]. While deterministic radiation effects are a possibility, radiation burns are not typical of standard fluoroscopic procedures. Most procedures sufficiently long in length to produce radiation burns are part of necessary life-saving operations. # Fluoroscopy Equipment The first fluoroscopes consisted of an x-ray source and fluorescent screen between which the patient would be placed. As the x rays pass through the patient, they are attenuated by varying amounts as they interact with the different internal structures of the body, casting a shadow of the structures on the fluorescent screen. Images on the screen are produced as the unattenuated x rays interact with atoms in the screen through the photoelectric effect, giving their energy to the electrons. While much of the energy given to the electrons is dissipated as heat, a fraction of it is given off as visible light, producing the images. Early radiologists would adapt their eyes to view the dim fluoroscopic images by sitting in darkened rooms, or by wearing red adaptation goggles. ## X-ray Image Intensifiers The invention of X-ray image intensifiers in the 1950s allowed the image on the screen to be visible under normal lighting conditions, as well as providing the option of recording the images with a conventional camera. Subsequent improvements included the coupling of, at first, video cameras and, later, CCD cameras to permit recording of moving images and electronic storage of still images. Modern image intensifiers no longer use a separate fluorescent screen. Instead, a caesium iodide phosphor is deposited directly on the photocathode of the intensifier tube. On a typical general purpose system, the output image is approximately 105 times brighter than the input image. This brightness gain comprises a flux gain (amplification of photon number) and minification gain (concentration of photons from a large input screen onto a small output screen) each of approximately 100. This level of gain is sufficient that quantum noise, due to the limited number of x-ray photons, is a significant factor limiting image quality. Image intensifiers are available with input diameters of up to 45 cm, and a resolution of approximately 2-3 line pairs mm-1. ## Flat-panel detectors The introduction of flat-panel detectors allows for the replacement of the image intensifier in fluoroscope design. Flat panel detectors offer increased sensitivity to X-rays, and therefore have the potential to reduce patient radiation dose. Temporal resolution is also improved over image intensifiers, reducing motion blurring. Contrast ratio is also improved over image intensifiers: flat-panel detectors are linear over a very wide latitude, whereas image intensifiers have a maximum contrast ratio of about 35:1. Spatial resolution is approximately equal, although an image intensifier operating in 'magnification' mode may be slightly better than a flat panel. Flat panel detectors are considerably more expensive to purchase and repair than image intensifiers, so their uptake is primarily in specialties that require high-speed imaging, e.g., vascular imaging and cardiac catheterization. # Imaging concerns In addition to spatial blurring factors that plague all x-ray imaging devices, caused by such things as Lubberts effect, K-fluorescence reabsorption and electron range, fluoroscopic systems also experience temporal blurring due to system lag. This temporal blurring has the effect of averaging frames together. While this helps reduce noise in images with stationary objects, it creates motion blurring for moving objects. Temporal blurring also complicates measurements of system performance for fluoroscopic systems. # Common procedures using fluoroscopy - Investigations of the gastrointestinal tract, including barium enemas, barium meals and barium swallows, and enteroclysis. - Orthopaedic surgery to guide fracture reduction and the placement of metalwork. - Angiography of the leg, heart and cerebral vessels. - Placement of a PICC (peripherally inserted central catheter) - Placement of a weighted feeding tube (e.g. Dobhoff) into the duodenum after previous attempts without fluoroscopy have failed. - Urological surgery – particularly in retrograde pyelography. - Implantation of cardiac rhythm management devices (pacemakers, implantable cardioverter defibrillators and cardiac resynchronization devices) Another common procedure is the modified barium swallow study during which barium-impregnated liquids and solids are ingested by the patient. A radiologist records and, with a speech pathologist, interprets the resulting images to diagnose oral and pharyngeal swallowing dysfunction. Modified barium swallow studies are also used in studying normal swallow function.	https://www.wikidoc.org/index.php/Fluoroscope
376ef8b4e091bcc73d328fdc5aa04ccff83b9b44	wikidoc	Flupentixol	Flupentixol Flupentixol (INN), also known as flupenthixol (former BAN), marketed under brand names such as Depixol and Fluanxol is a typical antipsychotic drug of the thioxanthene class. In addition to single drug preparations, it is also available as flupentixol/melitracen—a combination product containing both melitracen (a tricyclic antidepressant) and flupentixol. Flupentixol is not approved for use in the US. It is, however, approved for use in the UK, Australia, Canada, Russian Federation, South Africa, New Zealand, Philippines and various other countries. # Medical uses Flupentixol's main use is as a long-acting injection given once in every two or three weeks to individuals with schizophrenia who have poor compliance with medication and suffer frequent relapses of illness, though it is also commonly given as a tablet. There however is little evidence to support its use for this indication. Flupentixol is also used in low doses as an antidepressant. # Adverse effects Adverse effect incidence - Extrapyramidal side effects such as: (which usually become apparent soon after therapy is begun or soon after an increase in dose is made) - Dry mouth - Constipation - Hypersalivation — excessive salivation - Blurred vision - Diaphoresis — excessive sweating - Nausea - Dizziness - Somnolence - Restlessness - Insomnia - Overactivity - Headache - Nervousness - Fatigue - Myalgia - Hyperprolactinaemia and its complications such as: (acutely) - Dyspepsia — indigestion - Abdominal pain - Flatulence - Nasal congestion - Polyuria — passing more urine than usual. - Fainting - Palpitations - Blood dyscrasias (abnormalities in the cell composition of blood), such as: - Neuroleptic malignant syndrome — a potentially fatal condition that appear to result from central D2 receptor blockade. The symptoms include: - Jaundice - Abnormal liver function test results - Tardive dyskinesia — an often incurable movement disorder that usually results from years of continuous treatment with antipsychotic drugs, especially typical antipsychotics like flupenthixol. It presents with repetitive, involuntary, purposeless and slow movements. - Hypotension - Confusional state - Seizures - Mania - Hypomania - Depression - Hot flush - Anergia - Appetite changes - Weight changes - Hyperglycaemia — high blood glucose (sugar) levels - Abnormal glucose tolerance - Pruritus — itchiness - Rash - Dermatitis - Photosensitivity — sensitivity to light - Oculogyration - Accommodation disorder - Sleep disorder - Impaired concentration - Tachycardia - QTc interval prolongation — an abnormality in the electrical activity of the heart that can lead to potentially fatal changes in heart rhythm - Torsades de Pointes - Miosis — constriction of the pupil of the eye. - Paralytic ileus — paralysis of the bowel muscles leading to severe constipation, inability to pass wind, etc. - Mydriasis - Glaucoma ## Interactions It should be not used concomitantly with medications known to prolong the QTc interval (e.g. 5-HT3 antagonists, tricyclic antidepressants, citalopram, etc.) as this may lead to an increased risk of QTc interval prolongation. Neither should it be given concurrently with lithium (medication) as it may increase the risk of lithium toxicity and neuroleptic malignant syndrome. It should not be given concurrently with other antipsychotics due to the potential for this to increase the risk of side effects, especially neurological side effects such as neuroleptic malignant syndrome. It should be avoided in patients on CNS depressants such as opioids, alcohol and barbiturates. ## Contraindications It should not be given in the following disease states: - Phaeochromocytoma - Prolactin-dependent tumours such as pituitary prolactinomas and breast cancer. - Long QT syndrome - Coma - Circulatory collapse - Subcortical brain damage - Blood dyscrasia - Parkinson's disease - Dementia with lewy bodies # Pharmacology Binding profile Acronyms used: HFC - Human frontal cortex receptor MB - Mouse brain receptor RC - Cloned rat receptor Its antipsychotic effects are likely caused by D2 and/or 5-HT2A antagonism, whereas its antidepressant effects at lower doses may be mediated by preferential D2/D3 autoreceptor blockade, resulting in increased postsynaptic activation. # Society and culture The combination of flupenthixol and melitracen is banned by Indian regulatory body.	Flupentixol Flupentixol (INN), also known as flupenthixol (former BAN), marketed under brand names such as Depixol and Fluanxol is a typical antipsychotic drug of the thioxanthene class. In addition to single drug preparations, it is also available as flupentixol/melitracen—a combination product containing both melitracen (a tricyclic antidepressant) and flupentixol. Flupentixol is not approved for use in the US. It is, however, approved for use in the UK,[4] Australia,[5] Canada, Russian Federation,[6] South Africa, New Zealand, Philippines and various other countries. # Medical uses Flupentixol's main use is as a long-acting injection given once in every two or three weeks to individuals with schizophrenia who have poor compliance with medication and suffer frequent relapses of illness, though it is also commonly given as a tablet. There however is little evidence to support its use for this indication.[4][7] Flupentixol is also used in low doses as an antidepressant.[4][8][9][10][11][12][13] # Adverse effects Adverse effect incidence[2][4][5][14][15] - Extrapyramidal side effects such as: (which usually become apparent soon after therapy is begun or soon after an increase in dose is made) - Dry mouth - Constipation - Hypersalivation — excessive salivation - Blurred vision - Diaphoresis — excessive sweating - Nausea - Dizziness - Somnolence - Restlessness - Insomnia - Overactivity - Headache - Nervousness - Fatigue - Myalgia - Hyperprolactinaemia and its complications such as: (acutely) - Dyspepsia — indigestion - Abdominal pain - Flatulence - Nasal congestion - Polyuria — passing more urine than usual. - Fainting - Palpitations - Blood dyscrasias (abnormalities in the cell composition of blood), such as: - Neuroleptic malignant syndrome — a potentially fatal condition that appear to result from central D2 receptor blockade. The symptoms include: - Jaundice - Abnormal liver function test results - Tardive dyskinesia — an often incurable movement disorder that usually results from years of continuous treatment with antipsychotic drugs, especially typical antipsychotics like flupenthixol. It presents with repetitive, involuntary, purposeless and slow movements. - Hypotension - Confusional state - Seizures - Mania - Hypomania - Depression - Hot flush - Anergia - Appetite changes - Weight changes - Hyperglycaemia — high blood glucose (sugar) levels - Abnormal glucose tolerance - Pruritus — itchiness - Rash - Dermatitis - Photosensitivity — sensitivity to light - Oculogyration - Accommodation disorder - Sleep disorder - Impaired concentration - Tachycardia - QTc interval prolongation — an abnormality in the electrical activity of the heart that can lead to potentially fatal changes in heart rhythm - Torsades de Pointes - Miosis — constriction of the pupil of the eye. - Paralytic ileus — paralysis of the bowel muscles leading to severe constipation, inability to pass wind, etc. - Mydriasis - Glaucoma ## Interactions It should be not used concomitantly with medications known to prolong the QTc interval (e.g. 5-HT3 antagonists, tricyclic antidepressants, citalopram, etc.) as this may lead to an increased risk of QTc interval prolongation.[15][2] Neither should it be given concurrently with lithium (medication) as it may increase the risk of lithium toxicity and neuroleptic malignant syndrome.[4][5][15] It should not be given concurrently with other antipsychotics due to the potential for this to increase the risk of side effects, especially neurological side effects such as neuroleptic malignant syndrome.[4][5][15] It should be avoided in patients on CNS depressants such as opioids, alcohol and barbiturates.[15] ## Contraindications It should not be given in the following disease states:[2][4][5][15] - Phaeochromocytoma - Prolactin-dependent tumours such as pituitary prolactinomas and breast cancer. - Long QT syndrome - Coma - Circulatory collapse - Subcortical brain damage - Blood dyscrasia - Parkinson's disease - Dementia with lewy bodies # Pharmacology Binding profile[16] Acronyms used: HFC - Human frontal cortex receptor MB - Mouse brain receptor RC - Cloned rat receptor Its antipsychotic effects are likely caused by D2 and/or 5-HT2A antagonism, whereas its antidepressant effects at lower doses may be mediated by preferential D2/D3 autoreceptor blockade, resulting in increased postsynaptic activation. # Society and culture The combination of flupenthixol and melitracen is banned by Indian regulatory body.[18]	https://www.wikidoc.org/index.php/Flupentixol
9c31357c68274a3b0d2b83186b635419b9b0878b	wikidoc	Fluvalinate	Fluvalinate # Overview - Fluvalinate (trade names include Apistan, Klartan, Minadox) is a synthetic pyrethroid commonly used to control Diseases of the varroa mites in honey bee colonies. - Fluvalinate is a stable, non-volatile, fat-soluble compound. Although the compound may be found in drones, a study has found honey samples virtually absent of fluvalinate, on account of its affinity to beeswax. - Tau-fluvalinate (τ-fluvalinate) is the trivial name for (2R)-fluvalinate. The C atom in the valinate structure is in D-configuration, while the second chiral atom is a mixture of both R and S.	Fluvalinate Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview - Fluvalinate (trade names include Apistan, Klartan, Minadox) is a synthetic pyrethroid commonly used to control Diseases of the varroa mites in honey bee colonies. - Fluvalinate is a stable, non-volatile, fat-soluble compound. Although the compound may be found in drones, a study has found honey samples virtually absent of fluvalinate, on account of its affinity to beeswax.[1] - Tau-fluvalinate (τ-fluvalinate) is the trivial name for (2R)-fluvalinate. The C atom in the valinate structure is in D-configuration, while the second chiral atom is a mixture of both R and S.	https://www.wikidoc.org/index.php/Fluvalinate
e8b2562d9bcccb302c0d89089d21983f8d9c6bd2	wikidoc	Fluvastatin	Fluvastatin # Disclaimer WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here. # Overview Fluvastatin is a HMG-CoA reductase inhibitor that is FDA approved for the treatment of hypercholesterolemia (heterozygous familial and nonfamilial) and mixed dyslipidemia, secondary prevention of cardiovascular disease. Common adverse reactions include indigestion, nausea, headache. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) ## Fluvastatin Tablet - Dose range: 20 mg to 80 mg/ day. - Fluvastatin can be administered orally as a single dose, with or without food. - Do not break, crush or chew Fluvastatin tablets or open Fluvastatin capsules prior to administration. - Do not take two Fluvastatin40 mg capsules at one time. - Since the maximal effect of a given dose is seen within 4 weeks, periodic lipid determinations should be performed at this time and dosage adjusted according to the patient’s response to therapy and established treatment guidelines. - For patients requiring LDL-C reduction to a goal of ≥25%, the recommended starting dose is 40 mg as one capsule in the evening, 80 mg as one Fluvastatin tablet administered as a single dose at any time of the day or 80 mg in divided doses of the 40 mg capsule given twice daily. For patients requiring LDL-C reduction to a goal of <25% a starting dose of 20 mg may be used. ### Adult Patients with Hypercholesterolemia (Heterozygous Familial and Nonfamilial) and Mixed Dyslipidemia - Indication - as an adjunct to diet to reduce elevated total cholesterol (Total-C), low-density lipoprotein cholesterol (LDL-C), triglyceride (TG) and apolipoprotein B (Apo B) levels, and to increase high-density lipoprotein cholesterol (HDL-C) in patients with primary hypercholesterolemia and mixed dyslipidemia (Fredrickson Type IIa and IIb). - as an adjunct to diet to reduce Total-C, LDL-C, and Apo B levels in adolescent boys and adolescent girls who are at least one year post-menarche, 10 to 16 years of age, with heterozygous familial hypercholesterolemia and the following findings are present: - LDL-C remains ≥ 190 mg/dL or - LDL-C remains ≥ 160 mg/dL and - there is a positive family history of premature cardiovascular disease or - two or more other cardiovascular disease risk factors are present - The NCEP classification of cholesterol levels in pediatric patients with a familial history of hypercholesterolemia or premature CVD is summarized below. - Children treated with fluvastatin in adolescence should be re-evaluated in adulthood and appropriate changes made to their cholesterol-lowering regimen to achieve adult treatment goals. - Dosing information (Fluvastatin tablet) - 80 mg PO qd at any time of the day. - Dosing information (Fluvastatin capsule) - Recommended starting dosage for LESCOL: - 40 mg PO qd in the evening - or 40 mg PO bid - Do not take two Fluvastatin40 mg capsules at one time. ### Use with Cyclosporine - Do not exceed a dose of 20 mg b.i.d. Fluvastatin in patients taking cyclosporine. ### Use with Fluconazole - Do not exceed a dose of 20 mg b.i.d. Fluvastatinin patients taking fluconazole. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information about the Non-Guideline-Supported use. ### Non–Guideline-Supported Use ### Acute coronary syndrome - Dosing information - Higher doses ### Reduction of Cardiovascular event risk in patients with renal impairment - Dosing information - 20 mg- 80 mg/day ### Coronary artery bypass graft - Dosing information - 10-20 mg/day ### Nephrotic syndrome - Dosing information - 40 mg every evening ### Percutaneous Coronary Intervention - Dosing information - 40 mg bid ### Prophylaxis of Postoperative Cardiac Complication - Dosing information - 80 mg/day # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) ### Pediatric Patients (10-16 years of age) with Heterozygous Familial Hypercholesterolemia - Dosing information (capsule) - Recommended starting dosage: 20 mg PO qd , up to a maximum daily dose administered either as Fluvastatincapsules 40 mg PO bid - Doses should be individualized according to the goal of therapy, see NCEP Pediatric Panel Guidelines and CLINICAL STUDIES (14). - Dosing information (tablet) - 80 mg PO qd - Doses should be individualized according to the goal of therapy. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information about Off-Label Guideline-Supported Use of Fluvastatin in pediatric patients. ### Non–Guideline-Supported Use There is limited information about Off-Label Non–Guideline-Supported Use of Fluvastatin in pediatric patients. # Contraindications ## Hypersensitivity to any Component of this Medication - Fluvastatin and Fluvastatin are contraindicated in patients with hypersensitivity to any component of this medication. ## Active Liver Disease - Fluvastatinand Fluvastatin are contraindicated in patients with active liver disease or unexplained, persistent elevations in serum transaminases. ## Pregnancy - Fluvastatin and Fluvastatin are contraindicated in women who are pregnant or may become pregnant. Serum cholesterol and triglycerides increase during normal pregnancy, and cholesterol or cholesterol derivatives are essential for fetal development. Fluvastatin and Fluvastatin may cause fetal harm when administered to pregnant women. Atherosclerosis is a chronic process and the discontinuation of lipid-lowering drugs during pregnancy should have little impact on the outcome of long-term therapy of primary hypercholesterolemia. - Fluvastatin and Fluvastatin should be administered to women of childbearing age only when such patients are highly unlikely to conceive and have been informed of the potential hazards. If the patient becomes pregnant while taking this drug, Fluvastatin and Fluvastatin should be discontinued and the patient should be apprised of the potential hazard to the fetus. ## Nursing Mothers - Fluvastatin is secreted into the breast milk of animals and because HMG-CoA reductase inhibitors have the potential to cause serious adverse reactions in nursing infants, women who require treatment with Fluvastatin or Fluvastatin should be advised not to breastfeed their infants. # Warnings ## Skeletal Muscle - Rhabdomyolysis with acute renal failure secondary to myoglobinuria have been reported with Fluvastatin and other drugs in this class. - Fluvastatin should be prescribed with caution in patients with predisposing factors for myopathy. These factors include advanced age (>65 years), renal impairment, and inadequately treated hypothyroidism. - The risk of myopathy and/or rhabdomyolysis with statins is increased with concurrent therapy with cyclosporine, erythromycin, fibrates or niacin. Myopathy was not observed in a clinical trial in 74 patients involving patients who were treated with Fluvastatin together with niacin. Isolated cases of myopathy have been reported during post-marketing experience with concomitant administration of Fluvastatin and colchicine. No information is available on the pharmacokinetic interaction between Fluvastatin and colchicine. - Uncomplicated myalgia has also been reported in LESCOL-treated patients. In clinical trials, uncomplicated myalgia has been observed infrequently in patients treated with Fluvastatin at rates indistinguishable from placebo. myopathy, defined as muscle aching or muscle weakness in conjunction with increases in CPK values to greater than 10 times the upper limit of normal, was less than 0.1% in fluvastatin clinical trials. myopathy should be considered in any patient with diffuse myalgias, muscle tenderness or weakness, and/or marked elevation of CPK. - There have been rare reports of immune-mediated necrotizing myopathy (IMNM), an autoimmune myopathy, associated with statin use. IMNM is characterized by: proximal muscle weakness and elevated serum creatine kinase, which persist despite discontinuation of statin treatment; muscle biopsy showing necrotizing myopathy without significant inflammation; improvement with immunosuppressive agents. - All patients should be advised to promptly report to their physician unexplained muscle pain, tenderness, or weakness, particularly if accompanied by malaise or fever or if muscle signs and symptoms persist after discontinuing Fluvastatin. - Fluvastatin therapy should be discontinued if markedly elevated CPK levels occur or myopathy is diagnosed or suspected. Fluvastatin therapy should also be temporarily withheld in any patient experiencing an acute or serious condition predisposing to the development of renal failure secondary to rhabdomyolysis, e.g., sepsis; hypotension; major surgery; trauma; severe metabolic, endocrine, or electrolyte disorders; or uncontrolled epilepsy. ## Liver Enzymes - Increases in serum transaminases (aspartate aminotransferase (AST)/serum glutamic-oxaloacetic transaminase, or alanine aminotransferase (ALT)/serum glutamic-pyruvic transaminase) have been reported with HMG-CoA reductase inhibitors, including Fluvastatin. In most cases, the elevations were transient and resolved or improved on continued therapy or after a brief interruption in therapy. - Approximately 1.1% of patients treated with Fluvastatin capsules in worldwide trials developed dose-related, persistent elevations of serum transaminase levels to more than 3 times the upper limit of normal. Fourteen of these patients (0.6%) were discontinued from therapy. In all clinical trials, a total of 33/2969 patients (1.1%) had persistent transaminase elevations with an average Fluvastatinexposure of approximately 71.2 weeks; 19 of these patients (0.6%) were discontinued. The majority of patients with these abnormal biochemical findings were asymptomatic. - In a pooled analysis of all placebo-controlled studies in which Fluvastatincapsules were used, persistent transaminase elevations (greater than 3 times the upper limit of normal on two consecutive weekly measurements) occurred in 0.2%, 1.5%, and 2.7% of patients treated with daily doses of 20, 40, and 80 mg (titrated to 40 mg twice daily) Fluvastatincapsules, respectively. Ninety-one percent of the cases of persistent liver function test abnormalities (20 of 22 patients) occurred within 12 weeks of therapy and in all patients with persistent liver function test abnormalities there was an abnormal liver function test present at baseline or by Week 8. - In the pooled analysis of the 24-week controlled trials, persistent transaminase elevation occurred in 1.9%, 1.8% and 4.9% of patients treated with Fluvastatin 80 mg, Fluvastatin40 mg and Fluvastatin40 mg twice daily, respectively. In 13 of 16 patients treated with Fluvastatin the abnormality occurred within 12 weeks of initiation of treatment with Fluvastatin 80 mg. - It is recommended that liver enzyme tests be performed prior to the initiation of Fluvastatin, and if signs or symptoms of liver injury occur. - There have been rare postmarketing reports of fatal and non-fatal hepatic failure in patients taking ], including fluvastatin. If serious liver injury with clinical symptoms and/or hyperbilirubinemia or jaundice occurs during treatment with Fluvastatin, promptly interrupt therapy. If an alternate etiology is not found do not restart Fluvastatin. - In very rare cases, possibly drug-related hepatitis was observed that resolved upon discontinuation of treatment. Active liver disease or unexplained serum transaminase elevations are contraindications to the use of Fluvastatin. Caution should be exercised when Fluvastatinis administered to patients with a history of liver disease or heavy alcohol ingestion. Such patients should be closely monitored. ## Endocrine Effects - Increases in HbA1c and fasting serum glucose levels have been reported with HMG-CoA reductase inhibitors, including Fluvastatin. - Statins interfere with cholesterol synthesis and lower circulating cholesterol levels and, as such, might theoretically blunt adrenal or gonadal steroid hormone production. - Fluvastatin exhibited no effect upon non-stimulated cortisol levels and demonstrated no effect upon thyroid metabolism as assessed by measurement of thyroid stimulating hormone (TSH). Small declines in total serum testosterone have been noted in treated groups, but no commensurate elevation in LH occurred, suggesting that the observation was not due to a direct effect upon testosterone production. No effect upon FSH in males was noted. Due to the limited number of premenopausal females studied to date, no conclusions regarding the effect of Fluvastatin upon female sex hormones may be made. - Two clinical studies in patients receiving fluvastatin at doses up to 80 mg daily for periods of 24 to 28 weeks demonstrated no effect of treatment upon the adrenal response to ACTH stimulation. A clinical study evaluated the effect of Fluvastatin at doses up to 80 mg daily for 28 weeks upon the gonadal response to HCG stimulation. Although the mean total testosterone response was significantly reduced (p less than 0.05) relative to baseline in the 80 mg group, it was not significant in comparison to the changes noted in groups receiving either 40 mg of Fluvastatinor placebo. - Patients treated with Fluvastatin who develop clinical evidence of endocrine dysfunction should be evaluated appropriately. Caution should be exercised if a statin or other agent used to lower cholesterol levels is administered to patients receiving other drugs (e.g. ketoconazole, spironolactone, cimetidine) that may decrease the levels of endogenous steroid hormones. ## CNS Toxicity - CNS effects, as evidenced by decreased activity, ataxia, loss of righting reflex, and ptosis were seen in the following animal studies: the 18-month mouse carcinogenicity study at 50 mg/kg/day, the 6-month dog study at 36 mg/kg/day, the 6-month hamster study at 40 mg/kg/day, and in acute, high-dose studies in rats and hamsters (50 mg/kg), rabbits (300 mg/kg) and mice (1500 mg/kg). CNS toxicity in the acute high-dose studies was characterized (in mice) by conspicuous vacuolation in the ventral white columns of the spinal cord at a dose of 5000 mg/kg and (in rats) by edema with separation of myelinated fibers of the ventral spinal tracts and sciatic nerve at a dose of 1500 mg/kg. CNS toxicity, characterized by periaxonal vacuolation, was observed in the medulla of dogs that died after treatment for 5 weeks with 48 mg/kg/day; this finding was not observed in the remaining dogs when the dose level was lowered to 36 mg/kg/day. CNS vascular lesions, characterized by perivascular hemorrhages, edema, and mononuclear cell infiltration of perivascular spaces, have been observed in dogs treated with other members of this drug class. No CNS lesions have been observed after chronic treatment for up to 2 years with fluvastatin in the mouse (at doses up to 350 mg/kg/day), rat (up to 24 mg/kg/day), or dog (up to 16 mg/kg/day). - Prominent bilateral posterior Y suture lines in the ocular lens were seen in dogs after treatment with 1, 8, and 16 mg/kg/day for 2 years. # Adverse Reactions ## Clinical Trials Experience - The following serious adverse reactions are discussed in greater detail in other sections of the label: - Rhabdomyolysis with myoglobinuria and acute renal failure and myopathy (including myositis). ## Clinical Studies Experience in Adult Patients - Because clinical studies on Fluvastatin are conducted in varying study populations and study designs, the frequency of adverse reactions observed in the clinical studies of Fluvastatin cannot be directly compared with that in the clinical studies of other statins and may not reflect the frequency of adverse reactions observed in clinical practice. - In the Fluvastatin placebo-controlled clinical trials databases of 2326 patients treated with LESCOL1 (age range 18-75 years, 44% women, 94% Caucasians, 4% Blacks, 2% other ethnicities) with a median treatment duration of 24 weeks, 3.4% of patients on Fluvastatin and 2.3% patients on placebo discontinued due to adverse reactions regardless of causality. The most common adverreactions that led to treatment discontinuation and occurred at an incidence greater than placebo were: transaminase increased (0.8%), upper abdominal pain (0.3%), dyspepsia (0.3%), fatigue (0.2%) and diarrhea (0.2%). - In the Fluvastatin database of controlled clinical trials of 912 patients treated with Fluvastatin (age range 21-87 years, 52% women, 91% Caucasians, 4% Blacks, 5% other ethnicities) with a median treatment duration of 24 weeks, 3.9% of patients on Fluvastatin discontinued due to adverse reactions regardless of causality. The most common adverse reactions that led to treatment discontinuation were abdominal pain (0.7%), diarrhea (0.5%), nausea (0.4%), dyspepsia (0.4%) and chest pain (0.3%). - Clinically relevant adverse experiences occurring in the Fluvastatin and Fluvastatin controlled studies with a frequency greater than 2%, regardless of causality, included the following: ### FluvastatinIntervention Prevention Study - In the Fluvastatin Intervention Prevention Study (LIPS), the effect of Fluvastatin40 mg, administered twice daily on the risk of recurrent cardiac events was assessed in 1677 patients with CHD who had undergone a percutaneous coronary intervention (PCI) procedure. This was a multicenter, randomized, double-blind, placebo-controlled study, patients were treated with dietary/lifestyle counseling and either Fluvastatin40 mg (n=844) or placebo (n=833) given twice daily for a median of 3.9 years. ## Clinical Studies Experience in Pediatric Patients - In patients aged less than 18 years, efficacy and safety have not been studied for treatment periods longer than two years. - In two open-label, uncontrolled studies, 66 boys and 48 girls with heterozygous familial hypercholesterolemia ( 9-16 years of age, 80% Caucasian, 19% Other mixed ethnicity, 1% Asians) were treated with fluvastatin sodium administered as Fluvastatincapsules 20 mg -40 mg twice daily, or Fluvastatin 80 mg extended-release tablet. ## Postmarketing Experience - Because adverse reactions from spontaneous reports are reported voluntarily from a population of uncertain size, it is generally not possible to reliably estimate their frequency or establish a causal relationship to drug exposure. The following effects have been reported with drugs in this class. Not all the effects listed below have necessarily been associated with fluvastatin sodium therapy. Musculoskeletal Muscle cramps, myalgia, myopathy, Rhabdomyolysis, arthralgias, muscle spasms, muscle weakness, myositis. There have been rare reports of immune-mediated necrotizing myopathy associated with statin use. Neurological Dysfunction of certain cranial nerves (including alteration of taste, impairment of extra-ocular movement, facial paresis), tremor, dizziness, vertigo, paresthesia, hypoesthesia, dysesthesia, peripheral neuropathy, peripheral nerve palsy. There have been rare postmarketing reports of cognitive impairment (e.g., memory loss, forgetfulness, amnesia, memory impairment, confusion) associated with statin use. These cognitive issues have been reported for all statins. The reports are generally nonserious, and reversible upon statin discontinuation, with variable times to symptom onset (1 day to years) and symptom resolution (median of 3 weeks). Psychiatric Anxiety, insomnia, depression, psychic disturbances Hypersensitivity Reactions An apparent hypersensitivity syndrome has been reported rarely which has included one or more of the following features: anaphylaxis, angioedema, lupus erythematosus-like syndrome, polymyalgia rheumatica, vasculitis, purpura, thrombocytopenia, leukopenia, hemolytic anemia, positive ANA, ESR (erythrocyte sedimentation rate) increase, eosinophilia, arthritis, arthralgia, urticaria, asthenia, photosensitivity reaction, fever,chills,flushing, malaise , dyspnea, toxic epidermal necrolysis, erythema multiforme, including Stevens-Johnson syndrome. Gastrointestinal Pancreatitis, hepatitis, including chronic active hepatitis, cholestatic jaundice, fatty change in liver, cirrhosis, fulminant hepatic necrosis, hepatoma, anorexia,vomiting, fatal and non-fatal hepatic failure. Skin Rash, dermatitis, including bullous dermatitis, eczema, alopecia,pruritus, a variety of skin changes (e.g. nodules, discoloration, dryness of skin/mucous membranes, changes to hair/nails). Reproductive Gynecomastia, loss of libido, erectile dysfunction. Eye Progression of cataracts (lens opacities), ophthalmoplegia. Laboratory abnormalities Elevated transaminases, alkaline phosphatase, gamma-glutamyl transpeptidase and bilirubin; thyroid function abnormalities. # Drug Interactions Cyclosporine coadministration increases fluvastatin exposure. Therefore, in patients taking cyclosporine, therapy should be limited to Fluvastatin20 mg twice daily. - Administration of fluvastatin 40 mg single dose to healthy volunteers pre-treated with fluconazole for 4 days results in an increase of fluvastatin exposure. Therefore, in patients taking fluconazole, therapy should be limited to Fluvastatin 20 mg twice daily. - Due to an increased risk of myopathy/rhabdomyolysis when HMG-CoA reductase inhibitors are coadministered with gemfibrozil, concomitant administration of Fluvastatin with gemfibrozil should be avoided. - Because it is known that the risk of myopathy during treatment with HMG-CoA reductase inhibitors is increased with concurrent administration of other fibrates, Fluvastatin should be administered with caution when used concomitantly with other fibrates . - The risk of skeletal muscle effects may be enhanced when Fluvastatin is used in combination with lipid-modifying doses (≥1 g/day) of niacin; a reduction in Fluvastatindosage should be considered in this setting. - Concomitant administration of fluvastatin and glyburide increased glyburide exposures. Patients on concomitant therapy of glyburide and fluvastatin should continue to be monitored appropriately. - Concomitant administration of fluvastatin and phenytoin increased phenytoin exposures. Patients should continue to be monitored appropriately when fluvastatin therapy is initiated or when fluvastatin dose is changed. - Bleeding and/or increased prothrombin times have been reported in patients taking coumarin anticoagulants concomitantly with other HMG-CoA reductase inhibitors. Therefore, patients receiving warfarin-type anticoagulants should have their prothrombin times closely monitored when fluvastatin sodium is initiated or the dosage of fluvastatin sodium is changed. - Cases of myopathy, including rhabdomyolysis, have been reported with fluvastatin coadministered with colchicine, and caution should be exercised when prescribing fluvastatin with colchicine. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): X - Fluvastatin is contraindicated in women who are or may become pregnant. - Lipid lowering drugs are contraindicated during pregnancy, because cholesterol and cholesterol derivatives are needed for normal fetal development. Serum cholesterol and triglycerides increase during normal pregnancy. Atherosclerosisis a chronic process, and discontinuation of lipid-lowering drugs during pregnancy should have little impact on long-term outcomes of primary hypercholesterolemia therapy. - There are no adequate and well-controlled studies of use with Fluvastatin during pregnancy. Rare reports of congenital anomalies have been received following intrauterine exposure to other statins. In a review2 of about 100 prospectively followed pregnancies in women exposed to other statins, the incidences of congenital anomalies, spontaneous abortions, and fetal deaths/stillbirths did not exceed the rate expected in the general population. The number of cases is adequate only to exclude a 3- to 4-fold increase in congenital anomalies over background incidence. In 89% of prospectively followed pregnancies, drug treatment was initiated prior to pregnancy and was discontinued at some point in the first trimester when pregnancy was identified. - Teratology studies with fluvastatin in rats and rabbits showed maternal toxicity at high dose levels, but there was no evidence of embryotoxic or teratogenic potential. - Fluvastatinor Fluvastatin should be administered to women of child-bearing potential only when such patients are highly unlikely to conceive and have been informed of the potential hazards. If a woman becomes pregnant while taking Fluvastatinor Fluvastatin, the drug should be discontinued and the patient advised again as to the potential hazards to the fetus. Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Fluvastatin in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Fluvastatin during labor and delivery. ### Nursing Mothers - Based on animal data, fluvastatin is present in breast milk in a 2:1 ratio (milk:plasma). Because of the potential for serious adverse reactions in nursing infants, nursing women should not take Fluvastatinor Fluvastatin. ### Pediatric Use - The safety and efficacy of Fluvastatinand Fluvastatin in children and adolescent patients 9-16 years of age with heterozygous familial hypercholesterolemia have been evaluated in open-label, uncontrolled clinical trials for a duration of two years. The most common adverse events observed were influenza and infections. In these limited uncontrolled studies, there was no detectable effect on growth or sexual maturation in the adolescent boys or on menstrual cycle length in girls. Adolescent females should be counseled on appropriate contraceptive methods while on Fluvastatintherapy. ### Geriatic Use - Fluvastatin exposures were not significantly different between the nonelderly and elderly populations (age ≥ 65 years). Since advanced age (greater than 65 years) is a predisposing factor for myopathy, Fluvastatin should be prescribed with caution in the elderly. ### Gender - In a study evaluating the effect of age and gender on fluvastatin pharmacokinetics, there were no significant differences in fluvastatin exposures between males and females, except between younger females and younger males (both ages 21-49 years), where there was an approximate 30% increase in AUC in females. Adjusting for body weight decreases the magnitude of the differences seen. For Fluvastatin, the AUC increases 67% and 77% for women compared to men under fasted and high- fat meal fed conditions, respectively. ### Race There is no FDA guidance on the use of Fluvastatin with respect to specific racial populations. ### Renal Impairment - Dose adjustments for mild to moderate renal impairment are not necessary. Fluvastatin has not been studied at doses greater than 40 mg in patients with severe renal impairment; therefore caution should be exercised when treating such patients at higher doses. ### Hepatic Impairment - Fluvastatinand Fluvastatin are contraindicated in patients with active liver disease or unexplained, persistent elevations in serum transaminases. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Fluvastatin in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Fluvastatin in patients who are immunocompromised. # Administration and Monitoring ### Administration Oral ### Monitoring There is limited information about the drug monitoring. # IV Compatibility FDA Package Insert for Fluvastatin contains no information regarding IV compatibility. # Overdosage - To date, there has been limited experience with overdosage of fluvastatin. If an overdose occurs, it should be treated symptomatically with laboratory monitoring and supportive measures should be instituted as required. The dialyzability of fluvastatin sodium and of its metabolites in humans is not known at present. - In the pediatric population, there have been reports of overdosage with fluvastatin sodium in children including a 2 year-old and the other 3 years of age, either of whom may have possibly ingested fluvastatin sodium. The maximum amount of fluvastatin sodium that could have been ingested was 80 mg (4 x 20 mg capsules). Vomiting was induced by ipecac in both children and no capsules were noted in their emesis. Neither child experienced any adverse symptoms and both recovered from the incident without problems. - In the postmarketing experience there have been reports of accidental ingestion of Fluvastatintablets in infants up to 3 years of age. In one case, increased serum CPK values were noted. There have been reports of intentional overdose in adolescents with the development of hepatic enzyme elevations, convulsions and gastroenteritis/vomiting/diarrhea. One case of intentional overdose as suicide attempt in a 15 year-old female reported ingestion of 2,800 mg Fluvastatin with hepatic enzyme elevation. # Pharmacology ## Mechanism of Action - Fluvastatin is a competitive inhibitor of HMG-CoA reductase, the rate limiting enzyme that converts 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) to mevalonate, a precursor of sterols, including cholesterol. The inhibition of cholesterol biosynthesis reduces the cholesterol in hepatic cells, which stimulates the synthesis of LDL receptors and thereby increases the uptake of LDL particles. The end result of these biochemical processes is a reduction of the plasma cholesterol concentration. ## Structure - Fluvastatinis a water-soluble cholesterol lowering agent which acts through the inhibition of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase. - Fluvastatin sodium is -(±)-7--3,5-dihydroxy-6-heptenoic acid, monosodium salt. The empirical formula of fluvastatin sodium is C24H25FNO4Na, its molecular weight is 433.46 and its structural formula is: - This molecular entity is the first entirely synthetic HMG-CoA reductase inhibitor, and is in part structurally distinct from the fungal derivatives of this therapeutic class. - Fluvastatin sodium is a white to pale yellow, hygroscopic powder soluble in water, ethanol and methanol. Fluvastatinis supplied as capsules containing fluvastatin sodium, equivalent to 20 mg or 40 mg of fluvastatin, for oral administration. Fluvastatin is supplied as extended-release tablets containing fluvastatin sodium, equivalent to 80 mg of fluvastatin, for oral administration. Active Ingredient: fluvastatin sodium Inactive Ingredients in capsules: calcium carbonate, gelatin, magnesium stearate, microcrystalline cellulose, pregelatinized starch (corn), red iron oxide, sodium bicarbonate, talc, titanium dioxide, yellow iron oxide, and other ingredients. Capsules may also include: benzyl alcohol, black iron oxide, butylparaben, carboxymethylcellulose sodium, edetate calcium disodium, methylparaben, propylparaben, silicon dioxide, sodium lauryl sulfate, and sodium propionate. Inactive Ingredients in extended-release tablets: microcrystalline cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, potassium bicarbonate, povidone, magnesium stearate, yellow iron oxide, titanium dioxide and polyethylene glycol 8000. ## Pharmacodynamics FDA Package Insert for Fluvastatin contains no information regarding pharmacodynamics. ## Pharmacokinetics ### Absorption: - Following oral administration of the capsule, fluvastatin reaches peak concentrations in less than 1 hour. The absolute bioavailability is 24% (range 9%-50%) after administration of a 10 mg dose. - At steady state, administration of fluvastatin with the evening meal results in a 50% decrease in Cmax, an 11% decrease in AUC, and a more than two-fold increase in tmaxas compared to administration 4 hours after the evening meal. No significant differences in the lipid-lowering effects were observed between the two administrations. After single or multiple doses above 20 mg, fluvastatin exhibits saturable first-pass metabolism resulting in more than dose proportional plasma fluvastatin concentrations. - Fluvastatin administered as Fluvastatin 80 mg tablets reaches peak concentration in approximately 3 hours under fasting conditions, after a low-fat meal, or 2.5 hours after a low-fat meal. The mean relative bioavailability of the XL tablet is approximately 29% (range: 9%-66%) compared to that of the Fluvastatin immediate-release capsule administered under fasting conditions. Administration of a high-fat meal delayed the absorption (Tmax: 6h) and increased the bioavailability of the XL tablet by approximately 50%. However, the maximum concentration of Fluvastatin seen after a high-fat meal is less than the peak concentration following a single dose or twice daily dose of the 40 mg Fluvastatin capsule. ### Distribution: - Fluvastatin is 98% bound to plasma proteins. The mean volume of distribution (VDss) is estimated at 0.35 L/kg. At therapeutic concentrations, the protein binding of fluvastatin is not affected by warfarin, salicylic acid and glyburide. ### Metabolism: - Fluvastatin is metabolized in the liver, primarily via hydroxylation of the indole ring at the 5- and 6-positions. N-dealkylation and beta-oxidation of the side-chain also occurs. The hydroxy metabolites have some pharmacologic activity, but do not circulate in the blood. Fluvastatin has two enantiomers. Both enantiomers of fluvastatin are metabolized in a similar manner. - In vitro data indicate that fluvastatin metabolism involves multiple Cytochrome P450 (CYP) isozymes. CYP2C9 isoenzyme is primarily involved in the metabolism of fluvastatin (approximately 75%), while CYP2C8 and CYP3A4 isoenzymes are involved to a much less extent, i.e. approximately 5% and approximately 20%, respectively. ### Excretion: - Following oral administration, fluvastatin is primarily (about 90%) excreted in the feces as metabolites, with less than 2% present as unchanged drug. Approximately 5% of a radiolabeled oral dose were recovered in urine. The elimination half-life (t1/2) of fluvastatin is approximately 3 hours. ## Nonclinical Toxicology ## Carcinogenesis, Mutagenesis, Impairment of Fertility - A 2-year study was performed in rats at dose levels of 6, 9, and 18-24 (escalated after 1 year) mg/kg/day. These treatment levels represented plasma drug levels of approximately 9, 13, and 26-35 times the mean human plasma drug concentration after a 40 mg oral dose. A low incidence of forestomach squamous papillomas and 1 carcinoma of the forestomach at the 24 mg/kg/day dose level was considered to reflect the prolonged hyperplasia induced by direct contact exposure to fluvastatin sodium rather than to a systemic effect of the drug. In addition, an increased incidence of thyroid follicular cell adenomas and carcinomas was recorded for males treated with 18-24 mg/kg/day. The increased incidence of thyroid follicular cell neoplasm in male rats with fluvastatin sodium appears to be consistent with findings from other HMG-CoA reductase inhibitors. In contrast to other HMG-CoA reductase inhibitors, no hepatic adenomas or carcinomas were observed. - The carcinogenicity study conducted in mice at dose levels of 0.3, 15 and 30 mg/kg/day revealed, as in rats, a statistically significant increase in forestomach squamous cell papillomas in males and females at 30 mg/kg/day and in females at 15 mg/kg/day. These treatment levels represented plasma drug levels of approximately 0.05, 2, and 7 times the mean human plasma drug concentration after a 40 mg oral dose. - No evidence of mutagenicity was observed in vitro, with or without rat-liver metabolic activation, in the following studies: microbial mutagen tests using mutant strains of Salmonella typhimurium or Escherichia coli; malignant transformation assay in BALB/3T3 cells; unscheduled DNA synthesis in rat primary hepatocytes; chromosomal aberrations in V79 Chinese Hamster cells; HGPRT V79 Chinese Hamster cells. In addition, there was no evidence of mutagenicity in vivo in either a rat or mouse micronucleus test. - In a study in rats at dose levels for females of 0.6, 2 and 6 mg/kg/day and at dose levels for males of 2, 10 and 20 mg/kg/day, fluvastatin sodium had no adverse effects on the fertility or reproductive performance. - Seminal vesicles and testes were small in hamsters treated for 3 months at 20 mg/kg/day (approximately three times the 40 mg human daily dose based on surface area, mg/m2). There was tubular degeneration and aspermatogenesis in testes as well as vesiculitis of seminal vesicles. Vesiculitis of seminal vesicles and edema of the testes were also seen in rats treated for 2 years at 18 mg/kg/day (approximately 4 times the human Cmax achieved with a 40 mg daily dose). - Fluvastatin sodium produced delays in skeletal development in rats at doses of 12 mg/kg/day and in rabbits at doses of 10 mg/kg/day. Malaligned thoracic vertebrae were seen in rats at 36 mg/kg, a dose that produced maternal toxicity. These doses resulted in 2 times (rat at 12 mg/kg) or 5 times (rabbit at 10 mg/kg) the 40 mg human exposure based on mg/m2 surface area. A study in which female rats were dosed during the third trimester at 12 and 24 mg/kg/day resulted in maternal mortality at or near term and postpartum. In addition, fetal and neonatal lethality were apparent. No effects on the dam or fetus occurred at 2 mg/kg/day. A second study at levels of 2, 6, 12 and 24 mg/kg/day confirmed the findings in the first study with neonatal mortality beginning at 6 mg/kg. A modified Segment III study was performed at dose levels of 12 or 24 mg/kg/day with or without the presence of concurrent supplementation with mevalonic acid, a product of HMG-CoA reductase which is essential for cholesterol biosynthesis. The concurrent administration of mevalonic acid completely revented the maternal and neonatal mortality but did not prevent low body weights in pups at 24 mg/kg on days 0 and 7 postpartum. # Clinical Studies ## Hypercholesterolemia (Heterozygous Familial and Nonfamilial) and Mixed Dyslipidemia - In 12 placebo-controlled studies in patients with primary hypercholesterolemia and mixed dyslipidemia, Fluvastatinwas administered to 1621 patients in daily dose regimens of 20 mg, 40 mg, and 80 mg (40 mg twice daily) for at least 6 weeks duration (Table 5). After 24 weeks of treatment, treatment with Fluvastatinresulted in significantly reduced plasma LDL-C, TC, TG, and Apo B compared to placebo and was associated with variable increases in HDL-C across the dose range. - Fluvastatin has been studied in five controlled studies of patients with primary hypercholesterolemia and mixed dyslipidemia. Fluvastatin was administered to over 900 patients in trials from 4 to 26 weeks in duration. In the three largest of these studies, Fluvastatin given as a single daily dose of 80 mg significantly reduced Total-C, LDL-C, TG and Apo B and resulted in increases in HDL-C (Table 5). - In patients with primary mixed dyslipidemia as defined by baseline plasma TG levels ≥200 mg/dL and less than 400 mg/dL, treatment with Fluvastatin produced significant decreases in Total-C, LDL-C, TG and Apo B and variable increases in HDL-C (Table 5). ## Heterozygous Familial Hypercholesterolemia in Pediatric Patients - Fluvastatin was studied in two open-label, uncontrolled, dose-titration studies. The first study enrolled 29 pre-pubertal boys, 9-12 years of age, who had an LDL-C level >90th percentile for age and one parent with primary hypercholesterolemia and either a family history of premature ischemic heart disease or tendon xanthomas. The mean baseline LDL-C was 226 mg/dL (range: 137-354 mg/dL). All patients were started on Fluvastatin capsules 20 mg daily with dose adjustments every 6 weeks to 40 mg daily then 80 mg daily (40 mg b.i.d.) to achieve an LDL-C goal between 96.7 – 123.7 mg/dL. Endpoint analyses were performed at Year 2. Fluvastatin decreased plasma levels of Total-C and LDL-C by 21% and 27%, respectively. The mean achieved LDL-C was 161 mg/dL (range: 74-336 mg/dL). - The second study enrolled 85 male and female patients, 10 to 16 years of age, who had an LDL-C >190 mg/dL or LDL-C >160 mg/dL and one or more risk factors for coronary heart disease, or LDL-C >160 mg/dL and a proven LDL-receptor defect. The mean baseline LDL-C was 225 mg/dL (range: 148-343 mg/dL). All patients were started on Fluvastatin capsules 20 mg daily with dose adjustments every 6 weeks to 40 mg daily then 80 mg daily (Fluvastatin80 mg XL tablet) to achieve an LDL-C goal of less than 130 mg/dL. Endpoint analyses were performed at Week 114. Fluvastatin decreased plasma levels of Total-C and LDL-C by 22% and 28%, respectively. The mean achieved LDL-C was 159 mg/dL (range: 90-295 mg/dL). - The majority of patients in both studies (83% in the first study and 89% in the second study) were titrated to the maximum daily dose of 80 mg. At study endpoint, 26% to 30% of patients in both studies achieved a targeted LDL-C goal of less than 130 mg/dL. The long-term efficacy of Fluvastatin or Fluvastatin therapy in childhood to reduce morbidity and mortality in adulthood has not been established. - In the FluvastatinIntervention Prevention Study (LIPS), the effect of Fluvastatin40 mg administered twice daily on the risk of recurrent cardiac events (time to first occurrence of cardiac death, nonfatal myocardial infarction, or revascularization) was assessed in 1677 patients with CHD who had undergone a percutaneous coronary intervention (PCI) procedure (mean time from PCI to randomization=3 days). In this multicenter, randomized, double-blind, placebo-controlled study, patients were treated with dietary/lifestyle counseling and either Fluvastatin40 mg (n=844) or placebo (n=833) given twice daily for a median of 3.9 years. The study population was 84% male, 98% Caucasian, with 37% greater than 65 years of age. Mean baseline lipid concentrations were: total cholesterol 201 mg/dL, LDL-C 132 mg/dL, triglycerides 70 mg/dL and HDL-C 39 mg/dL. - Fluvastatin significantly reduced the risk of recurrent cardiac events (Figure 1) by 22% (p=0.013, 181 patients in the Fluvastatingroup vs. 222 patients in the placebo group). - Revascularization procedures comprised the majority of the initial recurrent cardiac events (143 revascularization procedures in the Fluvastatingroup and 171 in the placebo group). Consistent trends in risk reduction were observed in patients greater than 65 years of age. - Figure 1 Primary Endpoint – Recurrent Cardiac Events (Cardiac Death, Nonfatal MI or Revascularization Procedure) (ITT Population) - Outcome data for the FluvastatinIntervention Prevention Study are shown in Figure 2. After exclusion of revascularization procedures (CABG and repeat PCI) occurring within the first 6 months of the initial procedure involving the originally instrumental site, treatment with Fluvastatinwas associated with a 32% (p=0.002) reduction in risk of late revascularization procedures (CABG or PCI occurring at the original site greater than 6 months after the initial procedure, or at another site). - Figure 2 LESCOL® Intervention Prevention Study - Primary and Secondary Endpoints - In the Lipoprotein and Coronary Atherosclerosis Study (LCAS), the effect of Fluvastatintherapy on coronary atherosclerosis was assessed by quantitative coronary angiography (QCA) in patients with CAD and mild to moderate hypercholesterolemia (baseline LDL-C range 115-190 mg/dL). In this randomized double-blind, placebo- controlled trial, 429 patients were treated with conventional measures (Step 1 AHA Diet) and either Fluvastatin40 mg/day or placebo. In order to provide treatment to patients receiving placebo with LDL-C levels ≥160 mg/dL at baseline, adjunctive therapy with cholestyramine was added after Week 12 to all patients in the study with baseline LDL-C values of ≥160 mg/dL which were present in 25% of the study population. Quantitative coronary angiograms were evaluated at baseline and 2.5 years in 340 (79%) angiographic evaluable patients. - Compared to placebo, Fluvastatinsignificantly slowed the progression of coronary atherosclerosis as measured by within-patient per-lesion change in minimum lumen diameter (MLD), the primary endpoint (Figure 3 below), percent diameter stenosis (Figure 4), and the formation of new lesions (13% of all fluvastatin patients versus 22% of all placebo patients). A significant difference in favor of Fluvastatinwas found between all fluvastatin and all placebo patients in the distribution among the three categories of definite progression, definite regression, and mixed or no change. Beneficial angiographic results (change in MLD) were independent of patients’ gender and consistent across a range of baseline LDL-C levels. # How Supplied ## LESCOL® XL (fluvastatin sodium) Extended-Release Tablets - 80 mg - Yellow, round, slightly biconvex film-coated tablet with beveled edges debossed with “Fluvastatin” on one side and “80” on the other. - Bottles of 30 tablets…………………………………………………………………………………...NDC 0078-0354-15 - Bottles of 100 tablets…………………………………………………………………………………...NDC 0078-0354-05 ## Fluvastatin capsules USP - 20 mg - hard gelatin capsules with ivory opaque body and pink opaque cap, filled with an off-white to yellowish powder with small agglomerates, body imprinted with “TEVA” and cap imprinted with “7442”, in bottles of 30 and 100. - 40 mg - hard gelatin capsules with yellow opaque body and pink opaque cap, filled with an off-white to yellowish powder with small agglomerates, body imprinted with “TEVA” and cap imprinted with “7443”, in bottles of 30 and 100. ## Storage ## LESCOL® XL (fluvastatin sodium) Extended-Release Tablets - Store at 25ºC (77ºF); excursions permitted to 15 -30ºC (59 -86ºF). Dispense in a tight container. Protect from light. ## Fluvastatin capsules USP - Store at 20° to 25°C (68° to 77°F) . - Dispense in a tight, light-resistant container as defined in the USP, with a child-resistant closure (as required). Protect from light. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information - Information for Patients - Patients taking Fluvastatin should be advised that high cholesterol is a chronic condition and they should adhere to their medication along with their National Cholesterol Education Program (NCEP)-recommended diet, a regular exercise program, and periodic testing of a fasting lipid panel to determine goal attainment. - Patients should be advised about substances they should not take concomitantly with Fluvastatin. Patients should also be advised to inform other healthcare professionals prescribing a new medication that they are taking Fluvastatin. ## Muscle Pain - Patients starting therapy with Fluvastatin should be advised of the risk of myopathy and told to report promptly any unexplained muscle pain, tenderness or weakness, particularly if accompanied by malaise or fever or if these muscle signs or symptoms persist after discontinuing Fluvastatin. ## Liver Enzymes - It is recommended that liver enzyme tests be performed before the initiation of Fluvastatin and if signs or symptoms of liver injury occur. All patients treated with Fluvastatin should be advised to report promptly any symptoms that may indicate liver injury, including fatigue, anorexia, right upper abdominal discomfort, dark urine or jaundice. ## Pregnancy - Women of childbearing age should be advised to use an effective method of birth control to prevent pregnancy while using Fluvastatin. Discuss future pregnancy plans with your patients, and discuss when to stop taking Fluvastatin if they are trying to conceive. Patients should be advised that if they become pregnant they should stop taking Fluvastatin and call their healthcare professional. ## Breastfeeding - Women who are breastfeeding should not use Fluvastatin. Patients who have a lipid disorder and are breastfeeding should be advised to discuss the options with their healthcare professional. # Precautions with Alcohol - Caution should be exercised when Fluvastatin is administered to patients with a history of liver disease or heavy alcohol ingestion. Such patients should be closely monitored. # Brand Names There is limited information regarding Fluvastatin Brand Names in the drug label. # Look-Alike Drug Names There is limited information about the look-alike names . # Drug Shortage Status # Price	Fluvastatin Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Sheng Shi, M.D. [2], Rabin Bista, M.B.B.S. [3] # Disclaimer WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here. # Overview Fluvastatin is a HMG-CoA reductase inhibitor that is FDA approved for the treatment of hypercholesterolemia (heterozygous familial and nonfamilial) and mixed dyslipidemia, secondary prevention of cardiovascular disease. Common adverse reactions include indigestion, nausea, headache. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) ## Fluvastatin Tablet - Dose range: 20 mg to 80 mg/ day. - Fluvastatin can be administered orally as a single dose, with or without food. - Do not break, crush or chew Fluvastatin tablets or open Fluvastatin capsules prior to administration. - Do not take two Fluvastatin40 mg capsules at one time. - Since the maximal effect of a given dose is seen within 4 weeks, periodic lipid determinations should be performed at this time and dosage adjusted according to the patient’s response to therapy and established treatment guidelines. - For patients requiring LDL-C reduction to a goal of ≥25%, the recommended starting dose is 40 mg as one capsule in the evening, 80 mg as one Fluvastatin tablet administered as a single dose at any time of the day or 80 mg in divided doses of the 40 mg capsule given twice daily. For patients requiring LDL-C reduction to a goal of <25% a starting dose of 20 mg may be used. ### Adult Patients with Hypercholesterolemia (Heterozygous Familial and Nonfamilial) and Mixed Dyslipidemia - Indication - as an adjunct to diet to reduce elevated total cholesterol (Total-C), low-density lipoprotein cholesterol (LDL-C), triglyceride (TG) and apolipoprotein B (Apo B) levels, and to increase high-density lipoprotein cholesterol (HDL-C) in patients with primary hypercholesterolemia and mixed dyslipidemia (Fredrickson Type IIa and IIb). - as an adjunct to diet to reduce Total-C, LDL-C, and Apo B levels in adolescent boys and adolescent girls who are at least one year post-menarche, 10 to 16 years of age, with heterozygous familial hypercholesterolemia and the following findings are present: - LDL-C remains ≥ 190 mg/dL or - LDL-C remains ≥ 160 mg/dL and - there is a positive family history of premature cardiovascular disease or - two or more other cardiovascular disease risk factors are present - The NCEP classification of cholesterol levels in pediatric patients with a familial history of hypercholesterolemia or premature CVD is summarized below. - Children treated with fluvastatin in adolescence should be re-evaluated in adulthood and appropriate changes made to their cholesterol-lowering regimen to achieve adult treatment goals. - Dosing information (Fluvastatin tablet) - 80 mg PO qd at any time of the day. - Dosing information (Fluvastatin capsule) - Recommended starting dosage for LESCOL: - 40 mg PO qd in the evening - or 40 mg PO bid - Do not take two Fluvastatin40 mg capsules at one time. ### Use with Cyclosporine - Do not exceed a dose of 20 mg b.i.d. Fluvastatin in patients taking cyclosporine. ### Use with Fluconazole - Do not exceed a dose of 20 mg b.i.d. Fluvastatinin patients taking fluconazole. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information about the Non-Guideline-Supported use. ### Non–Guideline-Supported Use ### Acute coronary syndrome - Dosing information - Higher doses [1] ### Reduction of Cardiovascular event risk in patients with renal impairment - Dosing information - 20 mg- 80 mg/day[2] ### Coronary artery bypass graft - Dosing information - 10-20 mg/day [3] ### Nephrotic syndrome - Dosing information - 40 mg every evening [4] ### Percutaneous Coronary Intervention - Dosing information - 40 mg bid [5] ### Prophylaxis of Postoperative Cardiac Complication - Dosing information - 80 mg/day [6] # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) ### Pediatric Patients (10-16 years of age) with Heterozygous Familial Hypercholesterolemia - Dosing information (capsule) - Recommended starting dosage: 20 mg PO qd , up to a maximum daily dose administered either as Fluvastatincapsules 40 mg PO bid - Doses should be individualized according to the goal of therapy, see NCEP Pediatric Panel Guidelines and CLINICAL STUDIES (14). - Dosing information (tablet) - 80 mg PO qd - Doses should be individualized according to the goal of therapy. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information about Off-Label Guideline-Supported Use of Fluvastatin in pediatric patients. ### Non–Guideline-Supported Use There is limited information about Off-Label Non–Guideline-Supported Use of Fluvastatin in pediatric patients. # Contraindications ## Hypersensitivity to any Component of this Medication - Fluvastatin and Fluvastatin are contraindicated in patients with hypersensitivity to any component of this medication. ## Active Liver Disease - Fluvastatinand Fluvastatin are contraindicated in patients with active liver disease or unexplained, persistent elevations in serum transaminases. ## Pregnancy - Fluvastatin and Fluvastatin are contraindicated in women who are pregnant or may become pregnant. Serum cholesterol and triglycerides increase during normal pregnancy, and cholesterol or cholesterol derivatives are essential for fetal development. Fluvastatin and Fluvastatin may cause fetal harm when administered to pregnant women. Atherosclerosis is a chronic process and the discontinuation of lipid-lowering drugs during pregnancy should have little impact on the outcome of long-term therapy of primary hypercholesterolemia. - Fluvastatin and Fluvastatin should be administered to women of childbearing age only when such patients are highly unlikely to conceive and have been informed of the potential hazards. If the patient becomes pregnant while taking this drug, Fluvastatin and Fluvastatin should be discontinued and the patient should be apprised of the potential hazard to the fetus. ## Nursing Mothers - Fluvastatin is secreted into the breast milk of animals and because HMG-CoA reductase inhibitors have the potential to cause serious adverse reactions in nursing infants, women who require treatment with Fluvastatin or Fluvastatin should be advised not to breastfeed their infants. # Warnings ## Skeletal Muscle - Rhabdomyolysis with acute renal failure secondary to myoglobinuria have been reported with Fluvastatin and other drugs in this class. - Fluvastatin should be prescribed with caution in patients with predisposing factors for myopathy. These factors include advanced age (>65 years), renal impairment, and inadequately treated hypothyroidism. - The risk of myopathy and/or rhabdomyolysis with statins is increased with concurrent therapy with cyclosporine, erythromycin, fibrates or niacin. Myopathy was not observed in a clinical trial in 74 patients involving patients who were treated with Fluvastatin together with niacin. Isolated cases of myopathy have been reported during post-marketing experience with concomitant administration of Fluvastatin and colchicine. No information is available on the pharmacokinetic interaction between Fluvastatin and colchicine. - Uncomplicated myalgia has also been reported in LESCOL-treated patients. In clinical trials, uncomplicated myalgia has been observed infrequently in patients treated with Fluvastatin at rates indistinguishable from placebo. myopathy, defined as muscle aching or muscle weakness in conjunction with increases in CPK values to greater than 10 times the upper limit of normal, was less than 0.1% in fluvastatin clinical trials. myopathy should be considered in any patient with diffuse myalgias, muscle tenderness or weakness, and/or marked elevation of CPK. - There have been rare reports of immune-mediated necrotizing myopathy (IMNM), an autoimmune myopathy, associated with statin use. IMNM is characterized by: proximal muscle weakness and elevated serum creatine kinase, which persist despite discontinuation of statin treatment; muscle biopsy showing necrotizing myopathy without significant inflammation; improvement with immunosuppressive agents. - All patients should be advised to promptly report to their physician unexplained muscle pain, tenderness, or weakness, particularly if accompanied by malaise or fever or if muscle signs and symptoms persist after discontinuing Fluvastatin. - Fluvastatin therapy should be discontinued if markedly elevated CPK levels occur or myopathy is diagnosed or suspected. Fluvastatin therapy should also be temporarily withheld in any patient experiencing an acute or serious condition predisposing to the development of renal failure secondary to rhabdomyolysis, e.g., sepsis; hypotension; major surgery; trauma; severe metabolic, endocrine, or electrolyte disorders; or uncontrolled epilepsy. ## Liver Enzymes - Increases in serum transaminases (aspartate aminotransferase (AST)/serum glutamic-oxaloacetic transaminase, or alanine aminotransferase (ALT)/serum glutamic-pyruvic transaminase) have been reported with HMG-CoA reductase inhibitors, including Fluvastatin. In most cases, the elevations were transient and resolved or improved on continued therapy or after a brief interruption in therapy. - Approximately 1.1% of patients treated with Fluvastatin capsules in worldwide trials developed dose-related, persistent elevations of serum transaminase levels to more than 3 times the upper limit of normal. Fourteen of these patients (0.6%) were discontinued from therapy. In all clinical trials, a total of 33/2969 patients (1.1%) had persistent transaminase elevations with an average Fluvastatinexposure of approximately 71.2 weeks; 19 of these patients (0.6%) were discontinued. The majority of patients with these abnormal biochemical findings were asymptomatic. - In a pooled analysis of all placebo-controlled studies in which Fluvastatincapsules were used, persistent transaminase elevations (greater than 3 times the upper limit of normal [ULN] on two consecutive weekly measurements) occurred in 0.2%, 1.5%, and 2.7% of patients treated with daily doses of 20, 40, and 80 mg (titrated to 40 mg twice daily) Fluvastatincapsules, respectively. Ninety-one percent of the cases of persistent liver function test abnormalities (20 of 22 patients) occurred within 12 weeks of therapy and in all patients with persistent liver function test abnormalities there was an abnormal liver function test present at baseline or by Week 8. - In the pooled analysis of the 24-week controlled trials, persistent transaminase elevation occurred in 1.9%, 1.8% and 4.9% of patients treated with Fluvastatin 80 mg, Fluvastatin40 mg and Fluvastatin40 mg twice daily, respectively. In 13 of 16 patients treated with Fluvastatin the abnormality occurred within 12 weeks of initiation of treatment with Fluvastatin 80 mg. - It is recommended that liver enzyme tests be performed prior to the initiation of Fluvastatin, and if signs or symptoms of liver injury occur. - There have been rare postmarketing reports of fatal and non-fatal hepatic failure in patients taking [statins]], including fluvastatin. If serious liver injury with clinical symptoms and/or hyperbilirubinemia or jaundice occurs during treatment with Fluvastatin, promptly interrupt therapy. If an alternate etiology is not found do not restart Fluvastatin. - In very rare cases, possibly drug-related hepatitis was observed that resolved upon discontinuation of treatment. Active liver disease or unexplained serum transaminase elevations are contraindications to the use of Fluvastatin. Caution should be exercised when Fluvastatinis administered to patients with a history of liver disease or heavy alcohol ingestion. Such patients should be closely monitored. ## Endocrine Effects - Increases in HbA1c and fasting serum glucose levels have been reported with HMG-CoA reductase inhibitors, including Fluvastatin. - Statins interfere with cholesterol synthesis and lower circulating cholesterol levels and, as such, might theoretically blunt adrenal or gonadal steroid hormone production. - Fluvastatin exhibited no effect upon non-stimulated cortisol levels and demonstrated no effect upon thyroid metabolism as assessed by measurement of thyroid stimulating hormone (TSH). Small declines in total serum testosterone have been noted in treated groups, but no commensurate elevation in LH occurred, suggesting that the observation was not due to a direct effect upon testosterone production. No effect upon FSH in males was noted. Due to the limited number of premenopausal females studied to date, no conclusions regarding the effect of Fluvastatin upon female sex hormones may be made. - Two clinical studies in patients receiving fluvastatin at doses up to 80 mg daily for periods of 24 to 28 weeks demonstrated no effect of treatment upon the adrenal response to ACTH stimulation. A clinical study evaluated the effect of Fluvastatin at doses up to 80 mg daily for 28 weeks upon the gonadal response to HCG stimulation. Although the mean total testosterone response was significantly reduced (p less than 0.05) relative to baseline in the 80 mg group, it was not significant in comparison to the changes noted in groups receiving either 40 mg of Fluvastatinor placebo. - Patients treated with Fluvastatin who develop clinical evidence of endocrine dysfunction should be evaluated appropriately. Caution should be exercised if a statin or other agent used to lower cholesterol levels is administered to patients receiving other drugs (e.g. ketoconazole, spironolactone, cimetidine) that may decrease the levels of endogenous steroid hormones. ## CNS Toxicity - CNS effects, as evidenced by decreased activity, ataxia, loss of righting reflex, and ptosis were seen in the following animal studies: the 18-month mouse carcinogenicity study at 50 mg/kg/day, the 6-month dog study at 36 mg/kg/day, the 6-month hamster study at 40 mg/kg/day, and in acute, high-dose studies in rats and hamsters (50 mg/kg), rabbits (300 mg/kg) and mice (1500 mg/kg). CNS toxicity in the acute high-dose studies was characterized (in mice) by conspicuous vacuolation in the ventral white columns of the spinal cord at a dose of 5000 mg/kg and (in rats) by edema with separation of myelinated fibers of the ventral spinal tracts and sciatic nerve at a dose of 1500 mg/kg. CNS toxicity, characterized by periaxonal vacuolation, was observed in the medulla of dogs that died after treatment for 5 weeks with 48 mg/kg/day; this finding was not observed in the remaining dogs when the dose level was lowered to 36 mg/kg/day. CNS vascular lesions, characterized by perivascular hemorrhages, edema, and mononuclear cell infiltration of perivascular spaces, have been observed in dogs treated with other members of this drug class. No CNS lesions have been observed after chronic treatment for up to 2 years with fluvastatin in the mouse (at doses up to 350 mg/kg/day), rat (up to 24 mg/kg/day), or dog (up to 16 mg/kg/day). - Prominent bilateral posterior Y suture lines in the ocular lens were seen in dogs after treatment with 1, 8, and 16 mg/kg/day for 2 years. # Adverse Reactions ## Clinical Trials Experience - The following serious adverse reactions are discussed in greater detail in other sections of the label: - Rhabdomyolysis with myoglobinuria and acute renal failure and myopathy (including myositis). ## Clinical Studies Experience in Adult Patients - Because clinical studies on Fluvastatin are conducted in varying study populations and study designs, the frequency of adverse reactions observed in the clinical studies of Fluvastatin cannot be directly compared with that in the clinical studies of other statins and may not reflect the frequency of adverse reactions observed in clinical practice. - In the Fluvastatin placebo-controlled clinical trials databases of 2326 patients treated with LESCOL1 (age range 18-75 years, 44% women, 94% Caucasians, 4% Blacks, 2% other ethnicities) with a median treatment duration of 24 weeks, 3.4% of patients on Fluvastatin and 2.3% patients on placebo discontinued due to adverse reactions regardless of causality. The most common adverreactions that led to treatment discontinuation and occurred at an incidence greater than placebo were: transaminase increased (0.8%), upper abdominal pain (0.3%), dyspepsia (0.3%), fatigue (0.2%) and diarrhea (0.2%). - In the Fluvastatin database of controlled clinical trials of 912 patients treated with Fluvastatin (age range 21-87 years, 52% women, 91% Caucasians, 4% Blacks, 5% other ethnicities) with a median treatment duration of 24 weeks, 3.9% of patients on Fluvastatin discontinued due to adverse reactions regardless of causality. The most common adverse reactions that led to treatment discontinuation were abdominal pain (0.7%), diarrhea (0.5%), nausea (0.4%), dyspepsia (0.4%) and chest pain (0.3%). - Clinically relevant adverse experiences occurring in the Fluvastatin and Fluvastatin controlled studies with a frequency greater than 2%, regardless of causality, included the following: ### FluvastatinIntervention Prevention Study - In the Fluvastatin Intervention Prevention Study (LIPS), the effect of Fluvastatin40 mg, administered twice daily on the risk of recurrent cardiac events was assessed in 1677 patients with CHD who had undergone a percutaneous coronary intervention (PCI) procedure. This was a multicenter, randomized, double-blind, placebo-controlled study, patients were treated with dietary/lifestyle counseling and either Fluvastatin40 mg (n=844) or placebo (n=833) given twice daily for a median of 3.9 years. ## Clinical Studies Experience in Pediatric Patients - In patients aged less than 18 years, efficacy and safety have not been studied for treatment periods longer than two years. - In two open-label, uncontrolled studies, 66 boys and 48 girls with heterozygous familial hypercholesterolemia ( 9-16 years of age, 80% Caucasian, 19% Other mixed ethnicity, 1% Asians) were treated with fluvastatin sodium administered as Fluvastatincapsules 20 mg -40 mg twice daily, or Fluvastatin 80 mg extended-release tablet. ## Postmarketing Experience - Because adverse reactions from spontaneous reports are reported voluntarily from a population of uncertain size, it is generally not possible to reliably estimate their frequency or establish a causal relationship to drug exposure. The following effects have been reported with drugs in this class. Not all the effects listed below have necessarily been associated with fluvastatin sodium therapy. Musculoskeletal Muscle cramps, myalgia, myopathy, Rhabdomyolysis, arthralgias, muscle spasms, muscle weakness, myositis. There have been rare reports of immune-mediated necrotizing myopathy associated with statin use. Neurological Dysfunction of certain cranial nerves (including alteration of taste, impairment of extra-ocular movement, facial paresis), tremor, dizziness, vertigo, paresthesia, hypoesthesia, dysesthesia, peripheral neuropathy, peripheral nerve palsy. There have been rare postmarketing reports of cognitive impairment (e.g., memory loss, forgetfulness, amnesia, memory impairment, confusion) associated with statin use. These cognitive issues have been reported for all statins. The reports are generally nonserious, and reversible upon statin discontinuation, with variable times to symptom onset (1 day to years) and symptom resolution (median of 3 weeks). Psychiatric Anxiety, insomnia, depression, psychic disturbances Hypersensitivity Reactions An apparent hypersensitivity syndrome has been reported rarely which has included one or more of the following features: anaphylaxis, angioedema, lupus erythematosus-like syndrome, polymyalgia rheumatica, vasculitis, purpura, thrombocytopenia, leukopenia, hemolytic anemia, positive ANA, ESR (erythrocyte sedimentation rate) increase, eosinophilia, arthritis, arthralgia, urticaria, asthenia, photosensitivity reaction, fever,chills,flushing, malaise , dyspnea, toxic epidermal necrolysis, erythema multiforme, including Stevens-Johnson syndrome. Gastrointestinal Pancreatitis, hepatitis, including chronic active hepatitis, cholestatic jaundice, fatty change in liver, cirrhosis, fulminant hepatic necrosis, hepatoma, anorexia,vomiting, fatal and non-fatal hepatic failure. Skin Rash, dermatitis, including bullous dermatitis, eczema, alopecia,pruritus, a variety of skin changes (e.g. nodules, discoloration, dryness of skin/mucous membranes, changes to hair/nails). Reproductive Gynecomastia, loss of libido, erectile dysfunction. Eye Progression of cataracts (lens opacities), ophthalmoplegia. Laboratory abnormalities Elevated transaminases, alkaline phosphatase, gamma-glutamyl transpeptidase and bilirubin; thyroid function abnormalities. # Drug Interactions Cyclosporine coadministration increases fluvastatin exposure. Therefore, in patients taking cyclosporine, therapy should be limited to Fluvastatin20 mg twice daily. - Administration of fluvastatin 40 mg single dose to healthy volunteers pre-treated with fluconazole for 4 days results in an increase of fluvastatin exposure. Therefore, in patients taking fluconazole, therapy should be limited to Fluvastatin 20 mg twice daily. - Due to an increased risk of myopathy/rhabdomyolysis when HMG-CoA reductase inhibitors are coadministered with gemfibrozil, concomitant administration of Fluvastatin with gemfibrozil should be avoided. - Because it is known that the risk of myopathy during treatment with HMG-CoA reductase inhibitors is increased with concurrent administration of other fibrates, Fluvastatin should be administered with caution when used concomitantly with other fibrates . - The risk of skeletal muscle effects may be enhanced when Fluvastatin is used in combination with lipid-modifying doses (≥1 g/day) of niacin; a reduction in Fluvastatindosage should be considered in this setting. - Concomitant administration of fluvastatin and glyburide increased glyburide exposures. Patients on concomitant therapy of glyburide and fluvastatin should continue to be monitored appropriately. - Concomitant administration of fluvastatin and phenytoin increased phenytoin exposures. Patients should continue to be monitored appropriately when fluvastatin therapy is initiated or when fluvastatin dose is changed. - Bleeding and/or increased prothrombin times have been reported in patients taking coumarin anticoagulants concomitantly with other HMG-CoA reductase inhibitors. Therefore, patients receiving warfarin-type anticoagulants should have their prothrombin times closely monitored when fluvastatin sodium is initiated or the dosage of fluvastatin sodium is changed. - Cases of myopathy, including rhabdomyolysis, have been reported with fluvastatin coadministered with colchicine, and caution should be exercised when prescribing fluvastatin with colchicine. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): X - Fluvastatin is contraindicated in women who are or may become pregnant. - Lipid lowering drugs are contraindicated during pregnancy, because cholesterol and cholesterol derivatives are needed for normal fetal development. Serum cholesterol and triglycerides increase during normal pregnancy. Atherosclerosisis a chronic process, and discontinuation of lipid-lowering drugs during pregnancy should have little impact on long-term outcomes of primary hypercholesterolemia therapy. - There are no adequate and well-controlled studies of use with Fluvastatin during pregnancy. Rare reports of congenital anomalies have been received following intrauterine exposure to other statins. In a review2 of about 100 prospectively followed pregnancies in women exposed to other statins, the incidences of congenital anomalies, spontaneous abortions, and fetal deaths/stillbirths did not exceed the rate expected in the general population. The number of cases is adequate only to exclude a 3- to 4-fold increase in congenital anomalies over background incidence. In 89% of prospectively followed pregnancies, drug treatment was initiated prior to pregnancy and was discontinued at some point in the first trimester when pregnancy was identified. - Teratology studies with fluvastatin in rats and rabbits showed maternal toxicity at high dose levels, but there was no evidence of embryotoxic or teratogenic potential. - Fluvastatinor Fluvastatin should be administered to women of child-bearing potential only when such patients are highly unlikely to conceive and have been informed of the potential hazards. If a woman becomes pregnant while taking Fluvastatinor Fluvastatin, the drug should be discontinued and the patient advised again as to the potential hazards to the fetus. Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Fluvastatin in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Fluvastatin during labor and delivery. ### Nursing Mothers - Based on animal data, fluvastatin is present in breast milk in a 2:1 ratio (milk:plasma). Because of the potential for serious adverse reactions in nursing infants, nursing women should not take Fluvastatinor Fluvastatin. ### Pediatric Use - The safety and efficacy of Fluvastatinand Fluvastatin in children and adolescent patients 9-16 years of age with heterozygous familial hypercholesterolemia have been evaluated in open-label, uncontrolled clinical trials for a duration of two years. The most common adverse events observed were influenza and infections. In these limited uncontrolled studies, there was no detectable effect on growth or sexual maturation in the adolescent boys or on menstrual cycle length in girls. Adolescent females should be counseled on appropriate contraceptive methods while on Fluvastatintherapy. ### Geriatic Use - Fluvastatin exposures were not significantly different between the nonelderly and elderly populations (age ≥ 65 years). Since advanced age (greater than 65 years) is a predisposing factor for myopathy, Fluvastatin should be prescribed with caution in the elderly. ### Gender - In a study evaluating the effect of age and gender on fluvastatin pharmacokinetics, there were no significant differences in fluvastatin exposures between males and females, except between younger females and younger males (both ages 21-49 years), where there was an approximate 30% increase in AUC in females. Adjusting for body weight decreases the magnitude of the differences seen. For Fluvastatin, the AUC increases 67% and 77% for women compared to men under fasted and high- fat meal fed conditions, respectively. ### Race There is no FDA guidance on the use of Fluvastatin with respect to specific racial populations. ### Renal Impairment - Dose adjustments for mild to moderate renal impairment are not necessary. Fluvastatin has not been studied at doses greater than 40 mg in patients with severe renal impairment; therefore caution should be exercised when treating such patients at higher doses. ### Hepatic Impairment - Fluvastatinand Fluvastatin are contraindicated in patients with active liver disease or unexplained, persistent elevations in serum transaminases. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Fluvastatin in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Fluvastatin in patients who are immunocompromised. # Administration and Monitoring ### Administration Oral ### Monitoring There is limited information about the drug monitoring. # IV Compatibility FDA Package Insert for Fluvastatin contains no information regarding IV compatibility. # Overdosage - To date, there has been limited experience with overdosage of fluvastatin. If an overdose occurs, it should be treated symptomatically with laboratory monitoring and supportive measures should be instituted as required. The dialyzability of fluvastatin sodium and of its metabolites in humans is not known at present. - In the pediatric population, there have been reports of overdosage with fluvastatin sodium in children including a 2 year-old and the other 3 years of age, either of whom may have possibly ingested fluvastatin sodium. The maximum amount of fluvastatin sodium that could have been ingested was 80 mg (4 x 20 mg capsules). Vomiting was induced by ipecac in both children and no capsules were noted in their emesis. Neither child experienced any adverse symptoms and both recovered from the incident without problems. - In the postmarketing experience there have been reports of accidental ingestion of Fluvastatintablets in infants up to 3 years of age. In one case, increased serum CPK values were noted. There have been reports of intentional overdose in adolescents with the development of hepatic enzyme elevations, convulsions and gastroenteritis/vomiting/diarrhea. One case of intentional overdose as suicide attempt in a 15 year-old female reported ingestion of 2,800 mg Fluvastatin with hepatic enzyme elevation. # Pharmacology ## Mechanism of Action - Fluvastatin is a competitive inhibitor of HMG-CoA reductase, the rate limiting enzyme that converts 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) to mevalonate, a precursor of sterols, including cholesterol. The inhibition of cholesterol biosynthesis reduces the cholesterol in hepatic cells, which stimulates the synthesis of LDL receptors and thereby increases the uptake of LDL particles. The end result of these biochemical processes is a reduction of the plasma cholesterol concentration. ## Structure - Fluvastatinis a water-soluble cholesterol lowering agent which acts through the inhibition of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase. - Fluvastatin sodium is [R,S-(E)]-(±)-7-[3-(4-fluorophenyl)-1-(1-methylethyl)-1H-indol-2-yl]-3,5-dihydroxy-6-heptenoic acid, monosodium salt. The empirical formula of fluvastatin sodium is C24H25FNO4•Na, its molecular weight is 433.46 and its structural formula is: - This molecular entity is the first entirely synthetic HMG-CoA reductase inhibitor, and is in part structurally distinct from the fungal derivatives of this therapeutic class. - Fluvastatin sodium is a white to pale yellow, hygroscopic powder soluble in water, ethanol and methanol. Fluvastatinis supplied as capsules containing fluvastatin sodium, equivalent to 20 mg or 40 mg of fluvastatin, for oral administration. Fluvastatin is supplied as extended-release tablets containing fluvastatin sodium, equivalent to 80 mg of fluvastatin, for oral administration. Active Ingredient: fluvastatin sodium Inactive Ingredients in capsules: calcium carbonate, gelatin, magnesium stearate, microcrystalline cellulose, pregelatinized starch (corn), red iron oxide, sodium bicarbonate, talc, titanium dioxide, yellow iron oxide, and other ingredients. Capsules may also include: benzyl alcohol, black iron oxide, butylparaben, carboxymethylcellulose sodium, edetate calcium disodium, methylparaben, propylparaben, silicon dioxide, sodium lauryl sulfate, and sodium propionate. Inactive Ingredients in extended-release tablets: microcrystalline cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, potassium bicarbonate, povidone, magnesium stearate, yellow iron oxide, titanium dioxide and polyethylene glycol 8000. ## Pharmacodynamics FDA Package Insert for Fluvastatin contains no information regarding pharmacodynamics. ## Pharmacokinetics ### Absorption: - Following oral administration of the capsule, fluvastatin reaches peak concentrations in less than 1 hour. The absolute bioavailability is 24% (range 9%-50%) after administration of a 10 mg dose. - At steady state, administration of fluvastatin with the evening meal results in a 50% decrease in Cmax, an 11% decrease in AUC, and a more than two-fold increase in tmaxas compared to administration 4 hours after the evening meal. No significant differences in the lipid-lowering effects were observed between the two administrations. After single or multiple doses above 20 mg, fluvastatin exhibits saturable first-pass metabolism resulting in more than dose proportional plasma fluvastatin concentrations. - Fluvastatin administered as Fluvastatin 80 mg tablets reaches peak concentration in approximately 3 hours under fasting conditions, after a low-fat meal, or 2.5 hours after a low-fat meal. The mean relative bioavailability of the XL tablet is approximately 29% (range: 9%-66%) compared to that of the Fluvastatin immediate-release capsule administered under fasting conditions. Administration of a high-fat meal delayed the absorption (Tmax: 6h) and increased the bioavailability of the XL tablet by approximately 50%. However, the maximum concentration of Fluvastatin seen after a high-fat meal is less than the peak concentration following a single dose or twice daily dose of the 40 mg Fluvastatin capsule. ### Distribution: - Fluvastatin is 98% bound to plasma proteins. The mean volume of distribution (VDss) is estimated at 0.35 L/kg. At therapeutic concentrations, the protein binding of fluvastatin is not affected by warfarin, salicylic acid and glyburide. ### Metabolism: - Fluvastatin is metabolized in the liver, primarily via hydroxylation of the indole ring at the 5- and 6-positions. N-dealkylation and beta-oxidation of the side-chain also occurs. The hydroxy metabolites have some pharmacologic activity, but do not circulate in the blood. Fluvastatin has two enantiomers. Both enantiomers of fluvastatin are metabolized in a similar manner. - In vitro data indicate that fluvastatin metabolism involves multiple Cytochrome P450 (CYP) isozymes. CYP2C9 isoenzyme is primarily involved in the metabolism of fluvastatin (approximately 75%), while CYP2C8 and CYP3A4 isoenzymes are involved to a much less extent, i.e. approximately 5% and approximately 20%, respectively. ### Excretion: - Following oral administration, fluvastatin is primarily (about 90%) excreted in the feces as metabolites, with less than 2% present as unchanged drug. Approximately 5% of a radiolabeled oral dose were recovered in urine. The elimination half-life (t1/2) of fluvastatin is approximately 3 hours. ## Nonclinical Toxicology ## Carcinogenesis, Mutagenesis, Impairment of Fertility - A 2-year study was performed in rats at dose levels of 6, 9, and 18-24 (escalated after 1 year) mg/kg/day. These treatment levels represented plasma drug levels of approximately 9, 13, and 26-35 times the mean human plasma drug concentration after a 40 mg oral dose. A low incidence of forestomach squamous papillomas and 1 carcinoma of the forestomach at the 24 mg/kg/day dose level was considered to reflect the prolonged hyperplasia induced by direct contact exposure to fluvastatin sodium rather than to a systemic effect of the drug. In addition, an increased incidence of thyroid follicular cell adenomas and carcinomas was recorded for males treated with 18-24 mg/kg/day. The increased incidence of thyroid follicular cell neoplasm in male rats with fluvastatin sodium appears to be consistent with findings from other HMG-CoA reductase inhibitors. In contrast to other HMG-CoA reductase inhibitors, no hepatic adenomas or carcinomas were observed. - The carcinogenicity study conducted in mice at dose levels of 0.3, 15 and 30 mg/kg/day revealed, as in rats, a statistically significant increase in forestomach squamous cell papillomas in males and females at 30 mg/kg/day and in females at 15 mg/kg/day. These treatment levels represented plasma drug levels of approximately 0.05, 2, and 7 times the mean human plasma drug concentration after a 40 mg oral dose. - No evidence of mutagenicity was observed in vitro, with or without rat-liver metabolic activation, in the following studies: microbial mutagen tests using mutant strains of Salmonella typhimurium or Escherichia coli; malignant transformation assay in BALB/3T3 cells; unscheduled DNA synthesis in rat primary hepatocytes; chromosomal aberrations in V79 Chinese Hamster cells; HGPRT V79 Chinese Hamster cells. In addition, there was no evidence of mutagenicity in vivo in either a rat or mouse micronucleus test. - In a study in rats at dose levels for females of 0.6, 2 and 6 mg/kg/day and at dose levels for males of 2, 10 and 20 mg/kg/day, fluvastatin sodium had no adverse effects on the fertility or reproductive performance. - Seminal vesicles and testes were small in hamsters treated for 3 months at 20 mg/kg/day (approximately three times the 40 mg human daily dose based on surface area, mg/m2). There was tubular degeneration and aspermatogenesis in testes as well as vesiculitis of seminal vesicles. Vesiculitis of seminal vesicles and edema of the testes were also seen in rats treated for 2 years at 18 mg/kg/day (approximately 4 times the human Cmax achieved with a 40 mg daily dose). - Fluvastatin sodium produced delays in skeletal development in rats at doses of 12 mg/kg/day and in rabbits at doses of 10 mg/kg/day. Malaligned thoracic vertebrae were seen in rats at 36 mg/kg, a dose that produced maternal toxicity. These doses resulted in 2 times (rat at 12 mg/kg) or 5 times (rabbit at 10 mg/kg) the 40 mg human exposure based on mg/m2 surface area. A study in which female rats were dosed during the third trimester at 12 and 24 mg/kg/day resulted in maternal mortality at or near term and postpartum. In addition, fetal and neonatal lethality were apparent. No effects on the dam or fetus occurred at 2 mg/kg/day. A second study at levels of 2, 6, 12 and 24 mg/kg/day confirmed the findings in the first study with neonatal mortality beginning at 6 mg/kg. A modified Segment III study was performed at dose levels of 12 or 24 mg/kg/day with or without the presence of concurrent supplementation with mevalonic acid, a product of HMG-CoA reductase which is essential for cholesterol biosynthesis. The concurrent administration of mevalonic acid completely revented the maternal and neonatal mortality but did not prevent low body weights in pups at 24 mg/kg on days 0 and 7 postpartum. # Clinical Studies ## Hypercholesterolemia (Heterozygous Familial and Nonfamilial) and Mixed Dyslipidemia - In 12 placebo-controlled studies in patients with primary hypercholesterolemia and mixed dyslipidemia, Fluvastatinwas administered to 1621 patients in daily dose regimens of 20 mg, 40 mg, and 80 mg (40 mg twice daily) for at least 6 weeks duration (Table 5). After 24 weeks of treatment, treatment with Fluvastatinresulted in significantly reduced plasma LDL-C, TC, TG, and Apo B compared to placebo and was associated with variable increases in HDL-C across the dose range. - Fluvastatin has been studied in five controlled studies of patients with primary hypercholesterolemia and mixed dyslipidemia. Fluvastatin was administered to over 900 patients in trials from 4 to 26 weeks in duration. In the three largest of these studies, Fluvastatin given as a single daily dose of 80 mg significantly reduced Total-C, LDL-C, TG and Apo B and resulted in increases in HDL-C (Table 5). - In patients with primary mixed dyslipidemia as defined by baseline plasma TG levels ≥200 mg/dL and less than 400 mg/dL, treatment with Fluvastatin produced significant decreases in Total-C, LDL-C, TG and Apo B and variable increases in HDL-C (Table 5). ## Heterozygous Familial Hypercholesterolemia in Pediatric Patients - Fluvastatin was studied in two open-label, uncontrolled, dose-titration studies. The first study enrolled 29 pre-pubertal boys, 9-12 years of age, who had an LDL-C level >90th percentile for age and one parent with primary hypercholesterolemia and either a family history of premature ischemic heart disease or tendon xanthomas. The mean baseline LDL-C was 226 mg/dL (range: 137-354 mg/dL). All patients were started on Fluvastatin capsules 20 mg daily with dose adjustments every 6 weeks to 40 mg daily then 80 mg daily (40 mg b.i.d.) to achieve an LDL-C goal between 96.7 – 123.7 mg/dL. Endpoint analyses were performed at Year 2. Fluvastatin decreased plasma levels of Total-C and LDL-C by 21% and 27%, respectively. The mean achieved LDL-C was 161 mg/dL (range: 74-336 mg/dL). - The second study enrolled 85 male and female patients, 10 to 16 years of age, who had an LDL-C >190 mg/dL or LDL-C >160 mg/dL and one or more risk factors for coronary heart disease, or LDL-C >160 mg/dL and a proven LDL-receptor defect. The mean baseline LDL-C was 225 mg/dL (range: 148-343 mg/dL). All patients were started on Fluvastatin capsules 20 mg daily with dose adjustments every 6 weeks to 40 mg daily then 80 mg daily (Fluvastatin80 mg XL tablet) to achieve an LDL-C goal of less than 130 mg/dL. Endpoint analyses were performed at Week 114. Fluvastatin decreased plasma levels of Total-C and LDL-C by 22% and 28%, respectively. The mean achieved LDL-C was 159 mg/dL (range: 90-295 mg/dL). - The majority of patients in both studies (83% in the first study and 89% in the second study) were titrated to the maximum daily dose of 80 mg. At study endpoint, 26% to 30% of patients in both studies achieved a targeted LDL-C goal of less than 130 mg/dL. The long-term efficacy of Fluvastatin or Fluvastatin therapy in childhood to reduce morbidity and mortality in adulthood has not been established. - In the FluvastatinIntervention Prevention Study (LIPS), the effect of Fluvastatin40 mg administered twice daily on the risk of recurrent cardiac events (time to first occurrence of cardiac death, nonfatal myocardial infarction, or revascularization) was assessed in 1677 patients with CHD who had undergone a percutaneous coronary intervention (PCI) procedure (mean time from PCI to randomization=3 days). In this multicenter, randomized, double-blind, placebo-controlled study, patients were treated with dietary/lifestyle counseling and either Fluvastatin40 mg (n=844) or placebo (n=833) given twice daily for a median of 3.9 years. The study population was 84% male, 98% Caucasian, with 37% greater than 65 years of age. Mean baseline lipid concentrations were: total cholesterol 201 mg/dL, LDL-C 132 mg/dL, triglycerides 70 mg/dL and HDL-C 39 mg/dL. - Fluvastatin significantly reduced the risk of recurrent cardiac events (Figure 1) by 22% (p=0.013, 181 patients in the Fluvastatingroup vs. 222 patients in the placebo group). - Revascularization procedures comprised the majority of the initial recurrent cardiac events (143 revascularization procedures in the Fluvastatingroup and 171 in the placebo group). Consistent trends in risk reduction were observed in patients greater than 65 years of age. - Figure 1 Primary Endpoint – Recurrent Cardiac Events (Cardiac Death, Nonfatal MI or Revascularization Procedure) (ITT Population) - Outcome data for the FluvastatinIntervention Prevention Study are shown in Figure 2. After exclusion of revascularization procedures (CABG and repeat PCI) occurring within the first 6 months of the initial procedure involving the originally instrumental site, treatment with Fluvastatinwas associated with a 32% (p=0.002) reduction in risk of late revascularization procedures (CABG or PCI occurring at the original site greater than 6 months after the initial procedure, or at another site). - Figure 2 LESCOL® Intervention Prevention Study - Primary and Secondary Endpoints - In the Lipoprotein and Coronary Atherosclerosis Study (LCAS), the effect of Fluvastatintherapy on coronary atherosclerosis was assessed by quantitative coronary angiography (QCA) in patients with CAD and mild to moderate hypercholesterolemia (baseline LDL-C range 115-190 mg/dL). In this randomized double-blind, placebo- controlled trial, 429 patients were treated with conventional measures (Step 1 AHA Diet) and either Fluvastatin40 mg/day or placebo. In order to provide treatment to patients receiving placebo with LDL-C levels ≥160 mg/dL at baseline, adjunctive therapy with cholestyramine was added after Week 12 to all patients in the study with baseline LDL-C values of ≥160 mg/dL which were present in 25% of the study population. Quantitative coronary angiograms were evaluated at baseline and 2.5 years in 340 (79%) angiographic evaluable patients. - Compared to placebo, Fluvastatinsignificantly slowed the progression of coronary atherosclerosis as measured by within-patient per-lesion change in minimum lumen diameter (MLD), the primary endpoint (Figure 3 below), percent diameter stenosis (Figure 4), and the formation of new lesions (13% of all fluvastatin patients versus 22% of all placebo patients). A significant difference in favor of Fluvastatinwas found between all fluvastatin and all placebo patients in the distribution among the three categories of definite progression, definite regression, and mixed or no change. Beneficial angiographic results (change in MLD) were independent of patients’ gender and consistent across a range of baseline LDL-C levels. # How Supplied ## LESCOL® XL (fluvastatin sodium) Extended-Release Tablets - 80 mg - Yellow, round, slightly biconvex film-coated tablet with beveled edges debossed with “Fluvastatin” on one side and “80” on the other. - Bottles of 30 tablets…………………………………………………………………………………...NDC 0078-0354-15 - Bottles of 100 tablets…………………………………………………………………………………...NDC 0078-0354-05 ## Fluvastatin capsules USP - 20 mg - hard gelatin capsules with ivory opaque body and pink opaque cap, filled with an off-white to yellowish powder with small agglomerates, body imprinted with “TEVA” and cap imprinted with “7442”, in bottles of 30 and 100. - 40 mg - hard gelatin capsules with yellow opaque body and pink opaque cap, filled with an off-white to yellowish powder with small agglomerates, body imprinted with “TEVA” and cap imprinted with “7443”, in bottles of 30 and 100. ## Storage ## LESCOL® XL (fluvastatin sodium) Extended-Release Tablets - Store at 25ºC (77ºF); excursions permitted to 15 -30ºC (59 -86ºF). Dispense in a tight container. Protect from light. ## Fluvastatin capsules USP - Store at 20° to 25°C (68° to 77°F) [See USP Controlled Room Temperature]. - Dispense in a tight, light-resistant container as defined in the USP, with a child-resistant closure (as required). Protect from light. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information - Information for Patients - Patients taking Fluvastatin should be advised that high cholesterol is a chronic condition and they should adhere to their medication along with their National Cholesterol Education Program (NCEP)-recommended diet, a regular exercise program, and periodic testing of a fasting lipid panel to determine goal attainment. - Patients should be advised about substances they should not take concomitantly with Fluvastatin. Patients should also be advised to inform other healthcare professionals prescribing a new medication that they are taking Fluvastatin. ## Muscle Pain - Patients starting therapy with Fluvastatin should be advised of the risk of myopathy and told to report promptly any unexplained muscle pain, tenderness or weakness, particularly if accompanied by malaise or fever or if these muscle signs or symptoms persist after discontinuing Fluvastatin. ## Liver Enzymes - It is recommended that liver enzyme tests be performed before the initiation of Fluvastatin and if signs or symptoms of liver injury occur. All patients treated with Fluvastatin should be advised to report promptly any symptoms that may indicate liver injury, including fatigue, anorexia, right upper abdominal discomfort, dark urine or jaundice. ## Pregnancy - Women of childbearing age should be advised to use an effective method of birth control to prevent pregnancy while using Fluvastatin. Discuss future pregnancy plans with your patients, and discuss when to stop taking Fluvastatin if they are trying to conceive. Patients should be advised that if they become pregnant they should stop taking Fluvastatin and call their healthcare professional. ## Breastfeeding - Women who are breastfeeding should not use Fluvastatin. Patients who have a lipid disorder and are breastfeeding should be advised to discuss the options with their healthcare professional. # Precautions with Alcohol - Caution should be exercised when Fluvastatin is administered to patients with a history of liver disease or heavy alcohol ingestion. Such patients should be closely monitored. # Brand Names There is limited information regarding Fluvastatin Brand Names in the drug label. # Look-Alike Drug Names There is limited information about the look-alike names . # Drug Shortage Status # Price	https://www.wikidoc.org/index.php/Fluvastatin
66183c311b4766f1edc26103b34bf2d1e9979aa1	wikidoc	Fluvoxamine	Fluvoxamine Vignesh Ponnusamy, M.B.B.S. a serotonin reuptake inhibitor -bsessive compulsive disorder (OCD) Yes nausea, somnolence, insomnia, asthenia, nervousness, dyspepsia, abnormal ejaculation, sweating, anorexia, tremor, and vomiting WARNING SUICIDALITY AND ANTIDEPRESSANT DRUGS - Antidepressants increased the risk compared to placebo of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults in short-term studies of major depressive disorder (MDD) and other psychiatric disorders. Anyone considering the use of fluvoxamine maleate tablets or any other antidepressant in a child, adolescent, or young adult must balance this risk with the clinical need. Short-term studies did not show an increase in the risk of suicidality with antidepressants compared to placebo in adults beyond age 24; there was a reduction in risk with antidepressants compared to placebo in adults aged 65 and older. Depression and certain other psychiatric disorders are themselves associated with increases in the risk of suicide. Patients of all ages who are started on antidepressant therapy should be monitored appropriately and observed closely for clinical worsening, suicidality, or unusual changes in behavior. Families and caregivers should be advised of the need for close observation and communication with the prescriber. Fluvoxamine maleate tablets are not approved for use in pediatric patients except for patients with obsessive compulsive disorder (OCD). - Dosing Information - The recommended starting dose for fluvoxamine maleate tablets in adult patients is 50 mg, administered as a single daily dose at bedtime. In the controlled clinical trials establishing the effectiveness of fluvoxamine maleate tablets in OCD, patients were titrated within a dose range of 100 to 300 mg/day. Consequently, the dose should be increased in 50 mg increments every 4 to 7 days, as tolerated, until maximum therapeutic benefit is achieved, not to exceed 300 mg per day. It is advisable that a total daily dose of more than 100 mg should be given in two divided doses. If the doses are not equal, the larger dose should be given at bedtime. - Elderly or Hepatically Impaired Patients - Elderly patients and those with hepatic impairment have been observed to have a decreased clearance of fluvoxamine maleate. Consequently, it may be appropriate to modify the initial dose and the subsequent dose titration for these patient groups. - Pregnant Women During the Third Trimester - Neonates exposed to fluvoxamine maleate tablets and other SSRIs or SNRIs late in the third trimester have developed complications requiring prolonged hospitalization, respiratory support, and tube feeding and may be at risk for persistent pulmonary hypertension of the newborn (PPHN). When treating pregnant women with fluvoxamine maleate tablets during the third trimester, the physician should carefully consider the potential risks and benefits of treatment. - Switching a Patient to or from a Monoamine Oxidase Inhibitor (MAOI) Intended to Treat Psychiatric Disorders - At least 14 days should elapse between discontinuation of an MAOI intended to treat psychiatric disorders and initiation of therapy with fluvoxamine maleate tablets. Conversely, at least 14 days should be allowed after stopping fluvoxamine maleate tablets before starting an MAOI intended to treat psychiatric disorders. - Use of Fluvoxamine Maleate Tablets with Other MAOIs such as Linezolid or Methylene Blue - Do not start fluvoxamine maleate tablets in a patient who is being treated with linezolid or intravenous methylene blue because there is an increased risk of serotonin syndrome. In a patient who requires more urgent treatment of a psychiatric condition, other interventions, including hospitalization, should be considered. - In some cases, a patient already receiving fluvoxamine maleate tablets therapy may require urgent treatment with linezolid or intravenous methylene blue. If acceptable alternatives to linezolid or intravenous methylene blue treatment are not available and the potential benefits of linezolid or intravenous methylene blue treatment are judged to outweigh the risks of serotonin syndrome in a particular patient, fluvoxamine maleate tablets should be stopped promptly, and linezolid or intravenous methylene blue can be administered. The patient should be monitored for symptoms of serotonin syndrome for 2 weeks or until 24 hours after the last dose of linezolid or intravenous methylene blue, whichever comes first. Therapy with fluvoxamine maleate tablets may be resumed 24 hours after the last dose of linezolid or intravenous methylene blue. - The risk of administering methylene blue by non-intravenous routes (such as oral tablets or by local injection) or in intravenous doses much lower than 1 mg/kg with fluvoxamine maleate tablets is unclear. The clinician should, nevertheless, be aware of the possibility of emergent symptoms of serotonin syndrome with such use. - Maintenance/Continuation Extended Treatment - It is generally agreed that obsessive compulsive disorder requires several months or longer of sustained pharmacologic therapy. The benefit of maintaining patients with OCD on fluvoxamine maleate tablets after achieving a response for an average duration of about 4 weeks in a 10-week single-blind phase during which patients were titrated to effect was demonstrated in a controlled trial. The physician who elects to use fluvoxamine maleate tablets for extended periods should periodically reevaluate the long-term usefulness of the drug for the individual patient. - Discontinuation of Treatment with Fluvoxamine Maleate Tablets - Symptoms associated with discontinuation of other SSRIs or SNRIs have been reported. Patients should be monitored for these symptoms when discontinuing treatment. A gradual reduction in the dose rather than abrupt cessation is recommended whenever possible. If intolerable symptoms occur following a decrease in the dose or upon discontinuation of treatment, then resuming the previously prescribed dose may be considered. Subsequently, the physician may continue decreasing the dose but at a more gradual rate. There is limited information regarding Off-Label Guideline-Supported Use of Fluvoxamine in adult patients. - Fluvoxamine 100 mg daily days 1 through 3; 200 mg daily days 4 through 7; and 300 mg daily from day 8. - Fluvoxamine 50 milligrams (mg) daily titrated to a maximum dose of 300 mg daily. - Fluvoxamine initiated at 40 milligrams per day, increased to 100 milligrams on day 5 and to 150 milligrams on day 9. The dose increased at 50 milligram intervals each week until side effects occur; the maximum dose of 300 milligrams reached; or panic attack and depression resolved. - Fluvoxamine ER (initial, 100 milligrams (mg)/day, titrated weekly in 50 mg increments, as needed, to maximum of 300 mg/day) for 12 weeks. - Dosing Information - The recommended starting dose for fluvoxamine maleate tablets in pediatric populations (ages 8 to 17 years) is 25 mg, administered as a single daily dose at bedtime. In a controlled clinical trial establishing the effectiveness of fluvoxamine maleate tablets in OCD, pediatric patients (ages 8 to 17) were titrated within a dose range of 50 to 200 mg/day. Physicians should consider age and gender differences when dosing pediatric patients. The maximum dose in children up to age 11 should not exceed 200 mg/day. Therapeutic effect in female children may be achieved with lower doses. Dose adjustment in adolescents (up to the adult maximum dose of 300 mg) may be indicated to achieve therapeutic benefit. The dose should be increased in 25 mg increments every 4 to 7 days, as tolerated, until maximum therapeutic benefit is achieved. It is advisable that a total daily dose of more than 50 mg should be given in two divided doses. If the two divided doses are not equal, the larger dose should be given at bedtime. There is limited information regarding Off-Label Guideline-Supported Use of Fluvoxamine in pediatric patients. There is limited information regarding Off-Label Non–Guideline-Supported Use of Fluvoxamine in pediatric patients. - Coadministration of Tizanidine, Thioridazine, Alosetron or Pimozide with Fluvoxamine Maleate Tablets is Contraindicated - Serotonin Syndrome and Monoamine Oxidase Inhibitors (MAOIs) - The use of MAOIs intended to treat psychiatric disorders with fluvoxamine maleate tablets or within 14 days of stopping treatment with fluvoxamine maleate tablets is contraindicated because of an increased risk of serotonin syndrome. The use of fluvoxamine maleate tablets within 14 days of stopping an MAOI intended to treat psychiatric disorders is also contraindicated. - Starting fluvoxamine maleate tablets in a patient who is being treated with MAOIs such as linezolid or intravenous methylene blue is also contraindicated because of an increased risk of serotonin syndrome. ## Precautions - Clinical Worsening and Suicide Risk - Patients with major depressive disorder (MDD), both adult and pediatric, may experience worsening of their depression and/or the emergence of suicidal ideation and behavior (suicidality) or unusual changes in behavior, whether or not they are taking antidepressant medications, and this risk may persist until significant remission occurs. Suicide is a known risk of depression and certain other psychiatric disorders, and these disorders themselves are the strongest predictors of suicide. There has been a long-standing concern, however, that antidepressants may have a role in inducing worsening of depression and the emergence of suicidality in certain patients during the early phases of treatment. Pooled analyses of short-term placebo-controlled trials of antidepressant drugs (SSRIs and others) showed that these drugs increase the risk of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults (ages 18 to 24) with major depressive disorder (MDD) and other psychiatric disorders. Short-term studies did not show an increase in the risk of suicidality with antidepressants compared to placebo in adults beyond age 24; there was a reduction with antidepressants compared to placebo in adults aged 65 and older. - The pooled analyses of placebo-controlled trials in children and adolescents with MDD, obsessive compulsive disorder (OCD), or other psychiatric disorders included a total of 24 short-term trials of nine antidepressant drugs in over 4,400 patients. The pooled analyses of placebo-controlled trials in adults with MDD or other psychiatric disorders included a total of 295 short-term trials (median duration of 2 months) of 11 antidepressant drugs in over 77,000 patients. There was considerable variation in risk of suicidality among drugs, but a tendency toward an increase in the younger patients for almost all drugs studied. There were differences in absolute risk of suicidality across the different indications, with the highest incidence in MDD. The risk differences (drug vs. placebo), however, were relatively stable within age strata and across indications. These risk differences (drug-placebo difference in the number of cases of suicidality per 1,000 patients treated) are provided in Table 1. - No suicides occurred in any of the pediatric trials. There were suicides in the adult trials, but the number was not sufficient to reach any conclusion about the drug effect on suicide. - It is unknown whether the suicidality risk extends to longer-term use, i.e., beyond several months. However, there is substantial evidence from placebo-controlled maintenance trials in adults with depression that the use of antidepressants can delay the recurrence of depression. - All patients being treated with antidepressants for any indication should be monitored appropriately and observed closely for clinical worsening, suicidality, and unusual changes in behavior, especially during the initial few months of a course of drug therapy, or at times of dose changes, either increases or decreases. - The following symptoms, anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, and mania, have been reported in adult and pediatric patients being treated with antidepressants for major depressive disorder as well as for other indications, both psychiatric and nonpsychiatric. Although a causal link between the emergence of such symptoms and either the worsening of depression and/or the emergence of suicidal impulses has not been established, there is concern that such symptoms may represent precursors to emerging suicidality. - Consideration should be given to changing the therapeutic regimen, including possibly discontinuing the medication, in patients whose depression is persistently worse, or who are experiencing emergent suicidality or symptoms that might be precursors to worsening depression or suicidality, especially if these symptoms are severe, abrupt in onset, or were not part of the patient’s presenting symptoms. - If the decision has been made to discontinue treatment, medication should be tapered, as rapidly as is feasible, but with recognition that abrupt discontinuation can be associated with certain symptoms, for a description of the risks of discontinuation of fluvoxamine maleate tablets. - Families and caregivers of patients being treated with antidepressants for major depressive disorder or other indications, both psychiatric and nonpsychiatric, should be alerted about the need to monitor patients for the emergence of agitation, irritability, unusual changes in behavior, and the other symptoms described above, as well as the emergence of suicidality, and to report such symptoms immediately to healthcare providers. Such monitoring should include daily observation by families and caregivers. Prescriptions for fluvoxamine maleate tablets should be written for the smallest quantity of tablets consistent with good patient management, in order to reduce the risk of overdose. - Screening Patients for Bipolar Disorder - A major depressive episode may be the initial presentation of bipolar disorder. It is generally believed (though not established in controlled trials) that treating such an episode with an antidepressant alone may increase the likelihood of precipitation of a mixed/manic episode in patients at risk for bipolar disorder. Whether any of the symptoms described above represent such a conversion is unknown. However, prior to initiating treatment with an antidepressant, patients with depressive symptoms should be adequately screened to determine if they are at risk for bipolar disorder; such screening should include a detailed psychiatric history, including a family history of suicide, bipolar disorder, and depression. It should be noted that fluvoxamine maleate tablets are not approved for use in treating bipolar depression. - Serotonin Syndrome - The development of a potentially life-threatening serotonin syndrome has been reported with SNRIs and SSRIs, including fluvoxamine maleate tablets, alone but particularly with concomitant use of serotonergic drugs (including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan, buspirone, and St. John's Wort) and with drugs that impair metabolism of serotonin (in particular MAOIs, both those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue). - Serotonin syndrome symptoms may include mental status changes (e.g., agitation, hallucinations, delirium, and coma), autonomic instability (e.g., tachycardia, labile blood pressure, dizziness, diaphoresis, flushing, hyperthermia), neuromuscular aberrations (e.g., tremor, rigidity, myoclonus, hyperreflexia, incoordination), seizures, and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). Patients should be monitored for the emergence of serotonin syndrome. - The concomitant use of fluvoxamine maleate tablets with MAOIs intended to treat psychiatric disorders is contraindicated. Fluvoxamine maleate tablets should also not be started in a patient who is being treated with MAOIs such as linezolid or intravenous methylene blue. All reports with methylene blue that provided information on the route of administration involved intravenous administration in the dose range of 1 mg/kg to 8 mg/kg. No reports involved the administration of methylene blue by other routes (such as oral tablets or local tissue injection) or at lower doses. There may be circumstances when it is necessary to initiate treatment with an MAOI such as linezolid or intravenous methylene blue in a patient taking fluvoxamine maleate tablets. Fluvoxamine maleate tablets should be discontinued before initiating treatment with the MAOI. - If concomitant use of fluvoxamine maleate tablets with other serotonergic drugs, including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, buspirone, tryptophan and St. John's Wort is clinically warranted, patients should be made aware of a potential increased risk for serotonin syndrome, particularly during treatment initiation and dose increases. - Treatment with fluvoxamine maleate tablets and any concomitant serotonergic agents, should be discontinued immediately if the above events occur and supportive symptomatic treatment should be initiated. - Angle Closure Glaucoma - The pupillary dilation that occurs following use of many antidepressant drugs including fluvoxamine maleate tablets may trigger an angle closure attack in a patient with anatomically narrow angles who do not have a patent iridectomy. - Potential Thioridazine Interaction - The effect of fluvoxamine (25 mg b.i.d. for one week) on thioridazine steady-state concentrations was evaluated in ten male inpatients with schizophrenia. Concentrations of thioridazine and its two active metabolites, mesoridazine and sulforidazine, increased 3-fold following coadministration of fluvoxamine. - Thioridazine administration produces a dose-related prolongation of the QTc interval, which is associated with serious ventricular arrhythmias, such as torsades de pointes-type arrhythmias, and sudden death. It is likely that this experience underestimates the degree of risk that might occur with higher doses of thioridazine. Moreover, the effect of fluvoxamine may be even more pronounced when it is administered at higher doses. - Therefore, fluvoxamine and thioridazine should not be coadministered. - Potential Tizanidine Interaction - Fluvoxamine is a potent inhibitor of CYP1A2 and tizanidine is a CYP1A2 substrate. The effect of fluvoxamine (100 mg daily for 4 days) on the pharmacokinetics and pharmacodynamics of a single 4 mg dose of tizanidine has been studied in ten healthy male subjects. Tizanidine Cmax was increased approximately 12-fold (range 5-fold to 32-fold), elimination half-life was increased by almost 3-fold, and AUC increased 33-fold (range 14-fold to 103-fold). The mean maximal effect on blood pressure was a 35 mm Hg decrease in systolic blood pressure, a 20 mm Hg decrease in diastolic blood pressure, and a 4 beat/min decrease in heart rate. Drowsiness was significantly increased and performance on the psychomotor task was significantly impaired. Fluvoxamine and tizanidine should not be used together. - Potential Pimozide Interaction - Pimozide is metabolized by the cytochrome P4503A4 isoenzyme, and it has been demonstrated that ketoconazole, a potent inhibitor of CYP3A4, blocks the metabolism of this drug, resulting in increased plasma concentrations of parent drug. An increased plasma concentration of pimozide causes QT prolongation and has been associated with torsades de pointes-type ventricular tachycardia, sometimes fatal. As noted below, a substantial pharmacokinetic interaction has been observed for fluvoxamine in combination with alprazolam, a drug that is known to be metabolized by CYP3A4. Although it has not been definitively demonstrated that fluvoxamine is a potent CYP3A4 inhibitor, it is likely to be, given the substantial interaction of fluvoxamine with alprazolam. Consequently, it is recommended that fluvoxamine not be used in combination with pimozide. - Potential Alosetron Interaction - Because alosetron is metabolized by a variety of hepatic CYP drug metabolizing enzymes, inducers or inhibitors of these enzymes may change the clearance of alosetron. Fluvoxamine is a known potent inhibitor of CYP1A2 and also inhibits CYP3A4, CYP2C9, and CYP2C19. In a pharmacokinetic study, 40 healthy female subjects received fluvoxamine in escalating doses from 50 mg to 200 mg a day for 16 days, with coadministration of alosetron 1 mg on the last day. Fluvoxamine increased mean alosetron plasma concentration (AUC) approximately 6-fold and prolonged the half-life by approximately 3-fold. - Other Potentially Important Drug Interactions - Benzodiazepines - Benzodiazepines metabolized by hepatic oxidation (e.g., alprazolam, midazolam, triazolam, etc.) should be used with caution because the clearance of these drugs is likely to be reduced by fluvoxamine. The clearance of benzodiazepines metabolized by glucuronidation (e.g., lorazepam, oxazepam, temazepam) is unlikely to be affected by fluvoxamine. - Alprazolam - When fluvoxamine maleate (100 mg q.d.) and alprazolam (1 mg q.i.d.) were coadministered to steady state, plasma concentrations and other pharmacokinetic parameters (AUC, Cmax, T½) of alprazolam were approximately twice those observed when alprazolam was administered alone; oral clearance was reduced by about 50%. The elevated plasma alprazolam concentrations resulted in decreased psychomotor performance and memory. This interaction, which has not been investigated using higher doses of fluvoxamine, may be more pronounced if a 300 mg daily dose is coadministered, particularly since fluvoxamine exhibits non-linear pharmacokinetics over the dosage range 100 mg to 300 mg. If alprazolam is coadministered with fluvoxamine maleate tablets, the initial alprazolam dosage should be at least halved and titration to the lowest effective dose is recommended. No dosage adjustment is required for fluvoxamine maleate tablets. - Diazepam - The coadministration of fluvoxamine maleate tablets and diazepam is generally not advisable. Because fluvoxamine reduces the clearance of both diazepam and its active metabolite, N-desmethyldiazepam, there is a strong likelihood of substantial accumulation of both species during chronic coadministration. - Evidence supporting the conclusion that it is inadvisable to coadminister fluvoxamine and diazepam is derived from a study in which healthy volunteers taking 150 mg/day of fluvoxamine were administered a single oral dose of 10 mg of diazepam. In these subjects (N = 8), the clearance of diazepam was reduced by 65% and that of N-desmethyldiazepam to a level that was too low to measure over the course of the 2 week long study. - It is likely that this experience significantly underestimates the degree of accumulation that might occur with repeated diazepam administration. Moreover, as noted with alprazolam, the effect of fluvoxamine may even be more pronounced when it is administered at higher doses. - Accordingly, diazepam and fluvoxamine should not ordinarily be coadministered. - Clozapine - Elevated serum levels of clozapine have been reported in patients taking fluvoxamine maleate and clozapine. Since clozapine-related seizures and orthostatic hypotension appear to be dose related, the risk of these adverse events may be higher when fluvoxamine and clozapine are coadministered. Patients should be closely monitored when fluvoxamine maleate and clozapine are used concurrently. - Methadone - Significantly increased methadone (plasma level:dose) ratios have been reported when fluvoxamine maleate was administered to patients receiving maintenance methadone treatment, with symptoms of opioid intoxication in one patient. Opioid withdrawal symptoms were reported following fluvoxamine maleate discontinuation in another patient. - Mexiletine - The effect of steady-state fluvoxamine (50 mg b.i.d. for 7 days) on the single dose pharmacokinetics of mexiletine (200 mg) was evaluated in six healthy Japanese males. The clearance of mexiletine was reduced by 38% following coadministration with fluvoxamine compared to mexiletine alone. If fluvoxamine and mexiletine are coadministered, serum mexiletine levels should be monitored. - Ramelteon - When fluvoxamine 100 mg twice daily was administered for 3 days prior to single-dose coadministration of ramelteon 16 mg and fluvoxamine, the AUC for ramelteon increased approximately 190-fold and the Cmax increased approximately 70-fold compared to ramelteon administered alone. Ramelteon should not be used in combination with fluvoxamine. - Theophylline - The effect of steady-state fluvoxamine (50 mg bid) on the pharmacokinetics of a single dose of theophylline (375 mg as 442 mg aminophylline) was evaluated in 12 healthy non-smoking, male volunteers. The clearance of theophylline was decreased approximately 3-fold. Therefore, if theophylline is coadministered with fluvoxamine maleate, its dose should be reduced to one-third of the usual daily maintenance dose and plasma concentrations of theophylline should be monitored. No dosage adjustment is required for fluvoxamine maleate tablets. - Warfarin and Other Drugs that Interfere with Hemostasis (NSAIDs, Aspirin, etc.) - Serotonin release by platelets plays an important role in hemostasis. Epidemiological studies of the case-control and cohort design have demonstrated an association between use of psychotropic drugs that interfere with serotonin reuptake and the occurrence of upper gastrointestinal bleeding. These studies have also shown that concurrent use of an NSAID or aspirin may potentiate this risk of bleeding. Thus, patients should be cautioned about the use of such drugs concurrently with fluvoxamine. - Warfarin - When fluvoxamine maleate (50 mg t.i.d.) was administered concomitantly with warfarin for 2 weeks, warfarin plasma concentrations increased by 98% and prothrombin times were prolonged. Thus patients receiving oral anticoagulants and fluvoxamine maleate tablets should have their prothrombin time monitored and their anticoagulant dose adjusted accordingly. No dosage adjustment is required for fluvoxamine maleate tablets. - Discontinuation of Treatment with Fluvoxamine Maleate Tablets - During marketing of fluvoxamine maleate tablets and other SSRIs and SNRIs (serotonin and norepinephrine reuptake inhibitors), there have been spontaneous reports of adverse events occurring upon discontinuation of these drugs, particularly when abrupt, including the following: dysphoric mood, irritability, agitation, dizziness, sensory disturbances (e.g., paresthesias, such as electric shock sensations), anxiety, confusion, headache, lethargy, emotional lability, insomnia, and hypomania. While these events are generally self-limiting, there have been reports of serious discontinuation symptoms. - Patients should be monitored for these symptoms when discontinuing treatment with fluvoxamine maleate tablets. A gradual reduction in the dose rather than abrupt cessation is recommended whenever possible. If intolerable symptoms occur following a decrease in the dose or upon discontinuation of treatment, then resuming the previously prescribed dose may be considered. Subsequently, the physician may continue decreasing the dose but at a more gradual rate. - Abnormal Bleeding - SSRIs and SNRIs, including fluvoxamine maleate tablets, may increase the risk of bleeding events. Concomitant use of aspirin, nonsteroidal anti-inflammatory drugs, warfarin, and other anticoagulants may add to this risk. Case reports and epidemiological studies (case-control and cohort design) have demonstrated an association between use of drugs that interfere with serotonin reuptake and the occurrence of gastrointestinal bleeding. Bleeding events related to SSRIs and SNRIs have ranged from ecchymoses, hematomas, epistaxis, and petechiae to life-threatening hemorrhages. - Patients should be cautioned about the risk of bleeding associated with the concomitant use of fluvoxamine maleate tablets and NSAIDs, aspirin, or other drugs that affect coagulation. - Activation of Mania/Hypomania - During premarketing studies involving primarily depressed patients, hypomania or mania occurred in approximately 1% of patients treated with fluvoxamine. In a 10-week pediatric OCD study, 2 out of 57 patients (4%) treated with fluvoxamine experienced manic reactions, compared to none of 63 placebo patients. Activation of mania/hypomania has also been reported in a small proportion of patients with major affective disorder who were treated with other marketed antidepressants. As with all antidepressants, fluvoxamine maleate tablets should be used cautiously in patients with a history of mania. - Seizures - During premarketing studies, seizures were reported in 0.2% of fluvoxamine-treated patients. Caution is recommended when the drug is administered to patients with a history of convulsive disorders. Fluvoxamine should be avoided in patients with unstable epilepsy and patients with controlled epilepsy should be carefully monitored. Treatment with fluvoxamine should be discontinued if seizures occur or if seizure frequency increases. - Hyponatremia - Hyponatremia may occur as a result of treatment with SSRIs and SNRIs, including fluvoxamine maleate tablets. In many cases, this hyponatremia appears to be the result of the syndrome of inappropriate antidiuretic hormone (SIADH). Cases with serum sodium lower than 110 mmol/L have been reported. Elderly patients may be at greater risk of developing hyponatremia with SSRIs and SNRIs. Also, patients taking diuretics or who are otherwise volume depleted may be at greater risk. Discontinuation of fluvoxamine maleate tablets should be considered in patients with symptomatic hyponatremia and appropriate medical intervention should be instituted. - Signs and symptoms of hyponatremia include headache, difficulty concentrating, memory impairment, confusion, weakness, and unsteadiness, which may lead to falls. Signs and symptoms associated with more severe and/or acute cases have included hallucination, syncope, seizure, coma, respiratory arrest, and death. - Use in Patients with Concomitant Illness - Closely monitored clinical experience with fluvoxamine maleate tablets in patients with concomitant systemic illness is limited. Caution is advised in administering fluvoxamine maleate tablets to patients with diseases or conditions that could affect hemodynamic responses or metabolism. - Fluvoxamine maleate tablets have not been evaluated or used to any appreciable extent in patients with a recent history of myocardial infarction or unstable heart disease. Patients with these diagnoses were systematically excluded from many clinical studies during the product's premarketing testing. Evaluation of the electrocardiograms for patients with depression or OCD who participated in premarketing studies revealed no differences between fluvoxamine and placebo in the emergence of clinically important ECG changes. - Patients with Hepatic Impairment - In patients with liver dysfunction, fluvoxamine clearance was decreased by approximately 30%. Patients with liver dysfunction should begin with a low dose of fluvoxamine maleate tablets and increase it slowly with careful monitoring. - Adverse Reactions Leading to Treatment Discontinuation - Of the 1,087 OCD and depressed patients treated with fluvoxamine maleate in controlled clinical trials in North America, 22% discontinued due to an adverse reaction. Adverse reactions that led to discontinuation in at least 2% of fluvoxamine maleate-treated patients in these trials were: nausea (9%), insomnia (4%), somnolence (4%), headache (3%), and asthenia, vomiting, nervousness, agitation, and dizziness (2% each). - Commonly Observed Adverse Reactions in Controlled Clinical Trials - Fluvoxamine maleate tablets have been studied in 10-week short-term controlled trials of OCD (N = 320) and depression (N = 1,350). In general, adverse reaction rates were similar in the two data sets as well as in the pediatric OCD study. The most commonly observed adverse reactions associated with the use of fluvoxamine maleate tablets and likely to be drug-related (incidence of 5% or greater and at least twice that for placebo) derived from Table 2 were: nausea, somnolence, insomnia, asthenia, nervousness, dyspepsia, abnormal ejaculation, sweating, anorexia, tremor, and vomiting. In a pool of two studies involving only patients with OCD, the following additional reactions were identified using the above rule: anorgasmia, decreased libido, dry mouth, rhinitis, taste perversion, and urinary frequency. In a study of pediatric patients with OCD, the following additional reactions were identified using the above rule: agitation, depression, dysmenorrhea, flatulence, hyperkinesia, and rash. - Adverse Reactions Occurring at an Incidence of 1% - Table 2 enumerates adverse reactions that occurred in adults at a frequency of 1% or more, and were more frequent than in the placebo group, among patients treated with fluvoxamine maleate tablets in two short-term placebo-controlled OCD trials (10 week) and depression trials (6 week) in which patients were dosed in a range of generally 100 to 300 mg/day. This table shows the percentage of patients in each group who had at least one occurrence of a reaction at some time during their treatment. Reported adverse reactions were classified using a standard COSTART-based Dictionary terminology. - The prescriber should be aware that these figures cannot be used to predict the incidence of side effects in the course of usual medical practice where patient characteristics and other factors may differ from those that prevailed in the clinical trials. Similarly, the cited frequencies cannot be compared with figures obtained from other clinical investigations involving different treatments, uses, and investigators. The cited figures, however, do provide the prescribing physician with some basis for estimating the relative contribution of drug and non-drug factors to the side-effect incidence rate in the population studied. - Adverse Reactions in OCD Placebo-Controlled Studies which are Markedly Different (defined as at least a 2-fold difference) in Rate from the Pooled Reaction Rates in OCD and Depression Placebo-Controlled Studies - The reactions in OCD studies with a 2-fold decrease in rate compared to reaction rates in OCD and depression studies were dysphagia and amblyopia (mostly blurred vision). Additionally, there was an approximate 25% decrease in nausea. - The reactions in OCD studies with a 2-fold increase in rate compared to reaction rates in OCD and depression studies were: asthenia, abnormal ejaculation (mostly delayed ejaculation), anxiety, rhinitis, anorgasmia (in males), depression, libido decreased, pharyngitis, agitation, impotence, myoclonus/twitch, thirst, weight loss, leg cramps, myalgia, and urinary retention. These reactions are listed in order of decreasing rates in the OCD trials. - Other Adverse Reactions in OCD Pediatric Population - In pediatric patients (N = 57) treated with fluvoxamine maleate tablets, the overall profile of adverse reactions was generally similar to that seen in adult studies, as shown in Table 2. However, the following adverse reactions, not appearing in Table 2, were reported in two or more of the pediatric patients and were more frequent with fluvoxamine maleate tablets than with placebo: cough increase, dysmenorrhea, ecchymosis, emotional lability, epistaxis, hyperkinesia, manic reaction, rash, sinusitis, and weight decrease. - Male and Female Sexual Dysfunction with SSRIs - Although changes in sexual desire, sexual performance and sexual satisfaction often occur as manifestations of a psychiatric disorder and with aging, they may also be a consequence of pharmacologic treatment. In particular, some evidence suggests that selective serotonin reuptake inhibitors (SSRIs), can cause such untoward sexual experiences. - Reliable estimates of the incidence and severity of untoward experiences involving sexual desire, performance and satisfaction are difficult to obtain, however, in part because patients and physicians may be reluctant to discuss them. Accordingly, estimates of the incidence of untoward sexual experience and performance cited in product labeling are likely to underestimate their actual incidence. - Table 3 displays the incidence of sexual side effects reported by at least 2% of patients taking fluvoxamine maleate tablets in placebo-controlled trials in depression and OCD. - There are no adequate and well-controlled studies examining sexual dysfunction with fluvoxamine treatment. - Fluvoxamine treatment has been associated with several cases of priapism. In those cases with a known outcome, patients recovered without sequelae and upon discontinuation of fluvoxamine. - While it is difficult to know the precise risk of sexual dysfunction associated with the use of SSRIs, physicians should routinely inquire about such possible side effects. - Vital Sign Changes - Comparisons of fluvoxamine maleate and placebo groups in separate pools of short-term OCD and depression trials on (1) median change from baseline on various vital signs variables and on (2) incidence of patients meeting criteria for potentially important changes from baseline on various vital signs variables revealed no important differences between fluvoxamine maleate and placebo. - Laboratory Changes - Comparisons of fluvoxamine maleate and placebo groups in separate pools of short-term OCD and depression trials on (1) median change from baseline on various serum chemistry, hematology, and urinalysis variables and on (2) incidence of patients meeting criteria for potentially important changes from baseline on various serum chemistry, hematology, and urinalysis variables revealed no important differences between fluvoxamine maleate and placebo. - ECG Changes - Comparisons of fluvoxamine maleate and placebo groups in separate pools of short-term OCD and depression trials on (1) mean change from baseline on various ECG variables and on (2) incidence of patients meeting criteria for potentially important changes from baseline on various ECG variables revealed no important differences between fluvoxamine maleate and placebo. - Other Reactions Observed During the Premarketing Evaluation of Fluvoxamine Maleate Tablets - During premarketing clinical trials conducted in North America and Europe, multiple doses of fluvoxamine maleate were administered for a combined total of 2,737 patient exposures in patients suffering OCD or Major Depressive Disorder. Untoward reactions associated with this exposure were recorded by clinical investigators using descriptive terminology of their own choosing. Consequently, it is not possible to provide a meaningful estimate of the proportion of individuals experiencing adverse reactions without first grouping similar types of untoward reactions into a limited (i.e., reduced) number of standard reaction categories. - In the tabulations which follow, a standard COSTART-based Dictionary terminology has been used to classify reported adverse reactions. If the COSTART term for a reaction was so general as to be uninformative, it was replaced with a more informative term. The frequencies presented, therefore, represent the proportion of the 2,737 patient exposures to multiple doses of fluvoxamine maleate who experienced a reaction of the type cited on at least one occasion while receiving fluvoxamine maleate. All reported reactions are included in the list below, with the following exceptions: 1) those reactions already listed in Table 2, which tabulates incidence rates of common adverse experiences in placebo-controlled OCD and depression clinical trials, are excluded; 2) those reactions for which a drug cause was not considered likely are omitted; 3) reactions for which the COSTART term was too vague to be clinically meaningful and could not be replaced with a more informative term; and 4) reactions which were reported in only one patient and judged to not be potentially serious are not included. It is important to emphasize that, although the reactions reported did occur during treatment with fluvoxamine maleate, a causal relationship to fluvoxamine maleate has not been established. - Reactions are further classified within body system categories and enumerated in order of decreasing frequency using the following definitions: frequent adverse reactions are defined as those occurring on one or more occasions in at least 1/100 patients; infrequent adverse reactions are those occurring between 1/100 and 1/1000 patients; and rare adverse reactions are those occurring in less than 1/1000 patients. Frequent: malaise; Infrequent: photosensitivity reaction and suicide attempt. Frequent: syncope. Infrequent: gastrointestinal hemorrhage and melena; Rare: hematemesis. Infrequent: anemia and ecchymosis; Rare: purpura. Frequent: weight gain and weight loss. Frequent: hyperkinesia, manic reaction, and myoclonus; Infrequent: abnormal dreams, akathisia, convulsion, dyskinesia, dystonia, euphoria, extrapyramidal syndrome, and twitching; Rare: withdrawal syndrome. Infrequent: epistaxis. Rare: hemoptysis and laryngismus. Infrequent: urticaria. Infrequent: hematuria, menorrhagia, and vaginal hemorrhage; Rare: hematospermia. - Voluntary reports of adverse reactions in patients taking fluvoxamine maleate tablets that have been received since market introduction and are of unknown causal relationship to fluvoxamine maleate tablets use include: acute renal failure, agranulocytosis, amenorrhea, anaphylactic reaction, angioedema, aplastic anemia, bullous eruption, Henoch-Schoenlein purpura, hepatitis, ileus, pancreatitis, porphyria, Stevens-Johnson syndrome, toxic epidermal necrolysis, vasculitis, and ventricular tachycardia (including torsades de pointes). - Potential Thioridazine Interaction - The effect of fluvoxamine (25 mg b.i.d. for one week) on thioridazine steady-state concentrations was evaluated in ten male inpatients with schizophrenia. Concentrations of thioridazine and its two active metabolites, mesoridazine and sulforidazine, increased 3-fold following coadministration of fluvoxamine. - Thioridazine administration produces a dose-related prolongation of the QTc interval, which is associated with serious ventricular arrhythmias, such as torsades de pointes-type arrhythmias, and sudden death. It is likely that this experience underestimates the degree of risk that might occur with higher doses of thioridazine. Moreover, the effect of fluvoxamine may be even more pronounced when it is administered at higher doses. - Therefore, fluvoxamine and thioridazine should not be coadministered. - Potential Tizanidine Interaction - Fluvoxamine is a potent inhibitor of CYP1A2 and tizanidine is a CYP1A2 substrate. The effect of fluvoxamine (100 mg daily for 4 days) on the pharmacokinetics and pharmacodynamics of a single 4 mg dose of tizanidine has been studied in ten healthy male subjects. Tizanidine Cmax was increased approximately 12-fold (range 5-fold to 32-fold), elimination half-life was increased by almost 3-fold, and AUC increased 33-fold (range 14-fold to 103-fold). The mean maximal effect on blood pressure was a 35 mm Hg decrease in systolic blood pressure, a 20 mm Hg decrease in diastolic blood pressure, and a 4 beat/min decrease in heart rate. Drowsiness was significantly increased and performance on the psychomotor task was significantly impaired. Fluvoxamine and tizanidine should not be used together. - Potential Pimozide Interaction - Pimozide is metabolized by the cytochrome P4503A4 isoenzyme, and it has been demonstrated that ketoconazole, a potent inhibitor of CYP3A4, blocks the metabolism of this drug, resulting in increased plasma concentrations of parent drug. An increased plasma concentration of pimozide causes QT prolongation and has been associated with torsades de pointes-type ventricular tachycardia, sometimes fatal. As noted below, a substantial pharmacokinetic interaction has been observed for fluvoxamine in combination with alprazolam, a drug that is known to be metabolized by CYP3A4. Although it has not been definitively demonstrated that fluvoxamine is a potent CYP3A4 inhibitor, it is likely to be, given the substantial interaction of fluvoxamine with alprazolam. Consequently, it is recommended that fluvoxamine not be used in combination with pimozide. - Potential Alosetron Interaction - Because alosetron is metabolized by a variety of hepatic CYP drug metabolizing enzymes, inducers or inhibitors of these enzymes may change the clearance of alosetron. Fluvoxamine is a known potent inhibitor of CYP1A2 and also inhibits CYP3A4, CYP2C9, and CYP2C19. In a pharmacokinetic study, 40 healthy female subjects received fluvoxamine in escalating doses from 50 mg to 200 mg a day for 16 days, with coadministration of alosetron 1 mg on the last day. Fluvoxamine increased mean alosetron plasma concentration (AUC) approximately 6-fold and prolonged the half-life by approximately 3-fold. - Other Potentially Important Drug Interactions - Benzodiazepines - Benzodiazepines metabolized by hepatic oxidation (e.g., alprazolam, midazolam, triazolam, etc.) should be used with caution because the clearance of these drugs is likely to be reduced by fluvoxamine. The clearance of benzodiazepines metabolized by glucuronidation (e.g., lorazepam, oxazepam, temazepam) is unlikely to be affected by fluvoxamine. - Alprazolam - When fluvoxamine maleate (100 mg q.d.) and alprazolam (1 mg q.i.d.) were coadministered to steady state, plasma concentrations and other pharmacokinetic parameters (AUC, Cmax, T½) of alprazolam were approximately twice those observed when alprazolam was administered alone; oral clearance was reduced by about 50%. The elevated plasma alprazolam concentrations resulted in decreased psychomotor performance and memory. This interaction, which has not been investigated using higher doses of fluvoxamine, may be more pronounced if a 300 mg daily dose is coadministered, particularly since fluvoxamine exhibits non-linear pharmacokinetics over the dosage range 100 mg to 300 mg. If alprazolam is coadministered with fluvoxamine maleate tablets, the initial alprazolam dosage should be at least halved and titration to the lowest effective dose is recommended. No dosage adjustment is required for fluvoxamine maleate tablets. - Diazepam - The coadministration of fluvoxamine maleate tablets and diazepam is generally not advisable. Because fluvoxamine reduces the clearance of both diazepam and its active metabolite, N-desmethyldiazepam, there is a strong likelihood of substantial accumulation of both species during chronic coadministration. - Evidence supporting the conclusion that it is inadvisable to coadminister fluvoxamine and diazepam is derived from a study in which healthy volunteers taking 150 mg/day of fluvoxamine were administered a single oral dose of 10 mg of diazepam. In these subjects (N = 8), the clearance of diazepam was reduced by 65% and that of N-desmethyldiazepam to a level that was too low to measure over the course of the 2 week long study. - It is likely that this experience significantly underestimates the degree of accumulation that might occur with repeated diazepam administration. Moreover, as noted with alprazolam, the effect of fluvoxamine may even be more pronounced when it is administered at higher doses. - Accordingly, diazepam and fluvoxamine should not ordinarily be coadministered. - Clozapine - Elevated serum levels of clozapine have been reported in patients taking fluvoxamine maleate and clozapine. Since clozapine-related seizures and orthostatic hypotension appear to be dose related, the risk of these adverse events may be higher when fluvoxamine and clozapine are coadministered. Patients should be closely monitored when fluvoxamine maleate and clozapine are used concurrently. - Methadone - Significantly increased methadone (plasma level:dose) ratios have been reported when fluvoxamine maleate was administered to patients receiving maintenance methadone treatment, with symptoms of opioid intoxication in one patient. Opioid withdrawal symptoms were reported following fluvoxamine maleate discontinuation in another patient. - Mexiletine - The effect of steady-state fluvoxamine (50 mg b.i.d. for 7 days) on the single dose pharmacokinetics of mexiletine (200 mg) was evaluated in six healthy Japanese males. The clearance of mexiletine was reduced by 38% following coadministration with fluvoxamine compared to mexiletine alone. If fluvoxamine and mexiletine are coadministered, serum mexiletine levels should be monitored. - Ramelteon - When fluvoxamine 100 mg twice daily was administered for 3 days prior to single-dose coadministration of ramelteon 16 mg and fluvoxamine, the AUC for ramelteon increased approximately 190-fold and the Cmax increased approximately 70-fold compared to ramelteon administered alone. Ramelteon should not be used in combination with fluvoxamine. - Theophylline - The effect of steady-state fluvoxamine (50 mg bid) on the pharmacokinetics of a single dose of theophylline (375 mg as 442 mg aminophylline) was evaluated in 12 healthy non-smoking, male volunteers. The clearance of theophylline was decreased approximately 3-fold. Therefore, if theophylline is coadministered with fluvoxamine maleate, its dose should be reduced to one-third of the usual daily maintenance dose and plasma concentrations of theophylline should be monitored. No dosage adjustment is required for fluvoxamine maleate tablets. - Warfarin and Other Drugs that Interfere with Hemostasis (NSAIDs, Aspirin, etc.) - Serotonin release by platelets plays an important role in hemostasis. Epidemiological studies of the case-control and cohort design have demonstrated an association between use of psychotropic drugs that interfere with serotonin reuptake and the occurrence of upper gastrointestinal bleeding. These studies have also shown that concurrent use of an NSAID or aspirin may potentiate this risk of bleeding. Thus, patients should be cautioned about the use of such drugs concurrently with fluvoxamine. - Warfarin - When fluvoxamine maleate (50 mg t.i.d.) was administered concomitantly with warfarin for 2 weeks, warfarin plasma concentrations increased by 98% and prothrombin times were prolonged. Thus patients receiving oral anticoagulants and fluvoxamine maleate tablets should have their prothrombin time monitored and their anticoagulant dose adjusted accordingly. No dosage adjustment is required for fluvoxamine maleate tablets. - Effects of Smoking on Fluvoxamine Metabolism - Smokers had a 25% increase in the metabolism of fluvoxamine compared to nonsmokers. - Electroconvulsive Therapy (ECT) - There are no clinical studies establishing the benefits or risks of combined use of ECT and fluvoxamine maleate. - Pregnancy Category C - Teratogenic Effects - When pregnant rats were given oral doses of fluvoxamine (60, 120, or 240 mg/kg) throughout the period of organogenesis, developmental toxicity in the form of increased embryofetal death and increased incidences of fetal eye abnormalities (folded retinas) was observed at doses of 120 mg/kg or greater. Decreased fetal body weight was seen at the high dose. The no effect dose for developmental toxicity in this study was 60 mg/kg (approximately 2 times the MRHD on a mg/m2 basis). - In a study in which pregnant rabbits were administered doses of up to 40 mg/kg (approximately 2 times the MRHD on a mg/m2 basis) during organogenesis, no adverse effects on embryofetal development were observed. - In other reproduction studies in which female rats were dosed orally during pregnancy and lactation (5, 20, 80, or 160 mg/kg), increased pup mortality at birth was seen at doses of 80 mg/kg or greater and decreases in pup body weight and survival were observed at all doses (low effect dose approximately 0.1 times the MRHD on a mg/m2 basis). - Nonteratogenic Effects - Neonates exposed to fluvoxamine maleate tablets and other SSRIs or serotonin and norepinephrine reuptake inhibitors (SNRIs) late in the third trimester have developed complications requiring prolonged hospitalization, respiratory support, and tube feeding. Such complications can arise immediately upon delivery. Reported clinical findings have included respiratory distress, cyanosis, apnea, seizures, temperature instability, feeding difficulty, vomiting, hypoglycemia, hypotonia, hypertonia, hyperreflexia, tremor, jitteriness, irritability, and constant crying. These features are consistent with either a direct toxic effect of SSRIs and SNRIs or, possibly, a drug discontinuation syndrome. It should be noted that, in some cases, the clinical picture is consistent with serotonin syndrome. - Infants exposed to SSRIs in pregnancy may have an increased risk for persistent pulmonary hypertension of the newborn (PPHN). PPHN occurs in 1 to 2 per 1,000 live births in the general population and is associated with substantial neonatal morbidity and mortality. Several recent epidemiologic studies suggest a positive statistical association between SSRI use (including fluvoxamine maleate tablets) in pregnancy and PPHN. Other studies do not show a significant statistical association. - Physicians should also note the results of a prospective longitudinal study of 201 pregnant women with a history of major depression, who were either on antidepressants or had received antidepressants less than 12 weeks prior to their last menstrual period, and were in remission. Women who discontinued antidepressant medication during pregnancy showed a significant increase in relapse of their major depression compared to those women who remained on antidepressant medication throughout pregnancy. - When treating a pregnant woman with fluvoxamine maleate tablets, the physician should carefully consider both the potential risks of taking an SSRI, along with the established benefits of treating depression with an antidepressant. This decision can only be made on a case by case basis. - Australian Drug Evaluation Committee (ADEC) Pregnancy Category There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Fluvoxamine in women who are pregnant. - The effect of fluvoxamine on labor and delivery in humans is unknown. - As for many other drugs, fluvoxamine is secreted in human breast milk. The decision of whether to discontinue nursing or to discontinue the drug should take into account the potential for serious adverse effects from exposure to fluvoxamine in the nursing infant as well as the potential benefits of fluvoxamine maleate tablet therapy to the mother. - The efficacy of fluvoxamine maleate for the treatment of obsessive compulsive disorder was demonstrated in a 10-week multicenter placebo-controlled study with 120 outpatients ages 8 to 17. In addition, 99 of these outpatients continued open-label fluvoxamine maleate treatment for up to another 1 to 3 years, equivalent to 94 patient years. The adverse event profile observed in that study was generally similar to that observed in adult studies with fluvoxamine. - Decreased appetite and weight loss have been observed in association with the use of fluvoxamine as well as other SSRIs. Consequently, regular monitoring of weight and growth is recommended if treatment of a child with an SSRI is to be continued long-term. - The risks, if any, that may be associated with fluvoxamine’s extended use in children and adolescents with OCD have not been systematically assessed. The prescriber should be mindful that the evidence relied upon to conclude that fluvoxamine is safe for use in children and adolescents derives from relatively short-term clinical studies and from extrapolation of experience gained with adult patients. In particular, there are no studies that directly evaluate the effects of long-term fluvoxamine use on the growth, cognitive behavioral development, and maturation of children and adolescents. Although there is no affirmative finding to suggest that fluvoxamine possesses a capacity to adversely affect growth, development or maturation, the absence of such findings is not compelling evidence of the absence of the potential of fluvoxamine to have adverse effects in chronic use. - Safety and effectiveness in the pediatric population other than pediatric patients with OCD have not been established. Anyone considering the use of fluvoxamine maleate tablets in a child or adolescent must balance the potential risks with the clinical need. - Approximately 230 patients participating in controlled premarketing studies with fluvoxamine maleate tablets were 65 years of age or over. No overall differences in safety were observed between these patients and younger patients. Other reported clinical experience has not identified differences in response between the elderly and younger patients. However, SSRIs and SNRIs, including fluvoxamine maleate tablets, have been associated with several cases of clinically significant hyponatremia in elderly patients, who may be at greater risk for this adverse event. Furthermore, the clearance of fluvoxamine is decreased by about 50% in elderly compared to younger patients, and greater sensitivity of some older individuals also cannot be ruled out. Consequently, a lower starting dose should be considered in elderly patients and fluvoxamine maleate tablets should be slowly titrated during initiation of therapy. There is no FDA guidance on the use of Fluvoxamine with respect to specific gender populations. There is no FDA guidance on the use of Fluvoxamine with respect to specific racial populations. There is no FDA guidance on the use of Fluvoxamine in patients with renal impairment. There is no FDA guidance on the use of Fluvoxamine in patients with hepatic impairment. There is no FDA guidance on the use of Fluvoxamine in women of reproductive potentials and males. There is no FDA guidance one the use of Fluvoxamine in patients who are immunocompromised. - Oral There is limited information regarding Monitoring of Fluvoxamine in the drug label. There is limited information regarding IV Compatibility of Fluvoxamine in the drug label. # Acute Overdose ## Signs and Symptoms - Commonly (≥ 5%) observed adverse events associated with fluvoxamine maleate overdose include gastrointestinal complaints (nausea, vomiting and diarrhea), coma, hypokalemia, hypotension, respiratory difficulties, somnolence, and tachycardia. Other notable signs and symptoms seen with fluvoxamine maleate overdose (single or multiple drugs) include bradycardia, ECG abnormalities (such as heart arrest, QT interval prolongation, first degree atrioventricular block, bundle branch block, and junctional rhythm), convulsions, dizziness, liver function disturbances, tremor, and increased reflexes. ## Management - Treatment should consist of those general measures employed in the management of overdosage with any antidepressant. - Ensure an adequate airway, oxygenation, and ventilation. Monitor cardiac rhythm and vital signs. General supportive and symptomatic measures are also recommended. Induction of emesis is not recommended. Gastric lavage with a large-bore orogastric tube with appropriate airway protection, if needed, may be indicated if performed soon after ingestion, or in symptomatic patients. - Activated charcoal should be administered. Due to the large volume of distribution of this drug, forced diuresis, dialysis, hemoperfusion and exchange transfusion are unlikely to be of benefit. No specific antidotes for fluvoxamine are known. - A specific caution involves patients taking, or recently having taken, fluvoxamine who might ingest excessive quantities of a tricyclic antidepressant. In such a case, accumulation of the parent tricyclic and/or an active metabolite may increase the possibility of clinically significant sequelae and extend the time needed for close medical observation. - In managing overdosage, consider the possibility of multiple drug involvement. The physician should consider contacting a poison control center for additional information on the treatment of any overdose. Telephone numbers for certified poison control centers are listed in the Physicians’ Desk Reference (PDR). # Chronic Overdose There is limited information regarding Chronic Overdose of Fluvoxamine in the drug label. - The mechanism of action of fluvoxamine maleate in obsessive compulsive disorder is presumed to be linked to its specific serotonin reuptake inhibition in brain neurons. Fluvoxamine has been shown to be a potent inhibitor of the serotonin reuptake transporter in preclinical studies, both in vitro and in vivo. - Fluvoxamine maleate is a selective serotonin (5-HT) reuptake inhibitor (SSRI) belonging to the chemical series, the 2-aminoethyl oxime ethers of aralkylketones. - It is chemically designated as 5-methoxy-4′-(trifluoromethyl)valerophenone-(E)-O-(2-aminoethyl)oxime maleate (1:1) and has the molecular formula C15H21O2N2F3C4H4O4. Its molecular weight is 434.4. - The structural formula is: - Fluvoxamine maleate, USP is a white or off white, odorless, crystalline powder which is sparingly soluble in water, freely soluble in ethanol and chloroform and practically insoluble in diethyl ether. - Fluvoxamine maleate tablets, USP are available in 25 mg, 50 mg or 100 mg strengths for oral administration. In addition to the active ingredient, fluvoxamine maleate, each tablet contains the following inactive ingredients: colloidal silicon dioxide, FD&C Yellow No. 6 Aluminum Lake, hypromellose, mannitol, polydextrose, polyethylene glycol, povidone, pregelatinized starch (corn), sodium stearyl fumarate, titanium dioxide and triacetin. - In in vitro studies, fluvoxamine maleate had no significant affinity for histaminergic, alpha or beta adrenergic, muscarinic, or dopaminergic receptors. Antagonism of some of these receptors is thought to be associated with various sedative, cardiovascular, anticholinergic, and extrapyramidal effects of some psychotropic drugs. - Absorption - The absolute bioavailability of fluvoxamine maleate is 53%. Oral bioavailability is not significantly affected by food. - In a dose proportionality study involving fluvoxamine maleate at 100, 200 and 300 mg/day for 10 consecutive days in 30 normal volunteers, steady state was achieved after about a week of dosing. Maximum plasma concentrations at steady state occurred within 3 to 8 hours of dosing and reached concentrations averaging 88, 283 and 546 ng/mL, respectively. Thus, fluvoxamine had nonlinear pharmacokinetics over this dose range, i.e., higher doses of fluvoxamine maleate produced disproportionately higher concentrations than predicted from the lower dose. - Distribution - The mean apparent volume of distribution for fluvoxamine is approximately 25 L/kg, suggesting extensive tissue distribution. - Approximately 80% of fluvoxamine is bound to plasma protein, mostly albumin, over a concentration range of 20 to 2000 ng/mL. - Metabolism - Fluvoxamine maleate is extensively metabolized by the liver; the main metabolic routes are oxidative demethylation and deamination. Nine metabolites were identified following a 5 mg radiolabelled dose of fluvoxamine maleate, constituting approximately 85% of the urinary excretion products of fluvoxamine. The main human metabolite was fluvoxamine acid which, together with its N-acetylated analog, accounted for about 60% of the urinary excretion products. A third metabolite, fluvoxethanol, formed by oxidative deamination, accounted for about 10%. Fluvoxamine acid and fluvoxethanol were tested in an in vitro assay of serotonin and norepinephrine reuptake inhibition in rats; they were inactive except for a weak effect of the former metabolite on inhibition of serotonin uptake (1 to 2 orders of magnitude less potent than the parent compound). Approximately 2% of fluvoxamine was excreted in urine unchanged. - Elimination - Following a 14C-labelled oral dose of fluvoxamine maleate (5 mg), an average of 94% of drug-related products was recovered in the urine within 71 hours. - The mean plasma half-life of fluvoxamine at steady state after multiple oral doses of 100 mg/day in healthy, young volunteers was 15.6 hours. - Elderly Subjects - In a study of fluvoxamine maleate tablets at 50 mg and 100 mg comparing elderly (ages 66 to 73) and young subjects (ages 19 to 35), mean maximum plasma concentrations in the elderly were 40% higher. The multiple dose elimination half-life of fluvoxamine was 17.4 and 25.9 hours in the elderly compared to 13.6 and 15.6 hours in the young subjects at steady state for 50 mg and 100 mg doses, respectively. In elderly patients, the clearance of fluvoxamine was reduced by about 50% and, therefore, fluvoxamine maleate tablets should be slowly titrated during initiation of therapy. - Pediatric Subjects - The multiple-dose pharmacokinetics of fluvoxamine were determined in male and female children (ages 6 to 11) and adolescents (ages 12 to 17). Steady-state plasma fluvoxamine concentrations were 2- to 3-fold higher in children than in adolescents. AUC and Cmax in children were 1.5- to 2.7-fold higher than that in adolescents. (See Table 4.) As in adults, both children and adolescents exhibited nonlinear multiple-dose pharmacokinetics. Female children showed significantly higher AUC (0-12) and Cmax compared to male children and, therefore, lower doses of fluvoxamine maleate tablets may produce therapeutic benefit. (See Table 5.) No gender differences were observed in adolescents. Steady-state plasma fluvoxamine concentrations were similar in adults and adolescents at a dose of 300 mg/day, indicating that fluvoxamine exposure was similar in these two populations. (See Table 4.) Dose adjustment in adolescents (up to the adult maximum dose of 300 mg) may be indicated to achieve therapeutic benefit. - Hepatic and Renal Disease - A cross study comparison (healthy subjects vs. patients with hepatic dysfunction) suggested a 30% decrease in fluvoxamine clearance in association with hepatic dysfunction. The mean minimum plasma concentrations in renally impaired patients (creatinine clearance of 5 to 45 mL/min) after 4 and 6 weeks of treatment (50 mg b.i.d., N = 13) were comparable to each other, suggesting no accumulation of fluvoxamine in these patients. - Carcinogenesis - There was no evidence of carcinogenicity in rats treated orally with fluvoxamine maleate for 30 months or hamsters treated orally with fluvoxamine maleate for 20 (females) or 26 (males) months. The daily doses in the high dose groups in these studies were increased over the course of the study from a minimum of 160 mg/kg to a maximum of 240 mg/kg in rats, and from a minimum of 135 mg/kg to a maximum of 240 mg/kg in hamsters. The maximum dose of 240 mg/kg is approximately 6 times the maximum human daily dose on a mg/m2 basis. - Mutagenesis - No evidence of genotoxic potential was observed in a mouse micronucleus test, an in vitro chromosome aberration test, or the Ames microbial mutagen test with or without metabolic activation. - Impairment of Fertility - In a study in which male and female rats were administered fluvoxamine (60, 120, or 240 mg/kg) prior to and during mating and gestation, fertility was impaired at oral doses of 120 mg/kg or greater, as evidenced by increased latency to mating, decreased sperm count, decreased epididymal weight, and decreased pregnancy rate. In addition, the numbers of implantations and embryos were decreased at the highest dose. The no effect dose for fertility impairment was 60 mg/kg (approximately 2 times the maximum recommended human dose on a mg/m2 basis). - The effectiveness of fluvoxamine maleate tablets for the treatment of obsessive compulsive disorder (OCD) was demonstrated in two 10-week multicenter, parallel group studies of adult outpatients. Patients in these trials were titrated to a total daily fluvoxamine maleate dose of 150 mg/day over the first 2 weeks of the trial, following which the dose was adjusted within a range of 100 to 300 mg/day (on a b.i.d. schedule), on the basis of response and tolerance. Patients in these studies had moderate to severe OCD (DSM-III-R), with mean baseline ratings on the Yale-Brown Obsessive Compulsive Scale (Y-BOCS), total score of 23. Patients receiving fluvoxamine maleate experienced mean reductions of approximately four to five units on the Y-BOCS total score, compared to a two unit reduction for placebo patients. - Table 6 provides the outcome classification by treatment group on the Global Improvement item of the Clinical Global Impressions (CGI) scale for both studies combined. - Exploratory analyses for age and gender effects on outcomes did not suggest any differential responsiveness on the basis of age or sex. - In a maintenance trial of adult outpatients with OCD, 114 patients meeting DSM-IV criteria for OCD and with a Yale-Brown Obsessive Compulsive Scale (Y-BOCS) score ≥ 18 were titrated to an effective dose of fluvoxamine maleate tablets 100 to 300 mg/day as part of an initial 10-week single-blind treatment phase. Treatment response during this single-blind phase was defined as Y-BOCS scores at least 30% lower than baseline at the end of weeks 8 and 10. Of the patients who responded, their average duration of response was 4 weeks. Patients who responded during this initial phase were randomized either to continuation of fluvoxamine maleate tablets (N = 56) or to placebo (N = 58) in a double-blind phase for observation of relapse. Relapse during the double-blind phase was defined as an increase in the Y-BOCS score of at least 30% over the baseline for that phase or patient refusal to continue treatment due to a substantial increase in OCD symptoms. In the double-blind phase, patients receiving continued fluvoxamine maleate tablets treatment experienced, on average, a significantly lower relapse rate than those receiving placebo. - An examination of population subgroups from this trial did not reveal any clear evidence of a differential maintenance effect on the basis of age or gender. - The effectiveness of fluvoxamine maleate tablets for the treatment of OCD was also demonstrated in a 10-week multicenter, parallel group study in a pediatric outpatient population (children and adolescents, ages 8 to 17). Patients in this study were titrated to a total daily fluvoxamine dose of approximately 100 mg/day over the first 2 weeks of the trial, following which the dose was adjusted within a range of 50 to 200 mg/day (on a b.i.d. schedule) on the basis of response and tolerance. All patients had moderate to severe OCD (DSM-III-R) with mean baseline ratings on the Children's Yale-Brown Obsessive Compulsive Scale (CY-BOCS) total score of 24. Patients receiving fluvoxamine maleate experienced mean reductions of approximately six units on the CY-BOCS total score, compared to a three-unit reduction for placebo patients. - Table 7 provides the outcome classification by treatment group on the Global Improvement item of the Clinical Global Impression (CGI) scale for the pediatric study. - Post hoc exploratory analyses for gender effects on outcomes did not suggest any differential responsiveness on the basis of gender. Further exploratory analyses revealed a prominent treatment effect in the 8 to 11 age group and essentially no effect in the 12 to 17 age group. While the significance of these results is not clear, the 2- to 3-fold higher steady-state plasma fluvoxamine concentrations in children compared to adolescents is suggestive that decreased exposure in adolescents may have been a factor, and dose adjustment in adolescents (up to the adult maximum dose of 300 mg) may be indicated to achieve therapeutic benefit. - Fluvoxamine Maleate Tablets, USP are available containing 25 mg, 50 mg or 100 mg of fluvoxamine maleate, USP. - The 25 mg tablets are orange film-coated, oval, unscored tablets debossed with M407 on one side of the tablet and blank on the other side. They are available as follows: - NDC 0378-0407-01 - bottles of 100 tablets - The 50 mg tablets are orange film-coated, oval, scored tablets debossed with M412 on one side of the tablet and scored on the other side. They are available as follows: - NDC 0378-0412-01 - bottles of 100 tablets - The 100 mg tablets are orange film-coated, oval, scored tablets debossed with M414 on one side of the tablet and scored on the other side. They are available as follows: - NDC 0378-0414-01 - bottles of 100 tablets - Storage - Keep this and all medication out of the reach of children. - Protect from high humidity. - Store at 20° to 25°C (68° to 77°F). - Dispense in a tight, light-resistant container as defined in the USP using a child-resistant closure. - Prescribers or other health professionals should inform patients, their families, and their caregivers about the benefits and risks associated with treatment with fluvoxamine maleate tablets and should counsel them in the appropriate use. A patient Medication Guide about “Antidepressant Medicines, Depression and other Serious Mental Illnesses, and Suicidal Thoughts or Actions” is available for fluvoxamine maleate tablets. The prescriber or health professional should instruct patients, their families, and their caregivers to read the Medication Guide and should assist them in understanding its contents. Patients should be given the opportunity to discuss the contents of the Medication Guide and to obtain answers to any questions they may have. The complete text of the Medication Guide is reprinted at the end of this document. - Patients should be advised of the following issues and asked to alert their prescriber if these occur while taking fluvoxamine maleate tablets. - Clinical Worsening and Suicide Risk - Patients, their families, and their caregivers should be encouraged to be alert to the emergence of anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, mania, other unusual changes in behavior, worsening of depression, and suicidal ideation, especially early during antidepressant treatment and when the dose is adjusted up or down. Families and caregivers of patients should be advised to look for the emergence of such symptoms on a day-to-day basis, since changes may be abrupt. Such symptoms should be reported to the patient’s prescriber or health professional, especially if they are severe, abrupt in onset, or were not part of the patient’s presenting symptoms. Symptoms such as these may be associated with an increased risk for suicidal thinking and behavior and indicate the need for very close monitoring and possibly changes in the medication. - Serotonin Syndrome - Patients should be cautioned about the risk of serotonin syndrome particularly with the concomitant use of fluvoxamine with other serotonergic agents (including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan, buspirone and St. John's Wort). - Angle Closure Glaucoma - Patients should be advised that taking Fluvoxamine Maleate Tablets can cause mild pupillary dilation, which in susceptible individuals, can lead to an episode of angle closure glaucoma. Pre-existing glaucoma is almost always open-angle glaucoma because angle closure glaucoma, when diagnosed, can be treated definitively with iridectomy. Open-angle glaucoma is not a risk factor for angle closure glaucoma. Patients may wish to be examined to determine whether they are susceptible to angle closure, and have a prophylactic procedure (e.g., iridectomy), if they are susceptible. - Interference with Cognitive or Motor Performance - Since any psychoactive drug may impair judgment, thinking, or motor skills, patients should be cautioned about operating hazardous machinery, including automobiles, until they are certain that fluvoxamine maleate tablet therapy does not adversely affect their ability to engage in such activities. - Pregnancy - Patients should be advised to notify their physicians if they become pregnant or intend to become pregnant during therapy with fluvoxamine maleate tablets. - Nursing - Patients receiving fluvoxamine maleate tablets should be advised to notify their physicians if they are breast-feeding an infant. - Concomitant Medication - Patients should be advised to notify their physicians if they are taking, or plan to take, any prescription or over-the-counter drugs, since there is a potential for clinically important interactions with fluvoxamine maleate tablets. - Patients should be cautioned about the concomitant use of fluvoxamine and NSAIDs, aspirin, or other drugs that affect coagulation since the combined use of psychotropic drugs that interfere with serotonin reuptake and these agents has been associated with an increased risk of bleeding. - Because of the potential for the increased risk of serious adverse reactions including severe lowering of blood pressure and sedation when fluvoxamine and tizanidine are used together, fluvoxamine should not be used with tizanidine. - Because of the potential for the increased risk of serious adverse reactions when fluvoxamine and alosetron are used together, fluvoxamine should not be used with Lotronex™†(alosetron). - Alcohol - As with other psychotropic medications, patients should be advised to avoid alcohol while taking fluvoxamine maleate tablets. - Allergic Reactions - Patients should be advised to notify their physicians if they develop a rash, hives, or a related allergic phenomenon during therapy with fluvoxamine maleate tablets. - As with other psychotropic medications, patients should be advised to avoid alcohol while taking fluvoxamine maleate tablets. - FLUVOXAMINE MALEATE® - fluvoxaMINE® — flavoxATE® - fluvoxaMINE® — fluPHENAZine® - Luvox® — Lasix® - ↑ "Luvox". ChemSpider. Royal Society of Chemistry. Retrieved 21 October 2013..mw-parser-output cite.citation{font-style:inherit}.mw-parser-output q{quotes:"\"""\"""'""'"}.mw-parser-output code.cs1-code{color:inherit;background:inherit;border:inherit;padding:inherit}.mw-parser-output .cs1-lock-free a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-limited a,.mw-parser-output .cs1-lock-registration a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-subscription a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration{color:#555}.mw-parser-output .cs1-subscription span,.mw-parser-output .cs1-registration span{border-bottom:1px dotted;cursor:help}.mw-parser-output .cs1-hidden-error{display:none;font-size:100%}.mw-parser-output .cs1-visible-error{display:none;font-size:100%}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration,.mw-parser-output .cs1-format{font-size:95%}.mw-parser-output .cs1-kern-left,.mw-parser-output .cs1-kern-wl-left{padding-left:0.2em}.mw-parser-output .cs1-kern-right,.mw-parser-output .cs1-kern-wl-right{padding-right:0.2em} - ↑ "FLUVOXAMINE MALEATE- fluvoxamine maleate tablet, film coated". - ↑ Jump up to: 3.0 3.1 3.2 "". External link in \|title= (help)	Fluvoxamine Vignesh Ponnusamy, M.B.B.S. [1] a serotonin reuptake inhibitor obsessive compulsive disorder (OCD) Yes nausea, somnolence, insomnia, asthenia, nervousness, dyspepsia, abnormal ejaculation, sweating, anorexia, tremor, and vomiting WARNING SUICIDALITY AND ANTIDEPRESSANT DRUGS - Antidepressants increased the risk compared to placebo of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults in short-term studies of major depressive disorder (MDD) and other psychiatric disorders. Anyone considering the use of fluvoxamine maleate tablets or any other antidepressant in a child, adolescent, or young adult must balance this risk with the clinical need. Short-term studies did not show an increase in the risk of suicidality with antidepressants compared to placebo in adults beyond age 24; there was a reduction in risk with antidepressants compared to placebo in adults aged 65 and older. Depression and certain other psychiatric disorders are themselves associated with increases in the risk of suicide. Patients of all ages who are started on antidepressant therapy should be monitored appropriately and observed closely for clinical worsening, suicidality, or unusual changes in behavior. Families and caregivers should be advised of the need for close observation and communication with the prescriber. Fluvoxamine maleate tablets are not approved for use in pediatric patients except for patients with obsessive compulsive disorder (OCD). - Dosing Information - The recommended starting dose for fluvoxamine maleate tablets in adult patients is 50 mg, administered as a single daily dose at bedtime. In the controlled clinical trials establishing the effectiveness of fluvoxamine maleate tablets in OCD, patients were titrated within a dose range of 100 to 300 mg/day. Consequently, the dose should be increased in 50 mg increments every 4 to 7 days, as tolerated, until maximum therapeutic benefit is achieved, not to exceed 300 mg per day. It is advisable that a total daily dose of more than 100 mg should be given in two divided doses. If the doses are not equal, the larger dose should be given at bedtime. - Elderly or Hepatically Impaired Patients - Elderly patients and those with hepatic impairment have been observed to have a decreased clearance of fluvoxamine maleate. Consequently, it may be appropriate to modify the initial dose and the subsequent dose titration for these patient groups. - Pregnant Women During the Third Trimester - Neonates exposed to fluvoxamine maleate tablets and other SSRIs or SNRIs late in the third trimester have developed complications requiring prolonged hospitalization, respiratory support, and tube feeding and may be at risk for persistent pulmonary hypertension of the newborn (PPHN). When treating pregnant women with fluvoxamine maleate tablets during the third trimester, the physician should carefully consider the potential risks and benefits of treatment. - Switching a Patient to or from a Monoamine Oxidase Inhibitor (MAOI) Intended to Treat Psychiatric Disorders - At least 14 days should elapse between discontinuation of an MAOI intended to treat psychiatric disorders and initiation of therapy with fluvoxamine maleate tablets. Conversely, at least 14 days should be allowed after stopping fluvoxamine maleate tablets before starting an MAOI intended to treat psychiatric disorders. - Use of Fluvoxamine Maleate Tablets with Other MAOIs such as Linezolid or Methylene Blue - Do not start fluvoxamine maleate tablets in a patient who is being treated with linezolid or intravenous methylene blue because there is an increased risk of serotonin syndrome. In a patient who requires more urgent treatment of a psychiatric condition, other interventions, including hospitalization, should be considered. - In some cases, a patient already receiving fluvoxamine maleate tablets therapy may require urgent treatment with linezolid or intravenous methylene blue. If acceptable alternatives to linezolid or intravenous methylene blue treatment are not available and the potential benefits of linezolid or intravenous methylene blue treatment are judged to outweigh the risks of serotonin syndrome in a particular patient, fluvoxamine maleate tablets should be stopped promptly, and linezolid or intravenous methylene blue can be administered. The patient should be monitored for symptoms of serotonin syndrome for 2 weeks or until 24 hours after the last dose of linezolid or intravenous methylene blue, whichever comes first. Therapy with fluvoxamine maleate tablets may be resumed 24 hours after the last dose of linezolid or intravenous methylene blue. - The risk of administering methylene blue by non-intravenous routes (such as oral tablets or by local injection) or in intravenous doses much lower than 1 mg/kg with fluvoxamine maleate tablets is unclear. The clinician should, nevertheless, be aware of the possibility of emergent symptoms of serotonin syndrome with such use. - Maintenance/Continuation Extended Treatment - It is generally agreed that obsessive compulsive disorder requires several months or longer of sustained pharmacologic therapy. The benefit of maintaining patients with OCD on fluvoxamine maleate tablets after achieving a response for an average duration of about 4 weeks in a 10-week single-blind phase during which patients were titrated to effect was demonstrated in a controlled trial. The physician who elects to use fluvoxamine maleate tablets for extended periods should periodically reevaluate the long-term usefulness of the drug for the individual patient. - Discontinuation of Treatment with Fluvoxamine Maleate Tablets - Symptoms associated with discontinuation of other SSRIs or SNRIs have been reported. Patients should be monitored for these symptoms when discontinuing treatment. A gradual reduction in the dose rather than abrupt cessation is recommended whenever possible. If intolerable symptoms occur following a decrease in the dose or upon discontinuation of treatment, then resuming the previously prescribed dose may be considered. Subsequently, the physician may continue decreasing the dose but at a more gradual rate. There is limited information regarding Off-Label Guideline-Supported Use of Fluvoxamine in adult patients. - Fluvoxamine 100 mg daily days 1 through 3; 200 mg daily days 4 through 7; and 300 mg daily from day 8. - Fluvoxamine 50 milligrams (mg) daily titrated to a maximum dose of 300 mg daily. - Fluvoxamine initiated at 40 milligrams per day, increased to 100 milligrams on day 5 and to 150 milligrams on day 9. The dose increased at 50 milligram intervals each week until side effects occur; the maximum dose of 300 milligrams reached; or panic attack and depression resolved. - Fluvoxamine ER (initial, 100 milligrams (mg)/day, titrated weekly in 50 mg increments, as needed, to maximum of 300 mg/day) for 12 weeks. - Dosing Information - The recommended starting dose for fluvoxamine maleate tablets in pediatric populations (ages 8 to 17 years) is 25 mg, administered as a single daily dose at bedtime. In a controlled clinical trial establishing the effectiveness of fluvoxamine maleate tablets in OCD, pediatric patients (ages 8 to 17) were titrated within a dose range of 50 to 200 mg/day. Physicians should consider age and gender differences when dosing pediatric patients. The maximum dose in children up to age 11 should not exceed 200 mg/day. Therapeutic effect in female children may be achieved with lower doses. Dose adjustment in adolescents (up to the adult maximum dose of 300 mg) may be indicated to achieve therapeutic benefit. The dose should be increased in 25 mg increments every 4 to 7 days, as tolerated, until maximum therapeutic benefit is achieved. It is advisable that a total daily dose of more than 50 mg should be given in two divided doses. If the two divided doses are not equal, the larger dose should be given at bedtime. There is limited information regarding Off-Label Guideline-Supported Use of Fluvoxamine in pediatric patients. There is limited information regarding Off-Label Non–Guideline-Supported Use of Fluvoxamine in pediatric patients. - Coadministration of Tizanidine, Thioridazine, Alosetron or Pimozide with Fluvoxamine Maleate Tablets is Contraindicated - Serotonin Syndrome and Monoamine Oxidase Inhibitors (MAOIs) - The use of MAOIs intended to treat psychiatric disorders with fluvoxamine maleate tablets or within 14 days of stopping treatment with fluvoxamine maleate tablets is contraindicated because of an increased risk of serotonin syndrome. The use of fluvoxamine maleate tablets within 14 days of stopping an MAOI intended to treat psychiatric disorders is also contraindicated. - Starting fluvoxamine maleate tablets in a patient who is being treated with MAOIs such as linezolid or intravenous methylene blue is also contraindicated because of an increased risk of serotonin syndrome. ### Precautions - Clinical Worsening and Suicide Risk - Patients with major depressive disorder (MDD), both adult and pediatric, may experience worsening of their depression and/or the emergence of suicidal ideation and behavior (suicidality) or unusual changes in behavior, whether or not they are taking antidepressant medications, and this risk may persist until significant remission occurs. Suicide is a known risk of depression and certain other psychiatric disorders, and these disorders themselves are the strongest predictors of suicide. There has been a long-standing concern, however, that antidepressants may have a role in inducing worsening of depression and the emergence of suicidality in certain patients during the early phases of treatment. Pooled analyses of short-term placebo-controlled trials of antidepressant drugs (SSRIs and others) showed that these drugs increase the risk of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults (ages 18 to 24) with major depressive disorder (MDD) and other psychiatric disorders. Short-term studies did not show an increase in the risk of suicidality with antidepressants compared to placebo in adults beyond age 24; there was a reduction with antidepressants compared to placebo in adults aged 65 and older. - The pooled analyses of placebo-controlled trials in children and adolescents with MDD, obsessive compulsive disorder (OCD), or other psychiatric disorders included a total of 24 short-term trials of nine antidepressant drugs in over 4,400 patients. The pooled analyses of placebo-controlled trials in adults with MDD or other psychiatric disorders included a total of 295 short-term trials (median duration of 2 months) of 11 antidepressant drugs in over 77,000 patients. There was considerable variation in risk of suicidality among drugs, but a tendency toward an increase in the younger patients for almost all drugs studied. There were differences in absolute risk of suicidality across the different indications, with the highest incidence in MDD. The risk differences (drug vs. placebo), however, were relatively stable within age strata and across indications. These risk differences (drug-placebo difference in the number of cases of suicidality per 1,000 patients treated) are provided in Table 1. - No suicides occurred in any of the pediatric trials. There were suicides in the adult trials, but the number was not sufficient to reach any conclusion about the drug effect on suicide. - It is unknown whether the suicidality risk extends to longer-term use, i.e., beyond several months. However, there is substantial evidence from placebo-controlled maintenance trials in adults with depression that the use of antidepressants can delay the recurrence of depression. - All patients being treated with antidepressants for any indication should be monitored appropriately and observed closely for clinical worsening, suicidality, and unusual changes in behavior, especially during the initial few months of a course of drug therapy, or at times of dose changes, either increases or decreases. - The following symptoms, anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, and mania, have been reported in adult and pediatric patients being treated with antidepressants for major depressive disorder as well as for other indications, both psychiatric and nonpsychiatric. Although a causal link between the emergence of such symptoms and either the worsening of depression and/or the emergence of suicidal impulses has not been established, there is concern that such symptoms may represent precursors to emerging suicidality. - Consideration should be given to changing the therapeutic regimen, including possibly discontinuing the medication, in patients whose depression is persistently worse, or who are experiencing emergent suicidality or symptoms that might be precursors to worsening depression or suicidality, especially if these symptoms are severe, abrupt in onset, or were not part of the patient’s presenting symptoms. - If the decision has been made to discontinue treatment, medication should be tapered, as rapidly as is feasible, but with recognition that abrupt discontinuation can be associated with certain symptoms, for a description of the risks of discontinuation of fluvoxamine maleate tablets. - Families and caregivers of patients being treated with antidepressants for major depressive disorder or other indications, both psychiatric and nonpsychiatric, should be alerted about the need to monitor patients for the emergence of agitation, irritability, unusual changes in behavior, and the other symptoms described above, as well as the emergence of suicidality, and to report such symptoms immediately to healthcare providers. Such monitoring should include daily observation by families and caregivers. Prescriptions for fluvoxamine maleate tablets should be written for the smallest quantity of tablets consistent with good patient management, in order to reduce the risk of overdose. - Screening Patients for Bipolar Disorder - A major depressive episode may be the initial presentation of bipolar disorder. It is generally believed (though not established in controlled trials) that treating such an episode with an antidepressant alone may increase the likelihood of precipitation of a mixed/manic episode in patients at risk for bipolar disorder. Whether any of the symptoms described above represent such a conversion is unknown. However, prior to initiating treatment with an antidepressant, patients with depressive symptoms should be adequately screened to determine if they are at risk for bipolar disorder; such screening should include a detailed psychiatric history, including a family history of suicide, bipolar disorder, and depression. It should be noted that fluvoxamine maleate tablets are not approved for use in treating bipolar depression. - Serotonin Syndrome - The development of a potentially life-threatening serotonin syndrome has been reported with SNRIs and SSRIs, including fluvoxamine maleate tablets, alone but particularly with concomitant use of serotonergic drugs (including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan, buspirone, and St. John's Wort) and with drugs that impair metabolism of serotonin (in particular MAOIs, both those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue). - Serotonin syndrome symptoms may include mental status changes (e.g., agitation, hallucinations, delirium, and coma), autonomic instability (e.g., tachycardia, labile blood pressure, dizziness, diaphoresis, flushing, hyperthermia), neuromuscular aberrations (e.g., tremor, rigidity, myoclonus, hyperreflexia, incoordination), seizures, and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). Patients should be monitored for the emergence of serotonin syndrome. - The concomitant use of fluvoxamine maleate tablets with MAOIs intended to treat psychiatric disorders is contraindicated. Fluvoxamine maleate tablets should also not be started in a patient who is being treated with MAOIs such as linezolid or intravenous methylene blue. All reports with methylene blue that provided information on the route of administration involved intravenous administration in the dose range of 1 mg/kg to 8 mg/kg. No reports involved the administration of methylene blue by other routes (such as oral tablets or local tissue injection) or at lower doses. There may be circumstances when it is necessary to initiate treatment with an MAOI such as linezolid or intravenous methylene blue in a patient taking fluvoxamine maleate tablets. Fluvoxamine maleate tablets should be discontinued before initiating treatment with the MAOI. - If concomitant use of fluvoxamine maleate tablets with other serotonergic drugs, including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, buspirone, tryptophan and St. John's Wort is clinically warranted, patients should be made aware of a potential increased risk for serotonin syndrome, particularly during treatment initiation and dose increases. - Treatment with fluvoxamine maleate tablets and any concomitant serotonergic agents, should be discontinued immediately if the above events occur and supportive symptomatic treatment should be initiated. - Angle Closure Glaucoma - The pupillary dilation that occurs following use of many antidepressant drugs including fluvoxamine maleate tablets may trigger an angle closure attack in a patient with anatomically narrow angles who do not have a patent iridectomy. - Potential Thioridazine Interaction - The effect of fluvoxamine (25 mg b.i.d. for one week) on thioridazine steady-state concentrations was evaluated in ten male inpatients with schizophrenia. Concentrations of thioridazine and its two active metabolites, mesoridazine and sulforidazine, increased 3-fold following coadministration of fluvoxamine. - Thioridazine administration produces a dose-related prolongation of the QTc interval, which is associated with serious ventricular arrhythmias, such as torsades de pointes-type arrhythmias, and sudden death. It is likely that this experience underestimates the degree of risk that might occur with higher doses of thioridazine. Moreover, the effect of fluvoxamine may be even more pronounced when it is administered at higher doses. - Therefore, fluvoxamine and thioridazine should not be coadministered. - Potential Tizanidine Interaction - Fluvoxamine is a potent inhibitor of CYP1A2 and tizanidine is a CYP1A2 substrate. The effect of fluvoxamine (100 mg daily for 4 days) on the pharmacokinetics and pharmacodynamics of a single 4 mg dose of tizanidine has been studied in ten healthy male subjects. Tizanidine Cmax was increased approximately 12-fold (range 5-fold to 32-fold), elimination half-life was increased by almost 3-fold, and AUC increased 33-fold (range 14-fold to 103-fold). The mean maximal effect on blood pressure was a 35 mm Hg decrease in systolic blood pressure, a 20 mm Hg decrease in diastolic blood pressure, and a 4 beat/min decrease in heart rate. Drowsiness was significantly increased and performance on the psychomotor task was significantly impaired. Fluvoxamine and tizanidine should not be used together. - Potential Pimozide Interaction - Pimozide is metabolized by the cytochrome P4503A4 isoenzyme, and it has been demonstrated that ketoconazole, a potent inhibitor of CYP3A4, blocks the metabolism of this drug, resulting in increased plasma concentrations of parent drug. An increased plasma concentration of pimozide causes QT prolongation and has been associated with torsades de pointes-type ventricular tachycardia, sometimes fatal. As noted below, a substantial pharmacokinetic interaction has been observed for fluvoxamine in combination with alprazolam, a drug that is known to be metabolized by CYP3A4. Although it has not been definitively demonstrated that fluvoxamine is a potent CYP3A4 inhibitor, it is likely to be, given the substantial interaction of fluvoxamine with alprazolam. Consequently, it is recommended that fluvoxamine not be used in combination with pimozide. - Potential Alosetron Interaction - Because alosetron is metabolized by a variety of hepatic CYP drug metabolizing enzymes, inducers or inhibitors of these enzymes may change the clearance of alosetron. Fluvoxamine is a known potent inhibitor of CYP1A2 and also inhibits CYP3A4, CYP2C9, and CYP2C19. In a pharmacokinetic study, 40 healthy female subjects received fluvoxamine in escalating doses from 50 mg to 200 mg a day for 16 days, with coadministration of alosetron 1 mg on the last day. Fluvoxamine increased mean alosetron plasma concentration (AUC) approximately 6-fold and prolonged the half-life by approximately 3-fold. - Other Potentially Important Drug Interactions - Benzodiazepines - Benzodiazepines metabolized by hepatic oxidation (e.g., alprazolam, midazolam, triazolam, etc.) should be used with caution because the clearance of these drugs is likely to be reduced by fluvoxamine. The clearance of benzodiazepines metabolized by glucuronidation (e.g., lorazepam, oxazepam, temazepam) is unlikely to be affected by fluvoxamine. - Alprazolam - When fluvoxamine maleate (100 mg q.d.) and alprazolam (1 mg q.i.d.) were coadministered to steady state, plasma concentrations and other pharmacokinetic parameters (AUC, Cmax, T½) of alprazolam were approximately twice those observed when alprazolam was administered alone; oral clearance was reduced by about 50%. The elevated plasma alprazolam concentrations resulted in decreased psychomotor performance and memory. This interaction, which has not been investigated using higher doses of fluvoxamine, may be more pronounced if a 300 mg daily dose is coadministered, particularly since fluvoxamine exhibits non-linear pharmacokinetics over the dosage range 100 mg to 300 mg. If alprazolam is coadministered with fluvoxamine maleate tablets, the initial alprazolam dosage should be at least halved and titration to the lowest effective dose is recommended. No dosage adjustment is required for fluvoxamine maleate tablets. - Diazepam - The coadministration of fluvoxamine maleate tablets and diazepam is generally not advisable. Because fluvoxamine reduces the clearance of both diazepam and its active metabolite, N-desmethyldiazepam, there is a strong likelihood of substantial accumulation of both species during chronic coadministration. - Evidence supporting the conclusion that it is inadvisable to coadminister fluvoxamine and diazepam is derived from a study in which healthy volunteers taking 150 mg/day of fluvoxamine were administered a single oral dose of 10 mg of diazepam. In these subjects (N = 8), the clearance of diazepam was reduced by 65% and that of N-desmethyldiazepam to a level that was too low to measure over the course of the 2 week long study. - It is likely that this experience significantly underestimates the degree of accumulation that might occur with repeated diazepam administration. Moreover, as noted with alprazolam, the effect of fluvoxamine may even be more pronounced when it is administered at higher doses. - Accordingly, diazepam and fluvoxamine should not ordinarily be coadministered. - Clozapine - Elevated serum levels of clozapine have been reported in patients taking fluvoxamine maleate and clozapine. Since clozapine-related seizures and orthostatic hypotension appear to be dose related, the risk of these adverse events may be higher when fluvoxamine and clozapine are coadministered. Patients should be closely monitored when fluvoxamine maleate and clozapine are used concurrently. - Methadone - Significantly increased methadone (plasma level:dose) ratios have been reported when fluvoxamine maleate was administered to patients receiving maintenance methadone treatment, with symptoms of opioid intoxication in one patient. Opioid withdrawal symptoms were reported following fluvoxamine maleate discontinuation in another patient. - Mexiletine - The effect of steady-state fluvoxamine (50 mg b.i.d. for 7 days) on the single dose pharmacokinetics of mexiletine (200 mg) was evaluated in six healthy Japanese males. The clearance of mexiletine was reduced by 38% following coadministration with fluvoxamine compared to mexiletine alone. If fluvoxamine and mexiletine are coadministered, serum mexiletine levels should be monitored. - Ramelteon - When fluvoxamine 100 mg twice daily was administered for 3 days prior to single-dose coadministration of ramelteon 16 mg and fluvoxamine, the AUC for ramelteon increased approximately 190-fold and the Cmax increased approximately 70-fold compared to ramelteon administered alone. Ramelteon should not be used in combination with fluvoxamine. - Theophylline - The effect of steady-state fluvoxamine (50 mg bid) on the pharmacokinetics of a single dose of theophylline (375 mg as 442 mg aminophylline) was evaluated in 12 healthy non-smoking, male volunteers. The clearance of theophylline was decreased approximately 3-fold. Therefore, if theophylline is coadministered with fluvoxamine maleate, its dose should be reduced to one-third of the usual daily maintenance dose and plasma concentrations of theophylline should be monitored. No dosage adjustment is required for fluvoxamine maleate tablets. - Warfarin and Other Drugs that Interfere with Hemostasis (NSAIDs, Aspirin, etc.) - Serotonin release by platelets plays an important role in hemostasis. Epidemiological studies of the case-control and cohort design have demonstrated an association between use of psychotropic drugs that interfere with serotonin reuptake and the occurrence of upper gastrointestinal bleeding. These studies have also shown that concurrent use of an NSAID or aspirin may potentiate this risk of bleeding. Thus, patients should be cautioned about the use of such drugs concurrently with fluvoxamine. - Warfarin - When fluvoxamine maleate (50 mg t.i.d.) was administered concomitantly with warfarin for 2 weeks, warfarin plasma concentrations increased by 98% and prothrombin times were prolonged. Thus patients receiving oral anticoagulants and fluvoxamine maleate tablets should have their prothrombin time monitored and their anticoagulant dose adjusted accordingly. No dosage adjustment is required for fluvoxamine maleate tablets. - Discontinuation of Treatment with Fluvoxamine Maleate Tablets - During marketing of fluvoxamine maleate tablets and other SSRIs and SNRIs (serotonin and norepinephrine reuptake inhibitors), there have been spontaneous reports of adverse events occurring upon discontinuation of these drugs, particularly when abrupt, including the following: dysphoric mood, irritability, agitation, dizziness, sensory disturbances (e.g., paresthesias, such as electric shock sensations), anxiety, confusion, headache, lethargy, emotional lability, insomnia, and hypomania. While these events are generally self-limiting, there have been reports of serious discontinuation symptoms. - Patients should be monitored for these symptoms when discontinuing treatment with fluvoxamine maleate tablets. A gradual reduction in the dose rather than abrupt cessation is recommended whenever possible. If intolerable symptoms occur following a decrease in the dose or upon discontinuation of treatment, then resuming the previously prescribed dose may be considered. Subsequently, the physician may continue decreasing the dose but at a more gradual rate. - Abnormal Bleeding - SSRIs and SNRIs, including fluvoxamine maleate tablets, may increase the risk of bleeding events. Concomitant use of aspirin, nonsteroidal anti-inflammatory drugs, warfarin, and other anticoagulants may add to this risk. Case reports and epidemiological studies (case-control and cohort design) have demonstrated an association between use of drugs that interfere with serotonin reuptake and the occurrence of gastrointestinal bleeding. Bleeding events related to SSRIs and SNRIs have ranged from ecchymoses, hematomas, epistaxis, and petechiae to life-threatening hemorrhages. - Patients should be cautioned about the risk of bleeding associated with the concomitant use of fluvoxamine maleate tablets and NSAIDs, aspirin, or other drugs that affect coagulation. - Activation of Mania/Hypomania - During premarketing studies involving primarily depressed patients, hypomania or mania occurred in approximately 1% of patients treated with fluvoxamine. In a 10-week pediatric OCD study, 2 out of 57 patients (4%) treated with fluvoxamine experienced manic reactions, compared to none of 63 placebo patients. Activation of mania/hypomania has also been reported in a small proportion of patients with major affective disorder who were treated with other marketed antidepressants. As with all antidepressants, fluvoxamine maleate tablets should be used cautiously in patients with a history of mania. - Seizures - During premarketing studies, seizures were reported in 0.2% of fluvoxamine-treated patients. Caution is recommended when the drug is administered to patients with a history of convulsive disorders. Fluvoxamine should be avoided in patients with unstable epilepsy and patients with controlled epilepsy should be carefully monitored. Treatment with fluvoxamine should be discontinued if seizures occur or if seizure frequency increases. - Hyponatremia - Hyponatremia may occur as a result of treatment with SSRIs and SNRIs, including fluvoxamine maleate tablets. In many cases, this hyponatremia appears to be the result of the syndrome of inappropriate antidiuretic hormone (SIADH). Cases with serum sodium lower than 110 mmol/L have been reported. Elderly patients may be at greater risk of developing hyponatremia with SSRIs and SNRIs. Also, patients taking diuretics or who are otherwise volume depleted may be at greater risk. Discontinuation of fluvoxamine maleate tablets should be considered in patients with symptomatic hyponatremia and appropriate medical intervention should be instituted. - Signs and symptoms of hyponatremia include headache, difficulty concentrating, memory impairment, confusion, weakness, and unsteadiness, which may lead to falls. Signs and symptoms associated with more severe and/or acute cases have included hallucination, syncope, seizure, coma, respiratory arrest, and death. - Use in Patients with Concomitant Illness - Closely monitored clinical experience with fluvoxamine maleate tablets in patients with concomitant systemic illness is limited. Caution is advised in administering fluvoxamine maleate tablets to patients with diseases or conditions that could affect hemodynamic responses or metabolism. - Fluvoxamine maleate tablets have not been evaluated or used to any appreciable extent in patients with a recent history of myocardial infarction or unstable heart disease. Patients with these diagnoses were systematically excluded from many clinical studies during the product's premarketing testing. Evaluation of the electrocardiograms for patients with depression or OCD who participated in premarketing studies revealed no differences between fluvoxamine and placebo in the emergence of clinically important ECG changes. - Patients with Hepatic Impairment - In patients with liver dysfunction, fluvoxamine clearance was decreased by approximately 30%. Patients with liver dysfunction should begin with a low dose of fluvoxamine maleate tablets and increase it slowly with careful monitoring. - Adverse Reactions Leading to Treatment Discontinuation - Of the 1,087 OCD and depressed patients treated with fluvoxamine maleate in controlled clinical trials in North America, 22% discontinued due to an adverse reaction. Adverse reactions that led to discontinuation in at least 2% of fluvoxamine maleate-treated patients in these trials were: nausea (9%), insomnia (4%), somnolence (4%), headache (3%), and asthenia, vomiting, nervousness, agitation, and dizziness (2% each). - Commonly Observed Adverse Reactions in Controlled Clinical Trials - Fluvoxamine maleate tablets have been studied in 10-week short-term controlled trials of OCD (N = 320) and depression (N = 1,350). In general, adverse reaction rates were similar in the two data sets as well as in the pediatric OCD study. The most commonly observed adverse reactions associated with the use of fluvoxamine maleate tablets and likely to be drug-related (incidence of 5% or greater and at least twice that for placebo) derived from Table 2 were: nausea, somnolence, insomnia, asthenia, nervousness, dyspepsia, abnormal ejaculation, sweating, anorexia, tremor, and vomiting. In a pool of two studies involving only patients with OCD, the following additional reactions were identified using the above rule: anorgasmia, decreased libido, dry mouth, rhinitis, taste perversion, and urinary frequency. In a study of pediatric patients with OCD, the following additional reactions were identified using the above rule: agitation, depression, dysmenorrhea, flatulence, hyperkinesia, and rash. - Adverse Reactions Occurring at an Incidence of 1% - Table 2 enumerates adverse reactions that occurred in adults at a frequency of 1% or more, and were more frequent than in the placebo group, among patients treated with fluvoxamine maleate tablets in two short-term placebo-controlled OCD trials (10 week) and depression trials (6 week) in which patients were dosed in a range of generally 100 to 300 mg/day. This table shows the percentage of patients in each group who had at least one occurrence of a reaction at some time during their treatment. Reported adverse reactions were classified using a standard COSTART-based Dictionary terminology. - The prescriber should be aware that these figures cannot be used to predict the incidence of side effects in the course of usual medical practice where patient characteristics and other factors may differ from those that prevailed in the clinical trials. Similarly, the cited frequencies cannot be compared with figures obtained from other clinical investigations involving different treatments, uses, and investigators. The cited figures, however, do provide the prescribing physician with some basis for estimating the relative contribution of drug and non-drug factors to the side-effect incidence rate in the population studied. - Adverse Reactions in OCD Placebo-Controlled Studies which are Markedly Different (defined as at least a 2-fold difference) in Rate from the Pooled Reaction Rates in OCD and Depression Placebo-Controlled Studies - The reactions in OCD studies with a 2-fold decrease in rate compared to reaction rates in OCD and depression studies were dysphagia and amblyopia (mostly blurred vision). Additionally, there was an approximate 25% decrease in nausea. - The reactions in OCD studies with a 2-fold increase in rate compared to reaction rates in OCD and depression studies were: asthenia, abnormal ejaculation (mostly delayed ejaculation), anxiety, rhinitis, anorgasmia (in males), depression, libido decreased, pharyngitis, agitation, impotence, myoclonus/twitch, thirst, weight loss, leg cramps, myalgia, and urinary retention. These reactions are listed in order of decreasing rates in the OCD trials. - Other Adverse Reactions in OCD Pediatric Population - In pediatric patients (N = 57) treated with fluvoxamine maleate tablets, the overall profile of adverse reactions was generally similar to that seen in adult studies, as shown in Table 2. However, the following adverse reactions, not appearing in Table 2, were reported in two or more of the pediatric patients and were more frequent with fluvoxamine maleate tablets than with placebo: cough increase, dysmenorrhea, ecchymosis, emotional lability, epistaxis, hyperkinesia, manic reaction, rash, sinusitis, and weight decrease. - Male and Female Sexual Dysfunction with SSRIs - Although changes in sexual desire, sexual performance and sexual satisfaction often occur as manifestations of a psychiatric disorder and with aging, they may also be a consequence of pharmacologic treatment. In particular, some evidence suggests that selective serotonin reuptake inhibitors (SSRIs), can cause such untoward sexual experiences. - Reliable estimates of the incidence and severity of untoward experiences involving sexual desire, performance and satisfaction are difficult to obtain, however, in part because patients and physicians may be reluctant to discuss them. Accordingly, estimates of the incidence of untoward sexual experience and performance cited in product labeling are likely to underestimate their actual incidence. - Table 3 displays the incidence of sexual side effects reported by at least 2% of patients taking fluvoxamine maleate tablets in placebo-controlled trials in depression and OCD. - There are no adequate and well-controlled studies examining sexual dysfunction with fluvoxamine treatment. - Fluvoxamine treatment has been associated with several cases of priapism. In those cases with a known outcome, patients recovered without sequelae and upon discontinuation of fluvoxamine. - While it is difficult to know the precise risk of sexual dysfunction associated with the use of SSRIs, physicians should routinely inquire about such possible side effects. - Vital Sign Changes - Comparisons of fluvoxamine maleate and placebo groups in separate pools of short-term OCD and depression trials on (1) median change from baseline on various vital signs variables and on (2) incidence of patients meeting criteria for potentially important changes from baseline on various vital signs variables revealed no important differences between fluvoxamine maleate and placebo. - Laboratory Changes - Comparisons of fluvoxamine maleate and placebo groups in separate pools of short-term OCD and depression trials on (1) median change from baseline on various serum chemistry, hematology, and urinalysis variables and on (2) incidence of patients meeting criteria for potentially important changes from baseline on various serum chemistry, hematology, and urinalysis variables revealed no important differences between fluvoxamine maleate and placebo. - ECG Changes - Comparisons of fluvoxamine maleate and placebo groups in separate pools of short-term OCD and depression trials on (1) mean change from baseline on various ECG variables and on (2) incidence of patients meeting criteria for potentially important changes from baseline on various ECG variables revealed no important differences between fluvoxamine maleate and placebo. - Other Reactions Observed During the Premarketing Evaluation of Fluvoxamine Maleate Tablets - During premarketing clinical trials conducted in North America and Europe, multiple doses of fluvoxamine maleate were administered for a combined total of 2,737 patient exposures in patients suffering OCD or Major Depressive Disorder. Untoward reactions associated with this exposure were recorded by clinical investigators using descriptive terminology of their own choosing. Consequently, it is not possible to provide a meaningful estimate of the proportion of individuals experiencing adverse reactions without first grouping similar types of untoward reactions into a limited (i.e., reduced) number of standard reaction categories. - In the tabulations which follow, a standard COSTART-based Dictionary terminology has been used to classify reported adverse reactions. If the COSTART term for a reaction was so general as to be uninformative, it was replaced with a more informative term. The frequencies presented, therefore, represent the proportion of the 2,737 patient exposures to multiple doses of fluvoxamine maleate who experienced a reaction of the type cited on at least one occasion while receiving fluvoxamine maleate. All reported reactions are included in the list below, with the following exceptions: 1) those reactions already listed in Table 2, which tabulates incidence rates of common adverse experiences in placebo-controlled OCD and depression clinical trials, are excluded; 2) those reactions for which a drug cause was not considered likely are omitted; 3) reactions for which the COSTART term was too vague to be clinically meaningful and could not be replaced with a more informative term; and 4) reactions which were reported in only one patient and judged to not be potentially serious are not included. It is important to emphasize that, although the reactions reported did occur during treatment with fluvoxamine maleate, a causal relationship to fluvoxamine maleate has not been established. - Reactions are further classified within body system categories and enumerated in order of decreasing frequency using the following definitions: frequent adverse reactions are defined as those occurring on one or more occasions in at least 1/100 patients; infrequent adverse reactions are those occurring between 1/100 and 1/1000 patients; and rare adverse reactions are those occurring in less than 1/1000 patients. Frequent: malaise; Infrequent: photosensitivity reaction and suicide attempt. Frequent: syncope. Infrequent: gastrointestinal hemorrhage and melena; Rare: hematemesis. Infrequent: anemia and ecchymosis; Rare: purpura. Frequent: weight gain and weight loss. Frequent: hyperkinesia, manic reaction, and myoclonus; Infrequent: abnormal dreams, akathisia, convulsion, dyskinesia, dystonia, euphoria, extrapyramidal syndrome, and twitching; Rare: withdrawal syndrome. Infrequent: epistaxis. Rare: hemoptysis and laryngismus. Infrequent: urticaria. Infrequent: hematuria, menorrhagia, and vaginal hemorrhage; Rare: hematospermia. - Voluntary reports of adverse reactions in patients taking fluvoxamine maleate tablets that have been received since market introduction and are of unknown causal relationship to fluvoxamine maleate tablets use include: acute renal failure, agranulocytosis, amenorrhea, anaphylactic reaction, angioedema, aplastic anemia, bullous eruption, Henoch-Schoenlein purpura, hepatitis, ileus, pancreatitis, porphyria, Stevens-Johnson syndrome, toxic epidermal necrolysis, vasculitis, and ventricular tachycardia (including torsades de pointes). - Potential Thioridazine Interaction - The effect of fluvoxamine (25 mg b.i.d. for one week) on thioridazine steady-state concentrations was evaluated in ten male inpatients with schizophrenia. Concentrations of thioridazine and its two active metabolites, mesoridazine and sulforidazine, increased 3-fold following coadministration of fluvoxamine. - Thioridazine administration produces a dose-related prolongation of the QTc interval, which is associated with serious ventricular arrhythmias, such as torsades de pointes-type arrhythmias, and sudden death. It is likely that this experience underestimates the degree of risk that might occur with higher doses of thioridazine. Moreover, the effect of fluvoxamine may be even more pronounced when it is administered at higher doses. - Therefore, fluvoxamine and thioridazine should not be coadministered. - Potential Tizanidine Interaction - Fluvoxamine is a potent inhibitor of CYP1A2 and tizanidine is a CYP1A2 substrate. The effect of fluvoxamine (100 mg daily for 4 days) on the pharmacokinetics and pharmacodynamics of a single 4 mg dose of tizanidine has been studied in ten healthy male subjects. Tizanidine Cmax was increased approximately 12-fold (range 5-fold to 32-fold), elimination half-life was increased by almost 3-fold, and AUC increased 33-fold (range 14-fold to 103-fold). The mean maximal effect on blood pressure was a 35 mm Hg decrease in systolic blood pressure, a 20 mm Hg decrease in diastolic blood pressure, and a 4 beat/min decrease in heart rate. Drowsiness was significantly increased and performance on the psychomotor task was significantly impaired. Fluvoxamine and tizanidine should not be used together. - Potential Pimozide Interaction - Pimozide is metabolized by the cytochrome P4503A4 isoenzyme, and it has been demonstrated that ketoconazole, a potent inhibitor of CYP3A4, blocks the metabolism of this drug, resulting in increased plasma concentrations of parent drug. An increased plasma concentration of pimozide causes QT prolongation and has been associated with torsades de pointes-type ventricular tachycardia, sometimes fatal. As noted below, a substantial pharmacokinetic interaction has been observed for fluvoxamine in combination with alprazolam, a drug that is known to be metabolized by CYP3A4. Although it has not been definitively demonstrated that fluvoxamine is a potent CYP3A4 inhibitor, it is likely to be, given the substantial interaction of fluvoxamine with alprazolam. Consequently, it is recommended that fluvoxamine not be used in combination with pimozide. - Potential Alosetron Interaction - Because alosetron is metabolized by a variety of hepatic CYP drug metabolizing enzymes, inducers or inhibitors of these enzymes may change the clearance of alosetron. Fluvoxamine is a known potent inhibitor of CYP1A2 and also inhibits CYP3A4, CYP2C9, and CYP2C19. In a pharmacokinetic study, 40 healthy female subjects received fluvoxamine in escalating doses from 50 mg to 200 mg a day for 16 days, with coadministration of alosetron 1 mg on the last day. Fluvoxamine increased mean alosetron plasma concentration (AUC) approximately 6-fold and prolonged the half-life by approximately 3-fold. - Other Potentially Important Drug Interactions - Benzodiazepines - Benzodiazepines metabolized by hepatic oxidation (e.g., alprazolam, midazolam, triazolam, etc.) should be used with caution because the clearance of these drugs is likely to be reduced by fluvoxamine. The clearance of benzodiazepines metabolized by glucuronidation (e.g., lorazepam, oxazepam, temazepam) is unlikely to be affected by fluvoxamine. - Alprazolam - When fluvoxamine maleate (100 mg q.d.) and alprazolam (1 mg q.i.d.) were coadministered to steady state, plasma concentrations and other pharmacokinetic parameters (AUC, Cmax, T½) of alprazolam were approximately twice those observed when alprazolam was administered alone; oral clearance was reduced by about 50%. The elevated plasma alprazolam concentrations resulted in decreased psychomotor performance and memory. This interaction, which has not been investigated using higher doses of fluvoxamine, may be more pronounced if a 300 mg daily dose is coadministered, particularly since fluvoxamine exhibits non-linear pharmacokinetics over the dosage range 100 mg to 300 mg. If alprazolam is coadministered with fluvoxamine maleate tablets, the initial alprazolam dosage should be at least halved and titration to the lowest effective dose is recommended. No dosage adjustment is required for fluvoxamine maleate tablets. - Diazepam - The coadministration of fluvoxamine maleate tablets and diazepam is generally not advisable. Because fluvoxamine reduces the clearance of both diazepam and its active metabolite, N-desmethyldiazepam, there is a strong likelihood of substantial accumulation of both species during chronic coadministration. - Evidence supporting the conclusion that it is inadvisable to coadminister fluvoxamine and diazepam is derived from a study in which healthy volunteers taking 150 mg/day of fluvoxamine were administered a single oral dose of 10 mg of diazepam. In these subjects (N = 8), the clearance of diazepam was reduced by 65% and that of N-desmethyldiazepam to a level that was too low to measure over the course of the 2 week long study. - It is likely that this experience significantly underestimates the degree of accumulation that might occur with repeated diazepam administration. Moreover, as noted with alprazolam, the effect of fluvoxamine may even be more pronounced when it is administered at higher doses. - Accordingly, diazepam and fluvoxamine should not ordinarily be coadministered. - Clozapine - Elevated serum levels of clozapine have been reported in patients taking fluvoxamine maleate and clozapine. Since clozapine-related seizures and orthostatic hypotension appear to be dose related, the risk of these adverse events may be higher when fluvoxamine and clozapine are coadministered. Patients should be closely monitored when fluvoxamine maleate and clozapine are used concurrently. - Methadone - Significantly increased methadone (plasma level:dose) ratios have been reported when fluvoxamine maleate was administered to patients receiving maintenance methadone treatment, with symptoms of opioid intoxication in one patient. Opioid withdrawal symptoms were reported following fluvoxamine maleate discontinuation in another patient. - Mexiletine - The effect of steady-state fluvoxamine (50 mg b.i.d. for 7 days) on the single dose pharmacokinetics of mexiletine (200 mg) was evaluated in six healthy Japanese males. The clearance of mexiletine was reduced by 38% following coadministration with fluvoxamine compared to mexiletine alone. If fluvoxamine and mexiletine are coadministered, serum mexiletine levels should be monitored. - Ramelteon - When fluvoxamine 100 mg twice daily was administered for 3 days prior to single-dose coadministration of ramelteon 16 mg and fluvoxamine, the AUC for ramelteon increased approximately 190-fold and the Cmax increased approximately 70-fold compared to ramelteon administered alone. Ramelteon should not be used in combination with fluvoxamine. - Theophylline - The effect of steady-state fluvoxamine (50 mg bid) on the pharmacokinetics of a single dose of theophylline (375 mg as 442 mg aminophylline) was evaluated in 12 healthy non-smoking, male volunteers. The clearance of theophylline was decreased approximately 3-fold. Therefore, if theophylline is coadministered with fluvoxamine maleate, its dose should be reduced to one-third of the usual daily maintenance dose and plasma concentrations of theophylline should be monitored. No dosage adjustment is required for fluvoxamine maleate tablets. - Warfarin and Other Drugs that Interfere with Hemostasis (NSAIDs, Aspirin, etc.) - Serotonin release by platelets plays an important role in hemostasis. Epidemiological studies of the case-control and cohort design have demonstrated an association between use of psychotropic drugs that interfere with serotonin reuptake and the occurrence of upper gastrointestinal bleeding. These studies have also shown that concurrent use of an NSAID or aspirin may potentiate this risk of bleeding. Thus, patients should be cautioned about the use of such drugs concurrently with fluvoxamine. - Warfarin - When fluvoxamine maleate (50 mg t.i.d.) was administered concomitantly with warfarin for 2 weeks, warfarin plasma concentrations increased by 98% and prothrombin times were prolonged. Thus patients receiving oral anticoagulants and fluvoxamine maleate tablets should have their prothrombin time monitored and their anticoagulant dose adjusted accordingly. No dosage adjustment is required for fluvoxamine maleate tablets. - Effects of Smoking on Fluvoxamine Metabolism - Smokers had a 25% increase in the metabolism of fluvoxamine compared to nonsmokers. - Electroconvulsive Therapy (ECT) - There are no clinical studies establishing the benefits or risks of combined use of ECT and fluvoxamine maleate. - Pregnancy Category C - Teratogenic Effects - When pregnant rats were given oral doses of fluvoxamine (60, 120, or 240 mg/kg) throughout the period of organogenesis, developmental toxicity in the form of increased embryofetal death and increased incidences of fetal eye abnormalities (folded retinas) was observed at doses of 120 mg/kg or greater. Decreased fetal body weight was seen at the high dose. The no effect dose for developmental toxicity in this study was 60 mg/kg (approximately 2 times the MRHD on a mg/m2 basis). - In a study in which pregnant rabbits were administered doses of up to 40 mg/kg (approximately 2 times the MRHD on a mg/m2 basis) during organogenesis, no adverse effects on embryofetal development were observed. - In other reproduction studies in which female rats were dosed orally during pregnancy and lactation (5, 20, 80, or 160 mg/kg), increased pup mortality at birth was seen at doses of 80 mg/kg or greater and decreases in pup body weight and survival were observed at all doses (low effect dose approximately 0.1 times the MRHD on a mg/m2 basis). - Nonteratogenic Effects - Neonates exposed to fluvoxamine maleate tablets and other SSRIs or serotonin and norepinephrine reuptake inhibitors (SNRIs) late in the third trimester have developed complications requiring prolonged hospitalization, respiratory support, and tube feeding. Such complications can arise immediately upon delivery. Reported clinical findings have included respiratory distress, cyanosis, apnea, seizures, temperature instability, feeding difficulty, vomiting, hypoglycemia, hypotonia, hypertonia, hyperreflexia, tremor, jitteriness, irritability, and constant crying. These features are consistent with either a direct toxic effect of SSRIs and SNRIs or, possibly, a drug discontinuation syndrome. It should be noted that, in some cases, the clinical picture is consistent with serotonin syndrome. - Infants exposed to SSRIs in pregnancy may have an increased risk for persistent pulmonary hypertension of the newborn (PPHN). PPHN occurs in 1 to 2 per 1,000 live births in the general population and is associated with substantial neonatal morbidity and mortality. Several recent epidemiologic studies suggest a positive statistical association between SSRI use (including fluvoxamine maleate tablets) in pregnancy and PPHN. Other studies do not show a significant statistical association. - Physicians should also note the results of a prospective longitudinal study of 201 pregnant women with a history of major depression, who were either on antidepressants or had received antidepressants less than 12 weeks prior to their last menstrual period, and were in remission. Women who discontinued antidepressant medication during pregnancy showed a significant increase in relapse of their major depression compared to those women who remained on antidepressant medication throughout pregnancy. - When treating a pregnant woman with fluvoxamine maleate tablets, the physician should carefully consider both the potential risks of taking an SSRI, along with the established benefits of treating depression with an antidepressant. This decision can only be made on a case by case basis. - Australian Drug Evaluation Committee (ADEC) Pregnancy Category There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Fluvoxamine in women who are pregnant. - The effect of fluvoxamine on labor and delivery in humans is unknown. - As for many other drugs, fluvoxamine is secreted in human breast milk. The decision of whether to discontinue nursing or to discontinue the drug should take into account the potential for serious adverse effects from exposure to fluvoxamine in the nursing infant as well as the potential benefits of fluvoxamine maleate tablet therapy to the mother. - The efficacy of fluvoxamine maleate for the treatment of obsessive compulsive disorder was demonstrated in a 10-week multicenter placebo-controlled study with 120 outpatients ages 8 to 17. In addition, 99 of these outpatients continued open-label fluvoxamine maleate treatment for up to another 1 to 3 years, equivalent to 94 patient years. The adverse event profile observed in that study was generally similar to that observed in adult studies with fluvoxamine. - Decreased appetite and weight loss have been observed in association with the use of fluvoxamine as well as other SSRIs. Consequently, regular monitoring of weight and growth is recommended if treatment of a child with an SSRI is to be continued long-term. - The risks, if any, that may be associated with fluvoxamine’s extended use in children and adolescents with OCD have not been systematically assessed. The prescriber should be mindful that the evidence relied upon to conclude that fluvoxamine is safe for use in children and adolescents derives from relatively short-term clinical studies and from extrapolation of experience gained with adult patients. In particular, there are no studies that directly evaluate the effects of long-term fluvoxamine use on the growth, cognitive behavioral development, and maturation of children and adolescents. Although there is no affirmative finding to suggest that fluvoxamine possesses a capacity to adversely affect growth, development or maturation, the absence of such findings is not compelling evidence of the absence of the potential of fluvoxamine to have adverse effects in chronic use. - Safety and effectiveness in the pediatric population other than pediatric patients with OCD have not been established. Anyone considering the use of fluvoxamine maleate tablets in a child or adolescent must balance the potential risks with the clinical need. - Approximately 230 patients participating in controlled premarketing studies with fluvoxamine maleate tablets were 65 years of age or over. No overall differences in safety were observed between these patients and younger patients. Other reported clinical experience has not identified differences in response between the elderly and younger patients. However, SSRIs and SNRIs, including fluvoxamine maleate tablets, have been associated with several cases of clinically significant hyponatremia in elderly patients, who may be at greater risk for this adverse event. Furthermore, the clearance of fluvoxamine is decreased by about 50% in elderly compared to younger patients, and greater sensitivity of some older individuals also cannot be ruled out. Consequently, a lower starting dose should be considered in elderly patients and fluvoxamine maleate tablets should be slowly titrated during initiation of therapy. There is no FDA guidance on the use of Fluvoxamine with respect to specific gender populations. There is no FDA guidance on the use of Fluvoxamine with respect to specific racial populations. There is no FDA guidance on the use of Fluvoxamine in patients with renal impairment. There is no FDA guidance on the use of Fluvoxamine in patients with hepatic impairment. There is no FDA guidance on the use of Fluvoxamine in women of reproductive potentials and males. There is no FDA guidance one the use of Fluvoxamine in patients who are immunocompromised. - Oral There is limited information regarding Monitoring of Fluvoxamine in the drug label. There is limited information regarding IV Compatibility of Fluvoxamine in the drug label. ## Acute Overdose ### Signs and Symptoms - Commonly (≥ 5%) observed adverse events associated with fluvoxamine maleate overdose include gastrointestinal complaints (nausea, vomiting and diarrhea), coma, hypokalemia, hypotension, respiratory difficulties, somnolence, and tachycardia. Other notable signs and symptoms seen with fluvoxamine maleate overdose (single or multiple drugs) include bradycardia, ECG abnormalities (such as heart arrest, QT interval prolongation, first degree atrioventricular block, bundle branch block, and junctional rhythm), convulsions, dizziness, liver function disturbances, tremor, and increased reflexes. ### Management - Treatment should consist of those general measures employed in the management of overdosage with any antidepressant. - Ensure an adequate airway, oxygenation, and ventilation. Monitor cardiac rhythm and vital signs. General supportive and symptomatic measures are also recommended. Induction of emesis is not recommended. Gastric lavage with a large-bore orogastric tube with appropriate airway protection, if needed, may be indicated if performed soon after ingestion, or in symptomatic patients. - Activated charcoal should be administered. Due to the large volume of distribution of this drug, forced diuresis, dialysis, hemoperfusion and exchange transfusion are unlikely to be of benefit. No specific antidotes for fluvoxamine are known. - A specific caution involves patients taking, or recently having taken, fluvoxamine who might ingest excessive quantities of a tricyclic antidepressant. In such a case, accumulation of the parent tricyclic and/or an active metabolite may increase the possibility of clinically significant sequelae and extend the time needed for close medical observation. - In managing overdosage, consider the possibility of multiple drug involvement. The physician should consider contacting a poison control center for additional information on the treatment of any overdose. Telephone numbers for certified poison control centers are listed in the Physicians’ Desk Reference (PDR). ## Chronic Overdose There is limited information regarding Chronic Overdose of Fluvoxamine in the drug label. - The mechanism of action of fluvoxamine maleate in obsessive compulsive disorder is presumed to be linked to its specific serotonin reuptake inhibition in brain neurons. Fluvoxamine has been shown to be a potent inhibitor of the serotonin reuptake transporter in preclinical studies, both in vitro and in vivo. - Fluvoxamine maleate is a selective serotonin (5-HT) reuptake inhibitor (SSRI) belonging to the chemical series, the 2-aminoethyl oxime ethers of aralkylketones. - It is chemically designated as 5-methoxy-4′-(trifluoromethyl)valerophenone-(E)-O-(2-aminoethyl)oxime maleate (1:1) and has the molecular formula C15H21O2N2F3•C4H4O4. Its molecular weight is 434.4. - The structural formula is: - Fluvoxamine maleate, USP is a white or off white, odorless, crystalline powder which is sparingly soluble in water, freely soluble in ethanol and chloroform and practically insoluble in diethyl ether. - Fluvoxamine maleate tablets, USP are available in 25 mg, 50 mg or 100 mg strengths for oral administration. In addition to the active ingredient, fluvoxamine maleate, each tablet contains the following inactive ingredients: colloidal silicon dioxide, FD&C Yellow No. 6 Aluminum Lake, hypromellose, mannitol, polydextrose, polyethylene glycol, povidone, pregelatinized starch (corn), sodium stearyl fumarate, titanium dioxide and triacetin. - In in vitro studies, fluvoxamine maleate had no significant affinity for histaminergic, alpha or beta adrenergic, muscarinic, or dopaminergic receptors. Antagonism of some of these receptors is thought to be associated with various sedative, cardiovascular, anticholinergic, and extrapyramidal effects of some psychotropic drugs. - Absorption - The absolute bioavailability of fluvoxamine maleate is 53%. Oral bioavailability is not significantly affected by food. - In a dose proportionality study involving fluvoxamine maleate at 100, 200 and 300 mg/day for 10 consecutive days in 30 normal volunteers, steady state was achieved after about a week of dosing. Maximum plasma concentrations at steady state occurred within 3 to 8 hours of dosing and reached concentrations averaging 88, 283 and 546 ng/mL, respectively. Thus, fluvoxamine had nonlinear pharmacokinetics over this dose range, i.e., higher doses of fluvoxamine maleate produced disproportionately higher concentrations than predicted from the lower dose. - Distribution - The mean apparent volume of distribution for fluvoxamine is approximately 25 L/kg, suggesting extensive tissue distribution. - Approximately 80% of fluvoxamine is bound to plasma protein, mostly albumin, over a concentration range of 20 to 2000 ng/mL. - Metabolism - Fluvoxamine maleate is extensively metabolized by the liver; the main metabolic routes are oxidative demethylation and deamination. Nine metabolites were identified following a 5 mg radiolabelled dose of fluvoxamine maleate, constituting approximately 85% of the urinary excretion products of fluvoxamine. The main human metabolite was fluvoxamine acid which, together with its N-acetylated analog, accounted for about 60% of the urinary excretion products. A third metabolite, fluvoxethanol, formed by oxidative deamination, accounted for about 10%. Fluvoxamine acid and fluvoxethanol were tested in an in vitro assay of serotonin and norepinephrine reuptake inhibition in rats; they were inactive except for a weak effect of the former metabolite on inhibition of serotonin uptake (1 to 2 orders of magnitude less potent than the parent compound). Approximately 2% of fluvoxamine was excreted in urine unchanged. - Elimination - Following a 14C-labelled oral dose of fluvoxamine maleate (5 mg), an average of 94% of drug-related products was recovered in the urine within 71 hours. - The mean plasma half-life of fluvoxamine at steady state after multiple oral doses of 100 mg/day in healthy, young volunteers was 15.6 hours. - Elderly Subjects - In a study of fluvoxamine maleate tablets at 50 mg and 100 mg comparing elderly (ages 66 to 73) and young subjects (ages 19 to 35), mean maximum plasma concentrations in the elderly were 40% higher. The multiple dose elimination half-life of fluvoxamine was 17.4 and 25.9 hours in the elderly compared to 13.6 and 15.6 hours in the young subjects at steady state for 50 mg and 100 mg doses, respectively. In elderly patients, the clearance of fluvoxamine was reduced by about 50% and, therefore, fluvoxamine maleate tablets should be slowly titrated during initiation of therapy. - Pediatric Subjects - The multiple-dose pharmacokinetics of fluvoxamine were determined in male and female children (ages 6 to 11) and adolescents (ages 12 to 17). Steady-state plasma fluvoxamine concentrations were 2- to 3-fold higher in children than in adolescents. AUC and Cmax in children were 1.5- to 2.7-fold higher than that in adolescents. (See Table 4.) As in adults, both children and adolescents exhibited nonlinear multiple-dose pharmacokinetics. Female children showed significantly higher AUC (0-12) and Cmax compared to male children and, therefore, lower doses of fluvoxamine maleate tablets may produce therapeutic benefit. (See Table 5.) No gender differences were observed in adolescents. Steady-state plasma fluvoxamine concentrations were similar in adults and adolescents at a dose of 300 mg/day, indicating that fluvoxamine exposure was similar in these two populations. (See Table 4.) Dose adjustment in adolescents (up to the adult maximum dose of 300 mg) may be indicated to achieve therapeutic benefit. - Hepatic and Renal Disease - A cross study comparison (healthy subjects vs. patients with hepatic dysfunction) suggested a 30% decrease in fluvoxamine clearance in association with hepatic dysfunction. The mean minimum plasma concentrations in renally impaired patients (creatinine clearance of 5 to 45 mL/min) after 4 and 6 weeks of treatment (50 mg b.i.d., N = 13) were comparable to each other, suggesting no accumulation of fluvoxamine in these patients. - Carcinogenesis - There was no evidence of carcinogenicity in rats treated orally with fluvoxamine maleate for 30 months or hamsters treated orally with fluvoxamine maleate for 20 (females) or 26 (males) months. The daily doses in the high dose groups in these studies were increased over the course of the study from a minimum of 160 mg/kg to a maximum of 240 mg/kg in rats, and from a minimum of 135 mg/kg to a maximum of 240 mg/kg in hamsters. The maximum dose of 240 mg/kg is approximately 6 times the maximum human daily dose on a mg/m2 basis. - Mutagenesis - No evidence of genotoxic potential was observed in a mouse micronucleus test, an in vitro chromosome aberration test, or the Ames microbial mutagen test with or without metabolic activation. - Impairment of Fertility - In a study in which male and female rats were administered fluvoxamine (60, 120, or 240 mg/kg) prior to and during mating and gestation, fertility was impaired at oral doses of 120 mg/kg or greater, as evidenced by increased latency to mating, decreased sperm count, decreased epididymal weight, and decreased pregnancy rate. In addition, the numbers of implantations and embryos were decreased at the highest dose. The no effect dose for fertility impairment was 60 mg/kg (approximately 2 times the maximum recommended human dose [MRHD] on a mg/m2 basis). - The effectiveness of fluvoxamine maleate tablets for the treatment of obsessive compulsive disorder (OCD) was demonstrated in two 10-week multicenter, parallel group studies of adult outpatients. Patients in these trials were titrated to a total daily fluvoxamine maleate dose of 150 mg/day over the first 2 weeks of the trial, following which the dose was adjusted within a range of 100 to 300 mg/day (on a b.i.d. schedule), on the basis of response and tolerance. Patients in these studies had moderate to severe OCD (DSM-III-R), with mean baseline ratings on the Yale-Brown Obsessive Compulsive Scale (Y-BOCS), total score of 23. Patients receiving fluvoxamine maleate experienced mean reductions of approximately four to five units on the Y-BOCS total score, compared to a two unit reduction for placebo patients. - Table 6 provides the outcome classification by treatment group on the Global Improvement item of the Clinical Global Impressions (CGI) scale for both studies combined. - Exploratory analyses for age and gender effects on outcomes did not suggest any differential responsiveness on the basis of age or sex. - In a maintenance trial of adult outpatients with OCD, 114 patients meeting DSM-IV criteria for OCD and with a Yale-Brown Obsessive Compulsive Scale (Y-BOCS) score ≥ 18 were titrated to an effective dose of fluvoxamine maleate tablets 100 to 300 mg/day as part of an initial 10-week single-blind treatment phase. Treatment response during this single-blind phase was defined as Y-BOCS scores at least 30% lower than baseline at the end of weeks 8 and 10. Of the patients who responded, their average duration of response was 4 weeks. Patients who responded during this initial phase were randomized either to continuation of fluvoxamine maleate tablets (N = 56) or to placebo (N = 58) in a double-blind phase for observation of relapse. Relapse during the double-blind phase was defined as an increase in the Y-BOCS score of at least 30% over the baseline for that phase or patient refusal to continue treatment due to a substantial increase in OCD symptoms. In the double-blind phase, patients receiving continued fluvoxamine maleate tablets treatment experienced, on average, a significantly lower relapse rate than those receiving placebo. - An examination of population subgroups from this trial did not reveal any clear evidence of a differential maintenance effect on the basis of age or gender. - The effectiveness of fluvoxamine maleate tablets for the treatment of OCD was also demonstrated in a 10-week multicenter, parallel group study in a pediatric outpatient population (children and adolescents, ages 8 to 17). Patients in this study were titrated to a total daily fluvoxamine dose of approximately 100 mg/day over the first 2 weeks of the trial, following which the dose was adjusted within a range of 50 to 200 mg/day (on a b.i.d. schedule) on the basis of response and tolerance. All patients had moderate to severe OCD (DSM-III-R) with mean baseline ratings on the Children's Yale-Brown Obsessive Compulsive Scale (CY-BOCS) total score of 24. Patients receiving fluvoxamine maleate experienced mean reductions of approximately six units on the CY-BOCS total score, compared to a three-unit reduction for placebo patients. - Table 7 provides the outcome classification by treatment group on the Global Improvement item of the Clinical Global Impression (CGI) scale for the pediatric study. - Post hoc exploratory analyses for gender effects on outcomes did not suggest any differential responsiveness on the basis of gender. Further exploratory analyses revealed a prominent treatment effect in the 8 to 11 age group and essentially no effect in the 12 to 17 age group. While the significance of these results is not clear, the 2- to 3-fold higher steady-state plasma fluvoxamine concentrations in children compared to adolescents is suggestive that decreased exposure in adolescents may have been a factor, and dose adjustment in adolescents (up to the adult maximum dose of 300 mg) may be indicated to achieve therapeutic benefit. - Fluvoxamine Maleate Tablets, USP are available containing 25 mg, 50 mg or 100 mg of fluvoxamine maleate, USP. - The 25 mg tablets are orange film-coated, oval, unscored tablets debossed with M407 on one side of the tablet and blank on the other side. They are available as follows: - NDC 0378-0407-01 - bottles of 100 tablets - The 50 mg tablets are orange film-coated, oval, scored tablets debossed with M412 on one side of the tablet and scored on the other side. They are available as follows: - NDC 0378-0412-01 - bottles of 100 tablets - The 100 mg tablets are orange film-coated, oval, scored tablets debossed with M414 on one side of the tablet and scored on the other side. They are available as follows: - NDC 0378-0414-01 - bottles of 100 tablets - Storage - Keep this and all medication out of the reach of children. - Protect from high humidity. - Store at 20° to 25°C (68° to 77°F). - Dispense in a tight, light-resistant container as defined in the USP using a child-resistant closure. - Prescribers or other health professionals should inform patients, their families, and their caregivers about the benefits and risks associated with treatment with fluvoxamine maleate tablets and should counsel them in the appropriate use. A patient Medication Guide about “Antidepressant Medicines, Depression and other Serious Mental Illnesses, and Suicidal Thoughts or Actions” is available for fluvoxamine maleate tablets. The prescriber or health professional should instruct patients, their families, and their caregivers to read the Medication Guide and should assist them in understanding its contents. Patients should be given the opportunity to discuss the contents of the Medication Guide and to obtain answers to any questions they may have. The complete text of the Medication Guide is reprinted at the end of this document. - Patients should be advised of the following issues and asked to alert their prescriber if these occur while taking fluvoxamine maleate tablets. - Clinical Worsening and Suicide Risk - Patients, their families, and their caregivers should be encouraged to be alert to the emergence of anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, mania, other unusual changes in behavior, worsening of depression, and suicidal ideation, especially early during antidepressant treatment and when the dose is adjusted up or down. Families and caregivers of patients should be advised to look for the emergence of such symptoms on a day-to-day basis, since changes may be abrupt. Such symptoms should be reported to the patient’s prescriber or health professional, especially if they are severe, abrupt in onset, or were not part of the patient’s presenting symptoms. Symptoms such as these may be associated with an increased risk for suicidal thinking and behavior and indicate the need for very close monitoring and possibly changes in the medication. - Serotonin Syndrome - Patients should be cautioned about the risk of serotonin syndrome particularly with the concomitant use of fluvoxamine with other serotonergic agents (including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan, buspirone and St. John's Wort). - Angle Closure Glaucoma - Patients should be advised that taking Fluvoxamine Maleate Tablets can cause mild pupillary dilation, which in susceptible individuals, can lead to an episode of angle closure glaucoma. Pre-existing glaucoma is almost always open-angle glaucoma because angle closure glaucoma, when diagnosed, can be treated definitively with iridectomy. Open-angle glaucoma is not a risk factor for angle closure glaucoma. Patients may wish to be examined to determine whether they are susceptible to angle closure, and have a prophylactic procedure (e.g., iridectomy), if they are susceptible. - Interference with Cognitive or Motor Performance - Since any psychoactive drug may impair judgment, thinking, or motor skills, patients should be cautioned about operating hazardous machinery, including automobiles, until they are certain that fluvoxamine maleate tablet therapy does not adversely affect their ability to engage in such activities. - Pregnancy - Patients should be advised to notify their physicians if they become pregnant or intend to become pregnant during therapy with fluvoxamine maleate tablets. - Nursing - Patients receiving fluvoxamine maleate tablets should be advised to notify their physicians if they are breast-feeding an infant. - Concomitant Medication - Patients should be advised to notify their physicians if they are taking, or plan to take, any prescription or over-the-counter drugs, since there is a potential for clinically important interactions with fluvoxamine maleate tablets. - Patients should be cautioned about the concomitant use of fluvoxamine and NSAIDs, aspirin, or other drugs that affect coagulation since the combined use of psychotropic drugs that interfere with serotonin reuptake and these agents has been associated with an increased risk of bleeding. - Because of the potential for the increased risk of serious adverse reactions including severe lowering of blood pressure and sedation when fluvoxamine and tizanidine are used together, fluvoxamine should not be used with tizanidine. - Because of the potential for the increased risk of serious adverse reactions when fluvoxamine and alosetron are used together, fluvoxamine should not be used with Lotronex™†(alosetron). - Alcohol - As with other psychotropic medications, patients should be advised to avoid alcohol while taking fluvoxamine maleate tablets. - Allergic Reactions - Patients should be advised to notify their physicians if they develop a rash, hives, or a related allergic phenomenon during therapy with fluvoxamine maleate tablets. - As with other psychotropic medications, patients should be advised to avoid alcohol while taking fluvoxamine maleate tablets. - FLUVOXAMINE MALEATE®[2] - fluvoxaMINE® — flavoxATE®[3] - fluvoxaMINE® — fluPHENAZine®[3] - Luvox® — Lasix®[3] - ↑ "Luvox". ChemSpider. Royal Society of Chemistry. Retrieved 21 October 2013..mw-parser-output cite.citation{font-style:inherit}.mw-parser-output q{quotes:"\"""\"""'""'"}.mw-parser-output code.cs1-code{color:inherit;background:inherit;border:inherit;padding:inherit}.mw-parser-output .cs1-lock-free a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/6/65/Lock-green.svg/9px-Lock-green.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-limited a,.mw-parser-output .cs1-lock-registration a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/d/d6/Lock-gray-alt-2.svg/9px-Lock-gray-alt-2.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-subscription a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/a/aa/Lock-red-alt-2.svg/9px-Lock-red-alt-2.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration{color:#555}.mw-parser-output .cs1-subscription span,.mw-parser-output .cs1-registration span{border-bottom:1px dotted;cursor:help}.mw-parser-output .cs1-hidden-error{display:none;font-size:100%}.mw-parser-output .cs1-visible-error{display:none;font-size:100%}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration,.mw-parser-output .cs1-format{font-size:95%}.mw-parser-output .cs1-kern-left,.mw-parser-output .cs1-kern-wl-left{padding-left:0.2em}.mw-parser-output .cs1-kern-right,.mw-parser-output .cs1-kern-wl-right{padding-right:0.2em} - ↑ "FLUVOXAMINE MALEATE- fluvoxamine maleate tablet, film coated". - ↑ Jump up to: 3.0 3.1 3.2 "http://www.ismp.org". External link in \|title= (help)	https://www.wikidoc.org/index.php/Fluvoxamine
52fa621358162ccae8175d3fd424055185fa0824	wikidoc	Home remedy	Home remedy # Overview A home remedy is a treatment to cure a disease or ailment that employs certain spices, vegetables, or other common items from the kitchen. Home remedies may or may not have actual medicinal properties that serve to treat or cure the disease or ailment in question, as they are typically passed along by laypersons (which has been facilitated in recent years by the Internet).; many are merely used as a result of tradition or habit or because they are quite effective in inducing the placebo effect. A significant number, however, have been demonstrated to effectively treat ailments such as sprains, minor lacerations, headaches, fevers, and even the common cold. One of the more popular examples of a home remedy is the use of chicken soup to treat respiratory infections such as a cold or mild flu, and according to recent studies, this may actually be effective. Other examples of medically successful home remedies include: willow bark tea to cure headaches and fevers (willow bark contains a form of acetylsalicylic acid, also known as aspirin); duct tape to help with setting broken bones; and duct tape or superglue to treat plantar warts, and Kogel mogel to treat sore throat. In earlier times mothers were entrusted with all but serious remedies. Historic cookbooks are frequently full of remedies for dyspepsia, fevers and female complaints. Many of the European liqueurs or digestifs were originally medicinal remedies. In Chinese folk medicine, medicinal congees (long cooked rice soups with herbs), foods and soups are part of the healing repertoire. A common error is to confuse home remedies with homeopathic remedies. In fact, the two concepts are unrelated.	Home remedy # Overview A home remedy is a treatment to cure a disease or ailment that employs certain spices, vegetables, or other common items from the kitchen. Home remedies may or may not have actual medicinal properties that serve to treat or cure the disease or ailment in question, as they are typically passed along by laypersons (which has been facilitated in recent years by the Internet).; many are merely used as a result of tradition or habit or because they are quite effective in inducing the placebo effect. A significant number, however, have been demonstrated to effectively treat ailments such as sprains, minor lacerations, headaches, fevers, and even the common cold. One of the more popular examples of a home remedy is the use of chicken soup to treat respiratory infections such as a cold or mild flu, and according to recent studies, this may actually be effective.[1] Other examples of medically successful home remedies include: willow bark tea to cure headaches and fevers (willow bark contains a form of acetylsalicylic acid, also known as aspirin); duct tape to help with setting broken bones; and duct tape or superglue to treat plantar warts, and Kogel mogel to treat sore throat. In earlier times mothers were entrusted with all but serious remedies. Historic cookbooks are frequently full of remedies for dyspepsia, fevers and female complaints. [2] Many of the European liqueurs or digestifs were originally medicinal remedies. In Chinese folk medicine, medicinal congees (long cooked rice soups with herbs), foods and soups are part of the healing repertoire. [3] A common error is to confuse home remedies with homeopathic remedies. In fact, the two concepts are unrelated.	https://www.wikidoc.org/index.php/Folk_remedies
11708030345c15614dd756195dd4616d795242b7	wikidoc	Follistatin	Follistatin Follistatin also known as activin-binding protein is a protein that in humans is encoded by the FST gene. Follistatin is an autocrine glycoprotein that is expressed in nearly all tissues of higher animals. Its primary function is the binding and bioneutralization of members of the TGF-β superfamily, with a particular focus on activin, a paracrine hormone. An earlier name for the same protein was FSH-suppressing protein (FSP). At the time of its initial isolation from follicular fluid, it was found to inhibit the anterior pituitary's secretion of follicle-stimulating hormone (FSH). # Biochemistry Follistatin is part of the inhibin-activin-follistatin axis. Currently there are three reported isoforms, FS-288, FS-300, and FS-315. Two, FS-288 and FS-315, are known to be created by alternative splicing of the primary mRNA transcript. FS-300 (porcine follistatin) is thought to be the product of posttranslational modification via truncation of the C-terminal domain from the primary amino-acid chain. Although FS is ubiquitous its highest concentration has been found to be in the female ovary, followed by the skin. The activin-binding protein follistatin is produced by folliculostellate (FS) cells of the anterior pituitary. FS cells make numerous contacts with the classical endocrine cells of the anterior pituitary including gonadotrophs. In the tissues activin has a strong role in cellular proliferation, thereby making follistatin the safeguard against uncontrolled cellular proliferation and also allowing it to function as an instrument of cellular differentiation. Both of these roles are vital in tissue rebuilding and repair, and may account for follistatin's high presence in the skin. In the blood, activin and follistatin are both known to be involved in the inflammatory response following tissue injury or pathogenic incursion. The source of follistatin in circulating blood plasma has yet to be determined, but due to its autocrine nature speculation suggests the endothelial cells lining all blood vessels, or the macrophages and monocytes also circulating within the whole blood, may be sources. Follistatin is involved in the development of the embryo. It has inhibitory action on bone morphogenic proteins (BMPs); BMPs induce the ectoderm to become epidermal ectoderm. Inhibition of BMPs allows neuroectoderm to arise from ectoderm, a process which eventually forms the neural plate. Other inhibitors involved in this process are noggin and chordin. Follistatin and BMPs are also known to play a role in folliculogenesis within the ovary. The main role of follistatin in the oestrus/menstrus ovary, so far, appears to be progression of the follicle from early antral to antral/dominant, and importantly the promotion of cellular differentiation of the estrogen producing granulosa cells (GC) of the dominant follicle into the progesterone producing large lutein cells (LLC) of the corpus luteum. # Clinical significance Follistatin is being studied for its role in regulation of muscle growth in mice, as an antagonist to myostatin (also known as GDF-8, a TGF superfamily member) which inhibits excessive muscle growth. Lee & McPherron demonstrated that inhibition of GDF-8, either by genetic elimination (knockout mice) or by increasing the amount of follistatin, resulted in greatly increased muscle mass. In 2009, research with macaque monkeys demonstrated that regulating follistatin via gene therapy also resulted in muscle growth and increases in strength. This research paves the way for human clinical trials, which are hoped to begin in the summer of 2010 on Inclusion body myositis. A study has also shown that increased levels of follistatin, by leading to increased muscle mass of certain core muscular groups, can increase life expectancy in cases of spinal muscular atrophy (SMA) in animal models. It is also being investigated for its involvement in polycystic ovary syndrome (PCOS), though there is debate as to its direct role in this infertility disease.	Follistatin Follistatin also known as activin-binding protein is a protein that in humans is encoded by the FST gene.[1][2] Follistatin is an autocrine glycoprotein that is expressed in nearly all tissues of higher animals.[2] Its primary function is the binding and bioneutralization of members of the TGF-β superfamily, with a particular focus on activin, a paracrine hormone. An earlier name for the same protein was FSH-suppressing protein (FSP). At the time of its initial isolation from follicular fluid, it was found to inhibit the anterior pituitary's secretion of follicle-stimulating hormone (FSH). # Biochemistry Follistatin is part of the inhibin-activin-follistatin axis. Currently there are three reported isoforms, FS-288, FS-300, and FS-315. Two, FS-288 and FS-315, are known to be created by alternative splicing of the primary mRNA transcript. FS-300 (porcine follistatin) is thought to be the product of posttranslational modification via truncation of the C-terminal domain from the primary amino-acid chain. Although FS is ubiquitous its highest concentration has been found to be in the female ovary, followed by the skin. The activin-binding protein follistatin is produced by folliculostellate (FS) cells of the anterior pituitary. FS cells make numerous contacts with the classical endocrine cells of the anterior pituitary including gonadotrophs. In the tissues activin has a strong role in cellular proliferation, thereby making follistatin the safeguard against uncontrolled cellular proliferation and also allowing it to function as an instrument of cellular differentiation. Both of these roles are vital in tissue rebuilding and repair, and may account for follistatin's high presence in the skin. In the blood, activin and follistatin are both known to be involved in the inflammatory response following tissue injury or pathogenic incursion. The source of follistatin in circulating blood plasma has yet to be determined, but due to its autocrine nature speculation suggests the endothelial cells lining all blood vessels, or the macrophages and monocytes also circulating within the whole blood, may be sources. Follistatin is involved in the development of the embryo. It has inhibitory action on bone morphogenic proteins (BMPs); BMPs induce the ectoderm to become epidermal ectoderm. Inhibition of BMPs allows neuroectoderm to arise from ectoderm, a process which eventually forms the neural plate. Other inhibitors involved in this process are noggin and chordin. Follistatin and BMPs are also known to play a role in folliculogenesis within the ovary. The main role of follistatin in the oestrus/menstrus ovary, so far, appears to be progression of the follicle from early antral to antral/dominant, and importantly the promotion of cellular differentiation of the estrogen producing granulosa cells (GC) of the dominant follicle into the progesterone producing large lutein cells (LLC) of the corpus luteum. # Clinical significance Follistatin is being studied for its role in regulation of muscle growth in mice, as an antagonist to myostatin (also known as GDF-8, a TGF superfamily member) which inhibits excessive muscle growth. Lee & McPherron demonstrated that inhibition of GDF-8, either by genetic elimination (knockout mice) or by increasing the amount of follistatin, resulted in greatly increased muscle mass.[3][4] In 2009, research with macaque monkeys demonstrated that regulating follistatin via gene therapy also resulted in muscle growth and increases in strength. This research paves the way for human clinical trials, which are hoped to begin in the summer of 2010 on Inclusion body myositis.[5] A study has also shown that increased levels of follistatin, by leading to increased muscle mass of certain core muscular groups, can increase life expectancy in cases of spinal muscular atrophy (SMA) in animal models.[6] It is also being investigated for its involvement in polycystic ovary syndrome (PCOS), though there is debate as to its direct role in this infertility disease.	https://www.wikidoc.org/index.php/Follistatin
1a4dcf2b840bc6cf07aebb346092945a9cf3cd5c	wikidoc	Food safety	Food safety Food safety is a scientific discipline describing the handling, preparation, and storage of food in ways that prevent foodborne illness. This includes a number of routines that should be followed to avoid potentially severe health hazards. Food can transmit disease from person to person as well as serve as a growth medium for bacteria that can cause food poisoning. In developed countries there are intricate standards for food preparation, whereas in lesser developed countries the main issue is simply the availability of adequate safe water, which is usually a critical item. # Regulatory agencies ## UK regulation ### HACCP guidelines The UK Food Standards Agency publishes recommendations as part of its Hazard Analysis and Critical Control Points (HACCP) programme. The relevant guidelines at state that: "Cooking food until the CORE TEMPERATURE is 75 °C or above will ensure that harmful bacteria are destroyed. However, lower cooking temperatures are acceptable provided that the CORE TEMPERATURE is maintained for a specified period of time as follows : - 60 °C for a minimum of 45 minutes - 65 °C for a minimum of 10 minutes - 70 °C for a minimum of 2 minutes" ### UK Department Of Health Previous guidance from a leaflet produced by the UK Department Of Health “Handling Cooked Meats Safely A Ten Point Plan” also allowed for: - "75 °C for a minimum of 30 seconds - 80 °C for a minimum of 6 seconds" as well as the above. Secondary references for the above may be found at: - This document states that: "This publication may be freely reproduced, except for advertising, endorsement or likely that, in the interests of good customer relations they will be commercial purposes. Please acknowledge the source as Wigan Council Community Protection Department." Note that recommended cooking conditions are only appropriate if initial bacterial numbers in the uncooked food are small. Cooking does not replace poor hygiene. ## Australia Food safety Training is good for everyone www.cft.com.au Australian Food Authority is working toward ensuring that all food businesses implement food safety systems to ensure food is safe to consume in a bid to halt the increasing incidence of food poisoning, this includes basic food safety training for at least one person in each business. Smart business operators know that basic food safety training improves the bottom line, staff take more pride in their work; there is less waste; and customers can have more confidence in the food they consume. Food Safety training in units of competence from a relevant training package, must be delivered by a Registered Training Organization (RTO) to enable staff to be issued with a nationally-recognised unit of competency code on their certificate. Generally this training can be completed in less than one day. Training options are available to suit the needs of everyone. Training may be carried out in-house for a group, in a public class, via correspondence or online. (To find Food Safety Training available search Google or contact the local Health Department ) Basic Food Safety Training includes: - Understanding the hazards associated with the main types of food and the conditions to prevent the growth of bacteria which can cause food poisoning - The problems associated with product packaging such as leaks in vacuum packs, damage to packaging or pest infestation, as well as problems and diseases spread by pests. - Safe Food handling. This includes safe procedures for each process such as receiving, re-packing, food storage, preparation and cooking, cooling and re-heating, displaying products, handling products when serving customers, packaging, cleaning and sanitizing, pest control, transport and delivery. Also the causes of cross contamination. - Catering for customers who are particularly at risk of food-borne illness, including allergies and intolerance. - Correct cleaning and sanitizing procedures, cleaning products and their correct use, and the storage of cleaning items such as brushes, mops and cloths. - Personal hygiene, hand washing, illness, and protective clothing. People responsible for serving unsafe food can be liable for heavy fines under this new leglislation, consumers are pleased that industry will be forced to take food safety seriously. ## US regulation ### Federal-level regulation In the United States, federal regulations governing food safety are fragmented and complicated, according to a February 2007 report from the Government Accountability Office. There are 15 agencies sharing oversight responsibilities in the food safety system, although the two primary agencies are the U.S. Department of Agriculture (USDA), which is responsible for the safety of meat, poultry, and processed egg products, and the Food and Drug Administration (FDA), which is responsible for virtually all other foods. ### State and local regulation A number of states have their own meat inspection programs that substitute for USDA inspection for meats that are sold only in-state. Certain state programs have been criticized for undue leniency to bad practices. However, other state food safety programs supplement, rather than replace, Federal inspections, generally with the goal of increasing consumer confidence in the state's produce. For example, state health departments have a role in investigating outbreaks of food-borne disease bacteria, as in the case of the 2006 outbreak of E.coli O157:H7 from processed spinach. Health departments also promote better food processing practices to eliminate these threats. In addition to the US Food and Drug Administration, several states that are major producers of fresh fruits and vegetables (including California, Arizona and Florida) have their own state programs to test produce for pesticide residues. Restaurants and other retail food establishments fall under state law and are regulated by state or local health departments. Typically these regulations require official inspections of specific design features, best food-handling practices, and certification of food handlers. In some places a letter grade or numerical score must be prominently posted following each inspection. In some localities inspection deficiencies and remedial action are posted on the Internet. # Consumer labeling ## UK labels Food stuffs in the UK have one of two labels to indicate the nature of the deterioration of the product and any subsequent health issues: Best before indicates a future date beyond which the food product may lose quality in terms of taste or texture amongst others, but does not imply any serious health problems if food is consumed beyond this date (within reasonable limits). Use by indicates a legal date beyond which it is not permissible to sell a food product (usually one that deteriorates fairly rapidly after production) due to the potential serious nature of consumption of pathogens. Leeway is provided by producers in stating use by dates so that products are not at their limit of safe consumption on the actual date stated. This allows for the variability in production, storage and display methods. www.city-and-guilds.org.uk/documents/ind_hospitality-catering/HC-33-7247.pdf ## US labels With the exception of infant formula and baby foods which must be withdrawn by their expiration date, Federal law does not require expiration dates. For all other foods, except dairy products in some states, freshness dating is strictly voluntary on the part of manufacturers. In response to consumer demand, perishable foods are typically labeled with a Sell by date. It is up to the consumer to decide how long after the Sell by date a package is usable. Other common dating statements are Best if used by, Use-by date, Expiration date, Guaranteed fresh , and Pack date. # Codex Alimentaurius In 2003, the WHO and FAO published the Codex Alimentarius which serves as a guideline to food safety .	Food safety Template:Globalize Food safety is a scientific discipline describing the handling, preparation, and storage of food in ways that prevent foodborne illness. This includes a number of routines that should be followed to avoid potentially severe health hazards. Food can transmit disease from person to person as well as serve as a growth medium for bacteria that can cause food poisoning. In developed countries there are intricate standards for food preparation, whereas in lesser developed countries the main issue is simply the availability of adequate safe water, which is usually a critical item.[1] # Regulatory agencies ## UK regulation ### HACCP guidelines The UK Food Standards Agency[2] publishes recommendations as part of its Hazard Analysis and Critical Control Points (HACCP) programme. The relevant guidelines at http://www.food.gov.uk/multimedia/pdfs/csctcooking.pdf state that: "Cooking food until the CORE TEMPERATURE is 75 °C or above will ensure that harmful bacteria are destroyed. However, lower cooking temperatures are acceptable provided that the CORE TEMPERATURE is maintained for a specified period of time as follows : - 60 °C for a minimum of 45 minutes - 65 °C for a minimum of 10 minutes - 70 °C for a minimum of 2 minutes" ### UK Department Of Health Previous guidance from a leaflet produced by the UK Department Of Health “Handling Cooked Meats Safely A Ten Point Plan” also allowed for: - "75 °C for a minimum of 30 seconds - 80 °C for a minimum of 6 seconds" as well as the above. Secondary references for the above may be found at: - http://www.rushcliffe.gov.uk/doc.asp?cat=8455 - http://www.nottinghamcity.gov.uk/fs1694b.pdf - http://www.wiganmbc.gov.uk/pub/ehcp/eh/commlflt/cookmeat.pdf This document states that: "This publication may be freely reproduced, except for advertising, endorsement or likely that, in the interests of good customer relations they will be commercial purposes. Please acknowledge the source as Wigan Council Community Protection Department." - http://www.wollongong.nsw.gov.au/Downloads/Documents/Safer_Cooked_Meat_Production.pdf - http://www.west-norfolk.gov.uk/pdf/Food%20Safety%20-%20Ten%20Point%20Plan%20for%20Safer%20Cooked%20Meat.pdf Note that recommended cooking conditions are only appropriate if initial bacterial numbers in the uncooked food are small. Cooking does not replace poor hygiene. ## Australia Food safety Training is good for everyone www.cft.com.au Australian Food Authority is working toward ensuring that all food businesses implement food safety systems to ensure food is safe to consume in a bid to halt the increasing incidence of food poisoning, this includes basic food safety training for at least one person in each business. Smart business operators know that basic food safety training improves the bottom line, staff take more pride in their work; there is less waste; and customers can have more confidence in the food they consume. Food Safety training in units of competence from a relevant training package, must be delivered by a Registered Training Organization (RTO) to enable staff to be issued with a nationally-recognised unit of competency code on their certificate. Generally this training can be completed in less than one day. Training options are available to suit the needs of everyone. Training may be carried out in-house for a group, in a public class, via correspondence or online. (To find Food Safety Training available search Google or contact the local Health Department ) Basic Food Safety Training includes: • Understanding the hazards associated with the main types of food and the conditions to prevent the growth of bacteria which can cause food poisoning • The problems associated with product packaging such as leaks in vacuum packs, damage to packaging or pest infestation, as well as problems and diseases spread by pests. • Safe Food handling. This includes safe procedures for each process such as receiving, re-packing, food storage, preparation and cooking, cooling and re-heating, displaying products, handling products when serving customers, packaging, cleaning and sanitizing, pest control, transport and delivery. Also the causes of cross contamination. • Catering for customers who are particularly at risk of food-borne illness, including allergies and intolerance. • Correct cleaning and sanitizing procedures, cleaning products and their correct use, and the storage of cleaning items such as brushes, mops and cloths. • Personal hygiene, hand washing, illness, and protective clothing. People responsible for serving unsafe food can be liable for heavy fines under this new leglislation, consumers are pleased that industry will be forced to take food safety seriously. ## US regulation ### Federal-level regulation In the United States, federal regulations governing food safety are fragmented and complicated, according to a February 2007 report from the Government Accountability Office.[3] There are 15 agencies sharing oversight responsibilities in the food safety system, although the two primary agencies are the U.S. Department of Agriculture (USDA), which is responsible for the safety of meat, poultry, and processed egg products, and the Food and Drug Administration (FDA), which is responsible for virtually all other foods. ### State and local regulation A number of states have their own meat inspection programs that substitute for USDA inspection for meats that are sold only in-state.[4] Certain state programs have been criticized for undue leniency to bad practices.[5] However, other state food safety programs supplement, rather than replace, Federal inspections, generally with the goal of increasing consumer confidence in the state's produce. For example, state health departments have a role in investigating outbreaks of food-borne disease bacteria, as in the case of the 2006 outbreak of E.coli O157:H7 from processed spinach.[6] Health departments also promote better food processing practices to eliminate these threats.[7] In addition to the US Food and Drug Administration, several states that are major producers of fresh fruits and vegetables (including California, Arizona and Florida) have their own state programs to test produce for pesticide residues.[8] Restaurants and other retail food establishments fall under state law and are regulated by state or local health departments. Typically these regulations require official inspections of specific design features, best food-handling practices, and certification of food handlers.[9] In some places a letter grade or numerical score must be prominently posted following each inspection.[10] In some localities inspection deficiencies and remedial action are posted on the Internet.[11] # Consumer labeling ## UK labels Food stuffs in the UK have one of two labels to indicate the nature of the deterioration of the product and any subsequent health issues: Best before indicates a future date beyond which the food product may lose quality in terms of taste or texture amongst others, but does not imply any serious health problems if food is consumed beyond this date (within reasonable limits). Use by indicates a legal date beyond which it is not permissible to sell a food product (usually one that deteriorates fairly rapidly after production) due to the potential serious nature of consumption of pathogens. Leeway is provided by producers in stating use by dates so that products are not at their limit of safe consumption on the actual date stated. This allows for the variability in production, storage and display methods. www.city-and-guilds.org.uk/documents/ind_hospitality-catering/HC-33-7247.pdf ## US labels With the exception of infant formula and baby foods which must be withdrawn by their expiration date, Federal law does not require expiration dates. For all other foods, except dairy products in some states, freshness dating is strictly voluntary on the part of manufacturers. In response to consumer demand, perishable foods are typically labeled with a Sell by date.[12] It is up to the consumer to decide how long after the Sell by date a package is usable. Other common dating statements are Best if used by, Use-by date, Expiration date, Guaranteed fresh <date>, and Pack date.[13] # Codex Alimentaurius In 2003, the WHO and FAO published the Codex Alimentarius which serves as a guideline to food safety [14].	https://www.wikidoc.org/index.php/Food_hygiene
dc188dd82cd4ca6390b38a3cfea69bfc818b282e	wikidoc	Forecasting	Forecasting Forecasting is the process of estimation in unknown situations. Prediction is a similar, but more general term, and usually refers to estimation of time series, cross-sectional or longitudinal data. In more recent years, Forecasting has evolved into the practice of Demand Planning in every day business forecasting for manufacturing companies. The discipline of demand planning, also sometimes referred to as supply chain forecasting, embraces both statistical forecasting and consensus process. Forecasting is commonly used in discussion of time-series data. # Categories of forecasting methods ## Time series methods Time series methods use historical data as the basis for estimating future outcomes. - Moving average - Exponential smoothing - Extrapolation - Linear prediction - Trend estimation - Growth curve - Topics ## Causal / econometric methods Some forecasting methods use the assumption that it is possible to identify the underlying factors that might influence the variable that is being forecast. For example, sales of umbrellas might be associated with weather conditions. If the causes are understood, projections of the influencing variables can be made and used in the forecast. - Regression analysis using linear regression or non-linear regression - Autoregressive moving average (ARMA) - Autoregressive integrated moving average (ARIMA) - Econometrics ## Judgemental methods Judgemental forecasting methods incorporate intuitive judgements, opinions and probability estimates. - Composite forecasts - Surveys - Delphi method - Scenario building - Technology forecasting - Forecast by analogy ## Other methods - Simulation - Prediction market - Probabilistic forecasting and Ensemble forecasting # Forecasting accuracy The forecast error is the difference between the actual value and the forecast value for the corresponding period. \ E_t = Y_t - F_t where E is the forecast error at period t, Y is the actual value at period t, and F is the forecast for period t. Measures of aggregate error: Please note that the business forecasters and demand planners in the industry refer to the PMAD as the MAPE, although they compute this volume weighted MAPE. Difference between MAPE and WMAPE is explained in Calculating Demand Forecast Accuracy See also - Forecast error - Calculating Demand Forecast Accuracy - Predictability - Prediction interval, similar to confidence interval # Applications of forecasting Forecasting has application in many situations: - Supply chain management - Weather forecasting and Meteorology - Transport planning and Transportation forecasting - Economic forecasting - Technology forecasting - Earthquake prediction - Land use forecasting - Product forecasting - Player and team performance in sports - Telecommunications forecasting	Forecasting Forecasting is the process of estimation in unknown situations. Prediction is a similar, but more general term, and usually refers to estimation of time series, cross-sectional or longitudinal data. In more recent years, Forecasting has evolved into the practice of Demand Planning in every day business forecasting for manufacturing companies. The discipline of demand planning, also sometimes referred to as supply chain forecasting, embraces both statistical forecasting and consensus process. Forecasting is commonly used in discussion of time-series data. # Categories of forecasting methods ## Time series methods Time series methods use historical data as the basis for estimating future outcomes. - Moving average - Exponential smoothing - Extrapolation - Linear prediction - Trend estimation - Growth curve - Topics ## Causal / econometric methods Some forecasting methods use the assumption that it is possible to identify the underlying factors that might influence the variable that is being forecast. For example, sales of umbrellas might be associated with weather conditions. If the causes are understood, projections of the influencing variables can be made and used in the forecast. - Regression analysis using linear regression or non-linear regression - Autoregressive moving average (ARMA) - Autoregressive integrated moving average (ARIMA) - Econometrics ## Judgemental methods Judgemental forecasting methods incorporate intuitive judgements, opinions and probability estimates. - Composite forecasts - Surveys - Delphi method - Scenario building - Technology forecasting - Forecast by analogy ## Other methods - Simulation - Prediction market - Probabilistic forecasting and Ensemble forecasting # Forecasting accuracy The forecast error is the difference between the actual value and the forecast value for the corresponding period. <math>\ E_t = Y_t - F_t </math> where E is the forecast error at period t, Y is the actual value at period t, and F is the forecast for period t. Measures of aggregate error: Please note that the business forecasters and demand planners in the industry refer to the PMAD as the MAPE, although they compute this volume weighted MAPE. Difference between MAPE and WMAPE is explained in Calculating Demand Forecast Accuracy See also - Forecast error - Calculating Demand Forecast Accuracy - Predictability - Prediction interval, similar to confidence interval # Applications of forecasting Forecasting has application in many situations: - Supply chain management - Weather forecasting and Meteorology - Transport planning and Transportation forecasting - Economic forecasting - Technology forecasting - Earthquake prediction - Land use forecasting - Product forecasting - Player and team performance in sports - Telecommunications forecasting # External links - Forecasting Principles: "Evidence-based forecasting" - http://www.statsoft.com/textbook/sttimser.html - Applied Forecasting: news on forecasting	https://www.wikidoc.org/index.php/Forecasting
03ad15bd82a6882ff42b38eaa311e500d9c9de59	wikidoc	Formication	Formication # Overview Formication is a somewhat unusual, but medically well-known, abnormal sensation. This sensation closely resembles the feeling of insects crawling on and/or under the skin, and can also include sensations which resemble those of insects stinging or biting. There are many known causes of formication. The word is derived etymologically from the Latin word formica, meaning "ant", precisely because of this similarity in sensation to that of crawling insects. Formication is a specific form of the general set of abnormal skin sensations known as paresthesia, and thus it is related to the sensation known as "pins and needles", and other tingling sensations. Some people suffering the sensation of formication find it to be annoying, others find it painful, and some find it itchy. Those who find it to be itchy may in some cases repeatedly scratch themselves until they bleed, causing skin damage and sores. (In the subset of cases where the sufferer is delirious or intoxicated because of high fever, substance abuse, or extreme alcohol withdrawal, this repeated scratching is very common indeed.) Formication can on occasion lead to people becoming fixated on the sensation and its possible meaning, and these people may develop delusional parasitosis. This is a situation where individuals are convinced that there are real insects crawling on and/or under their skin, whereas in reality there are no insects involved, just a crawling sensation. It is fairly easy to misunderstand the significance and causality of the "creepy crawly" sensation of formication. # Causes Formication is a somewhat unusual, but medically well-known, abnormal sensation. This sensation closely resembles the feeling of insects crawling on and/or under the skin, and can also include sensations which resemble those of insects stinging or biting. There are many known causes of formication. The word is derived etymologically from the Latin word formica, meaning "ant", precisely because of this similarity in sensation to that of crawling insects. Formication is a specific form of the general set of abnormal skin sensations known as paresthesia, and thus it is related to the sensation known as "pins and needles", and other tingling sensations. Some people suffering the sensation of formication find it to be annoying, others find it painful, and some find it itchy. Those who find it to be itchy may in some cases repeatedly scratch themselves until they bleed, causing skin damage and sores. (In the subset of cases where the sufferer is delirious or intoxicated because of high fever, substance abuse, or extreme alcohol withdrawal, this repeated scratching is very common indeed.) Formication can on occasion lead to people becoming fixated on the sensation and its possible meaning, and these people may develop delusional parasitosis. This is a situation where individuals are convinced that there are real insects crawling on and/or under their skin, whereas in reality there are no insects involved, just a crawling sensation. It is fairly easy to misunderstand the significance and causality of the "creepy crawly" sensation of formication. ## Life Threatening Causes - Alcohol withdrawal - Benzodiazepine withdrawal - Carbon monoxide toxicity - Cerebrovascular accident - Cocaine intoxication - Melanoma - Mercury poisoning - Methamphetamine intoxication - Respiratory alkalosis ## Common Causes - Adderall use - Amifampridine - Amiodarone - Benzodiazepine withdrawal - Causalgia - Cerebrovascular accident - Cocaine intoxication - Colistimethate - Compartment syndrome - Delirium tremens - Diabetic neuropathy - Digoxin - Dimercaprol - Gopalan syndrome - Guillain-barre syndrome - Lanatoside c - Lidocaine - Lunesta - Mefloquine - Multiple sclerosis - Notalgia paraesthetica - Palifermin - Peripheral neuropathy - Posterior inferior cerebellar artery syndrome - Riluzole - Ritalin use - Tetrodotoxin - Thallium - Thoracic outlet syndrome - Topiramate - Transverse myelitis ## Causes by Organ System ## Causes in Alphabetical Order - 4-aminopyridine - Adderall use - Alcohol withdrawal - Amifampridine - Amiodarone - Benzodiazepine withdrawal - Carbon monoxide toxicity - Carpal tunnel syndrome - Causalgia - Cerebrovascular accident - Cocaine intoxication - Colistimethate - Compartment syndrome - Delirium tremens - Diabetic neuropathy - Digoxin - Dimercaprol - Gopalan syndrome - Guillain-barre syndrome - Herpes zoster - Hypocalcaemia - Hypothyroidism - Ito syndrome - Lanatoside c - Lepromatous leprosy - Lidocaine - Limb ischaemia - Lunesta - Lyme disease - Mefloquine - Melanoma - Menopause - Mercury poisoning - Methamphetamine intoxication - Multiple sclerosis - Notalgia paraesthetica - Opiate use - Osteomalacia - Palifermin - Peripheral neuropathy - Pesticide exposure - Posterior inferior cerebellar artery syndrome - Respiratory alkalosis - Riluzole - Ritalin use - Syphilis - Tetrodotoxin - Thallium - Thoracic outlet syndrome - Topiramate - Transverse myelitis - Volkmann ischaemic contracture # Referenced Formication was neatly described in 1890: A variety of itching, often encountered in the eczema of elderly people, is formication; this is described as exactly like the crawling of myriads of animals over the skin. It is probably due to the successive irritation of nerve fibrils in the skin. At times patients who suffer from it will scarcely be persuaded that it is not due to insects. Yielding to the temptation to scratch invariably makes the disease worse. The term formication has been in use for several hundred years. In the 1797 edition of the Encyclopædia Britannica, a description of the condition raphania includes the symptom: ...a formication, or sensation as of ants or other small insects creeping on the parts. # Depictions of formication in fiction - The novel A Scanner Darkly by Philip K Dick contains a scene where the character Jerry Fabin (and Charles Freck in the movie of the same name) suffers from formication and attempts to remedy the condition by showering for hours on end. - In the movie Old Boy, the main character experiences formication while imprisoned for 15 years.	Formication Template:DiseaseDisorder infobox Template:Search infobox Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Luke Rusowicz-Orazem, B.S. Cafer Zorkun, M.D., Ph.D. [2] # Overview Formication is a somewhat unusual, but medically well-known, abnormal sensation. This sensation closely resembles the feeling of insects crawling on and/or under the skin, and can also include sensations which resemble those of insects stinging or biting. There are many known causes of formication. The word is derived etymologically from the Latin word formica, meaning "ant", precisely because of this similarity in sensation to that of crawling insects. Formication is a specific form of the general set of abnormal skin sensations known as paresthesia, and thus it is related to the sensation known as "pins and needles", and other tingling sensations. Some people suffering the sensation of formication find it to be annoying, others find it painful, and some find it itchy. Those who find it to be itchy may in some cases repeatedly scratch themselves until they bleed, causing skin damage and sores. (In the subset of cases where the sufferer is delirious or intoxicated because of high fever, substance abuse, or extreme alcohol withdrawal, this repeated scratching is very common indeed.) Formication can on occasion lead to people becoming fixated on the sensation and its possible meaning, and these people may develop delusional parasitosis. This is a situation where individuals are convinced that there are real insects crawling on and/or under their skin, whereas in reality there are no insects involved, just a crawling sensation. It is fairly easy to misunderstand the significance and causality of the "creepy crawly" sensation of formication. # Causes Formication is a somewhat unusual, but medically well-known, abnormal sensation. This sensation closely resembles the feeling of insects crawling on and/or under the skin, and can also include sensations which resemble those of insects stinging or biting. There are many known causes of formication. The word is derived etymologically from the Latin word formica, meaning "ant", precisely because of this similarity in sensation to that of crawling insects. Formication is a specific form of the general set of abnormal skin sensations known as paresthesia, and thus it is related to the sensation known as "pins and needles", and other tingling sensations. Some people suffering the sensation of formication find it to be annoying, others find it painful, and some find it itchy. Those who find it to be itchy may in some cases repeatedly scratch themselves until they bleed, causing skin damage and sores. (In the subset of cases where the sufferer is delirious or intoxicated because of high fever, substance abuse, or extreme alcohol withdrawal, this repeated scratching is very common indeed.) Formication can on occasion lead to people becoming fixated on the sensation and its possible meaning, and these people may develop delusional parasitosis. This is a situation where individuals are convinced that there are real insects crawling on and/or under their skin, whereas in reality there are no insects involved, just a crawling sensation. It is fairly easy to misunderstand the significance and causality of the "creepy crawly" sensation of formication. ## Life Threatening Causes - Alcohol withdrawal - Benzodiazepine withdrawal - Carbon monoxide toxicity - Cerebrovascular accident - Cocaine intoxication - Melanoma - Mercury poisoning - Methamphetamine intoxication - Respiratory alkalosis ## Common Causes - Adderall use - Amifampridine - Amiodarone - Benzodiazepine withdrawal - Causalgia - Cerebrovascular accident - Cocaine intoxication - Colistimethate - Compartment syndrome - Delirium tremens - Diabetic neuropathy - Digoxin - Dimercaprol - Gopalan syndrome - Guillain-barre syndrome - Lanatoside c - Lidocaine - Lunesta - Mefloquine - Multiple sclerosis - Notalgia paraesthetica - Palifermin - Peripheral neuropathy - Posterior inferior cerebellar artery syndrome - Riluzole - Ritalin use - Tetrodotoxin - Thallium - Thoracic outlet syndrome - Topiramate - Transverse myelitis ## Causes by Organ System ## Causes in Alphabetical Order - 4-aminopyridine - Adderall use - Alcohol withdrawal - Amifampridine - Amiodarone - Benzodiazepine withdrawal - Carbon monoxide toxicity - Carpal tunnel syndrome - Causalgia - Cerebrovascular accident - Cocaine intoxication - Colistimethate - Compartment syndrome - Delirium tremens - Diabetic neuropathy - Digoxin - Dimercaprol - Gopalan syndrome - Guillain-barre syndrome - Herpes zoster - Hypocalcaemia - Hypothyroidism - Ito syndrome - Lanatoside c - Lepromatous leprosy - Lidocaine - Limb ischaemia - Lunesta - Lyme disease - Mefloquine - Melanoma - Menopause - Mercury poisoning - Methamphetamine intoxication - Multiple sclerosis - Notalgia paraesthetica - Opiate use - Osteomalacia - Palifermin - Peripheral neuropathy - Pesticide exposure - Posterior inferior cerebellar artery syndrome - Respiratory alkalosis - Riluzole - Ritalin use - Syphilis - Tetrodotoxin - Thallium - Thoracic outlet syndrome - Topiramate - Transverse myelitis - Volkmann ischaemic contracture # Referenced Formication was neatly described in 1890: A variety of itching, often encountered in the eczema of elderly people, is formication; this is described as exactly like the crawling of myriads of animals over the skin. It is probably due to the successive irritation of nerve fibrils in the skin. At times patients who suffer from it will scarcely be persuaded that it is not due to insects. Yielding to the temptation to scratch invariably makes the disease worse.[1] The term formication has been in use for several hundred years. In the 1797 edition of the Encyclopædia Britannica, a description of the condition raphania includes the symptom: ...a formication, or sensation as of ants or other small insects creeping on the parts.[2] # Depictions of formication in fiction - The novel A Scanner Darkly by Philip K Dick contains a scene where the character Jerry Fabin (and Charles Freck in the movie of the same name) suffers from formication and attempts to remedy the condition by showering for hours on end. - In the movie Old Boy, the main character experiences formication while imprisoned for 15 years.	https://www.wikidoc.org/index.php/Formication
01c7290b83e94ded0b2b328a15381937321578f6	wikidoc	Fospropofol	Fospropofol # Disclaimer WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here. # Overview Fospropofol is a general anesthetic that is FDA approved for the {{{indicationType}}} of monitored anesthesia care sedation.. Common adverse reactions include cardiovascular: hypoxemia (1% to 27% ), dermatologic: pruritus (16% to 28% ), neurologic: paresthesia (49% to 74%). # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) - Monitored anesthesia care sedation: healthy adults or adults with mild systemic disease (American Society of Anesthesiology physical status of P1 or P2) 18 to 65 years of age, initiation, 6.5 mg/kg IV bolus followed immediately by supplemental infusion; patients weighing less than 60 kg should be dosed at 60 kg and patients weighing greater than 90 kg should be dosed at 90 kg. - Monitored anesthesia care sedation: healthy adults or adults with mild systemic disease (American Society of Anesthesiology physical status of P1 or P2) 18 to 65 years of age, supplemental, 1.6 mg/kg IV no more frequently than every 4 min as needed to achieve the desired level of sedation; patients weighing less than 60 kg should be dosed at 60 kg and patients weighing greater than 90 kg should be dosed at 90 kg. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information about Off-Label Guideline-Supported Use of Fospropofol in adult patients. ### Non–Guideline-Supported Use There is limited information about Off-Label Non–Guideline-Supported Use of Fospropofol in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) - Safety and effectiveness of fospropofol injection has not been established in pediatric patients ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information about Off-Label Guideline-Supported Use of Fospropofol in pediatric patients. ### Non–Guideline-Supported Use There is limited information about Off-Label Non–Guideline-Supported Use of Fospropofol in pediatric patients. # Contraindications - None. # Warnings - Fospropofol should be administered only by persons trained in the administration of general anesthesia and not involved in the conduct of the diagnostic or therapeutic procedure. Sedated patients should be continuously monitored, and facilities for maintenance of a patent airway, providing artificial ventilation, administering supplemental oxygen, and instituting cardiovascular resuscitation must be immediately available. Patients should be continuously monitored during sedation and through the recovery process for early signs of hypotension, apnea, airway obstruction, and/or oxygen desaturation. - Fospropofol may cause loss of spontaneous respiration. Apnea was reported in 1/455 (< 1%) patients treated with Fospropofol using the standard or modified dosing regimen . In patients treated with greater than the recommended Fospropofol dose, apnea was reported in 14/556 (3%). - Supplemental oxygen is recommended for all patients receiving Fospropofol. Dosages of Fospropofol must be individualized for each patient and titrated to effect . Use lower doses of Fospropofol in patients who are ≥65 years of age or who have severe systemic disease . The additive cardiorespiratory effects of narcotic analgesics and sedative-hypnotic agents should be considered when administered concomitantly with Fospropofol. - Patients should be assessed for their ability to demonstrate purposeful response while sedated with Fospropofol as patients who are unable to do so may lose protective reflexes. Airway assistance maneuvers may be required in the management of respiratory depression (see Table 4). - Fospropofol may cause hypoxemia detectable by pulse oximetry. Hypoxemia was reported in 20/455 (4%) patients treated with Fospropofol using the standard or modified dosing regimen . Hypoxemia was reported among patients who retained the ability to respond purposefully to their health care provider following administration of Fospropofol. Therefore, retention of purposeful responsiveness did not prevent patients from becoming hypoxemic following administration of Fospropofol. In patients treated with greater than the recommended Fospropofol dose, hypoxemia was reported in 151/556 (27%). - The risk of hypoxemia is reduced by appropriate positioning of the patient and the use of supplemental oxygen in all patients receiving Fospropofol. Airway assistance maneuvers may be required in the management of hypoxemia (see Table 4). The additive cardiorespiratory effects of narcotic analgesics and other sedative-hypnotic agents should be considered when administered concomitantly with Fospropofol. - Fospropofol has not been studied for use in general anesthesia. However, administration of Fospropofol may inadvertently cause patients to become unresponsive or minimally responsive to vigorous tactile or painful stimulation. The incidence of patients sedated for colonoscopy who became minimally responsive or unresponsive to vigorous tactile or painful stimulation was 7/183 (4%). The duration of minimal or complete unresponsiveness in colonoscopy patients ranged from 2 to 16 minutes. Among patients sedated for bronchoscopy, the incidence of patients who became minimally or completely unresponsive to vigorous tactile or painful stimulation was 24/149 (16%). The duration of minimal to complete unresponsiveness in bronchoscopy patients ranged from 2 to 20 minutes. - Hypotension following the use of Fospropofol may occur. Hypotension was reported in 18/455 (4%) patients treated with Fospropofol using the standard or modified dosing regimen . In patients treated with greater than the recommended Fospropofol dose, hypotension was reported in 31/556 (6%). - Patients with compromised myocardial function, reduced vascular tone, or who have reduced intravascular volume may be at an increased risk for hypotension. A secure intravenous access catheter and supplemental volume replacement fluids should be readily available during the procedure. Additional pharmacological management may be necessary. # Adverse Reactions ## Clinical Trials Experience - The following serious adverse reactions are discussed elsewhere in the labeling: - Respiratory depression - Hypoxemia - Loss of purposeful responsiveness - Hypotension - The most common adverse reactions (reported in greater than 20%) are paresthesia and pruritus. - The most commonly reported reasons for discontinuation are paresthesia and cough. - Adverse reactions presented in this section are derived from 332 patients in 3 controlled clinical trials in patients undergoing colonoscopy or flexible bronchoscopy and 123 patients in one open-label study in patients undergoing minor procedures. Patients enrolled in the studies who received the standard or modified dosing regimen included males and females, ≥18 years of age and ranging from healthy (359/455 ASA P1 or P2) to those with severe systemic disease (96/455 ASA P3 or P4). Of the 455 patients enrolled, 345 (76%) were ≥18 to <65 years of age and 110 (24%) were ≥65 years of age. Adverse reactions are reported for patients who received the standard or the modified dosing regimen . The majority of procedures were less than thirty minutes in duration. All patients in these studies received 50 mcg fentanyl citrate intravenously as premedication, and some of the patients received additional 25 mcg fentanyl citrate supplemental doses. Adverse reactions occurring in ≥2% of patients in these studies are presented in Table 3. - Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not accurately reflect the rates observed in practice. - Paresthesias (including burning, tingling, stinging) and/or pruritus, usually manifested in the perineal region, were the most frequently recorded adverse reactions in clinical trials. Paresthesias and pruritus generally occurred within 5 minutes after administration of the initial dose of Fospropofol and were generally transient and mild to moderate in intensity. The pharmacologic basis of these sensory phenomena is unknown. No pretreatments, including the use of nonsteroidal anti-inflammatory drugs, opioids, or lidocaine, are known to have an effect on or to reduce the incidence of these sensations. - Sedation-related adverse reactions were experienced at the following rates for subjects receiving the standard or modified Fospropofol dosing regimen: 20/455 (4%) hypoxemia, 18/455 (4%) hypotension, 1/455 (< 1%) apnea. A greater rate of sedation-related adverse reactions necessitating intervention was observed in patients undergoing bronchoscopy compared with colonoscopy and minor surgical procedures. In the colonoscopy studies, 5/183 (3%) patients were ASA P3. In the minor surgical procedures study, 23/123 (19%) patients were ASA P3 or P4. In the flexible bronchoscopy study, 68/150 (46%) patients were ASA P3 or P4. The type and incidence of airway assistance interventions required for patients who experienced sedation-related adverse reactions are presented in Table 4. - The safety of Fospropofol for continuous sedation has not been established and therefore its use is not recommended. Fospropofol was administered to 38 intubated and mechanically ventilated patients in postoperative and intensive care settings. An occurrence of nonsustained ventricular tachycardia was observed as a serious adverse reaction in one patient in the study. Another patient with acute myeloid leukemia with renal and hepatic insufficiency experienced a further increase in plasma formate concentration from a baseline of 66 mcg/mL to a post-dose level of 212 mcg/mL after a 12-hour infusion. The clinical significance of these findings is unknown. ## Postmarketing Experience There is limited information regarding Fospropofol Postmarketing Experience in the drug label. # Drug Interactions - Fospropofol may produce additive cardiorespiratory effects when administered with other cardiorespiratory depressants such as sedative-hypnotics and narcotic analgesics. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): B - Pregnancy Category B. - There are no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed. - Reproduction studies have been performed in rats and rabbits at doses up to 0.6 and 1.7 times the anticipated human dose for a procedure of 16 minutes based on a comparison of doses expressed as mg/m2 and have revealed no evidence of impaired fertility or harm to the fetus due to Fospropofol. - Pregnant rats were treated with fospropofol disodium (5, 20, or 45 mg/kg/day, IV) from gestation day 7 through 17 (the highest dose is 0.6 times the anticipated human dose for a procedure of 16 minutes based on a comparison of doses expressed as mg/m2). Doses of 20 and 45 mg/kg/day produced significant maternal toxicity. No drug-related adverse effects on embryo-fetal development were noted. - Pregnant rabbits were treated with fospropofol disodium (14, 28, 56 or 70 mg/kg/day, IV) from gestation day 6 through 18 (the highest dose is 1.7 times the anticipated human dose for a procedure of 16 minutes based on a comparison of doses expressed as mg/m2). Significant maternal toxicity was noted at all doses. No drug-related adverse effects on embryo-fetal development were noted. - Pregnant rats were administered 0, 5, 10, or 20 mg/kg/day fospropofol disodium from gestation day 7 through lactation day 20 to evaluate perinatal and postnatal development (the highest dose is 0.2 times the anticipated human dose for a procedure of 16 minutes based on a comparison of doses expressed as mg/m2). There were no clear treatment-related effects on growth, development, behavior (passive avoidance and water maze) or fertility and mating capacity of the offspring. Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Fospropofol in women who are pregnant. ### Labor and Delivery - Fospropofol is not recommended for use in labor and delivery, including Cesarean section deliveries. It is not known if fospropofol crosses the placenta; however, propofol is known to cross the placenta, and as with other sedative-hypnotic agents, the administration of Fospropofol may be associated with neonatal respiratory and cardiovascular depression. ### Nursing Mothers - It is not known whether fospropofol is excreted in human milk; however, propofol has been reported to be excreted in human milk, and the effects of oral absorption of fospropofol or propofol are not known. Fospropofol is not recommended for use in nursing mothers. ### Pediatric Use - Safety and effectiveness in pediatric patients have not been established because Fospropofol has not been studied in persons <18 years of age. Fospropofol is not recommended for use in this population. ### Geriatic Use - In studies of Fospropofol for sedation in brief diagnostic and therapeutic procedures, 17% of patients were ≥65 years of age and 5% of patients were ≥75 years of age. Patients ≥65 years of age should receive the modified dosing regimen . Hypoxemia was reported more frequently among patients aged ≥75 years than among patients aged 65 to <75 years and less frequently among younger patients, aged 18 to < 65 years. ### Gender There is no FDA guidance on the use of Fospropofol with respect to specific gender populations. ### Race There is no FDA guidance on the use of Fospropofol with respect to specific racial populations. ### Renal Impairment - In studies of Fospropofol for sedation in brief diagnostic and therapeutic procedures, 21% of patients had a creatinine clearance <80 mL/min, and 4% had a creatinine clearance <50 mL/min. Pharmacokinetics of fospropofol or propofol were not altered in patients with mild to moderate renal insufficiency. No dosing adjustments are required for patients with creatinine clearance ≥30 mL/min. Limited safety and efficacy data are available for Fospropofol in patients with creatinine clearance < 30 mL/min. ### Hepatic Impairment - Fospropofol has not been adequately studied in patients with hepatic impairment. Caution should be exercised when using fospropofol disodium in patients with hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Fospropofol in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Fospropofol in patients who are immunocompromised. # Administration and Monitoring ### Administration There is limited information regarding Fospropofol Administration in the drug label. ### Monitoring There is limited information regarding Fospropofol Monitoring in the drug label. # IV Compatibility There is limited information regarding the compatibility of Fospropofol and IV administrations. # Overdosage - Overdosage with Fospropofol can cause cardiorespiratory depression. If overdosage occurs, Fospropofol administration should be discontinued immediately. Respiratory depression may require manual or mechanical ventilation. Cardiovascular depression may require elevation of lower extremities, intravascular volume replacement, and/or pharmacological management. - Formate and phosphate are metabolites of Fospropofol and may contribute to signs of toxicity following overdosage. Signs of formate toxicity are similar to those of methanol toxicity and are associated with anion-gap metabolic acidosis. Intravenous exposure to a large amount of phosphate could potentially cause hypocalcemia with paresthesia, muscle spasms, and seizures. # Pharmacology ## Mechanism of Action - Fospropofol disodium is a prodrug of propofol. Following intravenous injection, fospropofol is metabolized by alkaline phosphatases. For every millimole of fospropofol disodium administered, one millimole of propofol is produced (1.86 mg of fospropofol disodium is the molar equivalent of 1 mg propofol). ## Structure - Fospropofol is an injection solution intended for intravenous administration as a sedative-hypnotic agent. Fospropofol is an aqueous, sterile, nonpyrogenic, clear, colorless, iso-osmotic solution containing 35 mg/mL of fospropofol disodium. Fospropofol disodium is a water-soluble prodrug of propofol, chemically described as 2,6-diisopropylphenoxymethyl phosphate, disodium salt. The structural and molecular formulas are shown in Figure 1. - The inactive components include monothioglycerol (0.25 wt%) and tromethamine (0.12 wt%). LUSEDRA has a pH of 8.2 to 9.0. LUSEDRA does not contain any antimicrobial preservatives and is intended for single-use administration. ## Pharmacodynamics - The pharmacology of fospropofol, once metabolized to propofol, is comparable to that of propofol lipid emulsion; however, the liberation of propofol from fospropofol results in differences in the timing of the pharmacodynamic effects. To characterize the pharmacokinetic/pharmacodynamic (PK/PD) profile of propofol derived from Fospropofol, 12 healthy subjects were administered a 10-mg/kg intravenous bolus dose of Fospropofol, and the sedative effect was measured as a decrease in Modified Observer's Assessment of Alertness/Sedation (MOAA/S) score (Table 5).2 The PK and PD results are shown in Figure 2. Peak plasma levels of propofol (2.2 ± 0.4 μg/mL) released from fospropofol were noted by 8 minutes (range 4 - 13 minutes) and minimum mean MOAA/S score of 1.2 (range 0 - 3) was noted in 7 minutes (range 1 - 15 minutes). Subjects completely recovered from sedative effects between 21 to 45 minutes after Fospropofol administration. - Fospropofol was evaluated in randomized, blinded, dose-controlled studies for sedation in patients undergoing colonoscopy and flexible bronchoscopy . Figure 3 shows MOAA/S scores over time in each of the studies for those patients who received the standard and modified dosing regimens. In the study of patients undergoing colonoscopy, patients who received the standard and modified dosing regimens had a median time to sedation (time from first dose of sedative to the first of 2 consecutive MOAA/S scores of ≤ 4) of 8.0 minutes and a median time to Fully Alert (3 consecutive responses to their name spoken in a normal tone, measured every 2 minutes beginning at or after the end of the procedure) of 5.0 minutes. In the study of patients undergoing flexible bronchoscopy, patients who received the standard and modified Fospropofol dosing regimens had a median time to sedation of 4 minutes and a median time to Fully Alert of 5.5 minutes. Fospropofol-04 - Within the recommended dose range, there were no differences in matched QTc interval changes between Fospropofol and placebo. The effect of Fospropofol on the QTcF interval was measured in a crossover study in which healthy subjects (n=68) received the following treatments: 6-mg/kg intravenous Fospropofol; 18-mg/kg intravenous Fospropofol; moxifloxacin 400 mg orally (positive control); and normal saline IV. After baseline and placebo adjustment, the maximum mean QTcF change was 2 ms (1-sided 95% Upper CI: 6 ms) for the 6-mg/kg dose and 8 ms (1-sided 95% Upper CI: 12 ms) for the 18-mg/kg dose. Used as a positive control, moxifloxacin had a maximum mean change in QTcF of 12 ms (1-sided 95% Lower CI: 6 ms). ## Pharmacokinetics PK parameters were evaluated in a crossover study of 68 healthy subjects, 18 to 45 years of age, who received 6- and 18-mg/kg intravenous bolus doses of Fospropofol. PK parameters are shown in Table 6. The Cmax and AUC0-∞ values of fospropofol were dose proportional. The intersubject variability in Cmax and AUC0-∞ was low. Propofol was rapidly liberated reaching plasma Cmax at a median Tmax of 12 minutes for Fospropofol 6 mg/kg and 8 minutes for Fospropofol 18 mg/kg. Concentration-time profiles showed a biexponential decline. The increase in Cmax and AUC0-∞ of propofol was dose proportional. - Fospropofol has a low volume of distribution of 0.33±0.069 L/kg, and the liberated propofol has a large volume of distribution (5.8 L/kg). - Both fospropofol and its active metabolite propofol are highly protein bound (approximately 98%), primarily to albumin. Fospropofol does not affect the binding of propofol to albumin. - Fospropofol is completely metabolized by alkaline phosphatases to propofol, formaldehyde, and phosphate. Formaldehyde and phosphate plasma concentrations are comparable to endogenous levels when fospropofol disodium is administered as recommended. Formaldehyde is further metabolized to formate by several enzyme systems, including formaldehyde dehydrogenase, present in various tissues. Propofol liberated from fospropofol is further metabolized to major metabolites propofol glucuronide (34.8%), quinol-4-sulfate (4.6%), quinol-1-glucuronide (11.1%), and quinol-4-glucuronide (5.1%). Oxidation to CO2 is the primary means of eliminating excess formate. - Fospropofol is not a substrate of CYP450 enzymes. - After a single 400 mg intravenous dose of -fospropofol disodium in humans, approximately 71% of radioactivity was recovered in the urine within 192 hours. Total body clearance (CLp) of fospropofol was 0.280±0.053 L/h/kg, and renal elimination of fospropofol was insignificant (<0.02% of dose). The terminal phase elimination half-life (t1/2) of fospropofol was 0.81±0.08 and 0.88±0.08 hours in healthy subjects and patients, respectively. In healthy subjects, the apparent total body clearance of liberated propofol (CLp/F) was 1.95±0.345 L/h/kg and t1/2 was 2.06±0.77 hours. In patients, the CLp of fospropofol was 0.31±0.14 L/h/kg and CLp/F for propofol was 2.74±0.80 L/h/kg and is similar to that observed in healthy subjects. - Population pharmacokinetic analysis indicated no influence of race, gender, age, renal impairment or alkaline phosphatase concentrations on the pharmacokinetics of fospropofol. Pharmacokinetics of propofol derived from fospropofol was not influenced by race, gender, or renal impairment. - Fospropofol has not been adequately studied in patients with hepatic impairment. Caution should be exercised when using fospropofol disodium in patients with hepatic impairment. - There was no effect of analgesic premedication on plasma pharmacokinetics of fospropofol. - In an in vitro protein-binding study, there was no significant interaction between fospropofol and propofol at concentrations up to 200 mcg/mL and 5 mcg/mL, respectively. The interaction of fospropofol with other highly protein-bound drugs given concomitantly has not been studied. - Potential of fospropofol or its major metabolite, propofol, to inhibit or induce major cytochrome P450 enzymes is not known. ## Nonclinical Toxicology - Long-term studies in animals have not been performed to evaluate the carcinogenic potential of fospropofol disodium. - Fospropofol was not genotoxic in the Ames bacterial reverse mutation assay, with or without metabolic activation, and in the in vivo mouse micronucleus assay. Fospropofol was positive in the L5178Y TK+/- mouse lymphoma forward mutation assay in the presence of metabolic activation. In contrast, fospropofol was negative in this assay in the presence of formaldehyde-metabolizing enzymes suggesting that the positive finding is likely due to an artifact of the culture conditions. - Male rats were treated with 5, 10, or 20 mg/kg fospropofol for 4 weeks prior to mating. Male fertility was not altered in animals treated with 20 mg/kg (0.3-fold the total human dose for a procedure of 16 minutes based on a mg/m2 basis). - Female rats were treated with 5, 10, or 20 mg/kg fospropofol for two weeks prior to mating. There were no clear treatment-related effects on female fertility at a dose of 20 mg/kg (0.3-fold the total human dose for a procedure of 16 minutes based on a mg/m2 basis). # Clinical Studies - The standard and modified Fospropofol dosing regimens were evaluated in two controlled studies in patients dosed with Fospropofol who were over 18 years of age and undergoing diagnostic or therapeutic procedures. All patients received 50 mcg of fentanyl citrate intravenously before study sedative medication. The primary endpoint was the rate of "sedation success," defined as the proportion of patients who did not respond readily to their name spoken in a normal tone of voice (Modified Observer's Assessment of Alertness/Sedation Scale score of 4 or less) on 3 consecutive measurements taken every 2 minutes and who completed the procedure without the use of alternative sedative medication and without the use of manual or mechanical ventilation. 2 - In both studies, an initial bolus dose and up to 3 supplemental doses at 25 % of the initial bolus of study sedative medication were administered intravenously to sedate patients so that they did not respond readily to their name spoken in a normal tone and to allow the investigator to start the procedure. During the procedure, supplemental doses at 25% of the initial bolus were allowed to maintain sedation. Patients who were not adequately sedated with study drug received alternative sedative medication per the site's standard of care; however, sites were instructed not to use propofol as it would interfere with PK measurements. - The standard and modified Fospropofol dosing regimens were evaluated in a randomized, blinded, dose-controlled study for sedation in patients undergoing colonoscopy. All of the patients who received alternative sedative medication (n=19) received midazolam. Patients randomized to receive the Fospropofol standard or modified dosing regimen had a sedation success rate of 87% and required a mean number of supplemental doses of 2.3 (±1.4 SD). Patients randomized to receive Fospropofol had a median procedure duration of 11 minutes. - The standard and modified Fospropofol dosing regimens were also evaluated in a randomized, blinded, dose-controlled study for sedation in patients undergoing flexible bronchoscopy. All of the patients who received alternative sedative medication (n=12) received midazolam. Patients randomized to receive the Fospropofol standard or modified dosing regimen had a sedation success rate of 89% and required a mean number of supplemental doses of 1.7 (±1.6 SD). Patients randomized to Fospropofol had a median procedure duration of 10 minutes. # How Supplied - Fospropofol, 35 mg/mL (total of 1,050 mg/30 mL) fospropofol disodium, is supplied as a single-use, aqueous, sterile, nonpyrogenic, clear, colorless solution in glass vials ready for intravenous injection. Each vial is filled with 32.1 mL intended to deliver a minimum of 30 mL of fospropofol disodium solution. ## Storage - Store at controlled room temperature 25°C (77°F). Excursions permitted between 15° and 30°C (59° and 86°F). # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information - Paresthesias (including burning, tingling, stinging) and/or pruritus, usually manifested in the perineal region are frequently experienced upon injection of the initial dose of Fospropofol. Inform the patient that these sensations are typically mild to moderate in intensity, last a short time, and require no treatment. - Requirement for a patient escort should be considered. The decision as to when patients who have received Fospropofol, particularly on an outpatient basis, may again engage in activities requiring complete mental alertness, coordination and/or physical dexterity (e.g., operate hazardous machinery, sign legal documents, or drive a motor vehicle) must be individualized. # Precautions with Alcohol Alcohol-Fospropofol interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names There is limited information regarding Fospropofol Brand Names in the drug label. # Look-Alike Drug Names There is limited information regarding Fospropofol Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	Fospropofol Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Chetan Lokhande, M.B.B.S [2] # Disclaimer WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here. # Overview Fospropofol is a general anesthetic that is FDA approved for the {{{indicationType}}} of monitored anesthesia care sedation.. Common adverse reactions include cardiovascular: hypoxemia (1% to 27% ), dermatologic: pruritus (16% to 28% ), neurologic: paresthesia (49% to 74%). # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) - Monitored anesthesia care sedation: healthy adults or adults with mild systemic disease (American Society of Anesthesiology physical status of P1 or P2) 18 to 65 years of age, initiation, 6.5 mg/kg IV bolus followed immediately by supplemental infusion; patients weighing less than 60 kg should be dosed at 60 kg and patients weighing greater than 90 kg should be dosed at 90 kg. - Monitored anesthesia care sedation: healthy adults or adults with mild systemic disease (American Society of Anesthesiology physical status of P1 or P2) 18 to 65 years of age, supplemental, 1.6 mg/kg IV no more frequently than every 4 min as needed to achieve the desired level of sedation; patients weighing less than 60 kg should be dosed at 60 kg and patients weighing greater than 90 kg should be dosed at 90 kg. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information about Off-Label Guideline-Supported Use of Fospropofol in adult patients. ### Non–Guideline-Supported Use There is limited information about Off-Label Non–Guideline-Supported Use of Fospropofol in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) - Safety and effectiveness of fospropofol injection has not been established in pediatric patients ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information about Off-Label Guideline-Supported Use of Fospropofol in pediatric patients. ### Non–Guideline-Supported Use There is limited information about Off-Label Non–Guideline-Supported Use of Fospropofol in pediatric patients. # Contraindications - None. # Warnings - Fospropofol should be administered only by persons trained in the administration of general anesthesia and not involved in the conduct of the diagnostic or therapeutic procedure. Sedated patients should be continuously monitored, and facilities for maintenance of a patent airway, providing artificial ventilation, administering supplemental oxygen, and instituting cardiovascular resuscitation must be immediately available. Patients should be continuously monitored during sedation and through the recovery process for early signs of hypotension, apnea, airway obstruction, and/or oxygen desaturation. - Fospropofol may cause loss of spontaneous respiration. Apnea was reported in 1/455 (< 1%) patients treated with Fospropofol using the standard or modified dosing regimen [see Dosage and Administration]. In patients treated with greater than the recommended Fospropofol dose, apnea was reported in 14/556 (3%). - Supplemental oxygen is recommended for all patients receiving Fospropofol. Dosages of Fospropofol must be individualized for each patient and titrated to effect [see Dosage and Administration (2.1) and Clinical Pharmacology (12.2)]. Use lower doses of Fospropofol in patients who are ≥65 years of age or who have severe systemic disease [see Dosage and Administration (2.3)]. The additive cardiorespiratory effects of narcotic analgesics and sedative-hypnotic agents should be considered when administered concomitantly with Fospropofol. - Patients should be assessed for their ability to demonstrate purposeful response while sedated with Fospropofol as patients who are unable to do so may lose protective reflexes. Airway assistance maneuvers may be required in the management of respiratory depression (see Table 4). - Fospropofol may cause hypoxemia detectable by pulse oximetry. Hypoxemia was reported in 20/455 (4%) patients treated with Fospropofol using the standard or modified dosing regimen [see Dosage and Administration (2.2, 2.3)]. Hypoxemia was reported among patients who retained the ability to respond purposefully to their health care provider following administration of Fospropofol. Therefore, retention of purposeful responsiveness did not prevent patients from becoming hypoxemic following administration of Fospropofol. In patients treated with greater than the recommended Fospropofol dose, hypoxemia was reported in 151/556 (27%). - The risk of hypoxemia is reduced by appropriate positioning of the patient and the use of supplemental oxygen in all patients receiving Fospropofol. Airway assistance maneuvers may be required in the management of hypoxemia (see Table 4). The additive cardiorespiratory effects of narcotic analgesics and other sedative-hypnotic agents should be considered when administered concomitantly with Fospropofol. - Fospropofol has not been studied for use in general anesthesia. However, administration of Fospropofol may inadvertently cause patients to become unresponsive or minimally responsive to vigorous tactile or painful stimulation. The incidence of patients sedated for colonoscopy who became minimally responsive or unresponsive to vigorous tactile or painful stimulation was 7/183 (4%). The duration of minimal or complete unresponsiveness in colonoscopy patients ranged from 2 to 16 minutes. Among patients sedated for bronchoscopy, the incidence of patients who became minimally or completely unresponsive to vigorous tactile or painful stimulation was 24/149 (16%). The duration of minimal to complete unresponsiveness in bronchoscopy patients ranged from 2 to 20 minutes. - Hypotension following the use of Fospropofol may occur. Hypotension was reported in 18/455 (4%) patients treated with Fospropofol using the standard or modified dosing regimen [see Dosage and Administration]. In patients treated with greater than the recommended Fospropofol dose, hypotension was reported in 31/556 (6%). - Patients with compromised myocardial function, reduced vascular tone, or who have reduced intravascular volume may be at an increased risk for hypotension. A secure intravenous access catheter and supplemental volume replacement fluids should be readily available during the procedure. Additional pharmacological management may be necessary. # Adverse Reactions ## Clinical Trials Experience - The following serious adverse reactions are discussed elsewhere in the labeling: - Respiratory depression [see Warnings and Precautions] - Hypoxemia [see Warnings and Precautions] - Loss of purposeful responsiveness [see Warnings and Precautions] - Hypotension [see Warnings and Precautions] - The most common adverse reactions (reported in greater than 20%) are paresthesia and pruritus. - The most commonly reported reasons for discontinuation are paresthesia and cough. - Adverse reactions presented in this section are derived from 332 patients in 3 controlled clinical trials in patients undergoing colonoscopy or flexible bronchoscopy and 123 patients in one open-label study in patients undergoing minor procedures. Patients enrolled in the studies who received the standard or modified dosing regimen included males and females, ≥18 years of age and ranging from healthy (359/455 [79%] ASA P1 or P2) to those with severe systemic disease (96/455 [21%] ASA P3 or P4). Of the 455 patients enrolled, 345 (76%) were ≥18 to <65 years of age and 110 (24%) were ≥65 years of age. Adverse reactions are reported for patients who received the standard or the modified dosing regimen [see Dosage and Administration]. The majority of procedures were less than thirty minutes in duration. All patients in these studies received 50 mcg fentanyl citrate intravenously as premedication, and some of the patients received additional 25 mcg fentanyl citrate supplemental doses. Adverse reactions occurring in ≥2% of patients in these studies are presented in Table 3. - Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not accurately reflect the rates observed in practice. - Paresthesias (including burning, tingling, stinging) and/or pruritus, usually manifested in the perineal region, were the most frequently recorded adverse reactions in clinical trials. Paresthesias and pruritus generally occurred within 5 minutes after administration of the initial dose of Fospropofol and were generally transient and mild to moderate in intensity. The pharmacologic basis of these sensory phenomena is unknown. No pretreatments, including the use of nonsteroidal anti-inflammatory drugs, opioids, or lidocaine, are known to have an effect on or to reduce the incidence of these sensations. - Sedation-related adverse reactions were experienced at the following rates for subjects receiving the standard or modified Fospropofol dosing regimen: 20/455 (4%) hypoxemia, 18/455 (4%) hypotension, 1/455 (< 1%) apnea. A greater rate of sedation-related adverse reactions necessitating intervention was observed in patients undergoing bronchoscopy compared with colonoscopy and minor surgical procedures. In the colonoscopy studies, 5/183 (3%) patients were ASA P3. In the minor surgical procedures study, 23/123 (19%) patients were ASA P3 or P4. In the flexible bronchoscopy study, 68/150 (46%) patients were ASA P3 or P4. The type and incidence of airway assistance interventions required for patients who experienced sedation-related adverse reactions are presented in Table 4. - The safety of Fospropofol for continuous sedation has not been established and therefore its use is not recommended. Fospropofol was administered to 38 intubated and mechanically ventilated patients in postoperative and intensive care settings. An occurrence of nonsustained ventricular tachycardia was observed as a serious adverse reaction in one patient in the study. Another patient with acute myeloid leukemia with renal and hepatic insufficiency experienced a further increase in plasma formate concentration from a baseline of 66 mcg/mL to a post-dose level of 212 mcg/mL after a 12-hour infusion. The clinical significance of these findings is unknown. ## Postmarketing Experience There is limited information regarding Fospropofol Postmarketing Experience in the drug label. # Drug Interactions - Fospropofol may produce additive cardiorespiratory effects when administered with other cardiorespiratory depressants such as sedative-hypnotics and narcotic analgesics. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): B - Pregnancy Category B. - There are no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed. - Reproduction studies have been performed in rats and rabbits at doses up to 0.6 and 1.7 times the anticipated human dose for a procedure of 16 minutes based on a comparison of doses expressed as mg/m2 and have revealed no evidence of impaired fertility or harm to the fetus due to Fospropofol. - Pregnant rats were treated with fospropofol disodium (5, 20, or 45 mg/kg/day, IV) from gestation day 7 through 17 (the highest dose is 0.6 times the anticipated human dose for a procedure of 16 minutes based on a comparison of doses expressed as mg/m2). Doses of 20 and 45 mg/kg/day produced significant maternal toxicity. No drug-related adverse effects on embryo-fetal development were noted. - Pregnant rabbits were treated with fospropofol disodium (14, 28, 56 or 70 mg/kg/day, IV) from gestation day 6 through 18 (the highest dose is 1.7 times the anticipated human dose for a procedure of 16 minutes based on a comparison of doses expressed as mg/m2). Significant maternal toxicity was noted at all doses. No drug-related adverse effects on embryo-fetal development were noted. - Pregnant rats were administered 0, 5, 10, or 20 mg/kg/day fospropofol disodium from gestation day 7 through lactation day 20 to evaluate perinatal and postnatal development (the highest dose is 0.2 times the anticipated human dose for a procedure of 16 minutes based on a comparison of doses expressed as mg/m2). There were no clear treatment-related effects on growth, development, behavior (passive avoidance and water maze) or fertility and mating capacity of the offspring. Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Fospropofol in women who are pregnant. ### Labor and Delivery - Fospropofol is not recommended for use in labor and delivery, including Cesarean section deliveries. It is not known if fospropofol crosses the placenta; however, propofol is known to cross the placenta, and as with other sedative-hypnotic agents, the administration of Fospropofol may be associated with neonatal respiratory and cardiovascular depression. ### Nursing Mothers - It is not known whether fospropofol is excreted in human milk; however, propofol has been reported to be excreted in human milk, and the effects of oral absorption of fospropofol or propofol are not known. Fospropofol is not recommended for use in nursing mothers. ### Pediatric Use - Safety and effectiveness in pediatric patients have not been established because Fospropofol has not been studied in persons <18 years of age. Fospropofol is not recommended for use in this population. ### Geriatic Use - In studies of Fospropofol for sedation in brief diagnostic and therapeutic procedures, 17% of patients were ≥65 years of age and 5% of patients were ≥75 years of age. Patients ≥65 years of age should receive the modified dosing regimen [see Dosage and Administration (2.3)]. Hypoxemia was reported more frequently among patients aged ≥75 years than among patients aged 65 to <75 years and less frequently among younger patients, aged 18 to < 65 years. ### Gender There is no FDA guidance on the use of Fospropofol with respect to specific gender populations. ### Race There is no FDA guidance on the use of Fospropofol with respect to specific racial populations. ### Renal Impairment - In studies of Fospropofol for sedation in brief diagnostic and therapeutic procedures, 21% of patients had a creatinine clearance <80 mL/min, and 4% had a creatinine clearance <50 mL/min. Pharmacokinetics of fospropofol or propofol were not altered in patients with mild to moderate renal insufficiency. No dosing adjustments are required for patients with creatinine clearance ≥30 mL/min. Limited safety and efficacy data are available for Fospropofol in patients with creatinine clearance < 30 mL/min. ### Hepatic Impairment - Fospropofol has not been adequately studied in patients with hepatic impairment. Caution should be exercised when using fospropofol disodium in patients with hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Fospropofol in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Fospropofol in patients who are immunocompromised. # Administration and Monitoring ### Administration There is limited information regarding Fospropofol Administration in the drug label. ### Monitoring There is limited information regarding Fospropofol Monitoring in the drug label. # IV Compatibility There is limited information regarding the compatibility of Fospropofol and IV administrations. # Overdosage - Overdosage with Fospropofol can cause cardiorespiratory depression. If overdosage occurs, Fospropofol administration should be discontinued immediately. Respiratory depression may require manual or mechanical ventilation. Cardiovascular depression may require elevation of lower extremities, intravascular volume replacement, and/or pharmacological management. - Formate and phosphate are metabolites of Fospropofol and may contribute to signs of toxicity following overdosage. Signs of formate toxicity are similar to those of methanol toxicity and are associated with anion-gap metabolic acidosis. Intravenous exposure to a large amount of phosphate could potentially cause hypocalcemia with paresthesia, muscle spasms, and seizures. # Pharmacology ## Mechanism of Action - Fospropofol disodium is a prodrug of propofol. Following intravenous injection, fospropofol is metabolized by alkaline phosphatases. For every millimole of fospropofol disodium administered, one millimole of propofol is produced (1.86 mg of fospropofol disodium is the molar equivalent of 1 mg propofol). ## Structure - Fospropofol is an injection solution intended for intravenous administration as a sedative-hypnotic agent. Fospropofol is an aqueous, sterile, nonpyrogenic, clear, colorless, iso-osmotic solution containing 35 mg/mL of fospropofol disodium. Fospropofol disodium is a water-soluble prodrug of propofol, chemically described as 2,6-diisopropylphenoxymethyl phosphate, disodium salt. The structural and molecular formulas are shown in Figure 1. - The inactive components include monothioglycerol (0.25 wt%) and tromethamine (0.12 wt%). LUSEDRA has a pH of 8.2 to 9.0. LUSEDRA does not contain any antimicrobial preservatives and is intended for single-use administration. ## Pharmacodynamics - The pharmacology of fospropofol, once metabolized to propofol, is comparable to that of propofol lipid emulsion; however, the liberation of propofol from fospropofol results in differences in the timing of the pharmacodynamic effects. To characterize the pharmacokinetic/pharmacodynamic (PK/PD) profile of propofol derived from Fospropofol, 12 healthy subjects were administered a 10-mg/kg intravenous bolus dose of Fospropofol, and the sedative effect was measured as a decrease in Modified Observer's Assessment of Alertness/Sedation (MOAA/S) score (Table 5).2 The PK and PD results are shown in Figure 2. Peak plasma levels of propofol (2.2 ± 0.4 μg/mL) released from fospropofol were noted by 8 minutes (range 4 - 13 minutes) and minimum mean MOAA/S score of 1.2 (range 0 - 3) was noted in 7 minutes (range 1 - 15 minutes). Subjects completely recovered from sedative effects between 21 to 45 minutes after Fospropofol administration. - Fospropofol was evaluated in randomized, blinded, dose-controlled studies for sedation in patients undergoing colonoscopy and flexible bronchoscopy [see Clinical Studies (14.1)]. Figure 3 shows MOAA/S scores over time in each of the studies for those patients who received the standard and modified dosing regimens. In the study of patients undergoing colonoscopy, patients who received the standard and modified dosing regimens had a median [range] time to sedation (time from first dose of sedative to the first of 2 consecutive MOAA/S scores of ≤ 4) of 8.0 [2, 28] minutes and a median time to Fully Alert (3 consecutive responses to their name spoken in a normal tone, measured every 2 minutes beginning at or after the end of the procedure) of 5.0 [0, 47] minutes. In the study of patients undergoing flexible bronchoscopy, patients who received the standard and modified Fospropofol dosing regimens had a median time to sedation of 4 [2, 22] minutes and a median time to Fully Alert of 5.5 [0, 61] minutes. Fospropofol-04 - Within the recommended dose range, there were no differences in matched QTc interval changes between Fospropofol and placebo. The effect of Fospropofol on the QTcF interval was measured in a crossover study in which healthy subjects (n=68) received the following treatments: 6-mg/kg intravenous Fospropofol; 18-mg/kg intravenous Fospropofol; moxifloxacin 400 mg orally (positive control); and normal saline IV. After baseline and placebo adjustment, the maximum mean QTcF change was 2 ms (1-sided 95% Upper CI: 6 ms) for the 6-mg/kg dose and 8 ms (1-sided 95% Upper CI: 12 ms) for the 18-mg/kg dose. Used as a positive control, moxifloxacin had a maximum mean change in QTcF of 12 ms (1-sided 95% Lower CI: 6 ms). ## Pharmacokinetics PK parameters were evaluated in a crossover study of 68 healthy subjects, 18 to 45 years of age, who received 6- and 18-mg/kg intravenous bolus doses of Fospropofol. PK parameters are shown in Table 6. The Cmax and AUC0-∞ values of fospropofol were dose proportional. The intersubject variability in Cmax and AUC0-∞ was low. Propofol was rapidly liberated reaching plasma Cmax at a median Tmax of 12 minutes for Fospropofol 6 mg/kg and 8 minutes for Fospropofol 18 mg/kg. Concentration-time profiles showed a biexponential decline. The increase in Cmax and AUC0-∞ of propofol was dose proportional. - Fospropofol has a low volume of distribution of 0.33±0.069 L/kg, and the liberated propofol has a large volume of distribution (5.8 L/kg). - Both fospropofol and its active metabolite propofol are highly protein bound (approximately 98%), primarily to albumin. Fospropofol does not affect the binding of propofol to albumin. - Fospropofol is completely metabolized by alkaline phosphatases to propofol, formaldehyde, and phosphate. Formaldehyde and phosphate plasma concentrations are comparable to endogenous levels when fospropofol disodium is administered as recommended. Formaldehyde is further metabolized to formate by several enzyme systems, including formaldehyde dehydrogenase, present in various tissues. Propofol liberated from fospropofol is further metabolized to major metabolites propofol glucuronide (34.8%), quinol-4-sulfate (4.6%), quinol-1-glucuronide (11.1%), and quinol-4-glucuronide (5.1%). Oxidation to CO2 is the primary means of eliminating excess formate. - Fospropofol is not a substrate of CYP450 enzymes. - After a single 400 mg intravenous dose of [14C]-fospropofol disodium in humans, approximately 71% of radioactivity was recovered in the urine within 192 hours. Total body clearance (CLp) of fospropofol was 0.280±0.053 L/h/kg, and renal elimination of fospropofol was insignificant (<0.02% of dose). The terminal phase elimination half-life (t1/2) of fospropofol was 0.81±0.08 and 0.88±0.08 hours in healthy subjects and patients, respectively. In healthy subjects, the apparent total body clearance of liberated propofol (CLp/F) was 1.95±0.345 L/h/kg and t1/2 was 2.06±0.77 hours. In patients, the CLp of fospropofol was 0.31±0.14 L/h/kg and CLp/F for propofol was 2.74±0.80 L/h/kg and is similar to that observed in healthy subjects. - Population pharmacokinetic analysis indicated no influence of race, gender, age, renal impairment or alkaline phosphatase concentrations on the pharmacokinetics of fospropofol. Pharmacokinetics of propofol derived from fospropofol was not influenced by race, gender, or renal impairment. - Fospropofol has not been adequately studied in patients with hepatic impairment. Caution should be exercised when using fospropofol disodium in patients with hepatic impairment. - There was no effect of analgesic premedication [fentanyl (1 mcg/kg); meperidine (0.75 mg/kg); midazolam (0.01 mg/kg); morphine (0.1 mg/kg)] on plasma pharmacokinetics of fospropofol. - In an in vitro protein-binding study, there was no significant interaction between fospropofol and propofol at concentrations up to 200 mcg/mL and 5 mcg/mL, respectively. The interaction of fospropofol with other highly protein-bound drugs given concomitantly has not been studied. - Potential of fospropofol or its major metabolite, propofol, to inhibit or induce major cytochrome P450 enzymes is not known. ## Nonclinical Toxicology - Long-term studies in animals have not been performed to evaluate the carcinogenic potential of fospropofol disodium. - Fospropofol was not genotoxic in the Ames bacterial reverse mutation assay, with or without metabolic activation, and in the in vivo mouse micronucleus assay. Fospropofol was positive in the L5178Y TK+/- mouse lymphoma forward mutation assay in the presence of metabolic activation. In contrast, fospropofol was negative in this assay in the presence of formaldehyde-metabolizing enzymes suggesting that the positive finding is likely due to an artifact of the culture conditions. - Male rats were treated with 5, 10, or 20 mg/kg fospropofol for 4 weeks prior to mating. Male fertility was not altered in animals treated with 20 mg/kg (0.3-fold the total human dose for a procedure of 16 minutes based on a mg/m2 basis). - Female rats were treated with 5, 10, or 20 mg/kg fospropofol for two weeks prior to mating. There were no clear treatment-related effects on female fertility at a dose of 20 mg/kg (0.3-fold the total human dose for a procedure of 16 minutes based on a mg/m2 basis). # Clinical Studies - The standard and modified Fospropofol dosing regimens were evaluated in two controlled studies in patients dosed with Fospropofol who were over 18 years of age and undergoing diagnostic or therapeutic procedures. All patients received 50 mcg of fentanyl citrate intravenously before study sedative medication. The primary endpoint was the rate of "sedation success," defined as the proportion of patients who did not respond readily to their name spoken in a normal tone of voice (Modified Observer's Assessment of Alertness/Sedation Scale score of 4 or less) on 3 consecutive measurements taken every 2 minutes and who completed the procedure without the use of alternative sedative medication and without the use of manual or mechanical ventilation. 2 - In both studies, an initial bolus dose and up to 3 supplemental doses at 25 % of the initial bolus of study sedative medication were administered intravenously to sedate patients so that they did not respond readily to their name spoken in a normal tone and to allow the investigator to start the procedure. During the procedure, supplemental doses at 25% of the initial bolus were allowed to maintain sedation. Patients who were not adequately sedated with study drug received alternative sedative medication per the site's standard of care; however, sites were instructed not to use propofol as it would interfere with PK measurements. - The standard and modified Fospropofol dosing regimens were evaluated in a randomized, blinded, dose-controlled study for sedation in patients undergoing colonoscopy. All of the patients who received alternative sedative medication (n=19) received midazolam. Patients randomized to receive the Fospropofol standard or modified dosing regimen had a sedation success rate of 87% and required a mean number of supplemental doses of 2.3 (±1.4 SD). Patients randomized to receive Fospropofol had a median procedure duration of 11 minutes. - The standard and modified Fospropofol dosing regimens were also evaluated in a randomized, blinded, dose-controlled study for sedation in patients undergoing flexible bronchoscopy. All of the patients who received alternative sedative medication (n=12) received midazolam. Patients randomized to receive the Fospropofol standard or modified dosing regimen had a sedation success rate of 89% and required a mean number of supplemental doses of 1.7 (±1.6 SD). Patients randomized to Fospropofol had a median procedure duration of 10 minutes. # How Supplied - Fospropofol, 35 mg/mL (total of 1,050 mg/30 mL) fospropofol disodium, is supplied as a single-use, aqueous, sterile, nonpyrogenic, clear, colorless solution in glass vials ready for intravenous injection. Each vial is filled with 32.1 mL intended to deliver a minimum of 30 mL of fospropofol disodium solution. ## Storage - Store at controlled room temperature 25°C (77°F). Excursions permitted between 15° and 30°C (59° and 86°F). # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information - Paresthesias (including burning, tingling, stinging) and/or pruritus, usually manifested in the perineal region are frequently experienced upon injection of the initial dose of Fospropofol. Inform the patient that these sensations are typically mild to moderate in intensity, last a short time, and require no treatment. - Requirement for a patient escort should be considered. The decision as to when patients who have received Fospropofol, particularly on an outpatient basis, may again engage in activities requiring complete mental alertness, coordination and/or physical dexterity (e.g., operate hazardous machinery, sign legal documents, or drive a motor vehicle) must be individualized. # Precautions with Alcohol Alcohol-Fospropofol interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names There is limited information regarding Fospropofol Brand Names in the drug label. # Look-Alike Drug Names There is limited information regarding Fospropofol Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	https://www.wikidoc.org/index.php/Fospropofol
b207ec2d762812351eab450d699208e170a4ca17	wikidoc	Francisella	Francisella # Overview Francisella is a genus of pathogenic, Gram-negative bacteria.They are small coccobacillary or rod-shaped, non motile organisms, which are also facultative intracellular parasites of macrophages. Strict aerobes, Francisella colonies bear a morphological resemblance to those of the genus Brucella. The bacteria penetrate into the body through damaged skin and mucous membranes, or through inhalation. Humans are most often infected by tick bite or through handling an infected animal. Ingesting infected water, soil, or food can also cause infection. Tularemia can also be acquired by inhalation; hunters are at a higher risk for this disease because of the potential of inhaling the bacteria during the skinning process. Francisella tularensis is an intracellular bacterium, meaning that it is able to live as a parasite within host cells. It primarily infects macrophages, a type of white blood cell. It is thus able to evade the immune system. The course of disease involves spread of the organism to multiple organ systems, including the lungs, liver, spleen, and lymphatic system. # Causes ## Causative Agent - The type species, F. tularensis, causes the disease tularemia or rabbit fever. F. novicida and F. philomiragia (previously Yersinia philomiragia) are associated with septicemia and invasive systemic infections. - It should be noted that the taxonomy of the genus is somewhat uncertain, especially in the case of F. novicida (may be a subspecies of F. tularensis). - In general, identification of species is accomplished by biochemical profiling or 16S rRNA sequencing. - F. tularensis is found in widely diverse animal hosts and habitats and can be recovered from contaminated water, soil, and vegetation. - A variety of small mammals, including voles, mice, water rats, squirrels, rabbits, and hares are natural reservoirs of infection. - They acquire infection through tick, fly, and mosquito bites and by contact with contaminated environments. - Epizootics with sometimes extensive die-offs of animal hosts may herald outbreaks of tularemia in humans. - Humans can become incidentally infected through diverse environmental exposures: bites by infected arthropods; handling infectious animal tissues or fluids; direct contact with or ingestion of contaminated food, water, or soil; and inhalation of infective aerosols. - Humans can develop severe and sometimes fatal illness, but do not transmit the disease to others. ## Genomics - Studies conducted on a strain of the Schu S4 genome report a genome size of less than 2 Mbp. - F. tularensis is composed of a large majority of genes, unique to the species. - Lesser amount of genes responsible for the encoding of transport and binding. - There are few matches for genes responsible for gene regulation and energy metabolism between F. tularensis and other documented # Pathogenesis ## Mechanism of infection - Francisella tularensis is one of the most infectious bacteria known; fewer than ten organisms can cause disease leading to severe illness. - The bacteria penetrate into the body through damaged skin and mucous membranes, or through inhalation. - Humans are most often infected by tick bite or through handling an infected animal. Ingesting infected water, soil, or food can also cause infection. - Tularemia can also be acquired by inhalation; hunters are at a higher risk for this disease because of the potential of inhaling the bacteria during the skinning process. - Tularemia is not spread directly from person to person. - Francisella tularensis is an intracellular bacterium, meaning that it is able to live as a parasite within host cells. - It primarily infects macrophages, a type of white blood cell. It is thus able to evade the immune system. - The course of disease involves spread of the organism to multiple organ systems, including the lungs, liver, spleen, and lymphatic system. - The course of disease is similar regardless of the route of exposure. Mortality in untreated (pre-antibiotic-era) patients has been as high as 50% in the pneumonic and typhoidal forms of the disease, which however account for less than 10% of cases. - Overall mortality was 7% for untreated cases, and the disease responds well to antibiotics with a fatality rate of about 2%. - The exact cause of death is unclear, but it is thought be a combination of multiple organ system failures.	Francisella Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview Francisella is a genus of pathogenic, Gram-negative bacteria.They are small coccobacillary or rod-shaped, non motile organisms, which are also facultative intracellular parasites of macrophages.[1] Strict aerobes, Francisella colonies bear a morphological resemblance to those of the genus Brucella.[2] The bacteria penetrate into the body through damaged skin and mucous membranes, or through inhalation. Humans are most often infected by tick bite or through handling an infected animal. Ingesting infected water, soil, or food can also cause infection. Tularemia can also be acquired by inhalation; hunters are at a higher risk for this disease because of the potential of inhaling the bacteria during the skinning process. Francisella tularensis is an intracellular bacterium, meaning that it is able to live as a parasite within host cells. It primarily infects macrophages, a type of white blood cell. It is thus able to evade the immune system. The course of disease involves spread of the organism to multiple organ systems, including the lungs, liver, spleen, and lymphatic system. # Causes ## Causative Agent - The type species, F. tularensis, causes the disease tularemia or rabbit fever.[3] F. novicida and F. philomiragia (previously Yersinia philomiragia) are associated with septicemia and invasive systemic infections. - It should be noted that the taxonomy of the genus is somewhat uncertain, especially in the case of F. novicida (may be a subspecies of F. tularensis). - In general, identification of species is accomplished by biochemical profiling or 16S rRNA sequencing. - F. tularensis is found in widely diverse animal hosts and habitats and can be recovered from contaminated water, soil, and vegetation. - A variety of small mammals, including voles, mice, water rats, squirrels, rabbits, and hares are natural reservoirs of infection. [4] - They acquire infection through tick, fly, and mosquito bites and by contact with contaminated environments. [5] - Epizootics with sometimes extensive die-offs of animal hosts may herald outbreaks of tularemia in humans. - Humans can become incidentally infected through diverse environmental exposures: bites by infected arthropods; handling infectious animal tissues or fluids; direct contact with or ingestion of contaminated food, water, or soil; and inhalation of infective aerosols. - Humans can develop severe and sometimes fatal illness, but do not transmit the disease to others. [4] ## Genomics - Studies conducted on a strain of the Schu S4 genome report a genome size of less than 2 Mbp. - F. tularensis is composed of a large majority of genes, unique to the species. - Lesser amount of genes responsible for the encoding of transport and binding. - There are few matches for genes responsible for gene regulation and energy metabolism between F. tularensis and other documented # Pathogenesis ## Mechanism of infection - Francisella tularensis is one of the most infectious bacteria known; fewer than ten organisms can cause disease leading to severe illness. - The bacteria penetrate into the body through damaged skin and mucous membranes, or through inhalation. - Humans are most often infected by tick bite or through handling an infected animal. Ingesting infected water, soil, or food can also cause infection. - Tularemia can also be acquired by inhalation; hunters are at a higher risk for this disease because of the potential of inhaling the bacteria during the skinning process. - Tularemia is not spread directly from person to person. - Francisella tularensis is an intracellular bacterium, meaning that it is able to live as a parasite within host cells. - It primarily infects macrophages, a type of white blood cell. It is thus able to evade the immune system. - The course of disease involves spread of the organism to multiple organ systems, including the lungs, liver, spleen, and lymphatic system. - The course of disease is similar regardless of the route of exposure. Mortality in untreated (pre-antibiotic-era) patients has been as high as 50% in the pneumonic and typhoidal forms of the disease, which however account for less than 10% of cases.[6] - Overall mortality was 7% for untreated cases, and the disease responds well to antibiotics with a fatality rate of about 2%. - The exact cause of death is unclear, but it is thought be a combination of multiple organ system failures.	https://www.wikidoc.org/index.php/Francisella
f8c8b483100d9c72d0696e0dca8e755a2e7445a1	wikidoc	Statcoulomb	Statcoulomb The statcoulomb (statC) or franklin (Fr) or electrostatic unit of charge (esu) is the physical unit for electrical charge used in the centimetre-gram-second (cgs) electrostatic system of units. The SI system of units uses the coulomb (C) instead. The conversion is The conversion factor (≈ 3.33564Template:E) is equal to 10 divided by the numerical value of the speed of light, c, expressed in cm/s. In the electrostatic cgs system, electrical charge is a fundamental quantity defined via the electrostatic force (see below); in the SI system, electrical current is fundamental and defined via the electromagnetic force while electrical charge is a derived quantity. The electrostatic system derives the electric charge from Coulomb's law and takes the permittivity as a dimensionless quantity whose value in a vacuum is 1/(4π). Also the use of the permeability of vacuum, \mu_0 \,\!, is avoided, having the consequence that the speed of light appears explicitly in some of the equations interrelating quantities in this system. The statcoulomb is defined as follows: if two objects each carry a charge of 1 statC and are 1 cm apart, they will repel each other with a force of 1 dyne. As a result, in the electrostatic cgs system, Coulomb's law describing the force F between two charges q1 and q2 a distance r apart takes the simple form: Note that in order for the Coulomb's law formula to work using the electrostatic cgs system, the dimension of electrical charge must be 1/2 3/2 -1. This is different from the dimension of coulombs which accounts for the fact that the factor k mentioned below is not dimensionless. In SI units, the electrostatic constant k=\frac{1}{4\pi \epsilon_0} (where \epsilon_0 \ is the permittivity of vacuum) has to be used. Several other laws of electromagnetism also become easier when all quantities are expressed in electrostatic cgs units; this is the main reason that the cgs system of units is still in use in physics and electrical engineering. The main drawback of this approach is that two other sets of cgs units and equations are defined, the electromagnetic and symmetrical systems (the latter system mixes the first two). The equations in all three systems are usually written in non-rationalized form, so-called because the factors 2π or 4π appear often in unexpected places (in situations not involving circular or spherical symmetry, respectively). It is possible, albeit less often done, to write each set of equations in rationalized form. The coulomb is an extremely large charge rarely encountered in electrostatics, while the statcoulomb is closer to everyday charges. de:Franklin (Einheit) it:Statcoulomb nl:Statcoulomb	Statcoulomb The statcoulomb (statC) or franklin (Fr) or electrostatic unit of charge (esu) is the physical unit for electrical charge used in the centimetre-gram-second (cgs) electrostatic system of units. The SI system of units uses the coulomb (C) instead. The conversion is The conversion factor (≈ 3.33564Template:E) is equal to 10 divided by the numerical value of the speed of light, c, expressed in cm/s. In the electrostatic cgs system, electrical charge is a fundamental quantity defined via the electrostatic force (see below); in the SI system, electrical current is fundamental and defined via the electromagnetic force while electrical charge is a derived quantity. The electrostatic system derives the electric charge from Coulomb's law and takes the permittivity as a dimensionless quantity whose value in a vacuum is 1/(4π). Also the use of the permeability of vacuum, <math> \mu_0 \,\!</math>, is avoided, having the consequence that the speed of light appears explicitly in some of the equations interrelating quantities in this system. The statcoulomb is defined as follows: if two objects each carry a charge of 1 statC and are 1 cm apart, they will repel each other with a force of 1 dyne. As a result, in the electrostatic cgs system, Coulomb's law describing the force F between two charges q1 and q2 a distance r apart takes the simple form: Note that in order for the Coulomb's law formula to work using the electrostatic cgs system, the dimension of electrical charge must be [mass]1/2 [length]3/2 [time]-1. This is different from the dimension of coulombs which accounts for the fact that the factor k mentioned below is not dimensionless. In SI units, the electrostatic constant <math>k=\frac{1}{4\pi \epsilon_0}</math> (where <math> \epsilon_0 \ </math> is the permittivity of vacuum) has to be used. Several other laws of electromagnetism also become easier when all quantities are expressed in electrostatic cgs units; this is the main reason that the cgs system of units is still in use in physics and electrical engineering. The main drawback of this approach is that two other sets of cgs units and equations are defined, the electromagnetic and symmetrical systems (the latter system mixes the first two). The equations in all three systems are usually written in non-rationalized form, so-called because the factors 2π or 4π appear often in unexpected places (in situations not involving circular or spherical symmetry, respectively). It is possible, albeit less often done, to write each set of equations in rationalized form. The coulomb is an extremely large charge rarely encountered in electrostatics, while the statcoulomb is closer to everyday charges. de:Franklin (Einheit) it:Statcoulomb nl:Statcoulomb Template:WH Template:WS	https://www.wikidoc.org/index.php/Franklin_(unit)
4534f32537baf85d212318b57d41b6ab3a8c3a53	wikidoc	Fred Rosner	Fred Rosner Fred Rosner M.D., FACP is Assistant Dean and professor of medicine at Albert Einstein College of Medicine, Professor of Medicine at Mount Sinai School of Medicine, and Director of the Department of Medicine at Queens Hospital Centre. Dr. Rosner is the Chairman of the Medical Ethics Committee of the state of New York. Dr. Rosner has published almost 800 articles including 29 books and 39 chapters in books. These not only include all aspects of Jewish medical ethics and Jewish medical history, but also the multiple facets of haematology including leukemia and anaemia, immunology and general medicine. He has many publications including books on Maimonidies. Dr. Rosner is an internationally known authority on medical ethics, having lectured widely on Jewish Medical Ethics throughout USA and has served as visiting professor or lecturer in Israel, England, France, Germany, Mexico, Canada, Holland, South Africa, New Zealand and Australia.	Fred Rosner Fred Rosner M.D., FACP is Assistant Dean and professor of medicine at Albert Einstein College of Medicine, Professor of Medicine at Mount Sinai School of Medicine,[1] and Director of the Department of Medicine at Queens Hospital Centre. Dr. Rosner is the Chairman of the Medical Ethics Committee of the state of New York. Dr. Rosner has published almost 800 articles including 29 books and 39 chapters in books. These not only include all aspects of Jewish medical ethics and Jewish medical history, but also the multiple facets of haematology including leukemia and anaemia, immunology and general medicine. He has many publications including books on Maimonidies. Dr. Rosner is an internationally known authority on medical ethics, having lectured widely on Jewish Medical Ethics throughout USA and has served as visiting professor or lecturer in Israel, England, France, Germany, Mexico, Canada, Holland, South Africa, New Zealand and Australia.	https://www.wikidoc.org/index.php/Fred_Rosner
eeeaa9a8c363037de28c9c46672e2cd51bd92c52	wikidoc	Free energy	Free energy In thermodynamics, the term thermodynamic free energy is the amount -f mechanical (or other) work that can be extracted from a system, and is helpful in engineering applications. It is a subtraction of the entropy of a system ("useless energy") from the total energy, yielding a thermodynamic state function which represents the "useful energy". # Overview In short, free energy is that portion of any First-Law energy that is available for doing thermodynamic work; i.e., work mediated by thermal energy. Since free energy is subject to irreversible loss in the course of such work and First-Law energy is always conserved, it is evident that free energy is an expendable, Second-Law kind of energy that can make things happen within finite amounts of time. In solution chemistry and biochemistry, the Gibbs free energy change (denoted by ΔG) is commonly used merely as a surrogate for (−T times) the entropy produced by spontaneous chemical reactions in situations where there is no work done; or at least no "useful" work; i.e., other than pdV. As such, it serves as a particularization of the second law of thermodynamics, giving it the physical dimensions of energy, even though the inherent meaning in terms of entropy would be more to the point. The free energy functions are Legendre transforms of the internal energy. For processes involving a system at constant pressure p and temperature T, the Gibbs free energy is the most useful because, in addition to subsuming any entropy change due merely to heat flux, it does the same for the pdV work needed to "make space for additional molecules" produced by various processes. (Hence its utility to solution-phase chemists, including biochemists.) The Helmholtz free energy has a special theoretical importance since it is proportional to the logarithm of the partition function for the canonical ensemble in statistical mechanics. (Hence its utility to physicists; and to gas-phase chemists and engineers, who do not want to ignore pdV work.) The (historically earlier) Helmholtz free energy is defined as A = U − TS, where U is the internal energy, T is the absolute temperature, and S is the entropy. Its change is equal to the amount of reversible work done on, or obtainable from, a system at constant T. Thus its appellation "work content", and the designation A from arbeit, the German word for work. Since it makes no reference to any quantities involved in work (such as p and V), the Helmholtz function is completely general: its decrease is the maximum amount of work which can be done by a system, and it can increase at most by the amount of work done on a system. The Gibbs free energy G = H − TS, where H is the enthalpy. (H = U + pV, where p is the pressure and V is the volume.) There has been historical controversy: - In physics, “free energy” most often refers to the Helmholtz free energy, denoted by F. - In chemistry, “free energy” most often refers to the Gibbs free energy, also denoted by F. Since both fields use both functions, a compromise has been suggested, using A to denote the Helmholtz function, with G for the Gibbs function. While A is preferred by IUPAC, F is sometimes still in use, and the correct free energy function is often implicit in manuscripts and presentations. # Application The experimental usefulness of these functions is restricted to conditions where certain variables (T, and V or external p) are held constant, although they also have theoretical importance in deriving Maxwell relations. Work other than pdV may be added, e.g., for electrochemical cells, or f ˑdx work in elastic materials and in muscle contraction. Other forms of work which must sometimes be considered are stress-strain, magnetic, as in adiabatic demagnetization used in the approach to absolute zero, and work due to electric polarization. These are described by tensors. In most cases of interest there are internal degrees of freedom and processes, such as chemical reactions and phase transitions, which create entropy. Even for homogeneous "bulk" materials, the free energy functions depend on the (often suppressed) composition, as do all proper thermodynamic potentials (extensive functions), including the internal energy. Ni is the number of molecules (alternatively, moles) of type i in the system. If these quantities do not appear, it is impossible to describe compositional changes. The differentials for reversible processes are (assuming only pV work) where μi is the chemical potential for the i-th component in the system. The second relation is especially useful at constant T and p, conditions which are easy to achieve experimentally, and which approximately characterize living creatures. Any decrease in the Gibbs function of a system is the upper limit for any isothermal, isobaric work that can be captured in the surroundings, or it may simply be dissipated, appearing as T times a corresponding increase in the entropy of the system and/or its surrounding.	Free energy Template:Thermodynamic potentials In thermodynamics, the term thermodynamic free energy is the amount of mechanical (or other) work that can be extracted from a system, and is helpful in engineering applications. It is a subtraction of the entropy of a system ("useless energy") from the total energy, yielding a thermodynamic state function which represents the "useful energy". # Overview In short, free energy is that portion of any First-Law energy that is available for doing thermodynamic work; i.e., work mediated by thermal energy. Since free energy is subject to irreversible loss in the course of such work and First-Law energy is always conserved, it is evident that free energy is an expendable, Second-Law kind of energy that can make things happen within finite amounts of time. In solution chemistry and biochemistry, the Gibbs free energy change (denoted by ΔG) is commonly used merely as a surrogate for (−T times) the entropy produced by spontaneous chemical reactions in situations where there is no work done; or at least no "useful" work; i.e., other than pdV. As such, it serves as a particularization of the second law of thermodynamics, giving it the physical dimensions of energy, even though the inherent meaning in terms of entropy would be more to the point. The free energy functions are Legendre transforms of the internal energy. For processes involving a system at constant pressure p and temperature T, the Gibbs free energy is the most useful because, in addition to subsuming any entropy change due merely to heat flux, it does the same for the pdV work needed to "make space for additional molecules" produced by various processes. (Hence its utility to solution-phase chemists, including biochemists.) The Helmholtz free energy has a special theoretical importance since it is proportional to the logarithm of the partition function for the canonical ensemble in statistical mechanics. (Hence its utility to physicists; and to gas-phase chemists and engineers, who do not want to ignore pdV work.) The (historically earlier) Helmholtz free energy is defined as A = U − TS, where U is the internal energy, T is the absolute temperature, and S is the entropy. Its change is equal to the amount of reversible work done on, or obtainable from, a system at constant T. Thus its appellation "work content", and the designation A from arbeit, the German word for work. Since it makes no reference to any quantities involved in work (such as p and V), the Helmholtz function is completely general: its decrease is the maximum amount of work which can be done by a system, and it can increase at most by the amount of work done on a system. The Gibbs free energy G = H − TS, where H is the enthalpy. (H = U + pV, where p is the pressure and V is the volume.) There has been historical controversy: - In physics, “free energy” most often refers to the Helmholtz free energy, denoted by F. - In chemistry, “free energy” most often refers to the Gibbs free energy, also denoted by F. Since both fields use both functions, a compromise has been suggested, using A to denote the Helmholtz function, with G for the Gibbs function. While A is preferred by IUPAC, F is sometimes still in use, and the correct free energy function is often implicit in manuscripts and presentations. # Application The experimental usefulness of these functions is restricted to conditions where certain variables (T, and V or external p) are held constant, although they also have theoretical importance in deriving Maxwell relations. Work other than pdV may be added, e.g., for electrochemical cells, or f ˑdx work in elastic materials and in muscle contraction. Other forms of work which must sometimes be considered are stress-strain, magnetic, as in adiabatic demagnetization used in the approach to absolute zero, and work due to electric polarization. These are described by tensors. In most cases of interest there are internal degrees of freedom and processes, such as chemical reactions and phase transitions, which create entropy. Even for homogeneous "bulk" materials, the free energy functions depend on the (often suppressed) composition, as do all proper thermodynamic potentials (extensive functions), including the internal energy. Ni is the number of molecules (alternatively, moles) of type i in the system. If these quantities do not appear, it is impossible to describe compositional changes. The differentials for reversible processes are (assuming only pV work) where μi is the chemical potential for the i-th component in the system. The second relation is especially useful at constant T and p, conditions which are easy to achieve experimentally, and which approximately characterize living creatures. Any decrease in the Gibbs function of a system is the upper limit for any isothermal, isobaric work that can be captured in the surroundings, or it may simply be dissipated, appearing as T times a corresponding increase in the entropy of the system and/or its surrounding.	https://www.wikidoc.org/index.php/Free_energy
bfeda3a54a09b3b5a52cdbd2d4ff66917c8941f7	wikidoc	Frigophobia	Frigophobia # Overview Frigophobia is a phobia pertaining to the fear of becoming too cold. Sufferers of this problem bundle up in heavy clothes and blankets, regardless of the ambient air temperature. This disorder has been linked to other psychological disorders such as hypochondriasis and obsessive-compulsive disorder. In a 1975 study among ethnic Chinese in Taiwan, it was noted that frigophobia may be culturally linked to Genital retraction syndrome\|koro. Where that disorder causes male sufferers to feel that their penis is retracting into the body due to an insufficiency of "male element" (or yang), male frigophobia sufferers correlate coldness with an over-abundance of "female element" (or yin). # Definition Frigophobia is defined as a persistent, abnormal, and unwarranted fear of coldness despite conscious understanding by the phobic individual and reassurance by others that there is no danger. It is also known as cheimaphobia or cheimatophobia. # Cause Those who suffer from frigophobia are not born with it. Rather, the fear was developed somehow from past unpleasant experiences back in childhood, at school, at work, or even from a social event. Some people might not even remember how it started. Frigophobia are usually (but not always) caused by an intense negative experience from the past. Human mind can create fear without basis. Those with are at risk of developing frigophobia are characterized by one or more of the following: - Has a general tendency towards fear and anxiety - Characterized as “high strung” - Suffering from adrenal insufficiency # Symptoms Frigophobia symptoms can be mental, emotional or physical. The symptoms include, but are not limited to, the following: - Mental symptoms Obsessive thoughts Difficulty thinking about anything other than the fear Repetitive mental images of coldness Feelings of unreality or of being detached from oneself Fear of losing mental control Fear of fainting - Obsessive thoughts - Difficulty thinking about anything other than the fear - Repetitive mental images of coldness - Feelings of unreality or of being detached from oneself - Fear of losing mental control - Fear of fainting - Emotional symptoms Anticipatory anxiety: Persistent worrying about upcoming events that involve coldness Terror: A persistent and overwhelming fear of coldness Desire to flee: An intense instinct to leave the situation - Anticipatory anxiety: Persistent worrying about upcoming events that involve coldness - Terror: A persistent and overwhelming fear of coldness - Desire to flee: An intense instinct to leave the situation - Physical symptoms: Dizziness Shortness of breath or smothering sensation Palpitations, pounding heart, or accelerated heart rate Chest pain or discomfort Trembling or shaking Feeling of choking Sweating Nausea or stomach distress Feeling unsteady, dizzy, lightheaded, or faint Numbness or tingling sensations Hot or cold flashes - Dizziness - Shortness of breath or smothering sensation - Palpitations, pounding heart, or accelerated heart rate - Chest pain or discomfort - Trembling or shaking - Feeling of choking - Sweating - Nausea or stomach distress - Feeling unsteady, dizzy, lightheaded, or faint - Numbness or tingling sensations - Hot or cold flashes Because the list of symptoms varies between each person, it is advised that individuals should consult a doctor who can provide adequate diagnosis of any signs or symptoms and whether they are indeed Frigophobia symptoms. # Treatment It comes down to redirecting the unconscious mind. The patient must understand that there is nothing wrong with them, and take control of positive and negative emotional associations. The patient should seek professional medical advice about any treatment or change in treatment plans. Treatments for frigophobia include: - Behavior therapy - Anti-anxiety medication - Psychotherapy - Cognitive-behavioral therapy (CBT) - Exposure therapy: Involving patients to face the fear more and more, that they should be more familiar to coldness- this process technically known as “desensitization”. This process is often unnecessarily unpleasant and are only sometimes successful. This therapy reinforces the negative association, thus sometimes making the problem worse. - Relaxation techniques - controlled breathing, visualisation - Medication: Medications to treat anxiety may be utilised for treatment of symptoms, but there are no studies that support the efficacy of medication in the treatment of specific phobias. Furthermore, no drug was ever developed specifically to treat frigophobia, and no drug on market can cure the root cause of the problem. It might help in short term due to suppressing the symptoms. # Society and culture ## China In China, frigophobia is known as Wei Han Zheng (畏寒症). From the standpoint of traditional Chinese beliefs, the disorder is highly influenced by an imbalance of yin (the female element) and yang (the male element). Chinese traditional beliefs also states that working women are particularly susceptible to frigophobia, triggered by a combination of stress, menopause, pregnancy and other disorders such as anemia. During winter, these women are likely to experience coldness in extremities and back pains caused by the disorder. It is believed that the disorder can be treated using a combination of diet in order to re-balance the yin and yang. A common dietary treatment include: - Chicken soup - Turnip juice mixed with ginger juice and honey, three times a day - Red tea with ginger juice and sugar, two times a day - Foods containing yeast (e.g. bread) - Spices (ginger, chili pepper) - Vinegar diluted in water It is also believed that the dietary treatment will be more effective if taken in conjunction with an acupuncture routine. ## Singapore Singaporeans has similar cultural beliefs on frigophobia as the Chinese. The case study of a 45-year-old housewife with frigophobia was studied and the results concluded: frigophobia is closely related to, and strongly influenced by cultural beliefs. Generally speaking, in therapy, treatments would consist of using low dose of anxiolytics and antidepressants, and psychological interventions. But usually when Asian women are notified of the illness, they would adopt various measures to recover. These include withdrawal from workforce, avoid exposure to cold air and wind, and most importantly they will take dietary precautions. It would be rather important to consider the patient’s cultural beliefs about the “illness” in comparison to the therapist’s belief of the illness, and then find a negotiable approach for the treatment.	Frigophobia Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview Frigophobia is a phobia pertaining to the fear of becoming too cold. Sufferers of this problem bundle up in heavy clothes and blankets, regardless of the ambient air temperature. This disorder has been linked to other psychological disorders such as hypochondriasis and obsessive-compulsive disorder. In a 1975 study among ethnic Chinese in Taiwan, it was noted that frigophobia may be culturally linked to Genital retraction syndrome\|koro. Where that disorder causes male sufferers to feel that their penis is retracting into the body due to an insufficiency of "male element" (or yang), male frigophobia sufferers correlate coldness with an over-abundance of "female element" (or yin).[1] # Definition Frigophobia is defined as a persistent, abnormal, and unwarranted fear of coldness despite conscious understanding by the phobic individual and reassurance by others that there is no danger. It is also known as cheimaphobia or cheimatophobia.[citation needed] # Cause Those who suffer from frigophobia are not born with it. Rather, the fear was developed somehow from past unpleasant experiences back in childhood, at school, at work, or even from a social event. Some people might not even remember how it started. Frigophobia are usually (but not always) caused by an intense negative experience from the past.[citation needed] Human mind can create fear without basis. Those with are at risk of developing frigophobia are characterized by one or more of the following: - Has a general tendency towards fear and anxiety - Characterized as “high strung” - Suffering from adrenal insufficiency # Symptoms Frigophobia symptoms can be mental, emotional or physical. The symptoms include, but are not limited to, the following:[citation needed] - Mental symptoms Obsessive thoughts Difficulty thinking about anything other than the fear Repetitive mental images of coldness Feelings of unreality or of being detached from oneself Fear of losing mental control Fear of fainting - Obsessive thoughts - Difficulty thinking about anything other than the fear - Repetitive mental images of coldness - Feelings of unreality or of being detached from oneself - Fear of losing mental control - Fear of fainting - Emotional symptoms Anticipatory anxiety: Persistent worrying about upcoming events that involve coldness Terror: A persistent and overwhelming fear of coldness Desire to flee: An intense instinct to leave the situation - Anticipatory anxiety: Persistent worrying about upcoming events that involve coldness - Terror: A persistent and overwhelming fear of coldness - Desire to flee: An intense instinct to leave the situation - Physical symptoms: Dizziness Shortness of breath or smothering sensation Palpitations, pounding heart, or accelerated heart rate Chest pain or discomfort Trembling or shaking Feeling of choking Sweating Nausea or stomach distress Feeling unsteady, dizzy, lightheaded, or faint Numbness or tingling sensations Hot or cold flashes - Dizziness - Shortness of breath or smothering sensation - Palpitations, pounding heart, or accelerated heart rate - Chest pain or discomfort - Trembling or shaking - Feeling of choking - Sweating - Nausea or stomach distress - Feeling unsteady, dizzy, lightheaded, or faint - Numbness or tingling sensations - Hot or cold flashes Because the list of symptoms varies between each person, it is advised that individuals should consult a doctor who can provide adequate diagnosis of any signs or symptoms and whether they are indeed Frigophobia symptoms. # Treatment It comes down to redirecting the unconscious mind. The patient must understand that there is nothing wrong with them, and take control of positive and negative emotional associations. The patient should seek professional medical advice about any treatment or change in treatment plans.[citation needed] Treatments for frigophobia include: - Behavior therapy - Anti-anxiety medication - Psychotherapy - Cognitive-behavioral therapy (CBT) - Exposure therapy: Involving patients to face the fear more and more, that they should be more familiar to coldness- this process technically known as “desensitization”. This process is often unnecessarily unpleasant and are only sometimes successful. This therapy reinforces the negative association, thus sometimes making the problem worse. - Relaxation techniques - controlled breathing, visualisation - Medication: Medications to treat anxiety may be utilised for treatment of symptoms, but there are no studies that support the efficacy of medication in the treatment of specific phobias. Furthermore, no drug was ever developed specifically to treat frigophobia, and no drug on market can cure the root cause of the problem. It might help in short term due to suppressing the symptoms. # Society and culture ## China In China, frigophobia is known as Wei Han Zheng (畏寒症). From the standpoint of traditional Chinese beliefs, the disorder is highly influenced by an imbalance of yin (the female element) and yang (the male element). Chinese traditional beliefs also states that working women are particularly susceptible to frigophobia, triggered by a combination of stress, menopause, pregnancy and other disorders such as anemia. During winter, these women are likely to experience coldness in extremities and back pains caused by the disorder. It is believed that the disorder can be treated using a combination of diet in order to re-balance the yin and yang. A common dietary treatment include: - Chicken soup - Turnip juice mixed with ginger juice and honey, three times a day - Red tea with ginger juice and sugar, two times a day - Foods containing yeast (e.g. bread) - Spices (ginger, chili pepper) - Vinegar diluted in water It is also believed that the dietary treatment will be more effective if taken in conjunction with an acupuncture routine. ## Singapore Singaporeans has similar cultural beliefs on frigophobia as the Chinese. The case study of a 45-year-old housewife with frigophobia was studied and the results concluded: frigophobia is closely related to, and strongly influenced by cultural beliefs.[2] Generally speaking, in therapy, treatments would consist of using low dose of anxiolytics and antidepressants, and psychological interventions. But usually when Asian women are notified of the illness, they would adopt various measures to recover. These include withdrawal from workforce, avoid exposure to cold air and wind, and most importantly they will take dietary precautions. It would be rather important to consider the patient’s cultural beliefs about the “illness” in comparison to the therapist’s belief of the illness, and then find a negotiable approach for the treatment.	https://www.wikidoc.org/index.php/Frigophobia
c8b8263ed9c3eafeee6aa62bf372469703511ae6	wikidoc	Frustration	Frustration Frustration is an emotion that occurs in situations where one is blocked from reaching a personal goal. The more important the goal, the greater the frustration. It is comparable to anger. Sources of frustration may be internal or external. Internal sources of frustration involve personal deficiencies such as a lack of confidence or fear of social situations that prevent one from reaching a goal. Conflict can also be an internal source of frustration when one has competing goals that interfere with one another. External causes of frustration involve conditions outside the person such as a blocked road, lack of money, or lack of sexual activity. In terms of psychology, passive-aggressive behavior is a method of dealing with frustration. # The reasons of frustration ## Poor management in organisations Frustration can be a result of blocking motivated behavior. An individual may react in several different ways. He may respond with rational problem-solving methods to overcome the barrier. Failing in this, he may become frustrated and behave irrationally. An example of blockage of motivational energy would be the case of the worker who wants time off to go fishing but is denied permission by his supervisor. Another example would be the executive who wants a promotion but finds he lacks certain qualifications. If, in these cases, an appeal to reason does not succeed in reducing the barrier or in developing some reasonable alternative approach, the frustrated individual may resort to less adaptive methods of trying to reach his goal. He may, for example, attack the barrier physically or verbally or both. The worker who is refused time off to go fishing may "cuss out" his supervisor to his face or behind his back. If he is sufficiently aroused, he may strike out at him with his fists or with the nearest weapon. If the supervisor is not present or the worker's fear of the consequences of direct attack is stronger than his desire to attack, he may transfer his aggression to someone or something else. Taking his frustration out on his family or on some object like his car or his equipment are typical ways of transferring aggression. Another "solution" to frustration is regressive behavior — becoming childish or reverting to earlier and more primitive ways of coping with the goal barrier. Throwing a temper tantrum, bursting into tears, or sulking are examples of regression. Wearing a long face and a worried look are other signs of this method of dealing with frustration. Stubborn refusal to respond to new conditions affecting the goal, such as removal or modification of the barrier, sometimes occurs. As pointed out by Brown, severe punishment may cause individuals to continue nonadaptive behavior blindly: “Either it may have an effect opposite to that of reward and as such, discourage the repetition of the act, or, by functioning as a frustrating agent, it may lead to fixation and the other symptoms of frustration as well. It follows that punishment is a dangerous tool, since it often has effects which are entirely the opposite of those desired” An example of nonadaptive behavior of this sort might occur in the case of the executive who feels persecuted by his failure to be promoted. Even when offered a training course to improve his chances of promotion, he turns down this opportunity and continues to sulk. Flight, or leaving the scene, is another way people have of dealing with their frustrations. In the above example of the executive, we might find him quitting his job rather than face up to the consequences of being passed over for promotion. Or, a player quits the football squad because he is not given enough playing time or fails to win the starting berth as quarterback. Managers must learn to recognize the symptoms of frustration to avoid responding in ways that intensify rather than ameliorate the problem. The main point to remember is that the affected person is often not in a rational, problem-solving frame of mind and is, therefore, not attuned to the "facts" or to logical procedures for dealing with his situation. Some frustrated people need to be guided back to "reality". They cannot be reasoned with in their present mental state. Listening with understanding to such a person is one effective way to reduce frustration. Talking to a sympathetic listener provides a way for him to vent his feelings and regain control of himself. Motives provide energy and direction for behavior. Appropriate behavior, in turn, reduces the inner tensions that signal the motivated state. An understanding of the relationships among motives, behavior, and human goals provides the manager, administrator, or leader with a way of thinking about human activity and a framework within which to gather, sort, and analyze data related to behavioral problems. An increasingly common source of frustration is due strongly to the presence of computer technology. Because modern computing is marketed as user-friendly, it can be extremely frustating when one cannot achieve a goal due in part to a technological error, and because the user-friendly aspect is removed, many people find themselves unable to come to terms with their lack of options.	Frustration Template:Emotion Frustration is an emotion that occurs in situations where one is blocked from reaching a personal goal. The more important the goal, the greater the frustration. It is comparable to anger. Sources of frustration may be internal or external. Internal sources of frustration involve personal deficiencies such as a lack of confidence or fear of social situations that prevent one from reaching a goal. Conflict can also be an internal source of frustration when one has competing goals that interfere with one another. External causes of frustration involve conditions outside the person such as a blocked road, lack of money, or lack of sexual activity. In terms of psychology, passive-aggressive behavior is a method of dealing with frustration. # The reasons of frustration ## Poor management in organisations Frustration can be a result of blocking motivated behavior. An individual may react in several different ways. He may respond with rational problem-solving methods to overcome the barrier. Failing in this, he may become frustrated and behave irrationally. An example of blockage of motivational energy would be the case of the worker who wants time off to go fishing but is denied permission by his supervisor. Another example would be the executive who wants a promotion but finds he lacks certain qualifications. If, in these cases, an appeal to reason does not succeed in reducing the barrier or in developing some reasonable alternative approach, the frustrated individual may resort to less adaptive methods of trying to reach his goal. He may, for example, attack the barrier physically or verbally or both. The worker who is refused time off to go fishing may "cuss out" his supervisor to his face or behind his back. If he is sufficiently aroused, he may strike out at him with his fists or with the nearest weapon. If the supervisor is not present or the worker's fear of the consequences of direct attack is stronger than his desire to attack, he may transfer his aggression to someone or something else. Taking his frustration out on his family or on some object like his car or his equipment are typical ways of transferring aggression. Another "solution" to frustration is regressive behavior — becoming childish or reverting to earlier and more primitive ways of coping with the goal barrier. Throwing a temper tantrum, bursting into tears, or sulking are examples of regression. Wearing a long face and a worried look are other signs of this method of dealing with frustration. Stubborn refusal to respond to new conditions affecting the goal, such as removal or modification of the barrier, sometimes occurs. As pointed out by Brown, severe punishment may cause individuals to continue nonadaptive behavior blindly: “Either it may have an effect opposite to that of reward and as such, discourage the repetition of the act, or, by functioning as a frustrating agent, it may lead to fixation and the other symptoms of frustration as well. It follows that punishment is a dangerous tool, since it often has effects which are entirely the opposite of those desired” [1]. An example of nonadaptive behavior of this sort might occur in the case of the executive who feels persecuted by his failure to be promoted. Even when offered a training course to improve his chances of promotion, he turns down this opportunity and continues to sulk. Flight, or leaving the scene, is another way people have of dealing with their frustrations. In the above example of the executive, we might find him quitting his job rather than face up to the consequences of being passed over for promotion. Or, a player quits the football squad because he is not given enough playing time or fails to win the starting berth as quarterback. Managers must learn to recognize the symptoms of frustration to avoid responding in ways that intensify rather than ameliorate the problem. The main point to remember is that the affected person is often not in a rational, problem-solving frame of mind and is, therefore, not attuned to the "facts" or to logical procedures for dealing with his situation. Some frustrated people need to be guided back to "reality". They cannot be reasoned with in their present mental state. Listening with understanding to such a person is one effective way to reduce frustration. Talking to a sympathetic listener provides a way for him to vent his feelings and regain control of himself[1]. Motives provide energy and direction for behavior. Appropriate behavior, in turn, reduces the inner tensions that signal the motivated state. An understanding of the relationships among motives, behavior, and human goals provides the manager, administrator, or leader with a way of thinking about human activity and a framework within which to gather, sort, and analyze data related to behavioral problems. An increasingly common source of frustration is due strongly to the presence of computer technology. Because modern computing is marketed as user-friendly, it can be extremely frustating when one cannot achieve a goal due in part to a technological error, and because the user-friendly aspect is removed, many people find themselves unable to come to terms with their lack of options.	https://www.wikidoc.org/index.php/Frustration
73cae2f4fac551bf6c777d98a31b7764dbe88181	wikidoc	Fucosidosis	Fucosidosis # Overview Fucosidosis is a rare lysosomal storage disorder in which the FUCA1 gene experiences mutations that severely reduce or stop the activity of the alpha-L-fucosidase enzyme. The result is a buildup of complex sugars in parts of the body, which leads to death. Fucosidosis is one of nine identified glycoprotein storage diseases. The gene encoding the alpha-fucosidase, FUCA 1, was found to be located to the short arm of chromosome 1p36 - p34, by Carrit and co-workers, in 1982. # Disease Fucosidosis is an autosomal recessive disorder that affects many areas of the body. Mutations in the FUCA1 gene causes fucosidosis. The FUCA1 gene provides instructions for making an enzyme called alpha-L-fucosidase. The enzyme plays a role in the breakdown of complex sugars in the body. The disorder is characterized by lysosomal accumulation of a variety of glycoproteins, glycolipids, and oligosaccharides that contain fucose moieties. The deficiency of the enzyme alpha-L-fucosidase, which is used to metabolize complex compounds in the body (fucose-containing glycolipids and fucose-containing glycoproteins). With the lack of this enzyme activity, the result is incomplete breakdown of glycolipids and glycoproteins. These partially broken down compounds accumulate in various parts of the body and begin to cause malfunction in cells, and can eventually cause cell death. Brain cells are especially sensitive to this buildup. Other results are progressive neurological deterioration, skin abnormalities, growth retardation, skeletal disease, and coarsening of facial features. Fucosidosis is the consequence of faulty degradation of both sphingolipids and polysaccharides. Major accumulation of the H-antigen (a member of the ABO blood group antigens), a glycolipid, is seen primarily in the liver of fucosidosis patients. # History Fucosidosis is an extremely rare disorder first described in 1962 in two Italian siblings who showed progressive mental retardation and neurological deterioration. The disease itself is extremely rare (less than 100 documented cases) only affecting 1:2,000,000, with most cases being occurring in Italy, Cuba, and the southwest U.S. The disease has three different types. Type 1 and 2 are considered severe, and Type 3 being a mild disease. Symptoms are highly variable with mild cases being able to live to within the third or fourth decade. Type 1 and 2 are both linked with mental retardation. Severe cases can develop life-threatening complications early in childhood. Because the major accumulating glycoconjugate in fucosidosis patients is the blood group H-antigen, it is intriguing to speculate, but the evidence is not clear at this time, that blood type may affect the course of the disease. # Type 1 Type 1 usually begins somewhere in the first three to 18 months of age and in considered the most severe of the three types. Symptoms include: - Coarse facial features - Enlarged liver, spleen, and/or heart - Mental retardation - Seizures - Abnormal bone formation of many bones - Progressive deterioration of brain and spinal cord - Increased or decreased perspiration Patients have no vascular lesions, but have rapid psychomotor regression, severe and rapidly progressing neurologic signs, elevated sodium and chloride excretion in the sweat, and fatal outcome before the sixth year. # Type 2 Type 2 appears when a child is around 18 months of age and in considered milder than Type 1 but still severe. Symptoms include: - Symptoms similar to Type 1 but milder and progress more slowly. # Type 3 Type 3 appears around 1–2 years of age and is considered mild. # Treatment Treatment: There is no treatment or way to reverse the disease. Treatment will focus on the symptoms an individual has, such as seizure medication. - It is possible that if an individual receives a bone marrow transplant, they could receive healthy bone marrow cells which would produce normal amounts of fucosidase. But there not is enough research to prove this is an effective treatment. # Diagnosis Diagnosis: A special urine test is available to check for any partially broken-down-sugars. If they are present, a skin or blood sample will be taken to test for below-normal amounts of alpha-fucosidase. - Fucosidosis is an autosomal recessive disorder, which means that both parents have to have the mutation and pass it on to the child. When both parents have the mutation, there is a 25% chance of each child having fucosidosis. # Other forms Canine fucosidosis is found in the English Springer Spaniel. Typically affecting dogs between 18 months and four years, symptoms include: - Loss of learned behavior - Change in temperament - Blindness - Loss of balance - Deafness - Weight loss - From the onset, disease progress is quick and fatal. Just like the human version, canine fucosidosis is a recessive disorder and two copies of the gene must be present, one from each parent, in order to show symptoms of the disease.	Fucosidosis Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview Fucosidosis is a rare lysosomal storage disorder[1] in which the FUCA1 gene experiences mutations that severely reduce or stop the activity of the alpha-L-fucosidase enzyme.[2] The result is a buildup of complex sugars in parts of the body, which leads to death. Fucosidosis is one of nine identified glycoprotein storage diseases. The gene encoding the alpha-fucosidase, FUCA 1, was found to be located to the short arm of chromosome 1p36 - p34,[3] by Carrit and co-workers, in 1982.[4] # Disease Fucosidosis is an autosomal recessive disorder that affects many areas of the body. Mutations in the FUCA1 gene causes fucosidosis. The FUCA1 gene provides instructions for making an enzyme called alpha-L-fucosidase. The enzyme plays a role in the breakdown of complex sugars in the body.[2] The disorder is characterized by lysosomal accumulation of a variety of glycoproteins, glycolipids, and oligosaccharides that contain fucose moieties.[3] The deficiency of the enzyme alpha-L-fucosidase, which is used to metabolize complex compounds in the body (fucose-containing glycolipids and fucose-containing glycoproteins). With the lack of this enzyme activity, the result is incomplete breakdown of glycolipids and glycoproteins. These partially broken down compounds accumulate in various parts of the body and begin to cause malfunction in cells,[2] and can eventually cause cell death. Brain cells are especially sensitive to this buildup. Other results are progressive neurological deterioration, skin abnormalities, growth retardation, skeletal disease, and coarsening of facial features.[5] Fucosidosis is the consequence of faulty degradation of both sphingolipids and polysaccharides. Major accumulation of the H-antigen (a member of the ABO blood group antigens), a glycolipid, is seen primarily in the liver of fucosidosis patients.[3] # History Fucosidosis is an extremely rare disorder first described in 1962 in two Italian siblings who showed progressive mental retardation and neurological deterioration. The disease itself is extremely rare (less than 100 documented cases[3]) only affecting 1:2,000,000,[4] with most cases being occurring in Italy, Cuba, and the southwest U.S. The disease has three different types. Type 1 and 2 are considered severe, and Type 3 being a mild disease.[6] Symptoms are highly variable with mild cases being able to live to within the third or fourth decade. Type 1 and 2 are both linked with mental retardation. Severe cases can develop life-threatening complications early in childhood.[5] Because the major accumulating glycoconjugate in fucosidosis patients is the blood group H-antigen, it is intriguing to speculate, but the evidence is not clear at this time, that blood type may affect the course of the disease.[3] # Type 1 Type 1 usually begins somewhere in the first three to 18 months of age and in considered the most severe of the three types.[6] Symptoms include: - Coarse facial features - Enlarged liver, spleen, and/or heart - Mental retardation - Seizures - Abnormal bone formation of many bones - Progressive deterioration of brain and spinal cord - Increased or decreased perspiration Patients have no vascular lesions, but have rapid psychomotor regression, severe and rapidly progressing neurologic signs, elevated sodium and chloride excretion in the sweat, and fatal outcome before the sixth year. # Type 2 Type 2 appears when a child is around 18 months of age and in considered milder than Type 1 but still severe.[6] Symptoms include: - Symptoms similar to Type 1 but milder and progress more slowly. - # Type 3 Type 3 appears around 1–2 years of age and is considered mild.[6] # Treatment Treatment: There is no treatment or way to reverse the disease. Treatment will focus on the symptoms an individual has, such as seizure medication. - It is possible that if an individual receives a bone marrow transplant, they could receive healthy bone marrow cells which would produce normal amounts of fucosidase. But there not is enough research to prove this is an effective treatment.[6] # Diagnosis Diagnosis: A special urine test is available to check for any partially broken-down-sugars. If they are present, a skin or blood sample will be taken to test for below-normal amounts of alpha-fucosidase.[6] - Fucosidosis is an autosomal recessive disorder, which means that both parents have to have the mutation and pass it on to the child. When both parents have the mutation, there is a 25% chance of each child having fucosidosis. # Other forms Canine fucosidosis is found in the English Springer Spaniel.[1] Typically affecting dogs between 18 months and four years, symptoms include: - Loss of learned behavior - Change in temperament - Blindness - Loss of balance - Deafness - Weight loss - From the onset, disease progress is quick and fatal. Just like the human version, canine fucosidosis is a recessive disorder and two copies of the gene must be present, one from each parent, in order to show symptoms of the disease.	https://www.wikidoc.org/index.php/Fucosidosis
19600883e857bd09620f1ab2488facd236076ce1	wikidoc	Fungus gnat	Fungus gnat Fungus gnats are small, dark, short-lived flies, of the families Sciaridae and Mycetophilidae (order Diptera), whose larvae feed on plant roots or fungi and aid in the decomposition of organic matter. The adults are 2-5 mm long, and are important pollinators, and can also help spread mushroom spores. They can be controlled by Hypoaspis miles or biological larvicide that kills the gnats in their larval stage. Detergents and the nicotine from tobacco brewed into a toxic tea are used by some people to control fungus gnats. In houseplants the presence of fungus gnats may indicate overwatering. They may be feeding on roots that have sat in drain water too long and are rotting or may be attracted to fungus growing in saturated top soil. Typically draining the excess water from the plants drain pan and allowing the soil to dry will eliminate them. Fungus gnats are typically harmless to healthy plants, while their presence can be indicative of more serious problems.	Fungus gnat Fungus gnats are small, dark, short-lived flies, of the families Sciaridae and Mycetophilidae (order Diptera), whose larvae feed on plant roots or fungi and aid in the decomposition of organic matter. The adults are 2-5 mm long, and are important pollinators, and can also help spread mushroom spores. They can be controlled by Hypoaspis miles or biological larvicide that kills the gnats in their larval stage. Detergents and the nicotine from tobacco brewed into a toxic tea are used by some people to control fungus gnats. In houseplants the presence of fungus gnats may indicate overwatering. They may be feeding on roots that have sat in drain water too long and are rotting or may be attracted to fungus growing in saturated top soil. Typically draining the excess water from the plants drain pan and allowing the soil to dry will eliminate them. Fungus gnats are typically harmless to healthy plants, while their presence can be indicative of more serious problems. # External links - Fungus gnats on CultureSheet.org - Picture and prevention methods Template:Fly-stub de:Trauermücken it:Moscerini dei funghi fi:Harsosääsket Template:WH Template:WikiDoc Sources	https://www.wikidoc.org/index.php/Fungus_gnat
4995d6442ef4181236e308f959abc273259c187d	wikidoc	Spider bite	Spider bite # Overview A spider bite, also known as arachnidism, is an injury resulting from the bite of a spider. The effects of most bites are not serious. Most bites result in mild symptoms around the area of the bite. Rarely they may produce a necrotic skin wound or severe pain.:455 Most spiders do not cause bites that are of importance. For a bite to be significant, substantial envenomation is required. Bites from the widow spiders involve a neurotoxic venom which produces a condition known as latrodectism. Symptoms may include: pain which may be at the bite or involve the chest and abdomen, sweating, muscle cramps and vomiting among others. Bites from the recluse spiders cause the condition loxoscelism, in which local necrosis of the surrounding skin and widespread breakdown of red blood cells may occur. Headaches, vomiting and a mild fever may also occur. Other spiders that can cause significant bites include: the Australian funnel web spiders, the South American wandering spider, and the hobo spider. Efforts to prevent bites include clearing clutter and the use of pesticides. Most spider bites are managed with supportive care such as NSAIDs (including ibuprofen) for pain and antihistamines for itchiness. Opioids may be used if the pain is severe. While an antivenom exists for black widow spider venom it is associated with anaphylaxis and therefore not commonly used in the United States. Antivenom against funnel web spider venom improves outcomes. Surgery may be required to repair the area of injured skin from some recluse bites. Spider bites may be overdiagnosed or misdiagnosed. Historically a number of conditions were attributed to spider bites. In the Middle Ages a condition claimed to arise from spider bites was tarantism, where people danced wildly. While necrosis has been attributed to the bites of a number of spiders, good evidence only supports this for recluse spiders. # Signs and symptoms Almost all spiders are venomous, but not all spider bites result in the injection of venom. Pain from non-venomous, so-called "dry bites" typically lasts for 5 to 60 minutes while pain from envenomating spider bites may last for longer than 24 hours. Bleeding also may occur with a bite. Signs of a bacterial infection due to a spider bite occur infrequently (0.9%). A study of 750 definite spider bites in Australia indicated that 6% of spider bites cause significant effects, the vast majority of these being redback spider bites causing significant pain lasting more than 24 hours. Activation of the sympathetic nervous system can lead to sweating, high blood pressure and gooseflesh. Most recluse spider bites are minor with little or no necrosis. However, a small number of bites produce necrotic skin lesions. First pain and tenderness at the site begin. The redness changes over 2 to 3 days to a bluish sinking patch of dead skin—the hallmark of necrosis. The wound heals slowly over months but usually completely. and, rarely, widespread symptoms, including profound anemia. Rarely the bite may also produce the systemic condition with occasional fatalities # Cause Spiders do not feed on humans and typically bites occur as a defense mechanism. This can occur with from unintentional contact or trapping of the spider. Most spiders have fangs too small to penetrate human skin. Most bites by species large enough for their bites to be noticeable will have no serious medical consequences. Medically significant spider venoms include various combinations and concentrations of necrotic agents, neurotoxins, and pharmacologically active compounds such as serotonin. Worldwide only two spider venoms have impact on humans—those of the widow and recluse spiders. Unlike snake and scorpion envenomation, widow and recluse species bites rarely have fatal consequences. However, isolated spider families have a lethal neurotoxic venom: the wandering spider in Brazil and the funnel web in Australia. However, due to limited contact of humans with these spiders, deaths have always been rare, and since the introduction of anti-venom in Australia, there have been no funnel web related deaths. # Pathophysiology A primary concern of the bite of a spider is the effect of its venom. A spider envenomation occurs whenever a spider injects venom into the skin. Not all spider bites involve injection of venom, and the amount of venom injected can vary based on the type of spider and the circumstances of the encounter. The mechanical injury from a spider bite is not a serious concern for humans. However, it is generally the toxicity of spider venom that poses the most risk to human beings; several spiders are known to have venom that can cause injury to humans in the amounts that a spider could inject when biting. While venoms are by definition toxic substances, most spiders do not have venom that is directly toxic (in the quantities delivered) to require medical attention and, of those that do, severity is typically mild. Spider venoms work on one of two fundamental principles; they are either neurotoxic (attacking the nervous system) or necrotic (attacking tissues surrounding the bite). In some cases, the venom affects vital organs and systems. The venoms of the widow spiders, Brazilian wandering spider and Australian funnel-web are neurotoxic. Heart muscle damage is an unusual complications of widow venom that may lead to death. Pulmonary edema, fluid acumulation in the lungs, is a feared uncommon complication of funnel-web venom. Recluse and South African sand spider venoms are necrotic. Recluse venom may also cause severe hemolysis (destruction of red blood cells) # Diagnosis Assumption that a reported injury was caused by a spider is the most common source of false reports, which in some cases have led to misdiagnosis and mistreatment, with potentially life-threatening consequences. Many spider bites are relatively painless but the spider is often trapped and easily found. With neurotoxic envenomation, serious symptoms arise within a few hours. An affected person may think that a wound is a spider bite when it is actually an infection with methicillin-resistant Staphylococcus aureus (MRSA). Spider bites are commonly misdiagnosed. Unverified bite reports are frequent and likely represent many other conditions, both infectious and non-infectious can be confused with spider bites. Many of these conditions are far more common and more likely to be the source of necrotic wounds. # Management Most spider bites are harmless, and require no specific treatment. Treatment of bites may depend on the type of spider; thus, capture of the spider—either alive, or in a well-preserved condition, is useful. Treatment of spider bites includes washing the wound with soap and water and ice to reduce inflammation. Analgesics and antihistamines may be used, however antibiotics are not recommended unless there is also a bacterial infection present. Treatment of black widow envenomation seeks to control the pain and nausea that result. In the case of bites by widow spiders, Australian funnel-web spiders, or Brazilian wandering spiders, medical attention should be sought as in some cases the bites of these spiders develop into a medical emergency. Antivenom is available for severe widow and funnel-web envenomation. ## Necrosis In almost all cases, recluse bites are self-limited and typically heal without any medical intervention. Recommendations to limit the extent of damage include elevation and immobilization of the affected limb, application of ice. Both local wound care, and tetanus prophylaxis are simple standards. There is no established treatment for more extensive necrosis. Many therapies have been used including hyperbaric oxygen, dapsone, antihistamines (e.g., cyproheptadine), antibiotics, dextran, glucocorticoids, vasodilators, heparin, nitroglycerin, electric shock, curettage, surgical excision, and antivenom. None of these treatments conclusively show benefit. Studies have shown surgical intervention is ineffective and may worsen outcome. Excision may delay wound healing, cause abscesses, and lead to objectionable scarring. Dapsone, an antibiotic, is commonly used in the USA and Brazil for the treatment of necrosis. There have been conflicting reports with some supporting its efficacy and others have suggested it should no longer be used routinely, if at all. ## Antivenom Use of antivenom for severe spider bites may be indicated, especially in the case of neurotoxic venoms. Effective antivenoms exist for Latrodectus, Atrax, and Phoneutria venom. In the United States antivenom is intravenous but is used rarely as anaphylactic reaction to the antivenom has resulted in deaths. In Australia, intramuscular antivenom was commonly used, but the use has declined. Doubt has been raised bout the effectiveness of antivenom An antivenom for Loxosceles bites is available in South America, and it appears antivenom may be the most promising therapy. However, the recluse antivenom is more effective in experimental animals when given early, patients do not often present until 24 or more hours after the event, possibly limiting the effect of this intervention. # Epidemiology Estimating the number of spider bites that occur is difficult as the spider involvement may not be confirmed or identified. Several researchers recommend only evaluating verified bites: those that have an eyewitness to the bite, the spider is brought in, and identified by expert. With "suspected arachnidism" the diagnosis came without a spider positively identified. ## Africa Several Latrodectus spp (button spiders) live in Africa. South Africa also has the six-eyed sand spider that may cause skin necrosis. Physicians are advised that the diagnosis may be difficult without a spider. ## Australia Bites by the redbacks (Latrodectus hasselti) number a few thousand yearly throughout the country. Antivenom use is frequent but declining Children may have less complications of bite. Funnel web spider bites are few 30-40 per year and 10% requiring intervention. The Sydney funnel web and related species are only on the east coast of Australia. ## Europe In Switzerland about ten to one hundred spider bites occur per one million people per year. During epidemics of latrodectism from the European black widow upwards of 150 bites/year were documented. ## North America The American Association of Poison Control Centers reported that they received calls regarding nearly 10,000 spider bites in 1994. The spiders of most concern in North America are brown recluse spiders, with nearly 1500 bites in 2013 and black widow spiders with 1800 bites. The native habitat of brown recluse spiders is in the southern and central United States, as far north as Iowa. Encounters with brown recluse outside this native region is very rare and bites are thought to be suspect. A dozen major complications were reported in 2013. ## South America Numerous spider bites are recorded in Brazil with 5000/ annually. Loxosceles species are responsible for the majority of reports. Accidents are concentrated in the southern state of Parana with rates as high as 1/1000 people. Bite from Phoneutria (Brazilian wandering spider) number in the thousands with most being mild. Severe effects are noted in 0.5% of cases, mostly in children. # Historical remedies Recorded treatment from the 1890s for spider bites in general was rubbing in tobacco juice to the bitten skin, similar to some of the traditional uses of the tobacco plant for various bites and stings from Central and South America. Wild dancing and music was the cure for tarantism—the erotic frenzy believed to arise from the bite of a spider. An antivenom was developed against wolf spiders in Brazil and used for decades. Wolf spiders have since been exonerated—they never caused illness.	Spider bite Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview A spider bite, also known as arachnidism, is an injury resulting from the bite of a spider. The effects of most bites are not serious.[1] Most bites result in mild symptoms around the area of the bite.[1] Rarely they may produce a necrotic skin wound or severe pain.[2]:455 Most spiders do not cause bites that are of importance.[1] For a bite to be significant, substantial envenomation is required. Bites from the widow spiders involve a neurotoxic venom which produces a condition known as latrodectism.[3] Symptoms may include: pain which may be at the bite or involve the chest and abdomen, sweating, muscle cramps and vomiting among others.[1] Bites from the recluse spiders cause the condition loxoscelism, in which local necrosis of the surrounding skin and widespread breakdown of red blood cells may occur.[4] Headaches, vomiting and a mild fever may also occur.[4] Other spiders that can cause significant bites include: the Australian funnel web spiders,[5] the South American wandering spider,[1] and the hobo spider.[6] Efforts to prevent bites include clearing clutter and the use of pesticides.[1] Most spider bites are managed with supportive care such as NSAIDs (including ibuprofen) for pain and antihistamines for itchiness.[7] Opioids may be used if the pain is severe.[7] While an antivenom exists for black widow spider venom it is associated with anaphylaxis and therefore not commonly used in the United States.[7] Antivenom against funnel web spider venom improves outcomes.[1] Surgery may be required to repair the area of injured skin from some recluse bites.[7] Spider bites may be overdiagnosed or misdiagnosed.[1] Historically a number of conditions were attributed to spider bites. In the Middle Ages a condition claimed to arise from spider bites was tarantism, where people danced wildly.[8] While necrosis has been attributed to the bites of a number of spiders, good evidence only supports this for recluse spiders.[1] # Signs and symptoms Almost all spiders are venomous, but not all spider bites result in the injection of venom. Pain from non-venomous, so-called "dry bites" typically lasts for 5 to 60 minutes while pain from envenomating spider bites may last for longer than 24 hours.[9] Bleeding also may occur with a bite. Signs of a bacterial infection due to a spider bite occur infrequently (0.9%).[9] A study of 750 definite spider bites in Australia indicated that 6% of spider bites cause significant effects, the vast majority of these being redback spider bites causing significant pain lasting more than 24 hours.[10] Activation of the sympathetic nervous system can lead to sweating, high blood pressure and gooseflesh.[11] Most recluse spider bites are minor with little or no necrosis. However, a small number of bites produce necrotic skin lesions. First pain and tenderness at the site begin. The redness changes over 2 to 3 days to a bluish sinking patch of dead skin—the hallmark of necrosis. The wound heals slowly over months but usually completely.[12] and, rarely, widespread symptoms, including profound anemia. Rarely the bite may also produce the systemic condition with occasional fatalities[13] # Cause Spiders do not feed on humans and typically bites occur as a defense mechanism.[6] This can occur with from unintentional contact or trapping of the spider.[6] Most spiders have fangs too small to penetrate human skin.[14] Most bites by species large enough for their bites to be noticeable will have no serious medical consequences.[15] Medically significant spider venoms include various combinations and concentrations of necrotic agents, neurotoxins, and pharmacologically active compounds such as serotonin. Worldwide only two spider venoms have impact on humans—those of the widow and recluse spiders. Unlike snake and scorpion envenomation,[16] widow and recluse species bites rarely have fatal consequences. However, isolated spider families have a lethal neurotoxic venom: the wandering spider in Brazil and the funnel web in Australia. However, due to limited contact of humans with these spiders, deaths have always been rare, and since the introduction of anti-venom in Australia, there have been no funnel web related deaths.[17] # Pathophysiology A primary concern of the bite of a spider is the effect of its venom. A spider envenomation occurs whenever a spider injects venom into the skin. Not all spider bites involve injection of venom, and the amount of venom injected can vary based on the type of spider and the circumstances of the encounter. The mechanical injury from a spider bite is not a serious concern for humans. However, it is generally the toxicity of spider venom that poses the most risk to human beings; several spiders are known to have venom that can cause injury to humans in the amounts that a spider could inject when biting. While venoms are by definition toxic substances, most spiders do not have venom that is directly toxic (in the quantities delivered) to require medical attention and, of those that do, severity is typically mild. Spider venoms work on one of two fundamental principles; they are either neurotoxic (attacking the nervous system) or necrotic (attacking tissues surrounding the bite). In some cases, the venom affects vital organs and systems. The venoms of the widow spiders, Brazilian wandering spider and Australian funnel-web are neurotoxic. Heart muscle damage is an unusual complications of widow venom that may lead to death.[18] Pulmonary edema, fluid acumulation in the lungs, is a feared uncommon complication of funnel-web venom.[17] Recluse and South African sand spider venoms are necrotic. Recluse venom may also cause severe hemolysis (destruction of red blood cells)[19] # Diagnosis Assumption that a reported injury was caused by a spider is the most common source of false reports, which in some cases have led to misdiagnosis and mistreatment, with potentially life-threatening consequences.[20] Many spider bites are relatively painless but the spider is often trapped and easily found. With neurotoxic envenomation, serious symptoms arise within a few hours. An affected person may think that a wound is a spider bite when it is actually an infection with methicillin-resistant Staphylococcus aureus (MRSA).[21] Spider bites are commonly misdiagnosed. Unverified bite reports are frequent and likely represent many other conditions, both infectious and non-infectious can be confused with spider bites.[22] Many of these conditions are far more common and more likely to be the source of necrotic wounds.[4] # Management Most spider bites are harmless, and require no specific treatment. Treatment of bites may depend on the type of spider; thus, capture of the spider—either alive, or in a well-preserved condition, is useful.[23][24] Treatment of spider bites includes washing the wound with soap and water and ice to reduce inflammation.[25] Analgesics and antihistamines may be used, however antibiotics are not recommended unless there is also a bacterial infection present.[25] Treatment of black widow envenomation seeks to control the pain and nausea that result. In the case of bites by widow spiders, Australian funnel-web spiders, or Brazilian wandering spiders, medical attention should be sought as in some cases the bites of these spiders develop into a medical emergency.[26][27] Antivenom is available for severe widow and funnel-web envenomation.[1] ## Necrosis In almost all cases, recluse bites are self-limited and typically heal without any medical intervention.[4] Recommendations to limit the extent of damage include elevation and immobilization of the affected limb, application of ice. Both local wound care, and tetanus prophylaxis are simple standards. There is no established treatment for more extensive necrosis. Many therapies have been used including hyperbaric oxygen, dapsone, antihistamines (e.g., cyproheptadine), antibiotics, dextran, glucocorticoids, vasodilators, heparin, nitroglycerin, electric shock, curettage, surgical excision, and antivenom. None of these treatments conclusively show benefit. Studies have shown surgical intervention is ineffective and may worsen outcome. Excision may delay wound healing, cause abscesses, and lead to objectionable scarring.[28] Dapsone, an antibiotic, is commonly used in the USA and Brazil for the treatment of necrosis. There have been conflicting reports with some supporting its efficacy and others have suggested it should no longer be used routinely, if at all.[29] ## Antivenom Use of antivenom for severe spider bites may be indicated, especially in the case of neurotoxic venoms.[30] Effective antivenoms exist for Latrodectus, Atrax, and Phoneutria venom. In the United States antivenom is intravenous but is used rarely as anaphylactic reaction to the antivenom has resulted in deaths. In Australia, intramuscular antivenom was commonly used, but the use has declined. Doubt has been raised bout the effectiveness of antivenom[31][32] An antivenom for Loxosceles bites is available in South America, and it appears antivenom may be the most promising therapy. However, the recluse antivenom is more effective in experimental animals when given early, patients do not often present until 24 or more hours after the event, possibly limiting the effect of this intervention.[33] # Epidemiology Estimating the number of spider bites that occur is difficult as the spider involvement may not be confirmed or identified.[14] Several researchers recommend only evaluating verified bites: those that have an eyewitness to the bite, the spider is brought in, and identified by expert. With "suspected arachnidism" the diagnosis came without a spider positively identified.[4] ## Africa Several Latrodectus spp (button spiders) live in Africa. South Africa also has the six-eyed sand spider that may cause skin necrosis. Physicians are advised that the diagnosis may be difficult without a spider.[34] ## Australia Bites by the redbacks (Latrodectus hasselti) number a few thousand yearly throughout the country. Antivenom use is frequent but declining[35] Children may have less complications of bite.[36] Funnel web spider bites are few 30-40 per year and 10% requiring intervention. The Sydney funnel web and related species are only on the east coast of Australia.[37][38] ## Europe In Switzerland about ten to one hundred spider bites occur per one million people per year.[39] During epidemics of latrodectism from the European black widow upwards of 150 bites/year were documented.[40] ## North America The American Association of Poison Control Centers reported that they received calls regarding nearly 10,000 spider bites in 1994.[14] The spiders of most concern in North America are brown recluse spiders, with nearly 1500 bites in 2013[41] and black widow spiders with 1800 bites.[41] The native habitat of brown recluse spiders is in the southern and central United States, as far north as Iowa. Encounters with brown recluse outside this native region is very rare and bites are thought to be suspect.[4] A dozen major complications were reported in 2013.[41][42] ## South America Numerous spider bites are recorded in Brazil with 5000/ annually. Loxosceles species are responsible for the majority of reports. Accidents are concentrated in the southern state of Parana with rates as high as 1/1000 people.[43] Bite from Phoneutria (Brazilian wandering spider) number in the thousands with most being mild. Severe effects are noted in 0.5% of cases, mostly in children.[44] # Historical remedies Recorded treatment from the 1890s for spider bites in general was rubbing in tobacco juice to the bitten skin,[45] similar to some of the traditional uses of the tobacco plant for various bites and stings from Central and South America.[46] Wild dancing and music was the cure for tarantism—the erotic frenzy believed to arise from the bite of a spider.[47] An antivenom was developed against wolf spiders in Brazil and used for decades. Wolf spiders have since been exonerated—they never caused illness.[48]	https://www.wikidoc.org/index.php/Funnel_Web_spider_poisoning
39b09dc1e7334ced7ff21d6188399b44b40318fc	wikidoc	GI Cocktail	GI Cocktail In emergency medicine, a GI cocktail (gastrointestinal cocktail) is a generic term for a mixture of liquid antacid, viscous lidocaine, and an anticholinergic to treat dyspepsia. A common type includes a mixtures of Maalox, Donnatal, and Xylocaine in equal parts. The theory is since these all work by different mechanisms, the mixture will be more effective than just one. Many different combinations of GI cocktails are used, however, there is much dispute in recent research as to what is the best approach. Some researchers have found that many GI cocktails may not be as effective as one antacid.	GI Cocktail In emergency medicine, a GI cocktail (gastrointestinal cocktail) is a generic term for a mixture of liquid antacid, viscous lidocaine, and an anticholinergic to treat dyspepsia. A common type includes a mixtures of Maalox, Donnatal, and Xylocaine in equal parts. The theory is since these all work by different mechanisms, the mixture will be more effective than just one. Many different combinations of GI cocktails are used, however, there is much dispute in recent research as to what is the best approach. Some researchers have found that many GI cocktails may not be as effective as one antacid. Template:Pharma-stub Template:WikiDoc Sources	https://www.wikidoc.org/index.php/GI_Cocktail
85dec7d68a08c92da7e1d12a90be864e58a7bad1	wikidoc	GPX2 (gene)	GPX2 (gene) Glutathione peroxidase 2 is an enzyme that in humans is encoded by the GPX2 gene. This gene is a member of the glutathione peroxidase family encoding a selenium-dependent glutathione peroxidase that is one of two isoenzymes responsible for the majority of the glutathione-dependent hydrogen peroxide-reducing activity in the epithelium of the gastrointestinal tract. Studies in knockout mice indicate that mRNA expression levels respond to luminal microflora, suggesting a role of the ileal glutathione peroxidases in preventing inflammation in the GI tract. The antioxidant enzyme glutathione peroxidase 2 (Gpx2) is one out of eight known glutathione peroxidases (Gpx1-8) in humans. Mammalian Gpx1, GPx2 (this protein), Gpx3, and Gpx4 have been shown to be selenium-containing enzymes, whereas Gpx6 is a selenoprotein in humans with cysteine-containing homologues in rodents. In selenoproteins, the 21st amino acid selenocysteine is inserted in the nascent polypeptide chain during the process of translational recoding of the UGA stop codon.	GPX2 (gene) Glutathione peroxidase 2 is an enzyme that in humans is encoded by the GPX2 gene.[1][2][3] This gene is a member of the glutathione peroxidase family encoding a selenium-dependent glutathione peroxidase that is one of two isoenzymes responsible for the majority of the glutathione-dependent hydrogen peroxide-reducing activity in the epithelium of the gastrointestinal tract. Studies in knockout mice indicate that mRNA expression levels respond to luminal microflora, suggesting a role of the ileal glutathione peroxidases in preventing inflammation in the GI tract.[3] The antioxidant enzyme glutathione peroxidase 2 (Gpx2) is one out of eight known glutathione peroxidases (Gpx1-8) in humans. Mammalian Gpx1, GPx2 (this protein), Gpx3, and Gpx4 have been shown to be selenium-containing enzymes, whereas Gpx6 is a selenoprotein in humans with cysteine-containing homologues in rodents. In selenoproteins, the 21st amino acid selenocysteine is inserted in the nascent polypeptide chain during the process of translational recoding of the UGA stop codon.	https://www.wikidoc.org/index.php/GPX2_(gene)
c5e2a09a95a5e03bd08ccef54e962d20d79b5c9b	wikidoc	Gadodiamide	Gadodiamide # Disclaimer WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here. # Black Box Warning # Overview Gadodiamide is a gadolinium-based MRI contrast agent that is FDA approved for the procedure of visualizing lesions with abnormal vascularity in the brain, spine, and associated tissues and facilitate the visualization of lesions with abnormal vascularity within the thoracic, abdominal, pelvic cavities, and the retroperitoneal space. There is a Black Box Warning for this drug as shown here. Common adverse reactions include nausea, headache, dizziness. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) # Indications CNS (Central Nervous System) - Gadodiamide is a gadolinium-based contrast agent indicated for intravenous use in MRI to visualize lesions with abnormal vascularity (or those thought to cause abnormalities in the blood-brain barrier) in the brain (intracranial lesions), spine, and associated tissues. Body (Intrathoracic , Intra-abdominal, Pelvic and Retroperitoneal Regions) - Gadodiamide is a gadolinium-based contrast agent indicated for intravenous use in MRI to facilitate the visualization of lesions with abnormal vascularity within the thoracic (noncardiac), abdominal, pelvic cavities, and the retroperitoneal space. # Dosage CNS (Central Nervous System) - The recommended dose of Gadodiamide is 0.2 mL/kg (0.1 mmol/kg) administered as a bolus intravenous injection. Body (Intrathoracic , Intra-abdominal, Pelvic and Retroperitoneal Regions) - For imaging the kidney, the recommended dose of Gadodiamide is 0.1 mL/kg (0.05 mmol/kg). For imaging the intrathoracic (noncardiac), intra-abdominal, and pelvic cavities, the recommended dose of Gadodiamide is 0.2 mL/kg (0.1 mmol/kg). Dosage Chart Dosing Guidelines - Inspect Gadodiamide visually for particulate matter and discoloration before administration, whenever solution and container permit. - Do not use the solution if it is discolored or particulate matter is present. - Draw Gadodiamide into the syringe and use immediately. Discard any unused portion of Gadodiamide Injection. - To ensure complete delivery of the desired volume of contrast medium, follow the injection of Gadodiamide with a 5 mL flush of 0.9% sodium chloride, as provided in the Prefill Plus needle-free system. Complete the imaging procedure within 1 hour of administration of Gadodiamide. # DOSAGE FORMS AND STRENGTHS - Sterile aqueous solution for intravenous injection; 287 mg/mL. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Gadodiamide in adult patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Gadodiamide in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) # Indications CNS (Central Nervous System) - Gadodiamide is a gadolinium-based contrast agent indicated for intravenous use in MRI to visualize lesions with abnormal vascularity (or those thought to cause abnormalities in the blood-brain barrier) in the brain (intracranial lesions), spine, and associated tissues. Body (Intrathoracic , Intra-abdominal, Pelvic and Retroperitoneal Regions) - Gadodiamide is a gadolinium-based contrast agent indicated for intravenous use in MRI to facilitate the visualization of lesions with abnormal vascularity within the thoracic (noncardiac), abdominal, pelvic cavities, and the retroperitoneal space. # Dosage CNS (Central Nervous System) - Pediatric Patients (2-16 years): The recommended dose of gadodiamide is 0.2 mL/kg (0.1 mmol/kg) administered as a bolus intravenous injection. Body (Intrathoracic , Intra-abdominal, Pelvic and Retroperitoneal Regions) - Pediatric Patients (2-16 years of age):For imaging the kidney, the recommended dose of gadodiamide is 0.1 mL/kg (0.05 mmol/kg). For imaging the intrathoracic (noncardiac), intra-abdominal, and pelvic cavities, the recommended dose of gadodiamide is 0.2 mL/kg (0.1 mmol/kg). Dosage Chart Dosing Guidelines - Inspect gadodiamide visually for particulate matter and discoloration before administration, whenever solution and container permit. - Do not use the solution if it is discolored or particulate matter is present. - Draw gadodiamide into the syringe and use immediately. Discard any unused portion of gadodiamide Injection. - To ensure complete delivery of the desired volume of contrast medium, follow the injection of gadodiamide with a 5 mL flush of 0.9% sodium chloride, as provided in the Prefill Plus needle-free system. Complete the imaging procedure within 1 hour of administration of gadodiamide. # DOSAGE FORMS AND STRENGTHS - Sterile aqueous solution for intravenous injection; 287 mg/mL. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Gadodiamide in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Gadodiamide in pediatric patients. # Contraindications - Gadodiamide is contraindicated in patients with: - Chronic, severe kidney disease (glomerular filtration rate, GFR < 30 mL/min/1.73m2), or - Acute kidney injury - Prior hypersensitivity reaction to gadodiamide # Warnings There is limited information regarding Gadodiamide Warnings' in the drug label. # Adverse Reactions ## Clinical Trials Experience - The following adverse reactions are discussed in greater detail in other sections of the label: - Nephrogenic systemic fibrosis. - Hypersensitivity reactions. - Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice. Clinical Studies Experience (Adults) - In clinical studies 1160 patients were exposed to gadodiamide. The most frequent adverse reactions were nausea, headache, and dizziness that occurred in 3% or less of the patients. The majority of these reactions were of mild to moderate intensity. - The following adverse reactions occurred in 1% or less of patients: - Application Site Disorders: Injection site reaction. - Autonomic Nervous System Disorders: Vasodilation. - Body as a Whole-General Disorders: Anaphylactoid reactions (characterized by cardiovascular, respiratory, and cutaneous symptoms), fever, hot flushes, rigors, fatigue, malaise, pain, syncope. - Cardiovascular Disorders: Cardiac failure, rare arrhythmia and myocardial infarction resulting in death in patients with ischemic heart disease, flushing, chest pain, deep thrombophlebitis. - Central and Peripheral Nervous System Disorders: Convulsions including grand mal, ataxia, abnormal coordination, paresthesia, tremor, aggravated multiple sclerosis (characterized by sensory and motor disturbances), aggravated migraine. - Gastrointestinal System Disorders: Abdominal pain, diarrhea, eructation, dry mouth/vomiting, melena. - Hearing and Vestibular Disorders: Tinnitus. - Liver and Biliary System Disorders: Abnormal hepatic function. - Musculoskeletal System Disorders: Arthralgia, myalgia. - Respiratory System Disorders: Rhinitis, dyspnea. - Skin and Appendage Disorders: Pruritus, rash, erythematous rash, sweating increased, urticaria. - Special Senses, Other Disorders: Taste loss, taste perversion. - Urinary System Disorders: Acute reversible renal failure. - Vision Disorders: Abnormal vision. Clinical Studies Experience (Pediatrics) - In the 97 pediatric patients in CNS studies with gadodiamide and the 144 pediatric patients in published literature, the adverse reactions were similar to those reported in adults. ## Postmarketing Experience - Because postmarketing reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. - The following adverse reactions have been identified during the postmarketing use of Gadodiamide: - Nervous System Disorders: Inadvertent intrathecal use causes convulsions, coma, paresthesia, paresis. Convulsions have also been reported with intravenous use in patients with and without a history of convulsions or brain lesions. - General Disorders: Nephrogenic Systemic Fibrosis (NSF). - Renal and Urinary System Disorders: In patients with pre-existing renal insufficiency: acute renal failure, renal impairment, blood creatinine increased. # Drug Interactions - Specific drug interaction studies have not been conducted. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): Pregnancy Category C: Gadodiamide has been shown to have an adverse effect on embryo-fetal development in rabbits at dosages as low as 0.5 mmol/kg/day for 13 days during gestation (approximately 0.6 times the human dose based on a body surface area comparison). These adverse effects are observed as an increased incidence of flexed appendages and skeletal malformations which may be due to maternal toxicity since the body weight of the dams was reduced in response to gadodiamide administration during pregnancy. In rat studies, fetal abnormalities were not observed at doses up to 2.5 mmol/kg/day for 10 days during gestation (1.3 times the maximum human dose based on a body surface area comparison); however, maternal toxicity was not achieved in these studies and a definitive conclusion about teratogenicity in rats at doses above 2.5 mmol/kg/day cannot be made. Adequate and well controlled studies in pregnant women have not been conducted. Gadodiamide should only be used during pregnancy if the potential benefit justifies the potential risk to the fetus. Pregnancy Category (AUS): - Australian Drug Evaluation Committee (ADEC) Pregnancy Category There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Gadodiamide in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Gadodiamide during labor and delivery. ### Nursing Mothers - It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, exercise caution when administering Gadodiamide to a nursing woman. ### Pediatric Use - The safety and efficacy of gadodiamide at a single dose of 0.05 to 0.1 mmol/kg have been established in pediatric patients over 2 years of age based on adequate and well controlled studies of gadodiamide in adults, a pediatric CNS imaging study, and safety data in the scientific literature. However, the safety and efficacy of doses greater than 0.1 mmol/kg and of repeated doses have not been studied in pediatric patients. - Pharmacokinetics of gadodiamide have not been studied in pediatrics. The glomerular filtration rate of neonates and infants is much lower than that of adults. The pharmacokinetics volume of distribution is also different. Therefore, the optimal dosing regimen and imaging times in patients under 2 years of age have not been established. ### Geriatic Use - In clinical studies of gadodiamide, 243 patients were between 65 and 80 years of age while 15 were over 80. No overall differences in safety or effectiveness were observed between these patients and younger patients. Other reported clinical experience has not identified differences in response between the elderly and younger patients, but greater sensitivity in the elderly cannot be ruled out. In general, dose selection for an elderly patient should be cautious, reflecting the greater frequency of decreased hepatic, renal or cardiac function, and of concomitant disease or other drug therapy. - Gadodiamide is excreted by the kidney, and the risk of toxic reactions to gadodiamide is greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, select dose carefully and assess eGFR by laboratory testing before gadodiamide use. ### Gender There is no FDA guidance on the use of Gadodiamide with respect to specific gender populations. ### Race There is no FDA guidance on the use of Gadodiamide with respect to specific racial populations. ### Renal Impairment - Dose adjustments in renal impairment have not been studied. Caution should be exercised in patients with impaired renal insufficiency. ### Hepatic Impairment - Dose adjustments in hepatic impairment have not been studied. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Gadodiamide in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Gadodiamide in patients who are immunocompromised. # Administration and Monitoring ### Administration - Intravenous ### Monitoring There is limited information regarding Monitoring of Gadodiamide in the drug label. # IV Compatibility There is limited information regarding IV Compatibility of Gadodiamide in the drug label. # Overdosage - Clinical consequences of overdose with gadodiamide have not been reported. The minimum lethal dose of intravenously administered gadodiamide in rats and mice is greater than 20 mmol/kg (200 times the recommended human dose of 0.1 mmol/kg; 67 times the cumulative 0.3 mmol/kg dose). Gadodiamide is dialyzable. # Pharmacology ## Mechanism of Action There is limited information regarding Gadodiamide Mechanism of Action in the drug label. ## Structure - Gadodiamide (gadodiamide) Injection is the formulation of the gadolinium complex of diethylenetriamine pentaacetic acid bismethylamide, and is an injectable, nonionic extracellular enhancing agent for magnetic resonance imaging. Gadodiamide is administered by intravenous injection. - Gadodiamide is provided as a sterile, clear, colorless to slightly yellow, aqueous solution. Each 1 mL contains 287 mg gadodiamide and 12 mg caldiamide sodium in Water for Injection. The pH is adjusted between 5.5 and 7.0 with hydrochloric acid and/or sodium hydroxide. Gadodiamide contains no antimicrobial preservative. Gadodiamide is a 0.5 mol/L solution of aqua-3-oxo-2,5,8,11-tetraazatridecan-13-oato (3-)-N5, N8, N11, O3, O5, O8, O11, O13] gadolinium hydrate, with a molecular weight of 573.66 (anhydrous), an empirical formula of C16H28GdN5O9xH2O, and the following structural formula: - Pertinent physicochemical data for gadodiamide are noted below: - Gadodiamide has an osmolality approximately 2.8 times that of plasma at 37°C and is hypertonic under conditions of use. ## Pharmacodynamics - In magnetic resonance imaging, visualization of normal and pathologic tissue depends in part on variations in the radiofrequency signal intensity. These variations occur due to: changes in proton density; alteration of the spin-lattice or longitudinal relaxation time (T1); and variation of the spin-spin or transverse relaxation time (T2). Gadodiamide is a paramagnetic agent with unpaired electron spins which generate a local magnetic field. As water protons move through this local magnetic field, the changes in magnetic field experienced by the protons reorient them with the main magnetic field more quickly than in the absence of a paramagnetic agent. - By increasing the relaxation rate, gadodiamide decreases both the T1 and T2 relaxation times in tissues where it is distributed. At clinical doses, the effect is primarily on the T1 relaxation time, and produces an increase in signal intensity. Gadodiamide does not cross the intact blood-brain barrier and, therefore, does not accumulate in normal brain or in lesions that do not have an abnormal blood-brain barrier (e.g., cysts, mature postoperative scars). However, disruption of the blood-brain barrier or abnormal vascularity allows accumulation of gadodiamide in lesions such as neoplasms, abscesses, and subacute infarcts. The pharmacokinetic parameters of gadodiamide in various lesions are not known. There is no detectable biotransformation or decomposition of gadodiamide. ## Pharmacokinetics - The pharmacokinetics of intravenously administered gadodiamide in normal subjects conforms to an open, two-compartment model with mean distribution and elimination half-lives (reported as mean ± SD) of 3.7 ± 2.7 minutes and 77.8 ± 16 minutes, respectively. - Gadodiamide is eliminated primarily in the urine with 95.4 ± 5.5% (mean ± SD) of the administered dose eliminated by 24 hours. The renal and plasma clearance rates of gadodiamide are nearly identical (1.7 and 1.8 mL/min/kg, respectively), and are similar to that of substances excreted primarily by glomerular filtration. The volume of distribution of gadodiamide (200 ± 61 mL/kg) is equivalent to that of extracellular water. Gadodiamide does not bind to human serum proteins in vitro. Pharmacokinetic and pharmacodynamic studies have not been systematically conducted to determine the optimal dose and imaging time in patients with abnormal renal function or renal failure, in the elderly, or in pediatric patients with immature renal function ## Nonclinical Toxicology Carcinogenesis, Mutagenesis, Impairment of Fertility - Long term animal studies have not been performed to evaluate the carcinogenic potential of gadodiamide. The results of the following genotoxicity assays were negative: in vitro bacterial reverse mutation assay, in vitro Chinese Hamster Ovary (CHO)/Hypoxanthine Guanine Phosphoribosyl Transferase (HGPT) forward mutation assay, in vitro CHO chromosome aberration assay, and the in vivo mouse micronucleus assay at intravenous doses of 27 mmol/kg (approximately 7 times the maximum human dose based on a body surface area comparison). Impairment of male or female fertility was not observed in rats after intravenous administration three times per week at the maximum dose tested of 1.0 mmol/kg (approximately 0.5 times the maximum human dose based on a body surface area comparison). # Clinical Studies CNS (Central Nervous System) - Gadodiamide (0.1 mmol/kg) contrast enhancement in CNS MRI was evident in a study of 439 adults. In a study of sequential dosing, 57 adults received gadodiamide 0.1 mmol/kg followed by 0.2 mmol/kg within 20 minutes (for cumulative dose of 0.3 mmol/kg). The MRIs were compared blindly. In 54/56 (96%) patients, gadodiamide contrast enhancement was evident with both the 0.1 mmol/kg and cumulative 0.3 mmol/kg gadodiamide doses relative to non-contrast MRI. - In comparison to the non-contrast MRI, increased numbers of brain and spine lesions were noted in 42% of patients who received gadodiamide at any dose. In comparisons of 0.1 mmol/kg versus 0.3 mmol/kg, the results were comparable in 25/56 (45%); in 1/56 (2%) gadodiamide 0.1 mmol/kg dose provided more diagnostic value and in 30/56 (54%) the cumulative gadodiamide 0.3 mmol/kg dose provided more diagnostic value. - The usefulness of a single 0.3 mmol/kg bolus in comparison to the cumulative 0.3 mmol/kg (0.1 mmol/kg followed by 0.2 mmol/kg) has not been established. - Gadodiamide as a single 0.1 mmol/kg dose was evaluated in 97 pediatric patients with a mean age of 8.9 (2-18) years referred for CNS MRI. Postcontrast MRI provided added diagnostic information, diagnostic confidence, and new patient management information in 76%, 67%, and 52%, respectively, of pediatrics. Body (Intrathoracic , Intra-abdominal, Pelvic and Retroperitoneal Regions) - Gadodiamide was evaluated in a controlled trial of 276 patients referred for body MRI. These patients had a mean age of 57 (9-88) years. Patients received 0.1 mmol/kg gadodiamide for imaging the thorax (noncardiac), abdomen, and pelvic organs, or a dose of 0.05 mmol/kg for imaging the kidney. Pre- and post-gadodiamide images were evaluated blindly for the degree of diagnostic value rated on a scale of "remarkably improved, improved, no change, worse, and cannot be determined." The postcontrast results showed "remarkably improved" or "improved" diagnostic value in 90% of the thorax, liver, and pelvis patients, and in 95% of the kidney patients. - In a dose ranging study 258 patients referred for body MRI received gadodiamide 0.025, 0.05, 0.1 mmol/kg. The lowest effective dose of Gadodiamide for the kidney was 0.05 mmol/kg. # How Supplied - OMNISCAN (gadodiamide) Injection is a sterile, clear, colorless to slightly yellow, aqueous solution containing 287 mg/mL of gadodiamide in rubber stoppered vials and prefilled syringes. OMNSICAN is supplied in the following sizes: - 5 mL fill in 10 mL vial, box of 10 (NDC 0407-0690-05) - 10 mL vial, box of 10 (NDC 0407-0690-10) - 15 mL fill in 20 mL vial, box of 10 (NDC 0407-0690-15) - 20 mL vial, box of 10 (NDC 0407-0690-20) - 10 mL fill in 20 mL prefilled syringe, box of 10 (NDC 0407-0690-12) - 15 mL fill in 20 mL prefilled syringe, box of 10 (NDC 0407-0690-17) - 20 mL prefilled syringe, box of 10 (NDC 0407-0690-22) - Prefill Plus™ needle-free system OMNISCAN 15 mL, box of 10 (NDC 0407-0691-62) Contains: OMNISCAN 15 mL fill in 20 mL Single Dose Prefilled Syringe and 5 mL 0.9% Sodium Chloride Injection, USP I.V. Flush Syringe - Prefill Plus™ needle-free system OMNISCAN 20 mL, box of 10 (NDC 0407-0691-63) Contains: OMNISCAN 20 mL fill in 20 mL Single Dose Prefilled Syringe and 5 mL 0.9% Sodium Chloride Injection, USP I.V. Flush Syringe - Protect gadodiamide from strong daylight and direct exposure to sunlight. Do not freeze. Freezing can cause small cracks in the vials, which would compromise the sterility of the product. Do not use if the product is inadvertently frozen. ## Storage - Store gadodiamide at controlled room temperature 20°-25°C (68°-77°F); excursions permitted to 15°-30°C (59°-86°F) . # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information - Patients receiving gadodiamide should be instructed to inform their physician if they: - Are pregnant or breast feeding, or - Have a history of renal and/or liver disease, convulsions, asthma or allergic respiratory disorders, or recent administration of gadolinium-based contrast. - GBCAs increase the risk for NSF among patients with impaired elimination of the drugs. To counsel patients at risk for NSF: - Describe the clinical manifestations of NSF - Describe procedures to screen for the detection of renal impairment - Instruct the patients to contact their physician if they develop signs or symptoms of NSF following gadodiamide administration such as burning, itching, swelling, scaling, hardening and tightening of the skin; red or dark patches on the skin; stiffness in joints with trouble moving, bending or straightening the arms, hands, legs or feet; pain deep in the hip bones or ribs; or muscle weakness. # Precautions with Alcohol - Alcohol-Gadodiamide interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - OMNISCAN # Look-Alike Drug Names - A® — B® # Drug Shortage Status # Price	Gadodiamide Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Kiran Singh, M.D. [2] # Disclaimer WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here. # Black Box Warning # Overview Gadodiamide is a gadolinium-based MRI contrast agent that is FDA approved for the procedure of visualizing lesions with abnormal vascularity in the brain, spine, and associated tissues and facilitate the visualization of lesions with abnormal vascularity within the thoracic, abdominal, pelvic cavities, and the retroperitoneal space. There is a Black Box Warning for this drug as shown here. Common adverse reactions include nausea, headache, dizziness. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) # Indications CNS (Central Nervous System) - Gadodiamide is a gadolinium-based contrast agent indicated for intravenous use in MRI to visualize lesions with abnormal vascularity (or those thought to cause abnormalities in the blood-brain barrier) in the brain (intracranial lesions), spine, and associated tissues. Body (Intrathoracic [noncardiac], Intra-abdominal, Pelvic and Retroperitoneal Regions) - Gadodiamide is a gadolinium-based contrast agent indicated for intravenous use in MRI to facilitate the visualization of lesions with abnormal vascularity within the thoracic (noncardiac), abdominal, pelvic cavities, and the retroperitoneal space. # Dosage CNS (Central Nervous System) - The recommended dose of Gadodiamide is 0.2 mL/kg (0.1 mmol/kg) administered as a bolus intravenous injection. Body (Intrathoracic [noncardiac], Intra-abdominal, Pelvic and Retroperitoneal Regions) - For imaging the kidney, the recommended dose of Gadodiamide is 0.1 mL/kg (0.05 mmol/kg). For imaging the intrathoracic (noncardiac), intra-abdominal, and pelvic cavities, the recommended dose of Gadodiamide is 0.2 mL/kg (0.1 mmol/kg). Dosage Chart Dosing Guidelines - Inspect Gadodiamide visually for particulate matter and discoloration before administration, whenever solution and container permit. - Do not use the solution if it is discolored or particulate matter is present. - Draw Gadodiamide into the syringe and use immediately. Discard any unused portion of Gadodiamide Injection. - To ensure complete delivery of the desired volume of contrast medium, follow the injection of Gadodiamide with a 5 mL flush of 0.9% sodium chloride, as provided in the Prefill Plus needle-free system. Complete the imaging procedure within 1 hour of administration of Gadodiamide. # DOSAGE FORMS AND STRENGTHS - Sterile aqueous solution for intravenous injection; 287 mg/mL. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Gadodiamide in adult patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Gadodiamide in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) # Indications CNS (Central Nervous System) - Gadodiamide is a gadolinium-based contrast agent indicated for intravenous use in MRI to visualize lesions with abnormal vascularity (or those thought to cause abnormalities in the blood-brain barrier) in the brain (intracranial lesions), spine, and associated tissues. Body (Intrathoracic [noncardiac], Intra-abdominal, Pelvic and Retroperitoneal Regions) - Gadodiamide is a gadolinium-based contrast agent indicated for intravenous use in MRI to facilitate the visualization of lesions with abnormal vascularity within the thoracic (noncardiac), abdominal, pelvic cavities, and the retroperitoneal space. # Dosage CNS (Central Nervous System) - Pediatric Patients (2-16 years): The recommended dose of gadodiamide is 0.2 mL/kg (0.1 mmol/kg) administered as a bolus intravenous injection. Body (Intrathoracic [noncardiac], Intra-abdominal, Pelvic and Retroperitoneal Regions) - Pediatric Patients (2-16 years of age):For imaging the kidney, the recommended dose of gadodiamide is 0.1 mL/kg (0.05 mmol/kg). For imaging the intrathoracic (noncardiac), intra-abdominal, and pelvic cavities, the recommended dose of gadodiamide is 0.2 mL/kg (0.1 mmol/kg). Dosage Chart Dosing Guidelines - Inspect gadodiamide visually for particulate matter and discoloration before administration, whenever solution and container permit. - Do not use the solution if it is discolored or particulate matter is present. - Draw gadodiamide into the syringe and use immediately. Discard any unused portion of gadodiamide Injection. - To ensure complete delivery of the desired volume of contrast medium, follow the injection of gadodiamide with a 5 mL flush of 0.9% sodium chloride, as provided in the Prefill Plus needle-free system. Complete the imaging procedure within 1 hour of administration of gadodiamide. # DOSAGE FORMS AND STRENGTHS - Sterile aqueous solution for intravenous injection; 287 mg/mL. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Gadodiamide in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Gadodiamide in pediatric patients. # Contraindications - Gadodiamide is contraindicated in patients with: - Chronic, severe kidney disease (glomerular filtration rate, GFR < 30 mL/min/1.73m2), or - Acute kidney injury - Prior hypersensitivity reaction to gadodiamide # Warnings There is limited information regarding Gadodiamide Warnings' in the drug label. # Adverse Reactions ## Clinical Trials Experience - The following adverse reactions are discussed in greater detail in other sections of the label: - Nephrogenic systemic fibrosis. - Hypersensitivity reactions. - Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice. Clinical Studies Experience (Adults) - In clinical studies 1160 patients were exposed to gadodiamide. The most frequent adverse reactions were nausea, headache, and dizziness that occurred in 3% or less of the patients. The majority of these reactions were of mild to moderate intensity. - The following adverse reactions occurred in 1% or less of patients: - Application Site Disorders: Injection site reaction. - Autonomic Nervous System Disorders: Vasodilation. - Body as a Whole-General Disorders: Anaphylactoid reactions (characterized by cardiovascular, respiratory, and cutaneous symptoms), fever, hot flushes, rigors, fatigue, malaise, pain, syncope. - Cardiovascular Disorders: Cardiac failure, rare arrhythmia and myocardial infarction resulting in death in patients with ischemic heart disease, flushing, chest pain, deep thrombophlebitis. - Central and Peripheral Nervous System Disorders: Convulsions including grand mal, ataxia, abnormal coordination, paresthesia, tremor, aggravated multiple sclerosis (characterized by sensory and motor disturbances), aggravated migraine. - Gastrointestinal System Disorders: Abdominal pain, diarrhea, eructation, dry mouth/vomiting, melena. - Hearing and Vestibular Disorders: Tinnitus. - Liver and Biliary System Disorders: Abnormal hepatic function. - Musculoskeletal System Disorders: Arthralgia, myalgia. - Respiratory System Disorders: Rhinitis, dyspnea. - Skin and Appendage Disorders: Pruritus, rash, erythematous rash, sweating increased, urticaria. - Special Senses, Other Disorders: Taste loss, taste perversion. - Urinary System Disorders: Acute reversible renal failure. - Vision Disorders: Abnormal vision. Clinical Studies Experience (Pediatrics) - In the 97 pediatric patients in CNS studies with gadodiamide and the 144 pediatric patients in published literature, the adverse reactions were similar to those reported in adults. ## Postmarketing Experience - Because postmarketing reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. - The following adverse reactions have been identified during the postmarketing use of Gadodiamide: - Nervous System Disorders: Inadvertent intrathecal use causes convulsions, coma, paresthesia, paresis. Convulsions have also been reported with intravenous use in patients with and without a history of convulsions or brain lesions. - General Disorders: Nephrogenic Systemic Fibrosis (NSF). - Renal and Urinary System Disorders: In patients with pre-existing renal insufficiency: acute renal failure, renal impairment, blood creatinine increased. # Drug Interactions - Specific drug interaction studies have not been conducted. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): Pregnancy Category C: Gadodiamide has been shown to have an adverse effect on embryo-fetal development in rabbits at dosages as low as 0.5 mmol/kg/day for 13 days during gestation (approximately 0.6 times the human dose based on a body surface area comparison). These adverse effects are observed as an increased incidence of flexed appendages and skeletal malformations which may be due to maternal toxicity since the body weight of the dams was reduced in response to gadodiamide administration during pregnancy. In rat studies, fetal abnormalities were not observed at doses up to 2.5 mmol/kg/day for 10 days during gestation (1.3 times the maximum human dose based on a body surface area comparison); however, maternal toxicity was not achieved in these studies and a definitive conclusion about teratogenicity in rats at doses above 2.5 mmol/kg/day cannot be made. Adequate and well controlled studies in pregnant women have not been conducted. Gadodiamide should only be used during pregnancy if the potential benefit justifies the potential risk to the fetus. Pregnancy Category (AUS): - Australian Drug Evaluation Committee (ADEC) Pregnancy Category There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Gadodiamide in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Gadodiamide during labor and delivery. ### Nursing Mothers - It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, exercise caution when administering Gadodiamide to a nursing woman. ### Pediatric Use - The safety and efficacy of gadodiamide at a single dose of 0.05 to 0.1 mmol/kg have been established in pediatric patients over 2 years of age based on adequate and well controlled studies of gadodiamide in adults, a pediatric CNS imaging study, and safety data in the scientific literature. However, the safety and efficacy of doses greater than 0.1 mmol/kg and of repeated doses have not been studied in pediatric patients. - Pharmacokinetics of gadodiamide have not been studied in pediatrics. The glomerular filtration rate of neonates and infants is much lower than that of adults. The pharmacokinetics volume of distribution is also different. Therefore, the optimal dosing regimen and imaging times in patients under 2 years of age have not been established. ### Geriatic Use - In clinical studies of gadodiamide, 243 patients were between 65 and 80 years of age while 15 were over 80. No overall differences in safety or effectiveness were observed between these patients and younger patients. Other reported clinical experience has not identified differences in response between the elderly and younger patients, but greater sensitivity in the elderly cannot be ruled out. In general, dose selection for an elderly patient should be cautious, reflecting the greater frequency of decreased hepatic, renal or cardiac function, and of concomitant disease or other drug therapy. - Gadodiamide is excreted by the kidney, and the risk of toxic reactions to gadodiamide is greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, select dose carefully and assess eGFR by laboratory testing before gadodiamide use. ### Gender There is no FDA guidance on the use of Gadodiamide with respect to specific gender populations. ### Race There is no FDA guidance on the use of Gadodiamide with respect to specific racial populations. ### Renal Impairment - Dose adjustments in renal impairment have not been studied. Caution should be exercised in patients with impaired renal insufficiency. ### Hepatic Impairment - Dose adjustments in hepatic impairment have not been studied. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Gadodiamide in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Gadodiamide in patients who are immunocompromised. # Administration and Monitoring ### Administration - Intravenous ### Monitoring There is limited information regarding Monitoring of Gadodiamide in the drug label. # IV Compatibility There is limited information regarding IV Compatibility of Gadodiamide in the drug label. # Overdosage - Clinical consequences of overdose with gadodiamide have not been reported. The minimum lethal dose of intravenously administered gadodiamide in rats and mice is greater than 20 mmol/kg (200 times the recommended human dose of 0.1 mmol/kg; 67 times the cumulative 0.3 mmol/kg dose). Gadodiamide is dialyzable. # Pharmacology ## Mechanism of Action There is limited information regarding Gadodiamide Mechanism of Action in the drug label. ## Structure - Gadodiamide (gadodiamide) Injection is the formulation of the gadolinium complex of diethylenetriamine pentaacetic acid bismethylamide, and is an injectable, nonionic extracellular enhancing agent for magnetic resonance imaging. Gadodiamide is administered by intravenous injection. - Gadodiamide is provided as a sterile, clear, colorless to slightly yellow, aqueous solution. Each 1 mL contains 287 mg gadodiamide and 12 mg caldiamide sodium in Water for Injection. The pH is adjusted between 5.5 and 7.0 with hydrochloric acid and/or sodium hydroxide. Gadodiamide contains no antimicrobial preservative. Gadodiamide is a 0.5 mol/L solution of aqua[5,8-bis(carboxymethyl)-11-[2-(methylamino)-2-oxoethyl]-3-oxo-2,5,8,11-tetraazatridecan-13-oato (3-)-N5, N8, N11, O3, O5, O8, O11, O13] gadolinium hydrate, with a molecular weight of 573.66 (anhydrous), an empirical formula of C16H28GdN5O9•xH2O, and the following structural formula: - Pertinent physicochemical data for gadodiamide are noted below: - Gadodiamide has an osmolality approximately 2.8 times that of plasma at 37°C and is hypertonic under conditions of use. ## Pharmacodynamics - In magnetic resonance imaging, visualization of normal and pathologic tissue depends in part on variations in the radiofrequency signal intensity. These variations occur due to: changes in proton density; alteration of the spin-lattice or longitudinal relaxation time (T1); and variation of the spin-spin or transverse relaxation time (T2). Gadodiamide is a paramagnetic agent with unpaired electron spins which generate a local magnetic field. As water protons move through this local magnetic field, the changes in magnetic field experienced by the protons reorient them with the main magnetic field more quickly than in the absence of a paramagnetic agent. - By increasing the relaxation rate, gadodiamide decreases both the T1 and T2 relaxation times in tissues where it is distributed. At clinical doses, the effect is primarily on the T1 relaxation time, and produces an increase in signal intensity. Gadodiamide does not cross the intact blood-brain barrier and, therefore, does not accumulate in normal brain or in lesions that do not have an abnormal blood-brain barrier (e.g., cysts, mature postoperative scars). However, disruption of the blood-brain barrier or abnormal vascularity allows accumulation of gadodiamide in lesions such as neoplasms, abscesses, and subacute infarcts. The pharmacokinetic parameters of gadodiamide in various lesions are not known. There is no detectable biotransformation or decomposition of gadodiamide. ## Pharmacokinetics - The pharmacokinetics of intravenously administered gadodiamide in normal subjects conforms to an open, two-compartment model with mean distribution and elimination half-lives (reported as mean ± SD) of 3.7 ± 2.7 minutes and 77.8 ± 16 minutes, respectively. - Gadodiamide is eliminated primarily in the urine with 95.4 ± 5.5% (mean ± SD) of the administered dose eliminated by 24 hours. The renal and plasma clearance rates of gadodiamide are nearly identical (1.7 and 1.8 mL/min/kg, respectively), and are similar to that of substances excreted primarily by glomerular filtration. The volume of distribution of gadodiamide (200 ± 61 mL/kg) is equivalent to that of extracellular water. Gadodiamide does not bind to human serum proteins in vitro. Pharmacokinetic and pharmacodynamic studies have not been systematically conducted to determine the optimal dose and imaging time in patients with abnormal renal function or renal failure, in the elderly, or in pediatric patients with immature renal function ## Nonclinical Toxicology Carcinogenesis, Mutagenesis, Impairment of Fertility - Long term animal studies have not been performed to evaluate the carcinogenic potential of gadodiamide. The results of the following genotoxicity assays were negative: in vitro bacterial reverse mutation assay, in vitro Chinese Hamster Ovary (CHO)/Hypoxanthine Guanine Phosphoribosyl Transferase (HGPT) forward mutation assay, in vitro CHO chromosome aberration assay, and the in vivo mouse micronucleus assay at intravenous doses of 27 mmol/kg (approximately 7 times the maximum human dose based on a body surface area comparison). Impairment of male or female fertility was not observed in rats after intravenous administration three times per week at the maximum dose tested of 1.0 mmol/kg (approximately 0.5 times the maximum human dose based on a body surface area comparison). # Clinical Studies CNS (Central Nervous System) - Gadodiamide (0.1 mmol/kg) contrast enhancement in CNS MRI was evident in a study of 439 adults. In a study of sequential dosing, 57 adults received gadodiamide 0.1 mmol/kg followed by 0.2 mmol/kg within 20 minutes (for cumulative dose of 0.3 mmol/kg). The MRIs were compared blindly. In 54/56 (96%) patients, gadodiamide contrast enhancement was evident with both the 0.1 mmol/kg and cumulative 0.3 mmol/kg gadodiamide doses relative to non-contrast MRI. - In comparison to the non-contrast MRI, increased numbers of brain and spine lesions were noted in 42% of patients who received gadodiamide at any dose. In comparisons of 0.1 mmol/kg versus 0.3 mmol/kg, the results were comparable in 25/56 (45%); in 1/56 (2%) gadodiamide 0.1 mmol/kg dose provided more diagnostic value and in 30/56 (54%) the cumulative gadodiamide 0.3 mmol/kg dose provided more diagnostic value. - The usefulness of a single 0.3 mmol/kg bolus in comparison to the cumulative 0.3 mmol/kg (0.1 mmol/kg followed by 0.2 mmol/kg) has not been established. - Gadodiamide as a single 0.1 mmol/kg dose was evaluated in 97 pediatric patients with a mean age of 8.9 (2-18) years referred for CNS MRI. Postcontrast MRI provided added diagnostic information, diagnostic confidence, and new patient management information in 76%, 67%, and 52%, respectively, of pediatrics. Body (Intrathoracic [noncardiac], Intra-abdominal, Pelvic and Retroperitoneal Regions) - Gadodiamide was evaluated in a controlled trial of 276 patients referred for body MRI. These patients had a mean age of 57 (9-88) years. Patients received 0.1 mmol/kg gadodiamide for imaging the thorax (noncardiac), abdomen, and pelvic organs, or a dose of 0.05 mmol/kg for imaging the kidney. Pre- and post-gadodiamide images were evaluated blindly for the degree of diagnostic value rated on a scale of "remarkably improved, improved, no change, worse, and cannot be determined." The postcontrast results showed "remarkably improved" or "improved" diagnostic value in 90% of the thorax, liver, and pelvis patients, and in 95% of the kidney patients. - In a dose ranging study 258 patients referred for body MRI received gadodiamide 0.025, 0.05, 0.1 mmol/kg. The lowest effective dose of Gadodiamide for the kidney was 0.05 mmol/kg. # How Supplied - OMNISCAN (gadodiamide) Injection is a sterile, clear, colorless to slightly yellow, aqueous solution containing 287 mg/mL of gadodiamide in rubber stoppered vials and prefilled syringes. OMNSICAN is supplied in the following sizes: - 5 mL fill in 10 mL vial, box of 10 (NDC 0407-0690-05) - 10 mL vial, box of 10 (NDC 0407-0690-10) - 15 mL fill in 20 mL vial, box of 10 (NDC 0407-0690-15) - 20 mL vial, box of 10 (NDC 0407-0690-20) - 10 mL fill in 20 mL prefilled syringe, box of 10 (NDC 0407-0690-12) - 15 mL fill in 20 mL prefilled syringe, box of 10 (NDC 0407-0690-17) - 20 mL prefilled syringe, box of 10 (NDC 0407-0690-22) - Prefill Plus™ needle-free system OMNISCAN 15 mL, box of 10 (NDC 0407-0691-62) Contains: OMNISCAN 15 mL fill in 20 mL Single Dose Prefilled Syringe and 5 mL 0.9% Sodium Chloride Injection, USP I.V. Flush Syringe - Prefill Plus™ needle-free system OMNISCAN 20 mL, box of 10 (NDC 0407-0691-63) Contains: OMNISCAN 20 mL fill in 20 mL Single Dose Prefilled Syringe and 5 mL 0.9% Sodium Chloride Injection, USP I.V. Flush Syringe - Protect gadodiamide from strong daylight and direct exposure to sunlight. Do not freeze. Freezing can cause small cracks in the vials, which would compromise the sterility of the product. Do not use if the product is inadvertently frozen. ## Storage - Store gadodiamide at controlled room temperature 20°-25°C (68°-77°F); excursions permitted to 15°-30°C (59°-86°F) [see USP]. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information - Patients receiving gadodiamide should be instructed to inform their physician if they: - Are pregnant or breast feeding, or - Have a history of renal and/or liver disease, convulsions, asthma or allergic respiratory disorders, or recent administration of gadolinium-based contrast. - GBCAs increase the risk for NSF among patients with impaired elimination of the drugs. To counsel patients at risk for NSF: - Describe the clinical manifestations of NSF - Describe procedures to screen for the detection of renal impairment - Instruct the patients to contact their physician if they develop signs or symptoms of NSF following gadodiamide administration such as burning, itching, swelling, scaling, hardening and tightening of the skin; red or dark patches on the skin; stiffness in joints with trouble moving, bending or straightening the arms, hands, legs or feet; pain deep in the hip bones or ribs; or muscle weakness. # Precautions with Alcohol - Alcohol-Gadodiamide interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - OMNISCAN # Look-Alike Drug Names - A® — B®[1] # Drug Shortage Status # Price	https://www.wikidoc.org/index.php/Gadodiamide
7899510be12eb0a9863d5b1456515a82aed36e6e	wikidoc	Gadoteridol	Gadoteridol # Disclaimer WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here. # Overview Gadoteridol is a non-Ionic contrast media that is FDA approved for the diagnosis of lesions with abnormal vascularity in the brain (intracranial lesions), spine and associated tissues in adults and children over 2 years of age using MRI. Common adverse reactions include taste sense altered. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) - Gadoteridol injection is indicated for use in MRI in adults and children over 2 years of age to visualize lesions with abnormal vascularity in the brain (intracranial lesions), spine and associated tissues. - ProHance is indicated for use in MRI in adults to visualize lesions in the head and neck. - ADULTS: The recommended dose of Gadoteridol Injection is 0.1 mmol/kg (0.2 mL/kg) administered as a rapid intravenous infusion (10 mL/min-60 mL/min) or bolus (> 60 mL/min). In patients with normal renal function suspected of having poorly enhancing lesions, in the presence of negative or equivocal scans, a supplementary dose of 0.2 mmol/kg (0.4 mL/kg) may be given up to 30 minutes after the first dose. - ADULTS: The recommended dose of gadoteridol is 0.1 mmol/kg (0.2 mL/kg) administered as a rapid intravenous infusion (10 mL/min-60 mL/min) or bolus (> 60 mL/min). ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Gadoteridol in adult patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Gadoteridol in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) - CHILDREN (2-18 years): The recommended dose of gadoteridol is 0.1 mmol/kg (0.2 mL/kg) administered as a rapid intravenous infusion (10 mL/min-60 mL/min) or bolus (> 60 mL/min). The safety and efficacy of doses > 0.1 mmol/kg, and sequential and/or repeat procedures has not been studied. - Safety and efficacy for extracranial/extra-spinal tissues has not been established. - Dose adjustments in renal and liver impairment have not been studied. - To ensure complete injection of the contrast medium, the injection should be followed by a 5 mL normal saline flush. The imaging procedure should be completed within 1 hour of the first injection of gadoteridol injection. - Parenteral products should be inspected visually for particulate matter and discoloration prior to administration. Do not use the solution if it is discolored or particulate matter is present. Any unused portion must be discarded in accordance with regulations dealing with the disposal of such materials. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Gadoteridol in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Gadoteridol in pediatric patients. # Contraindications - Gadoteridol is contraindicated in patients with known allergic or hypersensitivity reactions to gadoteridol. # Warnings - Gadolinium-based contrast agents (GBCAs) increase the risk for nephrogenic systemic fibrosis (NSF) among patients with impaired elimination of the drugs. Avoid use of GBCAs among these patients unless the diagnostic information is essential and not available with non-contrast enhanced MRI or other modalities. The GBCA-associated NSF risk appears highest for patients with chronic, severe kidney disease (GFR <30 mL/min/1.73m2) as well as patients with acute kidney injury. The risk appears lower for patients with chronic, moderate kidney disease (GFR 30-59 mL/min/1.73m2) and little, if any, for patients with chronic, mild kidney disease (GFR 60-89 mL/min/1.73m2). NSF may result in fatal or debilitating fibrosis affecting the skin, muscle and internal organs. Report any diagnosis of NSF following gadoteridol administration to Bracco Diagnostics (1-800-257-8151) or FDA (1-800-FDA-1088 or www.fda.gov/medwatch). - Screen patients for acute kidney injury and other conditions that may reduce renal function. Features of acute kidney injury consist of rapid (over hours to days) and usually reversible decrease in kidney function, commonly in the setting of surgery, severe infection, injury or drug-induced kidney toxicity. Serum creatinine levels and estimated GFR may not reliably assess renal function in the setting of acute kidney injury. For patients at risk for chronically reduced renal function (e.g., age > 60 years, diabetes mellitus or chronic hypertension), estimate the GFR through laboratory testing. - Among the factors that may increase the risk for NSF are repeated or higher than recommended doses of a GBCA and the degree of renal impairment at the time of exposure. Record the specific GBCA and the dose administered to a patient. For patients at highest risk for NSF, do not exceed the recommended gadoteridol dose and allow a sufficient period of time for elimination of the drug prior to re-administration. For patients receiving hemodialysis, physicians may consider the prompt initiation of hemodialysis following the administration of a GBCA in order to enhance the contrast agent’s elimination. The usefulness of hemodialysis in the prevention of NSF is unknown. - In patients with chronically reduced renal function, acute kidney injury requiring dialysis has occurred with the use of GBCAs. The risk of acute kidney injury]] may increase with increasing dose of the contrast agent; administer the lowest dose necessary for adequate imaging. - Severe and fatal hypersensitivity reactions including anaphylaxis have been observed with administration of gadolinium products, including gadoteridol. Patients with a history of allergy, drug reactions or other hypersensitivity-like disorders should be closely observed during the procedure and for several hours after drug administration. If a reaction occurs, stop gadoteridol and immediately begin appropriate therapy including resuscitation. - Deoxygenated sickle erythrocytes have been shown in in vitro studies to align perpendicular to a magnetic field which may result in vaso-occlusive complications in vivo. The enhancement of magnetic moment by gadoteridol may possibly potentiate sickle erythrocyte alignment. Gadoteridol in patients with sickle cell anemia and other hemoglobinopathies has not been studied. - Patients with other hemolytic anemias have not been adequately evaluated following administration of gadoteridol to exclude the possibility of increased hemolysis. # Adverse Reactions ## Clinical Trials Experience - The adverse events described in this section were observed in clinical trials involving 1251 patients (670 males and 581 females). Adult patients ranged in age from 18-91 yrs. Pediatric patients ranged from 2-17 years. The racial breakdown was 83% Caucasian, 8% Black, 3% Hispanic, 2% Asian, and 1% other. In 2% of the patients, race was not reported. - The most commonly noted adverse experiences were nausea and taste perversion with an incidence of 1.4%. These events were mild to moderate in severity. Seizure is also found in patients taking gadoteridol. - The following additional adverse events occurred in fewer than 1% of the patients: ## Postmarketing Experience There is limited information regarding Postmarketing Experience of Gadoteridol in the drug label. # Drug Interactions There is limited information regarding Gadoteridol Drug Interactions in the drug label. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): C - Gadoteridol administered to rats at 10 mmol/kg/day (33 times the maximum recommended human dose of 0.3 mmol/kg or 6 times the human dose based on a mmol/m2 comparison) for 12 days during gestation doubled the incidence of postimplantation loss. When rats were administered 6.0 or 10.0 mmol/ kg/day for 12 days, an increase in spontaneous locomotor activity was observed in the offspring. Gadoteridol increased the incidence of spontaneous abortion and early delivery in rabbits administered 6 mmol/kg/day (20 times the maximum recommended human dose or 7 times the human dose based on a mmol/m2 comparison) for 13 days during gestation. - There are no adequate and well-controlled studies in pregnant women. Gadoteridol) injection should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Pregnancy Category (AUS): - Australian Drug Evaluation Committee (ADEC) Pregnancy Category There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Gadoteridol in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Gadoteridol during labor and delivery. ### Nursing Mothers - It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when gadoteridol is administered to a nursing woman. ### Pediatric Use - Safety and efficacy in children under the age of 2 years have not been established. The safety and efficacy of doses > 0.1 mmol/kg; and sequential and/or repeat procedures has not been studied in children. ### Geriatic Use There is no FDA guidance on the use of Gadoteridol with respect to geriatric patients. ### Gender There is no FDA guidance on the use of Gadoteridol with respect to specific gender populations. ### Race There is no FDA guidance on the use of Gadoteridol with respect to specific racial populations. ### Renal Impairment There is no FDA guidance on the use of Gadoteridol in patients with renal impairment. ### Hepatic Impairment There is no FDA guidance on the use of Gadoteridol in patients with hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Gadoteridol in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Gadoteridol in patients who are immunocompromised. # Administration and Monitoring ### Administration - Intravenous. ### Monitoring There is limited information regarding Monitoring of Gadoteridol in the drug label. # IV Compatibility There is limited information regarding IV Compatibility of Gadoteridol in the drug label. # Overdosage Clinical consequences of overdose with gadoteridol have not been reported. # Pharmacology ## Mechanism of Action There is limited information regarding Gadoteridol Mechanism of Action in the drug label. ## Structure - Gadoteridol injection is a nonionic contrast medium for magnetic resonance imaging (MRI), available as a 0.5M sterile clear colorless to slightly yellow aqueous solution in vials and syringes for intravenous injection. - Gadoteridol is the gadolinium complex of 10-(2-hydroxy-propyl)-1,4,7,10- tetraazacyclododecane-1,4,7-triacetic acid with a molecular weight of 558.7, an empirical formula of C17H29N4O7Gd and has the following structural formula: - Gadoteridol has an osmolality 2.2 times that of plasma (285 mOsmol/kg water) and is hypertonic under conditions of use. ## Pharmacodynamics - Gadoteridol is a paramagnetic agent and, as such, develops a magnetic moment when placed in a magnetic field. The relatively large magnetic moment produced by the paramagnetic agent results in a relatively large local magnetic field, which can enhance the relaxation rates of water protons in the vicinity of the paramagnetic agent. - In magnetic resonance imaging (MRI), visualization of normal and pathologic brain tissue depends in part on variations in the radiofrequency signal intensity that occur with 1) differences in proton density; 2) differences of the spin-lattice or longitudinal relaxation times (T1); and 3) differences in the spin-spin or transverse relaxation time (T2). When placed in a magnetic field, gadoteridol decreases T1 relaxation times in the target tissues. At recommended doses, the effect is observed with greatest sensitivity in the T1-weighted sequences. - Gadoteridol does not cross the intact blood-brain barrier and, therefore, does not accumulate in normal brain or in lesions that have a normal blood-brain barrier, e.g., cysts, mature post-operative scars, etc. However, disruption of the blood-brain barrier or abnormal vascularity allows accumulation of gadoteridol in lesions such as neoplasms, abscesses, and subacute infarcts. The pharmacokinetics of gadoteridol in various lesions is not known. ## Pharmacokinetics - The pharmacokinetics of intravenously administered gadoteridol in normal subjects conforms to a two-compartment open model with mean distribution and elimination half-lives (reported as mean ± SD) of about 0.20 ± 0.04 hours and 1.57 ± 0.08 hours, respectively. - Gadoteridol is eliminated in the urine with 94.4 ± 4.8% (mean ± SD) of the dose excreted within 24 hours post-injection. It is unknown if biotransformation or decomposition of gadoteridol occur in vivo. - The renal and plasma clearance rates (1.41 ± 0.33 mL/ min/kg and 1.50 ± 0.35 mL/ min/kg, respectively) of gadoteridol are essentially identical, indicating no alteration in elimination kinetics on passage through the kidneys and that the drug is essentially cleared through the kidney. The volume of distribution (204 ± 58 mL/kg) is equal to that of extracellular water, and clearance is similar to that of substances which are subject to glomerular filtration. - It is unknown if protein binding of gadoteridol occurs in vivo. ## Nonclinical Toxicology There is limited information regarding Nonclinical Toxicology of Gadoteridol in the drug label. # Clinical Studies - Gadoteridol was evaluated in two blinded read trials in a total of 133 adults who had an indication for head and neck extracranial or extraspinal magnetic resonance imaging. These 133 adults (74 men, 59 women) had a mean age of 53 with a range of 19 to 76 years. Of these patients, 85% were Caucasian, 13% Black, 2% Asian, and < 1% other. The results of the non-contrast and gadoteridol MRI scans were compared. In this database, approximately 75-82% of the scans were enhanced. 45-48% of the scans provided additional diagnostic information, and 8-25% of the diagnoses were changed. The relevance of the findings to disease sensitivity and specificity has not been fully evaluated. - Gadoteridol was evaluated in a multicenter clinical trial of 103 children who had an indication for a brain or spine MRI. These 103 children, (54 boys and 49 girls) had a mean age of 8.7 years with an age range of 2 to 20 years. Of these 103 children, 54 were between 2 and 12 years of age. Also, of these 103 children, 74% were Caucasian, 11% Black, 12% Hispanic, 2% Asian, and 2% other. The results of the non-contrast and gadoteridol MRI scans were compared. Gadoteridol was given in one single 0.1 mmol/kg dose. Repeat dosing was not studied. In this database, MRI enhancement was noted in approximately 60% of the scans and additional diagnostic information in 30-95% of the scans. # How Supplied - Gadoteridol injection is a clear, colorless to slightly yellow solution containing 279.3 mg/mL of gadoteridol in rubber stoppered vials. Gadoteridol is available in boxes of: ## Storage - Gadoteridol Injection should be stored at 25° C (77° F) excursions permitted to 15-30° C (59-86° F) . Protect from light. DO NOT FREEZE. Should freezing occur in the vial, gadoteridol should be brought to room temperature before use. If allowed to stand at room temperature for a minimum of 60 minutes, Gadoteridol Injection should return to a clear, colorless to slightly yellow solution. Before use, examine the product to assure that all solids are redissolved and that the container and closure have not been damaged. Should solids persist, discard vial. Frozen syringes should be discarded. - Directions for Use of the Gadoteridol Injection single dose syringe* - Screw the threaded tip of the plunger rod clockwise into the cartridge plunger and push forward a few millimeters to break any friction between the cartridge plunger and syringe barrel. - Holding syringe erect, unscrew the plastic tip cap from the tip of the syringe and attach either a sterile, disposable needle or tubing with a compatible luer lock using a push-twist action. - Hold the syringe erect and push plunger forward until all of the air is evacuated and fluid either appears at the tip of the needle or the tubing is filled. Following the usual aspiration procedure, complete the injection. To ensure complete delivery of the contrast medium, the injection should be followed by a normal saline flush. - Properly dispose of the syringe and any other materials used. - The syringe assembly is a HYPAK SCF® single dose syringe supplied by Becton Dickinson. - Holding syringe erect, unscrew the plastic tip cap from the tip of the syringe and attach either a sterile, disposable needle or tubing with a compatible luer lock using a push-twist action. - Hold the syringe erect and push plunger forward until all of the air is evacuated and fluid either appears at the tip of the needle or the tubing is filled. Following the usual aspiration procedure, complete the injection. To ensure complete delivery of the contrast medium, the injection should be followed by a normal saline flush. - Properly dispose of the syringe and any other materials used. - The syringe assembly is a HYPAK SCF® single dose syringe supplied by Becton Dickinson. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information There is limited information regarding Patient Counseling Information of Gadoteridol in the drug label. # Precautions with Alcohol - Alcohol-Gadoteridol interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - ProHance® # Look-Alike Drug Names There is limited information regarding Gadoteridol Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	Gadoteridol Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Ammu Susheela, M.D. [2] # Disclaimer WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here. # Overview Gadoteridol is a non-Ionic contrast media that is FDA approved for the diagnosis of lesions with abnormal vascularity in the brain (intracranial lesions), spine and associated tissues in adults and children over 2 years of age using MRI. Common adverse reactions include taste sense altered. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) - Gadoteridol injection is indicated for use in MRI in adults and children over 2 years of age to visualize lesions with abnormal vascularity in the brain (intracranial lesions), spine and associated tissues. - ProHance is indicated for use in MRI in adults to visualize lesions in the head and neck. - ADULTS: The recommended dose of Gadoteridol Injection is 0.1 mmol/kg (0.2 mL/kg) administered as a rapid intravenous infusion (10 mL/min-60 mL/min) or bolus (> 60 mL/min). In patients with normal renal function suspected of having poorly enhancing lesions, in the presence of negative or equivocal scans, a supplementary dose of 0.2 mmol/kg (0.4 mL/kg) may be given up to 30 minutes after the first dose. - ADULTS: The recommended dose of gadoteridol is 0.1 mmol/kg (0.2 mL/kg) administered as a rapid intravenous infusion (10 mL/min-60 mL/min) or bolus (> 60 mL/min). ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Gadoteridol in adult patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Gadoteridol in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) - CHILDREN (2-18 years): The recommended dose of gadoteridol is 0.1 mmol/kg (0.2 mL/kg) administered as a rapid intravenous infusion (10 mL/min-60 mL/min) or bolus (> 60 mL/min). The safety and efficacy of doses > 0.1 mmol/kg, and sequential and/or repeat procedures has not been studied. - Safety and efficacy for extracranial/extra-spinal tissues has not been established. - Dose adjustments in renal and liver impairment have not been studied. - To ensure complete injection of the contrast medium, the injection should be followed by a 5 mL normal saline flush. The imaging procedure should be completed within 1 hour of the first injection of gadoteridol injection. - Parenteral products should be inspected visually for particulate matter and discoloration prior to administration. Do not use the solution if it is discolored or particulate matter is present. Any unused portion must be discarded in accordance with regulations dealing with the disposal of such materials. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Gadoteridol in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Gadoteridol in pediatric patients. # Contraindications - Gadoteridol is contraindicated in patients with known allergic or hypersensitivity reactions to gadoteridol. # Warnings - Gadolinium-based contrast agents (GBCAs) increase the risk for nephrogenic systemic fibrosis (NSF) among patients with impaired elimination of the drugs. Avoid use of GBCAs among these patients unless the diagnostic information is essential and not available with non-contrast enhanced MRI or other modalities. The GBCA-associated NSF risk appears highest for patients with chronic, severe kidney disease (GFR <30 mL/min/1.73m2) as well as patients with acute kidney injury. The risk appears lower for patients with chronic, moderate kidney disease (GFR 30-59 mL/min/1.73m2) and little, if any, for patients with chronic, mild kidney disease (GFR 60-89 mL/min/1.73m2). NSF may result in fatal or debilitating fibrosis affecting the skin, muscle and internal organs. Report any diagnosis of NSF following gadoteridol administration to Bracco Diagnostics (1-800-257-8151) or FDA (1-800-FDA-1088 or www.fda.gov/medwatch). - Screen patients for acute kidney injury and other conditions that may reduce renal function. Features of acute kidney injury consist of rapid (over hours to days) and usually reversible decrease in kidney function, commonly in the setting of surgery, severe infection, injury or drug-induced kidney toxicity. Serum creatinine levels and estimated GFR may not reliably assess renal function in the setting of acute kidney injury. For patients at risk for chronically reduced renal function (e.g., age > 60 years, diabetes mellitus or chronic hypertension), estimate the GFR through laboratory testing. - Among the factors that may increase the risk for NSF are repeated or higher than recommended doses of a GBCA and the degree of renal impairment at the time of exposure. Record the specific GBCA and the dose administered to a patient. For patients at highest risk for NSF, do not exceed the recommended gadoteridol dose and allow a sufficient period of time for elimination of the drug prior to re-administration. For patients receiving hemodialysis, physicians may consider the prompt initiation of hemodialysis following the administration of a GBCA in order to enhance the contrast agent’s elimination. The usefulness of hemodialysis in the prevention of NSF is unknown. - In patients with chronically reduced renal function, acute kidney injury requiring dialysis has occurred with the use of GBCAs. The risk of [[]acute kidney injury]] may increase with increasing dose of the contrast agent; administer the lowest dose necessary for adequate imaging. - Severe and fatal hypersensitivity reactions including anaphylaxis have been observed with administration of gadolinium products, including gadoteridol. Patients with a history of allergy, drug reactions or other hypersensitivity-like disorders should be closely observed during the procedure and for several hours after drug administration. If a reaction occurs, stop gadoteridol and immediately begin appropriate therapy including resuscitation. - Deoxygenated sickle erythrocytes have been shown in in vitro studies to align perpendicular to a magnetic field which may result in vaso-occlusive complications in vivo. The enhancement of magnetic moment by gadoteridol may possibly potentiate sickle erythrocyte alignment. Gadoteridol in patients with sickle cell anemia and other hemoglobinopathies has not been studied. - Patients with other hemolytic anemias have not been adequately evaluated following administration of gadoteridol to exclude the possibility of increased hemolysis. # Adverse Reactions ## Clinical Trials Experience - The adverse events described in this section were observed in clinical trials involving 1251 patients (670 males and 581 females). Adult patients ranged in age from 18-91 yrs. Pediatric patients ranged from 2-17 years. The racial breakdown was 83% Caucasian, 8% Black, 3% Hispanic, 2% Asian, and 1% other. In 2% of the patients, race was not reported. - The most commonly noted adverse experiences were nausea and taste perversion with an incidence of 1.4%. These events were mild to moderate in severity. Seizure is also found in patients taking gadoteridol. - The following additional adverse events occurred in fewer than 1% of the patients: ## Postmarketing Experience There is limited information regarding Postmarketing Experience of Gadoteridol in the drug label. # Drug Interactions There is limited information regarding Gadoteridol Drug Interactions in the drug label. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): C - Gadoteridol administered to rats at 10 mmol/kg/day (33 times the maximum recommended human dose of 0.3 mmol/kg or 6 times the human dose based on a mmol/m2 comparison) for 12 days during gestation doubled the incidence of postimplantation loss. When rats were administered 6.0 or 10.0 mmol/ kg/day for 12 days, an increase in spontaneous locomotor activity was observed in the offspring. Gadoteridol increased the incidence of spontaneous abortion and early delivery in rabbits administered 6 mmol/kg/day (20 times the maximum recommended human dose or 7 times the human dose based on a mmol/m2 comparison) for 13 days during gestation. - There are no adequate and well-controlled studies in pregnant women. Gadoteridol) injection should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Pregnancy Category (AUS): - Australian Drug Evaluation Committee (ADEC) Pregnancy Category There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Gadoteridol in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Gadoteridol during labor and delivery. ### Nursing Mothers - It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when gadoteridol is administered to a nursing woman. ### Pediatric Use - Safety and efficacy in children under the age of 2 years have not been established. The safety and efficacy of doses > 0.1 mmol/kg; and sequential and/or repeat procedures has not been studied in children. ### Geriatic Use There is no FDA guidance on the use of Gadoteridol with respect to geriatric patients. ### Gender There is no FDA guidance on the use of Gadoteridol with respect to specific gender populations. ### Race There is no FDA guidance on the use of Gadoteridol with respect to specific racial populations. ### Renal Impairment There is no FDA guidance on the use of Gadoteridol in patients with renal impairment. ### Hepatic Impairment There is no FDA guidance on the use of Gadoteridol in patients with hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Gadoteridol in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Gadoteridol in patients who are immunocompromised. # Administration and Monitoring ### Administration - Intravenous. ### Monitoring There is limited information regarding Monitoring of Gadoteridol in the drug label. # IV Compatibility There is limited information regarding IV Compatibility of Gadoteridol in the drug label. # Overdosage Clinical consequences of overdose with gadoteridol have not been reported. # Pharmacology ## Mechanism of Action There is limited information regarding Gadoteridol Mechanism of Action in the drug label. ## Structure - Gadoteridol injection is a nonionic contrast medium for magnetic resonance imaging (MRI), available as a 0.5M sterile clear colorless to slightly yellow aqueous solution in vials and syringes for intravenous injection. - Gadoteridol is the gadolinium complex of 10-(2-hydroxy-propyl)-1,4,7,10- tetraazacyclododecane-1,4,7-triacetic acid with a molecular weight of 558.7, an empirical formula of C17H29N4O7Gd and has the following structural formula: - Gadoteridol has an osmolality 2.2 times that of plasma (285 mOsmol/kg water) and is hypertonic under conditions of use. ## Pharmacodynamics - Gadoteridol is a paramagnetic agent and, as such, develops a magnetic moment when placed in a magnetic field. The relatively large magnetic moment produced by the paramagnetic agent results in a relatively large local magnetic field, which can enhance the relaxation rates of water protons in the vicinity of the paramagnetic agent. - In magnetic resonance imaging (MRI), visualization of normal and pathologic brain tissue depends in part on variations in the radiofrequency signal intensity that occur with 1) differences in proton density; 2) differences of the spin-lattice or longitudinal relaxation times (T1); and 3) differences in the spin-spin or transverse relaxation time (T2). When placed in a magnetic field, gadoteridol decreases T1 relaxation times in the target tissues. At recommended doses, the effect is observed with greatest sensitivity in the T1-weighted sequences. - Gadoteridol does not cross the intact blood-brain barrier and, therefore, does not accumulate in normal brain or in lesions that have a normal blood-brain barrier, e.g., cysts, mature post-operative scars, etc. However, disruption of the blood-brain barrier or abnormal vascularity allows accumulation of gadoteridol in lesions such as neoplasms, abscesses, and subacute infarcts. The pharmacokinetics of gadoteridol in various lesions is not known. ## Pharmacokinetics - The pharmacokinetics of intravenously administered gadoteridol in normal subjects conforms to a two-compartment open model with mean distribution and elimination half-lives (reported as mean ± SD) of about 0.20 ± 0.04 hours and 1.57 ± 0.08 hours, respectively. - Gadoteridol is eliminated in the urine with 94.4 ± 4.8% (mean ± SD) of the dose excreted within 24 hours post-injection. It is unknown if biotransformation or decomposition of gadoteridol occur in vivo. - The renal and plasma clearance rates (1.41 ± 0.33 mL/ min/kg and 1.50 ± 0.35 mL/ min/kg, respectively) of gadoteridol are essentially identical, indicating no alteration in elimination kinetics on passage through the kidneys and that the drug is essentially cleared through the kidney. The volume of distribution (204 ± 58 mL/kg) is equal to that of extracellular water, and clearance is similar to that of substances which are subject to glomerular filtration. - It is unknown if protein binding of gadoteridol occurs in vivo. ## Nonclinical Toxicology There is limited information regarding Nonclinical Toxicology of Gadoteridol in the drug label. # Clinical Studies - Gadoteridol was evaluated in two blinded read trials in a total of 133 adults who had an indication for head and neck extracranial or extraspinal magnetic resonance imaging. These 133 adults (74 men, 59 women) had a mean age of 53 with a range of 19 to 76 years. Of these patients, 85% were Caucasian, 13% Black, 2% Asian, and < 1% other. The results of the non-contrast and gadoteridol MRI scans were compared. In this database, approximately 75-82% of the scans were enhanced. 45-48% of the scans provided additional diagnostic information, and 8-25% of the diagnoses were changed. The relevance of the findings to disease sensitivity and specificity has not been fully evaluated. - Gadoteridol was evaluated in a multicenter clinical trial of 103 children who had an indication for a brain or spine MRI. These 103 children, (54 boys and 49 girls) had a mean age of 8.7 years with an age range of 2 to 20 years. Of these 103 children, 54 were between 2 and 12 years of age. Also, of these 103 children, 74% were Caucasian, 11% Black, 12% Hispanic, 2% Asian, and 2% other. The results of the non-contrast and gadoteridol MRI scans were compared. Gadoteridol was given in one single 0.1 mmol/kg dose. Repeat dosing was not studied. In this database, MRI enhancement was noted in approximately 60% of the scans and additional diagnostic information in 30-95% of the scans. # How Supplied - Gadoteridol injection is a clear, colorless to slightly yellow solution containing 279.3 mg/mL of gadoteridol in rubber stoppered vials. Gadoteridol is available in boxes of: ## Storage - Gadoteridol Injection should be stored at 25° C (77° F) excursions permitted to 15-30° C (59-86° F) [See USP Controlled Room Temperature]. Protect from light. DO NOT FREEZE. Should freezing occur in the vial, gadoteridol should be brought to room temperature before use. If allowed to stand at room temperature for a minimum of 60 minutes, Gadoteridol Injection should return to a clear, colorless to slightly yellow solution. Before use, examine the product to assure that all solids are redissolved and that the container and closure have not been damaged. Should solids persist, discard vial. Frozen syringes should be discarded. - Directions for Use of the Gadoteridol Injection single dose syringe* - Screw the threaded tip of the plunger rod clockwise into the cartridge plunger and push forward a few millimeters to break any friction between the cartridge plunger and syringe barrel. - Holding syringe erect, unscrew the plastic tip cap from the tip of the syringe and attach either a sterile, disposable needle or tubing with a compatible luer lock using a push-twist action. - Hold the syringe erect and push plunger forward until all of the air is evacuated and fluid either appears at the tip of the needle or the tubing is filled. Following the usual aspiration procedure, complete the injection. To ensure complete delivery of the contrast medium, the injection should be followed by a normal saline flush. - Properly dispose of the syringe and any other materials used. - The syringe assembly is a HYPAK SCF® single dose syringe supplied by Becton Dickinson. - Holding syringe erect, unscrew the plastic tip cap from the tip of the syringe and attach either a sterile, disposable needle or tubing with a compatible luer lock using a push-twist action. - Hold the syringe erect and push plunger forward until all of the air is evacuated and fluid either appears at the tip of the needle or the tubing is filled. Following the usual aspiration procedure, complete the injection. To ensure complete delivery of the contrast medium, the injection should be followed by a normal saline flush. - Properly dispose of the syringe and any other materials used. - The syringe assembly is a HYPAK SCF® single dose syringe supplied by Becton Dickinson. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information There is limited information regarding Patient Counseling Information of Gadoteridol in the drug label. # Precautions with Alcohol - Alcohol-Gadoteridol interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - ProHance®[1] # Look-Alike Drug Names There is limited information regarding Gadoteridol Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	https://www.wikidoc.org/index.php/Gadoteridol
c96d7d9bc33524ec4b4674f536870b000de4a098	wikidoc	Galactocele	Galactocele Quick Start: You can begin to add to or edit text on this wiki doc page by clicking on the edit button above and to the left on this same page. Type in the text you want to add. Once you are done, click the save changes button at the bottom. Galactocele Apply to be Editor-In-Chief for this topic: There can be one or more than one Editor-In-Chief. You may also apply to be an Associate Editor-In-Chief of one of the subtopics below. Please email [email protected] to indicate your interest in serving either as an Editor-In-Chief of the entire topic or as an Associate Editor-In-Chief for a subtopic. Please be sure to attach your CV and or biographical sketch. # Overview # Epidemiology and Demographics # Risk Factors # Screening # Pathophysiology & Etiology # Molecular Biology # Genetics # Natural History # Diagnosis # Differential Diagnosis For differentiating galactocele from other causes of breast lump, click here. # History and Symptoms # Physical Examination ## Appearance of the Patient ## Eyes ## Ear Nose and Throat ## Heart ## Lungs ## Abdomen ## Extremities ## Neurologic ## Other # Laboratory Findings ## Electrolyte and Biomarker Studies ## Electrocardiogram ## Chest X Ray ## MRI and CT ## Echocardiography or Ultrasound ## Other Imaging Findings ## Other Diagnostic Studies # Risk Stratification and Prognosis # Treatment # Pharmacotherapy ## Acute Pharmacotherapies ## Chronic Pharmacotherapies # Surgery and Device Based Therapy ## Indications for Surgery ## Pre-Operative Assessment ## Post-Operative Management ## Transplantation # Primary Prevention # Secondary Prevention # Cost-Effectiveness of Therapy # Future or Investigational Therapies # Suggested Revisions to the Current Guidelines	Galactocele Quick Start: You can begin to add to or edit text on this wiki doc page by clicking on the edit button above and to the left on this same page. Type in the text you want to add. Once you are done, click the save changes button at the bottom. Galactocele ### Editor-In-Chief: Apply to be Editor-In-Chief for this topic: There can be one or more than one Editor-In-Chief. You may also apply to be an Associate Editor-In-Chief of one of the subtopics below. Please email [email protected] to indicate your interest in serving either as an Editor-In-Chief of the entire topic or as an Associate Editor-In-Chief for a subtopic. Please be sure to attach your CV and or biographical sketch. # Overview # Epidemiology and Demographics # Risk Factors # Screening # Pathophysiology & Etiology # Molecular Biology # Genetics # Natural History # Diagnosis # Differential Diagnosis For differentiating galactocele from other causes of breast lump, click here. # History and Symptoms # Physical Examination ## Appearance of the Patient ## Eyes ## Ear Nose and Throat ## Heart ## Lungs ## Abdomen ## Extremities ## Neurologic ## Other # Laboratory Findings ## Electrolyte and Biomarker Studies ## Electrocardiogram ## Chest X Ray ## MRI and CT ## Echocardiography or Ultrasound ## Other Imaging Findings ## Other Diagnostic Studies # Risk Stratification and Prognosis # Treatment # Pharmacotherapy ## Acute Pharmacotherapies ## Chronic Pharmacotherapies # Surgery and Device Based Therapy ## Indications for Surgery ## Pre-Operative Assessment ## Post-Operative Management ## Transplantation # Primary Prevention # Secondary Prevention # Cost-Effectiveness of Therapy # Future or Investigational Therapies # Suggested Revisions to the Current Guidelines	https://www.wikidoc.org/index.php/Galactocele
2b6e3b814c44fa811a23ffc92a65a3339f65e456	wikidoc	Gallbladder	Gallbladder # Overview The gallbladder (or cholecyst, sometimes gall bladder) is a pear-shaped organ that stores about 50 ml of bile (or "gall") until the body needs it for digestion. # Anatomy The gallbladder is about 100 to 120 mm long in humans and appears dark green because of its contents (bile), rather than its tissue. It is connected to the liver and the duodenum by the biliary tract. - The cystic duct connects the gallbladder to the common hepatic duct to form the common bile duct. - The common bile duct then joins the pancreatic duct, and enters through the hepatopancreatic ampulla at the major duodenal papilla. - The fundus of the gallbladder is the part farthest from the duct, located by the lower border of the liver . It's at the same level as the transpyloric plane. # Microscopic anatomy The different layers of the gallbladder are as follows: - The gallbladder has a simple columnar epithelial lining characterized by recesses called Aschoff's recesses, which are pouches inside the lining. - Under the epithelium there is a layer of connective tissue (lamina propria). - Beneath the connective tissue is a wall of smooth muscle (muscularis externa) that contracts in response to cholecystokinin, a peptide hormone secreted by the duodenum. - There is essentially no submucosa separating the connective tissue from serosa and adventitia. Section References # Function The gallbladder stores about 50 ml (1.7 US fluid ounces / 1.8 Imperial fluid ounces) of bile, which is released when food containing fat enters the digestive tract, stimulating the secretion of cholecystokinin (CCK). The bile, produced in the liver, emulsifies fats and neutralizes acids in partly digested food. After being stored in the gallbladder the bile becomes more concentrated than when it left the liver, increasing its potency and intensifying its effect on fats. Most digestion occurs in the duodenum. # Role in disease - Cholestasis is the blockage in the supply of bile into the digestive tract. It can be "intrahepatic" (the obstruction is in the liver) or "extrahepatic" (outside the liver). It can lead to jaundice, and is identified by the presence of elevated bilirubin level that is mainly conjugated. - Biliary colic is when a gallstone blocks either the common bile duct or the duct leading into it from the gallbladder. - Up to 25% of all people have gallstones (cholelithiasis), composed of lecithin and bile acids. These can cause abdominal pain, usually in relation with a meal, as the gallbladder contracts and gallstones pass through the bile duct. - Acute or chronic inflammation of the gallbladder (cholecystitis) causes abdominal pain. 90% of cases of acute cholecystitis are caused by the presence of gallstones. The actual inflammation is due to secondary infection with bacteria of an obstructed gallbladder, with the obstruction caused by the gallstone. - When gallstones obstruct the common bile duct (choledocholithiasis), the patient develops jaundice and liver cell damage. It can be a medical emergency, requiring endoscopic or surgical treatment such as a cholecystectomy. Most gallstones are eventually passed naturally, though the passing is typically quite painful. - A rare clinical entity is ileus (bowel) obstruction by a large gallstone, or gallstone ileus. This condition develops in patients with longstanding gallstone disease, in which the gallbladder forms a fistula with the digestive tract. Large stones pass into the bowel, and generally block the gut at the level of Treitz' ligament or the ileocecal valve, two narrow points in the digestive tract. The treatment is surgical. - Cancer of the gallbladder is a rare but highly fatal disease. It has been associated with gallstone disease, estrogens, cigarette smoking, alcohol consumption and obesity. Despite aggressive modern surgical approaches, advanced imaging techniques, and endoscopy, nearly 90% of patients die from advanced stages of the disease and experience pain, jaundice, weight loss, and ascites. - Polyps (growths) are sometimes detected during diagnostic tests for gallbladder disease. Small gallbladder polyps (up to 10 mm) pose little or no risk, but large ones (greater than 15 mm) pose some risk for cancer, so the gallbladder should be removed. Patients with polyps 10 mm to 15 mm have a lower risk but they should still discuss removal of their gallbladder with their physician. Of special note is a condition called primary sclerosing cholangitis, which causes inflammation and scarring in the bile duct. It is associated with a lifetime risk of 7% to 12% for gallbladder cancer. The cause is unknown, although primary sclerosing cholangitis tends to strike younger men who have ulcerative colitis. Polyps are often detected in this condition and have a very high likelihood of malignancy. # Additional images - The celiac artery and its branches. - Gall bladder - Transverse section of gall-bladder. - Topography of thoracic and abdominal viscera. - Digestive system diagram showing the bile duct - The portal vein and its tributaries. - Cholecystectomy seen through a laparoscope	Gallbladder Template:Infobox Anatomy Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview The gallbladder (or cholecyst, sometimes gall bladder) is a pear-shaped organ that stores about 50 ml of bile (or "gall") until the body needs it for digestion. # Anatomy The gallbladder is about 100 to 120 mm long in humans and appears dark green because of its contents (bile), rather than its tissue. It is connected to the liver and the duodenum by the biliary tract. - The cystic duct connects the gallbladder to the common hepatic duct to form the common bile duct. - The common bile duct then joins the pancreatic duct, and enters through the hepatopancreatic ampulla at the major duodenal papilla.[1][2] - The fundus of the gallbladder is the part farthest from the duct, located by the lower border of the liver [3]. It's at the same level as the transpyloric plane. # Microscopic anatomy The different layers of the gallbladder are as follows: - The gallbladder has a simple columnar epithelial lining characterized by recesses called Aschoff's recesses, which are pouches inside the lining. - Under the epithelium there is a layer of connective tissue (lamina propria). - Beneath the connective tissue is a wall of smooth muscle (muscularis externa) that contracts in response to cholecystokinin, a peptide hormone secreted by the duodenum. - There is essentially no submucosa separating the connective tissue from serosa and adventitia. Section References[4] # Function The gallbladder stores about 50 ml (1.7 US fluid ounces / 1.8 Imperial fluid ounces) of bile, which is released when food containing fat enters the digestive tract, stimulating the secretion of cholecystokinin (CCK). The bile, produced in the liver, emulsifies fats and neutralizes acids in partly digested food. After being stored in the gallbladder the bile becomes more concentrated than when it left the liver, increasing its potency and intensifying its effect on fats. Most digestion occurs in the duodenum. # Role in disease - Cholestasis is the blockage in the supply of bile into the digestive tract. It can be "intrahepatic" (the obstruction is in the liver) or "extrahepatic" (outside the liver). It can lead to jaundice, and is identified by the presence of elevated bilirubin level that is mainly conjugated. - Biliary colic is when a gallstone blocks either the common bile duct or the duct leading into it from the gallbladder. - Up to 25% of all people have gallstones (cholelithiasis), composed of lecithin and bile acids. These can cause abdominal pain, usually in relation with a meal, as the gallbladder contracts and gallstones pass through the bile duct. - Acute or chronic inflammation of the gallbladder (cholecystitis) causes abdominal pain. 90% of cases of acute cholecystitis are caused by the presence of gallstones. The actual inflammation is due to secondary infection with bacteria of an obstructed gallbladder, with the obstruction caused by the gallstone. - When gallstones obstruct the common bile duct (choledocholithiasis), the patient develops jaundice and liver cell damage. It can be a medical emergency, requiring endoscopic or surgical treatment such as a cholecystectomy. Most gallstones are eventually passed naturally, though the passing is typically quite painful. - A rare clinical entity is ileus (bowel) obstruction by a large gallstone, or gallstone ileus. This condition develops in patients with longstanding gallstone disease, in which the gallbladder forms a fistula with the digestive tract. Large stones pass into the bowel, and generally block the gut at the level of Treitz' ligament or the ileocecal valve, two narrow points in the digestive tract. The treatment is surgical. - Cancer of the gallbladder is a rare but highly fatal disease. It has been associated with gallstone disease, estrogens, cigarette smoking, alcohol consumption and obesity. Despite aggressive modern surgical approaches, advanced imaging techniques, and endoscopy, nearly 90% of patients die from advanced stages of the disease and experience pain, jaundice, weight loss, and ascites. - Polyps (growths) are sometimes detected during diagnostic tests for gallbladder disease. Small gallbladder polyps (up to 10 mm) pose little or no risk, but large ones (greater than 15 mm) pose some risk for cancer, so the gallbladder should be removed. Patients with polyps 10 mm to 15 mm have a lower risk but they should still discuss removal of their gallbladder with their physician. Of special note is a condition called primary sclerosing cholangitis, which causes inflammation and scarring in the bile duct. It is associated with a lifetime risk of 7% to 12% for gallbladder cancer. The cause is unknown, although primary sclerosing cholangitis tends to strike younger men who have ulcerative colitis. Polyps are often detected in this condition and have a very high likelihood of malignancy. # Additional images - The celiac artery and its branches. - Gall bladder - Transverse section of gall-bladder. - Topography of thoracic and abdominal viscera. - Digestive system diagram showing the bile duct - The portal vein and its tributaries. - Cholecystectomy seen through a laparoscope -	https://www.wikidoc.org/index.php/Gall-bladder
cb756b30c103c3da1761c78ea1fef9bbb6d4956f	wikidoc	HPV Vaccine	HPV Vaccine # Disclaimer WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here. # Overview HPV Vaccine is a Adrenergic receptor agonist that is FDA approved for the prophylaxis of HPV types 6, 11, 16 and 18 infections. Common adverse reactions include erythema at injection site, injection site pain, injection site pruritus, swelling at injection site, nausea, dizziness, headache, fever. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) GARDASIL should be administered intramuscularly as a 0.5-mL dose at the following schedule: 0, 2 months, 6 months. For intramuscular use only. Shake well before use. Thorough agitation immediately before administration is necessary to maintain suspension of the vaccine. Human papillomavirus quadrivalent vaccine should not be diluted or mixed with other vaccines. After thorough agitation, human papillomavirus quadrivalent vaccine is a white, cloudy liquid. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration. Do not use the product if particulates are present or if it appears discolored. human papillomavirus quadrivalent vaccine should be administered intramuscularly in the deltoid region of the upper arm or in the higher anterolateral area of the thigh. Syncope has been reported following vaccination with human papillomavirus quadrivalent vaccine and may result in falling with injury; observation for 15 minutes after administration is recommended. Withdraw the 0.5-mL dose of vaccine from the single-dose vial using a sterile needle and syringe and use promptly. This package does not contain a needle. Shake well before use. Attach the needle by twisting in a clockwise direction until the needle fits securely on the syringe. Administer the entire dose as per standard protocol. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of HPV Vaccine in adult patients. ### Non–Guideline-Supported Use - Dosing Information - IM injections day 1 and months 2 and 6 for patients 9-26 years of age. - Dosing Information - IM injections day 1 and months 2 and 6 for patients 9-26 years of age. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) There is limited information regarding HPV Vaccine FDA-Labeled Indications and Dosage (Pediatric) in the drug label. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of HPV Vaccine in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of HPV Vaccine in pediatric patients. # Contraindications Hypersensitivity, including severe allergic reactions to yeast (a vaccine component), or after a previous dose of GARDASIL. # Warnings Because vaccinees may develop syncope, sometimes resulting in falling with injury, observation for 15 minutes after administration is recommended. Syncope, sometimes associated with tonic-clonic movements and other seizure-like activity, has been reported following vaccination with human papillomavirus quadrivalent vaccine. When syncope is associated with tonic-clonic movements, the activity is usually transient and typically responds to restoring cerebral perfusion by maintaining a supine or Trendelenburg position. Appropriate medical treatment and supervision must be readily available in case of anaphylactic reactions following the administration of human papillomavirus quadrivalent vaccine. # Adverse Reactions ## Clinical Trials Experience Headache, fever, nausea, and dizziness; and local injection site reactions (pain, swelling, erythema, pruritus, and bruising) occurred after administration with human papillomavirus quadrivalent vaccine. Syncope, sometimes associated with tonic-clonic movements and other seizure-like activity, has been reported following vaccination with human papillomavirus quadrivalent vaccine and may result in falling with injury; observation for 15 minutes after administration is recommended. Anaphylaxis has been reported following vaccination with human papillomavirus quadrivalent vaccine. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a vaccine cannot be directly compared to rates in the clinical trials of another vaccine and may not reflect the rates observed in practice. In 7 clinical trials (5 Amorphous Aluminum Hydroxyphosphate Sulfate -controlled, 1 saline placebo-controlled, and 1 uncontrolled), 18,083 individuals were administered human papillomavirus quadrivalent vaccine or AAHS control or saline placebo on the day of enrollment, and approximately 2 and 6 months thereafter, and safety was evaluated using vaccination report cards (VRC)-aided surveillance for 14 days after each injection of human papillomavirus quadrivalent vaccine or AAHS control or saline placebo in these individuals. The individuals who were monitored using VRC-aided surveillance included 10,088 individuals 9 through 45 years of age at enrollment who received human papillomavirus quadrivalent vaccine and 7,995 individuals who received AAHS control or saline placebo. Few individuals (0.2%) discontinued due to adverse reactions. The race distribution of the 9- through 26-year-old girls and women in the safety population was as follows: 62.3% White; 17.6% Hispanic (Black and White); 6.8% Asian; 6.7% Other; 6.4% Black; and 0.3% American Indian. The race distribution of the 24- through 45-year-old women in the safety population of Study 6 was as follows: 20.6% White; 43.2% Hispanic (Black and White); 0.2% Other; 4.8% Black; 31.2% Asian; and 0.1% American Indian. The race distribution of the 9- through 26-year-old boys and men in the safety population was as follows: 42.0% White; 19.7% Hispanic (Black and White); 11.0% Asian; 11.2% Other; 15.9% Black; and 0.1% American Indian. The injection site adverse reactions that were observed among recipients of human papillomavirus quadrivalent vaccine at a frequency of at least 1.0% and also at a greater frequency than that observed among AAHS control or saline placebo recipients are shown in Table 1. The injection site adverse reactions that were observed among recipients of human papillomavirus quadrivalent vaccine at a frequency of at least 1.0% and also at a greater frequency than that observed among AAHS control or saline placebo recipients are shown in Table 2. An analysis of injection-site adverse reactions in girls and women by dose is shown in Table 3. Of those girls and women who reported an injection-site reaction, 94.3% judged their injection-site adverse reaction to be mild or moderate in intensity. An analysis of injection-site adverse reactions in boys and men by dose is shown in Table 4. Of those boys and men who reported an injection-site reaction, 96.4% judged their injection-site adverse reaction to be mild or moderate in intensity. Headache was the most commonly reported systemic adverse reaction in both treatment groups (human papillomavirus quadrivalent vaccine = 28.2% and AAHS control or saline placebo = 28.4%). Fever was the next most commonly reported systemic adverse reaction in both treatment groups (human papillomavirus quadrivalent vaccine = 13.0% and AAHS control or saline placebo = 11.2%). Adverse reactions that were observed among recipients of human papillomavirus quadrivalent vaccine, at a frequency of greater than or equal to 1.0% where the incidence in the human papillomavirus quadrivalent vaccine group was greater than or equal to the incidence in the AAHS control or saline placebo group, are shown in Table 5. Headache was the most commonly reported systemic adverse reaction in both treatment groups (human papillomavirus quadrivalent vaccine = 12.3% and AAHS control or saline placebo = 11.2%). Fever was the next most commonly reported systemic adverse reaction in both treatment groups (human papillomavirus quadrivalent vaccine = 8.3% and AAHS control or saline placebo = 6.5%). Adverse reactions that were observed among recipients of human papillomavirus quadrivalent vaccine, at a frequency of greater than or equal to 1.0% where the incidence in the group that received human papillomavirus quadrivalent vaccine was greater than or equal to the incidence in the AAHS control or saline placebo group, are shown in Table 6. An analysis of fever in girls and women by dose is shown in Table 7. An analysis of fever in boys and men by dose is shown in Table 8. Across the clinical studies, 258 individuals (human papillomavirus quadrivalent vaccine N = 128 or 0.8%; placebo N = 130 or 1.0%) out of 29,323 (human papillomavirus quadrivalent vaccine N = 15,706; AAHS control N = 13,023; or saline placebo N = 594) individuals (9- through 45-year-old girls and women; and 9- through 26-year-old boys and men) reported a serious systemic adverse reaction. Of the entire study population (29,323 individuals), 0.04% of the reported serious systemic adverse reactions were judged to be vaccine related by the study investigator. The most frequently (frequency of 4 cases or greater with either human papillomavirus quadrivalent vaccine, AAHS control, saline placebo, or the total of all three) reported serious systemic adverse reactions, regardless of causality, were: Headache , Gastroenteritis , Appendicitis , Pelvic inflammatory disease , Urinary tract infection , Pneumonia , Pyelonephritis , Pulmonary embolism . One case (0.006% human papillomavirus quadrivalent vaccine; 0.0% AAHS control or saline placebo) of bronchospasm; and 2 cases (0.01% human papillomavirus quadrivalent vaccine; 0.0% AAHS control or saline placebo) of asthma were reported as serious systemic adverse reactions that occurred following any vaccination visit. In addition, there was 1 individual in the clinical trials, in the group that received human papillomavirus quadrivalent vaccine, who reported two injection-site serious adverse reactions (injection-site pain and injection-site joint movement impairment). Across the clinical studies, 40 deaths (human papillomavirus quadrivalent vaccine N = 21 or 0.1%; placebo N = 19 or 0.1%) were reported in 29,323 (human papillomavirus quadrivalent vaccine N = 15,706; AAHS control N = 13,023, saline placebo N = 594) individuals (9- through 45-year-old girls and women; and 9- through 26-year-old boys and men). The events reported were consistent with events expected in healthy adolescent and adult populations. The most common cause of death was motor vehicle accident (5 individuals who received human papillomavirus quadrivalent vaccine and 4 individuals who received AAHS control), followed by drug overdose/suicide (2 individuals who received human papillomavirus quadrivalent vaccine and 6 individuals who received AAHS control), gunshot wound (1 individual who received human papillomavirus quadrivalent vaccine and 3 individuals who received AAHS control), and pulmonary embolus/deep vein thrombosis (1 individual who received human papillomavirus quadrivalent vaccine and 1 individual who received AAHS control). In addition, there were 2 cases of sepsis, 1 case of pancreatic cancer, 1 case of arrhythmia, 1 case of pulmonary tuberculosis, 1 case of hyperthyroidism, 1 case of post-operative pulmonary embolism and acute renal failure, 1 case of traumatic brain injury/cardiac arrest, 1 case of systemic lupus erythematosus, 1 case of cerebrovascular accident, 1 case of breast cancer, and 1 case of nasopharyngeal cancer in the group that received human papillomavirus quadrivalent vaccine; 1 case of asphyxia, 1 case of acute lymphocytic leukemia, 1 case of chemical poisoning, and 1 case of myocardial ischemia in the AAHS control group; and 1 case of medulloblastoma in the saline placebo group. In the clinical studies, 9- through 26-year-old girls and women were evaluated for new medical conditions that occurred over the course of follow-up. New medical conditions potentially indicative of a systemic autoimmune disorder seen in the group that received human papillomavirus quadrivalent vaccine or AAHS control or saline placebo are shown in Table 9. This population includes all girls and women who received at least one dose of human papillomavirus quadrivalent vaccine or AAHS control or saline placebo, and had safety data available. In the clinical studies, 9- through 26-year-old boys and men were evaluated for new medical conditions that occurred over the course of follow-up. New medical conditions potentially indicative of a systemic autoimmune disorder seen in the group that received human papillomavirus quadrivalent vaccine or AAHS control or saline placebo are shown in Table 10. This population includes all boys and men who received at least one dose of human papillomavirus quadrivalent vaccine or AAHS control or saline placebo, and had safety data available. The safety of human papillomavirus quadrivalent vaccine when administered concomitantly with hepatitis B vaccine (recombinant) was evaluated in an AAHS-controlled study of 1871 girls and women with a mean age of 20.4 years. The race distribution of the study individuals was as follows: 61.6% White; 23.8% Other; 11.9% Black; 1.6% Hispanic (Black and White); 0.8% Asian; and 0.3% American Indian. The rates of systemic and injection-site adverse reactions were similar among girls and women who received concomitant vaccination as compared with those who received human papillomavirus quadrivalent vaccine or hepatitis B vaccine (recombinant). The safety of human papillomavirus quadrivalent vaccine when administered concomitantly with Menactra and Adacel was evaluated in a randomized study of 1040 boys and girls with a mean age of 12.6 years. The race distribution of the study subjects was as follows: 77.7% White; 1.4% Multi-racial; 12.3% Black; 6.8% Hispanic (Black and White); 1.2% Asian; 0.4% American Indian, and 0.2% Indian. There was an increase in injection-site swelling reported at the injection site for human papillomavirus quadrivalent vaccine (concomitant = 10.9%, non-concomitant = 6.9%) when human papillomavirus quadrivalent vaccine was administered concomitantly with Menactra and Adacel as compared to non-concomitant (separated by 1 month) vaccination. The majority of injection-site swelling adverse experiences were reported as being mild to moderate in intensity. The adverse reaction profile in women 27 through 45 years of age was comparable to the profile seen in girls and women 9 through 26 years of age. ## Postmarketing Experience The following adverse events have been spontaneously reported during post-approval use of human papillomavirus quadrivalent vaccine. Because these events were reported voluntarily from a population of uncertain size, it is not possible to reliably estimate their frequency or to establish a causal relationship to vaccine exposure. - Blood and lymphatic system disorders: Autoimmune hemolytic anemia, idiopathic thrombocytopenic purpura, lymphadenopathy. - Respiratory, thoracic and mediastinal disorders: Pulmonary embolism. - Gastrointestinal disorders: Nausea, pancreatitis, vomiting. - General disorders and administration site conditions: Asthenia, chills, death, fatigue, malaise. - Immune system disorders: Autoimmune diseases, hypersensitivity reactions including anaphylaxis/anaphylactoid reactions, bronchospasm, and urticaria. - Musculoskeletal and connective tissue disorders: Arthralgia, myalgia. - Nervous system disorders: Acute disseminated encephalomyelitis, dizziness, Guillain-Barré syndrome, headache, motor neuron disease, paralysis, seizures, syncope (including syncope associated with tonic-clonic movements and other seizure-like activity) sometimes resulting in falling with injury, transverse myelitis. - Infections and infestations: cellulitis. - Vascular disorders: Deep venous thrombosis. # Drug Interactions Results from clinical studies indicate that human papillomavirus quadrivalent vaccine may be administered concomitantly (at a separate injection site) with hepatitis B vaccine (recombinant). Results from clinical studies indicate that human papillomavirus quadrivalent vaccine may be administered concomitantly (at a separate injection site) with Menactra and Adacel . In clinical studies of 16- through 26-year-old women, 13,912 (human papillomavirus quadrivalent vaccine N = 6952; AAHS control or saline placebo N = 6960) who had post-Month 7 follow-up used hormonal contraceptives for a total of 33,859 person-years (65.8% of the total follow-up time in the studies). In one clinical study of 24- through 45-year-old women, 1357 (human papillomavirus quadrivalent vaccine N = 690; AAHS control N = 667) who had post-Month 7 follow-up used hormonal contraceptives for a total of 3400 person-years (31.5% of the total follow-up time in the study). Use of hormonal contraceptives or lack of use of hormonal contraceptives among study participants did not impair the immune response in the per protocol immunogenicity (PPI) population. Immunosuppressive therapies, including irradiation, antimetabolites, alkylating agents, cytotoxic drugs, and corticosteroids (used in greater than physiologic doses), may reduce the immune responses to vaccines # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): B Reproduction studies have been performed in female rats at doses equivalent to the recommended human dose and have revealed no evidence of impaired female fertility or harm to the fetus due to human papillomavirus quadrivalent vaccine. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human responses, human papillomavirus quadrivalent vaccine should be used during pregnancy only if clearly needed. An evaluation of the effect of human papillomavirus quadrivalent vaccine on embryo-fetal, pre- and postweaning development was conducted using rats. One group of rats was administered human papillomavirus quadrivalent vaccine twice prior to gestation, during the period of organogenesis (gestation Day 6) and on lactation Day 7. A second group of pregnant rats was administered human papillomavirus quadrivalent vaccine during the period of organogenesis (gestation Day 6) and on lactation Day 7 only. Human papillomavirus quadrivalent vaccine was administered at 0.5 mL/rat/occasion (120 mcg total protein which is equivalent to the recommended human dose) by intramuscular injection. No adverse effects on mating, fertility, pregnancy, parturition, lactation, embryo-fetal or pre- and postweaning development were observed. There were no vaccine-related fetal malformations or other evidence of teratogenesis noted in this study. In addition, there were no treatment-related effects on developmental signs, behavior, reproductive performance, or fertility of the offspring. In clinical studies, women underwent urine pregnancy testing prior to administration of each dose of human papillomavirus quadrivalent vaccine. Women who were found to be pregnant before completion of a 3-dose regimen of human papillomavirus quadrivalent vaccine were instructed to defer completion of their vaccination regimen until resolution of the pregnancy. Human papillomavirus quadrivalent vaccine is not indicated for women 27 years of age or older. However, safety data in women 16 through 45 years of age was collected, and 3819 women (human papillomavirus quadrivalent vaccine N = 1894 vs. AAHS control or saline placebo N = 1925) reported at least 1 pregnancy each. The overall proportions of pregnancies that resulted in an adverse outcome, defined as the combined numbers of spontaneous abortion, late fetal death, and congenital anomaly cases out of the total number of pregnancy outcomes for which an outcome was known (and excluding elective terminations), were 22.6% (446/1973) in women who received human papillomavirus quadrivalent vaccine and 23.1% (460/1994) in women who received AAHS control or saline placebo. Overall, 55 and 65 women in the group that received human papillomavirus quadrivalent vaccine or AAHS control or saline placebo, respectively (2.9% and 3.4% of all women who reported a pregnancy in the respective vaccination groups), experienced a serious adverse reaction during pregnancy. The most common events reported were conditions that can result in Caesarean section (e.g., failure of labor, malpresentation, cephalopelvic disproportion), premature onset of labor (e.g., threatened abortions, premature rupture of membranes), and pregnancy-related medical problems (e.g., pre-eclampsia, hyperemesis). The proportions of pregnant women who experienced such events were comparable between the groups receiving human papillomavirus quadrivalent vaccine and AAHS control or saline placebo. There were 45 cases of congenital anomaly in pregnancies that occurred in women who received human papillomavirus quadrivalent vaccine and 34 cases of congenital anomaly in pregnancies that occurred in women who received AAHS control or saline placebo. Further sub-analyses were conducted to evaluate pregnancies with estimated onset within 30 days or more than 30 days from administration of a dose of human papillomavirus quadrivalent vaccine or AAHS control or saline placebo. For pregnancies with estimated onset within 30 days of vaccination, 5 cases of congenital anomaly were observed in the group that received human papillomavirus quadrivalent vaccine compared to 1 case of congenital anomaly in the group that received AAHS control or saline placebo. The congenital anomalies seen in pregnancies with estimated onset within 30 days of vaccination included pyloric stenosis, congenital megacolon, congenital hydronephrosis, hip dysplasia, and club foot. Conversely, in pregnancies with onset more than 30 days following vaccination, 40 cases of congenital anomaly were observed in the group that received human papillomavirus quadrivalent vaccine compared with 33 cases of congenital anomaly in the group that received AAHS control or saline placebo. Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of HPV Vaccine in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of HPV Vaccine during labor and delivery. ### Nursing Mothers It is not known whether human papillomavirus quadrivalent vaccine is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when human papillomavirus quadrivalent vaccine is administered to a nursing woman. Human papillomavirus quadrivalent vaccine or AAHS control were given to a total of 1133 women (vaccine N = 582, AAHS control N = 551) during the relevant Phase III clinical studies. Overall, 27 and 13 infants of women who received human papillomavirus quadrivalent vaccine or AAHS control, respectively (representing 4.6% and 2.4% of the total number of women who were breast-feeding during the period in which they received human papillomavirus quadrivalent vaccine or AAHS control, respectively), experienced a serious adverse reaction. In a post-hoc analysis of clinical studies, a higher number of breast-feeding infants (n = 7) whose mothers received human papillomavirus quadrivalent vaccine had acute respiratory illnesses within 30 days post vaccination of the mother as compared to infants (n = 2) whose mothers received AAHS control. ### Pediatric Use Safety and effectiveness have not been established in pediatric patients below 9 years of age. ### Geriatic Use The safety and effectiveness of human papillomavirus quadrivalent vaccine have not been evaluated in a geriatric population, defined as individuals aged 65 years and over. ### Gender There is no FDA guidance on the use of HPV Vaccine with respect to specific gender populations. ### Race There is no FDA guidance on the use of HPV Vaccine with respect to specific racial populations. ### Renal Impairment There is no FDA guidance on the use of HPV Vaccine in patients with renal impairment. ### Hepatic Impairment There is no FDA guidance on the use of HPV Vaccine in patients with hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of HPV Vaccine in women of reproductive potentials and males. ### Immunocompromised Patients The immunologic response to human papillomavirus quadrivalent vaccine may be diminished in immunocompromised individuals # Administration and Monitoring ### Administration Intramuscular ### Monitoring There is limited information regarding HPV Vaccine Monitoring in the drug label. # IV Compatibility There is limited information regarding the compatibility of HPV Vaccine and IV administrations. # Overdosage - There have been reports of administration of higher than recommended doses of human papillomavirus quadrivalent vaccine. - In general, the adverse event profile reported with overdose was comparable to recommended single doses of human papillomavirus quadrivalent vaccine. # Pharmacology ## Mechanism of Action HPV only infects human beings. Animal studies with analogous animal papillomaviruses suggest that the efficacy of L1 VLP vaccines may involve the development of humoral immune responses. Human beings develop a humoral immune response to the vaccine, although the exact mechanism of protection is unknown. ## Structure GARDASIL, Human Papillomavirus Quadrivalent (Types 6, 11, 16, and 18) Vaccine, Recombinant, is a non-infectious recombinant quadrivalent vaccine prepared from the purified virus-like particles (VLPs) of the major capsid (L1) protein of HPV Types 6, 11, 16, and 18. The L1 proteins are produced by separate fermentations in recombinant Saccharomyces cerevisiae and self-assembled into VLPs. The fermentation process involves growth of S. cerevisiae on chemically-defined fermentation media which include vitamins, amino acids, mineral salts, and carbohydrates. The VLPs are released from the yeast cells by cell disruption and purified by a series of chemical and physical methods. The purified VLPs are adsorbed on preformed aluminum-containing adjuvant (Amorphous Aluminum Hydroxyphosphate Sulfate). The quadrivalent HPV VLP vaccine is a sterile liquid suspension that is prepared by combining the adsorbed VLPs of each HPV type and additional amounts of the aluminum-containing adjuvant and the final purification buffer. human papillomavirus quadrivalent vaccine is a sterile suspension for intramuscular administration. Each 0.5-mL dose contains approximately 20 mcg of HPV 6 L1 protein, 40 mcg of HPV 11 L1 protein, 40 mcg of HPV 16 L1 protein, and 20 mcg of HPV 18 L1 protein. Each 0.5-mL dose of the vaccine contains approximately 225 mcg of aluminum (as Amorphous Aluminum Hydroxyphosphate Sulfate adjuvant), 9.56 mg of sodium chloride, 0.78 mg of L-histidine, 50 mcg of polysorbate 80, 35 mcg of sodium borate, <7 mcg yeast protein/dose, and water for injection. The product does not contain a preservative or antibiotics. After thorough agitation, human papillomavirus quadrivalent vaccine is a white, cloudy liquid. ## Pharmacodynamics There is limited information regarding HPV Vaccine Pharmacodynamics in the drug label. ## Pharmacokinetics There is limited information regarding HPV Vaccine Pharmacokinetics in the drug label. ## Nonclinical Toxicology Human papillomavirus quadrivalent vaccine has not been evaluated for the potential to cause carcinogenicity or genotoxicity. Human papillomavirus quadrivalent vaccine administered to female rats at a dose of 120 mcg total protein, which is equivalent to the recommended human dose, had no effects on mating performance, fertility, or embryonic/fetal survival. The effect of human papillomavirus quadrivalent vaccine on male fertility has been studied in male rats at an intramuscular dose of 0.5 mL/rat/occasion (120 mcg total protein which is equivalent to the recommended human dose). One group of male rats was administered human papillomavirus quadrivalent vaccine once, 3 days prior to cohabitation, and a second group of male rats was administered human papillomavirus quadrivalent vaccine three times, at 6 weeks, 3 weeks, and 3 days prior to cohabitation. There were no treatment-related effects on reproductive performance including fertility, sperm count, and sperm motility. There were no treatment-related gross or histomorphologic and weight changes on the testes. # Clinical Studies CIN 2/3 and AIS are the immediate and necessary precursors of adenocarcinoma and squamous cell carcinoma of the cervix, respectively. Their detection and removal has been shown to prevent cancer; thus, they serve as surrogate markers for prevention of cervical cancer. In the clinical studies in girls and women aged 16 through 26 years, cases of CIN 2/3 and AIS were the efficacy endpoints to assess prevention of cervical cancer. In addition, cases of VIN 2/3 and VaIN 2/3 were the efficacy endpoints to assess prevention of HPV-related vulvar cancer and vaginal cancer, and observations of external genital lesions were the efficacy endpoints for the prevention of genital warts. In clinical studies in boys and men aged 16 through 26 years, efficacy was evaluated using the following endpoints: external genital warts and penile/perineal/perianal intraepithelial neoplasia (PIN) grades 1/2/3 or penile/perineal/perianal cancer. In addition, cases of AIN grades 1/2/3 and anal cancer made up the composite efficacy endpoint used to assess prevention of HPV-related anal cancer. Anal HPV infection, AIN, and anal cancer were not endpoints in the studies conducted in women. The similarity of HPV-related anal disease in men and women supports bridging the indication of prevention of AIN and anal cancer to women. Efficacy was assessed in 6 AAHS-controlled, double-blind, randomized Phase II and III clinical studies. The first Phase II study evaluated the HPV 16 component of human papillomavirus quadrivalent vaccine (Study 1, N = 2391 16- through 26-year-old girls and women) and the second evaluated all components of human papillomavirus quadrivalent vaccine (Study 2, N = 551 16- through 26-year-old girls and women). Two Phase III studies evaluated human papillomavirus quadrivalent vaccine in 5442 (Study 3) and 12,157 (Study 4) 16- through 26-year-old girls and women. A third Phase III study, Study 5, evaluated human papillomavirus quadrivalent vaccine in 4055 16- through 26-year-old boys and men, including a subset of 598 (human papillomavirus quadrivalent vaccine = 299; placebo = 299) men who self-identified as having sex with men (MSM population). A fourth Phase III study, Study 6, evaluated human papillomavirus quadrivalent vaccine in 3817 24- through 45-year-old women. Together, these six studies evaluated 28,413 individuals (20,541 girls and women 16 through 26 years of age at enrollment with a mean age of 20.0 years, 4055 boys and men 16 through 26 years of age at enrollment with a mean age of 20.5 years, and 3817 women 24 through 45 years of age at enrollment with a mean age of 34.3 years). The race distribution of the 16- through 26-year-old girls and women in the clinical trials was as follows: 70.4% White; 12.2% Hispanic (Black and White); 8.8% Other; 4.6% Black; 3.8% Asian; and 0.2% American Indian. The race distribution of the 16- through 26-year-old boys and men in the clinical trials was as follows: 35.2% White; 20.5% Hispanic (Black and White); 14.4% Other; 19.8% Black; 10.0% Asian; and 0.1% American Indian. The race distribution of the 24- through 45-year-old women in the clinical trials was as follows: 20.6% White; 43.2% Hispanic (Black and White); 0.2% Other; 4.8% Black; 31.2% Asian; and 0.1% American Indian. The median duration of follow-up was 4.0, 3.0, 3.0, 3.0, 2.3, and 4.0 years for Study 1, Study 2, Study 3, Study 4, Study 5, and Study 6, respectively. Individuals received vaccine or AAHS control on the day of enrollment and 2 and 6 months thereafter. Efficacy was analyzed for each study individually and for all studies in girls and women combined according to a prospective clinical plan. Overall, 73% of 16- through 26-year-old girls and women, 67% of 24- through 45-year-old women, and 83% of 16- through 26-year-old boys and men were naïve (i.e., PCR negative and seronegative for all 4 vaccine HPV types) to all 4 vaccine HPV types at enrollment. A total of 27% of 16- through 26-year-old girls and women, 33% of 24- through 45-year-old women, and 17% of 16- through 26-year-old boys and men had evidence of prior exposure to or ongoing infection with at least 1 of the 4 vaccine HPV types. Among these individuals, 74% of 16- through 26-year-old girls and women, 71% of 24- through 45-year-old women, and 78% of 16- through 26-year-old boys and men had evidence of prior exposure to or ongoing infection with only 1 of the 4 vaccine HPV types and were naïve (PCR negative and seronegative) to the remaining 3 types. In 24- through 45-year-old individuals, 0.4% had been exposed to all 4 vaccine HPV types. In individuals who were naïve (PCR negative and seronegative) to all 4 vaccine HPV types, CIN, genital warts, VIN, VaIN, PIN, and persistent infection caused by any of the 4 vaccine HPV types were counted as endpoints. Among individuals who were positive (PCR positive and/or seropositive) for a vaccine HPV type at Day 1, endpoints related to that type were not included in the analyses of prophylactic efficacy. Endpoints related to the remaining types for which the individual was naïve (PCR negative and seronegative) were counted. For example, in individuals who were HPV 18 positive (PCR positive and/or seropositive) at Day 1, lesions caused by HPV 18 were not counted in the prophylactic efficacy evaluations. Lesions caused by HPV 6, 11, and 16 were included in the prophylactic efficacy evaluations. The same approach was used for the other types. Human papillomavirus quadrivalent vaccine was administered without prescreening for presence of HPV infection and the efficacy trials allowed enrollment of girls and women regardless of baseline HPV status (i.e., PCR status or serostatus). Girls and women with current or prior HPV infection with an HPV type contained in the vaccine were not eligible for prophylactic efficacy evaluations for that type. The primary analyses of efficacy with respect to HPV types 6, 11, 16, and 18 were conducted in the per-protocol efficacy (PPE) population, consisting of girls and women who received all 3 vaccinations within 1 year of enrollment, did not have major deviations from the study protocol, and were naïve (PCR negative in cervicovaginal specimens and seronegative) to the relevant HPV type(s) (Types 6, 11, 16, and 18) prior to dose 1 and through 1 month Postdose 3 (Month 7). Efficacy was measured starting after the Month 7 visit. Human papillomavirus quadrivalent vaccine was efficacious in reducing the incidence of CIN (any grade including CIN 2/3); AIS; genital warts; VIN (any grade); and VaIN (any grade) related to vaccine HPV types 6, 11, 16, or 18 in those who were PCR negative and seronegative at baseline (Table 11). In addition, girls and women who were already infected with 1 or more vaccine-related HPV types prior to vaccination were protected from precancerous cervical lesions and external genital lesions caused by the other vaccine HPV types. Prophylactic efficacy against overall cervical and genital disease related to HPV 6, 11, 16, and 18 in an extension phase of Study 2, that included data through Month 60, was noted to be 100% (95% CI: 12.3%, 100.0%) among girls and women in the per protocol population naïve to the relevant HPV types. Human papillomavirus quadrivalent vaccine was efficacious against HPV disease caused by HPV types 6, 11, 16, and 18 in girls and women who were naïve for those specific HPV types at baseline. The primary analyses of efficacy were conducted in the per-protocol efficacy (PPE) population. This population consisted of boys and men who received all 3 vaccinations within 1 year of enrollment, did not have major deviations from the study protocol, and were naïve (PCR negative and seronegative) to the relevant HPV type(s) (Types 6, 11, 16, and 18) prior to dose 1 and through 1 month postdose 3 (Month 7). Efficacy was measured starting after the Month 7 visit. Human papillomavirus quadrivalent vaccine was efficacious in reducing the incidence of genital warts related to vaccine HPV types 6 and 11 in those boys and men who were PCR negative and seronegative at baseline (Table 12). Efficacy against penile/perineal/perianal intraepithelial neoplasia (PIN) grades 1/2/3 or penile/perineal/perianal cancer was not demonstrated as the number of cases was too limited to reach statistical significance. A sub-study of Study 5 evaluated the efficacy of human papillomavirus quadrivalent vaccine against anal disease (anal intraepithelial neoplasia and anal cancer) in a population of 598 MSM. The primary analyses of efficacy were conducted in the per-protocol efficacy (PPE) population of Study 5. Human papillomavirus quadrivalent vaccine was efficacious in reducing the incidence of anal intraepithelial neoplasia (AIN) grades 1 (both condyloma and non-acuminate), 2, and 3 related to vaccine HPV types 6, 11, 16, and 18 in those boys and men who were PCR negative and seronegative at baseline (Table 13). The clinical trials included girls and women regardless of current or prior exposure to vaccine HPV types, and additional analyses were conducted to evaluate the impact of human papillomavirus quadrivalent vaccine with respect to HPV 6-, 11-, 16-, and 18-related cervical and genital disease in these girls and women. Here, analyses included events arising among girls and women regardless of baseline PCR status and serostatus, including HPV infections that were present at the start of vaccination as well as events that arose from infections that were acquired after the start of vaccination. The impact of human papillomavirus quadrivalent vaccine in girls and women regardless of current or prior exposure to a vaccine HPV type is shown in Table 14. Impact was measured starting 1 month Postdose 1. Prophylactic efficacy denotes the vaccine's efficacy in girls and women who are naïve (PCR negative and seronegative) to the relevant HPV types at Day 1. Vaccine impact in girls and women who were positive for vaccine HPV infection, as well as vaccine impact among girls and women regardless of baseline vaccine HPV PCR status and serostatus are also presented. The majority of CIN and genital warts, VIN, and VaIN related to a vaccine HPV type detected in the group that received human papillomavirus quadrivalent vaccine occurred as a consequence of HPV infection with the relevant HPV type that was already present at Day 1. There was no clear evidence of protection from disease caused by HPV types for which girls and women were PCR positive regardless of serostatus at baseline. The impact of human papillomavirus quadrivalent vaccine against the overall burden of dysplastic or papillomatous cervical, vulvar, and vaginal disease regardless of HPV detection, results from a combination of prophylactic efficacy against vaccine HPV types, disease contribution from vaccine HPV types present at time of vaccination, the disease contribution from HPV types not contained in the vaccine, and disease in which HPV was not detected. Additional efficacy analyses were conducted in 2 populations: (1) a generally HPV-naïve population (negative to 14 common HPV types and had a Pap test that was negative for SIL at Day 1), approximating a population of sexually-naïve girls and women and (2) the general study population of girls and women regardless of baseline HPV status, some of whom had HPV-related disease at Day 1. Among generally HPV-naïve girls and women and among all girls and women in the study population (including girls and women with HPV infection at Day 1), human papillomavirus quadrivalent vaccine reduced the overall incidence of CIN 2/3 or AIS; of VIN 2/3 or VaIN 2/3; of CIN (any grade) or AIS; and of Genital Warts (Table 15). These reductions were primarily due to reductions in lesions caused by HPV types 6, 11, 16, and 18 in girls and women naïve (seronegative and PCR negative) for the specific relevant vaccine HPV type. Infected girls and women may already have CIN 2/3 or AIS at Day 1 and some will develop CIN 2/3 or AIS during follow-up, either related to a vaccine or non-vaccine HPV type present at the time of vaccination or related to a non-vaccine HPV type not present at the time of vaccination. Study 5 included boys and men regardless of current or prior exposure to vaccine HPV types, and additional analyses were conducted to evaluate the impact of human papillomavirus quadrivalent vaccine with respect to HPV 6-, 11-, 16-, and 18-related anogenital disease in these boys and men. Here, analyses included events arising among boys and men regardless of baseline PCR status and serostatus, including HPV infections that were present at the start of vaccination as well as events that arose from infections that were acquired after the start of vaccination. The impact of human papillomavirus quadrivalent vaccine in boys and men regardless of current or prior exposure to a vaccine HPV type is shown in Table 16. Impact was measured starting at Day 1. Prophylactic efficacy denotes the vaccine's efficacy in boys and men who are naïve (PCR negative and seronegative) to the relevant HPV types at Day 1. Vaccine impact in boys and men who were positive for vaccine HPV infection, as well as vaccine impact among boys and men regardless of baseline vaccine HPV PCR status and serostatus are also presented. The majority of anogenital disease related to a vaccine HPV type detected in the group that received human papillomavirus quadrivalent vaccine occurred as a consequence of HPV infection with the relevant HPV type that was already present at Day 1. There was no clear evidence of protection from disease caused by HPV types for which boys and men were PCR positive regardless of serostatus at baseline. The impact of human papillomavirus quadrivalent vaccine against the overall burden of dysplastic or papillomatous anogenital disease regardless of HPV detection, results from a combination of prophylactic efficacy against vaccine HPV types, disease contribution from vaccine HPV types present at time of vaccination, the disease contribution from HPV types not contained in the vaccine, and disease in which HPV was not detected. Additional efficacy analyses from Study 5 were conducted in 2 populations: (1) a generally HPV-naïve population that consisted of boys and men who are seronegative and PCR negative to HPV 6, 11, 16, and 18 and PCR negative to HPV 31, 33, 35, 39, 45, 51, 52, 56, 58 and 59 at Day 1, approximating a population of sexually-naïve boys and men and (2) the general study population of boys and men regardless of baseline HPV status, some of whom had HPV-related disease at Day 1. Among generally HPV-naïve boys and men and among all boys and men in Study 5 (including boys and men with HPV infection at Day 1), human papillomavirus quadrivalent vaccine reduced the overall incidence of anogenital disease (Table 17). These reductions were primarily due to reductions in lesions caused by HPV types 6, 11, 16, and 18 in boys and men naïve (seronegative and PCR negative) for the specific relevant vaccine HPV type. Infected boys and men may already have anogenital disease at Day 1 and some will develop anogenital disease during follow-up, either related to a vaccine or non-vaccine HPV type present at the time of vaccination or related to a non-vaccine HPV type not present at the time of vaccination. The subject characteristics (e.g. lifetime sex partners, geographic distribution of the subjects) influence the HPV prevalence of the population and therefore the population benefit can vary widely. The overall efficacy of human papillomavirus quadrivalent vaccine will vary with the baseline prevalence of HPV infection and disease, the incidence of infections against which human papillomavirus quadrivalent vaccine has shown protection, and those infections against which human papillomavirus quadrivalent vaccine has not been shown to protect. The efficacy of human papillomavirus quadrivalent vaccine for HPV types not included in the vaccine (i.e., cross-protective efficacy) is a component of the overall impact of the vaccine on rates of disease caused by HPV. Cross-protective efficacy was not demonstrated against disease caused by non-vaccine HPV types in the combined database of the Study 3 and Study 4 trials. human papillomavirus quadrivalent vaccine does not protect against genital disease not related to HPV. One woman who received human papillomavirus quadrivalent vaccine in Study 3 developed an external genital well-differentiated squamous cell carcinoma at Month 24. No HPV DNA was detected in the lesion or in any other samples taken throughout the study. In 18,150 girls and women enrolled in Study 2, Study 3, and Study 4, human papillomavirus quadrivalent vaccine reduced definitive cervical therapy procedures by 23.9% (95% CI: 15.2%, 31.7%). Study 6 evaluated efficacy in 3253 women 27 through 45 years of age based on a combined endpoint of HPV 6-, 11-, 16- or 18-related persistent infection, genital warts, vulvar and vaginal dysplastic lesions of any grade, CIN of any grade, AIS, and cervical cancer. These women were randomized 1:1 to receive either human papillomavirus quadrivalent vaccine or AAHS control. The efficacy for the combined endpoint was driven primarily by prevention of persistent infection. There was no statistically significant efficacy demonstrated for CIN 2/3, AIS, or cervical cancer. In post hoc analyses conducted to assess the impact of human papillomavirus quadrivalent vaccine on the individual components of the combined endpoint, the results in the population of women naïve to the relevant HPV type at baseline were as follows: prevention of HPV 6-, 11-, 16- or 18-related persistent infection (80.5% ), prevention of HPV 6-, 11-, 16- or 18-related CIN (any grade) (85.8% ), and prevention of HPV 6-, 11-, 16- or 18-related genital warts (87.6% ). Efficacy for disease endpoints was diminished in a population impact assessment of women who were vaccinated regardless of baseline HPV status (full analysis set). In the full analysis set (FAS), efficacy was not demonstrated for the following endpoints: prevention of HPV 16- and 18-related CIN 2/3, AIS, or cervical cancer and prevention of HPV 6- and 11-related condyloma. No efficacy was demonstrated against CIN 2/3, AIS, or cervical cancer in the general population irrespective of HPV type (FAS any type analysis). The minimum anti-HPV titer that confers protective efficacy has not been determined. Because there were few disease cases in individuals naïve (PCR negative and seronegative) to vaccine HPV types at baseline in the group that received human papillomavirus quadrivalent vaccine, it has not been possible to establish minimum anti-HPV 6, anti-HPV 11, anti-HPV 16, and anti-HPV 18 antibody levels that protect against clinical disease caused by HPV 6, 11, 16, and/or 18. The immunogenicity of human papillomavirus quadrivalent vaccine was assessed in 23,951 9- through 45-year-old girls and women (human papillomavirus quadrivalent vaccine N = 12,634; AAHS control or saline placebo N = 11,317) and 5417 9- through 26-year-old boys and men (human papillomavirus quadrivalent vaccine N = 3109; AAHS control or saline placebo N = 2308). Type-specific immunoassays with type-specific standards were used to assess immunogenicity to each vaccine HPV type. These assays measured antibodies against neutralizing epitopes for each HPV type. The scales for these assays are unique to each HPV type; thus, comparisons across types and to other assays are not appropriate. The primary immunogenicity analyses were conducted in a per-protocol immunogenicity (PPI) population. This population consisted of individuals who were seronegative and PCR negative to the relevant HPV type(s) at enrollment, remained HPV PCR negative to the relevant HPV type(s) through 1 month postdose 3 (Month 7), received all 3 vaccinations, and did not deviate from the study protocol in ways that could interfere with the effects of the vaccine. Immunogenicity was measured by (1) the percentage of individuals who were seropositive for antibodies against the relevant vaccine HPV type, and (2) the Geometric Mean Titer (GMT). In clinical studies in 16- through 26-year-old girls and women, 99.8%, 99.8%, 99.8%, and 99.4% who received human papillomavirus quadrivalent vaccine became anti-HPV 6, anti-HPV 11, anti-HPV 16, and anti-HPV 18 seropositive, respectively, by 1 month postdose 3 across all age groups tested. In clinical studies in 27- through 45-year-old women, 98.2%, 97.9%, 98.6%, and 97.1% who received human papillomavirus quadrivalent vaccine became anti-HPV 6, anti-HPV 11, anti-HPV 16, and anti-HPV 18 seropositive, respectively, by 1 month postdose 3 across all age groups tested. In clinical studies in 16- through 26-year-old boys and men, 98.9%, 99.2%, 98.8%, and 97.4% who received GARDASIL became anti-HPV 6, anti-HPV 11, anti-HPV 16, and anti-HPV 18 seropositive, respectively, by 1 month postdose 3 across all age groups tested. Across all populations, anti-HPV 6, anti-HPV 11, anti-HPV 16, and anti-HPV 18 GMTs peaked at Month 7 (Table 18 and Table 19). GMTs declined through Month 24 and then stabilized through Month 36 at levels above baseline. Tables 20 and 21 display the persistence of anti-HPV cLIA geometric mean titers by gender and age group. The duration of immunity following a complete schedule of immunization with human papillomavirus quadrivalent vaccine has not been established. Tables 18 and 19 display the Month 7 immunogenicity data for girls and women and boys and men. Anti-HPV responses 1 month postdose 3 among 9- through 15-year-old adolescent girls were non-inferior to anti-HPV responses in 16- through 26-year-old girls and women in the combined database of immunogenicity studies for human papillomavirus quadrivalent vaccine. Anti-HPV responses 1 month postdose 3 among 9- through 15-year-old adolescent boys were non-inferior to anti-HPV responses in 16- through 26-year-old boys and men in Study 5. On the basis of this immunogenicity bridging, the efficacy of human papillomavirus quadrivalent vaccine in 9- through 15-year-old adolescent girls and boys is inferred. Girls and women evaluated in the PPE population of clinical studies received all 3 vaccinations within 1 year of enrollment. An analysis of immune response data suggests that flexibility of ±1 month for Dose 2 (i.e., Month 1 to Month 3 in the vaccination regimen) and flexibility of ±2 months for Dose 3 (i.e., Month 4 to Month 8 in the vaccination regimen) do not impact the immune responses to human papillomavirus quadrivalent vaccine. The duration of immunity following a complete schedule of immunization with human papillomavirus quadrivalent vaccine has not been established. The peak anti-HPV GMTs for HPV types 6, 11, 16, and 18 occurred at Month 7. Anti-HPV GMTs for HPV types 6, 11, 16, and 18 were similar between measurements at Month 24 and Month 60 in Study 2. The safety and immunogenicity of co-administration of human papillomavirus quadrivalent vaccine with hepatitis B vaccine (recombinant) (same visit, injections at separate sites) were evaluated in a randomized, double-blind, study of 1871 women aged 16 through 24 years at enrollment. The race distribution of the girls and women in the clinical trial was as follows: 61.6% White; 1.6% Hispanic (Black and White); 23.8% Other; 11.9% Black; 0.8% Asian; and 0.3% American Indian. Subjects either received human papillomavirus quadrivalent vaccine and hepatitis B vaccine (recombinant) (n = 466), human papillomavirus quadrivalent vaccine and hepatitis B vaccine (recombinant)-matched placebo (n = 468), hepatitis B vaccine (recombinant) and human papillomavirus quadrivalent vaccine-matched placebo (n = 467) or hepatitis B vaccine (recombinant)-matched placebo and human papillomavirus quadrivalent vaccine-matched placebo (n = 470) at Day 1, Month 2 and Month 6. Immunogenicity was assessed for all vaccines 1 month post completion of the vaccination series. Concomitant administration of human papillomavirus quadrivalent vaccine with hepatitis B vaccine (recombinant) did not interfere with the antibody response to any of the vaccine antigens when human papillomavirus quadrivalent vaccine was given concomitantly with hepatitis B vaccine (recombinant) or separately. The safety and immunogenicity of co-administration of human papillomavirus quadrivalent vaccine with Menactra (Meningococcal (Groups A, C, Y and W-135) Polysaccharide Diphtheria Toxoid Conjugate Vaccine) and Adacel (same visit, injections at separate sites) were evaluated in an open-labeled, randomized, controlled study of 1040 boys and girls 11 through 17 years of age at enrollment. The race distribution of the subjects in the clinical trial was as follows: 77.7% White; 6.8% Hispanic (Black and White); 1.4% Multi-racial; 12.3% Black; 1.2% Asian; 0.2% Indian; and 0.4% American Indian. One group received human papillomavirus quadrivalent vaccine in one limb and both Menactra and Adacel, as separate injections, in the opposite limb concomitantly on Day 1 (n = 517). The second group received the first dose of human papillomavirus quadrivalent vaccine on Day 1 in one limb then Menactra and Adacel, as separate injections, at Month 1 in the opposite limb (n = 523). Subjects in both vaccination groups received the second dose of human papillomavirus quadrivalent vaccine at Month 2 and the third dose at Month 6. Immunogenicity was assessed for all vaccines 1 month post completion of the vaccination series (1 dose for Menactra and Adacel and 3 doses for human papillomavirus quadrivalent vaccine). Concomitant administration of human papillomavirus quadrivalent vaccine with Menactra (Meningococcal (Groups A, C, Y and W-135) Polysaccharide Diphtheria Toxoid Conjugate Vaccine) and Adacel did not interfere with the antibody response to any of the vaccine antigens when human papillomavirus quadrivalent vaccine was given concomitantly with Menactra and Adacel or separately. # How Supplied All presentations for GARDASIL contain a suspension of 120 mcg L1 protein from HPV types 6, 11, 16, and 18 in a 0.5-mL dose. GARDASIL is supplied in vials and syringes. - Carton of one 0.5-mL single-dose vial. NDC 0006-4045-00. - Carton of ten 0.5-mL single-dose vials. NDC 0006-4045-41. - Carton of six 0.5-mL single-dose prefilled Luer-Lok® syringes with tip caps. NDC 0006-4109-09. - Carton of ten 0.5-mL single-dose prefilled Luer-Lok® syringes with tip caps. NDC 0006-4109-02. ## Storage - Store refrigerated at 2 to 8°C (36 to 46°F). Do not freeze. Protect from light. - GARDASIL should be administered as soon as possible after being removed from refrigeration. - GARDASIL can be out of refrigeration (at temperatures at or below 25°C/77°F), for a total time of not more than 72 hours. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information Advise the patient to read the FDA-approved patient labeling (Patient Information). Inform the patient, parent, or guardian: - Vaccination does not eliminate the necessity for women to continue to undergo recommended cervical cancer screening. Women who receive human papillomavirus quadrivalent vaccine should continue to undergo cervical cancer screening per standard of care. - Recipients of human papillomavirus quadrivalent vaccine should not discontinue anal cancer screening if it has been recommended by a health care provider. - Human papillomavirus quadrivalent vaccine has not been demonstrated to provide protection against disease from vaccine and non-vaccine HPV types to which a person has previously been exposed through sexual activity. - Since syncope has been reported following vaccination sometimes resulting in falling with injury, observation for 15 minutes after administration is recommended. - Vaccine information is required to be given with each vaccination to the patient, parent, or guardian. - Information regarding benefits and risks associated with vaccination. - Human papillomavirus quadrivalent vaccine is not recommended for use in pregnant women. - Importance of completing the immunization series unless contraindicated. - Report any adverse reactions to their health care provider. # Precautions with Alcohol Alcohol-HPV Vaccine interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names Gardasil # Look-Alike Drug Names There is limited information regarding HPV Vaccine Look-Alike Drug Names in the drug label. # Drug Shortage Status Drug Shortage # Price	HPV Vaccine Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Alonso Alvarado, M.D. [2] # Disclaimer WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here. # Overview HPV Vaccine is a Adrenergic receptor agonist that is FDA approved for the prophylaxis of HPV types 6, 11, 16 and 18 infections. Common adverse reactions include erythema at injection site, injection site pain, injection site pruritus, swelling at injection site, nausea, dizziness, headache, fever. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) GARDASIL should be administered intramuscularly as a 0.5-mL dose at the following schedule: 0, 2 months, 6 months. [See Clinical Studies (14.8).] For intramuscular use only. Shake well before use. Thorough agitation immediately before administration is necessary to maintain suspension of the vaccine. Human papillomavirus quadrivalent vaccine should not be diluted or mixed with other vaccines. After thorough agitation, human papillomavirus quadrivalent vaccine is a white, cloudy liquid. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration. Do not use the product if particulates are present or if it appears discolored. human papillomavirus quadrivalent vaccine should be administered intramuscularly in the deltoid region of the upper arm or in the higher anterolateral area of the thigh. Syncope has been reported following vaccination with human papillomavirus quadrivalent vaccine and may result in falling with injury; observation for 15 minutes after administration is recommended. Withdraw the 0.5-mL dose of vaccine from the single-dose vial using a sterile needle and syringe and use promptly. This package does not contain a needle. Shake well before use. Attach the needle by twisting in a clockwise direction until the needle fits securely on the syringe. Administer the entire dose as per standard protocol. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of HPV Vaccine in adult patients. ### Non–Guideline-Supported Use - Dosing Information - IM injections day 1 and months 2 and 6 for patients 9-26 years of age.[1][2] - Dosing Information - IM injections day 1 and months 2 and 6 for patients 9-26 years of age.[1][2] # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) There is limited information regarding HPV Vaccine FDA-Labeled Indications and Dosage (Pediatric) in the drug label. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of HPV Vaccine in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of HPV Vaccine in pediatric patients. # Contraindications Hypersensitivity, including severe allergic reactions to yeast (a vaccine component), or after a previous dose of GARDASIL. # Warnings Because vaccinees may develop syncope, sometimes resulting in falling with injury, observation for 15 minutes after administration is recommended. Syncope, sometimes associated with tonic-clonic movements and other seizure-like activity, has been reported following vaccination with human papillomavirus quadrivalent vaccine. When syncope is associated with tonic-clonic movements, the activity is usually transient and typically responds to restoring cerebral perfusion by maintaining a supine or Trendelenburg position. Appropriate medical treatment and supervision must be readily available in case of anaphylactic reactions following the administration of human papillomavirus quadrivalent vaccine. # Adverse Reactions ## Clinical Trials Experience Headache, fever, nausea, and dizziness; and local injection site reactions (pain, swelling, erythema, pruritus, and bruising) occurred after administration with human papillomavirus quadrivalent vaccine. Syncope, sometimes associated with tonic-clonic movements and other seizure-like activity, has been reported following vaccination with human papillomavirus quadrivalent vaccine and may result in falling with injury; observation for 15 minutes after administration is recommended. Anaphylaxis has been reported following vaccination with human papillomavirus quadrivalent vaccine. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a vaccine cannot be directly compared to rates in the clinical trials of another vaccine and may not reflect the rates observed in practice. In 7 clinical trials (5 Amorphous Aluminum Hydroxyphosphate Sulfate [AAHS]-controlled, 1 saline placebo-controlled, and 1 uncontrolled), 18,083 individuals were administered human papillomavirus quadrivalent vaccine or AAHS control or saline placebo on the day of enrollment, and approximately 2 and 6 months thereafter, and safety was evaluated using vaccination report cards (VRC)-aided surveillance for 14 days after each injection of human papillomavirus quadrivalent vaccine or AAHS control or saline placebo in these individuals. The individuals who were monitored using VRC-aided surveillance included 10,088 individuals 9 through 45 years of age at enrollment who received human papillomavirus quadrivalent vaccine and 7,995 individuals who received AAHS control or saline placebo. Few individuals (0.2%) discontinued due to adverse reactions. The race distribution of the 9- through 26-year-old girls and women in the safety population was as follows: 62.3% White; 17.6% Hispanic (Black and White); 6.8% Asian; 6.7% Other; 6.4% Black; and 0.3% American Indian. The race distribution of the 24- through 45-year-old women in the safety population of Study 6 was as follows: 20.6% White; 43.2% Hispanic (Black and White); 0.2% Other; 4.8% Black; 31.2% Asian; and 0.1% American Indian. The race distribution of the 9- through 26-year-old boys and men in the safety population was as follows: 42.0% White; 19.7% Hispanic (Black and White); 11.0% Asian; 11.2% Other; 15.9% Black; and 0.1% American Indian. The injection site adverse reactions that were observed among recipients of human papillomavirus quadrivalent vaccine at a frequency of at least 1.0% and also at a greater frequency than that observed among AAHS control or saline placebo recipients are shown in Table 1. The injection site adverse reactions that were observed among recipients of human papillomavirus quadrivalent vaccine at a frequency of at least 1.0% and also at a greater frequency than that observed among AAHS control or saline placebo recipients are shown in Table 2. An analysis of injection-site adverse reactions in girls and women by dose is shown in Table 3. Of those girls and women who reported an injection-site reaction, 94.3% judged their injection-site adverse reaction to be mild or moderate in intensity. An analysis of injection-site adverse reactions in boys and men by dose is shown in Table 4. Of those boys and men who reported an injection-site reaction, 96.4% judged their injection-site adverse reaction to be mild or moderate in intensity. Headache was the most commonly reported systemic adverse reaction in both treatment groups (human papillomavirus quadrivalent vaccine = 28.2% and AAHS control or saline placebo = 28.4%). Fever was the next most commonly reported systemic adverse reaction in both treatment groups (human papillomavirus quadrivalent vaccine = 13.0% and AAHS control or saline placebo = 11.2%). Adverse reactions that were observed among recipients of human papillomavirus quadrivalent vaccine, at a frequency of greater than or equal to 1.0% where the incidence in the human papillomavirus quadrivalent vaccine group was greater than or equal to the incidence in the AAHS control or saline placebo group, are shown in Table 5. Headache was the most commonly reported systemic adverse reaction in both treatment groups (human papillomavirus quadrivalent vaccine = 12.3% and AAHS control or saline placebo = 11.2%). Fever was the next most commonly reported systemic adverse reaction in both treatment groups (human papillomavirus quadrivalent vaccine = 8.3% and AAHS control or saline placebo = 6.5%). Adverse reactions that were observed among recipients of human papillomavirus quadrivalent vaccine, at a frequency of greater than or equal to 1.0% where the incidence in the group that received human papillomavirus quadrivalent vaccine was greater than or equal to the incidence in the AAHS control or saline placebo group, are shown in Table 6. An analysis of fever in girls and women by dose is shown in Table 7. An analysis of fever in boys and men by dose is shown in Table 8. Across the clinical studies, 258 individuals (human papillomavirus quadrivalent vaccine N = 128 or 0.8%; placebo N = 130 or 1.0%) out of 29,323 (human papillomavirus quadrivalent vaccine N = 15,706; AAHS control N = 13,023; or saline placebo N = 594) individuals (9- through 45-year-old girls and women; and 9- through 26-year-old boys and men) reported a serious systemic adverse reaction. Of the entire study population (29,323 individuals), 0.04% of the reported serious systemic adverse reactions were judged to be vaccine related by the study investigator. The most frequently (frequency of 4 cases or greater with either human papillomavirus quadrivalent vaccine, AAHS control, saline placebo, or the total of all three) reported serious systemic adverse reactions, regardless of causality, were: Headache [0.02% human papillomavirus quadrivalent vaccine (3 cases) vs. 0.02% AAHS control (2 cases)], Gastroenteritis [0.02% human papillomavirus quadrivalent vaccine (3 cases) vs. 0.02% AAHS control (2 cases)], Appendicitis [0.03% human papillomavirus quadrivalent vaccine (5 cases) vs. 0.01% AAHS control (1 case)], Pelvic inflammatory disease [0.02% human papillomavirus quadrivalent vaccine (3 cases) vs. 0.03% AAHS control (4 cases)], Urinary tract infection [0.01% human papillomavirus quadrivalent vaccine (2 cases) vs. 0.02% AAHS control (2 cases)], Pneumonia [0.01% human papillomavirus quadrivalent vaccine (2 cases) vs. 0.02% AAHS control (2 cases)], Pyelonephritis [0.01% human papillomavirus quadrivalent vaccine (2 cases) vs. 0.02% AAHS control (3 cases)], Pulmonary embolism [0.01% human papillomavirus quadrivalent vaccine (2 cases) vs. 0.02% AAHS control (2 cases)]. One case (0.006% human papillomavirus quadrivalent vaccine; 0.0% AAHS control or saline placebo) of bronchospasm; and 2 cases (0.01% human papillomavirus quadrivalent vaccine; 0.0% AAHS control or saline placebo) of asthma were reported as serious systemic adverse reactions that occurred following any vaccination visit. In addition, there was 1 individual in the clinical trials, in the group that received human papillomavirus quadrivalent vaccine, who reported two injection-site serious adverse reactions (injection-site pain and injection-site joint movement impairment). Across the clinical studies, 40 deaths (human papillomavirus quadrivalent vaccine N = 21 or 0.1%; placebo N = 19 or 0.1%) were reported in 29,323 (human papillomavirus quadrivalent vaccine N = 15,706; AAHS control N = 13,023, saline placebo N = 594) individuals (9- through 45-year-old girls and women; and 9- through 26-year-old boys and men). The events reported were consistent with events expected in healthy adolescent and adult populations. The most common cause of death was motor vehicle accident (5 individuals who received human papillomavirus quadrivalent vaccine and 4 individuals who received AAHS control), followed by drug overdose/suicide (2 individuals who received human papillomavirus quadrivalent vaccine and 6 individuals who received AAHS control), gunshot wound (1 individual who received human papillomavirus quadrivalent vaccine and 3 individuals who received AAHS control), and pulmonary embolus/deep vein thrombosis (1 individual who received human papillomavirus quadrivalent vaccine and 1 individual who received AAHS control). In addition, there were 2 cases of sepsis, 1 case of pancreatic cancer, 1 case of arrhythmia, 1 case of pulmonary tuberculosis, 1 case of hyperthyroidism, 1 case of post-operative pulmonary embolism and acute renal failure, 1 case of traumatic brain injury/cardiac arrest, 1 case of systemic lupus erythematosus, 1 case of cerebrovascular accident, 1 case of breast cancer, and 1 case of nasopharyngeal cancer in the group that received human papillomavirus quadrivalent vaccine; 1 case of asphyxia, 1 case of acute lymphocytic leukemia, 1 case of chemical poisoning, and 1 case of myocardial ischemia in the AAHS control group; and 1 case of medulloblastoma in the saline placebo group. In the clinical studies, 9- through 26-year-old girls and women were evaluated for new medical conditions that occurred over the course of follow-up. New medical conditions potentially indicative of a systemic autoimmune disorder seen in the group that received human papillomavirus quadrivalent vaccine or AAHS control or saline placebo are shown in Table 9. This population includes all girls and women who received at least one dose of human papillomavirus quadrivalent vaccine or AAHS control or saline placebo, and had safety data available. In the clinical studies, 9- through 26-year-old boys and men were evaluated for new medical conditions that occurred over the course of follow-up. New medical conditions potentially indicative of a systemic autoimmune disorder seen in the group that received human papillomavirus quadrivalent vaccine or AAHS control or saline placebo are shown in Table 10. This population includes all boys and men who received at least one dose of human papillomavirus quadrivalent vaccine or AAHS control or saline placebo, and had safety data available. The safety of human papillomavirus quadrivalent vaccine when administered concomitantly with hepatitis B vaccine (recombinant) was evaluated in an AAHS-controlled study of 1871 girls and women with a mean age of 20.4 years. The race distribution of the study individuals was as follows: 61.6% White; 23.8% Other; 11.9% Black; 1.6% Hispanic (Black and White); 0.8% Asian; and 0.3% American Indian. The rates of systemic and injection-site adverse reactions were similar among girls and women who received concomitant vaccination as compared with those who received human papillomavirus quadrivalent vaccine or hepatitis B vaccine (recombinant). The safety of human papillomavirus quadrivalent vaccine when administered concomitantly with Menactra [Meningococcal (Groups A, C, Y and W-135) Polysaccharide Diphtheria Toxoid Conjugate Vaccine] and Adacel [Tetanus Toxoid, Reduced Diphtheria Toxoid and Acellular Pertussis Vaccine Adsorbed (Tdap)] was evaluated in a randomized study of 1040 boys and girls with a mean age of 12.6 years. The race distribution of the study subjects was as follows: 77.7% White; 1.4% Multi-racial; 12.3% Black; 6.8% Hispanic (Black and White); 1.2% Asian; 0.4% American Indian, and 0.2% Indian. There was an increase in injection-site swelling reported at the injection site for human papillomavirus quadrivalent vaccine (concomitant = 10.9%, non-concomitant = 6.9%) when human papillomavirus quadrivalent vaccine was administered concomitantly with Menactra and Adacel as compared to non-concomitant (separated by 1 month) vaccination. The majority of injection-site swelling adverse experiences were reported as being mild to moderate in intensity. The adverse reaction profile in women 27 through 45 years of age was comparable to the profile seen in girls and women 9 through 26 years of age. ## Postmarketing Experience The following adverse events have been spontaneously reported during post-approval use of human papillomavirus quadrivalent vaccine. Because these events were reported voluntarily from a population of uncertain size, it is not possible to reliably estimate their frequency or to establish a causal relationship to vaccine exposure. - Blood and lymphatic system disorders: Autoimmune hemolytic anemia, idiopathic thrombocytopenic purpura, lymphadenopathy. - Respiratory, thoracic and mediastinal disorders: Pulmonary embolism. - Gastrointestinal disorders: Nausea, pancreatitis, vomiting. - General disorders and administration site conditions: Asthenia, chills, death, fatigue, malaise. - Immune system disorders: Autoimmune diseases, hypersensitivity reactions including anaphylaxis/anaphylactoid reactions, bronchospasm, and urticaria. - Musculoskeletal and connective tissue disorders: Arthralgia, myalgia. - Nervous system disorders: Acute disseminated encephalomyelitis, dizziness, Guillain-Barré syndrome, headache, motor neuron disease, paralysis, seizures, syncope (including syncope associated with tonic-clonic movements and other seizure-like activity) sometimes resulting in falling with injury, transverse myelitis. - Infections and infestations: cellulitis. - Vascular disorders: Deep venous thrombosis. # Drug Interactions Results from clinical studies indicate that human papillomavirus quadrivalent vaccine may be administered concomitantly (at a separate injection site) with hepatitis B vaccine (recombinant). Results from clinical studies indicate that human papillomavirus quadrivalent vaccine may be administered concomitantly (at a separate injection site) with Menactra [Meningococcal (Groups A, C, Y and W-135) Polysaccharide Diphtheria Toxoid Conjugate Vaccine] and Adacel [Tetanus Toxoid, Reduced Diphtheria Toxoid and Acellular Pertussis Vaccine Adsorbed (Tdap)]. In clinical studies of 16- through 26-year-old women, 13,912 (human papillomavirus quadrivalent vaccine N = 6952; AAHS control or saline placebo N = 6960) who had post-Month 7 follow-up used hormonal contraceptives for a total of 33,859 person-years (65.8% of the total follow-up time in the studies). In one clinical study of 24- through 45-year-old women, 1357 (human papillomavirus quadrivalent vaccine N = 690; AAHS control N = 667) who had post-Month 7 follow-up used hormonal contraceptives for a total of 3400 person-years (31.5% of the total follow-up time in the study). Use of hormonal contraceptives or lack of use of hormonal contraceptives among study participants did not impair the immune response in the per protocol immunogenicity (PPI) population. Immunosuppressive therapies, including irradiation, antimetabolites, alkylating agents, cytotoxic drugs, and corticosteroids (used in greater than physiologic doses), may reduce the immune responses to vaccines # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): B Reproduction studies have been performed in female rats at doses equivalent to the recommended human dose and have revealed no evidence of impaired female fertility or harm to the fetus due to human papillomavirus quadrivalent vaccine. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human responses, human papillomavirus quadrivalent vaccine should be used during pregnancy only if clearly needed. An evaluation of the effect of human papillomavirus quadrivalent vaccine on embryo-fetal, pre- and postweaning development was conducted using rats. One group of rats was administered human papillomavirus quadrivalent vaccine twice prior to gestation, during the period of organogenesis (gestation Day 6) and on lactation Day 7. A second group of pregnant rats was administered human papillomavirus quadrivalent vaccine during the period of organogenesis (gestation Day 6) and on lactation Day 7 only. Human papillomavirus quadrivalent vaccine was administered at 0.5 mL/rat/occasion (120 mcg total protein which is equivalent to the recommended human dose) by intramuscular injection. No adverse effects on mating, fertility, pregnancy, parturition, lactation, embryo-fetal or pre- and postweaning development were observed. There were no vaccine-related fetal malformations or other evidence of teratogenesis noted in this study. In addition, there were no treatment-related effects on developmental signs, behavior, reproductive performance, or fertility of the offspring. In clinical studies, women underwent urine pregnancy testing prior to administration of each dose of human papillomavirus quadrivalent vaccine. Women who were found to be pregnant before completion of a 3-dose regimen of human papillomavirus quadrivalent vaccine were instructed to defer completion of their vaccination regimen until resolution of the pregnancy. Human papillomavirus quadrivalent vaccine is not indicated for women 27 years of age or older. However, safety data in women 16 through 45 years of age was collected, and 3819 women (human papillomavirus quadrivalent vaccine N = 1894 vs. AAHS control or saline placebo N = 1925) reported at least 1 pregnancy each. The overall proportions of pregnancies that resulted in an adverse outcome, defined as the combined numbers of spontaneous abortion, late fetal death, and congenital anomaly cases out of the total number of pregnancy outcomes for which an outcome was known (and excluding elective terminations), were 22.6% (446/1973) in women who received human papillomavirus quadrivalent vaccine and 23.1% (460/1994) in women who received AAHS control or saline placebo. Overall, 55 and 65 women in the group that received human papillomavirus quadrivalent vaccine or AAHS control or saline placebo, respectively (2.9% and 3.4% of all women who reported a pregnancy in the respective vaccination groups), experienced a serious adverse reaction during pregnancy. The most common events reported were conditions that can result in Caesarean section (e.g., failure of labor, malpresentation, cephalopelvic disproportion), premature onset of labor (e.g., threatened abortions, premature rupture of membranes), and pregnancy-related medical problems (e.g., pre-eclampsia, hyperemesis). The proportions of pregnant women who experienced such events were comparable between the groups receiving human papillomavirus quadrivalent vaccine and AAHS control or saline placebo. There were 45 cases of congenital anomaly in pregnancies that occurred in women who received human papillomavirus quadrivalent vaccine and 34 cases of congenital anomaly in pregnancies that occurred in women who received AAHS control or saline placebo. Further sub-analyses were conducted to evaluate pregnancies with estimated onset within 30 days or more than 30 days from administration of a dose of human papillomavirus quadrivalent vaccine or AAHS control or saline placebo. For pregnancies with estimated onset within 30 days of vaccination, 5 cases of congenital anomaly were observed in the group that received human papillomavirus quadrivalent vaccine compared to 1 case of congenital anomaly in the group that received AAHS control or saline placebo. The congenital anomalies seen in pregnancies with estimated onset within 30 days of vaccination included pyloric stenosis, congenital megacolon, congenital hydronephrosis, hip dysplasia, and club foot. Conversely, in pregnancies with onset more than 30 days following vaccination, 40 cases of congenital anomaly were observed in the group that received human papillomavirus quadrivalent vaccine compared with 33 cases of congenital anomaly in the group that received AAHS control or saline placebo. Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of HPV Vaccine in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of HPV Vaccine during labor and delivery. ### Nursing Mothers It is not known whether human papillomavirus quadrivalent vaccine is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when human papillomavirus quadrivalent vaccine is administered to a nursing woman. Human papillomavirus quadrivalent vaccine or AAHS control were given to a total of 1133 women (vaccine N = 582, AAHS control N = 551) during the relevant Phase III clinical studies. Overall, 27 and 13 infants of women who received human papillomavirus quadrivalent vaccine or AAHS control, respectively (representing 4.6% and 2.4% of the total number of women who were breast-feeding during the period in which they received human papillomavirus quadrivalent vaccine or AAHS control, respectively), experienced a serious adverse reaction. In a post-hoc analysis of clinical studies, a higher number of breast-feeding infants (n = 7) whose mothers received human papillomavirus quadrivalent vaccine had acute respiratory illnesses within 30 days post vaccination of the mother as compared to infants (n = 2) whose mothers received AAHS control. ### Pediatric Use Safety and effectiveness have not been established in pediatric patients below 9 years of age. ### Geriatic Use The safety and effectiveness of human papillomavirus quadrivalent vaccine have not been evaluated in a geriatric population, defined as individuals aged 65 years and over. ### Gender There is no FDA guidance on the use of HPV Vaccine with respect to specific gender populations. ### Race There is no FDA guidance on the use of HPV Vaccine with respect to specific racial populations. ### Renal Impairment There is no FDA guidance on the use of HPV Vaccine in patients with renal impairment. ### Hepatic Impairment There is no FDA guidance on the use of HPV Vaccine in patients with hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of HPV Vaccine in women of reproductive potentials and males. ### Immunocompromised Patients The immunologic response to human papillomavirus quadrivalent vaccine may be diminished in immunocompromised individuals # Administration and Monitoring ### Administration Intramuscular ### Monitoring There is limited information regarding HPV Vaccine Monitoring in the drug label. # IV Compatibility There is limited information regarding the compatibility of HPV Vaccine and IV administrations. # Overdosage - There have been reports of administration of higher than recommended doses of human papillomavirus quadrivalent vaccine. - In general, the adverse event profile reported with overdose was comparable to recommended single doses of human papillomavirus quadrivalent vaccine. # Pharmacology ## Mechanism of Action HPV only infects human beings. Animal studies with analogous animal papillomaviruses suggest that the efficacy of L1 VLP vaccines may involve the development of humoral immune responses. Human beings develop a humoral immune response to the vaccine, although the exact mechanism of protection is unknown. ## Structure GARDASIL, Human Papillomavirus Quadrivalent (Types 6, 11, 16, and 18) Vaccine, Recombinant, is a non-infectious recombinant quadrivalent vaccine prepared from the purified virus-like particles (VLPs) of the major capsid (L1) protein of HPV Types 6, 11, 16, and 18. The L1 proteins are produced by separate fermentations in recombinant Saccharomyces cerevisiae and self-assembled into VLPs. The fermentation process involves growth of S. cerevisiae on chemically-defined fermentation media which include vitamins, amino acids, mineral salts, and carbohydrates. The VLPs are released from the yeast cells by cell disruption and purified by a series of chemical and physical methods. The purified VLPs are adsorbed on preformed aluminum-containing adjuvant (Amorphous Aluminum Hydroxyphosphate Sulfate). The quadrivalent HPV VLP vaccine is a sterile liquid suspension that is prepared by combining the adsorbed VLPs of each HPV type and additional amounts of the aluminum-containing adjuvant and the final purification buffer. human papillomavirus quadrivalent vaccine is a sterile suspension for intramuscular administration. Each 0.5-mL dose contains approximately 20 mcg of HPV 6 L1 protein, 40 mcg of HPV 11 L1 protein, 40 mcg of HPV 16 L1 protein, and 20 mcg of HPV 18 L1 protein. Each 0.5-mL dose of the vaccine contains approximately 225 mcg of aluminum (as Amorphous Aluminum Hydroxyphosphate Sulfate adjuvant), 9.56 mg of sodium chloride, 0.78 mg of L-histidine, 50 mcg of polysorbate 80, 35 mcg of sodium borate, <7 mcg yeast protein/dose, and water for injection. The product does not contain a preservative or antibiotics. After thorough agitation, human papillomavirus quadrivalent vaccine is a white, cloudy liquid. ## Pharmacodynamics There is limited information regarding HPV Vaccine Pharmacodynamics in the drug label. ## Pharmacokinetics There is limited information regarding HPV Vaccine Pharmacokinetics in the drug label. ## Nonclinical Toxicology Human papillomavirus quadrivalent vaccine has not been evaluated for the potential to cause carcinogenicity or genotoxicity. Human papillomavirus quadrivalent vaccine administered to female rats at a dose of 120 mcg total protein, which is equivalent to the recommended human dose, had no effects on mating performance, fertility, or embryonic/fetal survival. The effect of human papillomavirus quadrivalent vaccine on male fertility has been studied in male rats at an intramuscular dose of 0.5 mL/rat/occasion (120 mcg total protein which is equivalent to the recommended human dose). One group of male rats was administered human papillomavirus quadrivalent vaccine once, 3 days prior to cohabitation, and a second group of male rats was administered human papillomavirus quadrivalent vaccine three times, at 6 weeks, 3 weeks, and 3 days prior to cohabitation. There were no treatment-related effects on reproductive performance including fertility, sperm count, and sperm motility. There were no treatment-related gross or histomorphologic and weight changes on the testes. # Clinical Studies CIN 2/3 and AIS are the immediate and necessary precursors of adenocarcinoma and squamous cell carcinoma of the cervix, respectively. Their detection and removal has been shown to prevent cancer; thus, they serve as surrogate markers for prevention of cervical cancer. In the clinical studies in girls and women aged 16 through 26 years, cases of CIN 2/3 and AIS were the efficacy endpoints to assess prevention of cervical cancer. In addition, cases of VIN 2/3 and VaIN 2/3 were the efficacy endpoints to assess prevention of HPV-related vulvar cancer and vaginal cancer, and observations of external genital lesions were the efficacy endpoints for the prevention of genital warts. In clinical studies in boys and men aged 16 through 26 years, efficacy was evaluated using the following endpoints: external genital warts and penile/perineal/perianal intraepithelial neoplasia (PIN) grades 1/2/3 or penile/perineal/perianal cancer. In addition, cases of AIN grades 1/2/3 and anal cancer made up the composite efficacy endpoint used to assess prevention of HPV-related anal cancer. Anal HPV infection, AIN, and anal cancer were not endpoints in the studies conducted in women. The similarity of HPV-related anal disease in men and women supports bridging the indication of prevention of AIN and anal cancer to women. Efficacy was assessed in 6 AAHS-controlled, double-blind, randomized Phase II and III clinical studies. The first Phase II study evaluated the HPV 16 component of human papillomavirus quadrivalent vaccine (Study 1, N = 2391 16- through 26-year-old girls and women) and the second evaluated all components of human papillomavirus quadrivalent vaccine (Study 2, N = 551 16- through 26-year-old girls and women). Two Phase III studies evaluated human papillomavirus quadrivalent vaccine in 5442 (Study 3) and 12,157 (Study 4) 16- through 26-year-old girls and women. A third Phase III study, Study 5, evaluated human papillomavirus quadrivalent vaccine in 4055 16- through 26-year-old boys and men, including a subset of 598 (human papillomavirus quadrivalent vaccine = 299; placebo = 299) men who self-identified as having sex with men (MSM population). A fourth Phase III study, Study 6, evaluated human papillomavirus quadrivalent vaccine in 3817 24- through 45-year-old women. Together, these six studies evaluated 28,413 individuals (20,541 girls and women 16 through 26 years of age at enrollment with a mean age of 20.0 years, 4055 boys and men 16 through 26 years of age at enrollment with a mean age of 20.5 years, and 3817 women 24 through 45 years of age at enrollment with a mean age of 34.3 years). The race distribution of the 16- through 26-year-old girls and women in the clinical trials was as follows: 70.4% White; 12.2% Hispanic (Black and White); 8.8% Other; 4.6% Black; 3.8% Asian; and 0.2% American Indian. The race distribution of the 16- through 26-year-old boys and men in the clinical trials was as follows: 35.2% White; 20.5% Hispanic (Black and White); 14.4% Other; 19.8% Black; 10.0% Asian; and 0.1% American Indian. The race distribution of the 24- through 45-year-old women in the clinical trials was as follows: 20.6% White; 43.2% Hispanic (Black and White); 0.2% Other; 4.8% Black; 31.2% Asian; and 0.1% American Indian. The median duration of follow-up was 4.0, 3.0, 3.0, 3.0, 2.3, and 4.0 years for Study 1, Study 2, Study 3, Study 4, Study 5, and Study 6, respectively. Individuals received vaccine or AAHS control on the day of enrollment and 2 and 6 months thereafter. Efficacy was analyzed for each study individually and for all studies in girls and women combined according to a prospective clinical plan. Overall, 73% of 16- through 26-year-old girls and women, 67% of 24- through 45-year-old women, and 83% of 16- through 26-year-old boys and men were naïve (i.e., PCR [Polymerase Chain Reaction] negative and seronegative for all 4 vaccine HPV types) to all 4 vaccine HPV types at enrollment. A total of 27% of 16- through 26-year-old girls and women, 33% of 24- through 45-year-old women, and 17% of 16- through 26-year-old boys and men had evidence of prior exposure to or ongoing infection with at least 1 of the 4 vaccine HPV types. Among these individuals, 74% of 16- through 26-year-old girls and women, 71% of 24- through 45-year-old women, and 78% of 16- through 26-year-old boys and men had evidence of prior exposure to or ongoing infection with only 1 of the 4 vaccine HPV types and were naïve (PCR negative and seronegative) to the remaining 3 types. In 24- through 45-year-old individuals, 0.4% had been exposed to all 4 vaccine HPV types. In individuals who were naïve (PCR negative and seronegative) to all 4 vaccine HPV types, CIN, genital warts, VIN, VaIN, PIN, and persistent infection caused by any of the 4 vaccine HPV types were counted as endpoints. Among individuals who were positive (PCR positive and/or seropositive) for a vaccine HPV type at Day 1, endpoints related to that type were not included in the analyses of prophylactic efficacy. Endpoints related to the remaining types for which the individual was naïve (PCR negative and seronegative) were counted. For example, in individuals who were HPV 18 positive (PCR positive and/or seropositive) at Day 1, lesions caused by HPV 18 were not counted in the prophylactic efficacy evaluations. Lesions caused by HPV 6, 11, and 16 were included in the prophylactic efficacy evaluations. The same approach was used for the other types. Human papillomavirus quadrivalent vaccine was administered without prescreening for presence of HPV infection and the efficacy trials allowed enrollment of girls and women regardless of baseline HPV status (i.e., PCR status or serostatus). Girls and women with current or prior HPV infection with an HPV type contained in the vaccine were not eligible for prophylactic efficacy evaluations for that type. The primary analyses of efficacy with respect to HPV types 6, 11, 16, and 18 were conducted in the per-protocol efficacy (PPE) population, consisting of girls and women who received all 3 vaccinations within 1 year of enrollment, did not have major deviations from the study protocol, and were naïve (PCR negative in cervicovaginal specimens and seronegative) to the relevant HPV type(s) (Types 6, 11, 16, and 18) prior to dose 1 and through 1 month Postdose 3 (Month 7). Efficacy was measured starting after the Month 7 visit. Human papillomavirus quadrivalent vaccine was efficacious in reducing the incidence of CIN (any grade including CIN 2/3); AIS; genital warts; VIN (any grade); and VaIN (any grade) related to vaccine HPV types 6, 11, 16, or 18 in those who were PCR negative and seronegative at baseline (Table 11). In addition, girls and women who were already infected with 1 or more vaccine-related HPV types prior to vaccination were protected from precancerous cervical lesions and external genital lesions caused by the other vaccine HPV types. Prophylactic efficacy against overall cervical and genital disease related to HPV 6, 11, 16, and 18 in an extension phase of Study 2, that included data through Month 60, was noted to be 100% (95% CI: 12.3%, 100.0%) among girls and women in the per protocol population naïve to the relevant HPV types. Human papillomavirus quadrivalent vaccine was efficacious against HPV disease caused by HPV types 6, 11, 16, and 18 in girls and women who were naïve for those specific HPV types at baseline. The primary analyses of efficacy were conducted in the per-protocol efficacy (PPE) population. This population consisted of boys and men who received all 3 vaccinations within 1 year of enrollment, did not have major deviations from the study protocol, and were naïve (PCR negative and seronegative) to the relevant HPV type(s) (Types 6, 11, 16, and 18) prior to dose 1 and through 1 month postdose 3 (Month 7). Efficacy was measured starting after the Month 7 visit. Human papillomavirus quadrivalent vaccine was efficacious in reducing the incidence of genital warts related to vaccine HPV types 6 and 11 in those boys and men who were PCR negative and seronegative at baseline (Table 12). Efficacy against penile/perineal/perianal intraepithelial neoplasia (PIN) grades 1/2/3 or penile/perineal/perianal cancer was not demonstrated as the number of cases was too limited to reach statistical significance. A sub-study of Study 5 evaluated the efficacy of human papillomavirus quadrivalent vaccine against anal disease (anal intraepithelial neoplasia and anal cancer) in a population of 598 MSM. The primary analyses of efficacy were conducted in the per-protocol efficacy (PPE) population of Study 5. Human papillomavirus quadrivalent vaccine was efficacious in reducing the incidence of anal intraepithelial neoplasia (AIN) grades 1 (both condyloma and non-acuminate), 2, and 3 related to vaccine HPV types 6, 11, 16, and 18 in those boys and men who were PCR negative and seronegative at baseline (Table 13). The clinical trials included girls and women regardless of current or prior exposure to vaccine HPV types, and additional analyses were conducted to evaluate the impact of human papillomavirus quadrivalent vaccine with respect to HPV 6-, 11-, 16-, and 18-related cervical and genital disease in these girls and women. Here, analyses included events arising among girls and women regardless of baseline PCR status and serostatus, including HPV infections that were present at the start of vaccination as well as events that arose from infections that were acquired after the start of vaccination. The impact of human papillomavirus quadrivalent vaccine in girls and women regardless of current or prior exposure to a vaccine HPV type is shown in Table 14. Impact was measured starting 1 month Postdose 1. Prophylactic efficacy denotes the vaccine's efficacy in girls and women who are naïve (PCR negative and seronegative) to the relevant HPV types at Day 1. Vaccine impact in girls and women who were positive for vaccine HPV infection, as well as vaccine impact among girls and women regardless of baseline vaccine HPV PCR status and serostatus are also presented. The majority of CIN and genital warts, VIN, and VaIN related to a vaccine HPV type detected in the group that received human papillomavirus quadrivalent vaccine occurred as a consequence of HPV infection with the relevant HPV type that was already present at Day 1. There was no clear evidence of protection from disease caused by HPV types for which girls and women were PCR positive regardless of serostatus at baseline. The impact of human papillomavirus quadrivalent vaccine against the overall burden of dysplastic or papillomatous cervical, vulvar, and vaginal disease regardless of HPV detection, results from a combination of prophylactic efficacy against vaccine HPV types, disease contribution from vaccine HPV types present at time of vaccination, the disease contribution from HPV types not contained in the vaccine, and disease in which HPV was not detected. Additional efficacy analyses were conducted in 2 populations: (1) a generally HPV-naïve population (negative to 14 common HPV types and had a Pap test that was negative for SIL [Squamous Intraepithelial Lesion] at Day 1), approximating a population of sexually-naïve girls and women and (2) the general study population of girls and women regardless of baseline HPV status, some of whom had HPV-related disease at Day 1. Among generally HPV-naïve girls and women and among all girls and women in the study population (including girls and women with HPV infection at Day 1), human papillomavirus quadrivalent vaccine reduced the overall incidence of CIN 2/3 or AIS; of VIN 2/3 or VaIN 2/3; of CIN (any grade) or AIS; and of Genital Warts (Table 15). These reductions were primarily due to reductions in lesions caused by HPV types 6, 11, 16, and 18 in girls and women naïve (seronegative and PCR negative) for the specific relevant vaccine HPV type. Infected girls and women may already have CIN 2/3 or AIS at Day 1 and some will develop CIN 2/3 or AIS during follow-up, either related to a vaccine or non-vaccine HPV type present at the time of vaccination or related to a non-vaccine HPV type not present at the time of vaccination. Study 5 included boys and men regardless of current or prior exposure to vaccine HPV types, and additional analyses were conducted to evaluate the impact of human papillomavirus quadrivalent vaccine with respect to HPV 6-, 11-, 16-, and 18-related anogenital disease in these boys and men. Here, analyses included events arising among boys and men regardless of baseline PCR status and serostatus, including HPV infections that were present at the start of vaccination as well as events that arose from infections that were acquired after the start of vaccination. The impact of human papillomavirus quadrivalent vaccine in boys and men regardless of current or prior exposure to a vaccine HPV type is shown in Table 16. Impact was measured starting at Day 1. Prophylactic efficacy denotes the vaccine's efficacy in boys and men who are naïve (PCR negative and seronegative) to the relevant HPV types at Day 1. Vaccine impact in boys and men who were positive for vaccine HPV infection, as well as vaccine impact among boys and men regardless of baseline vaccine HPV PCR status and serostatus are also presented. The majority of anogenital disease related to a vaccine HPV type detected in the group that received human papillomavirus quadrivalent vaccine occurred as a consequence of HPV infection with the relevant HPV type that was already present at Day 1. There was no clear evidence of protection from disease caused by HPV types for which boys and men were PCR positive regardless of serostatus at baseline. The impact of human papillomavirus quadrivalent vaccine against the overall burden of dysplastic or papillomatous anogenital disease regardless of HPV detection, results from a combination of prophylactic efficacy against vaccine HPV types, disease contribution from vaccine HPV types present at time of vaccination, the disease contribution from HPV types not contained in the vaccine, and disease in which HPV was not detected. Additional efficacy analyses from Study 5 were conducted in 2 populations: (1) a generally HPV-naïve population that consisted of boys and men who are seronegative and PCR negative to HPV 6, 11, 16, and 18 and PCR negative to HPV 31, 33, 35, 39, 45, 51, 52, 56, 58 and 59 at Day 1, approximating a population of sexually-naïve boys and men and (2) the general study population of boys and men regardless of baseline HPV status, some of whom had HPV-related disease at Day 1. Among generally HPV-naïve boys and men and among all boys and men in Study 5 (including boys and men with HPV infection at Day 1), human papillomavirus quadrivalent vaccine reduced the overall incidence of anogenital disease (Table 17). These reductions were primarily due to reductions in lesions caused by HPV types 6, 11, 16, and 18 in boys and men naïve (seronegative and PCR negative) for the specific relevant vaccine HPV type. Infected boys and men may already have anogenital disease at Day 1 and some will develop anogenital disease during follow-up, either related to a vaccine or non-vaccine HPV type present at the time of vaccination or related to a non-vaccine HPV type not present at the time of vaccination. The subject characteristics (e.g. lifetime sex partners, geographic distribution of the subjects) influence the HPV prevalence of the population and therefore the population benefit can vary widely. The overall efficacy of human papillomavirus quadrivalent vaccine will vary with the baseline prevalence of HPV infection and disease, the incidence of infections against which human papillomavirus quadrivalent vaccine has shown protection, and those infections against which human papillomavirus quadrivalent vaccine has not been shown to protect. The efficacy of human papillomavirus quadrivalent vaccine for HPV types not included in the vaccine (i.e., cross-protective efficacy) is a component of the overall impact of the vaccine on rates of disease caused by HPV. Cross-protective efficacy was not demonstrated against disease caused by non-vaccine HPV types in the combined database of the Study 3 and Study 4 trials. human papillomavirus quadrivalent vaccine does not protect against genital disease not related to HPV. One woman who received human papillomavirus quadrivalent vaccine in Study 3 developed an external genital well-differentiated squamous cell carcinoma at Month 24. No HPV DNA was detected in the lesion or in any other samples taken throughout the study. In 18,150 girls and women enrolled in Study 2, Study 3, and Study 4, human papillomavirus quadrivalent vaccine reduced definitive cervical therapy procedures by 23.9% (95% CI: 15.2%, 31.7%). Study 6 evaluated efficacy in 3253 women 27 through 45 years of age based on a combined endpoint of HPV 6-, 11-, 16- or 18-related persistent infection, genital warts, vulvar and vaginal dysplastic lesions of any grade, CIN of any grade, AIS, and cervical cancer. These women were randomized 1:1 to receive either human papillomavirus quadrivalent vaccine or AAHS control. The efficacy for the combined endpoint was driven primarily by prevention of persistent infection. There was no statistically significant efficacy demonstrated for CIN 2/3, AIS, or cervical cancer. In post hoc analyses conducted to assess the impact of human papillomavirus quadrivalent vaccine on the individual components of the combined endpoint, the results in the population of women naïve to the relevant HPV type at baseline were as follows: prevention of HPV 6-, 11-, 16- or 18-related persistent infection (80.5% [95% CI: 68.3, 88.6]), prevention of HPV 6-, 11-, 16- or 18-related CIN (any grade) (85.8% [95% CI: 52.4, 97.3]), and prevention of HPV 6-, 11-, 16- or 18-related genital warts (87.6% [95% CI: 7.3, 99.7]). Efficacy for disease endpoints was diminished in a population impact assessment of women who were vaccinated regardless of baseline HPV status (full analysis set). In the full analysis set (FAS), efficacy was not demonstrated for the following endpoints: prevention of HPV 16- and 18-related CIN 2/3, AIS, or cervical cancer and prevention of HPV 6- and 11-related condyloma. No efficacy was demonstrated against CIN 2/3, AIS, or cervical cancer in the general population irrespective of HPV type (FAS any type analysis). The minimum anti-HPV titer that confers protective efficacy has not been determined. Because there were few disease cases in individuals naïve (PCR negative and seronegative) to vaccine HPV types at baseline in the group that received human papillomavirus quadrivalent vaccine, it has not been possible to establish minimum anti-HPV 6, anti-HPV 11, anti-HPV 16, and anti-HPV 18 antibody levels that protect against clinical disease caused by HPV 6, 11, 16, and/or 18. The immunogenicity of human papillomavirus quadrivalent vaccine was assessed in 23,951 9- through 45-year-old girls and women (human papillomavirus quadrivalent vaccine N = 12,634; AAHS control or saline placebo N = 11,317) and 5417 9- through 26-year-old boys and men (human papillomavirus quadrivalent vaccine N = 3109; AAHS control or saline placebo N = 2308). Type-specific immunoassays with type-specific standards were used to assess immunogenicity to each vaccine HPV type. These assays measured antibodies against neutralizing epitopes for each HPV type. The scales for these assays are unique to each HPV type; thus, comparisons across types and to other assays are not appropriate. The primary immunogenicity analyses were conducted in a per-protocol immunogenicity (PPI) population. This population consisted of individuals who were seronegative and PCR negative to the relevant HPV type(s) at enrollment, remained HPV PCR negative to the relevant HPV type(s) through 1 month postdose 3 (Month 7), received all 3 vaccinations, and did not deviate from the study protocol in ways that could interfere with the effects of the vaccine. Immunogenicity was measured by (1) the percentage of individuals who were seropositive for antibodies against the relevant vaccine HPV type, and (2) the Geometric Mean Titer (GMT). In clinical studies in 16- through 26-year-old girls and women, 99.8%, 99.8%, 99.8%, and 99.4% who received human papillomavirus quadrivalent vaccine became anti-HPV 6, anti-HPV 11, anti-HPV 16, and anti-HPV 18 seropositive, respectively, by 1 month postdose 3 across all age groups tested. In clinical studies in 27- through 45-year-old women, 98.2%, 97.9%, 98.6%, and 97.1% who received human papillomavirus quadrivalent vaccine became anti-HPV 6, anti-HPV 11, anti-HPV 16, and anti-HPV 18 seropositive, respectively, by 1 month postdose 3 across all age groups tested. In clinical studies in 16- through 26-year-old boys and men, 98.9%, 99.2%, 98.8%, and 97.4% who received GARDASIL became anti-HPV 6, anti-HPV 11, anti-HPV 16, and anti-HPV 18 seropositive, respectively, by 1 month postdose 3 across all age groups tested. Across all populations, anti-HPV 6, anti-HPV 11, anti-HPV 16, and anti-HPV 18 GMTs peaked at Month 7 (Table 18 and Table 19). GMTs declined through Month 24 and then stabilized through Month 36 at levels above baseline. Tables 20 and 21 display the persistence of anti-HPV cLIA geometric mean titers by gender and age group. The duration of immunity following a complete schedule of immunization with human papillomavirus quadrivalent vaccine has not been established. Tables 18 and 19 display the Month 7 immunogenicity data for girls and women and boys and men. Anti-HPV responses 1 month postdose 3 among 9- through 15-year-old adolescent girls were non-inferior to anti-HPV responses in 16- through 26-year-old girls and women in the combined database of immunogenicity studies for human papillomavirus quadrivalent vaccine. Anti-HPV responses 1 month postdose 3 among 9- through 15-year-old adolescent boys were non-inferior to anti-HPV responses in 16- through 26-year-old boys and men in Study 5. On the basis of this immunogenicity bridging, the efficacy of human papillomavirus quadrivalent vaccine in 9- through 15-year-old adolescent girls and boys is inferred. Girls and women evaluated in the PPE population of clinical studies received all 3 vaccinations within 1 year of enrollment. An analysis of immune response data suggests that flexibility of ±1 month for Dose 2 (i.e., Month 1 to Month 3 in the vaccination regimen) and flexibility of ±2 months for Dose 3 (i.e., Month 4 to Month 8 in the vaccination regimen) do not impact the immune responses to human papillomavirus quadrivalent vaccine. The duration of immunity following a complete schedule of immunization with human papillomavirus quadrivalent vaccine has not been established. The peak anti-HPV GMTs for HPV types 6, 11, 16, and 18 occurred at Month 7. Anti-HPV GMTs for HPV types 6, 11, 16, and 18 were similar between measurements at Month 24 and Month 60 in Study 2. The safety and immunogenicity of co-administration of human papillomavirus quadrivalent vaccine with hepatitis B vaccine (recombinant) (same visit, injections at separate sites) were evaluated in a randomized, double-blind, study of 1871 women aged 16 through 24 years at enrollment. The race distribution of the girls and women in the clinical trial was as follows: 61.6% White; 1.6% Hispanic (Black and White); 23.8% Other; 11.9% Black; 0.8% Asian; and 0.3% American Indian. Subjects either received human papillomavirus quadrivalent vaccine and hepatitis B vaccine (recombinant) (n = 466), human papillomavirus quadrivalent vaccine and hepatitis B vaccine (recombinant)-matched placebo (n = 468), hepatitis B vaccine (recombinant) and human papillomavirus quadrivalent vaccine-matched placebo (n = 467) or hepatitis B vaccine (recombinant)-matched placebo and human papillomavirus quadrivalent vaccine-matched placebo (n = 470) at Day 1, Month 2 and Month 6. Immunogenicity was assessed for all vaccines 1 month post completion of the vaccination series. Concomitant administration of human papillomavirus quadrivalent vaccine with hepatitis B vaccine (recombinant) did not interfere with the antibody response to any of the vaccine antigens when human papillomavirus quadrivalent vaccine was given concomitantly with hepatitis B vaccine (recombinant) or separately. The safety and immunogenicity of co-administration of human papillomavirus quadrivalent vaccine with Menactra (Meningococcal (Groups A, C, Y and W-135) Polysaccharide Diphtheria Toxoid Conjugate Vaccine) and Adacel [Tetanus Toxoid, Reduced Diphtheria Toxoid and Acellular Pertussis Vaccine Adsorbed (Tdap)] (same visit, injections at separate sites) were evaluated in an open-labeled, randomized, controlled study of 1040 boys and girls 11 through 17 years of age at enrollment. The race distribution of the subjects in the clinical trial was as follows: 77.7% White; 6.8% Hispanic (Black and White); 1.4% Multi-racial; 12.3% Black; 1.2% Asian; 0.2% Indian; and 0.4% American Indian. One group received human papillomavirus quadrivalent vaccine in one limb and both Menactra and Adacel, as separate injections, in the opposite limb concomitantly on Day 1 (n = 517). The second group received the first dose of human papillomavirus quadrivalent vaccine on Day 1 in one limb then Menactra and Adacel, as separate injections, at Month 1 in the opposite limb (n = 523). Subjects in both vaccination groups received the second dose of human papillomavirus quadrivalent vaccine at Month 2 and the third dose at Month 6. Immunogenicity was assessed for all vaccines 1 month post completion of the vaccination series (1 dose for Menactra and Adacel and 3 doses for human papillomavirus quadrivalent vaccine). Concomitant administration of human papillomavirus quadrivalent vaccine with Menactra (Meningococcal (Groups A, C, Y and W-135) Polysaccharide Diphtheria Toxoid Conjugate Vaccine) and Adacel [Tetanus Toxoid, Reduced Diphtheria Toxoid and Acellular Pertussis Vaccine Adsorbed (Tdap)] did not interfere with the antibody response to any of the vaccine antigens when human papillomavirus quadrivalent vaccine was given concomitantly with Menactra and Adacel or separately. # How Supplied All presentations for GARDASIL contain a suspension of 120 mcg L1 protein from HPV types 6, 11, 16, and 18 in a 0.5-mL dose. GARDASIL is supplied in vials and syringes. - Carton of one 0.5-mL single-dose vial. NDC 0006-4045-00. - Carton of ten 0.5-mL single-dose vials. NDC 0006-4045-41. - Carton of six 0.5-mL single-dose prefilled Luer-Lok® syringes with tip caps. NDC 0006-4109-09. - Carton of ten 0.5-mL single-dose prefilled Luer-Lok® syringes with tip caps. NDC 0006-4109-02. ## Storage - Store refrigerated at 2 to 8°C (36 to 46°F). Do not freeze. Protect from light. - GARDASIL should be administered as soon as possible after being removed from refrigeration. - GARDASIL can be out of refrigeration (at temperatures at or below 25°C/77°F), for a total time of not more than 72 hours. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information Advise the patient to read the FDA-approved patient labeling (Patient Information). Inform the patient, parent, or guardian: - Vaccination does not eliminate the necessity for women to continue to undergo recommended cervical cancer screening. Women who receive human papillomavirus quadrivalent vaccine should continue to undergo cervical cancer screening per standard of care. - Recipients of human papillomavirus quadrivalent vaccine should not discontinue anal cancer screening if it has been recommended by a health care provider. - Human papillomavirus quadrivalent vaccine has not been demonstrated to provide protection against disease from vaccine and non-vaccine HPV types to which a person has previously been exposed through sexual activity. - Since syncope has been reported following vaccination sometimes resulting in falling with injury, observation for 15 minutes after administration is recommended. - Vaccine information is required to be given with each vaccination to the patient, parent, or guardian. - Information regarding benefits and risks associated with vaccination. - Human papillomavirus quadrivalent vaccine is not recommended for use in pregnant women. - Importance of completing the immunization series unless contraindicated. - Report any adverse reactions to their health care provider. # Precautions with Alcohol Alcohol-HPV Vaccine interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names Gardasil # Look-Alike Drug Names There is limited information regarding HPV Vaccine Look-Alike Drug Names in the drug label. # Drug Shortage Status Drug Shortage # Price	https://www.wikidoc.org/index.php/Gardasil
58a6b21fa00c8a6a5423acdcf9d5c630c1e9aaba	wikidoc	Garenoxacin	Garenoxacin # Overview Garenoxacin (INN) is a quinolone antibiotic for the treatment of Gram-positive and Gram-negative bacterial infections. Garenoxacin was discovered by Toyama Chemical Co., Ltd. of Tokyo, Japan, and is currently being marketed in Japan under the tradename Geninax. Schering-Plough holds worldwide rights for garenoxacin, except for Japan, South Korea, and China. On February 13, 2006, Schering-Plough announced that the United States Food and Drug Administration has accepted the New Drug Application (NDA) for garenoxacin, and has been granted a 10-month review. Schering-Plough later withdrew its application to the United States Food and Drug Administration, FDA, (August 20, 2006) for approval of the antibiotic Garenoxacin. The European Medicines Agency (EMEA) had also been formally notified by Schering-Plough Europe (July 28 2007) of its decision to withdraw the application for a centralized marketing authorization for garenoxacin as well. Based on the CHMP review of the data regarding safety and efficacy (risk/benefit), the CHMP considered the application for garenoxacin to be unapprovable.	Garenoxacin Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview Garenoxacin (INN) is a quinolone antibiotic for the treatment of Gram-positive and Gram-negative bacterial infections. Garenoxacin was discovered by Toyama Chemical Co., Ltd. of Tokyo, Japan, and is currently being marketed in Japan under the tradename Geninax. Schering-Plough holds worldwide rights for garenoxacin, except for Japan, South Korea, and China. On February 13, 2006, Schering-Plough announced that the United States Food and Drug Administration has accepted the New Drug Application (NDA) for garenoxacin, and has been granted a 10-month review.[1] Schering-Plough later withdrew its application to the United States Food and Drug Administration, FDA, (August 20, 2006) for approval of the antibiotic Garenoxacin.[2] The European Medicines Agency (EMEA) had also been formally notified by Schering-Plough Europe (July 28 2007) of its decision to withdraw the application for a centralized marketing authorization for garenoxacin as well.[3][4][5] Based on the CHMP review of the data regarding safety and efficacy (risk/benefit), the CHMP considered the application for garenoxacin to be unapprovable.[6]	https://www.wikidoc.org/index.php/Garenoxacin
7c7361fff0b3494bb40242d7a060aba5c227829a	wikidoc	Gaslighting	Gaslighting # Overview Gaslighting is a form of psychological abuse in which false information is presented with the intent of making a victim doubt his or her own memory and perception. It may simply be the denial by an abuser that previous abusive incidents ever occurred, or it could be the staging of bizarre events by the abuser with the intention of disorienting the victim. The term "gaslighting" comes from the play Gas Light and its film adaptations. In those works a character uses a variety of tricks to convince his spouse that she is crazy, so that she won't be believed when she reports strange things that are genuinely occurring, including the dimming of the gas lamps in the house (which happens when her husband turns on the normally unused gas lamps in the attic to conduct clandestine activities there). Since then, it has become a colloquial expression that is now also used in clinical and research literature. # Etymology The term derives from the 1938 stage play Gas Light (originally known as Angel Street in the United States), and the 1940 and 1944 film adaptations. The plot concerns a husband who attempts to convince his wife and others that she is insane by manipulating small elements of their environment, and insisting that she is mistaken or misremembering when she points out these changes. The title stems from the husband's subtle dimming of the house's gas lights, which she accurately notices and which the husband insists she's imagining. The term "gaslighting" has been used colloquially since at least the late 1970s to describe efforts to manipulate someone's sense of reality. In a 1980 book on child sex abuse, Florence Rush summarized George Cukor's 1944 film version of Gas Light, and writes, "even today the word is used to describe an attempt to destroy another's perception of reality". # Introjection In an influential article "Some Clinical Consequences of Introjection: Gaslighting", the authors argue that gaslighting involves the projection and introjection of psychic conflicts from the perpetrator to the victim: 'this imposition is based on a very special kind of "transfer"...of painful and potentially painful mental conflicts'. They explore a variety of reasons why the victims may have 'a tendency to incorporate and assimilate what others externalize and project onto them', and conclude that gaslighting can be 'a very complex, highly structured configuration which encompasses contributions from many elements of the psychic apparatus'. # Resisting With respect to women in particular, Hilde Lindemann argued that "in gaslighting cases...ability to resist depends on her ability to trust her own judgements." Establishing "counterstories" to that of the gaslighter may help the victim re-acquire or even for the first time "acquire ordinary levels of free agency". # Clinical examples Psychologist Martha Stout states that psychopaths frequently use gaslighting tactics. Psychopaths consistently transgress social mores, break laws, and exploit others, but are also typically charming and convincing liars who consistently deny wrongdoing. Thus, some who have been victimized by sociopaths may doubt their perceptions. Jacobson and Gottman report that some physically abusive spouses may gaslight their partners, even flatly denying that they have used violence. Psychologists Gertrude Gass and William C. Nichols use the term "gaslighting" to describe a dynamic observed in some cases of marital infidelity: "Therapists may contribute to the victim's distress through mislabeling the women's reactions. The gaslighting behaviors of the husband provide a recipe for the so-called 'nervous breakdown' for some women suicide in some of the worst situations."	Gaslighting Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview Gaslighting is a form of psychological abuse in which false information is presented with the intent of making a victim doubt his or her own memory and perception. It may simply be the denial by an abuser that previous abusive incidents ever occurred, or it could be the staging of bizarre events by the abuser with the intention of disorienting the victim. The term "gaslighting" comes from the play Gas Light and its film adaptations. In those works a character uses a variety of tricks to convince his spouse that she is crazy, so that she won't be believed when she reports strange things that are genuinely occurring, including the dimming of the gas lamps in the house (which happens when her husband turns on the normally unused gas lamps in the attic to conduct clandestine activities there). Since then, it has become a colloquial expression that is now also used in clinical and research literature.[1][2] # Etymology The term derives from the 1938 stage play Gas Light (originally known as Angel Street in the United States), and the 1940 and 1944 film adaptations. The plot concerns a husband who attempts to convince his wife and others that she is insane by manipulating small elements of their environment, and insisting that she is mistaken or misremembering when she points out these changes. The title stems from the husband's subtle dimming of the house's gas lights, which she accurately notices and which the husband insists she's imagining. The term "gaslighting" has been used colloquially since at least the late 1970s to describe efforts to manipulate someone's sense of reality. In a 1980 book on child sex abuse, Florence Rush summarized George Cukor's 1944 film version of Gas Light, and writes, "even today the word [gaslight] is used to describe an attempt to destroy another's perception of reality".[3] # Introjection In an influential article "Some Clinical Consequences of Introjection: Gaslighting", the authors argue that gaslighting involves the projection and introjection of psychic conflicts from the perpetrator to the victim: 'this imposition is based on a very special kind of "transfer"...of painful and potentially painful mental conflicts'.[4] They explore a variety of reasons why the victims may have 'a tendency to incorporate and assimilate what others externalize and project onto them', and conclude that gaslighting can be 'a very complex, highly structured configuration which encompasses contributions from many elements of the psychic apparatus'.[4] # Resisting With respect to women in particular, Hilde Lindemann argued that "in gaslighting cases...ability to resist depends on her ability to trust her own judgements."[5] Establishing "counterstories" to that of the gaslighter may help the victim re-acquire or even for the first time "acquire ordinary levels of free agency".[5] # Clinical examples Psychologist Martha Stout states that psychopaths frequently use gaslighting tactics. Psychopaths consistently transgress social mores, break laws, and exploit others, but are also typically charming and convincing liars who consistently deny wrongdoing. Thus, some who have been victimized by sociopaths may doubt their perceptions.[6] Jacobson and Gottman report that some physically abusive spouses may gaslight their partners, even flatly denying that they have used violence.[citation needed] Psychologists Gertrude Gass and William C. Nichols use the term "gaslighting" to describe a dynamic observed in some cases of marital infidelity: "Therapists may contribute to the victim's distress through mislabeling the women's reactions. [...] The gaslighting behaviors of the husband provide a recipe for the so-called 'nervous breakdown' for some women [and] suicide in some of the worst situations."[7]	https://www.wikidoc.org/index.php/Gaslighting
f34bc67c9e33c8397ee99dc876ce009c400dcf84	wikidoc	Gastrectomy	Gastrectomy A gastrectomy is a partial or full surgical removal of the stomach. The first successful gastrectomy was performed by Theodor Billroth in 1881 for cancer of the stomach. Gastrectomies are performed to treat cancer, severe cases of peptic ulcer disease, and perforations of the stomach wall. This procedure is becoming less common as peptic ulcers are now often treated with antibiotics for Helicobacter pylori or by endoscopy. In severe duodenal ulcers it may be necessary to remove the lower portion of the stomach called the pylorus and the upper portion of the small intestine called the duodenum. If there is a sufficient portion of the upper duodenum remaining a Billroth I procedure is performed, where the remaining portion of the stomach is reattached to the duodenum before the bile duct and the duct of the pancreas. If the stomach cannot be reattached to the duodenum a Billroth II is performed, where the remaining portion of the duodenum is sealed off, a hole is cut into the next section of the small intestine called the jejunum and the stomach is reattached at this hole. As the pylorus is used to grind food and slowly release the food into the small intestine, removal of the pylorus can cause food to move into the small intestine faster than normal, leading to gastric dumping syndrome. In the past a gastrectomy for peptic ulcer disease was often accompanied by a vagotomy, where the vagus nerve is cut to reduce acid production in the stomach. Nowadays, this problem is managed with proton pump inhibitors. # Polya's operation A type of posterior gastroenterostomy which is a modification of the Billroth II operation. Resection of 2/3 of the stomach with blind closure of the duodenal stump and retrocolic anastomosis of the full circumference of the open stomach to jejunum See also Finsterer-Hofmeister operation under Hans Finsterer, German surgeon, 1877–1955.	Gastrectomy Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] A gastrectomy is a partial or full surgical removal of the stomach. The first successful gastrectomy was performed by Theodor Billroth in 1881 for cancer of the stomach. Gastrectomies are performed to treat cancer, severe cases of peptic ulcer disease, and perforations of the stomach wall. This procedure is becoming less common as peptic ulcers are now often treated with antibiotics for Helicobacter pylori or by endoscopy.[1] [2] In severe duodenal ulcers it may be necessary to remove the lower portion of the stomach called the pylorus and the upper portion of the small intestine called the duodenum. If there is a sufficient portion of the upper duodenum remaining a Billroth I procedure is performed, where the remaining portion of the stomach is reattached to the duodenum before the bile duct and the duct of the pancreas. If the stomach cannot be reattached to the duodenum a Billroth II is performed, where the remaining portion of the duodenum is sealed off, a hole is cut into the next section of the small intestine called the jejunum and the stomach is reattached at this hole. As the pylorus is used to grind food and slowly release the food into the small intestine, removal of the pylorus can cause food to move into the small intestine faster than normal, leading to gastric dumping syndrome. In the past a gastrectomy for peptic ulcer disease was often accompanied by a vagotomy, where the vagus nerve is cut to reduce acid production in the stomach. Nowadays, this problem is managed with proton pump inhibitors. # Polya's operation A type of posterior gastroenterostomy which is a modification of the Billroth II operation. Resection of 2/3 of the stomach with blind closure of the duodenal stump and retrocolic anastomosis of the full circumference of the open stomach to jejunum See also Finsterer-Hofmeister operation under Hans Finsterer, German surgeon, 1877–1955.	https://www.wikidoc.org/index.php/Gastrectomy
37229936c4b1cae109a1ad2770ebdfb5ea992150	wikidoc	Gemcitabine	Gemcitabine # Disclaimer WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here. # Overview Gemcitabine is a nucleoside metabolic inhibitor that is FDA approved for the treatment of advanced ovarian cancer, metastatic breast cancer after failure of prior anthracycline-containing adjuvant chemotherapy, non-small cell lung cancer, and pancreatic cancer. Common adverse reactions include nausea/vomiting, anemia, hepatic transaminitis, neutropenia, increased alkaline phosphatase, proteinuria, fever, hematuria, rash, thrombocytopenia, dyspnea, and peripheral edema. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) - Recommended Dose and Schedule - The recommended dose of Gemzar is 1000 mg/m2 as an intravenous infusion over 30 minutes on Days 1 and 8 of each 21-day cycle, in combination with carboplatin AUC 4 intravenously after Gemzar administration on Day 1 of each 21-day cycle. Refer to carboplatin prescribing information for additional information. - Dose Modifications - Recommended Gemzar dose modifications for myelosuppression are described in TABLE 1 and TABLE 2. - Recommended Dose and Schedule - The recommended dose of Gemzar is 1250 mg/m2 intravenously over 30 minutes on Days 1 and 8 of each 21-day cycle that includes paclitaxel. Paclitaxel should be administered at 175 mg/m2 on Day 1 as a 3 hour intravenous infusion before Gemzar administration. - Dose Modifications - Recommended dose modifications for Gemzar for myelosuppression are described in TABLE 3. - Recommended Dose and Schedule - Every 4-week schedule - The recommended dose of Gemzar is 1000 mg/m2 intravenously over 30 minutes on Days 1, 8, and 15 in combination with cisplatin therapy. Administer cisplatin intravenously at 100 mg/m2 on Day 1 after the infusion of Gemzar. - Every 3-week schedule - The recommended dose of Gemzar is 1250 mg/m2 intravenously over 30 minutes on Days 1 and 8 in combination with cisplatin therapy. Administer cisplatin intravenously at 100 mg/m2 on Day 1 after the infusion of Gemzar. - Dose Modifications - Recommended dose modifications for Gemzar myelosuppression are described in TABLE 4. - Recommended Dose and Schedule - The recommended dose of Gemzar is 1000 mg/m2 over 30 minutes intravenously. The recommended treatment schedule is as follows: - Weeks 1-8: weekly dosing for the first 7 weeks followed by one week rest. - After week 8: weekly dosing on Days 1, 8, and 15 of 28-day cycles. - Dose Modifications - Recommended dose modifications for Gemzar for myelosuppression are described in TABLE 4. - Patients receiving Gemzar should be monitored prior to each dose with a complete blood count (CBC), including differential and platelet count. If marrow suppression is detected, therapy should be modified or suspended according to the guidelines in TABLE 4. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Gemcitabine in adult patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Gemcitabine in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) There is limited information regarding FDA-Labeled Use of Gemcitabine in pediatric patients. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Gemcitabine in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Gemcitabine in pediatric patients. # Contraindications - Gemzar is contraindicated in patients with a known hypersensitivity to gemcitabine. # Warnings ### Precautions - Schedule-dependent Toxicity - In clinical trials evaluating the maximum tolerated dose of Gemzar, prolongation of the infusion time beyond 60 minutes or more frequent than weekly dosing resulted in an increased incidence of clinically significant hypotension, severe flu-like symptoms, myelosuppression, and asthenia. The half-life of Gemzar is influenced by the length of the infusion. - Myelosuppression - Myelosuppression manifested by neutropenia, thrombocytopenia, and anemia occurs with Gemzar as a single agent and the risks are increased when Gemzar is combined with other cytotoxic drugs. In clinical trials, Grade 3-4 neutropenia, anemia, and thrombocytopenia occurred in 25%, 8%, and 5%, respectively of patients receiving single-agent Gemzar. The frequencies of Grade 3-4 neutropenia, anemia, and thrombocytopenia varied from 48% to 71%, 8 to 28%, and 5 to 55%, respectively, in patients receiving Gemzar in combination with another drug. - Pulmonary Toxicity and Respiratory Failure - Pulmonary toxicity, including interstitial pneumonitis, pulmonary fibrosis, pulmonary edema, and adult respiratory distress syndrome (ARDS), has been reported. In some cases, these pulmonary events can lead to fatal respiratory failure despite discontinuation of therapy. The onset of pulmonary symptoms may occur up to 2 weeks after the last dose of Gemzar. Discontinue Gemzar in patients who develop unexplained dyspnea, with or without bronchospasm, or have any evidence of pulmonary toxicity. - Hemolytic Uremic Syndrome - Hemolytic uremic syndrome, including fatalities from renal failure or the requirement for dialysis, can occur in patients treated with Gemzar. In clinical trials, HUS was reported in 6 of 2429 patients (0.25%). Most fatal cases of renal failure were due to HUS. Assess renal function prior to initiation of Gemzar and periodically during treatment. Consider the diagnosis of HUS in patients who develops anemia with evidence of microangiopathic hemolysis, elevation of bilirubin or LDH, or reticulocytosis; severe thrombocytopenia; or evidence of renal failure (elevation of serum creatinine or BUN). Permanently discontinue Gemzar in patients with HUS or severe renal impairment. Renal failure may not be reversible even with discontinuation of therapy. - Hepatic Toxicity - Drug-induced liver injury, including liver failure and death, has been reported in patients receiving Gemzar alone or in combination with other potentially hepatotoxic drugs. Administration of Gemzar in patients with concurrent liver metastases or a pre-existing medical history or hepatitis, alcoholism, or liver cirrhosis can lead to exacerbation of the underlying hepatic insufficiency. Assess hepatic function prior to initiation of Gemzar and periodically during treatment. Discontinue Gemzar in patients that develop severe liver injury. - Embryofetal Toxicity - Gemzar can cause fetal harm when administered to a pregnant woman, based on its mechanism of action. Gemcitabine was teratogenic, embryotoxic, and fetotoxic in mice and rabbits. If this drug is used during pregnancy, or if a woman becomes pregnant while taking Gemzar, the patient should be apprised of the potential hazard to a fetus. - Exacerbation of Radiation Therapy Toxicity - Gemzar is not indicated for use in combination with radiation therapy. - Concurrent (given together or ≤7 days apart) — Life-threatening mucositis, especially esophagitis and pneumonitis occurred in a trial in which Gemzar was administered at a dose of 1000 mg/m2 to patients with non-small cell lung cancer for up to 6 consecutive weeks concurrently with thoracic radiation. - Non-concurrent (given >7 days apart) — Excessive toxicity has not been observed when Gemzar is administered more than 7 days before or after radiation. Radiation recall has been reported in patients who receive Gemzar after prior radiation. - Capillary Leak Syndrome - Capillary leak syndrome (CLS) with severe consequences has been reported in patients receiving Gemzar as a single agent or in combination with other chemotherapeutic agents. Discontinue Gemzar if CLS develops during therapy. - Posterior Reversible Encephalopathy Syndrome - Posterior reversible encephalopathy syndrome (PRES) has been reported in patients receiving Gemzar as a single agent or in combination with other chemotherapeutic agents. PRES can present with headache, seizure, lethargy, hypertension, confusion, blindness, and other visual and neurologic disturbances. Confirm the diagnosis of PRES with magnetic resonance imaging (MRI) and discontinue Gemzar if PRES develops during therapy. # Adverse Reactions ## Clinical Trials Experience - Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. - Single-Agent Use: - The data described below reflect exposure to Gemzar as a single agent administered at doses between 800 mg/m2 to 1250 mg/m2 over 30 minutes intravenously, once weekly, in 979 patients with a variety of malignancies. The most common (≥20%) adverse reactions of single-agent Gemzar are nausea/vomiting, anemia, increased ALT, increased AST, neutropenia, increased alkaline phosphatase, proteinuria, fever, hematuria, rash, thrombocytopenia, dyspnea, and edema. The most common (≥5%) Grade 3 or 4 adverse reactions were neutropenia, nausea/vomiting; increased ALT, increase alkaline phosphatase, anemia, increased AST, and thrombocytopenia. Approximately 10% of the 979 patients discontinued Gemzar due to adverse reactions. Adverse reactions resulting in discontinuation of Gemzar in 2% of 979 patients were cardiovascular adverse events (myocardial infarction, cerebrovascular accident, arrhythmia, and hypertension) and adverse reactions resulting in discontinuation of Gemzar in less than 1% of the 979 patients were anemia, thrombocytopenia, hepatic dysfunction, renal dysfunction, nausea/vomiting, fever, rash, dyspnea, hemorrhage, infection, stomatitis, somnolence, flu-like syndrome, and edema. - TABLE 5 presents the incidence of adverse reactions reported in 979 patients with various malignancies receiving single-agent Gemzar across 5 clinical trials. TABLE 5 includes all clinical adverse reactions, reported in at least 10% of patients. A listing of clinically significant adverse reactions is provided following the table. - Transfusion requirements — Red blood cell transfusions (19%); platelet transfusions (<1%) - Fever — Fever occurred in the absence of clinical infection and frequently in combination with other flu-like symptoms. - Pulmonary — Dyspnea unrelated to underlying disease and sometimes accompanied by bronchospasm. - Edema — Edema (13%), peripheral edema (20%), and generalized edema (<1%); <1% of patients. discontinued Gemzar due to edema. - Flu-like Symptoms — Characterized by fever, asthenia, anorexia, headache, cough, chills, myalgia, asthenia, insomnia, rhinitis, sweating, and/or malaise (19%); <1% of patients discontinued Gemzar due to flu-like symptoms - Infection — Sepsis (<1%) - Extravasation — Injection-site reactions (4%) - Allergic — Bronchospasm (<2%); anaphylactoid reactions. - TABLE 6 presents the incidence of selected adverse reactions, occurring in ≥10% of Gemzar-treated patients and at a higher incidence in the Gemzar plus cisplatin arm, reported in a randomized trial of Gemzar plus cisplatin (n=262) administered in 28-day cycles as compared to cisplatin alone (n=260) in patients receiving first-line treatment for locally advanced or metastatic non-small cell lung cancer (NSCLC). Patients randomized to Gemzar plus cisplatin received a median of 4 cycles of treatment and those randomized to cisplatin received a median of 2 cycles of treatment. In this trial, the requirement for dose adjustments (>90% versus 16%), discontinuation of treatment for adverse reactions (15% versus 8%), and the proportion of patients hospitalized (36% versus 23%) were all higher for patients receiving Gemzar plus cisplatin arm compared to those receiving cisplatin alone. The incidence of febrile neutropenia (9/262 versus 2/260), sepsis (4% versus 1%), Grade 3 cardiac dysrhythmias (3% versus <1%) were all higher in the Gemzar plus cisplatin arm compared to the cisplatin alone arm. The two-drug combination was more myelosuppressive with 4 (1.5%) possibly treatment-related deaths, including 3 resulting from myelosuppression with infection and one case of renal failure associated with pancytopenia and infection. No deaths due to treatment were reported on the cisplatin arm. - TABLE 7 presents the incidence of selected adverse reactions, occurring in ≥10% of Gemzar-treated patients and at a higher incidence in the Gemzar plus cisplatin arm, reported in a randomized trial of Gemzar plus cisplatin (n=69) administered in 21-day cycles as compared to etoposide plus cisplatin alone (n=66) in patients receiving first-line treatment for locally advanced or metastatic non-small cell lung cancer (NSCLC) . A listing of clinically significant adverse reactions is provided following the table. - Patients in the Gemzar cisplatin (GC) arm received a median of 5 cycles and those in the etoposide/cisplatin (EC) arm received a median of 4 cycles. The majority of patients receiving more than one cycle of treatment required dose adjustments; 81% in the (GC) arm and 68% in the (EC) arm. The incidence of hospitalizations for treatment-related adverse events was 22% (GC) and 27% in the (EC) arm. The proportion of discontinuation of treatment for treatment-related adverse reactions was higher for patients in the (GC) arm (14% versus 8%). The proportion of patients hospitalized for febrile neutropenia was lower in the (GC) arm (7% versus 12%). There was one death attributed to treatment, a patient with febrile neutropenia and renal failure, which occurred in the Gemzar/cisplatin arm. - TABLE 8 presents the incidence of selected adverse reactions, occurring in ≥10% of Gemzar-treated patients and at a higher incidence in the Gemzar plus paclitaxel arm, reported in a randomized trial of Gemzar plus paclitaxel (n=262) compared to paclitaxel alone (n=259) for the first-line treatment of metastatic breast cancer (MBC) in women who received anthracycline-containing chemotherapy in the adjuvant/neo-adjuvant setting or for whom anthracyclines were contraindicated. - The requirement for dose reduction of paclitaxel were higher for patients in the Gemzar/paclitaxel arm (5% versus 2%). The number of paclitaxel doses omitted (<1%), the proportion of patients discontinuing treatment for treatment-related adverse reactions (7% versus 5%), and the number of treatment-related deaths (1 patient in each arm) were similar between the two arms. - Clinically relevant Grade 3 or 4 dyspnea occurred with a higher incidence in the Gemzar plus paclitaxel arm compared with the paclitaxel arm (1.9% versus 0). - TABLE 9 presents the incidence of selected adverse reactions, occurring in ≥10% of gemcitabine-treated patients and at a higher incidence in the Gemzar plus carboplatin arm, reported in a randomized trial of Gemzar plus carboplatin (n=175) compared to carboplatin alone (n=174) for the second-line treatment of ovarian cancer in women with disease that had relapsed more than 6 months following first-line platinum-based chemotherapy. Additional clinically significant adverse reactions, occurring in less than 10% of patients, are provided following TABLE 9. - The proportion of patients with dose adjustments for carboplatin (1.8% versus 3.8%), doses of carboplatin omitted (0.2% versus 0), and discontinuing treatment for treatment-related adverse reactions (10.9% versus 9.8%), were similar between arms. Dose adjustment for Gemzar occurred in 10.4% of patients and Gemzar dose was omitted in 13.7% of patients in the Gemzar /carboplatin arm. - Hematopoietic growth factors were administered more frequently in the Gemzar-containing arm: granulocyte growth factors (23.6% and 10.1%) and erythropoietic agents (7.3% and 3.9%). - The following clinically relevant, Grade 3 and 4 adverse reactions occurred more frequently in the Gemzar plus carboplatin arm: dyspnea (3.4% versus 2.9%), febrile neutropenia (1.1% versus 0), hemorrhagic event (2.3% versus 1.1 %), motor neuropathy (1.1% versus 0.6%), and rash/desquamation (0.6% versus 0). ## Postmarketing Experience - The following adverse reactions have been identified during post-approval use of Gemzar. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Congestive heart failure, myocardial infarction, arrhythmias, supraventricular arrhythmias Peripheral vasculitis, gangrene, and capillary leak syndrome Cellulitis, severe skin reactions, including desquamation and bullous skin eruptions Hepatic failure, hepatic veno-occlusive disease Interstitial pneumonitis, pulmonary fibrosis, pulmonary edema, and adult respiratory distress syndrome (ARDS) Posterior reversible encephalopathy syndrome (PRES) # Drug Interactions - No drug interaction studies have been conducted. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): - Pregnancy Category D - Risk Summary - Gemzar can cause fetal harm when administered to a pregnant woman. Based on its mechanism of action, Gemzar is expected to result in adverse reproductive effects. Gemcitabine was teratogenic, embryotoxic, and fetotoxic in mice and rabbits. If Gemzar is used during pregnancy, or if the patient becomes pregnant while taking Gemzar, the patient should be apprised of the potential hazard to a fetus. - Animal Data - Gemcitabine is embryotoxic causing fetal malformations (cleft palate, incomplete ossification) at doses of 1.5 mg/kg/day in mice (approximately 0.005 times the recommended human dose on a mg/m2 basis). Gemcitabine is fetotoxic causing fetal malformations (fused pulmonary artery, absence of gall bladder) at doses of 0.1 mg/kg/day in rabbits (about 0.002 times the recommended human dose on a mg/m2 basis). Embryotoxicity was characterized by decreased fetal viability, reduced live litter sizes, and developmental delays. Pregnancy Category (AUS): - Australian Drug Evaluation Committee (ADEC) Pregnancy Category There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Gemcitabine in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Gemcitabine during labor and delivery. ### Nursing Mothers - It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from Gemzar, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. ### Pediatric Use - The safety and effectiveness of Gemzar have not been established in pediatric patients. The safety and pharmacokinetics of gemcitabine were evaluated in a trial in pediatric patients with refractory leukemia. The maximum tolerated dose was 10 mg/m2/min for 360 minutes three times weekly followed by a one-week rest period. The safety and activity of Gemzar were evaluated in a trial of pediatric patients with relapsed acute lymphoblastic leukemia (22 patients) and acute myelogenous leukemia (10 patients) at a dose of 10 mg/m2/min administered over 360 minutes three times weekly followed by a one-week rest period. Toxicities observed included bone marrow suppression, febrile neutropenia, elevation of serum transaminases, nausea, and rash/desquamation. No meaningful clinical activity was observed in this trial. ### Geriatic Use - In clinical studies of GEMZAR, enrolling 979 patients with various cancers who received GEMZAR as a single agent, no overall differences in safety were observed between patients aged 65 and older and younger patients, with the exception of a higher rate of Grade 3-4 thrombocytopenia in older patients as compared to younger patients. In a randomized trial in women with ovarian cancer, 175 women received GEMZAR plus carboplatin, of which 29% were age 65 years or older. Similar effectiveness was observed between older and younger women. There was significantly higher Grade 3/4 neutropenia in women 65 years of age or older. - GEMZAR clearance is affected by age, however there are no recommended dose adjustments based on patients' age. ### Gender - Gemzar clearance is affected by gender. In single-agent studies of Gemzar, women, especially older women, were more likely not to proceed to a subsequent cycle and to experience Grade 3/4 neutropenia and thrombocytopenia. ### Race There is no FDA guidance on the use of Gemcitabine with respect to specific racial populations. ### Renal Impairment There is no FDA guidance on the use of Gemcitabine in patients with renal impairment. ### Hepatic Impairment There is no FDA guidance on the use of Gemcitabine in patients with hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Gemcitabine in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Gemcitabine in patients who are immunocompromised. # Administration and Monitoring ### Administration - Intravenous ### Monitoring There is limited information regarding Monitoring of Gemcitabine in the drug label. # IV Compatibility - Reconstitute the vials with 0.9% Sodium Chloride Injection without preservatives. - Add 5 mL to the 200-mg vial or 25 mL to the 1-g vial. These dilutions each yield a Gemzar concentration of 38 mg/mL. Complete withdrawal of the vial contents will provide 200 mg or 1 g of Gemzar. Prior to administration the appropriate amount of drug must be diluted with 0.9% Sodium Chloride Injection. Final concentrations may be as low as 0.1 mg/mL. - Reconstituted Gemzar is a clear, colorless to light straw-colored solution. Inspect visually prior to administration and discard for particulate matter or discoloration. Gemzar solutions are stable for 24 hours at controlled room temperature of 20° to 25°C (68° to 77°F). Do not refrigerate as crystallization can occur. - No incompatibilities have been observed with infusion bottles or polyvinyl chloride bags and administration sets. # Overdosage - Myelosuppression, paresthesias, and severe rash were the principal toxicities seen when a single dose as high as 5700 mg/m2 was administered by intravenous infusion over 30 minutes every 2 weeks to several patients in a dose-escalation study. # Pharmacology ## Mechanism of Action - Gemcitabine kills cells undergoing DNA synthesis and blocks the progression of cells through the G1/S-phase boundary. Gemcitabine is metabolized by nucleoside kinases to diphosphate (dFdCDP) and triphosphate (dFdCTP) nucleosides. Gemcitabine diphosphate inhibits ribonucleotide reductase, an enzyme responsible for catalyzing the reactions that generate deoxynucleoside triphosphates for DNA synthesis, resulting in reductions in deoxynucleotide concentrations, including dCTP. Gemcitabine triphosphate competes with dCTP for incorporation into DNA. The reduction in the intracellular concentration of dCTP by the action of the diphosphate enhances the incorporation of gemcitabine triphosphate into DNA (self-potentiation). After the gemcitabine nucleotide is incorporated into DNA, only one additional nucleotide is added to the growing DNA strands, which eventually results in the initiation of apoptotic cell death. ## Structure - Gemzar (gemcitabine for injection, USP) is a nucleoside metabolic inhibitor that exhibits antitumor activity. Gemcitabine HCl is 2′-deoxy-2′,2′-difluorocytidine monohydrochloride (β-isomer). - The structural formula is as follows: - The empirical formula for gemcitabine HCl is C9H11F2N3O4 - HCl. It has a molecular weight of 299.66. - Gemcitabine HCl is soluble in water, slightly soluble in methanol, and practically insoluble in ethanol and polar organic solvents. - Gemzar is supplied in a sterile form for intravenous use only. Vials of Gemzar contain either 200 mg or 1 g of gemcitabine HCl (expressed as free base) formulated with mannitol (200 mg or 1 g, respectively) and sodium acetate (12.5 mg or 62.5 mg, respectively) as a sterile lyophilized powder. Hydrochloric acid and/or sodium hydroxide may have been added for pH adjustment. ## Pharmacodynamics There is limited information regarding Pharmacodynamics of Gemcitabine in the drug label. ## Pharmacokinetics - Absorption and Distribution - The pharmacokinetics of gemcitabine were examined in 353 patients, with various solid tumors. Pharmacokinetic parameters were derived using data from patients treated for varying durations of therapy given weekly with periodic rest weeks and using both short infusions (<70 minutes) and long infusions (70 to 285 minutes). The total Gemzar dose varied from 500 to 3600 mg/m2. - The volume of distribution was increased with infusion length. Volume of distribution of gemcitabine was 50 L/m2 following infusions lasting <70 minutes. For long infusions, the volume of distribution rose to 370 L/m2. - Gemcitabine pharmacokinetics are linear and are described by a 2-compartment model. Population pharmacokinetic analyses of combined single and multiple dose studies showed that the volume of distribution of gemcitabine was significantly influenced by duration of infusion and gender. Gemcitabine plasma protein binding is negligible. - Metabolism - Gemcitabine disposition was studied in 5 patients who received a single 1000 mg/m2/30 minute infusion of radiolabeled drug. Within one (1) week, 92% to 98% of the dose was recovered, almost entirely in the urine. Gemcitabine (<10%) and the inactive uracil metabolite, 2′-deoxy-2′,2′-difluorouridine (dFdU), accounted for 99% of the excreted dose. The metabolite dFdU is also found in plasma. - The active metabolite, gemcitabine triphosphate, can be extracted from peripheral blood mononuclear cells. The half-life of the terminal phase for gemcitabine triphosphate from mononuclear cells ranges from 1.7 to 19.4 hours. - Elimination - Clearance of gemcitabine was affected by age and gender. The lower clearance in women and the elderly results in higher concentrations of gemcitabine for any given dose. Differences in either clearance or volume of distribution based on patient characteristics or the duration of infusion result in changes in half-life and plasma concentrations. TABLE 10 shows plasma clearance and half-life of gemcitabine following short infusions for typical patients by age and gender. - Gemcitabine half-life for short infusions ranged from 42 to 94 minutes, and the value for long infusions varied from 245 to 638 minutes, depending on age and gender, reflecting a greatly increased volume of distribution with longer infusions. - Drug Interactions - When Gemzar (1250 mg/m2 on Days 1 and 8) and cisplatin (75 mg/m2 on Day 1) were administered in NSCLC patients, the clearance of gemcitabine on Day 1 was 128 L/hr/m2 and on Day 8 was 107 L/hr/m2. Analysis of data from metastatic breast cancer patients shows that, on average, Gemzar has little or no effect on the pharmacokinetics (clearance and half-life) of paclitaxel and paclitaxel has little or no effect on the pharmacokinetics of gemcitabine. Data from NSCLC patients demonstrate that Gemzar and carboplatin given in combination does not alter the pharmacokinetics of gemcitabine or carboplatin compared to administration of either single agent. However, due to wide confidence intervals and small sample size, interpatient variability may be observed. ## Nonclinical Toxicology - Long-term animal studies to evaluate the carcinogenic potential of Gemzar have not been conducted. Gemcitabine was mutagenic in an in vitro mouse lymphoma (L5178Y) assay and was clastogenic in an in vivo mouse micronucleus assay. Gemcitabine IP doses of 0.5 mg/kg/day (about 1/700 the human dose on a mg/m2 basis) in male mice had an effect on fertility with moderate to severe hypospermatogenesis, decreased fertility, and decreased implantations. In female mice, fertility was not affected but maternal toxicities were observed at 1.5 mg/kg/day administered intravenously (about 1/200 the human dose on a mg/m2 basis) and fetotoxicity or embryolethality was observed at 0.25 mg/kg/day administered intravenously (about 1/1300 the human dose on a mg/m2 basis). # Clinical Studies - The safety and efficacy of Gemzar was studied in a randomized trial of 356 women with advanced ovarian cancer that had relapsed at least 6 months after first-line platinum-based therapy. Patients were randomized to receive either Gemzar 1000 mg/m2 on Days 1 and 8 of a 21-day cycle and carboplatin AUC 4 administered after Gemzar infusion on Day 1 of each cycle (n=178) or to carboplatin AUC 5 administered on Day 1 of each 21-day cycle (n=178). The primary efficacy outcome measure was progression free survival (PFS). - Patient characteristics are shown in TABLE 11. The addition of Gemzar to carboplatin resulted in statistically significant improvements in PFS and overall response rate as shown in TABLE 12 and FIGURE 1. Approximately 75% of patients in each arm received additional chemotherapy for disease progression; 13 of 120 patients in the carboplatin alone arm received Gemzar for treatment of disease progression. There was no significant difference in overall survival between the treatment arms. - The safety and efficacy of Gemzar were evaluated in a multi-national, randomized, open-label trial conducted in women receiving initial treatment for metastatic breast cancer in women who have received prior adjuvant/neoadjuvant anthracycline chemotherapy unless clinically contraindicated. Patients were randomized to receive Gemzar 1250 mg/m2 on Days 1 and 8 of a 21-day cycle and paclitaxel 175 mg/m2 administered prior to Gemzar on Day 1 of each cycle (n=267) or to receive paclitaxel 175 mg/m2 was administered on Day 1 of each 21-day cycle (n=262). The primary efficacy outcome measure was time to documented disease progression. - A total of 529 patients were enrolled; 267 were randomized to Gemzar and paclitaxel and 262 to paclitaxel alone. Demographic and baseline characteristics were similar between treatment arms (see TABLE 13). Efficacy results are presented in TABLE 13 and FIGURE 2. The addition of Gemzar to paclitaxel resulted in statistically significant improvement in time to documented disease progression and overall response rate compared to paclitaxel alone. There was no significant difference in overall survival. - The safety and efficacy of Gemzar was evaluated in two randomized, multicenter trials. - 28-Day Schedule - A multinational, randomized trial compared Gemzar plus cisplatin to cisplatin alone in the treatment of patients with inoperable Stage IIIA, IIIB, or IV NSCLC who had not received prior chemotherapy. Patients were randomized to receive Gemzar 1000 mg/m2 on Days 1, 8, and 15 of a 28-day cycle with cisplatin 100 mg/m2 administered on Day 1 of each cycle or to receive cisplatin 100 mg/m2 on Day 1 of each 28-day cycle. The primary efficacy outcome measure was overall survival. A total of 522 patients were enrolled at clinical centers in Europe, the US, and Canada. Patient demographics and baseline characteristics (shown in TABLE 14) were similar between arms with the exception of histologic subtype of NSCLC, with 48% of patients on the cisplatin arm and 37% of patients on the Gemzar plus cisplatin arm having adenocarcinoma. Efficacy results are presented in TABLE 14 and FIGURE 3 for overall survival. - 21-Day Schedule - A randomized (1:1), multicenter trial was conducted in 135 patients with Stage IIIB or IV NSCLC. Patients were randomized to receive Gemzar 1250 mg/m2 on Days 1 and 8, and cisplatin 100 mg/m2 on Day 1 of a 21-day cycle or to receive etoposide 100 mg/m2 intravenously on Days 1, 2, and 3 and cisplatin 100 mg/m2 on Day 1 of a 21 -day cycle. - There was no significant difference in survival between the two treatment arms (Log rank p=0.18, two-sided, see TABLE 14). The median survival was 8.7 months for the Gemzar plus cisplatin arm versus 7.0 months for the etoposide plus cisplatin arm. Median time to disease progression for the Gemzar plus cisplatin arm was 5.0 months compared to 4.1 months on the etoposide plus cisplatin arm (Log rank p=0.015, two-sided). The objective response rate for the Gemzar plus cisplatin arm was 33% compared to 14% on the etoposide plus cisplatin arm (Fisher's Exact p=0.01, two-sided). - The safety and efficacy of Gemzar was evaluated in two trials, a randomized, single-blind, two-arm, active-controlled trial conducted in patients with locally advanced or metastatic pancreatic cancer who had received no prior chemotherapy and in a single-arm, open-label, multicenter trial conducted in patients with locally advanced or metastatic pancreatic cancer previously treated with 5-FU or a 5-FU-containing regimen. The first trial randomized patients to receive Gemzar 1000 mg/m2 intravenously over 30 minutes once weekly for 7 weeks followed by a one-week rest, then once weekly dosing for 3 consecutive weeks every 28-days in subsequent cycles (n=63) or to 5-fluorouracil (5-FU) 600 mg/m2 intravenously over 30 minutes once weekly (n=63). In the second trial, all patients received Gemzar 1000 mg/m2 intravenously over 30 minutes once weekly for 7 weeks followed by a one-week rest, then once weekly dosing for 3 consecutive weeks every 28-days in subsequent cycles. - The primary efficacy outcome measure in both trials was "clinical benefit response". A patient was considered to have had a clinical benefit response if either of the following occurred: - The patient achieved a ≥50% reduction in pain intensity (Memorial Pain Assessment Card) or analgesic consumption, or a 20-point or greater improvement in performance status (Karnofsky Performance Status) for a period of at least 4 consecutive weeks, without showing any sustained worsening in any of the other parameters. Sustained worsening was defined as 4 consecutive weeks with either any increase in pain intensity or analgesic consumption or a 20-point decrease in performance status occurring during the first 12 weeks of therapy. OR - The patient was stable on all of the aforementioned parameters, and showed a marked, sustained weight gain (≥7% increase maintained for ≥4 weeks) not due to fluid accumulation. - The randomized trial enrolled 126 patients across 17 sites in the US and Canada. The demographic and entry characteristics were similar between the arms (TABLE 15). The efficacy outcome results are shown in TABLE 15 and for overall survival in FIGURE 4. Patients treated with Gemzar had statistically significant increases in clinical benefit response, survival, and time to disease progression compared to those randomized to receive 5-FU. No confirmed objective tumor responses were observed in either treatment arm. # How Supplied - Gemzar (gemcitabine for injection, USP), is available in sterile single-use vials individually packaged in a carton containing: - 200 mg white to off-white, lyophilized powder in a 10-mL size sterile single-use vial – NDC 0002-7501-01 (No. 7501) - 1 g white to off-white, lyophilized powder in a 50-mL size sterile single-use vial – NDC 0002-7502-01 (No. 7502) - Storage and Handling - Unopened vials of Gemzar are stable until the expiration date indicated on the package when stored at controlled room temperature 20° to 25°C (68° to 77°F) and that allows for excursions between 15° and 30°C (59° and 86°F). ## Storage There is limited information regarding Gemcitabine Storage in the drug label. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information - Advise patients of the risks of low blood cell counts and the potential need for blood transfusions and increased susceptibility to infections. Instruct patients to immediately contact their healthcare provided for development of signs or symptoms of infection, fever, prolonged or unexpected bleeding, bruising, or shortness of breath. - Advise patients of the risks of pulmonary toxicity including respiratory failure and death. Instruct patients to immediately contact their healthcare provider for development of shortness of breath, wheezing, or cough. - Advise patients of the risks of hemolytic-uremic syndrome and associated renal failure. Instruct patients to immediately contact their healthcare provider for changes in the color or volume of urine output or for increased bruising or bleeding. - Advise patients of the risks of hepatic toxicity including liver failure and death. Instruct patients to immediately contact their healthcare provider for signs of jaundice or for pain/tenderness in the right upper abdominal quadrant. # Precautions with Alcohol - Alcohol-Gemcitabine interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - GEMZAR® # Look-Alike Drug Names There is limited information regarding Gemcitabine Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	Gemcitabine Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Vignesh Ponnusamy, M.B.B.S. [2] # Disclaimer WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here. # Overview Gemcitabine is a nucleoside metabolic inhibitor that is FDA approved for the treatment of advanced ovarian cancer, metastatic breast cancer after failure of prior anthracycline-containing adjuvant chemotherapy, non-small cell lung cancer, and pancreatic cancer. Common adverse reactions include nausea/vomiting, anemia, hepatic transaminitis, neutropenia, increased alkaline phosphatase, proteinuria, fever, hematuria, rash, thrombocytopenia, dyspnea, and peripheral edema. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) - Recommended Dose and Schedule - The recommended dose of Gemzar is 1000 mg/m2 as an intravenous infusion over 30 minutes on Days 1 and 8 of each 21-day cycle, in combination with carboplatin AUC 4 intravenously after Gemzar administration on Day 1 of each 21-day cycle. Refer to carboplatin prescribing information for additional information. - Dose Modifications - Recommended Gemzar dose modifications for myelosuppression are described in TABLE 1 and TABLE 2. - Recommended Dose and Schedule - The recommended dose of Gemzar is 1250 mg/m2 intravenously over 30 minutes on Days 1 and 8 of each 21-day cycle that includes paclitaxel. Paclitaxel should be administered at 175 mg/m2 on Day 1 as a 3 hour intravenous infusion before Gemzar administration. - Dose Modifications - Recommended dose modifications for Gemzar for myelosuppression are described in TABLE 3. - Recommended Dose and Schedule - Every 4-week schedule - The recommended dose of Gemzar is 1000 mg/m2 intravenously over 30 minutes on Days 1, 8, and 15 in combination with cisplatin therapy. Administer cisplatin intravenously at 100 mg/m2 on Day 1 after the infusion of Gemzar. - Every 3-week schedule - The recommended dose of Gemzar is 1250 mg/m2 intravenously over 30 minutes on Days 1 and 8 in combination with cisplatin therapy. Administer cisplatin intravenously at 100 mg/m2 on Day 1 after the infusion of Gemzar. - Dose Modifications - Recommended dose modifications for Gemzar myelosuppression are described in TABLE 4. - Recommended Dose and Schedule - The recommended dose of Gemzar is 1000 mg/m2 over 30 minutes intravenously. The recommended treatment schedule is as follows: - Weeks 1-8: weekly dosing for the first 7 weeks followed by one week rest. - After week 8: weekly dosing on Days 1, 8, and 15 of 28-day cycles. - Dose Modifications - Recommended dose modifications for Gemzar for myelosuppression are described in TABLE 4. - Patients receiving Gemzar should be monitored prior to each dose with a complete blood count (CBC), including differential and platelet count. If marrow suppression is detected, therapy should be modified or suspended according to the guidelines in TABLE 4. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Gemcitabine in adult patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Gemcitabine in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) There is limited information regarding FDA-Labeled Use of Gemcitabine in pediatric patients. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Gemcitabine in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Gemcitabine in pediatric patients. # Contraindications - Gemzar is contraindicated in patients with a known hypersensitivity to gemcitabine. # Warnings ### Precautions - Schedule-dependent Toxicity - In clinical trials evaluating the maximum tolerated dose of Gemzar, prolongation of the infusion time beyond 60 minutes or more frequent than weekly dosing resulted in an increased incidence of clinically significant hypotension, severe flu-like symptoms, myelosuppression, and asthenia. The half-life of Gemzar is influenced by the length of the infusion. - Myelosuppression - Myelosuppression manifested by neutropenia, thrombocytopenia, and anemia occurs with Gemzar as a single agent and the risks are increased when Gemzar is combined with other cytotoxic drugs. In clinical trials, Grade 3-4 neutropenia, anemia, and thrombocytopenia occurred in 25%, 8%, and 5%, respectively of patients receiving single-agent Gemzar. The frequencies of Grade 3-4 neutropenia, anemia, and thrombocytopenia varied from 48% to 71%, 8 to 28%, and 5 to 55%, respectively, in patients receiving Gemzar in combination with another drug. - Pulmonary Toxicity and Respiratory Failure - Pulmonary toxicity, including interstitial pneumonitis, pulmonary fibrosis, pulmonary edema, and adult respiratory distress syndrome (ARDS), has been reported. In some cases, these pulmonary events can lead to fatal respiratory failure despite discontinuation of therapy. The onset of pulmonary symptoms may occur up to 2 weeks after the last dose of Gemzar. Discontinue Gemzar in patients who develop unexplained dyspnea, with or without bronchospasm, or have any evidence of pulmonary toxicity. - Hemolytic Uremic Syndrome - Hemolytic uremic syndrome, including fatalities from renal failure or the requirement for dialysis, can occur in patients treated with Gemzar. In clinical trials, HUS was reported in 6 of 2429 patients (0.25%). Most fatal cases of renal failure were due to HUS. Assess renal function prior to initiation of Gemzar and periodically during treatment. Consider the diagnosis of HUS in patients who develops anemia with evidence of microangiopathic hemolysis, elevation of bilirubin or LDH, or reticulocytosis; severe thrombocytopenia; or evidence of renal failure (elevation of serum creatinine or BUN). Permanently discontinue Gemzar in patients with HUS or severe renal impairment. Renal failure may not be reversible even with discontinuation of therapy. - Hepatic Toxicity - Drug-induced liver injury, including liver failure and death, has been reported in patients receiving Gemzar alone or in combination with other potentially hepatotoxic drugs. Administration of Gemzar in patients with concurrent liver metastases or a pre-existing medical history or hepatitis, alcoholism, or liver cirrhosis can lead to exacerbation of the underlying hepatic insufficiency. Assess hepatic function prior to initiation of Gemzar and periodically during treatment. Discontinue Gemzar in patients that develop severe liver injury. - Embryofetal Toxicity - Gemzar can cause fetal harm when administered to a pregnant woman, based on its mechanism of action. Gemcitabine was teratogenic, embryotoxic, and fetotoxic in mice and rabbits. If this drug is used during pregnancy, or if a woman becomes pregnant while taking Gemzar, the patient should be apprised of the potential hazard to a fetus. - Exacerbation of Radiation Therapy Toxicity - Gemzar is not indicated for use in combination with radiation therapy. - Concurrent (given together or ≤7 days apart) — Life-threatening mucositis, especially esophagitis and pneumonitis occurred in a trial in which Gemzar was administered at a dose of 1000 mg/m2 to patients with non-small cell lung cancer for up to 6 consecutive weeks concurrently with thoracic radiation. - Non-concurrent (given >7 days apart) — Excessive toxicity has not been observed when Gemzar is administered more than 7 days before or after radiation. Radiation recall has been reported in patients who receive Gemzar after prior radiation. - Capillary Leak Syndrome - Capillary leak syndrome (CLS) with severe consequences has been reported in patients receiving Gemzar as a single agent or in combination with other chemotherapeutic agents. Discontinue Gemzar if CLS develops during therapy. - Posterior Reversible Encephalopathy Syndrome - Posterior reversible encephalopathy syndrome (PRES) has been reported in patients receiving Gemzar as a single agent or in combination with other chemotherapeutic agents. PRES can present with headache, seizure, lethargy, hypertension, confusion, blindness, and other visual and neurologic disturbances. Confirm the diagnosis of PRES with magnetic resonance imaging (MRI) and discontinue Gemzar if PRES develops during therapy. # Adverse Reactions ## Clinical Trials Experience - Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. - Single-Agent Use: - The data described below reflect exposure to Gemzar as a single agent administered at doses between 800 mg/m2 to 1250 mg/m2 over 30 minutes intravenously, once weekly, in 979 patients with a variety of malignancies. The most common (≥20%) adverse reactions of single-agent Gemzar are nausea/vomiting, anemia, increased ALT, increased AST, neutropenia, increased alkaline phosphatase, proteinuria, fever, hematuria, rash, thrombocytopenia, dyspnea, and edema. The most common (≥5%) Grade 3 or 4 adverse reactions were neutropenia, nausea/vomiting; increased ALT, increase alkaline phosphatase, anemia, increased AST, and thrombocytopenia. Approximately 10% of the 979 patients discontinued Gemzar due to adverse reactions. Adverse reactions resulting in discontinuation of Gemzar in 2% of 979 patients were cardiovascular adverse events (myocardial infarction, cerebrovascular accident, arrhythmia, and hypertension) and adverse reactions resulting in discontinuation of Gemzar in less than 1% of the 979 patients were anemia, thrombocytopenia, hepatic dysfunction, renal dysfunction, nausea/vomiting, fever, rash, dyspnea, hemorrhage, infection, stomatitis, somnolence, flu-like syndrome, and edema. - TABLE 5 presents the incidence of adverse reactions reported in 979 patients with various malignancies receiving single-agent Gemzar across 5 clinical trials. TABLE 5 includes all clinical adverse reactions, reported in at least 10% of patients. A listing of clinically significant adverse reactions is provided following the table. - Transfusion requirements — Red blood cell transfusions (19%); platelet transfusions (<1%) - Fever — Fever occurred in the absence of clinical infection and frequently in combination with other flu-like symptoms. - Pulmonary — Dyspnea unrelated to underlying disease and sometimes accompanied by bronchospasm. - Edema — Edema (13%), peripheral edema (20%), and generalized edema (<1%); <1% of patients. discontinued Gemzar due to edema. - Flu-like Symptoms — Characterized by fever, asthenia, anorexia, headache, cough, chills, myalgia, asthenia, insomnia, rhinitis, sweating, and/or malaise (19%); <1% of patients discontinued Gemzar due to flu-like symptoms - Infection — Sepsis (<1%) - Extravasation — Injection-site reactions (4%) - Allergic — Bronchospasm (<2%); anaphylactoid reactions. - TABLE 6 presents the incidence of selected adverse reactions, occurring in ≥10% of Gemzar-treated patients and at a higher incidence in the Gemzar plus cisplatin arm, reported in a randomized trial of Gemzar plus cisplatin (n=262) administered in 28-day cycles as compared to cisplatin alone (n=260) in patients receiving first-line treatment for locally advanced or metastatic non-small cell lung cancer (NSCLC). Patients randomized to Gemzar plus cisplatin received a median of 4 cycles of treatment and those randomized to cisplatin received a median of 2 cycles of treatment. In this trial, the requirement for dose adjustments (>90% versus 16%), discontinuation of treatment for adverse reactions (15% versus 8%), and the proportion of patients hospitalized (36% versus 23%) were all higher for patients receiving Gemzar plus cisplatin arm compared to those receiving cisplatin alone. The incidence of febrile neutropenia (9/262 versus 2/260), sepsis (4% versus 1%), Grade 3 cardiac dysrhythmias (3% versus <1%) were all higher in the Gemzar plus cisplatin arm compared to the cisplatin alone arm. The two-drug combination was more myelosuppressive with 4 (1.5%) possibly treatment-related deaths, including 3 resulting from myelosuppression with infection and one case of renal failure associated with pancytopenia and infection. No deaths due to treatment were reported on the cisplatin arm. - TABLE 7 presents the incidence of selected adverse reactions, occurring in ≥10% of Gemzar-treated patients and at a higher incidence in the Gemzar plus cisplatin arm, reported in a randomized trial of Gemzar plus cisplatin (n=69) administered in 21-day cycles as compared to etoposide plus cisplatin alone (n=66) in patients receiving first-line treatment for locally advanced or metastatic non-small cell lung cancer (NSCLC) [see Clinical Studies (14.3)]. A listing of clinically significant adverse reactions is provided following the table. - Patients in the Gemzar cisplatin (GC) arm received a median of 5 cycles and those in the etoposide/cisplatin (EC) arm received a median of 4 cycles. The majority of patients receiving more than one cycle of treatment required dose adjustments; 81% in the (GC) arm and 68% in the (EC) arm. The incidence of hospitalizations for treatment-related adverse events was 22% (GC) and 27% in the (EC) arm. The proportion of discontinuation of treatment for treatment-related adverse reactions was higher for patients in the (GC) arm (14% versus 8%). The proportion of patients hospitalized for febrile neutropenia was lower in the (GC) arm (7% versus 12%). There was one death attributed to treatment, a patient with febrile neutropenia and renal failure, which occurred in the Gemzar/cisplatin arm. - TABLE 8 presents the incidence of selected adverse reactions, occurring in ≥10% of Gemzar-treated patients and at a higher incidence in the Gemzar plus paclitaxel arm, reported in a randomized trial of Gemzar plus paclitaxel (n=262) compared to paclitaxel alone (n=259) for the first-line treatment of metastatic breast cancer (MBC) in women who received anthracycline-containing chemotherapy in the adjuvant/neo-adjuvant setting or for whom anthracyclines were contraindicated. - The requirement for dose reduction of paclitaxel were higher for patients in the Gemzar/paclitaxel arm (5% versus 2%). The number of paclitaxel doses omitted (<1%), the proportion of patients discontinuing treatment for treatment-related adverse reactions (7% versus 5%), and the number of treatment-related deaths (1 patient in each arm) were similar between the two arms. - Clinically relevant Grade 3 or 4 dyspnea occurred with a higher incidence in the Gemzar plus paclitaxel arm compared with the paclitaxel arm (1.9% versus 0). - TABLE 9 presents the incidence of selected adverse reactions, occurring in ≥10% of gemcitabine-treated patients and at a higher incidence in the Gemzar plus carboplatin arm, reported in a randomized trial of Gemzar plus carboplatin (n=175) compared to carboplatin alone (n=174) for the second-line treatment of ovarian cancer in women with disease that had relapsed more than 6 months following first-line platinum-based chemotherapy. Additional clinically significant adverse reactions, occurring in less than 10% of patients, are provided following TABLE 9. - The proportion of patients with dose adjustments for carboplatin (1.8% versus 3.8%), doses of carboplatin omitted (0.2% versus 0), and discontinuing treatment for treatment-related adverse reactions (10.9% versus 9.8%), were similar between arms. Dose adjustment for Gemzar occurred in 10.4% of patients and Gemzar dose was omitted in 13.7% of patients in the Gemzar /carboplatin arm. - Hematopoietic growth factors were administered more frequently in the Gemzar-containing arm: granulocyte growth factors (23.6% and 10.1%) and erythropoietic agents (7.3% and 3.9%). - The following clinically relevant, Grade 3 and 4 adverse reactions occurred more frequently in the Gemzar plus carboplatin arm: dyspnea (3.4% versus 2.9%), febrile neutropenia (1.1% versus 0), hemorrhagic event (2.3% versus 1.1 %), motor neuropathy (1.1% versus 0.6%), and rash/desquamation (0.6% versus 0). ## Postmarketing Experience - The following adverse reactions have been identified during post-approval use of Gemzar. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Congestive heart failure, myocardial infarction, arrhythmias, supraventricular arrhythmias Peripheral vasculitis, gangrene, and capillary leak syndrome Cellulitis, severe skin reactions, including desquamation and bullous skin eruptions Hepatic failure, hepatic veno-occlusive disease Interstitial pneumonitis, pulmonary fibrosis, pulmonary edema, and adult respiratory distress syndrome (ARDS) Posterior reversible encephalopathy syndrome (PRES) # Drug Interactions - No drug interaction studies have been conducted. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): - Pregnancy Category D - Risk Summary - Gemzar can cause fetal harm when administered to a pregnant woman. Based on its mechanism of action, Gemzar is expected to result in adverse reproductive effects. Gemcitabine was teratogenic, embryotoxic, and fetotoxic in mice and rabbits. If Gemzar is used during pregnancy, or if the patient becomes pregnant while taking Gemzar, the patient should be apprised of the potential hazard to a fetus. - Animal Data - Gemcitabine is embryotoxic causing fetal malformations (cleft palate, incomplete ossification) at doses of 1.5 mg/kg/day in mice (approximately 0.005 times the recommended human dose on a mg/m2 basis). Gemcitabine is fetotoxic causing fetal malformations (fused pulmonary artery, absence of gall bladder) at doses of 0.1 mg/kg/day in rabbits (about 0.002 times the recommended human dose on a mg/m2 basis). Embryotoxicity was characterized by decreased fetal viability, reduced live litter sizes, and developmental delays. Pregnancy Category (AUS): - Australian Drug Evaluation Committee (ADEC) Pregnancy Category There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Gemcitabine in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Gemcitabine during labor and delivery. ### Nursing Mothers - It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from Gemzar, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. ### Pediatric Use - The safety and effectiveness of Gemzar have not been established in pediatric patients. The safety and pharmacokinetics of gemcitabine were evaluated in a trial in pediatric patients with refractory leukemia. The maximum tolerated dose was 10 mg/m2/min for 360 minutes three times weekly followed by a one-week rest period. The safety and activity of Gemzar were evaluated in a trial of pediatric patients with relapsed acute lymphoblastic leukemia (22 patients) and acute myelogenous leukemia (10 patients) at a dose of 10 mg/m2/min administered over 360 minutes three times weekly followed by a one-week rest period. Toxicities observed included bone marrow suppression, febrile neutropenia, elevation of serum transaminases, nausea, and rash/desquamation. No meaningful clinical activity was observed in this trial. ### Geriatic Use - In clinical studies of GEMZAR, enrolling 979 patients with various cancers who received GEMZAR as a single agent, no overall differences in safety were observed between patients aged 65 and older and younger patients, with the exception of a higher rate of Grade 3-4 thrombocytopenia in older patients as compared to younger patients. In a randomized trial in women with ovarian cancer, 175 women received GEMZAR plus carboplatin, of which 29% were age 65 years or older. Similar effectiveness was observed between older and younger women. There was significantly higher Grade 3/4 neutropenia in women 65 years of age or older. - GEMZAR clearance is affected by age, however there are no recommended dose adjustments based on patients' age. ### Gender - Gemzar clearance is affected by gender. In single-agent studies of Gemzar, women, especially older women, were more likely not to proceed to a subsequent cycle and to experience Grade 3/4 neutropenia and thrombocytopenia. ### Race There is no FDA guidance on the use of Gemcitabine with respect to specific racial populations. ### Renal Impairment There is no FDA guidance on the use of Gemcitabine in patients with renal impairment. ### Hepatic Impairment There is no FDA guidance on the use of Gemcitabine in patients with hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Gemcitabine in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Gemcitabine in patients who are immunocompromised. # Administration and Monitoring ### Administration - Intravenous ### Monitoring There is limited information regarding Monitoring of Gemcitabine in the drug label. # IV Compatibility - Reconstitute the vials with 0.9% Sodium Chloride Injection without preservatives. - Add 5 mL to the 200-mg vial or 25 mL to the 1-g vial. These dilutions each yield a Gemzar concentration of 38 mg/mL. Complete withdrawal of the vial contents will provide 200 mg or 1 g of Gemzar. Prior to administration the appropriate amount of drug must be diluted with 0.9% Sodium Chloride Injection. Final concentrations may be as low as 0.1 mg/mL. - Reconstituted Gemzar is a clear, colorless to light straw-colored solution. Inspect visually prior to administration and discard for particulate matter or discoloration. Gemzar solutions are stable for 24 hours at controlled room temperature of 20° to 25°C (68° to 77°F). Do not refrigerate as crystallization can occur. - No incompatibilities have been observed with infusion bottles or polyvinyl chloride bags and administration sets. # Overdosage - Myelosuppression, paresthesias, and severe rash were the principal toxicities seen when a single dose as high as 5700 mg/m2 was administered by intravenous infusion over 30 minutes every 2 weeks to several patients in a dose-escalation study. # Pharmacology ## Mechanism of Action - Gemcitabine kills cells undergoing DNA synthesis and blocks the progression of cells through the G1/S-phase boundary. Gemcitabine is metabolized by nucleoside kinases to diphosphate (dFdCDP) and triphosphate (dFdCTP) nucleosides. Gemcitabine diphosphate inhibits ribonucleotide reductase, an enzyme responsible for catalyzing the reactions that generate deoxynucleoside triphosphates for DNA synthesis, resulting in reductions in deoxynucleotide concentrations, including dCTP. Gemcitabine triphosphate competes with dCTP for incorporation into DNA. The reduction in the intracellular concentration of dCTP by the action of the diphosphate enhances the incorporation of gemcitabine triphosphate into DNA (self-potentiation). After the gemcitabine nucleotide is incorporated into DNA, only one additional nucleotide is added to the growing DNA strands, which eventually results in the initiation of apoptotic cell death. ## Structure - Gemzar (gemcitabine for injection, USP) is a nucleoside metabolic inhibitor that exhibits antitumor activity. Gemcitabine HCl is 2′-deoxy-2′,2′-difluorocytidine monohydrochloride (β-isomer). - The structural formula is as follows: - The empirical formula for gemcitabine HCl is C9H11F2N3O4 • HCl. It has a molecular weight of 299.66. - Gemcitabine HCl is soluble in water, slightly soluble in methanol, and practically insoluble in ethanol and polar organic solvents. - Gemzar is supplied in a sterile form for intravenous use only. Vials of Gemzar contain either 200 mg or 1 g of gemcitabine HCl (expressed as free base) formulated with mannitol (200 mg or 1 g, respectively) and sodium acetate (12.5 mg or 62.5 mg, respectively) as a sterile lyophilized powder. Hydrochloric acid and/or sodium hydroxide may have been added for pH adjustment. ## Pharmacodynamics There is limited information regarding Pharmacodynamics of Gemcitabine in the drug label. ## Pharmacokinetics - Absorption and Distribution - The pharmacokinetics of gemcitabine were examined in 353 patients, with various solid tumors. Pharmacokinetic parameters were derived using data from patients treated for varying durations of therapy given weekly with periodic rest weeks and using both short infusions (<70 minutes) and long infusions (70 to 285 minutes). The total Gemzar dose varied from 500 to 3600 mg/m2. - The volume of distribution was increased with infusion length. Volume of distribution of gemcitabine was 50 L/m2 following infusions lasting <70 minutes. For long infusions, the volume of distribution rose to 370 L/m2. - Gemcitabine pharmacokinetics are linear and are described by a 2-compartment model. Population pharmacokinetic analyses of combined single and multiple dose studies showed that the volume of distribution of gemcitabine was significantly influenced by duration of infusion and gender. Gemcitabine plasma protein binding is negligible. - Metabolism - Gemcitabine disposition was studied in 5 patients who received a single 1000 mg/m2/30 minute infusion of radiolabeled drug. Within one (1) week, 92% to 98% of the dose was recovered, almost entirely in the urine. Gemcitabine (<10%) and the inactive uracil metabolite, 2′-deoxy-2′,2′-difluorouridine (dFdU), accounted for 99% of the excreted dose. The metabolite dFdU is also found in plasma. - The active metabolite, gemcitabine triphosphate, can be extracted from peripheral blood mononuclear cells. The half-life of the terminal phase for gemcitabine triphosphate from mononuclear cells ranges from 1.7 to 19.4 hours. - Elimination - Clearance of gemcitabine was affected by age and gender. The lower clearance in women and the elderly results in higher concentrations of gemcitabine for any given dose. Differences in either clearance or volume of distribution based on patient characteristics or the duration of infusion result in changes in half-life and plasma concentrations. TABLE 10 shows plasma clearance and half-life of gemcitabine following short infusions for typical patients by age and gender. - Gemcitabine half-life for short infusions ranged from 42 to 94 minutes, and the value for long infusions varied from 245 to 638 minutes, depending on age and gender, reflecting a greatly increased volume of distribution with longer infusions. - Drug Interactions - When Gemzar (1250 mg/m2 on Days 1 and 8) and cisplatin (75 mg/m2 on Day 1) were administered in NSCLC patients, the clearance of gemcitabine on Day 1 was 128 L/hr/m2 and on Day 8 was 107 L/hr/m2. Analysis of data from metastatic breast cancer patients shows that, on average, Gemzar has little or no effect on the pharmacokinetics (clearance and half-life) of paclitaxel and paclitaxel has little or no effect on the pharmacokinetics of gemcitabine. Data from NSCLC patients demonstrate that Gemzar and carboplatin given in combination does not alter the pharmacokinetics of gemcitabine or carboplatin compared to administration of either single agent. However, due to wide confidence intervals and small sample size, interpatient variability may be observed. ## Nonclinical Toxicology - Long-term animal studies to evaluate the carcinogenic potential of Gemzar have not been conducted. Gemcitabine was mutagenic in an in vitro mouse lymphoma (L5178Y) assay and was clastogenic in an in vivo mouse micronucleus assay. Gemcitabine IP doses of 0.5 mg/kg/day (about 1/700 the human dose on a mg/m2 basis) in male mice had an effect on fertility with moderate to severe hypospermatogenesis, decreased fertility, and decreased implantations. In female mice, fertility was not affected but maternal toxicities were observed at 1.5 mg/kg/day administered intravenously (about 1/200 the human dose on a mg/m2 basis) and fetotoxicity or embryolethality was observed at 0.25 mg/kg/day administered intravenously (about 1/1300 the human dose on a mg/m2 basis). # Clinical Studies - The safety and efficacy of Gemzar was studied in a randomized trial of 356 women with advanced ovarian cancer that had relapsed at least 6 months after first-line platinum-based therapy. Patients were randomized to receive either Gemzar 1000 mg/m2 on Days 1 and 8 of a 21-day cycle and carboplatin AUC 4 administered after Gemzar infusion on Day 1 of each cycle (n=178) or to carboplatin AUC 5 administered on Day 1 of each 21-day cycle (n=178). The primary efficacy outcome measure was progression free survival (PFS). - Patient characteristics are shown in TABLE 11. The addition of Gemzar to carboplatin resulted in statistically significant improvements in PFS and overall response rate as shown in TABLE 12 and FIGURE 1. Approximately 75% of patients in each arm received additional chemotherapy for disease progression; 13 of 120 patients in the carboplatin alone arm received Gemzar for treatment of disease progression. There was no significant difference in overall survival between the treatment arms. - The safety and efficacy of Gemzar were evaluated in a multi-national, randomized, open-label trial conducted in women receiving initial treatment for metastatic breast cancer in women who have received prior adjuvant/neoadjuvant anthracycline chemotherapy unless clinically contraindicated. Patients were randomized to receive Gemzar 1250 mg/m2 on Days 1 and 8 of a 21-day cycle and paclitaxel 175 mg/m2 administered prior to Gemzar on Day 1 of each cycle (n=267) or to receive paclitaxel 175 mg/m2 was administered on Day 1 of each 21-day cycle (n=262). The primary efficacy outcome measure was time to documented disease progression. - A total of 529 patients were enrolled; 267 were randomized to Gemzar and paclitaxel and 262 to paclitaxel alone. Demographic and baseline characteristics were similar between treatment arms (see TABLE 13). Efficacy results are presented in TABLE 13 and FIGURE 2. The addition of Gemzar to paclitaxel resulted in statistically significant improvement in time to documented disease progression and overall response rate compared to paclitaxel alone. There was no significant difference in overall survival. - The safety and efficacy of Gemzar was evaluated in two randomized, multicenter trials. - 28-Day Schedule - A multinational, randomized trial compared Gemzar plus cisplatin to cisplatin alone in the treatment of patients with inoperable Stage IIIA, IIIB, or IV NSCLC who had not received prior chemotherapy. Patients were randomized to receive Gemzar 1000 mg/m2 on Days 1, 8, and 15 of a 28-day cycle with cisplatin 100 mg/m2 administered on Day 1 of each cycle or to receive cisplatin 100 mg/m2 on Day 1 of each 28-day cycle. The primary efficacy outcome measure was overall survival. A total of 522 patients were enrolled at clinical centers in Europe, the US, and Canada. Patient demographics and baseline characteristics (shown in TABLE 14) were similar between arms with the exception of histologic subtype of NSCLC, with 48% of patients on the cisplatin arm and 37% of patients on the Gemzar plus cisplatin arm having adenocarcinoma. Efficacy results are presented in TABLE 14 and FIGURE 3 for overall survival. - 21-Day Schedule - A randomized (1:1), multicenter trial was conducted in 135 patients with Stage IIIB or IV NSCLC. Patients were randomized to receive Gemzar 1250 mg/m2 on Days 1 and 8, and cisplatin 100 mg/m2 on Day 1 of a 21-day cycle or to receive etoposide 100 mg/m2 intravenously on Days 1, 2, and 3 and cisplatin 100 mg/m2 on Day 1 of a 21 -day cycle. - There was no significant difference in survival between the two treatment arms (Log rank p=0.18, two-sided, see TABLE 14). The median survival was 8.7 months for the Gemzar plus cisplatin arm versus 7.0 months for the etoposide plus cisplatin arm. Median time to disease progression for the Gemzar plus cisplatin arm was 5.0 months compared to 4.1 months on the etoposide plus cisplatin arm (Log rank p=0.015, two-sided). The objective response rate for the Gemzar plus cisplatin arm was 33% compared to 14% on the etoposide plus cisplatin arm (Fisher's Exact p=0.01, two-sided). - The safety and efficacy of Gemzar was evaluated in two trials, a randomized, single-blind, two-arm, active-controlled trial conducted in patients with locally advanced or metastatic pancreatic cancer who had received no prior chemotherapy and in a single-arm, open-label, multicenter trial conducted in patients with locally advanced or metastatic pancreatic cancer previously treated with 5-FU or a 5-FU-containing regimen. The first trial randomized patients to receive Gemzar 1000 mg/m2 intravenously over 30 minutes once weekly for 7 weeks followed by a one-week rest, then once weekly dosing for 3 consecutive weeks every 28-days in subsequent cycles (n=63) or to 5-fluorouracil (5-FU) 600 mg/m2 intravenously over 30 minutes once weekly (n=63). In the second trial, all patients received Gemzar 1000 mg/m2 intravenously over 30 minutes once weekly for 7 weeks followed by a one-week rest, then once weekly dosing for 3 consecutive weeks every 28-days in subsequent cycles. - The primary efficacy outcome measure in both trials was "clinical benefit response". A patient was considered to have had a clinical benefit response if either of the following occurred: - The patient achieved a ≥50% reduction in pain intensity (Memorial Pain Assessment Card) or analgesic consumption, or a 20-point or greater improvement in performance status (Karnofsky Performance Status) for a period of at least 4 consecutive weeks, without showing any sustained worsening in any of the other parameters. Sustained worsening was defined as 4 consecutive weeks with either any increase in pain intensity or analgesic consumption or a 20-point decrease in performance status occurring during the first 12 weeks of therapy. OR - The patient was stable on all of the aforementioned parameters, and showed a marked, sustained weight gain (≥7% increase maintained for ≥4 weeks) not due to fluid accumulation. - The randomized trial enrolled 126 patients across 17 sites in the US and Canada. The demographic and entry characteristics were similar between the arms (TABLE 15). The efficacy outcome results are shown in TABLE 15 and for overall survival in FIGURE 4. Patients treated with Gemzar had statistically significant increases in clinical benefit response, survival, and time to disease progression compared to those randomized to receive 5-FU. No confirmed objective tumor responses were observed in either treatment arm. # How Supplied - Gemzar (gemcitabine for injection, USP), is available in sterile single-use vials individually packaged in a carton containing: - 200 mg white to off-white, lyophilized powder in a 10-mL size sterile single-use vial – NDC 0002-7501-01 (No. 7501) - 1 g white to off-white, lyophilized powder in a 50-mL size sterile single-use vial – NDC 0002-7502-01 (No. 7502) - Storage and Handling - Unopened vials of Gemzar are stable until the expiration date indicated on the package when stored at controlled room temperature 20° to 25°C (68° to 77°F) and that allows for excursions between 15° and 30°C (59° and 86°F). ## Storage There is limited information regarding Gemcitabine Storage in the drug label. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information - Advise patients of the risks of low blood cell counts and the potential need for blood transfusions and increased susceptibility to infections. Instruct patients to immediately contact their healthcare provided for development of signs or symptoms of infection, fever, prolonged or unexpected bleeding, bruising, or shortness of breath. - Advise patients of the risks of pulmonary toxicity including respiratory failure and death. Instruct patients to immediately contact their healthcare provider for development of shortness of breath, wheezing, or cough. - Advise patients of the risks of hemolytic-uremic syndrome and associated renal failure. Instruct patients to immediately contact their healthcare provider for changes in the color or volume of urine output or for increased bruising or bleeding. - Advise patients of the risks of hepatic toxicity including liver failure and death. Instruct patients to immediately contact their healthcare provider for signs of jaundice or for pain/tenderness in the right upper abdominal quadrant. # Precautions with Alcohol - Alcohol-Gemcitabine interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - GEMZAR®[1] # Look-Alike Drug Names There is limited information regarding Gemcitabine Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	https://www.wikidoc.org/index.php/Gemcitabine
0a82146af7aa94b785d57f226f4d74db8aff5c34	wikidoc	Gemfibrozil	Gemfibrozil # Disclaimer WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here. # Overview Gemfibrozil is a peroxisome proliferator receptor alpha agonist that is FDA approved for the {{{indicationType}}} of types IV and V hyperlipidemia at risk of pancreatitis and who do not respond adequately to a determined dietary effort to control them, and reducing the risk of developing coronary heart disease only in Type IIb patients without history of or symptoms of existing coronary heart disease who have had an inadequate response to weight loss, dietary therapy, exercise, and other pharmacologic agents (such as bile acid sequestrants and nicotinic acid) and who have the following triad of lipid abnormalities: low HDL-cholesterol levels in addition to elevated LDL-cholesterol and elevated triglycerides. Common adverse reactions include dyspepsia, abdominal pain, acute appendicitis, atrial fibrillation, diarrhea, fatigue, eczema, rash, vertigo, constipation, headache. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) ### Hyperlipidemia type IV and V - Dosing Information - 600 mg PO every 12 hours (30 minutes before the morning and evening meals) ### Prophylaxis for Disorder of Cardiovascular System - Dosing Information - 600 mg PO every 12 hours (30 minutes before the morning and evening meals) ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information about Off-Label Guideline-Supported Use of Gemfibrozil in adult patients. ### Non–Guideline-Supported Use ### Antiviral Drug Adverse Reaction, Antiretroviral - Hyperlipidemia - Dosing Information - 600 mg PO every 12 hours ### Prophylaxis for Cerebrovascular Accident - Dosing Information - 600 mg PO every 12 hours ### Hyperlipidemia - Dosing Information - 600 mg PO every 12 hours # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) There is limited information regarding Gemfibrozil FDA-Labeled Indications and Dosage (Pediatric) in the drug label. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information about Off-Label Guideline-Supported Use of Gemfibrozil in pediatric patients. ### Non–Guideline-Supported Use There is limited information about Off-Label Non–Guideline-Supported Use of Gemfibrozil in pediatric patients. # Contraindications - Hepatic or severe renal dysfunction, including primary biliary cirrhosis. - Preexisting gallbladder disease. - Hypersensitivity to gemfibrozil. - Combination therapy of gemfibrozil with repaglinide - Combination therapy of gemfibrozil with simvastatin # Warnings 1. Because of chemical, pharmacological, and clinical similarities between gemfibrozil and clofibrate, the adverse findings with clofibrate in two large clinical studies may also apply to gemfibrozil. In the first of those studies, the Coronary Drug Project, 1000 subjects with previous myocardial infarction were treated for five years with clofibrate. There was no difference in mortality between the clofibrate-treated subjects and 3000 placebo-treated subjects, but twice as many clofibrate-treated subjects developed cholelithiasis and cholecystitis requiring surgery. In the other study, conducted by the World Health Organization (WHO), 5000 subjects without known coronary heart disease were treated with clofibrate for five years and followed one year beyond. There was a statistically significant (44%) higher age-adjusted total mortality in the clofibrate-treated group than in a comparable placebo-treated control group during the trial period. The excess mortality was due to a 33% increase in non-cardiovascular causes, including malignancy, post-cholecystectomy complications, and pancreatitis. The higher risk of clofibrate-treated subjects for gallbladder disease was confirmed. Because of the more limited size of the Helsinki Heart Study, the observed difference in mortality from any cause between the gemfibrozil and placebo groups is not statistically significantly different from the 29% excess mortality reported in the clofibrate group in the separate WHO study at the nine year follow-up. Noncoronary heart disease related mortality showed an excess in the group originally randomized to gemfibrozil primarily due to cancer deaths observed during the open-label extension. During the five year primary prevention component of the Helsinki Heart Study, mortality from any cause was 44 (2.2%) in the gemfibrozil group and 43 (2.1%) in the placebo group; including the 3.5 year follow-up period since the trial was completed, cumulative mortality from any cause was 101 (4.9%) in the gemfibrozil group and 83 (4.1%) in the group originally randomized to placebo (hazard ratio 1:20 in favor of placebo). Because of the more limited size of the Helsinki Heart Study, the observed difference in mortality from any cause between the gemfibrozil and placebo groups at Year-5 or at Year-8.5 is not statistically significantly different from the 29% excess mortality reported in the clofibrate group in the separate WHO study at the nine year follow-up. Noncoronary heart disease related mortality showed an excess in the group originally randomized to gemfibrozil at the 8.5 year follow-up (65 gemfibrozil versus 45 placebo noncoronary deaths). The incidence of cancer (excluding basal cell carcinoma) discovered during the trial and in the 3.5 years after the trial was completed was 51 (2.5%) in both originally randomized groups. In addition, there were 16 basal cell carcinomas in the group originally randomized to gemfibrozil and 9 in the group originally randomized to placebo (p=0.22). There were 30 (1.5%) deaths attributed to cancer in the group originally randomized to gemfibrozil and 18 (0.9%) in the group originally randomized to placebo (p=0.11). Adverse outcomes, including coronary events, were higher in gemfibrozil patients in a corresponding study in men with a history of known or suspected coronary heart disease in the secondary prevention component of the Helsinki Heart Study. A comparative carcinogenicity study was also done in rats comparing three drugs in this class: fenofibrate (10 and 60 mg/kg; 0.3 and 1.6 times the human dose, respectively), clofibrate (400 mg/kg; 1.6 times the human dose), and gemfibrozil (250 mg/kg; 1.7 times the human dose). Pancreatic acinar adenomas were increased in males and females on fenofibrate; hepatocellular carcinoma and pancreatic acinar adenomas were increased in males and hepatic neoplastic nodules in females treated with clofibrate; hepatic neoplastic nodules were increased in males and females treated with clofibrate; hepatic neoplastic nodules were increased in males and females treated with gemfibrozil while testicular interstitial cell (Leydig cell) tumors were increased in males on all three drugs. 2. A gallstone prevalence substudy of 450 Helsinki Heart Study participants showed a trend toward a greater prevalence of gallstones during the study within the gemfibrozil treatment group (7.5% versus 4.9% for the placebo group, a 55% excess for the gemfibrozil group). A trend toward a greater incidence of gallbladder surgery was observed for the gemfibrozil group (17 versus 11 subjects, a 54% excess). This result did not differ statistically from the increased incidence of cholecystectomy observed in the WHO study in the group treated with clofibrate. Both clofibrate and gemfibrozil may increase cholesterol excretion into the bile, leading to cholelithiasis. If cholelithiasis is suspected, gallbladder studies are indicated. gemfibrozil therapy should be discontinued if gallstones are found. Cases of cholelithiasis have been reported with gemfibrozil therapy. 3. Since a reduction of mortality from coronary heart disease has not been demonstrated and because liver and interstitial cell testicular tumors were increased in rats, gemfibrozil should be administered only to those patients described before. If a significant serum lipid response is not obtained, gemfibrozil should be discontinued. 4. Concomitant Anticoagulants – Caution should be exercised when anticoagulants are given in conjunction with gemfibrozil . The dosage of the anticoagulant should be reduced to maintain the prothrombin time at the desired level to prevent bleeding complications. Frequent prothrombin determinations are advisable until it has been definitely determined that the prothrombin level has stabilized. 5. The concomitant administration of gemfibrozil with simvastatin is contraindicated. Concomitant therapy with gemfibrozil and an HMG-CoA reductase inhibitor is associated with an increased risk of skeletal muscle toxicity manifested as rhabdomyolysis, markedly elevated creatine kinase (CPK) levels, and myoglobinuria, leading in a high proportion of cases to acute renal failure and death. IN PATIENTS WHO HAVE HAD AN UNSATISFACTORY LIPID RESPONSE TO EITHER DRUG ALONE, THE BENEFIT OF COMBINED THERAPY WITH GEMFBROZIL AND an HMG-CoA REDUCTASE INHIBITOR DOES NOT OUTWEIGH THE RISKS OF SEVERE MYOPATHY, rhabdomyolysis, AND ACUTE RENAL FAILURE. The use of fibrates alone, including gemfibrozil , may occasionally be associated with myositis. Patients receiving gemfibrozil and complaining of muscle pain, tenderness, or weakness should have prompt medical evaluation for myositis, including serum creatine–kinase level determination. If myositis is suspected or diagnosed, gemfibrozil therapy should be withdrawn. 6. Cataracts – Subcapsular bilateral cataracts occurred in 10%, and unilateral in 6.3%, of male rats treated with gemfibrozil at 10 times the human dose. # Adverse Reactions ## Clinical Trials Experience ### Gastrointestinal - Cholestatic jaundice ### Central Nervous System - Dizziness - Somnolence - Paresthesia - Peripheral neuritis - Decreased libido - Depression - Headache - Blurred vision ### Genitourinary - Impotence ### Musculoskeletal - Myopathy - Myasthenia - Myalgia - Painful extremities - Arthralgia - Synovitis - Rhabdomyolysis ### Clinical Laboratory - Increased creatine phosphokinase (CPK) - Increased bilirubin - Increased liver transaminases (AST , ALT) - Increased alkaline phosphatase ### Hematopoietic - Anemia - Leukopenia - Bone marrow hypoplasia - Eosinophilia ### Immunologic - Angioedema - Laryngeal edema - Exfoliative dermatitis ### Dermatologic - Rash - Dermatitis - Pruritus ## Postmarketing Experience There is limited information regarding Gemfibrozil Postmarketing Experience in the drug label. # Drug Interactions ### HMG-CoA Reductase Inhibitors The concomitant administration of Gemfibrozil with simvastatin is contraindicated. The risk of myopathy and rhabdomyolysis is increased with combined gemfibrozil and HMG-CoA reductase inhibitor therapy. Myopathy or rhabdomyolysis with or without acute renal failure have been reported as early as three weeks after initiation of combined therapy or after several months. There is no assurance that periodic monitoring of creatine kinase will prevent the occurrence of severe myopathy and kidney damage. ### Anticoagulants Caution should be exercised when anti-coagulants are given in conjunction with gemfibrozil . The dosage of the anticoagulant should be reduced to maintain the prothrombin time at the desired level to prevent bleeding complications. Frequent prothrombin determinations are advisable until it has been definitely determined that the prothrombin level has stabilized. ### Repaglinide In healthy volunteers, co-administration with gemfibrozil (600 mg twice daily for 3 days) resulted in an 8.1-fold (range 5.5- to 15.0- fold) higher repaglinide AUC and a 28.6-fold (range 18.5- to 80.1-fold) higher repaglinide plasma concentration 7 hours after the dose. In the same study, gemfibrozil (600 mg twice daily for 3 days) + itraconazole (200 mg in the morning and 100 mg in the evening at Day 1, then 100 mg twice daily at Day 2–3) resulted in a 19.4- (range 12.9- to 24.7-fold) higher repaglinideAUC and a 70.4-fold (range 42.9- to 119.2-fold) higher repaglinideplasma concentration 7 hours after the dose. In addition, gemfibrozil alone or gemfibrozil + itraconazole prolonged the hypoglycemic effects of repaglinide. Co-administration of gemfibrozil and repaglinideincreases the risk of severe hypoglycemia and is contraindicated. ### Bile Acid-Binding Resins Gemfibrozil AUC was reduced by 30% when gemfibrozil was given (600 mg) simultaneously with resin-granule drugs such as colestipol (5 g). Administration of the drugs two hours or more apart is recommended because gemfibrozil exposure was not significantly affected when it was administered two hours apart from colestipol. ### Colchicine Myopathy, including rhabdomyolysis, has been reported with chronic administration of colchicine at therapeutic doses. Concomitant use of gemfibrozil may potentiate the development of myopathy. Patients with renal dysfunction and elderly patients are at increased risk. Caution should be exercised when prescribing gemfibrozil with colchicine, especially in elderly patients or patients with renal dysfunction. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): C Gemfibrozil has been shown to produce adverse effects in rats and rabbits at doses between 0.5 and 3 times the human dose (based on surface area). There are no adequate and well-controlled studies in pregnant women. Gemfibrozil should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Administration of gemfibrozil to female rats at 2 times the human dose (based on surface area) before and throughout gestation caused a dose-related decrease in conception rate, an increase in stillborns and a slight reduction in pup weight during lactation. There were also dose-related increased skeletal variations. Anophthalmia occurred, but rarely. Administration of 0.6 and 2 times the human dose (based on surface area) of gemfibrozil to female rats from gestation day 15 through weaning caused dose-related decreases in birth weight and suppressions of pup growth during lactation. Administration of 1 and 3 times the human dose (based on surface area) of gemfibrozil to female rabbits during organogenesis caused a dose-related decrease in litter size and, at the high dose, an increased incidence of parietal bone variations. Pregnancy Category (AUS): B3 Drugs which have been taken by only a limited number of pregnant women and women of childbearing age, without an increase in the frequency of malformation or other direct or indirect harmful effects on the human fetus having been observed. Studies in animals have shown evidence of an increased occurrence of fetal damage, the significance of which is considered uncertain in humans. ### Labor and Delivery There is no FDA guidance on use of Gemfibrozil during labor and delivery. ### Nursing Mothers It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for tumorigenicity shown for gemfibrozil in animal studies, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. ### Pediatric Use Safety and efficacy in pediatric patients have not been established. ### Geriatic Use Safety and efficacy in geriatric patients have not been established. ### Gender There is no FDA guidance on the use of Gemfibrozil with respect to specific gender populations. ### Race There is no FDA guidance on the use of Gemfibrozil with respect to specific racial populations. ### Renal Impairment There have been reports of worsening renal insufficiency upon the addition of Gemfibrozil therapy in individuals with baseline plasma creatinine >2.0 mg/dL. In such patients, the use of alternative therapy should be considered against the risks and benefits of a lower dose of Gemfibrozil. ### Hepatic Impairment Abnormal liver function tests have been observed occasionally during Gemfibrozil administration, including elevations of AST,ALT, LDH, ], and alkaline phosphatase. These are usually reversible when Gemfibrozil is discontinued. Therefore, periodic liver function studies are recommended and Gemfibrozil therapy should be terminated if abnormalities persist. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Gemfibrozil in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Gemfibrozil in patients who are immunocompromised. # Administration and Monitoring ### Administration Oral ### Monitoring There is limited information regarding Gemfibrozil Monitoring in the drug label. # IV Compatibility There is limited information regarding the compatibility of Gemfibrozil and IV administrations. # Overdosage There have been reported cases of overdosage with gemfibrozil. In one case, a 7-year-old child recovered after ingesting up to 9 grams of gemfibrozil. Symptoms reported with overdosage were abdominal cramps, abnormal liver function tests, diarrhea, increased CPK, joint and muscle pain, nausea and vomiting. Symptomatic supportive measures should be taken, should an overdose occur. # Pharmacology ## Mechanism of Action The mechanism of action of gemfibrozil has not been definitely established. In man, gemfibrozil has been shown to inhibit peripheral lipolysis and to decrease the hepatic extraction of free fatty acids, thus reducing hepatic triglyceride production. Gemfibrozil inhibits synthesis and increases clearance of VLDL carrier apolipoprotein B, leading to a decrease in VLDL production. Animal studies suggest that gemfibrozil may, in addition to elevating HDL-cholesterol, reduce incorporation of long-chain fatty acids into newly formed triglycerides, accelerate turnover and removal of cholesterol from the liver, and increase excretion of cholesterol in the feces. ## Structure The empirical formula is C15H22O3 and the molecular weight is 250.35; the solubility in water and acid is 0.0019% and in dilute base it is greater than 1%. The melting point is 58°–61° C. Gemfibrozil is a white solid which is stable under ordinary conditions ## Pharmacodynamics Gemfibrozil is well absorbed from the gastrointestinal tract after oral administration. Peak plasma levels occur in 1 to 2 hours with a plasma half-life of 1.5 hours following multiple doses. Gemfibrozil mainly undergoes oxidation of a ring methyl group to successively form a hydroxymethyl and a carboxyl metabolite. ## Pharmacokinetics Gemfibrozil is completely absorbed after oral administration of gemfibrozil tablets, reaching peak plasma concentrations 1 to 2 hours after dosing. Gemfibrozil pharmacokinetics are affected by the timing of meals relative to time of dosing. Approximately seventy percent of the administered human dose is excreted in the urine, mostly as the glucuronide conjugate, with less than 2% excreted as unchanged gemfibrozil. Six percent of the dose is accounted for in the feces. Gemfibrozil is highly bound to plasma proteins and there is potential for displacement interactions with other drugs In one study both the rate and extent of absorption of the drug were significantly increased when administered 0.5 hour before meals. Average AUC (area under the curve) was reduced by 14-44% when gemfibrozil was administered after meals compared to 0.5 hour before meals. In a subsequent study, rate of absorption of gemfibrozil was maximum when administered 0.5 hour before meals with the Cmax 50-60% greater than when given either with meals or fasting. In this study, there were no significant effects on AUC of timing of dose relative to meals ## Nonclinical Toxicology ### Carcinogenesis, Mutagenesis, Impairment of Fertility Long-term studies have been conducted in rats at 0.2 and 1.3 times the human exposure (based on AUC). The incidence of benign liver nodules and liver carcinomas was significantly increased in high dose male rats. The incidence of liver carcinomas increased also in low dose males, but this increase was not statistically significant (p=0.1). Male rats had a dose-related and statistically significant increase of benign Leydig cell tumors. The higher dose female rats had a significant increase in the combined incidence of benign and malignant liver neoplasms. Long-term studies have been conducted in mice at 0.1 and 0.7 times the human exposure (based on AUC). There were no statistically significant differences from controls in the incidence of liver tumors, but the doses tested were lower than those shown to be carcinogenic with other fibrates. Electron microscopy studies have demonstrated a florid hepatic peroxisome proliferation following gemfibrozil administration to the male rat. An adequate study to test for peroxisome proliferation has not been done in humans but changes in peroxisome morphology have been observed. Peroxisome proliferation has been shown to occur in humans with either of two other drugs of the fibrate class when liver biopsies were compared before and after treatment in the same individual. Administration of approximately 2 times the human dose (based on surface area) to male rats for 10 weeks resulted in a dose-related decrease of fertility. Subsequent studies demonstrated that this effect was reversed after a drug-free period of about eight weeks, and it was not transmitted to the offspring. # Clinical Studies In the primary prevention component of the Helsinki Heart Study, in which 4081 male patients between the ages of 40 and 55 were studied in a randomized, double-blind, placebo-controlled fashion, gemfibrozil therapy was associated with significant reductions in total plasma triglycerides and a significant increase in high density lipoprotein cholesterol. Moderate reductions in total plasma cholesterol and low density lipoprotein cholesterol were observed for the gemfibrozil treatment group as a whole, but the lipid response was heterogeneous, especially among different Fredrickson types. The study involved subjects with serum non-HDL-cholesterol of over 200 mg/dL and no previous history of coronary heart disease. Over the five-year study period, the gemfibrozil group experienced a 1.4% absolute (34% relative) reduction in the rate of serious coronary events (sudden cardiac deaths plus fatal and nonfatal myocardial infarctions) compared to placebo, p=0.04 (see Table I). There was a 37% relative reduction in the rate of nonfatal myocardial infarction compared to placebo, equivalent to a treatment-related difference of 13.1 events per thousand persons. Deaths from any cause during the double-blind portion of the study totaled 44 (2.2%) in the gemfibrozil randomization group and 43 (2.1%) in the placebo group. Among Fredrickson types, during the 5-year double-blind portion of the primary prevention component of the Helsinki Heart Study, the greatest reduction in the incidence of serious coronary events occurred in Type IIb patients who had elevations of both LDL-cholesterol and total plasma triglycerides. This subgroup of Type IIb gemfibrozil group patients had a lower mean HDL-cholesterol level at baseline than the Type IIa subgroup that had elevations of LDL-cholesterol and normal plasma triglycerides. The mean increase in HDL-cholesterol among the Type IIb patients in this study was 12.6% compared to placebo. The mean change in LDL-cholesterol among Type IIb patients was –4.1% with gemfibrozil compared to a rise of 3.9% in the placebo subgroup. The Type IIb subjects in the Helsinki Heart Study had 26 fewer coronary events per thousand persons over five years in the gemfibrozil group compared to placebo. The difference in coronary events was substantially greater between gemfibrozil and placebo for that subgroup of patients with the triad of LDL-cholesterol >175 mg/dL (>4.5 mmol), triglycerides >200 mg/dL (>2.2 mmol), and HDL-cholesterol <35 mg/dL (<0.90 mmol) (see Table I). Further information is available from a 3.5 year (8.5 year cumulative) follow-up of all subjects who had participated in the Helsinki Heart Study. At the completion of the Helsinki Heart Study, subjects could choose to start, stop, or continue to receive gemfibrozil; without knowledge of their own lipid values or double-blind treatment, 60% of patients originally randomized to placebo began therapy with gemfibrozil and 60% of patients originally randomized to gemfibrozil continued medication. After approximately 6.5 years following randomization, all patients were informed of their original treatment group and lipid values during the five years of the double-blind treatment. After further elective changes in gemfibrozil treatment status, 61% of patients in the group originally randomized to gemfibrozil were taking drug; in the group originally randomized to placebo, 65% were taking gemfibrozil. The event rate per 1000 occurring during the open-label follow-up period is detailed in Table II. Cumulative mortality through 8.5 years showed a 20% relative excess of deaths in the group originally randomized to gemfibrozil versus the originally randomized placebo group and a 20% relative decrease in cardiac events in the group originally randomized to gemfibrozil versus the originally randomized placebo group (see Table III). This analysis of the originally randomized "intent-to-treat population neglects the possible complicating effects of treatment switching during the open-label phase. Adjustment of hazard ratios taking into account open-label treatment status from years 6.5 to 8.5, could change the reported hazard ratios for mortality toward unity. It is not clear to what extent the findings of the primary prevention component of the Helsinki Heart Study can be extrapolated to other segments of the dyslipidemic population not studied (such as women, younger or older males, or those with lipid abnormalities limited solely to HDL-cholesterol) or to other lipid-altering drugs. The secondary prevention component of the Helsinki Heart Study was conducted over five years in parallel and at the same centers in Finland in 628 middle-aged males excluded from the primary prevention component of the Helsinki Heart Study because of a history of angina, myocardial infarction, or unexplained ECG changes. The primary efficacy endpoint of the study was cardiac events (the sum of fatal and non-fatal myocardial infarctions and sudden cardiac deaths). The hazard ratio (gemfibrozil:placebo) for cardiac events was 1.47 (95% confidence limits 0.88–2.48, p=0.14). Of the 35 patients in the gemfibrozil group who experienced cardiac events, 12 patients suffered events after discontinuation from the study. Of the 24 patients in the placebo group with cardiac events, 4 patients suffered events after discontinuation from the study. There were 17 cardiac deaths in the gemfibrozil group and 8 in the placebo group (hazard ratio 2.18; 95% confidence limits 0.94–5.05, p=0.06). Ten of these deaths in the gemfibrozil group and 3 in the placebo group occurred after discontinuation from therapy. In this study of patients with known or suspected coronary heart disease, no benefit from gemfibrozil treatment was observed in reducing cardiac events or cardiac deaths. Thus, gemfibrozil has shown benefit only in selected dyslipidemic patients without suspected or established coronary heart disease. Even in patients with coronary heart disease and the triad of elevated LDL-cholesterol, elevated triglycerides, plus low HDL-cholesterol, the possible effect of gemfibrozil on coronary events has not been adequately studied. No efficacy in the patients with established coronary heart disease was observed during the Coronary Drug Project with the chemically and pharmacologically related drug, clofibrate. The Coronary Drug Project was a 6-year randomized, double-blind study involving 1000 clofibrate, 1000 nicotinic acid, and 3000 placebo patients with known coronary heart disease. A clinically and statistically significant reduction in myocardial infarctions was seen in the concurrent nicotinic acid group compared to placebo; no reduction was seen with clofibrate. # How Supplied Gemfibrozil Tablets USP, 600 mg, white, capsule-shaped tablets with the logo "B260" debossed on one side and bisected on the other side of the tablet, each containing 600 mg gemfibrozil, are available as follows: NDC 24658-260-30: Bottles of 30 NDC 24658-260-60: Bottles of 60 NDC 24658-260-90: Bottles of 90 NDC 24658-260-18: Bottles of 180 NDC 24658-260-05: Bottles of 500 ## Storage Store at 20° - 25°C (68° - 77°F). Protect from light and humidity. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information ### Why this medication is prescribed Gemfibrozil is used with diet changes (restriction of cholesterol and fat intake) to reduce the amount of cholesterol and certain fatty substances in your blood. Accumulation of cholesterol and fats along the walls of your arteries (a process known as atherosclerosis) decreases blood flow and, therefore, the oxygen supply to your heart, brain, and other parts of your body. Lowering your blood level of cholesterol and fats may help to prevent heart disease, angina (chest pain), strokes, and heart attacks. This medication is sometimes prescribed for other uses; ask your doctor or pharmacist for more information. ### How this medication should be used Gemfibrozil comes in tablets and capsules to take by mouth. It usually is taken twice a day, 30 minutes before the morning and evening meals. Follow the directions on your prescription label carefully, and ask your doctor or pharmacist to explain any part you do not understand. Take gemfibrozil exactly as directed. Do not take more or less of it or take it more often than prescribed by your doctor. Continue to take gemfibrozil even if you feel well. Do not stop taking gemfibrozil without talking to your doctor. ### Special precautions Before taking gemfibrozil: - tell your doctor and pharmacist if you are allergic to gemfibrozil or any other drugs. - tell your doctor and pharmacist what prescription and nonprescription medications you are taking, especially anticoagulants ('blood thinners') such as warfarin (Coumadin) and vitamins. If you take insulin or oral diabetes medications, your dose may need to be changed because gemfibrozil can increase the amount of sugar in your blood. Talk to your doctor before changing your dose. - tell your doctor if you have or have ever had ulcers; diabetes; or gallbladder, kidney, or liver disease. - tell your doctor if you are pregnant, plan to become pregnant, or are breast-feeding. If you become pregnant while taking gemfibrozil, call your doctor. - if you are having surgery, including dental surgery, tell the doctor or dentist that you are taking gemfibrozil. ### Special dietary instructions Eat a low-cholesterol, low-fat diet. This kind of diet includes cottage cheese, fat-free milk, fish (not canned in oil), vegetables, poultry, egg whites, and polyunsaturated oils and margarines (corn, safflower, canola, and soybean oils). Avoid foods with excess fat in them such as meat (especially liver and fatty meat), egg yolks, whole milk, cream, butter, shortening, lard, pastries, cakes, cookies, gravy, peanut butter, chocolate, olives, potato chips, coconut, cheese (other than cottage cheese), coconut oil, palm oil, and fried foods. ### What to do if you forget a dose Take the missed dose as soon as you remember it. However, if it is almost time for the next dose, skip the missed dose and continue your regular dosing schedule. Do not take a double dose to make up for a missed one. ### Side Effects Gemfibrozil may cause side effects. Tell your doctor if any of these symptoms are severe or do not go away: - stomach pain - diarrhea - constipation - vomiting - gas - headache - dizziness - blurred vision - flushing If you experience either of the following symptoms, call your doctor immediately: - muscle pain - weakness If you experience a serious side effect, you or your doctor may send a report to the Food and Drug Administration's (FDA) MedWatch Adverse Event Reporting program online or by phone . ### Storage conditions needed for this medication Keep this medication in the container it came in, tightly closed, and out of reach of children. Store it at room temperature and away from excess heat and moisture (not in the bathroom). Throw away any medication that is outdated or no longer needed. Talk to your pharmacist about the proper disposal of your medication. ### In case of emergency/overdose In case of overdose, call your local poison control center at 1-800-222-1222. If the victim has collapsed or is not breathing, call local emergency services at 911. ### Other information Keep all appointments with your doctor and the laboratory. Your doctor will order certain lab tests to check your response to gemfibrozil. Do not let anyone else take your medication. Ask your pharmacist any questions you have about refilling your prescription. ### Brand names - Lopid® # Precautions with Alcohol Alcohol-Gemfibrozil interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - Lopid # Look-Alike Drug Names There is limited information regarding Gemfibrozil Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	Gemfibrozil Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Alejandro Lemor, M.D. [2] # Disclaimer WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here. # Overview Gemfibrozil is a peroxisome proliferator receptor alpha agonist that is FDA approved for the {{{indicationType}}} of types IV and V hyperlipidemia at risk of pancreatitis and who do not respond adequately to a determined dietary effort to control them, and reducing the risk of developing coronary heart disease only in Type IIb patients without history of or symptoms of existing coronary heart disease who have had an inadequate response to weight loss, dietary therapy, exercise, and other pharmacologic agents (such as bile acid sequestrants and nicotinic acid) and who have the following triad of lipid abnormalities: low HDL-cholesterol levels in addition to elevated LDL-cholesterol and elevated triglycerides. Common adverse reactions include dyspepsia, abdominal pain, acute appendicitis, atrial fibrillation, diarrhea, fatigue, eczema, rash, vertigo, constipation, headache. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) ### Hyperlipidemia type IV and V - Dosing Information - 600 mg PO every 12 hours (30 minutes before the morning and evening meals) ### Prophylaxis for Disorder of Cardiovascular System - Dosing Information - 600 mg PO every 12 hours (30 minutes before the morning and evening meals) ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information about Off-Label Guideline-Supported Use of Gemfibrozil in adult patients. ### Non–Guideline-Supported Use ### Antiviral Drug Adverse Reaction, Antiretroviral - Hyperlipidemia - Dosing Information - 600 mg PO every 12 hours ### Prophylaxis for Cerebrovascular Accident - Dosing Information - 600 mg PO every 12 hours ### Hyperlipidemia - Dosing Information - 600 mg PO every 12 hours # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) There is limited information regarding Gemfibrozil FDA-Labeled Indications and Dosage (Pediatric) in the drug label. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information about Off-Label Guideline-Supported Use of Gemfibrozil in pediatric patients. ### Non–Guideline-Supported Use There is limited information about Off-Label Non–Guideline-Supported Use of Gemfibrozil in pediatric patients. # Contraindications - Hepatic or severe renal dysfunction, including primary biliary cirrhosis. - Preexisting gallbladder disease. - Hypersensitivity to gemfibrozil. - Combination therapy of gemfibrozil with repaglinide - Combination therapy of gemfibrozil with simvastatin # Warnings 1. Because of chemical, pharmacological, and clinical similarities between gemfibrozil and clofibrate, the adverse findings with clofibrate in two large clinical studies may also apply to gemfibrozil. In the first of those studies, the Coronary Drug Project, 1000 subjects with previous myocardial infarction were treated for five years with clofibrate. There was no difference in mortality between the clofibrate-treated subjects and 3000 placebo-treated subjects, but twice as many clofibrate-treated subjects developed cholelithiasis and cholecystitis requiring surgery. In the other study, conducted by the World Health Organization (WHO), 5000 subjects without known coronary heart disease were treated with clofibrate for five years and followed one year beyond. There was a statistically significant (44%) higher age-adjusted total mortality in the clofibrate-treated group than in a comparable placebo-treated control group during the trial period. The excess mortality was due to a 33% increase in non-cardiovascular causes, including malignancy, post-cholecystectomy complications, and pancreatitis. The higher risk of clofibrate-treated subjects for gallbladder disease was confirmed. Because of the more limited size of the Helsinki Heart Study, the observed difference in mortality from any cause between the gemfibrozil and placebo groups is not statistically significantly different from the 29% excess mortality reported in the clofibrate group in the separate WHO study at the nine year follow-up. Noncoronary heart disease related mortality showed an excess in the group originally randomized to gemfibrozil primarily due to cancer deaths observed during the open-label extension. During the five year primary prevention component of the Helsinki Heart Study, mortality from any cause was 44 (2.2%) in the gemfibrozil group and 43 (2.1%) in the placebo group; including the 3.5 year follow-up period since the trial was completed, cumulative mortality from any cause was 101 (4.9%) in the gemfibrozil group and 83 (4.1%) in the group originally randomized to placebo (hazard ratio 1:20 in favor of placebo). Because of the more limited size of the Helsinki Heart Study, the observed difference in mortality from any cause between the gemfibrozil and placebo groups at Year-5 or at Year-8.5 is not statistically significantly different from the 29% excess mortality reported in the clofibrate group in the separate WHO study at the nine year follow-up. Noncoronary heart disease related mortality showed an excess in the group originally randomized to gemfibrozil at the 8.5 year follow-up (65 gemfibrozil versus 45 placebo noncoronary deaths). The incidence of cancer (excluding basal cell carcinoma) discovered during the trial and in the 3.5 years after the trial was completed was 51 (2.5%) in both originally randomized groups. In addition, there were 16 basal cell carcinomas in the group originally randomized to gemfibrozil and 9 in the group originally randomized to placebo (p=0.22). There were 30 (1.5%) deaths attributed to cancer in the group originally randomized to gemfibrozil and 18 (0.9%) in the group originally randomized to placebo (p=0.11). Adverse outcomes, including coronary events, were higher in gemfibrozil patients in a corresponding study in men with a history of known or suspected coronary heart disease in the secondary prevention component of the Helsinki Heart Study. A comparative carcinogenicity study was also done in rats comparing three drugs in this class: fenofibrate (10 and 60 mg/kg; 0.3 and 1.6 times the human dose, respectively), clofibrate (400 mg/kg; 1.6 times the human dose), and gemfibrozil (250 mg/kg; 1.7 times the human dose). Pancreatic acinar adenomas were increased in males and females on fenofibrate; hepatocellular carcinoma and pancreatic acinar adenomas were increased in males and hepatic neoplastic nodules in females treated with clofibrate; hepatic neoplastic nodules were increased in males and females treated with clofibrate; hepatic neoplastic nodules were increased in males and females treated with gemfibrozil while testicular interstitial cell (Leydig cell) tumors were increased in males on all three drugs. 2. A gallstone prevalence substudy of 450 Helsinki Heart Study participants showed a trend toward a greater prevalence of gallstones during the study within the gemfibrozil treatment group (7.5% versus 4.9% for the placebo group, a 55% excess for the gemfibrozil group). A trend toward a greater incidence of gallbladder surgery was observed for the gemfibrozil group (17 versus 11 subjects, a 54% excess). This result did not differ statistically from the increased incidence of cholecystectomy observed in the WHO study in the group treated with clofibrate. Both clofibrate and gemfibrozil may increase cholesterol excretion into the bile, leading to cholelithiasis. If cholelithiasis is suspected, gallbladder studies are indicated. gemfibrozil therapy should be discontinued if gallstones are found. Cases of cholelithiasis have been reported with gemfibrozil therapy. 3. Since a reduction of mortality from coronary heart disease has not been demonstrated and because liver and interstitial cell testicular tumors were increased in rats, gemfibrozil should be administered only to those patients described before. If a significant serum lipid response is not obtained, gemfibrozil should be discontinued. 4. Concomitant Anticoagulants – Caution should be exercised when anticoagulants are given in conjunction with gemfibrozil . The dosage of the anticoagulant should be reduced to maintain the prothrombin time at the desired level to prevent bleeding complications. Frequent prothrombin determinations are advisable until it has been definitely determined that the prothrombin level has stabilized. 5. The concomitant administration of gemfibrozil with simvastatin is contraindicated. Concomitant therapy with gemfibrozil and an HMG-CoA reductase inhibitor is associated with an increased risk of skeletal muscle toxicity manifested as rhabdomyolysis, markedly elevated creatine kinase (CPK) levels, and myoglobinuria, leading in a high proportion of cases to acute renal failure and death. IN PATIENTS WHO HAVE HAD AN UNSATISFACTORY LIPID RESPONSE TO EITHER DRUG ALONE, THE BENEFIT OF COMBINED THERAPY WITH GEMFBROZIL AND an HMG-CoA REDUCTASE INHIBITOR DOES NOT OUTWEIGH THE RISKS OF SEVERE MYOPATHY, rhabdomyolysis, AND ACUTE RENAL FAILURE. The use of fibrates alone, including gemfibrozil , may occasionally be associated with myositis. Patients receiving gemfibrozil and complaining of muscle pain, tenderness, or weakness should have prompt medical evaluation for myositis, including serum creatine–kinase level determination. If myositis is suspected or diagnosed, gemfibrozil therapy should be withdrawn. 6. Cataracts – Subcapsular bilateral cataracts occurred in 10%, and unilateral in 6.3%, of male rats treated with gemfibrozil at 10 times the human dose. # Adverse Reactions ## Clinical Trials Experience ### Gastrointestinal - Cholestatic jaundice ### Central Nervous System - Dizziness - Somnolence - Paresthesia - Peripheral neuritis - Decreased libido - Depression - Headache - Blurred vision ### Genitourinary - Impotence ### Musculoskeletal - Myopathy - Myasthenia - Myalgia - Painful extremities - Arthralgia - Synovitis - Rhabdomyolysis ### Clinical Laboratory - Increased creatine phosphokinase (CPK) - Increased bilirubin - Increased liver transaminases (AST , ALT) - Increased alkaline phosphatase ### Hematopoietic - Anemia - Leukopenia - Bone marrow hypoplasia - Eosinophilia ### Immunologic - Angioedema - Laryngeal edema - Exfoliative dermatitis ### Dermatologic - Rash - Dermatitis - Pruritus ## Postmarketing Experience There is limited information regarding Gemfibrozil Postmarketing Experience in the drug label. # Drug Interactions ### HMG-CoA Reductase Inhibitors The concomitant administration of Gemfibrozil with simvastatin is contraindicated. The risk of myopathy and rhabdomyolysis is increased with combined gemfibrozil and HMG-CoA reductase inhibitor therapy. Myopathy or rhabdomyolysis with or without acute renal failure have been reported as early as three weeks after initiation of combined therapy or after several months. There is no assurance that periodic monitoring of creatine kinase will prevent the occurrence of severe myopathy and kidney damage. ### Anticoagulants Caution should be exercised when anti-coagulants are given in conjunction with gemfibrozil . The dosage of the anticoagulant should be reduced to maintain the prothrombin time at the desired level to prevent bleeding complications. Frequent prothrombin determinations are advisable until it has been definitely determined that the prothrombin level has stabilized. ### Repaglinide In healthy volunteers, co-administration with gemfibrozil (600 mg twice daily for 3 days) resulted in an 8.1-fold (range 5.5- to 15.0- fold) higher repaglinide AUC and a 28.6-fold (range 18.5- to 80.1-fold) higher repaglinide plasma concentration 7 hours after the dose. In the same study, gemfibrozil (600 mg twice daily for 3 days) + itraconazole (200 mg in the morning and 100 mg in the evening at Day 1, then 100 mg twice daily at Day 2–3) resulted in a 19.4- (range 12.9- to 24.7-fold) higher repaglinideAUC and a 70.4-fold (range 42.9- to 119.2-fold) higher repaglinideplasma concentration 7 hours after the dose. In addition, gemfibrozil alone or gemfibrozil + itraconazole prolonged the hypoglycemic effects of repaglinide. Co-administration of gemfibrozil and repaglinideincreases the risk of severe hypoglycemia and is contraindicated. ### Bile Acid-Binding Resins Gemfibrozil AUC was reduced by 30% when gemfibrozil was given (600 mg) simultaneously with resin-granule drugs such as colestipol (5 g). Administration of the drugs two hours or more apart is recommended because gemfibrozil exposure was not significantly affected when it was administered two hours apart from colestipol. ### Colchicine Myopathy, including rhabdomyolysis, has been reported with chronic administration of colchicine at therapeutic doses. Concomitant use of gemfibrozil may potentiate the development of myopathy. Patients with renal dysfunction and elderly patients are at increased risk. Caution should be exercised when prescribing gemfibrozil with colchicine, especially in elderly patients or patients with renal dysfunction. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): C Gemfibrozil has been shown to produce adverse effects in rats and rabbits at doses between 0.5 and 3 times the human dose (based on surface area). There are no adequate and well-controlled studies in pregnant women. Gemfibrozil should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Administration of gemfibrozil to female rats at 2 times the human dose (based on surface area) before and throughout gestation caused a dose-related decrease in conception rate, an increase in stillborns and a slight reduction in pup weight during lactation. There were also dose-related increased skeletal variations. Anophthalmia occurred, but rarely. Administration of 0.6 and 2 times the human dose (based on surface area) of gemfibrozil to female rats from gestation day 15 through weaning caused dose-related decreases in birth weight and suppressions of pup growth during lactation. Administration of 1 and 3 times the human dose (based on surface area) of gemfibrozil to female rabbits during organogenesis caused a dose-related decrease in litter size and, at the high dose, an increased incidence of parietal bone variations. Pregnancy Category (AUS): B3 Drugs which have been taken by only a limited number of pregnant women and women of childbearing age, without an increase in the frequency of malformation or other direct or indirect harmful effects on the human fetus having been observed. Studies in animals have shown evidence of an increased occurrence of fetal damage, the significance of which is considered uncertain in humans. ### Labor and Delivery There is no FDA guidance on use of Gemfibrozil during labor and delivery. ### Nursing Mothers It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for tumorigenicity shown for gemfibrozil in animal studies, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. ### Pediatric Use Safety and efficacy in pediatric patients have not been established. ### Geriatic Use Safety and efficacy in geriatric patients have not been established. ### Gender There is no FDA guidance on the use of Gemfibrozil with respect to specific gender populations. ### Race There is no FDA guidance on the use of Gemfibrozil with respect to specific racial populations. ### Renal Impairment There have been reports of worsening renal insufficiency upon the addition of Gemfibrozil therapy in individuals with baseline plasma creatinine >2.0 mg/dL. In such patients, the use of alternative therapy should be considered against the risks and benefits of a lower dose of Gemfibrozil. ### Hepatic Impairment Abnormal liver function tests have been observed occasionally during Gemfibrozil administration, including elevations of AST,ALT, LDH, [bilirubin]], and alkaline phosphatase. These are usually reversible when Gemfibrozil is discontinued. Therefore, periodic liver function studies are recommended and Gemfibrozil therapy should be terminated if abnormalities persist. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Gemfibrozil in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Gemfibrozil in patients who are immunocompromised. # Administration and Monitoring ### Administration Oral ### Monitoring There is limited information regarding Gemfibrozil Monitoring in the drug label. # IV Compatibility There is limited information regarding the compatibility of Gemfibrozil and IV administrations. # Overdosage There have been reported cases of overdosage with gemfibrozil. In one case, a 7-year-old child recovered after ingesting up to 9 grams of gemfibrozil. Symptoms reported with overdosage were abdominal cramps, abnormal liver function tests, diarrhea, increased CPK, joint and muscle pain, nausea and vomiting. Symptomatic supportive measures should be taken, should an overdose occur. # Pharmacology ## Mechanism of Action The mechanism of action of gemfibrozil has not been definitely established. In man, gemfibrozil has been shown to inhibit peripheral lipolysis and to decrease the hepatic extraction of free fatty acids, thus reducing hepatic triglyceride production. Gemfibrozil inhibits synthesis and increases clearance of VLDL carrier apolipoprotein B, leading to a decrease in VLDL production. Animal studies suggest that gemfibrozil may, in addition to elevating HDL-cholesterol, reduce incorporation of long-chain fatty acids into newly formed triglycerides, accelerate turnover and removal of cholesterol from the liver, and increase excretion of cholesterol in the feces. ## Structure The empirical formula is C15H22O3 and the molecular weight is 250.35; the solubility in water and acid is 0.0019% and in dilute base it is greater than 1%. The melting point is 58°–61° C. Gemfibrozil is a white solid which is stable under ordinary conditions ## Pharmacodynamics Gemfibrozil is well absorbed from the gastrointestinal tract after oral administration. Peak plasma levels occur in 1 to 2 hours with a plasma half-life of 1.5 hours following multiple doses. Gemfibrozil mainly undergoes oxidation of a ring methyl group to successively form a hydroxymethyl and a carboxyl metabolite. ## Pharmacokinetics Gemfibrozil is completely absorbed after oral administration of gemfibrozil tablets, reaching peak plasma concentrations 1 to 2 hours after dosing. Gemfibrozil pharmacokinetics are affected by the timing of meals relative to time of dosing. Approximately seventy percent of the administered human dose is excreted in the urine, mostly as the glucuronide conjugate, with less than 2% excreted as unchanged gemfibrozil. Six percent of the dose is accounted for in the feces. Gemfibrozil is highly bound to plasma proteins and there is potential for displacement interactions with other drugs In one study both the rate and extent of absorption of the drug were significantly increased when administered 0.5 hour before meals. Average AUC (area under the curve) was reduced by 14-44% when gemfibrozil was administered after meals compared to 0.5 hour before meals. In a subsequent study, rate of absorption of gemfibrozil was maximum when administered 0.5 hour before meals with the Cmax 50-60% greater than when given either with meals or fasting. In this study, there were no significant effects on AUC of timing of dose relative to meals ## Nonclinical Toxicology ### Carcinogenesis, Mutagenesis, Impairment of Fertility Long-term studies have been conducted in rats at 0.2 and 1.3 times the human exposure (based on AUC). The incidence of benign liver nodules and liver carcinomas was significantly increased in high dose male rats. The incidence of liver carcinomas increased also in low dose males, but this increase was not statistically significant (p=0.1). Male rats had a dose-related and statistically significant increase of benign Leydig cell tumors. The higher dose female rats had a significant increase in the combined incidence of benign and malignant liver neoplasms. Long-term studies have been conducted in mice at 0.1 and 0.7 times the human exposure (based on AUC). There were no statistically significant differences from controls in the incidence of liver tumors, but the doses tested were lower than those shown to be carcinogenic with other fibrates. Electron microscopy studies have demonstrated a florid hepatic peroxisome proliferation following gemfibrozil administration to the male rat. An adequate study to test for peroxisome proliferation has not been done in humans but changes in peroxisome morphology have been observed. Peroxisome proliferation has been shown to occur in humans with either of two other drugs of the fibrate class when liver biopsies were compared before and after treatment in the same individual. Administration of approximately 2 times the human dose (based on surface area) to male rats for 10 weeks resulted in a dose-related decrease of fertility. Subsequent studies demonstrated that this effect was reversed after a drug-free period of about eight weeks, and it was not transmitted to the offspring. # Clinical Studies In the primary prevention component of the Helsinki Heart Study, in which 4081 male patients between the ages of 40 and 55 were studied in a randomized, double-blind, placebo-controlled fashion, gemfibrozil therapy was associated with significant reductions in total plasma triglycerides and a significant increase in high density lipoprotein cholesterol. Moderate reductions in total plasma cholesterol and low density lipoprotein cholesterol were observed for the gemfibrozil treatment group as a whole, but the lipid response was heterogeneous, especially among different Fredrickson types. The study involved subjects with serum non-HDL-cholesterol of over 200 mg/dL and no previous history of coronary heart disease. Over the five-year study period, the gemfibrozil group experienced a 1.4% absolute (34% relative) reduction in the rate of serious coronary events (sudden cardiac deaths plus fatal and nonfatal myocardial infarctions) compared to placebo, p=0.04 (see Table I). There was a 37% relative reduction in the rate of nonfatal myocardial infarction compared to placebo, equivalent to a treatment-related difference of 13.1 events per thousand persons. Deaths from any cause during the double-blind portion of the study totaled 44 (2.2%) in the gemfibrozil randomization group and 43 (2.1%) in the placebo group. Among Fredrickson types, during the 5-year double-blind portion of the primary prevention component of the Helsinki Heart Study, the greatest reduction in the incidence of serious coronary events occurred in Type IIb patients who had elevations of both LDL-cholesterol and total plasma triglycerides. This subgroup of Type IIb gemfibrozil group patients had a lower mean HDL-cholesterol level at baseline than the Type IIa subgroup that had elevations of LDL-cholesterol and normal plasma triglycerides. The mean increase in HDL-cholesterol among the Type IIb patients in this study was 12.6% compared to placebo. The mean change in LDL-cholesterol among Type IIb patients was –4.1% with gemfibrozil compared to a rise of 3.9% in the placebo subgroup. The Type IIb subjects in the Helsinki Heart Study had 26 fewer coronary events per thousand persons over five years in the gemfibrozil group compared to placebo. The difference in coronary events was substantially greater between gemfibrozil and placebo for that subgroup of patients with the triad of LDL-cholesterol >175 mg/dL (>4.5 mmol), triglycerides >200 mg/dL (>2.2 mmol), and HDL-cholesterol <35 mg/dL (<0.90 mmol) (see Table I). Further information is available from a 3.5 year (8.5 year cumulative) follow-up of all subjects who had participated in the Helsinki Heart Study. At the completion of the Helsinki Heart Study, subjects could choose to start, stop, or continue to receive gemfibrozil; without knowledge of their own lipid values or double-blind treatment, 60% of patients originally randomized to placebo began therapy with gemfibrozil and 60% of patients originally randomized to gemfibrozil continued medication. After approximately 6.5 years following randomization, all patients were informed of their original treatment group and lipid values during the five years of the double-blind treatment. After further elective changes in gemfibrozil treatment status, 61% of patients in the group originally randomized to gemfibrozil were taking drug; in the group originally randomized to placebo, 65% were taking gemfibrozil. The event rate per 1000 occurring during the open-label follow-up period is detailed in Table II. Cumulative mortality through 8.5 years showed a 20% relative excess of deaths in the group originally randomized to gemfibrozil versus the originally randomized placebo group and a 20% relative decrease in cardiac events in the group originally randomized to gemfibrozil versus the originally randomized placebo group (see Table III). This analysis of the originally randomized "intent-to-treat population neglects the possible complicating effects of treatment switching during the open-label phase. Adjustment of hazard ratios taking into account open-label treatment status from years 6.5 to 8.5, could change the reported hazard ratios for mortality toward unity. It is not clear to what extent the findings of the primary prevention component of the Helsinki Heart Study can be extrapolated to other segments of the dyslipidemic population not studied (such as women, younger or older males, or those with lipid abnormalities limited solely to HDL-cholesterol) or to other lipid-altering drugs. The secondary prevention component of the Helsinki Heart Study was conducted over five years in parallel and at the same centers in Finland in 628 middle-aged males excluded from the primary prevention component of the Helsinki Heart Study because of a history of angina, myocardial infarction, or unexplained ECG changes. The primary efficacy endpoint of the study was cardiac events (the sum of fatal and non-fatal myocardial infarctions and sudden cardiac deaths). The hazard ratio (gemfibrozil:placebo) for cardiac events was 1.47 (95% confidence limits 0.88–2.48, p=0.14). Of the 35 patients in the gemfibrozil group who experienced cardiac events, 12 patients suffered events after discontinuation from the study. Of the 24 patients in the placebo group with cardiac events, 4 patients suffered events after discontinuation from the study. There were 17 cardiac deaths in the gemfibrozil group and 8 in the placebo group (hazard ratio 2.18; 95% confidence limits 0.94–5.05, p=0.06). Ten of these deaths in the gemfibrozil group and 3 in the placebo group occurred after discontinuation from therapy. In this study of patients with known or suspected coronary heart disease, no benefit from gemfibrozil treatment was observed in reducing cardiac events or cardiac deaths. Thus, gemfibrozil has shown benefit only in selected dyslipidemic patients without suspected or established coronary heart disease. Even in patients with coronary heart disease and the triad of elevated LDL-cholesterol, elevated triglycerides, plus low HDL-cholesterol, the possible effect of gemfibrozil on coronary events has not been adequately studied. No efficacy in the patients with established coronary heart disease was observed during the Coronary Drug Project with the chemically and pharmacologically related drug, clofibrate. The Coronary Drug Project was a 6-year randomized, double-blind study involving 1000 clofibrate, 1000 nicotinic acid, and 3000 placebo patients with known coronary heart disease. A clinically and statistically significant reduction in myocardial infarctions was seen in the concurrent nicotinic acid group compared to placebo; no reduction was seen with clofibrate. # How Supplied Gemfibrozil Tablets USP, 600 mg, white, capsule-shaped tablets with the logo "B260" debossed on one side and bisected on the other side of the tablet, each containing 600 mg gemfibrozil, are available as follows: NDC 24658-260-30: Bottles of 30 NDC 24658-260-60: Bottles of 60 NDC 24658-260-90: Bottles of 90 NDC 24658-260-18: Bottles of 180 NDC 24658-260-05: Bottles of 500 ## Storage Store at 20° - 25°C (68° - 77°F). Protect from light and humidity. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information ### Why this medication is prescribed Gemfibrozil is used with diet changes (restriction of cholesterol and fat intake) to reduce the amount of cholesterol and certain fatty substances in your blood. Accumulation of cholesterol and fats along the walls of your arteries (a process known as atherosclerosis) decreases blood flow and, therefore, the oxygen supply to your heart, brain, and other parts of your body. Lowering your blood level of cholesterol and fats may help to prevent heart disease, angina (chest pain), strokes, and heart attacks. This medication is sometimes prescribed for other uses; ask your doctor or pharmacist for more information. ### How this medication should be used Gemfibrozil comes in tablets and capsules to take by mouth. It usually is taken twice a day, 30 minutes before the morning and evening meals. Follow the directions on your prescription label carefully, and ask your doctor or pharmacist to explain any part you do not understand. Take gemfibrozil exactly as directed. Do not take more or less of it or take it more often than prescribed by your doctor. Continue to take gemfibrozil even if you feel well. Do not stop taking gemfibrozil without talking to your doctor. ### Special precautions Before taking gemfibrozil: - tell your doctor and pharmacist if you are allergic to gemfibrozil or any other drugs. - tell your doctor and pharmacist what prescription and nonprescription medications you are taking, especially anticoagulants ('blood thinners') such as warfarin (Coumadin) and vitamins. If you take insulin or oral diabetes medications, your dose may need to be changed because gemfibrozil can increase the amount of sugar in your blood. Talk to your doctor before changing your dose. - tell your doctor if you have or have ever had ulcers; diabetes; or gallbladder, kidney, or liver disease. - tell your doctor if you are pregnant, plan to become pregnant, or are breast-feeding. If you become pregnant while taking gemfibrozil, call your doctor. - if you are having surgery, including dental surgery, tell the doctor or dentist that you are taking gemfibrozil. ### Special dietary instructions Eat a low-cholesterol, low-fat diet. This kind of diet includes cottage cheese, fat-free milk, fish (not canned in oil), vegetables, poultry, egg whites, and polyunsaturated oils and margarines (corn, safflower, canola, and soybean oils). Avoid foods with excess fat in them such as meat (especially liver and fatty meat), egg yolks, whole milk, cream, butter, shortening, lard, pastries, cakes, cookies, gravy, peanut butter, chocolate, olives, potato chips, coconut, cheese (other than cottage cheese), coconut oil, palm oil, and fried foods. ### What to do if you forget a dose Take the missed dose as soon as you remember it. However, if it is almost time for the next dose, skip the missed dose and continue your regular dosing schedule. Do not take a double dose to make up for a missed one. ### Side Effects Gemfibrozil may cause side effects. Tell your doctor if any of these symptoms are severe or do not go away: - stomach pain - diarrhea - constipation - vomiting - gas - headache - dizziness - blurred vision - flushing If you experience either of the following symptoms, call your doctor immediately: - muscle pain - weakness If you experience a serious side effect, you or your doctor may send a report to the Food and Drug Administration's (FDA) MedWatch Adverse Event Reporting program online [at http://www.fda.gov/MedWatch/report.htm] or by phone [1-800-332-1088]. ### Storage conditions needed for this medication Keep this medication in the container it came in, tightly closed, and out of reach of children. Store it at room temperature and away from excess heat and moisture (not in the bathroom). Throw away any medication that is outdated or no longer needed. Talk to your pharmacist about the proper disposal of your medication. ### In case of emergency/overdose In case of overdose, call your local poison control center at 1-800-222-1222. If the victim has collapsed or is not breathing, call local emergency services at 911. ### Other information Keep all appointments with your doctor and the laboratory. Your doctor will order certain lab tests to check your response to gemfibrozil. Do not let anyone else take your medication. Ask your pharmacist any questions you have about refilling your prescription. ### Brand names - Lopid® # Precautions with Alcohol Alcohol-Gemfibrozil interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - Lopid # Look-Alike Drug Names There is limited information regarding Gemfibrozil Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	https://www.wikidoc.org/index.php/Gemfibrozil
af2f125e7ac9df2e16f0e7ea827aac886d147c06	wikidoc	Gemigliptin	Gemigliptin # Overview Gemigliptin (rINN), previously identified as LC15-0444, is an oral anti-hyperglycemic agent (anti-diabetic drug) of the new dipeptidyl peptidase-4 (DPP-4) inhibitor class of drugs. It is well known that glucose lowering effects of DPP-4 inhibitors are mainly mediated by GLP-1 and gastric inhibitory polypeptide (GIP) incretin hormones which are inactivated by DPP-4. Gemigliptin was initially developed solely by LG Life Sciences. In 2010, Double-Crane Pharmaceutical Co. (DCPC) joined with LGLS to co-develop the final compound and collaborate on the marketing of the drug in China. LGLS also announced on Nov., 2010 that NOBEL Ilac has been granted rights to develop and commercialize gemigliptin in Turkey. A New Drug Application (NDA) for gemigliptin in the treatment of type 2 diabetes was submitted to the Korea Food & Drug Administration (KFDA) in July 2011. Then on June 27, 2012, the KFDA has approved the manufacture and distribution of LG Life Sciences’ diabetes treatment, Zemiglo, the main substance of which is gemigliptin. Clinical trials for evaluating the safety and efficacy of gemigliptin in combination with metformin have been completed. # History The NDA for gemigliptin was submitted to KFDA in July, 2011 and it was approved on June 27, 2012. By the end of 2012, gemigliptin will be marketed in Korea as Zemiglo which is the fifth new DPP-4 inhibitor diabetes treatment in the world. # Mechanism of action DPP-4 is a serine protease located on the cell surfaces throughout the body. In plasma, DPP-4 enzyme rapidly inactivates incretins including GLP-1 and GIP which are produced in the intestine depending on the blood glucose level and contribute to the physiological regulation of glucose homeostatis. Active GLP-1 and GIP increase the production and release of insulin by pancreatinc beta cells. GLP-1 also reduces the scretion of glucacon by pancreatic alpha cells, thereby resulting in a decreased hepatic glucose production. However these incretins are rapidly cleaved by DPP-4 and their effects last only for a few minutes. DPP-4 inhibitors block the cleavage of the gliptins and thus lead to an increasee insulin level and a reduced glucagon level in a glucose-dependent way. This results in a decrease of fasting and postprandial glycemia, as well as HbA1c levels. # Preclinical studies Gemigliptin is a competitive, reversible DPP-4 inhibitor (IC50 = 16 nM) with excellent selectivity over other critical human proteases such as DPP-2, DPP-8, DPP-9, elastase, trypsin, urokinase and cathepsin G. Gemigliptin was rapidly absorbed after single oral dosing and the compound was eliminated with a half-life of 3.6 h, 5.2 h, and 5.4 h in the rat, dog, and monkey, respectively. The bioavailability of gemigliptin in the rat, dog, and monkey was species-dependent with the values of 94%, 73%, and 26%, respectively. Following the oral administration of gemigliptin in the rat, dog and monkey, about 80% inhibition of plasma DPP-4 activity were observed at the plasma levels of 18 nM, 14 nM and 4 nM, respectively. In the diet-induced obese (DIO) mice, gemigliptin reduced glucose excursion during OGTT in a dose dependent manner with the minimum effective dose of 0.3 mg/kg and enhanced glucose-stimulated plasma GLP-1 increase in a dose dependent manner reaching the maximum effect at the dose of 1 mg/kg. Following 4 week oral repeat dosing in the DIO mice, gemigliptin reduced significantly HbA1c with the minimum effective dose of 3 mg/kg. In the beagle dog, gemigliptin significantly enhanced active GLP-1, decreased glucagon, and reduced glucose excursion during OGTT following a single dosing. Studies on animals suggest its positive effect on hepatic and renal fibrosis . Data on human patients are still inconclusive # Clinical studies The dose-range finding phase 2 study was performed and 145 patients (91men and 54 women) with type 2 diabetes mellitus were enrolled. All three doses (50,100 and 200 mg groups) of gemigliptin significantly reduced the HbA1c from baseline compared to the placebo group without a significant difference between the doses. Subjects with a higher baseline HbA1c (≥8.5%) had a greater reduction in HbA1c. Insulin secretory function, as assessed using homeostasis model assessment-beta cell, C-peptide and the insulinogenic index, improved significantly with gemigliptin treatment. Insulin sensitivity, as assessed using homeostasis model assessment-insulin resistance, also improved significantly after 12 weeks of treatment. The 50 and 200 mg groups had significantly reduced total cholesterol and low-density lipoprotein cholesterol levels at 12 weeks compared to the placebo group. The incidences of adverse events were similar in all study subjects. Gemigliptin monotherapy (50 mg for 12 weeks) improved the HbA1c, FPG level, oral glucose tolerance test results, β-cell function and insulin sensitivity measures, and was well tolerated in subjects with type 2 diabetes. Results of Phase 3 clinical trials which have been finished recently will be updated near future.	Gemigliptin Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview Gemigliptin (rINN), previously identified as LC15-0444, is an oral anti-hyperglycemic agent (anti-diabetic drug) of the new dipeptidyl peptidase-4 (DPP-4) inhibitor class of drugs.[1] It is well known that glucose lowering effects of DPP-4 inhibitors are mainly mediated by GLP-1 and gastric inhibitory polypeptide (GIP) incretin hormones which are inactivated by DPP-4. Gemigliptin was initially developed solely by LG Life Sciences. In 2010, Double-Crane Pharmaceutical Co. (DCPC) joined with LGLS to co-develop the final compound and collaborate on the marketing of the drug in China. LGLS also announced on Nov., 2010 that NOBEL Ilac has been granted rights to develop and commercialize gemigliptin in Turkey. A New Drug Application (NDA) for gemigliptin in the treatment of type 2 diabetes was submitted to the Korea Food & Drug Administration (KFDA) in July 2011. Then on June 27, 2012, the KFDA has approved the manufacture and distribution of LG Life Sciences’ diabetes treatment, Zemiglo, the main substance of which is gemigliptin. Clinical trials for evaluating the safety and efficacy of gemigliptin in combination with metformin have been completed. # History The NDA for gemigliptin was submitted to KFDA in July, 2011 and it was approved on June 27, 2012. By the end of 2012, gemigliptin will be marketed in Korea as Zemiglo which is the fifth new DPP-4 inhibitor diabetes treatment in the world. # Mechanism of action DPP-4 is a serine protease located on the cell surfaces throughout the body. In plasma, DPP-4 enzyme rapidly inactivates incretins including GLP-1 and GIP which are produced in the intestine depending on the blood glucose level and contribute to the physiological regulation of glucose homeostatis. Active GLP-1 and GIP increase the production and release of insulin by pancreatinc beta cells. GLP-1 also reduces the scretion of glucacon by pancreatic alpha cells, thereby resulting in a decreased hepatic glucose production. However these incretins are rapidly cleaved by DPP-4 and their effects last only for a few minutes. DPP-4 inhibitors block the cleavage of the gliptins and thus lead to an increasee insulin level and a reduced glucagon level in a glucose-dependent way. This results in a decrease of fasting and postprandial glycemia, as well as HbA1c levels.[2] # Preclinical studies Gemigliptin is a competitive, reversible DPP-4 inhibitor (IC50 = 16 nM) with excellent selectivity over other critical human proteases such as DPP-2, DPP-8, DPP-9, elastase, trypsin, urokinase and cathepsin G. Gemigliptin was rapidly absorbed after single oral dosing and the compound was eliminated with a half-life of 3.6 h, 5.2 h, and 5.4 h in the rat, dog, and monkey, respectively. The bioavailability of gemigliptin in the rat, dog, and monkey was species-dependent with the values of 94%, 73%, and 26%, respectively. Following the oral administration of gemigliptin in the rat, dog and monkey, about 80% inhibition of plasma DPP-4 activity were observed at the plasma levels of 18 nM, 14 nM and 4 nM, respectively. In the diet-induced obese (DIO) mice, gemigliptin reduced glucose excursion during OGTT in a dose dependent manner with the minimum effective dose of 0.3 mg/kg and enhanced glucose-stimulated plasma GLP-1 increase in a dose dependent manner reaching the maximum effect at the dose of 1 mg/kg. Following 4 week oral repeat dosing in the DIO mice, gemigliptin reduced significantly HbA1c with the minimum effective dose of 3 mg/kg. In the beagle dog, gemigliptin significantly enhanced active GLP-1, decreased glucagon, and reduced glucose excursion during OGTT following a single dosing. Studies on animals suggest its positive effect on hepatic and renal fibrosis .[3][4] Data on human patients are still inconclusive .[5] # Clinical studies The dose-range finding phase 2 study was performed and 145 patients (91men and 54 women) with type 2 diabetes mellitus were enrolled. All three doses (50,100 and 200 mg groups) of gemigliptin significantly reduced the HbA1c from baseline compared to the placebo group without a significant difference between the doses. Subjects with a higher baseline HbA1c (≥8.5%) had a greater reduction in HbA1c. Insulin secretory function, as assessed using homeostasis model assessment-beta cell, C-peptide and the insulinogenic index, improved significantly with gemigliptin treatment. Insulin sensitivity, as assessed using homeostasis model assessment-insulin resistance, also improved significantly after 12 weeks of treatment. The 50 and 200 mg groups had significantly reduced total cholesterol and low-density lipoprotein cholesterol levels at 12 weeks compared to the placebo group. The incidences of adverse events were similar in all study subjects. Gemigliptin monotherapy (50 mg for 12 weeks) improved the HbA1c, FPG level, oral glucose tolerance test results, β-cell function and insulin sensitivity measures, and was well tolerated in subjects with type 2 diabetes. Results of Phase 3 clinical trials which have been finished recently will be updated near future.	https://www.wikidoc.org/index.php/Gemigliptin
eb37916a9c43f2d073b09be7f89ccd1b6edf1ce0	wikidoc	Gentianales	Gentianales Gentianales are an order of flowering plants, included within the asterid group of dicotyledons. The circumscription of Gentiales in the Cronquist system included a broadly defined Loganiaceae (since broken up into several families), Retziaceae, Gentianaceae, Saccifoliaceae, Apocynaceae, and Asclepiadaceae. The circumscription recognized by the Angiosperm Phylogeny Group (APG) includes Apocynaceae (including Asclepiadaceae), Gelsemiaceae (segregated from Loganiaceae), Gentianaceae (including Saccifoliaceae), Loganiaceae, and Rubiaceae. Under the APG definition some well-known members of Gentianales are coffee, gardenias, and frangipani. APG includes Retziaceae in Stilbaceae (order Lamiales).	Gentianales Gentianales are an order of flowering plants, included within the asterid group of dicotyledons. The circumscription of Gentiales in the Cronquist system included a broadly defined Loganiaceae (since broken up into several families), Retziaceae, Gentianaceae, Saccifoliaceae, Apocynaceae, and Asclepiadaceae. The circumscription recognized by the Angiosperm Phylogeny Group (APG) includes Apocynaceae (including Asclepiadaceae), Gelsemiaceae (segregated from Loganiaceae), Gentianaceae (including Saccifoliaceae), Loganiaceae, and Rubiaceae. Under the APG definition some well-known members of Gentianales are coffee, gardenias, and frangipani. APG includes Retziaceae in Stilbaceae (order Lamiales).	https://www.wikidoc.org/index.php/Gentianales
e4ab3120cf5eebf6b7458e01ad8e77c88e89740f	wikidoc	Genu valgum	Genu valgum # Overview Genu valgum, commonly called "knock-knees", is a condition where the knees angle in and touch one another when the legs are straightened. Individuals with severe valgus deformities are typically unable to touch their feet together while simultaneously straightening the legs. The term originates from the Latin genu, "knee", and valgum, "bowlegged". Mild genu valgum is relatively common in children up to two years of age, and is often corrected naturally as children grow and develop. However, the condition may continue or worsen with age, particularly when it is the result of a disease, such as rickets or obesity. Idiopathic is the term used to describe genu valgum that is congenital or has no known cause. Other systemic conditions may be associated, such as Schnyder Central Corneal Dystrophy, an autosomal dominant condition frequently reported with hyperlipidemia. # Causes ## Life Threatening Causes - Osteochondroma ## Common Causes - Acrocephalopolysyndactyly type 2 - Alves castelo dos santos syndrome - Ampola syndrome - Aromatase deficiency - Chondroectodermal dysplasia - Chromosome 7 - Chromosome 7p duplication syndrome - Cohen syndrome - Down syndrome - Duplication 7p - Ellis-van creveld syndrome - Epiphyseal dysplasia - Fibular hemimelia - Focal fibrocartilaginous dysplasia - Galactosamine-6-sulfatase deficiency - Hereditary multiple exostoses - Metaphyseal chondrodysplasia - Mucopolysaccharidosis type iv - Multiple epiphyseal dysplasia syndrome - Multiple hereditary exostoses - Osteogenesis imperfecta - Oto-facio-osseous-gonadal syndrome - Parastremmatic dwarfism - Pseudoachondroplasia - Wagner syndrome ## Causes by Organ System ## Causes in Alphabetical Order - Acrocephalopolysyndactyly type 2 - Alves castelo dos santos syndrome - Ampola syndrome - Aromatase deficiency - Blounts disease - Chondroectodermal dysplasia - Chromosome 7, trisomy 7q - Chromosome 7q duplication syndrome - Cohen syndrome - Cozen fracture - Distal femoral physeal fracture - Down syndrome - Ellis-van creveld syndrome - Epiphyseal dysplasia - Fibular hemimelia - Focal fibrocartilaginous dysplasia - Galactosamine-6-sulfatase deficiency - Hemophilic arthritis - Hereditary multiple exostoses - Homocystinuria - Hypophosphatemic rickets - Iliotibial band tightness - Injury to growth plates - Limb deficiencies - Mental retardation - Metaphyseal chondrodysplasia - Morquio's disease - Mucopolysaccharidosis type iv - Multiple epiphyseal dysplasia syndrome - Multiple hereditary exostoses - Neurofibromatosis - Obesity - Ollier's disease - Osteoarthritis - Osteochondroma - Osteogenesis imperfecta - Osteomalacia - Osteomyelitis - Osteopetrosis - Oto-facio-osseous-gonadal syndrome - Parastremmatic dwarfism - Physiologic valgus - Proximal tibial physeal fracture - Pseudoachondroplasia - Renal osteodystrophy - Rhematoid arthritis - Rheumatoid disease - Rickets - Sclerosteosis - Spondyloepiphyseal dysplasia tarda - Vitamin c deficiency - Wagner syndrome # Treatment Generally, there is no known cure for knock knees post-childhood. Contrary to common belief, no amount of orthotic treatment or bodybuilding exercise will straighten knock knees for adults. If the condition persists or worsens into late childhood and adulthood, a corrective osteotomy may be recommended to straighten the legs. This however is more of a cosmetic remedy, and may hamper athletic performance in the future. Adults with uncorrected genu valgum are typically prone to injury and chronic knee problems such as chondromalacia and osteoarthritis. In some cases, total knee replacement (TKR) surgery may be required later in life to relieve pain and complications resulting from severe genu valgum. # Diagnostic test The Q angle which is formed by a line drawn from the anterosuperior iliac spine through the center of the patella and a line drawn from the center of the patella to the center of the tibial tubercle, should be measured next. In women, the Q angle should be less than 22 degrees with the knee in extension and less than 9 degrees with the knee in 90 degrees of flexion. In men, the Q angle should be less than 18 degrees with the knee in extension and less than 8 degrees with the knee in 90 degrees of flexion.	Genu valgum Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Cafer Zorkun, M.D., Ph.D. [2] Luke Rusowicz-Orazem, B.S. # Overview Genu valgum, commonly called "knock-knees", is a condition where the knees angle in and touch one another when the legs are straightened. Individuals with severe valgus deformities are typically unable to touch their feet together while simultaneously straightening the legs. The term originates from the Latin genu, "knee", and valgum, "bowlegged".[1] Mild genu valgum is relatively common in children up to two years of age, and is often corrected naturally as children grow and develop. However, the condition may continue or worsen with age, particularly when it is the result of a disease, such as rickets or obesity. Idiopathic is the term used to describe genu valgum that is congenital or has no known cause. Other systemic conditions may be associated, such as Schnyder Central Corneal Dystrophy, an autosomal dominant condition frequently reported with hyperlipidemia. # Causes ## Life Threatening Causes - Osteochondroma ## Common Causes - Acrocephalopolysyndactyly type 2 - Alves castelo dos santos syndrome - Ampola syndrome - Aromatase deficiency - Chondroectodermal dysplasia - Chromosome 7 - Chromosome 7p duplication syndrome - Cohen syndrome - Down syndrome - Duplication 7p - Ellis-van creveld syndrome - Epiphyseal dysplasia - Fibular hemimelia - Focal fibrocartilaginous dysplasia - Galactosamine-6-sulfatase deficiency - Hereditary multiple exostoses - Metaphyseal chondrodysplasia - Mucopolysaccharidosis type iv - Multiple epiphyseal dysplasia syndrome - Multiple hereditary exostoses - Osteogenesis imperfecta - Oto-facio-osseous-gonadal syndrome - Parastremmatic dwarfism - Pseudoachondroplasia - Wagner syndrome ## Causes by Organ System ## Causes in Alphabetical Order - Acrocephalopolysyndactyly type 2 - Alves castelo dos santos syndrome - Ampola syndrome - Aromatase deficiency - Blounts disease - Chondroectodermal dysplasia - Chromosome 7, trisomy 7q - Chromosome 7q duplication syndrome - Cohen syndrome - Cozen fracture - Distal femoral physeal fracture - Down syndrome - Ellis-van creveld syndrome - Epiphyseal dysplasia - Fibular hemimelia - Focal fibrocartilaginous dysplasia - Galactosamine-6-sulfatase deficiency - Hemophilic arthritis - Hereditary multiple exostoses - Homocystinuria - Hypophosphatemic rickets - Iliotibial band tightness - Injury to growth plates - Limb deficiencies - Mental retardation - Metaphyseal chondrodysplasia - Morquio's disease - Mucopolysaccharidosis type iv - Multiple epiphyseal dysplasia syndrome - Multiple hereditary exostoses - Neurofibromatosis - Obesity - Ollier's disease - Osteoarthritis - Osteochondroma - Osteogenesis imperfecta - Osteomalacia - Osteomyelitis - Osteopetrosis - Oto-facio-osseous-gonadal syndrome - Parastremmatic dwarfism - Physiologic valgus - Proximal tibial physeal fracture - Pseudoachondroplasia - Renal osteodystrophy - Rhematoid arthritis - Rheumatoid disease - Rickets - Sclerosteosis - Spondyloepiphyseal dysplasia tarda - Vitamin c deficiency - Wagner syndrome # Treatment Generally, there is no known cure for knock knees post-childhood. Contrary to common belief, no amount of orthotic treatment or bodybuilding exercise will straighten knock knees for adults. If the condition persists or worsens into late childhood and adulthood, a corrective osteotomy may be recommended to straighten the legs. This however is more of a cosmetic remedy, and may hamper athletic performance in the future. Adults with uncorrected genu valgum are typically prone to injury and chronic knee problems such as chondromalacia and osteoarthritis. In some cases, total knee replacement (TKR) surgery may be required later in life to relieve pain and complications resulting from severe genu valgum. # Diagnostic test The Q angle which is formed by a line drawn from the anterosuperior iliac spine through the center of the patella and a line drawn from the center of the patella to the center of the tibial tubercle, should be measured next. In women, the Q angle should be less than 22 degrees with the knee in extension and less than 9 degrees with the knee in 90 degrees of flexion. In men, the Q angle should be less than 18 degrees with the knee in extension and less than 8 degrees with the knee in 90 degrees of flexion.	https://www.wikidoc.org/index.php/Genu_valgum
db69ccf76974e88ffcac4bab1f8d8258ee7b0159	wikidoc	Germination	Germination Germination is the process whereby growth emerges from a period of dormancy. The most common example of germination is the sprouting of a seedling from a seed of an angiosperm or gymnosperm. However, the growth of a sporeling from a spore, for example the growth of hyphae from fungal spores, is also germination. In a more general sense, germination can imply anything expanding into greater being from a small existence or germ. # Seed germination Germination is the growth of an embryonic plant contained within a seed, it results in the formation of the seedling. The seed of a higher plant is a small package produced in a fruit or cone after the union of male and female sex cells. Most seeds go through a period of quiescences where there is no active growth, during this time the seed can be safely transported to a new location and/or survive adverse climate conditions until it is favorable for growth. The seed contains an embryo and in most plants stored food reserves wrapped in a seed coat. Under favorable conditions, the seed begins to germinate, and the embryonic tissues resume growth, developing towards a seedling. ## Requirements for seed germination The germination of seeds is dependent on both internal and external conditions. The most important external factors include: temperature, water, oxygen and sometimes light or darkness. Often different varieties of seeds require distinctive variables for successful germination; some seeds germinate while the soil is cold, while most germinate while the soil is warm. This depends on the individual seed variety and is closely linked to the ecological conditions of the plants' natural habitat. - Water - is required for germination. Mature seeds are often extremely dry and need to take in significant amounts of water, relative to the seeds dry weight, before cellular metabolism and growth can resume. Most seeds respond best when there is enough water to moisten the seeds but not soak them. The uptake of water by seeds is called imbibition which leads to the swelling and the breaking of the seed coat. When seeds are formed, most plants store food, such as starch, proteins, or oils, to provide nourishment to the growing embryo inside the seed. When the seed imbibes water, hydrolytic enzymes are activated that break down these stored food resources in to metabolically useful chemicals, allowing the cells of the embryo to divide and grow, so the seedling can emerge from the seed. Once the seedling starts growing and the food reserves are exhausted, it requires a continuous supply of water, nutrients and light for photosynthesis, which now provides the energy needed for continued growth. - Oxygen - is required by the germinating seed for metabolism: If the soil is waterlogged or the seed is buried within the soil, it might be cut off from the necessary oxygen it needs. Oxygen is used in aerobic respiration, the main source of the seedling's energy until it has leaves, which can photosynthesize its energy requirements. Some seeds have impermeable seed coats that prevent oxygen from entering the seeds, causing seed dormancy. Impermeable seed coats to oxygen or water, are types of physical dormancy which is broken when the seed coat is worn away enough to allow gas exchange or water uptake between the seed and its surrounds. - Temperature - affects cellular metabolic and growth rates. Different seeds germinate over a wide range of temperatures, with many preferring temperatures slightly higher than room-temperature while others germinate just above freezing and others responding to alternation in temperature between warm to cool. Often, seeds have a set of temperature ranges where they will germinate and will not do so above or below this range. In addition, some seeds may require exposure to cold temperature (vernalization) to break dormancy before they can germinate. As long as the seed is in its dormant state, it will not germinate even if conditions are favorable. Seeds that are dependent on temperature to end dormancy, have a type of physiological dormancy. For example, seeds requiring the cold of winter are inhibited from germinating until they experience cooler temperatures. For most seeds that require cold for germination 4C is cool enough to end dormancy, but some groups especially with in the family Ranunculaceae and others, need less than -5C. Some seeds will only germinate when temperatures reach hundreds of degrees, as during a forest fire. Without fire, they are unable to crack their seed coats, this is a type of physical dormancy. - Light or darkness - can be a type of environmental trigger for germination in seeds and is a type of physiological dormancy. Most seeds are not affected by light or darkness, but many seeds, including species found in forest settings will not germinate until an opening in the canopy allows them to receive sufficient light for the growing seedling. Stratification mimics natural processes that weaken the seed coat before germination. In nature, some seeds require particular conditions to germinate, such as the heat of a fire (e.g., many Australian native plants), or soaking in a body of water for a long period of time. Others have to be passed through an animal's digestive tract to weaken the seed coat and enable germination. ## Dormancy Many live seeds have dormancy, meaning they will not germinate even if they have water and it is warm enough for the seedling to grow. Dormancy factors include conditions affecting many different parts of the seed, from the embryo to the seed coat. Dormancy is broken or ended by a number of different conditions and cues both internal and external to the seed. Environmental factors like light, temperature, fire, ingestion by animals and others are conditions that can end seed dormancy. Internally seeds can be dormant because of plant hormones such as absciscic acid, which affects seed dormancy and prevents germination, while the production and application of the hormone gibberellin can break dormancy and induces seed germination. This effect is used in brewing where barley is treated with gibberellin to ensure uniform seed germination to produce barley malt. ## Seedling establishment In some definitions, the appearance of the radicle marks the end of germination and the beginning of "establishment", a period that ends when the seedling has exhausted the food reserves stored in the seed. Germination and establishment as an independent organism are critical phases in the life of a plant when they are the most vulnerable to injury, disease, and water stress. The germination index can be used as an indicator of phytotoxicity in soils. The mortality between dispersal of seeds and completion of establishment can be so high, that many species survive only by producing huge numbers of seeds. # Germination rate In agriculture and gardening, germination rate is the number of seeds of a particular plant species, variety or particular seedlot that are likely to germinate. This is usually expressed as a percentage, e.g. an 85% germination rate indicates that about 85 out of 100 seeds will probably germinate under proper conditions. Germination rate is useful in calculating seed requirements for a given area or desired number of plants. ## Dicot germination The part of the plant that emerges from the seed first is the embryonic root, termed radicle or primary root. This allows the seedling to become anchored in the ground and start absorbing water. After the root absorbs water, the embryonic shoot emerges from the seed. The shoot comprises three main parts: the cotyledons (seed leaves), the section of shoot below the cotyledons (hypocotyl), and the section of shoot above the cotyledons (epicotyl). The way the shoot emerges differs between plant groups. ### Epigeous In epigeous (or epigeal) germination, the hypocotyl elongates and forms a hook, pulling rather than pushing the cotyledons and apical meristem through the soil. Once it reaches the surface, it straightens and pulls the cotyledons and shoot tip of the growing seedlings into the air. Beans, tamarind, and papaya are examples of plant that germinate this way. ### Hypogeous Another way of germination is hypogeous (or hypogeal) where the epicotyl elongates and forms the hook. In this type of germination, the cotyledons stay underground where they eventually decompose. Peas, for example, germinate this way. ## Monocot germination In monocot seeds, the embryo's radicle and cotyledon are covered by a coleorhiza and coleoptile, respectively. The coleorhiza is the first part to grow out of the seed, followed by the radicle. The coleoptile is then pushed up through the ground until it reaches the surface. There, it stops elongating and the first leaves emerge through an opening as it is. ## Precocious germination While not a class of germination, this refers to germination of the seed occurring inside the fruit before it has begun to decay. The seeds of the green apple commonly germinate in this manner. # Pollen germination Another germination event during the life cycle of gymnosperms and flowering plants is the germination of a pollen grain after pollination. Like seeds, pollen grains are severely dehydrated before being released to facilitate their dispersal from one plant to another. They consist of a protective coat containing several cells (up to 8 in gymnosperms, 2-3 in flowering plants). One of these cells is a tube cell. Once the pollen grain lands on the stigma of a receptive flower (or a female cone in gymnosperms), it takes up water and germinates. Pollen germination is facilitated by hydration on the stigma, as well as the structure and physiology of the stigma and style. Pollen can also be induced to germinate in vitro (in a petri dish or test tube). During germination, the tube cell elongates into a pollen tube. In the flower, the pollen tube then grows towards the ovule where it discharges the sperm produced in the pollen grain for fertilization. The germinated pollen grain with its two sperm cells is the mature male microgametophyte of these plants. ## Self-incompatibility Since most plants carry both male and female reproductive organs in their flowers, there is a high risk for self-pollination and thus inbreeding. Some plants use the control of pollen germination as a way to prevent this selfing. Germination and growth of the pollen tube involve molecular signaling between stigma and pollen. In self-incompatibility in plants, the stigma of certain plants can molecularly recognize pollen from the same plant and prevents it from germinating. # Spore germination Germination can also refer to the emergence of cells from resting spores and the growth of sporeling hyphae or thalli from spores in fungi, algae, and some plants. ## Resting spores In resting spores, germination involves cracking the thick cell wall of the dormant spore. For example, in zygomycetes the thick-walled zygosporangium cracks open and the zygospore inside gives rise to the emerging sporangiophore. In slime molds, germination refers to the emergence of amoeboid cells from the hardened spore. After cracking the spore coat, further development involves cell division, but not necessarily the development of a multicellular organism (for example in the free-living amoebas of slime molds). ## Zoospores In motile zoospores, germination frequently means a lack of motility and changes in cell shape, which allow the organism to become sessile. ## Ferns and mosses In plants such as bryophytes, ferns, and a few others, spores germinate into independent gametophytes. In the bryophytes (e.g. mosses and liverworts), spores germinate into protonemata, similar to fungal hyphae, from which the gametophyte grows. In ferns, the gametophytes are small, heart-shaped prothalli that can often be found underneath a spore-shedding adult plant.	Germination Template:Distinguish2 Germination is the process whereby growth emerges from a period of dormancy. The most common example of germination is the sprouting of a seedling from a seed of an angiosperm or gymnosperm. However, the growth of a sporeling from a spore, for example the growth of hyphae from fungal spores, is also germination. In a more general sense, germination can imply anything expanding into greater being from a small existence or germ. # Seed germination Germination is the growth of an embryonic plant contained within a seed, it results in the formation of the seedling. The seed of a higher plant is a small package produced in a fruit or cone after the union of male and female sex cells. Most seeds go through a period of quiescences where there is no active growth, during this time the seed can be safely transported to a new location and/or survive adverse climate conditions until it is favorable for growth. The seed contains an embryo and in most plants stored food reserves wrapped in a seed coat. Under favorable conditions, the seed begins to germinate, and the embryonic tissues resume growth, developing towards a seedling. ## Requirements for seed germination The germination of seeds is dependent on both internal and external conditions. The most important external factors include: temperature, water, oxygen and sometimes light or darkness.[1] Often different varieties of seeds require distinctive variables for successful germination; some seeds germinate while the soil is cold, while most germinate while the soil is warm. This depends on the individual seed variety and is closely linked to the ecological conditions of the plants' natural habitat. - Water - is required for germination. Mature seeds are often extremely dry and need to take in significant amounts of water, relative to the seeds dry weight, before cellular metabolism and growth can resume. Most seeds respond best when there is enough water to moisten the seeds but not soak them. The uptake of water by seeds is called imbibition which leads to the swelling and the breaking of the seed coat. When seeds are formed, most plants store food, such as starch, proteins, or oils, to provide nourishment to the growing embryo inside the seed. When the seed imbibes water, hydrolytic enzymes are activated that break down these stored food resources in to metabolically useful chemicals, allowing the cells of the embryo to divide and grow, so the seedling can emerge from the seed.[1] Once the seedling starts growing and the food reserves are exhausted, it requires a continuous supply of water, nutrients and light for photosynthesis, which now provides the energy needed for continued growth. - Oxygen - is required by the germinating seed for metabolism:[2] If the soil is waterlogged or the seed is buried within the soil, it might be cut off from the necessary oxygen it needs. Oxygen is used in aerobic respiration, the main source of the seedling's energy until it has leaves, which can photosynthesize its energy requirements.[1] Some seeds have impermeable seed coats that prevent oxygen from entering the seeds, causing seed dormancy. Impermeable seed coats to oxygen or water, are types of physical dormancy which is broken when the seed coat is worn away enough to allow gas exchange or water uptake between the seed and its surrounds. - Temperature - affects cellular metabolic and growth rates. Different seeds germinate over a wide range of temperatures, with many preferring temperatures slightly higher than room-temperature while others germinate just above freezing and others responding to alternation in temperature between warm to cool. Often, seeds have a set of temperature ranges where they will germinate and will not do so above or below this range. In addition, some seeds may require exposure to cold temperature (vernalization) to break dormancy before they can germinate. As long as the seed is in its dormant state, it will not germinate even if conditions are favorable. Seeds that are dependent on temperature to end dormancy, have a type of physiological dormancy. For example, seeds requiring the cold of winter are inhibited from germinating until they experience cooler temperatures. For most seeds that require cold for germination 4C is cool enough to end dormancy, but some groups especially with in the family Ranunculaceae and others, need less than -5C. Some seeds will only germinate when temperatures reach hundreds of degrees, as during a forest fire. Without fire, they are unable to crack their seed coats, this is a type of physical dormancy. - Light or darkness - can be a type of environmental trigger for germination in seeds and is a type of physiological dormancy. Most seeds are not affected by light or darkness, but many seeds, including species found in forest settings will not germinate until an opening in the canopy allows them to receive sufficient light for the growing seedling.[1] Stratification mimics natural processes that weaken the seed coat before germination. In nature, some seeds require particular conditions to germinate, such as the heat of a fire (e.g., many Australian native plants), or soaking in a body of water for a long period of time. Others have to be passed through an animal's digestive tract to weaken the seed coat and enable germination.[1] ## Dormancy Many live seeds have dormancy, meaning they will not germinate even if they have water and it is warm enough for the seedling to grow. Dormancy factors include conditions affecting many different parts of the seed, from the embryo to the seed coat. Dormancy is broken or ended by a number of different conditions and cues both internal and external to the seed. Environmental factors like light, temperature, fire, ingestion by animals and others are conditions that can end seed dormancy. Internally seeds can be dormant because of plant hormones such as absciscic acid, which affects seed dormancy and prevents germination, while the production and application of the hormone gibberellin can break dormancy and induces seed germination. This effect is used in brewing where barley is treated with gibberellin to ensure uniform seed germination to produce barley malt.[1] ## Seedling establishment In some definitions, the appearance of the radicle marks the end of germination and the beginning of "establishment", a period that ends when the seedling has exhausted the food reserves stored in the seed. Germination and establishment as an independent organism are critical phases in the life of a plant when they are the most vulnerable to injury, disease, and water stress.[1] The germination index can be used as an indicator of phytotoxicity in soils. The mortality between dispersal of seeds and completion of establishment can be so high, that many species survive only by producing huge numbers of seeds. # Germination rate In agriculture and gardening, germination rate is the number of seeds of a particular plant species, variety or particular seedlot that are likely to germinate. This is usually expressed as a percentage, e.g. an 85% germination rate indicates that about 85 out of 100 seeds will probably germinate under proper conditions. Germination rate is useful in calculating seed requirements for a given area or desired number of plants. ## Dicot germination The part of the plant that emerges from the seed first is the embryonic root, termed radicle or primary root. This allows the seedling to become anchored in the ground and start absorbing water. After the root absorbs water, the embryonic shoot emerges from the seed. The shoot comprises three main parts: the cotyledons (seed leaves), the section of shoot below the cotyledons (hypocotyl), and the section of shoot above the cotyledons (epicotyl). The way the shoot emerges differs between plant groups.[1] ### Epigeous In epigeous (or epigeal) germination, the hypocotyl elongates and forms a hook, pulling rather than pushing the cotyledons and apical meristem through the soil. Once it reaches the surface, it straightens and pulls the cotyledons and shoot tip of the growing seedlings into the air. Beans, tamarind, and papaya are examples of plant that germinate this way.[1] ### Hypogeous Another way of germination is hypogeous (or hypogeal) where the epicotyl elongates and forms the hook. In this type of germination, the cotyledons stay underground where they eventually decompose. Peas, for example, germinate this way.[1] ## Monocot germination In monocot seeds, the embryo's radicle and cotyledon are covered by a coleorhiza and coleoptile, respectively. The coleorhiza is the first part to grow out of the seed, followed by the radicle. The coleoptile is then pushed up through the ground until it reaches the surface. There, it stops elongating and the first leaves emerge through an opening as it is.[1] ## Precocious germination While not a class of germination, this refers to germination of the seed occurring inside the fruit before it has begun to decay. The seeds of the green apple commonly germinate in this manner.[citation needed] # Pollen germination Another germination event during the life cycle of gymnosperms and flowering plants is the germination of a pollen grain after pollination. Like seeds, pollen grains are severely dehydrated before being released to facilitate their dispersal from one plant to another. They consist of a protective coat containing several cells (up to 8 in gymnosperms, 2-3 in flowering plants). One of these cells is a tube cell. Once the pollen grain lands on the stigma of a receptive flower (or a female cone in gymnosperms), it takes up water and germinates. Pollen germination is facilitated by hydration on the stigma, as well as the structure and physiology of the stigma and style.[1] Pollen can also be induced to germinate in vitro (in a petri dish or test tube).[3][4] During germination, the tube cell elongates into a pollen tube. In the flower, the pollen tube then grows towards the ovule where it discharges the sperm produced in the pollen grain for fertilization. The germinated pollen grain with its two sperm cells is the mature male microgametophyte of these plants.[1] ## Self-incompatibility Since most plants carry both male and female reproductive organs in their flowers, there is a high risk for self-pollination and thus inbreeding. Some plants use the control of pollen germination as a way to prevent this selfing. Germination and growth of the pollen tube involve molecular signaling between stigma and pollen. In self-incompatibility in plants, the stigma of certain plants can molecularly recognize pollen from the same plant and prevents it from germinating.[5] # Spore germination Germination can also refer to the emergence of cells from resting spores and the growth of sporeling hyphae or thalli from spores in fungi, algae, and some plants. ## Resting spores In resting spores, germination involves cracking the thick cell wall of the dormant spore. For example, in zygomycetes the thick-walled zygosporangium cracks open and the zygospore inside gives rise to the emerging sporangiophore. In slime molds, germination refers to the emergence of amoeboid cells from the hardened spore. After cracking the spore coat, further development involves cell division, but not necessarily the development of a multicellular organism (for example in the free-living amoebas of slime molds).[1] ## Zoospores In motile zoospores, germination frequently means a lack of motility and changes in cell shape, which allow the organism to become sessile.[1] ## Ferns and mosses In plants such as bryophytes, ferns, and a few others, spores germinate into independent gametophytes. In the bryophytes (e.g. mosses and liverworts), spores germinate into protonemata, similar to fungal hyphae, from which the gametophyte grows. In ferns, the gametophytes are small, heart-shaped prothalli that can often be found underneath a spore-shedding adult plant.[1]	https://www.wikidoc.org/index.php/Germination
6220d28036030efda8a06c041d3fd460559bf919	wikidoc	Hinge joint	Hinge joint # Overview In the hinge joint (ginglymus), the articular surfaces are moulded to each other in such a manner as to permit motion only in one plane, forward and backward, the extent of motion at the same time being considerable. The direction which the distal bone takes in this motion is seldom in the same plane as that of the axis of the proximal bone; there is usually a certain amount of deviation from the straight line during flexion. The articular surfaces are connected together by weak collateral ligaments, which form their chief bond of union. The best examples of ginglymus are the interphalangeal joints and the joint between the humerus and ulna; the knee- and ankle-joints are less typical, as they allow a slight degree of rotation or of side-to-side movement in certain positions of the limb.	Hinge joint Template:Infobox Anatomy # Overview In the hinge joint (ginglymus), the articular surfaces are moulded to each other in such a manner as to permit motion only in one plane, forward and backward, the extent of motion at the same time being considerable. The direction which the distal bone takes in this motion is seldom in the same plane as that of the axis of the proximal bone; there is usually a certain amount of deviation from the straight line during flexion. The articular surfaces are connected together by weak collateral ligaments, which form their chief bond of union. The best examples of ginglymus are the interphalangeal joints and the joint between the humerus and ulna; the knee- and ankle-joints are less typical, as they allow a slight degree of rotation or of side-to-side movement in certain positions of the limb.	https://www.wikidoc.org/index.php/Ginglymus
96c2a95cdbb6c8c4cd21a2948ce76503915dd483	wikidoc	Glucosamine	Glucosamine # Overview Glucosamine (C6H13NO5) is an amino sugar and a prominent precursor in the biochemical synthesis of glycosylated proteins and lipids. Glucosamine is found as a major component of the exoskeletons of crustaceans and other arthropods, in fungi and many higher organisms and is one of the most abundant monosaccharides. It is produced commercially by the hydrolysis of crustacean exoskeletons. Glucosamine is commonly used as a treatment for osteoarthritis, although its acceptance as a medical therapy varies. # Biochemistry Glucosamine was first identified in 1876 by G. Ledderhose, but the stereochemistry was not fully defined until 1939 by the work of Walter Haworth. D-Glucosamine is made naturally in the form of glucosamine-6-phosphate, and is the biochemical precursor of all nitrogen-containing sugars. Specifically, glucosamine-6-phosphate is synthesized from fructose-6-phosphate and glutamine as the first step of the hexosamine biosynthesis pathway. The end-product of this pathway is UDP-N-acetylglucosamine, which is then used for making glycosaminoglycans, proteoglycans, and glycolipids. As the formation of glucosamine-6-phosphate is the first step for the synthesis of these products, glucosamine may be important in regulating their production. However, the way that the hexosamine biosynthesis pathway is actually regulated, and whether this could be involved in contributing to human disease, remains unclear. # Health effects Oral glucosamine is commonly used for the treatment of osteoarthritis. Since glucosamine is a precursor for glycosaminoglycans, and glycosaminoglycans are a major component of joint cartilage, supplemental glucosamine may help to rebuild cartilage and treat arthritis. Its use as a therapy for osteoarthritis appears safe, but there is conflicting evidence as to its effectiveness. ### Use A typical dosage of glucosamine salt is 1,500 mg per day. Glucosamine contains an amino group that is positively charged at physiological pH. The anion included in the salt may vary. Commonly sold forms of glucosamine are glucosamine sulphate and glucosamine hydrochloride. The amount of glucosamine present in 1500 mg of glucosamine salt will depend on which anion is present and whether additional salts are included in the manufacturer's calculation. Glucosamine is often sold in combination with other supplements such as chondroitin sulfate and methylsulfonylmethane. Glucosamine is a popular alternative medicine used by consumers for the treatment of osteoarthritis. Glucosamine is also extensively used in veterinary medicine as an unregulated but widely accepted supplement. ### Safety Clinical studies have consistently reported that glucosamine appears safe. Since glucosamine is usually derived from shellfish, those allergic to shellfish or who have kosher concerns may wish to avoid it. However, since glucosamine is derived from the shells of these animals while the allergen is within the flesh of the animals, it is probably safe even for those with shellfish allergy. Alternative sources using fungal fermentation of corn are available. Another concern has been that the extra glucosamine could contribute to diabetes by interfering with the normal regulation of the hexosamine biosynthesis pathway, but several investigations have found no evidence that this occurs. The U.S. National Institutes of Health is currently conducting a study of supplemental glucosamine in obese patients, since this population may be particularly sensitive to any effects of glucosamine on insulin resistance. In the United States, glucosamine is not approved by the Food and Drug Administration for medical use in humans. Since glucosamine is classified as a dietary supplement, safety and formulation are solely the responsibility of the manufacturer; evidence of safety and efficacy is not required as long as it is not advertised as a treatment for a medical condition. In Europe, glucosamine is approved as a medical drug and is sold in the form of glucosamine sulphate. ### Clinical studies There have been multiple clinical trials of glucosamine as a medical therapy for osteoarthritis, but results have been conflicting. The evidence both for and against glucosamine's efficacy has led to debate among physicians about whether to recommend glucosamine treatment to their patients. Multiple clinical trials in the 1980s and 1990s, all sponsored by the European patent-holder, Rottapharm, demonstrated a benefit for glucosamine. However, these studies were of poor quality due to shortcomings in their methods, including small size, short duration, poor analysis of drop-outs, and unclear procedures for blinding. Rottapharm then sponsored two large (at least 100 patients per group), three-year-long, placebo-controlled clinical trials of the Rottapharm brand of glucosamine sulfate. These studies both demonstrated a clear benefit for glucosamine treatment. There was not only an improvement in symptoms but also an improvement in joint space narrowing on radiographs. This suggested that glucosamine, unlike pain relievers such as NSAIDs, can actually help prevent the destruction of cartilage that is the hallmark of osteoarthritis. On the other hand, several subsequent studies, independent of Rottapharm, but smaller and shorter, did not detect any benefit of glucosamine. This situation led the National Institutes of Health to fund a large, multicenter clinical trial studying reported pain in osteoarthritis of the knee, comparing groups treated with chondroitin sulfate, glucosamine, and the combination, as well as both placebo and celecoxib. The results of this 6-month trial found that patients taking glucosamine HCl, chondroitin sulfate, or a combination of the two had no statistically significant improvement in their symptoms compared to patients taking a placebo. The group of patients who took celecoxib did have a statistically significant improvement in their symptoms. These results suggest that glucosamine and chondroitin did not effectively relieve pain in the overall group of osteoarthritis patients. However, exploratory analysis of a subgroup of patients suggested that the supplements may be effective in patients with pain classified as moderate to severe (see testing hypotheses suggested by the data). In an accompanying editorial, Dr. Marc Hochberg also noted that "It is disappointing that the GAIT investigators did not use glucosamine sulfate ... since the results would then have provided important information that might have explained in part the heterogeneity in the studies reviewed by Towheed and colleagues" But this concern is not shared by pharmacologists at the PDR who state, "The counter anion of the glucosamine salt (i.e. chloride or sulfate) is unlikely to play any role in the action or pharmacokinetics of glucosamine". Thus the question of glucosamine's efficacy will not be resolved without further updates or trials. A subsequent meta-analysis of randomized controlled trials, including the NIH trial by Clegg, concluded that hydrochloride is not effective and that there was too much heterogeneity among trials of glucosamine sulfate to draw a conclusion.	Glucosamine Template:Chembox new Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview Glucosamine (C6H13NO5) is an amino sugar and a prominent precursor in the biochemical synthesis of glycosylated proteins and lipids. Glucosamine is found as a major component of the exoskeletons of crustaceans and other arthropods, in fungi and many higher organisms and is one of the most abundant monosaccharides[1]. It is produced commercially by the hydrolysis of crustacean exoskeletons. Glucosamine is commonly used as a treatment for osteoarthritis, although its acceptance as a medical therapy varies. # Biochemistry Glucosamine was first identified in 1876 by G. Ledderhose, but the stereochemistry was not fully defined until 1939 by the work of Walter Haworth.[1] D-Glucosamine is made naturally in the form of glucosamine-6-phosphate, and is the biochemical precursor of all nitrogen-containing sugars.[2] Specifically, glucosamine-6-phosphate is synthesized from fructose-6-phosphate and glutamine[3] as the first step of the hexosamine biosynthesis pathway.[4] The end-product of this pathway is UDP-N-acetylglucosamine, which is then used for making glycosaminoglycans, proteoglycans, and glycolipids. As the formation of glucosamine-6-phosphate is the first step for the synthesis of these products, glucosamine may be important in regulating their production. However, the way that the hexosamine biosynthesis pathway is actually regulated, and whether this could be involved in contributing to human disease, remains unclear.[5] # Health effects Oral glucosamine is commonly used for the treatment of osteoarthritis. Since glucosamine is a precursor for glycosaminoglycans, and glycosaminoglycans are a major component of joint cartilage, supplemental glucosamine may help to rebuild cartilage and treat arthritis. Its use as a therapy for osteoarthritis appears safe, but there is conflicting evidence as to its effectiveness.[6][7] ### Use A typical dosage of glucosamine salt is 1,500 mg per day. Glucosamine contains an amino group that is positively charged at physiological pH. The anion included in the salt may vary. Commonly sold forms of glucosamine are glucosamine sulphate and glucosamine hydrochloride. The amount of glucosamine present in 1500 mg of glucosamine salt will depend on which anion is present and whether additional salts are included in the manufacturer's calculation.[8] Glucosamine is often sold in combination with other supplements such as chondroitin sulfate and methylsulfonylmethane. Glucosamine is a popular alternative medicine used by consumers for the treatment of osteoarthritis. Glucosamine is also extensively used in veterinary medicine as an unregulated but widely accepted supplement.[9] ### Safety Clinical studies have consistently reported that glucosamine appears safe. Since glucosamine is usually derived from shellfish, those allergic to shellfish or who have kosher concerns may wish to avoid it. However, since glucosamine is derived from the shells of these animals while the allergen is within the flesh of the animals, it is probably safe even for those with shellfish allergy.[10] Alternative sources using fungal fermentation of corn are available. Another concern has been that the extra glucosamine could contribute to diabetes by interfering with the normal regulation of the hexosamine biosynthesis pathway,[5] but several investigations have found no evidence that this occurs.[11] The U.S. National Institutes of Health is currently conducting a study of supplemental glucosamine in obese patients, since this population may be particularly sensitive to any effects of glucosamine on insulin resistance.[12] In the United States, glucosamine is not approved by the Food and Drug Administration for medical use in humans. Since glucosamine is classified as a dietary supplement, safety and formulation are solely the responsibility of the manufacturer; evidence of safety and efficacy is not required as long as it is not advertised as a treatment for a medical condition.[13] In Europe, glucosamine is approved as a medical drug and is sold in the form of glucosamine sulphate. ### Clinical studies There have been multiple clinical trials of glucosamine as a medical therapy for osteoarthritis, but results have been conflicting. The evidence both for and against glucosamine's efficacy has led to debate among physicians about whether to recommend glucosamine treatment to their patients.[14] Multiple clinical trials in the 1980s and 1990s, all sponsored by the European patent-holder, Rottapharm, demonstrated a benefit for glucosamine. However, these studies were of poor quality due to shortcomings in their methods, including small size, short duration, poor analysis of drop-outs, and unclear procedures for blinding.[15][16] Rottapharm then sponsored two large (at least 100 patients per group), three-year-long, placebo-controlled clinical trials of the Rottapharm brand of glucosamine sulfate. These studies both demonstrated a clear benefit for glucosamine treatment.[17][18] There was not only an improvement in symptoms but also an improvement in joint space narrowing on radiographs. This suggested that glucosamine, unlike pain relievers such as NSAIDs, can actually help prevent the destruction of cartilage that is the hallmark of osteoarthritis. On the other hand, several subsequent studies, independent of Rottapharm, but smaller and shorter, did not detect any benefit of glucosamine.[19][20] This situation led the National Institutes of Health to fund a large, multicenter clinical trial studying reported pain in osteoarthritis of the knee, comparing groups treated with chondroitin sulfate, glucosamine, and the combination, as well as both placebo and celecoxib.[21] The results of this 6-month trial found that patients taking glucosamine HCl, chondroitin sulfate, or a combination of the two had no statistically significant improvement in their symptoms compared to patients taking a placebo.[22] The group of patients who took celecoxib did have a statistically significant improvement in their symptoms. These results suggest that glucosamine and chondroitin did not effectively relieve pain in the overall group of osteoarthritis patients. However, exploratory analysis of a subgroup of patients suggested that the supplements may be effective in patients with pain classified as moderate to severe (see testing hypotheses suggested by the data). In an accompanying editorial, Dr. Marc Hochberg also noted that "It is disappointing that the GAIT investigators did not use glucosamine sulfate ... since the results would then have provided important information that might have explained in part the heterogeneity in the studies reviewed by Towheed and colleagues[PMID 15846645]"[23] But this concern is not shared by pharmacologists at the PDR who state, "The counter anion of the glucosamine salt (i.e. chloride or sulfate) is unlikely to play any role in the action or pharmacokinetics of glucosamine".[24] Thus the question of glucosamine's efficacy will not be resolved without further updates or trials. A subsequent meta-analysis of randomized controlled trials, including the NIH trial by Clegg, concluded that hydrochloride is not effective and that there was too much heterogeneity among trials of glucosamine sulfate to draw a conclusion.[25]	https://www.wikidoc.org/index.php/Glucosamine
c70ca1bd5490babba34451856347604979e909d2	wikidoc	Mitiglinide	Mitiglinide # Overview Mitiglinide (INN, trade name Glufast) is a drug for the treatment of type 2 diabetes. Mitiglinide belongs to the meglitinide class of blood glucose-lowering drugs and is currently co-marketed in Japan by Kissei and Takeda. The North America rights to mitiglinide are held by Elixir Pharmaceuticals. Mitiglinide has not yet gained FDA approval. # Pharmacology Mitiglinide is thought to stimulate insulin secretion by closing the ATP-sensitive K(+) K(ATP) channels in pancreatic beta-cells. # Dosage Mitiglinide is delivered in tablet form.	Mitiglinide Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview Mitiglinide (INN, trade name Glufast) is a drug for the treatment of type 2 diabetes.[1] Mitiglinide belongs to the meglitinide class of blood glucose-lowering drugs and is currently co-marketed in Japan by Kissei and Takeda. The North America rights to mitiglinide are held by Elixir Pharmaceuticals. Mitiglinide has not yet gained FDA approval. # Pharmacology Mitiglinide is thought to stimulate insulin secretion by closing the ATP-sensitive K(+) K(ATP) channels in pancreatic beta-cells. # Dosage Mitiglinide is delivered in tablet form.	https://www.wikidoc.org/index.php/Glufast
dd34cb4f70ca56bda3eb67a61b628bb6a944dc8c	wikidoc	Glutaminase	Glutaminase Glutaminase (EC 3.5.1.2, glutaminase I, L-glutaminase, glutamine aminohydrolase) is an amidohydrolase enzyme that generates glutamate from glutamine. Glutaminase has tissue-specific isoenzymes. Glutaminase has an important role in glial cells. Glutaminase catalyzes the following reaction: Glutamine + H2O → glutamate + NH3 # Tissue distribution Glutaminase is expressed and active in periportal hepatocytes, where it generates NH3 (ammonia) for urea synthesis, as does glutamate dehydrogenase. Glutaminase is also expressed in the epithelial cells of the renal tubules, where the produced ammonia is excreted as ammonium ions. This excretion of ammonium ions is an important mechanism of renal acid-base regulation. During chronic acidosis, glutaminase is induced in the kidney, which leads to an increase in the amount of ammonium ions excreted. Glutaminase can also be found in the intestines, whereby hepatic portal ammonia can reach as high as 0.26 mM (compared to an arterial blood ammonia of 0.02 mM). One of the most important roles of glutaminase is found in the axonal terminals of neurons in the central nervous system. Glutamate is the most abundantly used excitatory neurotransmitter in the CNS. After being released into the synapse for neurotransmission, glutamate is rapidly taken up by nearby astrocytes, which convert it to glutamine. This glutamine is then supplied to the presynaptic terminals of the neurons, where glutaminases convert it back to glutamate for loading into synaptic vesicles. Although both "kidney-type" (GLS1) and "liver-type" (GLS2) glutaminases are expressed in brain, GLS2 has been reported to exist only in cellular nuclei in CNS neurons. # Regulation ADP is the strongest adenine nucleotide activator of glutaminase. Studies have also suggested ADP lowered the K(m) for glutamine and increased the V(max). They found that these effects were increased even more when ATP was present. Phosphate-activated mitochondrial glutaminase (GLS1) is suggested to be linked with elevated metabolism, decreased intracellular reactive oxygen species (ROS) levels, and overall decreased DNA oxidation in both normal and stressed cells. It is suggested that GLS1’s control of ROS levels facilitates “the ability of p53 to protect cells from accumulation of genomic damage and allows cells to survive after mild and repairable genotoxic stress.” # Structure The structure of glutaminase has been determined using X-ray diffraction to a resolution of up to 1.73 Å. There are 2 chains containing 305 residues that make up the length of this dimeric protein. On each strand, 23% of the amino acid content, or 71 residues, are found in the 8 helices. Twenty-one percent, or 95 residues, make up the 23 beta sheet strands. # Isozymes Humans express 4 isoforms of glutaminase. GLS1 encodes 2 types of kidney-type glutaminase with a high activity and low Km. GLS2 encodes 2 forms of liver-type glutaminase with a low activity and allosteric regulation. # Related proteins Glutaminases belong to a larger family that includes serine-dependent beta-lactamases and penicillin-binding proteins. Many bacteria have two isozymes. This model is based on selected known glutaminases and their homologs within prokaryotes, with the exclusion of highly derived (long-branch) and architecturally varied homologs, so as to achieve conservative assignments. A sharp drop in scores occurs below 250, and cutoffs are set accordingly. The enzyme converts glutamine to glutamate, with the release of ammonia. Members tend to be described as glutaminase A (glsA), where B (glsB) is unknown and may not be homologous (as in Rhizobium etli; some species have two isozymes that may both be designated A (GlsA1 and GlsA2). # Clinical significance Many cancers rely on glutaminase thus glutaminase inhibitors have been proposed as a cancer treatment. As of July 2018 some glutaminase inhibitors are in mid-stage clinical trials.	Glutaminase Glutaminase (EC 3.5.1.2, glutaminase I, L-glutaminase, glutamine aminohydrolase) is an amidohydrolase enzyme that generates glutamate from glutamine. Glutaminase has tissue-specific isoenzymes. Glutaminase has an important role in glial cells. Glutaminase catalyzes the following reaction: Glutamine + H2O → glutamate + NH3 # Tissue distribution Glutaminase is expressed and active in periportal hepatocytes, where it generates NH3 (ammonia) for urea synthesis, as does glutamate dehydrogenase.[2] Glutaminase is also expressed in the epithelial cells of the renal tubules, where the produced ammonia is excreted as ammonium ions. This excretion of ammonium ions is an important mechanism of renal acid-base regulation. During chronic acidosis, glutaminase is induced in the kidney, which leads to an increase in the amount of ammonium ions excreted. Glutaminase can also be found in the intestines, whereby hepatic portal ammonia can reach as high as 0.26 mM (compared to an arterial blood ammonia of 0.02 mM). One of the most important roles of glutaminase is found in the axonal terminals of neurons in the central nervous system. Glutamate is the most abundantly used excitatory neurotransmitter in the CNS. After being released into the synapse for neurotransmission, glutamate is rapidly taken up by nearby astrocytes, which convert it to glutamine. This glutamine is then supplied to the presynaptic terminals of the neurons, where glutaminases convert it back to glutamate for loading into synaptic vesicles. Although both "kidney-type" (GLS1) and "liver-type" (GLS2) glutaminases are expressed in brain, GLS2 has been reported to exist only in cellular nuclei in CNS neurons.[3] # Regulation ADP is the strongest adenine nucleotide activator of glutaminase. Studies have also suggested ADP lowered the K(m) for glutamine and increased the V(max). They found that these effects were increased even more when ATP was present.[4] Phosphate-activated mitochondrial glutaminase (GLS1) is suggested to be linked with elevated metabolism, decreased intracellular reactive oxygen species (ROS) levels, and overall decreased DNA oxidation in both normal and stressed cells. It is suggested that GLS1’s control of ROS levels facilitates “the ability of p53 to protect cells from accumulation of genomic damage and allows cells to survive after mild and repairable genotoxic stress.”[5] # Structure The structure of glutaminase has been determined using X-ray diffraction to a resolution of up to 1.73 Å. There are 2 chains containing 305 residues that make up the length of this dimeric protein. On each strand, 23% of the amino acid content, or 71 residues, are found in the 8 helices. Twenty-one percent, or 95 residues, make up the 23 beta sheet strands.[1] # Isozymes Humans express 4 isoforms of glutaminase. GLS1 encodes 2 types of kidney-type glutaminase with a high activity and low Km. GLS2 encodes 2 forms of liver-type glutaminase with a low activity and allosteric regulation.[2] # Related proteins Glutaminases belong to a larger family that includes serine-dependent beta-lactamases and penicillin-binding proteins. Many bacteria have two isozymes. This model is based on selected known glutaminases and their homologs within prokaryotes, with the exclusion of highly derived (long-branch) and architecturally varied homologs, so as to achieve conservative assignments. A sharp drop in scores occurs below 250, and cutoffs are set accordingly. The enzyme converts glutamine to glutamate, with the release of ammonia. Members tend to be described as glutaminase A (glsA), where B (glsB) is unknown and may not be homologous (as in Rhizobium etli; some species have two isozymes that may both be designated A (GlsA1 and GlsA2). # Clinical significance Many cancers rely on glutaminase thus glutaminase inhibitors have been proposed as a cancer treatment.[6][7] As of July 2018[update] some glutaminase inhibitors are in mid-stage clinical trials.	https://www.wikidoc.org/index.php/Glutaminase
6a8e29332bd8e08a0ebb8b13aa3c65fb8b3ef129	wikidoc	Glutathione	Glutathione # Disclaimer WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here. NOTE: Most over the counter (OTC) are not reviewed and approved by the FDA. However, they may be marketed if they comply with applicable regulations and policies. FDA has not evaluated whether this product complies. # Overview Glutathione is an amino acid supplement that is FDA approved for the treatment of chronic fatigue, muscle aches and pain. Common adverse reactions include cutaneous eruptions. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) # Indications - For temporary relief of chronic fatigue, muscle aches and pain, lowered immune response, and sensitivity to environmental chemicals. # Dosage - 10 drops orally, 3 times a day. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Glutathione in adult patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Glutathione in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) There is limited information regarding FDA-Labeled Use of Glutathione in pediatric patients. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Glutathione in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Glutathione in pediatric patients. # Contraindications - Prior hypersensitivity to glutathione # Warnings - If pregnant or breast-feeding, ask a health care professional before use. - Keep out of reach of children. In case of overdose, get medical help or contact a Poison Control Center right away. - Do not use if tamper evident seal is broken or missing. Store in a cool, dry place. # Adverse Reactions ## Clinical Trials Experience - cutaneous eruptions ## Postmarketing Experience There is limited information regarding Postmarketing Experience of Glutathione in the drug label. # Drug Interactions There is limited information regarding Glutathione Drug Interactions in the drug label. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): There is no FDA guidance on usage of Glutathione in women who are pregnant. Pregnancy Category (AUS): - Australian Drug Evaluation Committee (ADEC) Pregnancy Category There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Glutathione in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Glutathione during labor and delivery. ### Nursing Mothers There is no FDA guidance on the use of Glutathione with respect to nursing mothers. ### Pediatric Use There is no FDA guidance on the use of Glutathione with respect to pediatric patients. ### Geriatic Use There is no FDA guidance on the use of Glutathione with respect to geriatric patients. ### Gender There is no FDA guidance on the use of Glutathione with respect to specific gender populations. ### Race There is no FDA guidance on the use of Glutathione with respect to specific racial populations. ### Renal Impairment There is no FDA guidance on the use of Glutathione in patients with renal impairment. ### Hepatic Impairment There is no FDA guidance on the use of Glutathione in patients with hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Glutathione in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Glutathione in patients who are immunocompromised. # Administration and Monitoring ### Administration - Oral ### Monitoring There is limited information regarding Monitoring of Glutathione in the drug label. # IV Compatibility There is limited information regarding IV Compatibility of Glutathione in the drug label. # Overdosage There is limited information regarding Glutathione overdosage. If you suspect drug poisoning or overdose, please contact the National Poison Help hotline (1-800-222-1222) immediately. # Pharmacology ## Mechanism of Action There is limited information regarding Glutathione Mechanism of Action in the drug label. ## Structure There is limited information regarding Glutathione Structure in the drug label. ## Pharmacodynamics There is limited information regarding Pharmacodynamics of Glutathione in the drug label. ## Pharmacokinetics There is limited information regarding Pharmacokinetics of Glutathione in the drug label. ## Nonclinical Toxicology There is limited information regarding Nonclinical Toxicology of Glutathione in the drug label. # Clinical Studies There is limited information regarding Clinical Studies of Glutathione in the drug label. # How Supplied There is limited information regarding Glutathione How Supplied in the drug label. ## Storage There is limited information regarding Glutathione Storage in the drug label. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information There is limited information regarding Patient Counseling Information of Glutathione in the drug label. # Precautions with Alcohol - Alcohol-Glutathione interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names GLUTATHIONE # Look-Alike Drug Names There is limited information regarding Glutathione Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	Glutathione Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Kiran Singh, M.D. [2] # Disclaimer WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here. NOTE: Most over the counter (OTC) are not reviewed and approved by the FDA. However, they may be marketed if they comply with applicable regulations and policies. FDA has not evaluated whether this product complies. # Overview Glutathione is an amino acid supplement that is FDA approved for the treatment of chronic fatigue, muscle aches and pain. Common adverse reactions include cutaneous eruptions. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) # Indications - For temporary relief of chronic fatigue, muscle aches and pain, lowered immune response, and sensitivity to environmental chemicals. # Dosage - 10 drops orally, 3 times a day. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Glutathione in adult patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Glutathione in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) There is limited information regarding FDA-Labeled Use of Glutathione in pediatric patients. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Glutathione in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Glutathione in pediatric patients. # Contraindications - Prior hypersensitivity to glutathione # Warnings - If pregnant or breast-feeding, ask a health care professional before use. - Keep out of reach of children. In case of overdose, get medical help or contact a Poison Control Center right away. - Do not use if tamper evident seal is broken or missing. Store in a cool, dry place. # Adverse Reactions ## Clinical Trials Experience - cutaneous eruptions ## Postmarketing Experience There is limited information regarding Postmarketing Experience of Glutathione in the drug label. # Drug Interactions There is limited information regarding Glutathione Drug Interactions in the drug label. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): There is no FDA guidance on usage of Glutathione in women who are pregnant. Pregnancy Category (AUS): - Australian Drug Evaluation Committee (ADEC) Pregnancy Category There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Glutathione in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Glutathione during labor and delivery. ### Nursing Mothers There is no FDA guidance on the use of Glutathione with respect to nursing mothers. ### Pediatric Use There is no FDA guidance on the use of Glutathione with respect to pediatric patients. ### Geriatic Use There is no FDA guidance on the use of Glutathione with respect to geriatric patients. ### Gender There is no FDA guidance on the use of Glutathione with respect to specific gender populations. ### Race There is no FDA guidance on the use of Glutathione with respect to specific racial populations. ### Renal Impairment There is no FDA guidance on the use of Glutathione in patients with renal impairment. ### Hepatic Impairment There is no FDA guidance on the use of Glutathione in patients with hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Glutathione in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Glutathione in patients who are immunocompromised. # Administration and Monitoring ### Administration - Oral ### Monitoring There is limited information regarding Monitoring of Glutathione in the drug label. # IV Compatibility There is limited information regarding IV Compatibility of Glutathione in the drug label. # Overdosage There is limited information regarding Glutathione overdosage. If you suspect drug poisoning or overdose, please contact the National Poison Help hotline (1-800-222-1222) immediately. # Pharmacology ## Mechanism of Action There is limited information regarding Glutathione Mechanism of Action in the drug label. ## Structure There is limited information regarding Glutathione Structure in the drug label. ## Pharmacodynamics There is limited information regarding Pharmacodynamics of Glutathione in the drug label. ## Pharmacokinetics There is limited information regarding Pharmacokinetics of Glutathione in the drug label. ## Nonclinical Toxicology There is limited information regarding Nonclinical Toxicology of Glutathione in the drug label. # Clinical Studies There is limited information regarding Clinical Studies of Glutathione in the drug label. # How Supplied There is limited information regarding Glutathione How Supplied in the drug label. ## Storage There is limited information regarding Glutathione Storage in the drug label. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information There is limited information regarding Patient Counseling Information of Glutathione in the drug label. # Precautions with Alcohol - Alcohol-Glutathione interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names GLUTATHIONE # Look-Alike Drug Names There is limited information regarding Glutathione Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	https://www.wikidoc.org/index.php/Glutathione
718695342691ddfba637923795cf1721986a8d11	wikidoc	Goblet cell	Goblet cell # Overview Goblet cells are glandular simple columnar epithelial cells whose sole function is to secrete mucus. They secrete using both apocrine and merocrine methods of secretion. The majority of the cell's cytoplasm is occupied by mucinogen granules, except at the bottom. Rough endoplasmic reticulum, mitochondria, the nucleus, and other organelles are concentrated in the basal portion. The apical plasma membrane projects microvilli to increase surface area for secretion. # Locations They are found scattered among the epithelial lining of many organs, especially the intestinal and respiratory tracts. In the respiratory tract, they are found inside the trachea, bronchus, and larger bronchioles. # Histology In mucicarmine stains, goblet cells can be easily identified by the deep red mucin found within their cell bodies. The nuclei of goblet cells tend to be displaced toward the basal end of the cell body, close to basement membrane, leading to intense basophilic staining. # Etymology The term goblet refers to these cells' goblet-like shape. The apical portion is shaped like a cup, as it is distended by abundant mucinogen granules; its basal portion is shaped like a stem, as it is narrow for lack of these granules. There are other cells which secrete mucus (as in the fundic glands of the stomach), but they are not usually called "goblet cells" because they do not have this distinctive shape. # Basal secretion This is the normal base level secretion of mucus. The continuous secretion is accomplished by cytoskeletal movement of secretory granules. # Stimulated secretion Secretion may be stimulated by dust, smoke, etc. Other stimuli include viruses, bacteria, etc. # Additional images - An intestinal gland from the human intestine. - Goblet cell in ileum	Goblet cell Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview Template:Infobox Anatomy Goblet cells are glandular simple columnar epithelial cells whose sole function is to secrete mucus. They secrete using both apocrine and merocrine methods of secretion. The majority of the cell's cytoplasm is occupied by mucinogen granules, except at the bottom. Rough endoplasmic reticulum, mitochondria, the nucleus, and other organelles are concentrated in the basal portion. The apical plasma membrane projects microvilli to increase surface area for secretion. # Locations They are found scattered among the epithelial lining of many organs, especially the intestinal and respiratory tracts. In the respiratory tract, they are found inside the trachea, bronchus, and larger bronchioles. # Histology In mucicarmine stains, goblet cells can be easily identified by the deep red mucin found within their cell bodies. The nuclei of goblet cells tend to be displaced toward the basal end of the cell body, close to basement membrane, leading to intense basophilic staining. # Etymology The term goblet refers to these cells' goblet-like shape. The apical portion is shaped like a cup, as it is distended by abundant mucinogen granules; its basal portion is shaped like a stem, as it is narrow for lack of these granules. There are other cells which secrete mucus (as in the fundic glands of the stomach[1]), but they are not usually called "goblet cells" because they do not have this distinctive shape. # Basal secretion This is the normal base level secretion of mucus. The continuous secretion is accomplished by cytoskeletal movement of secretory granules. # Stimulated secretion Secretion may be stimulated by dust, smoke, etc. Other stimuli include viruses, bacteria, etc. # Additional images - An intestinal gland from the human intestine. - Goblet cell in ileum	https://www.wikidoc.org/index.php/Goblet_cell
08cefeeaa1ba7c9d139350ff239750bd03154b53	wikidoc	Gonadotrope	Gonadotrope # Overview Pituitary gonadotropes are one of the 6 major cell types in the anterior pituitary. They produce two hormones called gonadotropins which stimulate the ovaries. One of these is follicle stimulating hormone (FSH) which stimulates the development of the ovarian follicle in which the ova (egg) matures. The other is luteinizing hormone (LH) which is secreted in a peak just before ovulation. LH stimulates the development of the corpus luteum which prepares the uterus for pregnancy. These hormones are secreted in parallel and non-parallel patterns during the reproductive cycle. Secretion is stimulated by neuroendocrine mechanisms The secretory neurons are cells scattered in a special region of the brain (gonadotropin releasing hormone-GnRH). These nerve cells originally migrated from the olfactory bulb during fetal development and then became specialized to control the reproductive system. The GnRH is secreted into the blood stream in the pituitary stalk.	Gonadotrope Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview Pituitary gonadotropes are one of the 6 major cell types in the anterior pituitary. They produce two hormones called gonadotropins which stimulate the ovaries. One of these is follicle stimulating hormone (FSH) which stimulates the development of the ovarian follicle in which the ova (egg) matures. The other is luteinizing hormone (LH) which is secreted in a peak just before ovulation. LH stimulates the development of the corpus luteum which prepares the uterus for pregnancy. These hormones are secreted in parallel and non-parallel patterns during the reproductive cycle. Secretion is stimulated by neuroendocrine mechanisms The secretory neurons are cells scattered in a special region of the brain (gonadotropin releasing hormone-GnRH). These nerve cells originally migrated from the olfactory bulb during fetal development and then became specialized to control the reproductive system. The GnRH is secreted into the blood stream in the pituitary stalk. Template:Pituitary gland Template:WikiDoc Sources	https://www.wikidoc.org/index.php/Gonadotrope
ab82407168ad417418681317e6edb8076025f287	wikidoc	Goose bumps	Goose bumps Goose bumps, also called goose pimples, goose flesh, chill bumps, chicken skin, or the medical term cutis anserina, are the bumps on a person's skin at the base of body hairs which involuntarily develop when a person is cold or experiences strong emotions such as fear or awe. The reflex of producing goose bumps is known as horripilation, piloerection, or the pilomotor reflex. It occurs not only in humans but also in many other mammals; a prominent example are porcupines which raise their quills when threatened. Goose bumps are created when tiny muscles at the base of each hair, known as arrectores pilorum, contract and pull the hair erect. The reflex is started by the sympathetic nervous system, which is in general responsible for many fight-or-flight responses. Goose bumps are often a response to cold: in animals covered with fur or hair, the erect hairs trap air to create a layer of insulation. Goose bumps can also be a response to anger or fear: the erect hairs make the animal appear larger, in order to intimidate enemies. This can for example be observed in the intimidation displays of chimpanzees, in stressed mice and rats, and in frightened cats. In humans, it can even extend to piloerection as a reaction to hearing nails scratch on a chalkboard or listening to awe-inspiring music. Piloerection as a response to cold or fear is vestigial in humans; as humans retain only very little body hair, the reflex (in humans) now serves no known purpose. In humans, goose bumps are strongest on the forearms, but also occur on the legs, back, and other areas of the skin that have hair. In some people, they even occur in the face or on the head. Piloerection is also a (rare) symptom of some diseases, such as temporal lobe epilepsy, some brain tumors, and autonomic hyperreflexia. Goose bumps can also be caused by heroin withdrawal. A skin condition that mimics goose bumps in appearance is keratosis pilaris. Goose bumps can occur only in mammals, since other animals do not have hair. The term "goose bumps" is therefore misleading: the bumps on the skin of a plucked goose technically do not qualify as piloerection even though this is where the term comes from. Birds do however have a similar reflex of raising their feathers in order to keep warm. The Latin horrere is the root of words such as "horrific" or "horror"; it means "to tremble". In other languages, the "goose" may be replaced by other kinds of poultry. For instance, "hen" is used in French (la chair de poule), Dutch (kippenvel), Spanish (la carne de gallina) and Chinese (雞皮疙瘩).	Goose bumps Goose bumps, also called goose pimples, goose flesh, chill bumps, chicken skin, or the medical term cutis anserina, are the bumps on a person's skin at the base of body hairs which involuntarily develop when a person is cold or experiences strong emotions such as fear or awe. The reflex of producing goose bumps is known as horripilation, piloerection, or the pilomotor reflex. It occurs not only in humans but also in many other mammals; a prominent example are porcupines which raise their quills when threatened. Goose bumps are created when tiny muscles at the base of each hair, known as arrectores pilorum, contract and pull the hair erect. The reflex is started by the sympathetic nervous system, which is in general responsible for many fight-or-flight responses. Goose bumps are often a response to cold: in animals covered with fur or hair, the erect hairs trap air to create a layer of insulation. Goose bumps can also be a response to anger or fear: the erect hairs make the animal appear larger, in order to intimidate enemies. This can for example be observed in the intimidation displays of chimpanzees[1], in stressed mice[2] and rats, and in frightened cats. In humans, it can even extend to piloerection as a reaction to hearing nails scratch on a chalkboard or listening to awe-inspiring music.[3] Piloerection as a response to cold or fear is vestigial in humans; as humans retain only very little body hair, the reflex (in humans) now serves no known purpose. In humans, goose bumps are strongest on the forearms, but also occur on the legs, back, and other areas of the skin that have hair. In some people, they even occur in the face or on the head. Piloerection is also a (rare) symptom of some diseases, such as temporal lobe epilepsy, some brain tumors, and autonomic hyperreflexia. Goose bumps can also be caused by heroin withdrawal. A skin condition that mimics goose bumps in appearance is keratosis pilaris. Goose bumps can occur only in mammals, since other animals do not have hair. The term "goose bumps" is therefore misleading: the bumps on the skin of a plucked goose technically do not qualify as piloerection even though this is where the term comes from. Birds do however have a similar reflex of raising their feathers in order to keep warm. The Latin horrere is the root of words such as "horrific" or "horror"; it means "to tremble". In other languages, the "goose" may be replaced by other kinds of poultry. For instance, "hen" is used in French (la chair de poule), Dutch (kippenvel), Spanish (la carne de gallina) and Chinese (雞皮疙瘩).	https://www.wikidoc.org/index.php/Goose_bump
e5ff4d574d2ca33c38dc5b9251ebfac79b49a8a0	wikidoc	Gossypiboma	Gossypiboma Gossypiboma is the technical term for a surgical sponge accidentally left inside a patient's body. It is derived from the Latin "gossypium" (cotton) and the Swahili "boma" (place of concealment). Actual occurrences are difficult to come by since nearly all cases are settled out of court. Statistical studies by researchers however put the number of occurrences between 3,000 and 5,000 cases a year. Sponges are counted by hand before and after surgeries. This method was codified into recommended guidelines in the 1970's by the A.O.R.N. # Computerized Solutions No significant and successful advancements had been made in the field until late 20th century. The first break through came in 1997 when an UCLA MBA student and his urologist father co-developed and patented a turn-key system that would require the adherence of special labels at the manufacturing level to the sponges a hospital uses. These sponges then could easily be read by a handheld scanner while the nursing staff followed their established sponge counting protocols and procedures, much like at a grocery store checkout counter. Since each item has a unique code, the system will assist the nurse in keeping an accurate count by not letting the same sponge be counted twice accidentally. Ohio University's Center For Auto Identification recent studies had compelling results: data matrix tags had at worst a 1 in 10 million scan error rate and at best a 1 in 612 million scan error rate. After sustained testing, development, and studies while operating under an FDA exemption, the developer, SurgiCount Medical, received 510(k) clearance by the FDA for the system in March of 2006 to commercially roll out the system. Currently the Safety Sponge System is the only FDA approved system and is the only system that is market ready. # Radio Frequency Identification Technology In 2004, Gautam Gandhi and Steve Fleck, MBA students from Carnegie Mellon won several national business plan competitions for ClearCount Medical Solutions. RFID technology is used instead of the line-of-sight approach to lost sponges. RFID is an appealing concept because it requires just waving a wand over an area to communicate wirelessly with a tag. The company obtained FDA clearance in 2007. # The Future Using the high of the range (5,000) of retained sponges per year with the 30 million relevant surgeries per annum, an accuracy rate of 99.98% is the norm of hospitals.	Gossypiboma Gossypiboma is the technical term for a surgical sponge accidentally left inside a patient's body. It is derived from the Latin "gossypium" (cotton) and the Swahili "boma" (place of concealment). Actual occurrences are difficult to come by since nearly all cases are settled out of court. Statistical studies by researchers however put the number of occurrences between 3,000 and 5,000 cases a year. Sponges are counted by hand before and after surgeries. This method was codified into recommended guidelines in the 1970's by the A.O.R.N. # Computerized Solutions No significant and successful advancements had been made in the field until late 20th century. The first break through came in 1997 when an UCLA MBA student and his urologist father co-developed and patented a turn-key system that would require the adherence of special labels at the manufacturing level to the sponges a hospital uses. These sponges then could easily be read by a handheld scanner while the nursing staff followed their established sponge counting protocols and procedures, much like at a grocery store checkout counter. Since each item has a unique code, the system will assist the nurse in keeping an accurate count by not letting the same sponge be counted twice accidentally. Ohio University's Center For Auto Identification recent studies had compelling results: data matrix tags had at worst a 1 in 10 million scan error rate and at best a 1 in 612 million scan error rate. After sustained testing, development, and studies while operating under an FDA exemption, the developer, SurgiCount Medical, received 510(k) clearance by the FDA for the system in March of 2006 to commercially roll out the system. Currently the Safety Sponge System is the only FDA approved system and is the only system that is market ready. # Radio Frequency Identification Technology In 2004, Gautam Gandhi and Steve Fleck, MBA students from Carnegie Mellon won several national business plan competitions for ClearCount Medical Solutions. RFID technology is used instead of the line-of-sight approach to lost sponges. RFID is an appealing concept because it requires just waving a wand over an area to communicate wirelessly with a tag. The company obtained FDA clearance in 2007. # The Future Using the high of the range (5,000) of retained sponges per year with the 30 million relevant surgeries per annum, an accuracy rate of 99.98% is the norm of hospitals. # External links - Case description and discussion - ClearCount Medical - SurgiCount Medical - Ohio University, Data Matrix Integrity Test Template:Disease-stub Template:WikiDoc Sources	https://www.wikidoc.org/index.php/Gossypiboma
c49915de5e3f15842ecc56946109cd193e1e2ad7	wikidoc	PMEL (gene)	PMEL (gene) Melanocyte protein PMEL also known as premelanosome protein (PMEL) or silver locus protein homolog (SILV) is a protein that in humans is encoded by the PMEL gene. Its gene product may be referred to as PMEL, silver, ME20, gp100 or Pmel17. # Structure and function PMEL is a 100 kDa type I transmembrane glycoprotein that is expressed primarily in pigment cells of the skin and eye. The transmembrane form of PMEL is modified in the secretory pathway by elaboration of N-linked oligosaccharides and addition and modification of O-linked oligosaccharides. It is then targeted to precursors of the pigment organelle, the melanosome, where it is proteolytically processed to several small fragments. Some of these fragments form non-pathological amyloid that assemble into sheets and form the striated pattern that underlies melanosomal ultrastructure. PMEL cleavage is mediated by several proteases including a proprotein convertase of the furin family, a "sheddase" that might include members of the a disintegrin and metalloproteinase (ADAM) family, and additional proteases in melanosomes or their precursors. After the amyloidogenic region is cleaved, the small remaining integral membrane fragment is digested by γ-secretase. The expression of the PMEL gene is regulated by the microphthalmia-associated transcription factor (MITF).	PMEL (gene) Melanocyte protein PMEL also known as premelanosome protein (PMEL) or silver locus protein homolog (SILV) is a protein that in humans is encoded by the PMEL gene.[1][2] Its gene product may be referred to as PMEL, silver, ME20, gp100 or Pmel17. # Structure and function PMEL is a 100 kDa type I transmembrane glycoprotein that is expressed primarily in pigment cells of the skin and eye. The transmembrane form of PMEL is modified in the secretory pathway by elaboration of N-linked oligosaccharides and addition and modification of O-linked oligosaccharides. It is then targeted to precursors of the pigment organelle, the melanosome, where it is proteolytically processed to several small fragments. Some of these fragments form non-pathological amyloid that assemble into sheets and form the striated pattern that underlies melanosomal ultrastructure. PMEL cleavage is mediated by several proteases including a proprotein convertase of the furin family, a "sheddase" that might include members of the a disintegrin and metalloproteinase (ADAM) family, and additional proteases in melanosomes or their precursors. After the amyloidogenic region is cleaved, the small remaining integral membrane fragment is digested by γ-secretase. The expression of the PMEL gene is regulated by the microphthalmia-associated transcription factor (MITF).[3][4]	https://www.wikidoc.org/index.php/Gp100
5545386877610c3f5b97a8ddc9adc325d0d733b8	wikidoc	Mole (unit)	Mole (unit) # Overview The mole (symbol: mol) is the SI base unit that measures an amount of substance. The mole is a counting unit. One mole contains Avogadro's number (approximately ]) entities (atoms or molecules). A mole is much like "a dozen" in that both are absolute numbers (having no units) and can describe any type of elementary object (object made up of atoms). The mole's use, however, is usually limited to measurement of subatomic, atomic, and molecular structures; tradition and its magnitude compared to more common units make it impractical for other uses. In practice, one often measures an amount of the substance in a gram-mole, which is the quantity of a substance whose mass in grams is equal to its formula weight. Thus a gram-mole for Carbon-12 has a mass of 12 grams, while a gram-mole of water has a mass of 18.016 grams. The entity counted is usually an atom (as in C) or a molecule (as in H2O, molecular formula weight = 2 H atoms + 1 O atom ≈18). # Definitions A mole is the amount of substance of a system, which contains as many elementary entities as there are atoms in 0.012 kilogram (or 12 grams) of carbon-12, where the carbon-12 atoms are unbound, at rest and in their ground state. The number of atoms in 0.012 kilogram of carbon-12 is known as the Avogadro constant, and is determined empirically. The currently accepted value is 6.02214279(30)Template:E mol-1 (2007 CODATA). According to the SI, the mole is not dimensionless, but has its very own dimension, namely "amount of substance", comparable to other dimensions such as mass and luminous intensity. (By contrast, the SI specifically defines the radian and the steradian as special names for the dimensionless unit one.) The SI additionally defines the Avogadro constant as having the unit reciprocal mole, as it is the ratio of a dimensionless quantity and a quantity with the unit mole. However, if in the future the kilogram is redefined in terms of a specific number of carbon-12 atoms (see below), then the value of Avogadro's number will be defined rather than measured, and the mole will cease to be a unit of physical significance. The relationship of the atomic mass unit (u) to Avogadro's number means that a mole can also be defined as: That quantity of a substance whose mass in grams is the same as its formula weight. For example, iron has a relative atomic mass of 55.845 u, so a mole of iron has a mass of 55.845 grams. This notation is very commonly used by chemists and physicists. Scientists and engineers (chemical engineers in particular) sometimes measure amount of substance in units of gram-moles, kilogram-moles, pound-moles, or ounce-moles; these measure the quantity of a substance whose mass in grams, kilograms, pounds, or ounces (respectively) is equal to its formula weight. The SI mole is identical to the gram-mole. # Elementary entities When the mole is used to specify the amount of a substance, the kind of elementary entities (particles) in the substance must be identified. The particles can be atoms, molecules, ions, formula units, electrons, photons or other particles. For example, one mole of water is equivalent to 18.016 grams of water and contains one mole of H2O molecules, but three moles of atoms (two moles H and one mole O). When the substance of interest is a gas, the particles are usually molecules. However, the noble gases (He, Ar, Ne, Kr, Xe, Rn) are all monoatomic, that is each particle of gas is a single atom. An ideal gas has a molar volume of 22.4 litres per mole at STP (see Avogadro's Law). A mole of atoms or molecules is also called a "gram atom" or "gram molecule", respectively. # History The name mole (German Mol) is attributed to Wilhelm Ostwald who introduced the concept in the year 1902. It is an abbreviation for molecule (German Molekül), which is in turn derived from Latin moles "mass, massive structure". He used it to express the gram molecular weight of a substance. So, for example, 1 mole of hydrochloric acid (HCl) has a mass of 36.5 grams (atomic masses Cl: 35.5 u, H: 1.0 u). Prior to 1959 both the IUPAP and IUPAC used oxygen to define the mole, the chemists defining the mole as the number of atoms of oxygen which had mass 16 g, the physicists using a similar definition but with the oxygen-16 isotope only. The two organizations agreed in 1959/1960 to define the mole as such: This was adopted by the ICPM (International Committee for Weights and Measures) in 1967, and in 1971 it was adopted by the 14th GCPM (General Conference on Weights and Measures). In 1980 the ICPM clarified the above definition, defining that the carbon-12 atoms are unbound and in their ground state. ## Proposed future definition As with other SI base units, there have been proposals to redefine the kilogram in such a way as to define some presently measured physical constants to fixed values. One proposed definition of the kilogram is: This would have the effect of defining Avogadro's number to be precisely NA = 6.0221415Template:E elementary entities per mole, and, consequently, the mole would become merely a unit of counting, like the dozen. Another proposed definition of NA is: This has the convenient properties of being a perfect cube, and of being near the current experimental bounds of measurement. # Utility of moles The mole is useful in chemistry because it allows different substances to be measured in a comparable way. Using the same number of moles of two substances, both amounts have the same number of molecules or atoms. The mole makes it easier to interpret chemical equations in practical terms. Thus the equation: can be understood as "two moles of hydrogen plus one mole of oxygen yields two moles of water." Moles are useful in chemical calculations because they enable the calculation of yields and other values when dealing with particles of different mass. Number of particles is a more useful unit in chemistry than mass or weight, because reactions take place between atoms (for example, two hydrogen atoms and one oxygen atom make one molecule of water) that have very different weights (one oxygen atom weighs almost 16 times as much as a hydrogen atom). However, the raw numbers of atoms in a reaction are not convenient, because they are very large; for example, two mL of water contain over 6.02Template:E molecules.	Mole (unit) # Overview The mole (symbol: mol) is the SI base unit that measures an amount of substance. The mole is a counting unit. One mole contains Avogadro's number (approximately [[Avogadro constant\|6.02214Template:E]]) entities (atoms or molecules). A mole is much like "a dozen" in that both are absolute numbers (having no units) and can describe any type of elementary object (object made up of atoms). The mole's use, however, is usually limited to measurement of subatomic, atomic, and molecular structures; tradition and its magnitude compared to more common units make it impractical for other uses. In practice, one often measures an amount of the substance in a gram-mole, which is the quantity of a substance whose mass in grams is equal to its formula weight. Thus a gram-mole for Carbon-12 has a mass of 12 grams, while a gram-mole of water has a mass of 18.016 grams. The entity counted is usually an atom (as in C) or a molecule (as in H2O, molecular formula weight = 2 H atoms + 1 O atom ≈18). # Definitions A mole is the amount of substance of a system, which contains as many elementary entities as there are atoms in 0.012 kilogram (or 12 grams) of carbon-12, where the carbon-12 atoms are unbound, at rest and in their ground state.[1] The number of atoms in 0.012 kilogram of carbon-12 is known as the Avogadro constant, and is determined empirically. The currently accepted value is 6.02214279(30)Template:E mol-1 (2007 CODATA). According to the SI, the mole is not dimensionless, but has its very own dimension, namely "amount of substance", comparable to other dimensions such as mass and luminous intensity.[2] (By contrast, the SI specifically defines the radian and the steradian as special names for the dimensionless unit one.)[3] The SI additionally defines the Avogadro constant as having the unit reciprocal mole, as it is the ratio of a dimensionless quantity and a quantity with the unit mole.[3] However, if in the future the kilogram is redefined in terms of a specific number of carbon-12 atoms (see below), then the value of Avogadro's number will be defined rather than measured, and the mole will cease to be a unit of physical significance.[4] The relationship of the atomic mass unit (u[5]) to Avogadro's number means that a mole can also be defined as: That quantity of a substance whose mass in grams is the same as its formula weight. For example, iron has a relative atomic mass of 55.845 u, so a mole of iron has a mass of 55.845 grams. This notation is very commonly used by chemists and physicists. Scientists and engineers (chemical engineers in particular) sometimes measure amount of substance in units of gram-moles, kilogram-moles, pound-moles, or ounce-moles; these measure the quantity of a substance whose mass in grams, kilograms, pounds, or ounces (respectively) is equal to its formula weight. The SI mole is identical to the gram-mole. # Elementary entities When the mole is used to specify the amount of a substance, the kind of elementary entities (particles) in the substance must be identified. The particles can be atoms, molecules, ions, formula units, electrons, photons or other particles. For example, one mole of water is equivalent to 18.016 grams of water and contains one mole of H2O molecules, but three moles of atoms (two moles H and one mole O). When the substance of interest is a gas, the particles are usually molecules. However, the noble gases (He, Ar, Ne, Kr, Xe, Rn) are all monoatomic, that is each particle of gas is a single atom. An ideal gas has a molar volume of 22.4 litres per mole at STP (see Avogadro's Law). A mole of atoms or molecules is also called a "gram atom" or "gram molecule", respectively. # History The name mole (German Mol) is attributed to Wilhelm Ostwald who introduced the concept in the year 1902. It is an abbreviation for molecule (German Molekül), which is in turn derived from Latin moles "mass, massive structure". He used it to express the gram molecular weight of a substance. So, for example, 1 mole of hydrochloric acid (HCl) has a mass of 36.5 grams (atomic masses Cl: 35.5 u, H: 1.0 u). Prior to 1959 both the IUPAP and IUPAC used oxygen to define the mole, the chemists defining the mole as the number of atoms of oxygen which had mass 16 g, the physicists using a similar definition but with the oxygen-16 isotope only. The two organizations agreed in 1959/1960 to define the mole as such: This was adopted by the ICPM (International Committee for Weights and Measures) in 1967, and in 1971 it was adopted by the 14th GCPM (General Conference on Weights and Measures). In 1980 the ICPM clarified the above definition, defining that the carbon-12 atoms are unbound and in their ground state. ## Proposed future definition As with other SI base units, there have been proposals to redefine the kilogram in such a way as to define some presently measured physical constants to fixed values. One proposed definition of the kilogram is: This would have the effect of defining Avogadro's number to be precisely NA = 6.0221415Template:E elementary entities per mole, and, consequently, the mole would become merely a unit of counting, like the dozen. Another proposed definition of NA is: This has the convenient properties of being a perfect cube, and of being near the current experimental bounds of measurement.[7] # Utility of moles The mole is useful in chemistry because it allows different substances to be measured in a comparable way. Using the same number of moles of two substances, both amounts have the same number of molecules or atoms. The mole makes it easier to interpret chemical equations in practical terms. Thus the equation: can be understood as "two moles of hydrogen plus one mole of oxygen yields two moles of water." Moles are useful in chemical calculations because they enable the calculation of yields and other values when dealing with particles of different mass. Number of particles is a more useful unit in chemistry than mass or weight, because reactions take place between atoms (for example, two hydrogen atoms and one oxygen atom make one molecule of water) that have very different weights (one oxygen atom weighs almost 16 times as much as a hydrogen atom). However, the raw numbers of atoms in a reaction are not convenient, because they are very large; for example, two mL of water contain over 6.02Template:E molecules.	https://www.wikidoc.org/index.php/Gram-molecular_weight
03c14d31addc0db2a14be9494c0dcd83b7e01b9a	wikidoc	Gramicidine	Gramicidine Gramicidin is a heterogeneous mixture of six antibiotic compounds, Gramicidins A, B and C, making up 80%, 6%, and 14% respectively, all of which are obtained from the soil bacterial species Bacillus brevis and called collectively Gramicidin D. Gramicidin D are linear pentadecapeptides; that is chains made up of 15 amino acids. This is in contrast to Gramicidin S which is a cyclic peptide chain. Gramicidin is active against Gram-positive bacteria, except for the Gram-positive bacilli, and against select Gram-negative organisms, such as Neisseria bacteria. Its therapeutic use is limited to topical application as it induces hemolysis in lower concentrations than bacteria cell death thus cannot be administered internally. The exterior epidermis is composed of dead cells, thus applying it to the surface of the skin will not cause harm. It is used primarily as a topical antibiotic and is one of the three constituents of consumer antibiotic Neosporin Ophthalmic Solution. In 1939 the French-American microbiologist René Dubos isolated the substance tyrothricin and later showed that it was composed of two substances, gramicidin (20%) and tyrocidine (80%). These were the first antibiotics to be manufactured commercially. # Composition and Structure Gramicidin is composed of the general formula: formyl-L-X-Gly-L-Ala-D-Leu-L-Ala-D-Val-L-Val-D-Val-L-Trp-D-Leu-L-Y-D-Leu-L-Trp-D-Leu-L-Trp-ethanolamine X and Y depend upon the gramicidin molecule. There exists valine and isoleucine variants of all three gramicidin species and 'X' can be either. Y determines which is which; in the place of Y Gramicidin A contains Tryptophan, B contains Phenylalanine and C contains Tyrosine. Also note the alternating stereochemical configurations (in the form of D and L) of the amino acids: this is vital to the formation of the β-helix. The chain assembles inside of the hydrophobic interior of the cellular lipid bilayer to form a β-helix. The helix itself is not long enough to span the membrane but it dimerizes to form the elongated channel needed to span the whole membrane. The structure of gramicidin head-to-head dimer in micelles and lipid bilayers was determined by solution and solid state NMR. In organic solvents and crystals, this peptide forms different types of non-native double helices. # Pharmacological Effect Gramicidin's bactericidal activity is a result of increasing the permeability of the bacterial cell wall allowing inorganic monovalent cations (e.g. H+) to travel through unrestricted, thereby destroying the ion gradient between the cytoplasm and the extracellular environment. That gramicidin D functions as a channel was demonstrated by Hladky and Haydon, who investigated the unit conductance channel. In general, gramicidin channels are ideally selective for monovalent cations and the single-channel conductances for the alkali cations are ranked in the same order as the aqueous mobilities of these ions. Divalent cations like Ca-2+ block the channel by binding near the mouth of the channel. So it is basically impermeable to divalent cations. It also excludes anions. Cl- in particular is excluded from the channel because its hydration shell is thermodynamically stronger than that of most monovalent cations. The channel is permeable to most monovalent cations, which move through the channel in single file. The channel is filled with about six water molecules, almost all of which must be displaced when an ion is transported. Thus, ions moving through the gramicidin pore carry along a single file of water molecules. Such a flux of ion and water molecules is known as flux coupling. In the presence of a second type of permeable ion, the two ions couple their flux as well. Like Valinomycin and Nonactin, the gramicidin channel is selective for potassium over sodium but only slightly so. It has a permeability ration of 2.9. It is impermeable to anions but there are conditions under which some anion permeation may be observed. Its ability to bind and transport cations is due to the presence of cation-binding sites in the channel. Specifically, there are two such binding sites, one strong and the other weak.	Gramicidine Gramicidin is a heterogeneous mixture of six antibiotic compounds, Gramicidins A, B and C, making up 80%, 6%, and 14% respectively[1], all of which are obtained from the soil bacterial species Bacillus brevis and called collectively Gramicidin D. Gramicidin D are linear pentadecapeptides; that is chains made up of 15 amino acids[2]. This is in contrast to Gramicidin S which is a cyclic peptide chain. Gramicidin is active against Gram-positive bacteria, except for the Gram-positive bacilli, and against select Gram-negative organisms, such as Neisseria bacteria. Its therapeutic use is limited to topical application as it induces hemolysis in lower concentrations than bacteria cell death thus cannot be administered internally. The exterior epidermis is composed of dead cells, thus applying it to the surface of the skin will not cause harm. It is used primarily as a topical antibiotic and is one of the three constituents of consumer antibiotic Neosporin Ophthalmic Solution. In 1939 the French-American microbiologist René Dubos isolated the substance tyrothricin and later showed that it was composed of two substances, gramicidin (20%) and tyrocidine (80%). These were the first antibiotics to be manufactured commercially. # Composition and Structure Gramicidin is composed of the general formula: formyl-L-X-Gly-L-Ala-D-Leu-L-Ala-D-Val-L-Val-D-Val-L-Trp-D-Leu-L-Y-D-Leu-L-Trp-D-Leu-L-Trp-ethanolamine X and Y depend upon the gramicidin molecule. There exists valine and isoleucine variants of all three gramicidin species and 'X' can be either. Y determines which is which; in the place of Y Gramicidin A contains Tryptophan, B contains Phenylalanine and C contains Tyrosine. Also note the alternating stereochemical configurations (in the form of D and L) of the amino acids: this is vital to the formation of the β-helix. The chain assembles inside of the hydrophobic interior of the cellular lipid bilayer to form a β-helix. The helix itself is not long enough to span the membrane but it dimerizes to form the elongated channel needed to span the whole membrane. The structure of gramicidin head-to-head dimer in micelles and lipid bilayers was determined by solution and solid state NMR. In organic solvents and crystals, this peptide forms different types of non-native double helices. # Pharmacological Effect Gramicidin's bactericidal activity is a result of increasing the permeability of the bacterial cell wall allowing inorganic monovalent cations (e.g. H+) to travel through unrestricted, thereby destroying the ion gradient between the cytoplasm and the extracellular environment. That gramicidin D functions as a channel was demonstrated by Hladky and Haydon, who investigated the unit conductance channel. In general, gramicidin channels are ideally selective for monovalent cations and the single-channel conductances for the alkali cations are ranked in the same order as the aqueous mobilities of these ions. Divalent cations like Ca-2+ block the channel by binding near the mouth of the channel. So it is basically impermeable to divalent cations. It also excludes anions. Cl- in particular is excluded from the channel because its hydration shell is thermodynamically stronger than that of most monovalent cations. The channel is permeable to most monovalent cations, which move through the channel in single file. The channel is filled with about six water molecules, almost all of which must be displaced when an ion is transported. Thus, ions moving through the gramicidin pore carry along a single file of water molecules. Such a flux of ion and water molecules is known as flux coupling. In the presence of a second type of permeable ion, the two ions couple their flux as well. Like Valinomycin and Nonactin, the gramicidin channel is selective for potassium over sodium but only slightly so. It has a permeability ration of 2.9. It is impermeable to anions but there are conditions under which some anion permeation may be observed. Its ability to bind and transport cations is due to the presence of cation-binding sites in the channel. Specifically, there are two such binding sites, one strong and the other weak.	https://www.wikidoc.org/index.php/Gramicidine
25c243e5ed4a6bef02702701078399c91c93f713	wikidoc	Granularity	Granularity $(document).ready(function(){ $('#go').click(function(){ if(wgAction === "view"){ console.log(wgCategories); var api = new mw.Api(); api.get( { action: 'query', prop: 'categories', titles: wgTitle, } ).done ( function ( data ) { console.log( data );	Granularity $(document).ready(function(){ $('#go').click(function(){ if(wgAction === "view"){ console.log(wgCategories[0]); } var api = new mw.Api(); api.get( { action: 'query', prop: 'categories', titles: wgTitle, } ).done ( function ( data ) { console.log( data ); } ); }); });	https://www.wikidoc.org/index.php/Granularity
211fde58f31c414b53ab540ba30766138d8efba5	wikidoc	Granulocyte	Granulocyte # Overview Granulocytes are a category of white blood cells characterised by the presence of granules in their cytoplasm. They are also called polymorphonuclear leukocytes (PMN or PML) because of the varying shapes of the nucleus, which is usually lobed into three segments. In common parlance, the term polymorphonuclear leukocyte often refers specifically to neutrophil granulocytes, the most abundant of the granulocytes. Granulocytes or PMN are released from the bone marrow by the regulatory complement proteins. # Classification There are three types of granulocytes, distinguished by their appearance under Wright's stain: - Neutrophil granulocytes - Eosinophil granulocytes - Basophil granulocytes. - Eosinophil granulocyte - Basophil granulocyte Their names are derived from their staining characteristics; for example, the most abundant granulocyte is the neutrophil granulocyte, which has neutrally-staining cytoplasmic granules. Other white blood cells which are not granulocytes ("agranulocytes") are mainly lymphocytes and monocytes. # Toxic materials produced or released Examples of toxic materials produced or released by degranulation by granulocytes on the ingestion of microorganism includes: - Low pH vesicles (3.5~4.0) - Toxic oxygen-derived products (e.g. superoxide, hydrogen peroxide, hydroxy radicals, singlet oxygen, hypohalite) - Toxic nitrogen oxides (nitric oxide) - Antimicrobial agents (Defensins and cationic proteins) - Enzymes (Lysozyme- dissolves cell walls of some gram positive bacteria, acid hydrolases- further digest bacteria). # Pathology Granulocytopenia is an abnormally low concentration of granulocytes in the blood. This condition reduces the body's resistance to many infections. Closely-related terms include agranulocytosis and neutropenia. A granuloma is a tumor containing granulocytes, and a "granulomatosis" is a necrotizing granuloma. There is usually a granulocyte chemotactic defect in individuals who suffer from insulin dependent diabetes mellitus. # Additional images - Blood cell lineage - Hematopoiesis	Granulocyte Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview Granulocytes are a category of white blood cells characterised by the presence of granules in their cytoplasm.[1] They are also called polymorphonuclear leukocytes (PMN or PML) because of the varying shapes of the nucleus, which is usually lobed into three segments. In common parlance, the term polymorphonuclear leukocyte often refers specifically to neutrophil granulocytes,[2] the most abundant of the granulocytes. Granulocytes or PMN are released from the bone marrow by the regulatory complement proteins. # Classification There are three types of granulocytes, distinguished by their appearance under Wright's stain: - Neutrophil granulocytes - Eosinophil granulocytes - Basophil granulocytes. - Eosinophil granulocyte - Basophil granulocyte Their names are derived from their staining characteristics; for example, the most abundant granulocyte is the neutrophil granulocyte, which has neutrally-staining cytoplasmic granules. Other white blood cells which are not granulocytes ("agranulocytes") are mainly lymphocytes and monocytes. # Toxic materials produced or released Examples of toxic materials produced or released by degranulation by granulocytes on the ingestion of microorganism includes: - Low pH vesicles (3.5~4.0) - Toxic oxygen-derived products (e.g. superoxide, hydrogen peroxide, hydroxy radicals, singlet oxygen, hypohalite) - Toxic nitrogen oxides (nitric oxide) - Antimicrobial agents (Defensins and cationic proteins) - Enzymes (Lysozyme- dissolves cell walls of some gram positive bacteria, acid hydrolases- further digest bacteria). # Pathology Granulocytopenia is an abnormally low concentration of granulocytes in the blood. This condition reduces the body's resistance to many infections. Closely-related terms include agranulocytosis and neutropenia. A granuloma is a tumor containing granulocytes, and a "granulomatosis" is a necrotizing granuloma. There is usually a granulocyte chemotactic defect in individuals who suffer from insulin dependent diabetes mellitus. # Additional images - Blood cell lineage - Hematopoiesis	https://www.wikidoc.org/index.php/Granulocyte
8b6e333c917c33b998ed3855aa195d44839b0eea	wikidoc	Gravitation	Gravitation Lua error in Module:Redirect at line 65: could not parse redirect on page "Gravity". Gravitation is a natural phenomenon by which all objects with mass attract each other, and is one of the fundamental forces of physics. In everyday life, gravitation is most commonly thought of as the agency that gives objects weight. It is responsible for keeping the Earth and the other planets in their orbits around the Sun; for keeping the Moon in its orbit around the Earth, for the formation of tides; for convection (by which hot fluids rise); for heating the interiors of forming stars and planets to very high temperatures; and for various other phenomena that we observe. Gravitation is also the reason for the very existence of the Earth, the Sun, and most macroscopic objects in the universe; without it, matter would not have coalesced into these large masses and life, as we know it, would not exist. Modern physics describes gravitation using the general theory of relativity, but the much simpler Newton's law of universal gravitation provides an excellent approximation in most cases. The terms gravitation and gravity are mostly interchangeable in everyday use, but in scientific usage a distinction may be made. "Gravitation" is a general term describing the attractive influence that all objects with mass exert on each other, while "gravity" specifically refers to a force that is supposed in some theories (such as Newton's) to be the cause of this attraction. By contrast, in general relativity gravitation is due to spacetime curvatures that cause inertially moving objects to accelerate towards each other. # History of gravitational theory ## Early history Efforts to understand gravity began in ancient times. Philosophers in ancient India explained the phenomenon from the 8th century BC. According to Kanada, founder of the Vaisheshika school, "Weight causes falling; it is imperceptible and known by inference." In the 4th century BC, the Greek philosopher Aristotle believed that there was no effect without a cause, and therefore no motion without a force. He hypothesized that everything tried to move towards its proper place in the crystalline spheres of the heavens, and that physical bodies fell toward the center of the Earth in proportion to their weight. Brahmagupta, in the Brahmasphuta Siddhanta (628 AD), responded to critics of the heliocentric system of Aryabhata (476–550 AD) stating that "all heavy things are attracted towards the center of the earth" and that "all heavy things fall down to the earth by a law of nature, for it is the nature of the earth to attract and to keep things, as it is the nature of water to flow, that of fire to burn, and that of wind to set in motion... The earth is the only low thing, and seeds always return to it, in whatever direction you may throw them away, and never rise upwards from the earth." In the 9th century, the eldest Banū Mūsā brother, Muhammad ibn Musa, in his Astral Motion and The Force of Attraction, hypothesized that there was a force of attraction between heavenly bodies, foreshadowing Newton's law of universal gravitation. In the 1000s, the Persian scientist Ibn al-Haytham (Alhacen), in the Mizan al-Hikmah, discussed the theory of attraction between masses, and it seems that he was aware of the magnitude of acceleration due to gravity. In 1121, Al-Khazini, in The Book of the Balance of Wisdom, differentiated between force, mass, and weight, and discovered that gravity varies with the distance from the centre of the Earth, though he believed that the weight of heavy bodies increase as they are farther from the centre of the Earth. All these early attempts at trying to explain the force of gravity were philosophical in nature and it would be Isaac Newton that gave the first correct desciption of gravity. ## Scientific revolution Modern work on gravitational theory began with the work of Galileo Galilei in the late 16th century and early 17th century. In his famous (though probably apocryphal) experiment dropping balls from the Tower of Pisa, and later with careful measurements of balls rolling down inclines, Galileo showed that gravitation accelerates all objects at the same rate. This was a major departure from Aristotle's belief that heavier objects are accelerated faster. (Galileo correctly postulated air resistance as the reason that lighter objects may fall more slowly in an atmosphere.) Galileo's work set the stage for the formulation of Newton's theory of gravity. ## Newton's theory of gravitation In 1687, English mathematician Sir Isaac Newton published Principia, which hypothesizes the inverse-square law of universal gravitation. In his own words, “I deduced that the forces which keep the planets in their orbs must be reciprocally as the squares of their distances from the centers about which they revolve; and thereby compared the force requisite to keep the Moon in her orb with the force of gravity at the surface of the Earth; and found them answer pretty nearly.” Newton's theory enjoyed its greatest success when it was used to predict the existence of Neptune based on motions of Uranus that could not be accounted by the actions of the other planets. Calculations by John Couch Adams and Urbain Le Verrier both predicted the general position of the planet, and Le Verrier's calculations are what led Johann Gottfried Galle to the discovery of Neptune. Ironically, it was another discrepancy in a planet's orbit that helped to point out flaws in Newton's theory. By the end of the 19th century, it was known that the orbit of Mercury could not be accounted for entirely under Newton's theory, but all searches for another perturbing body (such as a planet orbiting the Sun even closer than Mercury) had been fruitless. The issue was resolved in 1915 by Albert Einstein's new General Theory of Relativity, which accounted for the discrepancy in Mercury's orbit. Although Newton's theory has been superseded, most modern non-relativistic gravitational calculations are still made using Newton's theory because it is a much simpler theory to work with than General Relativity, and gives sufficiently accurate results for most applications. ## General relativity In general relativity, the effects of gravitation are ascribed to spacetime curvature instead of a force. The starting point for general relativity is the equivalence principle, which equates free fall with inertial motion. The issue that this creates is that free-falling objects can accelerate with respect to each other. In Newtonian physics, no such acceleration can occur unless at least one of the objects is being operated on by a force (and therefore is not moving inertially). To deal with this difficulty, Einstein proposed that spacetime is curved by matter, and that free-falling objects are moving along locally straight paths in curved spacetime. (This type of path is called a geodesic.) More specifically, Einstein discovered the field equations of general relativity, which relate the presence of matter and the curvature of spacetime and are named after him. The Einstein field equations are a set of 10 simultaneous, non-linear, differential equations. The solutions of the field equations are the components of the metric tensor of spacetime. A metric tensor describes a geometry of spacetime. The geodesic paths for a spacetime are calculated from the metric tensor. Notable solutions of the Einstein field equations include: - The Schwarzschild solution, which describes spacetime surrounding a spherically symmetric non-rotating uncharged massive object. For compact enough objects, this solution generated a black hole with a central singularity. For radial distances from the center which are much greater than the Schwarzschild radius, the accelerations predicted by the Schwarzschild solution are practically identical to those predicted by Newton's theory of gravity. - The Reissner-Nordström solution, in which the central object has an electrical charge. For charges with a geometrized length which are less than the geometrized length of the mass of the object, this solution produces black holes with two event horizons. - The Kerr solution for rotating massive objects. This solution also produces black holes with multiple event horizons. - The Kerr-Newman solution for charged, rotating massive objects. This solution also produces black holes with multiple event horizons. - The cosmological Robertson-Walker solution, which predicts the expansion of the universe. General relativity has enjoyed much success because of how its predictions of phenomena which are not called for by the theory of gravity have been regularly confirmed. For example: - General relativity accounts for the anomalous perihelion precession of the planet Mercury. - The prediction that time runs slower at lower potentials has been confirmed by the Pound-Rebka experiment, the Hafele-Keating experiment, and the GPS. - The prediction of the deflection of light was first confirmed by Arthur Eddington in 1919, and has more recently been strongly confirmed through the use of a quasar which passes behind the Sun as seen from the Earth. See also gravitational lensing. - The time delay of light passing close to a massive object was first identified by Irwin Shapiro in 1964 in interplanetary spacecraft signals. - Gravitational radiation has been indirectly confirmed through studies of binary pulsars. - The expansion of the universe (predicted by the Alexander Friedmann) was confirmed by Edwin Hubble in 1929. ## Gravity and quantum mechanics Several decades after the discovery of general relativity it was realized that general relativity is incompatible with quantum mechanics. It is possible to describe gravity in the framework of quantum field theory like the other fundamental forces, with the attractive force of gravity arises due to exchange of virtual gravitons, in the same way as the electromagnetic force arises from exchange of virtual photons. This reproduces general relativity in the classical limit. However, this approach fails at short distances of the order of the Planck length, where a more complete theory of quantum gravity (or a new approach to quantum mechanics) is required. Many believe the complete theory to be string theory, or more currently M Theory. # Specifics ## Earth's gravity Every planetary body (including the Earth) is surrounded by its own gravitational field, which exerts an attractive force on all objects. Assuming a spherically symmetrical planet (a reasonable approximation), the strength of this field at any given point is proportional to the planetary body's mass and inversely proportional to the square of the distance from the center of the body. The strength of the gravitational field is numerically equal to the acceleration of objects under its influence, and its value at the Earth's surface, denoted g, is approximately 9.81 m/s² (32.2 ft/s²) as the standard average. This means that, ignoring air resistance, an object falling freely near the earth's surface increases its velocity with 9.81 m/s (32.2 ft/s or 22 mph) for each second of its descent. Thus, an object starting from rest will attain a velocity of 9.81 m/s (32 ft/s) after one second, 19.6 m/s (64 ft/s) after two seconds, and so on, adding 9.8 m/s to each resulting velocity. According to Newton's 3rd Law, the Earth itself experiences an equal and opposite force to that acting on the falling object, meaning that the Earth also accelerates towards the object. However, because the mass of the Earth is huge, the acceleration of the Earth by this same force is negligible, when measured relative to the system's center of mass. ## Equations for a falling body The kinematical and dynamical equations describing the trajectories of falling bodies are considerably simpler if the gravitational force is assumed constant. This assumption is reasonable for objects falling to Earth over the relatively short vertical distances of our everyday experience, but does not hold over larger distances, such as spacecraft trajectories, since the acceleration due to Earth's gravity is much smaller at large distances. Under an assumption of constant gravity, Newton’s law of gravitation simplifies to F = mg, where m is the mass of the body and g is a constant vector with an average magnitude of 9.81 m/s². The acceleration due to gravity is equal to this g. An initially-stationary object which is allowed to fall freely under gravity drops a distance which is proportional to the square of the elapsed time. The image on the right, spanning half a second, was captured with a stroboscopic flash at 20 flashes per second. During the first 1/20th of a second the ball drops one unit of distance (here, a unit is about 12 mm); by 2/20ths it has dropped at total of 4 units; by 3/20ths, 9 units and so on. Under the same constant gravity assumptions, the potential energy, Ep, of a body at height h is given by Ep = mgh (or Ep = Wh, with W meaning weight). This expression is valid only over small distances h from the surface of the Earth. Similarly, the expression h = v^2/2g for the maximum height reached by a vertically projected body with velocity v is useful for small heights and small initial velocities only. In case of large initial velocities we have to use the principle of conservation of energy to find the maximum height reached. This same expression can be solved for v to determine the velocity of an object dropped from a height h immediately before hitting the ground, v=\sqrt{2gh}, assuming negligible air resistance. ## Gravity and astronomy The discovery and application of Newton's law of gravity accounts for the detailed information we have about the planets in our solar system, the mass of the Sun, the distance to stars, quasars and even the theory of dark matter. Although we have not traveled to all the planets nor to the Sun, we know their masses. These masses are obtained by applying the laws of gravity to the measured characteristics of the orbit. In space an object maintains its orbit because of the force of gravity acting upon it. Planets orbit stars, stars orbit galactic centers, galaxies orbit a center of mass in clusters, and clusters orbit in superclusters. The force of gravity is proportional to the mass of an object and inversely proportional to the square of the distance between the objects. ## Gravitational radiation In general relativity, gravitational radiation is generated in situations where the curvature of spacetime is oscillating, such as is the case with co-orbiting objects. The gravitational radiation emitted by the solar system is far too small to measure. However, gravitational radiation has been indirectly observed as an energy loss over time in binary pulsar systems such as PSR 1913+16. It is believed that neutron star mergers and black hole formation may create detectable amounts of gravitational radiation. Gravitational radiation observatories such as LIGO have been created to study the problem. No confirmed detections have been made of this hypothetical radiation, but as the science behind LIGO is refined and as the instruments themselves are endowed with greater sensitivity over the next decade, this may change. # Alternative theories ## Historical alternative theories - Aristotelian theory of gravity - Le Sage's theory of gravitation (1784) also called LeSage gravity, proposed by Georges-Louis Le Sage, based on a fluid-based explanation where a light gas fills the entire universe. - Nordström's theory of gravitation (1912, 1913), an early competitor of general relativity. - Whitehead's theory of gravitation (1922), another early competitor of general relativity. ## Recent alternative theories - Brans-Dicke theory of gravity (1961) - Induced gravity (1967), a proposal by Andrei Sakharov according to which general relativity might arise from quantum field theories of matter. - Rosen bi-metric theory of gravity - In the modified Newtonian dynamics (MOND) (1981), Mordehai Milgrom proposes a modification of Newton's Second Law of motion for small accelerations. - The new and highly controversial Process Physics theory attempts to address gravity - The self-creation cosmology theory of gravity (1982) by G.A. Barber in which the Brans-Dicke theory is modified to allow mass creation. - Nonsymmetric gravitational theory (NGT) (1994) by John Moffat - Tensor-vector-scalar gravity (TeVeS) (2004), a relativistic modification of MOND by Jacob Bekenstein	Gravitation Lua error in Module:Redirect at line 65: could not parse redirect on page "Gravity". Template:Otheruses4 Gravitation is a natural phenomenon by which all objects with mass attract each other, and is one of the fundamental forces of physics. In everyday life, gravitation is most commonly thought of as the agency that gives objects weight. It is responsible for keeping the Earth and the other planets in their orbits around the Sun; for keeping the Moon in its orbit around the Earth, for the formation of tides; for convection (by which hot fluids rise); for heating the interiors of forming stars and planets to very high temperatures; and for various other phenomena that we observe. Gravitation is also the reason for the very existence of the Earth, the Sun, and most macroscopic objects in the universe; without it, matter would not have coalesced into these large masses and life, as we know it, would not exist. Modern physics describes gravitation using the general theory of relativity, but the much simpler Newton's law of universal gravitation provides an excellent approximation in most cases. The terms gravitation and gravity are mostly interchangeable in everyday use, but in scientific usage a distinction may be made. "Gravitation" is a general term describing the attractive influence that all objects with mass exert on each other, while "gravity" specifically refers to a force that is supposed in some theories (such as Newton's) to be the cause of this attraction. By contrast, in general relativity gravitation is due to spacetime curvatures that cause inertially moving objects to accelerate towards each other. # History of gravitational theory ## Early history Efforts to understand gravity began in ancient times. Philosophers in ancient India explained the phenomenon from the 8th century BC.[1] According to Kanada, founder of the Vaisheshika school, "Weight causes falling; it is imperceptible and known by inference."[2] In the 4th century BC, the Greek philosopher Aristotle believed that there was no effect without a cause, and therefore no motion without a force. He hypothesized that everything tried to move towards its proper place in the crystalline spheres of the heavens, and that physical bodies fell toward the center of the Earth in proportion to their weight. Brahmagupta, in the Brahmasphuta Siddhanta (628 AD), responded to critics of the heliocentric system of Aryabhata (476–550 AD) stating that "all heavy things are attracted towards the center of the earth" and that "all heavy things fall down to the earth by a law of nature, for it is the nature of the earth to attract and to keep things, as it is the nature of water to flow, that of fire to burn, and that of wind to set in motion... The earth is the only low thing, and seeds always return to it, in whatever direction you may throw them away, and never rise upwards from the earth."[3][4] In the 9th century, the eldest Banū Mūsā brother, Muhammad ibn Musa, in his Astral Motion and The Force of Attraction, hypothesized that there was a force of attraction between heavenly bodies,[5] foreshadowing Newton's law of universal gravitation.[6] In the 1000s, the Persian scientist Ibn al-Haytham (Alhacen), in the Mizan al-Hikmah, discussed the theory of attraction between masses, and it seems that he was aware of the magnitude of acceleration due to gravity.[7] In 1121, Al-Khazini, in The Book of the Balance of Wisdom, differentiated between force, mass, and weight,[8] and discovered that gravity varies with the distance from the centre of the Earth,[9] though he believed that the weight of heavy bodies increase as they are farther from the centre of the Earth.[10] All these early attempts at trying to explain the force of gravity were philosophical in nature and it would be Isaac Newton that gave the first correct desciption of gravity. ## Scientific revolution Modern work on gravitational theory began with the work of Galileo Galilei in the late 16th century and early 17th century. In his famous (though probably apocryphal) experiment dropping balls from the Tower of Pisa, and later with careful measurements of balls rolling down inclines, Galileo showed that gravitation accelerates all objects at the same rate. This was a major departure from Aristotle's belief that heavier objects are accelerated faster. (Galileo correctly postulated air resistance as the reason that lighter objects may fall more slowly in an atmosphere.) Galileo's work set the stage for the formulation of Newton's theory of gravity. ## Newton's theory of gravitation In 1687, English mathematician Sir Isaac Newton published Principia, which hypothesizes the inverse-square law of universal gravitation. In his own words, “I deduced that the forces which keep the planets in their orbs must be reciprocally as the squares of their distances from the centers about which they revolve; and thereby compared the force requisite to keep the Moon in her orb with the force of gravity at the surface of the Earth; and found them answer pretty nearly.” Newton's theory enjoyed its greatest success when it was used to predict the existence of Neptune based on motions of Uranus that could not be accounted by the actions of the other planets. Calculations by John Couch Adams and Urbain Le Verrier both predicted the general position of the planet, and Le Verrier's calculations are what led Johann Gottfried Galle to the discovery of Neptune. Ironically, it was another discrepancy in a planet's orbit that helped to point out flaws in Newton's theory. By the end of the 19th century, it was known that the orbit of Mercury could not be accounted for entirely under Newton's theory, but all searches for another perturbing body (such as a planet orbiting the Sun even closer than Mercury) had been fruitless. The issue was resolved in 1915 by Albert Einstein's new General Theory of Relativity, which accounted for the discrepancy in Mercury's orbit. Although Newton's theory has been superseded, most modern non-relativistic gravitational calculations are still made using Newton's theory because it is a much simpler theory to work with than General Relativity, and gives sufficiently accurate results for most applications. ## General relativity In general relativity, the effects of gravitation are ascribed to spacetime curvature instead of a force. The starting point for general relativity is the equivalence principle, which equates free fall with inertial motion. The issue that this creates is that free-falling objects can accelerate with respect to each other. In Newtonian physics, no such acceleration can occur unless at least one of the objects is being operated on by a force (and therefore is not moving inertially). To deal with this difficulty, Einstein proposed that spacetime is curved by matter, and that free-falling objects are moving along locally straight paths in curved spacetime. (This type of path is called a geodesic.) More specifically, Einstein discovered the field equations of general relativity, which relate the presence of matter and the curvature of spacetime and are named after him. The Einstein field equations are a set of 10 simultaneous, non-linear, differential equations. The solutions of the field equations are the components of the metric tensor of spacetime. A metric tensor describes a geometry of spacetime. The geodesic paths for a spacetime are calculated from the metric tensor. Notable solutions of the Einstein field equations include: - The Schwarzschild solution, which describes spacetime surrounding a spherically symmetric non-rotating uncharged massive object. For compact enough objects, this solution generated a black hole with a central singularity. For radial distances from the center which are much greater than the Schwarzschild radius, the accelerations predicted by the Schwarzschild solution are practically identical to those predicted by Newton's theory of gravity. - The Reissner-Nordström solution, in which the central object has an electrical charge. For charges with a geometrized length which are less than the geometrized length of the mass of the object, this solution produces black holes with two event horizons. - The Kerr solution for rotating massive objects. This solution also produces black holes with multiple event horizons. - The Kerr-Newman solution for charged, rotating massive objects. This solution also produces black holes with multiple event horizons. - The cosmological Robertson-Walker solution, which predicts the expansion of the universe. General relativity has enjoyed much success because of how its predictions of phenomena which are not called for by the theory of gravity have been regularly confirmed. For example: - General relativity accounts for the anomalous perihelion precession of the planet Mercury. - The prediction that time runs slower at lower potentials has been confirmed by the Pound-Rebka experiment, the Hafele-Keating experiment, and the GPS. - The prediction of the deflection of light was first confirmed by Arthur Eddington in 1919, and has more recently been strongly confirmed through the use of a quasar which passes behind the Sun as seen from the Earth. See also gravitational lensing. - The time delay of light passing close to a massive object was first identified by Irwin Shapiro in 1964 in interplanetary spacecraft signals. - Gravitational radiation has been indirectly confirmed through studies of binary pulsars. - The expansion of the universe (predicted by the Alexander Friedmann) was confirmed by Edwin Hubble in 1929. ## Gravity and quantum mechanics Several decades after the discovery of general relativity it was realized that general relativity is incompatible with quantum mechanics.[11] It is possible to describe gravity in the framework of quantum field theory like the other fundamental forces, with the attractive force of gravity arises due to exchange of virtual gravitons, in the same way as the electromagnetic force arises from exchange of virtual photons.[12][13] This reproduces general relativity in the classical limit. However, this approach fails at short distances of the order of the Planck length,[14] where a more complete theory of quantum gravity (or a new approach to quantum mechanics) is required. Many believe the complete theory to be string theory,[15] or more currently M Theory. # Specifics ## Earth's gravity Every planetary body (including the Earth) is surrounded by its own gravitational field, which exerts an attractive force on all objects. Assuming a spherically symmetrical planet (a reasonable approximation), the strength of this field at any given point is proportional to the planetary body's mass and inversely proportional to the square of the distance from the center of the body. The strength of the gravitational field is numerically equal to the acceleration of objects under its influence, and its value at the Earth's surface, denoted g, is approximately 9.81 m/s² (32.2 ft/s²) as the standard average. This means that, ignoring air resistance, an object falling freely near the earth's surface increases its velocity with 9.81 m/s (32.2 ft/s or 22 mph) for each second of its descent. Thus, an object starting from rest will attain a velocity of 9.81 m/s (32 ft/s) after one second, 19.6 m/s (64 ft/s) after two seconds, and so on, adding 9.8 m/s to each resulting velocity. According to Newton's 3rd Law, the Earth itself experiences an equal and opposite force to that acting on the falling object, meaning that the Earth also accelerates towards the object. However, because the mass of the Earth is huge, the acceleration of the Earth by this same force is negligible, when measured relative to the system's center of mass. ## Equations for a falling body The kinematical and dynamical equations describing the trajectories of falling bodies are considerably simpler if the gravitational force is assumed constant. This assumption is reasonable for objects falling to Earth over the relatively short vertical distances of our everyday experience, but does not hold over larger distances, such as spacecraft trajectories, since the acceleration due to Earth's gravity is much smaller at large distances. Under an assumption of constant gravity, Newton’s law of gravitation simplifies to F = mg, where m is the mass of the body and g is a constant vector with an average magnitude of 9.81 m/s². The acceleration due to gravity is equal to this g. An initially-stationary object which is allowed to fall freely under gravity drops a distance which is proportional to the square of the elapsed time. The image on the right, spanning half a second, was captured with a stroboscopic flash at 20 flashes per second. During the first 1/20th of a second the ball drops one unit of distance (here, a unit is about 12 mm); by 2/20ths it has dropped at total of 4 units; by 3/20ths, 9 units and so on. Under the same constant gravity assumptions, the potential energy, Ep, of a body at height h is given by Ep = mgh (or Ep = Wh, with W meaning weight). This expression is valid only over small distances h from the surface of the Earth. Similarly, the expression <math>h = v^2/2g</math> for the maximum height reached by a vertically projected body with velocity v is useful for small heights and small initial velocities only. In case of large initial velocities we have to use the principle of conservation of energy to find the maximum height reached. This same expression can be solved for v to determine the velocity of an object dropped from a height h immediately before hitting the ground, <math>v=\sqrt{2gh}</math>, assuming negligible air resistance. ## Gravity and astronomy The discovery and application of Newton's law of gravity accounts for the detailed information we have about the planets in our solar system, the mass of the Sun, the distance to stars, quasars and even the theory of dark matter. Although we have not traveled to all the planets nor to the Sun, we know their masses. These masses are obtained by applying the laws of gravity to the measured characteristics of the orbit. In space an object maintains its orbit because of the force of gravity acting upon it. Planets orbit stars, stars orbit galactic centers, galaxies orbit a center of mass in clusters, and clusters orbit in superclusters. The force of gravity is proportional to the mass of an object and inversely proportional to the square of the distance between the objects. ## Gravitational radiation In general relativity, gravitational radiation is generated in situations where the curvature of spacetime is oscillating, such as is the case with co-orbiting objects. The gravitational radiation emitted by the solar system is far too small to measure. However, gravitational radiation has been indirectly observed as an energy loss over time in binary pulsar systems such as PSR 1913+16. It is believed that neutron star mergers and black hole formation may create detectable amounts of gravitational radiation. Gravitational radiation observatories such as LIGO have been created to study the problem. No confirmed detections have been made of this hypothetical radiation, but as the science behind LIGO is refined and as the instruments themselves are endowed with greater sensitivity over the next decade, this may change. # Alternative theories ## Historical alternative theories - Aristotelian theory of gravity - Le Sage's theory of gravitation (1784) also called LeSage gravity, proposed by Georges-Louis Le Sage, based on a fluid-based explanation where a light gas fills the entire universe. - Nordström's theory of gravitation (1912, 1913), an early competitor of general relativity. - Whitehead's theory of gravitation (1922), another early competitor of general relativity. ## Recent alternative theories - Brans-Dicke theory of gravity (1961) - Induced gravity (1967), a proposal by Andrei Sakharov according to which general relativity might arise from quantum field theories of matter. - Rosen bi-metric theory of gravity - In the modified Newtonian dynamics (MOND) (1981), Mordehai Milgrom proposes a modification of Newton's Second Law of motion for small accelerations. - The new and highly controversial Process Physics theory attempts to address gravity - The self-creation cosmology theory of gravity (1982) by G.A. Barber in which the Brans-Dicke theory is modified to allow mass creation. - Nonsymmetric gravitational theory (NGT) (1994) by John Moffat - Tensor-vector-scalar gravity (TeVeS) (2004), a relativistic modification of MOND by Jacob Bekenstein	https://www.wikidoc.org/index.php/Gravitation
d4ec8337b4285fce8ec1a86ec0bc5a9459601594	wikidoc	Grey matter	Grey matter Grey matter (or gray matter) is a major component of the central nervous system, consisting of nerve cell bodies, glial cells (astroglia and oligodendrocytes), capillaries, and short nerve cell extensions/processes (axons and dendrites). # Composition Grey matter is composed of unmyelinated neurons as opposed to white matter (myelinated neurons). It has a grey brown color which comes from the capillary blood vessels and the neuronal cell bodies. # Distribution Grey matter is distributed at the surface of the cerebral hemispheres (cerebral cortex) and of the cerebellum (cerebellar cortex), as well as in the depth of the cerebral (thalamus; hypothalamus; subthalamus, basal ganglia - putamen, globus pallidus, nucleus accumbens; septal nuclei), cerebellar (deep cerebellar nuclei - dentate nucleus, globose nucleus, emboliform nucleus, fastigial nucleus), brainstem (substantia nigra, red nucleus, olivary nuclei, cranial nerve nuclei) and spinal white matter (anterior horn, lateral horn, posterior horn). # Function The function of grey matter is to route sensory or motor stimulus to interneurons of the CNS in order to create a response to the stimulus through chemical synapse activity. Research has shown that the amount of gray matter in a brain is positively correlated with human intelligence. (Andreason & Others, 1994) Grey matter structures (cortex, deep nuclei) process information originating in the sensory organs or in other grey matter regions. This information is conveyed via specialized nerve cell extensions (long axons), which form the bulk of the cerebral, cerebellar, and spinal white matter.	Grey matter Template:Infobox Anatomy Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Grey matter (or gray matter) is a major component of the central nervous system, consisting of nerve cell bodies, glial cells (astroglia and oligodendrocytes), capillaries, and short nerve cell extensions/processes (axons and dendrites). # Composition Grey matter is composed of unmyelinated neurons as opposed to white matter (myelinated neurons). It has a grey brown color which comes from the capillary blood vessels and the neuronal cell bodies. # Distribution Grey matter is distributed at the surface of the cerebral hemispheres (cerebral cortex) and of the cerebellum (cerebellar cortex), as well as in the depth of the cerebral (thalamus; hypothalamus; subthalamus, basal ganglia - putamen, globus pallidus, nucleus accumbens; septal nuclei), cerebellar (deep cerebellar nuclei - dentate nucleus, globose nucleus, emboliform nucleus, fastigial nucleus), brainstem (substantia nigra, red nucleus, olivary nuclei, cranial nerve nuclei) and spinal white matter (anterior horn, lateral horn, posterior horn). # Function The function of grey matter is to route sensory or motor stimulus to interneurons of the CNS in order to create a response to the stimulus through chemical synapse activity. Research has shown that the amount of gray matter in a brain is positively correlated with human intelligence. (Andreason & Others, 1994) Grey matter structures (cortex, deep nuclei) process information originating in the sensory organs or in other grey matter regions. This information is conveyed via specialized nerve cell extensions (long axons), which form the bulk of the cerebral, cerebellar, and spinal white matter.	https://www.wikidoc.org/index.php/Gray_matter
4729784cc626ba3eb7f5712d833f9ab843b456e0	wikidoc	Griffithsin	Griffithsin # Overview Griffithsin, is a protein isolated from the red algae Griffithsia. It has a 121-amino acid sequence. It has been shown in vitro to be a highly potent HIV entry inhibitor. It is currently being investigated as a potential microbicide for use in the prevention of the transmission of HIV. - ↑ Mori T, O'Keefe BR, Sowder RC; et al. (2005). "Isolation and characterization of griffithsin, a novel HIV-inactivating protein, from the red alga Griffithsia sp". J. Biol. Chem. 280 (10): 9345–53. doi:10.1074/jbc.M411122200. PMID 15613479.CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link) .mw-parser-output cite.citation{font-style:inherit}.mw-parser-output q{quotes:"\"""\"""'""'"}.mw-parser-output code.cs1-code{color:inherit;background:inherit;border:inherit;padding:inherit}.mw-parser-output .cs1-lock-free a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-limited a,.mw-parser-output .cs1-lock-registration a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-subscription a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration{color:#555}.mw-parser-output .cs1-subscription span,.mw-parser-output .cs1-registration span{border-bottom:1px dotted;cursor:help}.mw-parser-output .cs1-hidden-error{display:none;font-size:100%}.mw-parser-output .cs1-visible-error{display:none;font-size:100%}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration,.mw-parser-output .cs1-format{font-size:95%}.mw-parser-output .cs1-kern-left,.mw-parser-output .cs1-kern-wl-left{padding-left:0.2em}.mw-parser-output .cs1-kern-right,.mw-parser-output .cs1-kern-wl-right{padding-right:0.2em} - ↑ Emau P, Tian B, O'keefe BR; et al. (2007). "Griffithsin, a potent HIV entry inhibitor, is an excellent candidate for anti-HIV microbicide". J. Med. Primatol. 36 (4–5): 244–53. doi:10.1111/j.1600-0684.2007.00242.x. PMID 17669213.CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link)	Griffithsin # Overview Griffithsin, is a protein isolated from the red algae Griffithsia. It has a 121-amino acid sequence.[1] It has been shown in vitro to be a highly potent HIV entry inhibitor. It is currently being investigated as a potential microbicide for use in the prevention of the transmission of HIV.[2] - ↑ Mori T, O'Keefe BR, Sowder RC; et al. (2005). "Isolation and characterization of griffithsin, a novel HIV-inactivating protein, from the red alga Griffithsia sp". J. Biol. Chem. 280 (10): 9345–53. doi:10.1074/jbc.M411122200. PMID 15613479.CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link) .mw-parser-output cite.citation{font-style:inherit}.mw-parser-output q{quotes:"\"""\"""'""'"}.mw-parser-output code.cs1-code{color:inherit;background:inherit;border:inherit;padding:inherit}.mw-parser-output .cs1-lock-free a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/6/65/Lock-green.svg/9px-Lock-green.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-limited a,.mw-parser-output .cs1-lock-registration a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/d/d6/Lock-gray-alt-2.svg/9px-Lock-gray-alt-2.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-subscription a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/a/aa/Lock-red-alt-2.svg/9px-Lock-red-alt-2.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration{color:#555}.mw-parser-output .cs1-subscription span,.mw-parser-output .cs1-registration span{border-bottom:1px dotted;cursor:help}.mw-parser-output .cs1-hidden-error{display:none;font-size:100%}.mw-parser-output .cs1-visible-error{display:none;font-size:100%}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration,.mw-parser-output .cs1-format{font-size:95%}.mw-parser-output .cs1-kern-left,.mw-parser-output .cs1-kern-wl-left{padding-left:0.2em}.mw-parser-output .cs1-kern-right,.mw-parser-output .cs1-kern-wl-right{padding-right:0.2em} - ↑ Emau P, Tian B, O'keefe BR; et al. (2007). "Griffithsin, a potent HIV entry inhibitor, is an excellent candidate for anti-HIV microbicide". J. Med. Primatol. 36 (4–5): 244–53. doi:10.1111/j.1600-0684.2007.00242.x. PMID 17669213.CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link) Template:WikiDoc Sources Template:WH	https://www.wikidoc.org/index.php/Griffithsin
c9cde856867de0fc674ea02766a61bb8cf7ed6a4	wikidoc	Grifulvin V	Grifulvin V This is one of two common brand names for the prescription medication Griseofulvin (GRISS-ee-oh-FULL-vin). It is used to treat fungal infections of the skin, hair, fingernails and toenails. Particularly ringworm, athlete's foot, jock itch, sweat rash, and many other fungal infections. Griseofulivin is not effective against infections caused by yeast or bacteria. # Other Common Brand Names for Griseofulvin Grifulvin V, Gris-PEG # Uses Taken as an oral tablet. Best taken with a meal that has a high fat content. It may take from several days to several months for treatment to be completed, depending on type and location of infection. Medication is taken in full prescribed amount until finished even if symptoms have disappeared for a few days. Stopping or missing medication may allow infection to re-occur. # Side effects Headache, diarrhea, gas, nausea, fatigue, vomiting, dizziness, trouble sleeping, increased sunlight sensitivity, (sunburn-like effect) may occur. If side effects worsen, doctor should be contacted promptly. Immediately contact doctor if the following occurs: yellowing of the eyes or skin, signs of infection (e.g., fever, chills, persistent sore throat), soreness of the mouth or tongue, mental/mood changes, tingling or numbness of the hands/feet. In the unlikely event of an allergic reaction, seek immediate medical attention. Symptoms of an allergic reaction: trouble breathing, skin rash, itching, hives, swelling, severe dizziness. If any other effects are noticed contact doctor immediately. # Precautions Medication should be avoided if patient has a blood disorder or a severe liver disease(hepatic failure). Alcoholic beverages should be avoided while drug is taken, unless doctor approves permission. Drinking alcohol can result in a rapid heart rate and flushing of the skin. Griseofulvin may increase sunlight sensitivity, and sunlight should be avoided, or sunscreen and protective clothing worn. ## Pregnancy Warning This drug interferes with birth control pills. This drug is not to be used during conception of children. It should not be used while pregnant and it has harmful effects on the human sperm and can cause birth defects. Males should wait at least six months after medication before fathering of children. This drug may also pass into breast milk. # Drug Interactions Doctor should evaluate each and every prescription and over the counter drug before treatment. Especially the blood thinners heparin and wafarin. # Overdose If overdose is suspected contact the US national poison control hot line at 1-800-222-1222 or your nations poison control. # Notes Dry it, treat it, and prevent it. Avoid sticky wet creams at all costs, wetness and warmth are the breeding grounds for the infections. Use dry powders and keep well ventilated.	Grifulvin V Template:Cleanup This is one of two common brand names for the prescription medication Griseofulvin (GRISS-ee-oh-FULL-vin). It is used to treat fungal infections of the skin, hair, fingernails and toenails. Particularly ringworm, athlete's foot, jock itch, sweat rash, and many other fungal infections. Griseofulivin is not effective against infections caused by yeast or bacteria. # Other Common Brand Names for Griseofulvin Grifulvin V, Gris-PEG # Uses Taken as an oral tablet. Best taken with a meal that has a high fat content. It may take from several days to several months for treatment to be completed, depending on type and location of infection. Medication is taken in full prescribed amount until finished even if symptoms have disappeared for a few days. Stopping or missing medication may allow infection to re-occur. # Side effects Headache, diarrhea, gas, nausea, fatigue, vomiting, dizziness, trouble sleeping, increased sunlight sensitivity, (sunburn-like effect) may occur. If side effects worsen, doctor should be contacted promptly. Immediately contact doctor if the following occurs: yellowing of the eyes or skin, signs of infection (e.g., fever, chills, persistent sore throat), soreness of the mouth or tongue, mental/mood changes, tingling or numbness of the hands/feet. In the unlikely event of an allergic reaction, seek immediate medical attention. Symptoms of an allergic reaction: trouble breathing, skin rash, itching, hives, swelling, severe dizziness. If any other effects are noticed contact doctor immediately. # Precautions Medication should be avoided if patient has a blood disorder or a severe liver disease(hepatic failure). Alcoholic beverages should be avoided while drug is taken, unless doctor approves permission. Drinking alcohol can result in a rapid heart rate and flushing of the skin. Griseofulvin may increase sunlight sensitivity, and sunlight should be avoided, or sunscreen and protective clothing worn. ## Pregnancy Warning This drug interferes with birth control pills. This drug is not to be used during conception of children. It should not be used while pregnant and it has harmful effects on the human sperm and can cause birth defects. Males should wait at least six months after medication before fathering of children. This drug may also pass into breast milk. # Drug Interactions Doctor should evaluate each and every prescription and over the counter drug before treatment. Especially the blood thinners heparin and wafarin. # Overdose If overdose is suspected contact the US national poison control hot line at 1-800-222-1222 or your nations poison control. # Notes Dry it, treat it, and prevent it. Avoid sticky wet creams at all costs, wetness and warmth are the breeding grounds for the infections. Use dry powders and keep well ventilated.	https://www.wikidoc.org/index.php/Grifulvin_V
0a249972354f92009659fb2c7f608566cf3a01c8	wikidoc	Guaiazulene	Guaiazulene # Overview Guaiazulene, also azulon or 1,4-dimethyl-7-isopropylazulene, is a dark blue crystalline hydrocarbon and a derivative of azulene. Specifically, it is a bicyclic sesquiterpene that occurs naturally as a constituent of some essential oils, mainly oil of guaiac and chamomile oil, which also serve as its commercial sources. Various soft corals also contain guaiazulene as a principal pigment. Guaiazulene is an FDA-approved cosmetic color additive. It is also a common component of cosmetics like shampoos or skin care products with other skin soothing compounds such as allantoin. Guaiazulene has applications as an anti-ulcer drug, and can be also used as a volatile dye with a known evaporation rate to indicate end of use of various products (such as insecticide strips.)	Guaiazulene Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview Guaiazulene, also azulon or 1,4-dimethyl-7-isopropylazulene, is a dark blue crystalline hydrocarbon and a derivative of azulene. Specifically, it is a bicyclic sesquiterpene that occurs naturally as a constituent of some essential oils, mainly oil of guaiac and chamomile oil, which also serve as its commercial sources. Various soft corals also contain guaiazulene as a principal pigment. Guaiazulene is an FDA-approved cosmetic color additive. It is also a common component of cosmetics like shampoos or skin care products with other skin soothing compounds such as allantoin. Guaiazulene has applications as an anti-ulcer drug, and can be also used as a volatile dye with a known evaporation rate to indicate end of use of various products (such as insecticide strips.) # External links Template:WikiDoc Sources	https://www.wikidoc.org/index.php/Guaiazulene
02a022259918fdbc1323acfc6dc9b9e460a71efa	wikidoc	Guaifenesin	Guaifenesin # Disclaimer WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here. NOTE: Most over the counter (OTC) are not reviewed and approved by the FDA. However, they may be marketed if they comply with applicable regulations and policies. FDA has not evaluated whether this product complies. # Overview Guaifenesin is an expectorant that is FDA approved for the treatment of loosening phlegm (mucus) and thinning of bronchial secretions to make coughs more productive.. Common adverse reactions include nausea, vomiting. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) # Indications - Helps loosen phlegm (mucus) and thin bronchial secretions to make coughs more productive. # Dosage - Follow dosage below or use as directed by a physician. - Do not take more than 6 doses in any 24-hour period. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Guaifenesin in adult patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Guaifenesin in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) # Indication - Helps loosen phlegm (mucus) and thin bronchial secretions to make coughs more productive. # Dosage - Follow dosage below or use as directed by a physician. - Do not take more than 6 doses in any 24-hour period. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Guaifenesin in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Guaifenesin in pediatric patients. # Contraindications There is limited information regarding Guaifenesin Contraindications in the drug label. # Warnings Ask a doctor before use if you have - Cough that occurs with too much phlegm (mucus) - Cough that lasts or is chronic such as occurs with smoking, asthma, chronic bronchitis, or emphysema Stop use and ask a doctor if Cough lasts more than 7 days, comes back, or is accompanied by fever, rash, or persistent headache. These could be signs of a serious condition. - You are hypersensitive to any of the ingredients. If pregnant or breast-feeding - Ask a health professional before use. Keep out of reach of children - In case of overdose, get medical help or contact a Poison Control Center right away. # Adverse Reactions ## Clinical Trials Experience There is limited information regarding Clinical Trial Experience of Guaifenesin in the drug label. ## Postmarketing Experience Common Gastrointestinal: nausea, vomiting # Drug Interactions There is limited information regarding Guaifenesin Drug Interactions in the drug label. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): There is no FDA guidance on usage of Guaifenesin in women who are pregnant. Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of guaifenesin in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of guaifenesin during labor and delivery. ### Nursing Mothers There is no FDA guidance on the use of guaifenesin with respect to nursing mothers. ### Pediatric Use There is no FDA guidance on the use of guaifenesin with respect to pediatric patients. ### Geriatic Use There is no FDA guidance on the use of guaifenesin with respect to geriatric patients. ### Gender There is no FDA guidance on the use of guaifenesin with respect to specific gender populations. ### Race There is no FDA guidance on the use of guaifenesin with respect to specific racial populations. ### Renal Impairment There is no FDA guidance on the use of guaifenesin in patients with renal impairment. ### Hepatic Impairment There is no FDA guidance on the use of guaifenesin in patients with hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of guaifenesin in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of guaifenesin in patients who are immunocompromised. # Administration and Monitoring ### Administration - Oral ### Monitoring There is limited information regarding Monitoring of guaifenesin in the drug label. # IV Compatibility There is limited information regarding IV Compatibility of guaifenesin in the drug label. # Overdosage There is limited information regarding Guaifenesin overdosage. If you suspect drug poisoning or overdose, please contact the National Poison Help hotline (1-800-222-1222) immediately. # Pharmacology There is limited information regarding Guaifenesin Pharmacology in the drug label. ## Mechanism of Action There is limited information regarding Guaifenesin Mechanism of Action in the drug label. ## Structure There is limited information regarding Guaifenesin Structure in the drug label. ## Pharmacodynamics There is limited information regarding Pharmacodynamics of guaifenesin in the drug label. ## Pharmacokinetics There is limited information regarding Pharmacokinetics of guaifenesin in the drug label. ## Nonclinical Toxicology There is limited information regarding Nonclinical Toxicology of guaifenesin in the drug label. # Clinical Studies There is limited information regarding Guaifenesin Clinical Studies in the drug label. # How Supplied There is limited information regarding Guaifenesin How Supplied in the drug label. ## Storage - Keep tightly closed. Store at controlled room temperature, 20°-25°C (68°-77°F). Protect from light. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information There is limited information regarding Patient Counseling Information of guaifenesin in the drug label. # Precautions with Alcohol - Alcohol-guaifenesin interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - GUAIFENESIN # Look-Alike Drug Names There is limited information regarding Guaifenesin Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	Guaifenesin Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Kiran Singh, M.D. [2] # Disclaimer WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here. NOTE: Most over the counter (OTC) are not reviewed and approved by the FDA. However, they may be marketed if they comply with applicable regulations and policies. FDA has not evaluated whether this product complies. # Overview Guaifenesin is an expectorant that is FDA approved for the treatment of loosening phlegm (mucus) and thinning of bronchial secretions to make coughs more productive.. Common adverse reactions include nausea, vomiting. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) # Indications - Helps loosen phlegm (mucus) and thin bronchial secretions to make coughs more productive. # Dosage - Follow dosage below or use as directed by a physician. - Do not take more than 6 doses in any 24-hour period. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Guaifenesin in adult patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Guaifenesin in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) # Indication - Helps loosen phlegm (mucus) and thin bronchial secretions to make coughs more productive. # Dosage - Follow dosage below or use as directed by a physician. - Do not take more than 6 doses in any 24-hour period. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Guaifenesin in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Guaifenesin in pediatric patients. # Contraindications There is limited information regarding Guaifenesin Contraindications in the drug label. # Warnings Ask a doctor before use if you have - Cough that occurs with too much phlegm (mucus) - Cough that lasts or is chronic such as occurs with smoking, asthma, chronic bronchitis, or emphysema Stop use and ask a doctor if Cough lasts more than 7 days, comes back, or is accompanied by fever, rash, or persistent headache. These could be signs of a serious condition. - You are hypersensitive to any of the ingredients. If pregnant or breast-feeding - Ask a health professional before use. Keep out of reach of children - In case of overdose, get medical help or contact a Poison Control Center right away. # Adverse Reactions ## Clinical Trials Experience There is limited information regarding Clinical Trial Experience of Guaifenesin in the drug label. ## Postmarketing Experience Common Gastrointestinal: nausea, vomiting # Drug Interactions There is limited information regarding Guaifenesin Drug Interactions in the drug label. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): There is no FDA guidance on usage of Guaifenesin in women who are pregnant. Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of guaifenesin in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of guaifenesin during labor and delivery. ### Nursing Mothers There is no FDA guidance on the use of guaifenesin with respect to nursing mothers. ### Pediatric Use There is no FDA guidance on the use of guaifenesin with respect to pediatric patients. ### Geriatic Use There is no FDA guidance on the use of guaifenesin with respect to geriatric patients. ### Gender There is no FDA guidance on the use of guaifenesin with respect to specific gender populations. ### Race There is no FDA guidance on the use of guaifenesin with respect to specific racial populations. ### Renal Impairment There is no FDA guidance on the use of guaifenesin in patients with renal impairment. ### Hepatic Impairment There is no FDA guidance on the use of guaifenesin in patients with hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of guaifenesin in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of guaifenesin in patients who are immunocompromised. # Administration and Monitoring ### Administration - Oral ### Monitoring There is limited information regarding Monitoring of guaifenesin in the drug label. # IV Compatibility There is limited information regarding IV Compatibility of guaifenesin in the drug label. # Overdosage There is limited information regarding Guaifenesin overdosage. If you suspect drug poisoning or overdose, please contact the National Poison Help hotline (1-800-222-1222) immediately. # Pharmacology There is limited information regarding Guaifenesin Pharmacology in the drug label. ## Mechanism of Action There is limited information regarding Guaifenesin Mechanism of Action in the drug label. ## Structure There is limited information regarding Guaifenesin Structure in the drug label. ## Pharmacodynamics There is limited information regarding Pharmacodynamics of guaifenesin in the drug label. ## Pharmacokinetics There is limited information regarding Pharmacokinetics of guaifenesin in the drug label. ## Nonclinical Toxicology There is limited information regarding Nonclinical Toxicology of guaifenesin in the drug label. # Clinical Studies There is limited information regarding Guaifenesin Clinical Studies in the drug label. # How Supplied There is limited information regarding Guaifenesin How Supplied in the drug label. ## Storage - Keep tightly closed. Store at controlled room temperature, 20°-25°C (68°-77°F). [See USP] Protect from light. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information There is limited information regarding Patient Counseling Information of guaifenesin in the drug label. # Precautions with Alcohol - Alcohol-guaifenesin interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - GUAIFENESIN # Look-Alike Drug Names There is limited information regarding Guaifenesin Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	https://www.wikidoc.org/index.php/Guaifenesin
33b1292b2a4be6ece190ed92cc4ea6c941c92f02	wikidoc	Gymnophobia	Gymnophobia # Background Gymnophobia is a fear or anxiety about being seen naked, and/or about seeing others naked, even in situations where it is socially acceptable. Gymnophobes may experience their fear of nudity before all people, or only certain people, and may regard their fear as irrational. This phobia often arises from a feeling of inadequacy that their bodies are physically inferior, particularly due to comparison with idealized images portrayed in the media. The fear may also stem from anxiety about sexuality in general, or from a persistent feeling of vulnerability associated with the thought that those who have seen the gymnophobe naked will continue to imagine the gymnophobe nude. Gymnophobia is derived from the Greek gymnos (naked) and phobos (fear). In the television series Arrested Development, character Tobias Fünke suffers from a similar fear and is described as a "never nude." Note that Tobias's case, as presented for humorous purposes, does not represent typical gymnophobia, which is usually not as extreme.	Gymnophobia Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Background Gymnophobia is a fear or anxiety about being seen naked, and/or about seeing others naked, even in situations where it is socially acceptable. Gymnophobes may experience their fear of nudity before all people, or only certain people, and may regard their fear as irrational. This phobia often arises from a feeling of inadequacy that their bodies are physically inferior, particularly due to comparison with idealized images portrayed in the media. The fear may also stem from anxiety about sexuality in general, or from a persistent feeling of vulnerability associated with the thought that those who have seen the gymnophobe naked will continue to imagine the gymnophobe nude. Gymnophobia is derived from the Greek gymnos (naked) and phobos (fear). In the television series Arrested Development, character Tobias Fünke suffers from a similar fear and is described as a "never nude."[2] Note that Tobias's case, as presented for humorous purposes, does not represent typical gymnophobia, which is usually not as extreme.[citation needed]	https://www.wikidoc.org/index.php/Gymnophobia
ee67f7ffd48346b17152cf20072d0054c6855032	wikidoc	Gynaecology	Gynaecology # Overview Gynaecology or gynecology (see spelling differences) refers to the surgical specialty dealing with health of the female reproductive system (uterus, vagina and ovaries). Literally, outside medicine, it means "the science of women". Almost all modern gynaecologists are also obstetricians; see Obstetrics and gynaecology. # History According to the Suda, the ancient Greek physician Soranus practiced in Alexandria and subsequently Rome. He was the chief representative of the school of physicians known as "Methodists." His treatise Gynaecology is extant (first published in 1838, later by V. Rose, in 1882, with a 6th-century Latin translation by Moschio, a physician of the same school). In the United States, J. Marion Sims is considered the father of American gynaecology. Practitioners included Dr. Benjamin B. Weinstein (1913-1974) of Tulane University in New Orleans, who specialized in fertility studies. # Examination Gynaecology is typically considered a consultant specialty. In some countries, women must first see a general practitioner (GP; also known as a family practitioner (FP)) prior to seeing a gynaecologist. If their condition requires training, knowledge, surgical technique, or equipment unavailable to the GP, the patient is then referred to a gynaecologist. In the United States, however, law and many health insurance plans allow/force gynaecologists to provide primary care in addition to aspects of their own specialty. With this option available, some women opt to see a gynaecological surgeon without another physician's referral. As in all of medicine, the main tools of diagnosis are clinical history and examination. Gynaecological examination is quite intimate, moreso than a routine physical exam. It also requires unique instrumentation such as the speculum. The speculum consists of two hinged blades of concave metal or plastic which are used to retract the tissues of the vagina and permit examination of the cervix, the lower part of the uterus located within the upper portion of the vagina. Gynaecologists typically do a bimanual examination (one hand on the abdomen and one or two fingers in the vagina) to palpate the cervix, uterus, ovaries and bony pelvis. It is not uncommon to do a rectovaginal exam for complete evaluation of the pelvis, particularly if any suspicious masses are appreciated. Male gynaecologists often have a female chaperone (nurse or medical student) for their examination. An abdominal and/or vaginal ultrasound can be used to confirm any abnormalities appreciated with the bimanual examination or when indicated by the patient's history. # Diseases The main conditions dealt with by a gynaecologist are: - Cancer and pre-cancerous diseases of the reproductive organs including ovaries, fallopian tubes, uterus, vagina, and vulva - Incontinence of urine. - Amenorrhea (absent menstrual periods) - Dysmenorrhoea (painful menstrual periods) - Infertility - Menorrhagia (heavy menstrual periods). This is a common indication for hysterectomy. - Prolapse of pelvic organs - Scabies There is some crossover in these areas. For example a woman with incontinence may be referred to a urologist. # Therapies As with all surgical specialties, gynaecologists may employ medical or surgical therapies (or many times, both), depending on the exact nature of the problem that they are treating. Pre- and post-operative medical management will often employ many "standard" drug therapies, such as antibiotics, diuretics, antihypertensives, and antiemetics. Additionally, gynaecologists make frequent use of "specialized" hormone-modulating therapies (such as Clomifene citrate and hormonal contraception) to treat disorders of the female genital tract that are responsive to pituitary and/or gonadal signals. Surgery, however, is the mainstay of gynaecological therapy. For historical and political reasons, gynaecologists were previously not considered "surgeons", although this point has always been the source of some controversy. Modern advancements in both general surgery and gynaecology, however, have blurred many of the once rigid lines of distinction. The rise of sub-specialties within gynaecology which are primarily surgical in nature (for example urogynaecology and gynaecological oncology) have strengthened the reputations of gynaecologists as surgical practitioners, and many surgeons and surgical societies have come to view gynaecologists as comrades of sorts. As proof of this changing attitude, gynaecologists are now eligible for fellowship in both the American and Royal Colleges of Surgeons, and many newer surgical textbooks include chapters on (at least basic) gynaecological surgery. Some of the more common operations that gynaecologists perform include: - Dilation and curettage (removal of the uterine contents for various reasons, including partial miscarriage and dysfunctional uterine bleeding refractive to medical therapy) - Hysterectomy (removal of the uterus) - Oophorectomy (removal of the ovaries) - Tubal ligation - Hysteroscopy - Diagnostic laparoscopy - used to diagnose and treat sources of pelvic and abdominal pain; perhaps most famously used to provide definitive diagnosis of endometriosis. - Exploratory laparotomy - may be used to investigate the level of progression of benign or malignant disease, or to assess and repair damage to the pelvic organs. - Various surgical treatments for urinary incontinence, including cystoscopy and sub-urethral slings. - Surgical treatment of pelvic organ prolapse, including correction of cystocele and rectocele. - Appendectomy - often performed to remove site of painful endometriosis implantation and/or prophylactically (against future acute appendicitis) at the time of hysterectomy or Cesarean section. May also be performed as part of a staging operation for ovarian cancer. - Cervical Excision Procedures (including cryosurgery, LLETZ, LEEP) - removal of the surface of the cervix containing pre-cancerous cells which have been previously identified on Pap smear.	Gynaecology # Overview Gynaecology or gynecology (see spelling differences) refers to the surgical specialty dealing with health of the female reproductive system (uterus, vagina and ovaries). Literally, outside medicine, it means "the science of women". Almost all modern gynaecologists are also obstetricians; see Obstetrics and gynaecology. # History According to the Suda, the ancient Greek physician Soranus practiced in Alexandria and subsequently Rome. He was the chief representative of the school of physicians known as "Methodists." His treatise Gynaecology is extant (first published in 1838, later by V. Rose, in 1882, with a 6th-century Latin translation by Moschio, a physician of the same school). In the United States, J. Marion Sims is considered the father of American gynaecology. Practitioners included Dr. Benjamin B. Weinstein (1913-1974) of Tulane University in New Orleans, who specialized in fertility studies. # Examination Gynaecology is typically considered a consultant specialty. In some countries, women must first see a general practitioner (GP; also known as a family practitioner (FP)) prior to seeing a gynaecologist. If their condition requires training, knowledge, surgical technique, or equipment unavailable to the GP, the patient is then referred to a gynaecologist. In the United States, however, law and many health insurance plans allow/force gynaecologists to provide primary care in addition to aspects of their own specialty. With this option available, some women opt to see a gynaecological surgeon without another physician's referral. As in all of medicine, the main tools of diagnosis are clinical history and examination. Gynaecological examination is quite intimate, moreso than a routine physical exam. It also requires unique instrumentation such as the speculum. The speculum consists of two hinged blades of concave metal or plastic which are used to retract the tissues of the vagina and permit examination of the cervix, the lower part of the uterus located within the upper portion of the vagina. Gynaecologists typically do a bimanual examination (one hand on the abdomen and one or two fingers in the vagina) to palpate the cervix, uterus, ovaries and bony pelvis. It is not uncommon to do a rectovaginal exam for complete evaluation of the pelvis, particularly if any suspicious masses are appreciated. Male gynaecologists often have a female chaperone (nurse or medical student) for their examination. An abdominal and/or vaginal ultrasound can be used to confirm any abnormalities appreciated with the bimanual examination or when indicated by the patient's history. # Diseases The main conditions dealt with by a gynaecologist are: - Cancer and pre-cancerous diseases of the reproductive organs including ovaries, fallopian tubes, uterus, vagina, and vulva - Incontinence of urine. - Amenorrhea (absent menstrual periods) - Dysmenorrhoea (painful menstrual periods) - Infertility - Menorrhagia (heavy menstrual periods). This is a common indication for hysterectomy. - Prolapse of pelvic organs - Scabies There is some crossover in these areas. For example a woman with incontinence may be referred to a urologist. # Therapies As with all surgical specialties, gynaecologists may employ medical or surgical therapies (or many times, both), depending on the exact nature of the problem that they are treating. Pre- and post-operative medical management will often employ many "standard" drug therapies, such as antibiotics, diuretics, antihypertensives, and antiemetics. Additionally, gynaecologists make frequent use of "specialized" hormone-modulating therapies (such as Clomifene citrate and hormonal contraception) to treat disorders of the female genital tract that are responsive to pituitary and/or gonadal signals. Surgery, however, is the mainstay of gynaecological therapy. For historical and political reasons, gynaecologists were previously not considered "surgeons", although this point has always been the source of some controversy. Modern advancements in both general surgery and gynaecology, however, have blurred many of the once rigid lines of distinction. The rise of sub-specialties within gynaecology which are primarily surgical in nature (for example urogynaecology and gynaecological oncology) have strengthened the reputations of gynaecologists as surgical practitioners, and many surgeons and surgical societies have come to view gynaecologists as comrades of sorts. As proof of this changing attitude, gynaecologists are now eligible for fellowship in both the American and Royal Colleges of Surgeons, and many newer surgical textbooks include chapters on (at least basic) gynaecological surgery. Some of the more common operations that gynaecologists perform include: - Dilation and curettage (removal of the uterine contents for various reasons, including partial miscarriage and dysfunctional uterine bleeding refractive to medical therapy) - Hysterectomy (removal of the uterus) - Oophorectomy (removal of the ovaries) - Tubal ligation - Hysteroscopy - Diagnostic laparoscopy - used to diagnose and treat sources of pelvic and abdominal pain; perhaps most famously used to provide definitive diagnosis of endometriosis. - Exploratory laparotomy - may be used to investigate the level of progression of benign or malignant disease, or to assess and repair damage to the pelvic organs. - Various surgical treatments for urinary incontinence, including cystoscopy and sub-urethral slings. - Surgical treatment of pelvic organ prolapse, including correction of cystocele and rectocele. - Appendectomy - often performed to remove site of painful endometriosis implantation and/or prophylactically (against future acute appendicitis) at the time of hysterectomy or Cesarean section. May also be performed as part of a staging operation for ovarian cancer. - Cervical Excision Procedures (including cryosurgery, LLETZ, LEEP) - removal of the surface of the cervix containing pre-cancerous cells which have been previously identified on Pap smear.	https://www.wikidoc.org/index.php/Gynaecologist
d85458ec6d29c340bb02c2a26e9ec14397baceb2	wikidoc	H-Y antigen	H-Y antigen H-Y antigen is a male tissue specific antigen. Originally thought to trigger the formation of testes (via loci, an autosomal gene that generates the antigen and one that generates the receptor,) it is now known that it does not trigger the formation of testes but may be activated by the formation of testes. There are several antigens which qualify as H-Y as defined by rejection of male skin grafts in female hosts or detected by cytotoxic T cells or antibodies. One H-Y, secreted by the testis, defined by antibodies, is identical to müllerian-inhibiting substance (AMH gene). Another H-Y, minor histocompatibility antigen, seemed to be encoded in the SMCY gene (acronym for 'selected mouse cDNA on Y'), later identified as an 11-residue peptide from the Lysine-Specific Demethylase 5D protein (KDM5D gene) presented by HLA-B7. A third example is MEA1. # Association with spermatogenesis It has been shown that male mice lacking in the H-Y antigen, hence lacking in the gene producing it, have also lost genetic information responsible for spermatogenesis. This result also identified a gene on the mouse Y chromosome, distinct from the testis-determining gene, that was essential for spermatogenesis, thus raising the possibility that the very product of this "spermatogenesis gene" is the H-Y antigen. # Male homosexuality and the birth order effect Among humans, it has been observed that men with more older brothers tend to have a higher chance of being homosexual. For every additional older brother, a man's chance of being homosexual can rise by up to 33%. One theory to explain this involves H-Y antigens, which suggests that a maternal immune reaction to these antigens has, to an extent, an inhibitory effect on the masculinization of the brain, and therefore, the more male foetuses that the mother of a man has had, the greater the maternal immune response towards him and thus the greater the inhibitory effect on brain masculinization, which is believed to be a factor in sexual orientation. This hypothesis is supported by evidence that older sisters have no discernible influence on the sexual orientation of later-born males, which would be expected since H-Y antigen is male tissue specific, the 'probable involvement of H-Y antigen in the development of sex-typical traits, and the detrimental effects of immunization of female mice to H-Y antigen on the reproductive performance of subsequent male offspring'.	H-Y antigen H-Y antigen is a male tissue specific antigen.[1] Originally thought to trigger the formation of testes (via loci, an autosomal gene that generates the antigen and one that generates the receptor,[2]) it is now known that it does not trigger the formation of testes but may be activated by the formation of testes.[3] There are several antigens which qualify as H-Y as defined by rejection of male skin grafts in female hosts or detected by cytotoxic T cells or antibodies. One H-Y, secreted by the testis, defined by antibodies, is identical to müllerian-inhibiting substance (AMH gene).[1] Another H-Y, minor histocompatibility antigen, seemed to be encoded in the SMCY gene (acronym for 'selected mouse cDNA on Y'), later identified as an 11-residue peptide from the Lysine-Specific Demethylase 5D protein (KDM5D gene) presented by HLA-B7. A third example is MEA1. # Association with spermatogenesis It has been shown that male mice lacking in the H-Y antigen, hence lacking in the gene producing it, have also lost genetic information responsible for spermatogenesis.[4] This result also identified a gene on the mouse Y chromosome, distinct from the testis-determining gene, that was essential for spermatogenesis, thus raising the possibility that the very product of this "spermatogenesis gene" is the H-Y antigen.[4] # Male homosexuality and the birth order effect Among humans, it has been observed that men with more older brothers tend to have a higher chance of being homosexual. For every additional older brother, a man's chance of being homosexual can rise by up to 33%.[5] One theory to explain this involves H-Y antigens, which suggests that a maternal immune reaction to these antigens has, to an extent, an inhibitory effect on the masculinization of the brain, and therefore, the more male foetuses that the mother of a man has had, the greater the maternal immune response towards him[6] and thus the greater the inhibitory effect on brain masculinization, which is believed to be a factor in sexual orientation.[5] This hypothesis is supported by evidence that older sisters have no discernible influence on the sexual orientation of later-born males, which would be expected since H-Y antigen is male tissue specific, the 'probable involvement of H-Y antigen in the development of sex-typical traits, and the detrimental effects of immunization of female mice to H-Y antigen on the reproductive performance of subsequent male offspring'.[7]	https://www.wikidoc.org/index.php/H-Y_antigen
d427250ac381eaa72f1452fc3791472173686ba5	wikidoc	HCCS (gene)	HCCS (gene) Cytochrome c-type heme lyase is an enzyme that in humans is encoded by the HCCS gene on chromosome X. # Structure The HCCS gene is located on the Xp22 region of chromosome X and encodes a protein that is ~30 kDa in size. The HCCS protein is localized to the inner mitochondrial membrane and is expressed in multiple tissue including prominently in the cardiovascular system and the central nervous system. # Function The HCCS protein functions as a lyase to covalently attach the heme group to the apoprotein of cytochrome c on the inner mitochondrial membrane of the mitochondrion. The heme group is required for cytochrome c to transport electrons from complex III to complex IV of the electron transport chain during respiration. Heme attachment to cytochrome c takes place in the intermembrane space and requires conserved heme-interacting residues on HCCS on one of the two heme-binding domains on HCCS, including His154. The HCCS protein may function to regulate mitochondrial lipid and total mitochondrial mass in response to mitochondrial dysfunctions. # Clinical Significance Mutations in the MCCS gene cause Microphthalmia with linear skin defects (MLS) syndrome, also known as MIDAS syndrome, microphthalmia, syndromic 7 (MCOPS7), or microphthalmia, dermal aplasia, and sclerocornea. MLS is a rare X-linked dominant male-lethal disease characterized by unilateral or bilateral microphthalmia and linear skin defects in affected females, and in utero lethality for affected males.	HCCS (gene) Cytochrome c-type heme lyase is an enzyme that in humans is encoded by the HCCS gene on chromosome X.[1] # Structure The HCCS gene is located on the Xp22 region of chromosome X and encodes a protein that is ~30 kDa in size. The HCCS protein is localized to the inner mitochondrial membrane and is expressed in multiple tissue including prominently in the cardiovascular system and the central nervous system.[2] # Function The HCCS protein functions as a lyase to covalently attach the heme group to the apoprotein of cytochrome c on the inner mitochondrial membrane of the mitochondrion.[3] The heme group is required for cytochrome c to transport electrons from complex III to complex IV of the electron transport chain during respiration. Heme attachment to cytochrome c takes place in the intermembrane space and requires conserved heme-interacting residues on HCCS on one of the two heme-binding domains on HCCS, including His154.[4] The HCCS protein may function to regulate mitochondrial lipid and total mitochondrial mass in response to mitochondrial dysfunctions.[5] # Clinical Significance Mutations in the MCCS gene cause Microphthalmia with linear skin defects (MLS) syndrome,[6] also known as MIDAS syndrome, microphthalmia, syndromic 7 (MCOPS7), or microphthalmia, dermal aplasia, and sclerocornea.[7][8] MLS is a rare X-linked dominant male-lethal disease characterized by unilateral or bilateral microphthalmia and linear skin defects in affected females, and in utero lethality for affected males.[7]	https://www.wikidoc.org/index.php/HCCS_(gene)
e470ef900694fa6b2d15f81699c7138172f059b9	wikidoc	HIV vaccine	HIV vaccine For microbiologic aspects of the causative organism(s), see Human Immunodeficiency Virus (HIV) For clinical aspects of this desease, see HIV # Overview HIV infection is a major global health issue, affecting 36.7 million people worldwide. The number of people living with HIV on antiretroviral therapy (ART) reached 17 million in 2015. Although ART has dramatically reduced morbidity and mortality in individuals with HIV infection and can also prevent HIV transmission but it cannot eradicate HIV infection due to the persistence of a latent viral reservoir, hence the need for antiretroviral therapy ART is lifelong and the cost is substantial. Although antiretroviral therapy ART is highly efficacious in preventing transmission in the setting of mother to child transmission, in sexual transmission through the treatment of infected partners in relationships, through pre-exposure or or post-exposure prophylaxis, but all these scale-up difficulties and costs may make widespread implementation challenging. Thus an HIV vaccine is essential as it is a more sustainable solution.The development of a universal effective HIV vaccine is an exceptionally difficult biomedical challenge. Firstly, no case of natural eradication of HIV infection has been identified, thus mechanisms of protection have not been definitively established. Secondly, the extreme diversity of HIV is a major obstacle as strains belonging to different subtypes can differ by up to 35% in their envelope (Env) proteins.Thus, vaccine immunogens derived from a particular strain may not be effective against other strain. To generate an efficacious global vaccine, immunogens capable of generating protective responses covering most major strains are required. # Historical Perspective - Ever since HIV was formally identified as the cause of AIDS, there have been ongoing efforts on vaccines against the disease. - On April 24, 1984, the US Secretary of Health and Human Services, Margaret Heckler, announced that vaccines will be researched and made ready for preliminary testing by the year 1986. - Traditional approaches of using live attenuated or whole inactivated viruses were considered unsafe because of the risk of permanently integrating proviral DNA within host chromosomes. - Advancements in vaccine development had to wait until mid-1980's when recombinant DNA technologies were becoming available for research applications. - Following the success of recombinant Hepatitis B vaccine, recombinant DNA technologies were also being researched for HIV vaccines. - All these efforts came to a standstill with growing knowledge about extreme mutability and immune evasion mechanisms of existing HIV strains. - It was further complicated by the fact that neutralizing antibodies had no protective effects and their titers were similar among asymptomatic carriers and patients with active disease. # Clinical trials for HIV vaccine The 6 HIV-1 vaccine efficacy trials done to date, to delineate potential protective responses, and to explore new vaccine candidates that are currently being developed are as follows. ## VAX003 and 004 - VAX003 was a double-blind, randomized trial of AIDSVAX® B/E (a bivalent vaccine composed of recombinant gp120 from subtype B, strain MN and subtype CRF01_AE, strain A244) in injection drug users (IDU) in Thailand. - VAX004 was a double-blind, randomized trial of AIDSVAX® B/B (a bivalent vaccine composed of subtype B rgp120 from strains MN and GNE8) conducted among men who have sex with men (MSM) and women at high risk for heterosexual transmission of HIV-1 in North America and The Netherlands. - Despite the development of anti-glyco-proteins 120 antibody responses, both vaccines did not demonstrate protection. - The disappointing results from the VAX003 and VAX004 trials and data supporting the importance of cell mediated immunity in controlling viral replication in rhesus macaques and human elite controllers,attention turned to the use of T-cell vaccines to induce HIV-specific cellular immune responses. ## STEP and Phambili studies - The STEP study was a double-blind, randomized trial of the MRKAd5 HIV-1 gag/pol/nef sub-type B vaccine in individuals at high risk of HIV-1 acquisition in the Americas, Caribbean and Australia. - The Phambili study was a double-blind, randomized trial designed to evaluate the MRKAd5 HIV-1 gag/pol/nef sub-type B vaccine in individuals in South Africa where HIV clade C is predominant. This study was halted following the Step study's interim analysis and subsequent analysis also found no efficacy. ## RV144 - RV144 was a randomized, double-blind trial that evaluated 4 priming injections of ALVAC-HIV , recombinant canarypox vector expressing HIV-1 Gag and Pro (subtype B LAI strain) and CRF01_AE (subtype E) HIV-1 gp120 (92TH023) linked to the transmembrane anchoring portion of gp41 (LAI) plus 2 booster injections, AIDSVAX® B/E (bivalent HIV-1 gp120 subunit vaccine containing a subtype E Env from strain A244 (CM244) and a subtype B Env from strain MN), co-formulated with alum. - The rationale for the prime boost strategy was to induce both cellular and humoral responses. - The RV144 trial was the only efficacy trial to date that demonstrated efficacy. ## HVTN 505 - The last efficacy trial conducted to date is the HVTN 505 trial, a randomized, placebo-controlled trial of a prime boost, DNA/rAd5 vaccine consisting of a 6-plasmid DNA vaccine. - The vaccine induced both cellular and humoral responses. However, these were not associated with protection. ## Conclusions - None of the vaccine candidates that have completed efficacy trials to date induced strong broadly neutralizing antibodies (bnAb) responses. - CD8+ T cell responses were induced in STEP, Phambili and HVTN505 studies but were not associated with protection. - Only one trial, RV144 demonstrated efficacy and protection was associated with functional binding antibodies. However, efficacy was of suboptimal magnitude and was not durable. # Broadly neutralizing antibodies - They are antibodies capable of neutralizing diverse circulating strains from multiple clade groups, can be present in 20–30% of individuals with HIV-1 infection. - They usually develop 2–4 years after HIV-1 infection, in the presence of continual antigen stimulation from viral replication. - HIV envelope protein, composed of gp120 and gp41 monomers, is the main target for broadly neutralizing antibodies. ## Passive immunization using broadly neutralizing antibodies - The efficacy of broadly neutralizing antibodies as passive immunotherapy has been demonstrated in Rhesus monkey models. - A single infusion of broadly neutralizing antibody can prevent infection from a single high-dose Simian/Human Immunodeficiency Virus (SHIV) challenge. - The use of broadly neutralizing antibodies as passive immunotherapy in its current form will be challenging to implement widely, due to the production costs, the healthcare infrastructures necessary for infusions and the need for repeated administrations. - New research is taking place to explore the introduction of broadly neutralizing antibodies(bnAb) using vectored immunoprophylaxis, where adeno-associated virus (AAV) vectors are used to deliver the genes encoding broadly neutralizing antibodies to muscle tissues, thereby enabling long-term production and systemic distribution. This technique has been shown to protect humanized mice as well as rhesus monkey against high dose intravenous and repeated mucosal challenges. ## Eliciting broadly neutralizing antibodies through immunization - An immunogen that can elicit broadly neutralizing antibodies (bnAb) responses has still not been identified and the high levels of somatic mutations in bnAb suggest complex maturation pathways. - The SOSIP gp140 trimer is a mimic of the natural envelope (Env) trimer, where the gp120-gp41 interactions are stabilized by an intermolecular disulfide bond, and the gp41-gp41 interactions are stabilized by an isoleucine-to-proline substitution at position 559 in the N-terminal heptad repeat region of gp41. - Immunization with SOSIP trimers induced neutralizing antibodies in rabbits and to a lesser extent in Rhesus monkeys but broadly neutralizing antibody responses were not generated. ## CD4 Binding Site Antibodies - The virus entry into targeted cells is dependent on viral attachment to the CD4 receptor and is mediated through binding to a conformational epitope on the trimeric envelop glycoprotein termed the CD4 binding site (CD4bs). - Any antibody that is specific to CD4 binding sites can block the entry of virus into the cell. - Many such antibodies have now been isolated from human donors, and they share common features, such as heavy chain mimicry of the CD4 receptor. - One of first CD4 biniding site antibodies that was isolated from human infected individual that had been living with untreated infection for over 15 years is VRC01. - A study demonstrated that VRC01 neutralized 91% of pseudovirions at a half maximal inhibitory concentration (IC50) of <50 μg/ml, and neutralized 72% of primary isolates at an IC50 of <1 μg/ml. # Mosaic vaccine - All the HIV-1 vaccines that have progressed to efficacy trials to date have predominantly been regional and clade-specific. - The goal of mosaic HIV-1 vaccine is to generate immune responses that cover the diverse spectrum of circulating HIV-1 isolates, potentially resulting in a single vaccine that can be rolled out globally. - Mosaic HIV-1 antigens delivered by replication-incompetent Ad26 vectors or DNA prime-recombinant vaccinia boost regimens have been shown to augment both the breadth and depth of antigen-specific T cell responses when compared with consensus or natural sequence HIV-1 antigens in Rhesus monkeys. # T-cell based vaccine concepts - Most current vaccine concepts aim at inducing antibody responses in the context of appropriate CD4+ T-cell help, while pure CD8+ T-cell approaches have mostly fallen out of favor. Nevertheless, a couple of promising T-cell focused approaches have been developed over the last years, and are scheduled to move into phase 1 trials in the near future. - One immunogen, based on a CMV vector, has consistently led to complete control of virus replication in 50–60% of animals in non-human primate challenge studies. - The vector used in these studies was based on attenuated Rhesus CMV; whether these interesting immunological features will translate to clinical trials using a human CMV vector remains to be determined. - Recent advances in T cell based vaccines have focused on incorporating the near complete gene sequences of several proteins expressed by the viral strains in HIV controllers. These composite immunogens aim at maximizing the incorporation of variable viral epitopes. - In a study among rhesus monkeys, it was observed that the mosaic antigens incorporating several phenotypes of HIV-1 Gag, Pol, and Env antigens administered through replication-incompetent adenovirus serotype 26 vectors markedly increased the depth and breadth of T lymphocyte responses. # Conclusion - Developing an HIV vaccine is a challenge due to global HIV-1 diversity and the difficulties in inducing protective antibody responses and cellular immune responses. - One of the major hurdles for the HIV vaccine field has been the lack of a fully predictive animal model. New humanized mouse models may provide a unique preclinical framework for testing the induction of broadly neutralizing antibodies. - The past few years have seen an explosion in the depth of knowledge and number of new potential approaches to generating an effective HIV vaccine, and each new idea has promising concepts in the pipeline aimed at achieving its goals.	HIV vaccine Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Marjan Khan M.B.B.S.[2] For microbiologic aspects of the causative organism(s), see Human Immunodeficiency Virus (HIV) For clinical aspects of this desease, see HIV # Overview HIV infection is a major global health issue, affecting 36.7 million people worldwide. The number of people living with HIV on antiretroviral therapy (ART) reached 17 million in 2015. Although ART has dramatically reduced morbidity and mortality in individuals with HIV infection and can also prevent HIV transmission but it cannot eradicate HIV infection due to the persistence of a latent viral reservoir, hence the need for antiretroviral therapy ART is lifelong and the cost is substantial. Although antiretroviral therapy ART is highly efficacious in preventing transmission in the setting of mother to child transmission, in sexual transmission through the treatment of infected partners in relationships, through pre-exposure or or post-exposure prophylaxis, but all these scale-up difficulties and costs may make widespread implementation challenging. Thus an HIV vaccine is essential as it is a more sustainable solution.The development of a universal effective HIV vaccine is an exceptionally difficult biomedical challenge. Firstly, no case of natural eradication of HIV infection has been identified, thus mechanisms of protection have not been definitively established. Secondly, the extreme diversity of HIV is a major obstacle as strains belonging to different subtypes can differ by up to 35% in their envelope (Env) proteins.Thus, vaccine immunogens derived from a particular strain may not be effective against other strain. To generate an efficacious global vaccine, immunogens capable of generating protective responses covering most major strains are required. # Historical Perspective - Ever since HIV was formally identified as the cause of AIDS, there have been ongoing efforts on vaccines against the disease. - On April 24, 1984, the US Secretary of Health and Human Services, Margaret Heckler, announced that vaccines will be researched and made ready for preliminary testing by the year 1986.[1] - Traditional approaches of using live attenuated or whole inactivated viruses were considered unsafe because of the risk of permanently integrating proviral DNA within host chromosomes.[2] - Advancements in vaccine development had to wait until mid-1980's when recombinant DNA technologies were becoming available for research applications. - Following the success of recombinant Hepatitis B vaccine, recombinant DNA technologies were also being researched for HIV vaccines.[3] - All these efforts came to a standstill with growing knowledge about extreme mutability and immune evasion mechanisms of existing HIV strains.[4] - It was further complicated by the fact that neutralizing antibodies had no protective effects and their titers were similar among asymptomatic carriers and patients with active disease. [5] # Clinical trials for HIV vaccine The 6 HIV-1 vaccine efficacy trials done to date, to delineate potential protective responses, and to explore new vaccine candidates that are currently being developed are as follows. ## VAX003 and 004 - VAX003 was a double-blind, randomized trial of AIDSVAX® B/E (a bivalent vaccine composed of recombinant gp120 from subtype B, strain MN and subtype CRF01_AE, strain A244) in injection drug users (IDU) in Thailand.[6] - VAX004 was a double-blind, randomized trial of AIDSVAX® B/B (a bivalent vaccine composed of subtype B rgp120 from strains MN and GNE8) conducted among men who have sex with men (MSM) and women at high risk for heterosexual transmission of HIV-1 in North America and The Netherlands.[7] - Despite the development of anti-glyco-proteins 120 antibody responses, both vaccines did not demonstrate protection. - The disappointing results from the VAX003 and VAX004 trials and data supporting the importance of cell mediated immunity in controlling viral replication in rhesus macaques and human elite controllers,attention turned to the use of T-cell vaccines to induce HIV-specific cellular immune responses.[8] [9] [10] ## STEP and Phambili studies - The STEP study was a double-blind, randomized trial of the MRKAd5 HIV-1 gag/pol/nef sub-type B vaccine in individuals at high risk of HIV-1 acquisition in the Americas, Caribbean and Australia. [11] - The Phambili study was a double-blind, randomized trial designed to evaluate the MRKAd5 HIV-1 gag/pol/nef sub-type B vaccine in individuals in South Africa where HIV clade C is predominant. This study was halted following the Step study's interim analysis and subsequent analysis also found no efficacy.[12] ## RV144 - RV144 was a randomized, double-blind trial that evaluated 4 priming injections of ALVAC-HIV [vCP1521], recombinant canarypox vector expressing HIV-1 Gag and Pro (subtype B LAI strain) and CRF01_AE (subtype E) HIV-1 gp120 (92TH023) linked to the transmembrane anchoring portion of gp41 (LAI) plus 2 booster injections, AIDSVAX® B/E (bivalent HIV-1 gp120 subunit vaccine containing a subtype E Env from strain A244 (CM244) and a subtype B Env from strain MN), co-formulated with alum.[13] - The rationale for the prime boost strategy was to induce both cellular and humoral responses. - The RV144 trial was the only efficacy trial to date that demonstrated efficacy.[14] ## HVTN 505 - The last efficacy trial conducted to date is the HVTN 505 trial, a randomized, placebo-controlled trial of a prime boost, DNA/rAd5 vaccine consisting of a 6-plasmid DNA vaccine. [15] - The vaccine induced both cellular and humoral responses. However, these were not associated with protection.[15] ## Conclusions - None of the vaccine candidates that have completed efficacy trials to date induced strong broadly neutralizing antibodies (bnAb) responses. - CD8+ T cell responses were induced in STEP, Phambili and HVTN505 studies but were not associated with protection. - Only one trial, RV144 demonstrated efficacy and protection was associated with functional binding antibodies. However, efficacy was of suboptimal magnitude and was not durable. # Broadly neutralizing antibodies - They are antibodies capable of neutralizing diverse circulating strains from multiple clade groups, can be present in 20–30% of individuals with HIV-1 infection.[16] - They usually develop 2–4 years after HIV-1 infection, in the presence of continual antigen stimulation from viral replication.[17] - HIV envelope protein, composed of gp120 and gp41 monomers, is the main target for broadly neutralizing antibodies. [18] ## Passive immunization using broadly neutralizing antibodies - The efficacy of broadly neutralizing antibodies as passive immunotherapy has been demonstrated in Rhesus monkey models. - A single infusion of broadly neutralizing antibody can prevent infection from a single high-dose Simian/Human Immunodeficiency Virus (SHIV) challenge.[19] - The use of broadly neutralizing antibodies as passive immunotherapy in its current form will be challenging to implement widely, due to the production costs, the healthcare infrastructures necessary for infusions and the need for repeated administrations. - New research is taking place to explore the introduction of broadly neutralizing antibodies(bnAb) using vectored immunoprophylaxis, where adeno-associated virus (AAV) vectors are used to deliver the genes encoding broadly neutralizing antibodies to muscle tissues, thereby enabling long-term production and systemic distribution. This technique has been shown to protect humanized mice as well as rhesus monkey against high dose intravenous and repeated mucosal challenges.[20] ## Eliciting broadly neutralizing antibodies through immunization - An immunogen that can elicit broadly neutralizing antibodies (bnAb) responses has still not been identified and the high levels of somatic mutations in bnAb suggest complex maturation pathways. - The SOSIP gp140 trimer is a mimic of the natural envelope (Env) trimer, where the gp120-gp41 interactions are stabilized by an intermolecular disulfide bond, and the gp41-gp41 interactions are stabilized by an isoleucine-to-proline substitution at position 559 in the N-terminal heptad repeat region of gp41.[21] - Immunization with SOSIP trimers induced neutralizing antibodies in rabbits and to a lesser extent in Rhesus monkeys but broadly neutralizing antibody responses were not generated.[22] ## CD4 Binding Site Antibodies - The virus entry into targeted cells is dependent on viral attachment to the CD4 receptor and is mediated through binding to a conformational epitope on the trimeric envelop glycoprotein termed the CD4 binding site (CD4bs).[23] - Any antibody that is specific to CD4 binding sites can block the entry of virus into the cell. - Many such antibodies have now been isolated from human donors, and they share common features, such as heavy chain mimicry of the CD4 receptor.[23] - One of first CD4 biniding site antibodies that was isolated from human infected individual that had been living with untreated infection for over 15 years is VRC01.[24] - A study demonstrated that VRC01 neutralized 91% of pseudovirions at a half maximal inhibitory concentration (IC50) of <50 μg/ml, and neutralized 72% of primary isolates at an IC50 of <1 μg/ml.[24] - # Mosaic vaccine - All the HIV-1 vaccines that have progressed to efficacy trials to date have predominantly been regional and clade-specific. - The goal of mosaic HIV-1 vaccine is to generate immune responses that cover the diverse spectrum of circulating HIV-1 isolates, potentially resulting in a single vaccine that can be rolled out globally.[25] - Mosaic HIV-1 antigens delivered by replication-incompetent Ad26 vectors or DNA prime-recombinant vaccinia boost regimens have been shown to augment both the breadth and depth of antigen-specific T cell responses when compared with consensus or natural sequence HIV-1 antigens in Rhesus monkeys.[26] # T-cell based vaccine concepts - Most current vaccine concepts aim at inducing antibody responses in the context of appropriate CD4+ T-cell help, while pure CD8+ T-cell approaches have mostly fallen out of favor. Nevertheless, a couple of promising T-cell focused approaches have been developed over the last years, and are scheduled to move into phase 1 trials in the near future.[27] - One immunogen, based on a CMV vector, has consistently led to complete control of virus replication in 50–60% of animals in non-human primate challenge studies.[27] - The vector used in these studies was based on attenuated Rhesus CMV; whether these interesting immunological features will translate to clinical trials using a human CMV vector remains to be determined. - Recent advances in T cell based vaccines have focused on incorporating the near complete gene sequences of several proteins expressed by the viral strains in HIV controllers. These composite immunogens aim at maximizing the incorporation of variable viral epitopes.[26] - In a study among rhesus monkeys, it was observed that the mosaic antigens incorporating several phenotypes of HIV-1 Gag, Pol, and Env antigens administered through replication-incompetent adenovirus serotype 26 vectors markedly increased the depth and breadth of T lymphocyte responses.[26] # Conclusion - Developing an HIV vaccine is a challenge due to global HIV-1 diversity and the difficulties in inducing protective antibody responses and cellular immune responses. - One of the major hurdles for the HIV vaccine field has been the lack of a fully predictive animal model. New humanized mouse models may provide a unique preclinical framework for testing the induction of broadly neutralizing antibodies. - The past few years have seen an explosion in the depth of knowledge and number of new potential approaches to generating an effective HIV vaccine, and each new idea has promising concepts in the pipeline aimed at achieving its goals.	https://www.wikidoc.org/index.php/HIV_vaccine
40792efbb96097d6d707f0d0f69d766d931f03a0	wikidoc	HSAB theory	HSAB theory The HSAB concept is an acronym for 'hard and soft acids and bases'. Also known as the Pearson acid base concept, HSAB is widely used in chemistry for explaining stability of compounds, reaction mechanisms and pathways. It assigns the terms 'hard' or 'soft', and 'acid' or 'base' to chemical species. 'Hard' applies to species which are small, have high charge states (the charge criterion applies mainly to acids, to a lesser extent to bases), and are weakly polarizable. 'Soft' applies to species which are big, have low charge states and are strongly polarizable. The theory is used in contexts where a qualitative, rather than quantitative description would help in understanding the predominant factors which drive chemical properties and reactions. This is especially so in transition metal chemistry, where numerous experiments have been done to determine the relative ordering of ligands and transition metal ions in terms of their hardness and softness. HSAB theory is also useful in predicting the products of metathesis reactions. Quite recently it has been shown that even the sensitivity and performance of explosive materials can be explained on basis of HSAB theory Ralph Pearson introduced the HSAB principle in the early 1960s as an attempt to unify inorganic and organic reaction chemistry.. # Theory The gist of this theory is that soft acids react faster and form stronger bonds with soft bases, whereas hard acids react faster and form stronger bonds with hard bases, all other factors being equal. The classification in the original work was mostly based on equilibrium constants for reaction of two Lewis bases competing for a Lewis acid. Hard acids and hard bases tend to have: - small atomic/ionic radius - high oxidation state - low polarizability - high electronegativity - energy low-lying HOMO (bases) or energy high-lying LUMO (acids). Examples of hard acids are: H+, alkali ions, Ti4+, Cr3+, Cr6+, BF3. Examples of hard bases are: OH–, F–, Cl–, NH3, CH3COO–, CO32–. The affinity of hard acids and hard bases for each other is mainly ionic in nature. Soft acids and soft bases tend to have: - large atomic/ionic radius - low or zero oxidation state - high polarizability - low electronegativity - energy high-lying HOMO (bases) and energy-low lying LUMO (acids). Examples of soft acids are: CH3Hg+, Pt4+, Pd2+, Ag+, Au+, Hg2+, Hg22+, Cd2+, BH3. Examples of soft bases are: H–, R3P, SCN–, I–. The affinity of soft acids and bases for each other is mainly covalent in nature. Borderline cases are also identified: borderline acids are trimethylborane, sulfur dioxide and ferrous Fe2+, cobalt Co2+ and lead Pb2+ cations. Borderline bases are: aniline, pyridine, nitrogen N2 and the azide, bromine, nitrate and sulfate anions. Generally speaking, acids and bases interact and the most stable interactions are hard-hard (ionogenic character) and soft-soft (covalent character). An attempt to quantify the 'softness' of a base consists in determining the equilibrium constant for the following equilibrium: Where CH3Hg+ (methylmercury ion) is a very soft acid and H+ (proton) is a hard acid, which compete for B (the base to be classified). Some examples illustrating the effectiveness of the theory: - Bulk metals are soft acids and are poisoned by soft bases such as phosphines and sulfides. - Hard solvents such as hydrogen fluoride, water and the protic solvents tend to solvatate strong solute bases such as the fluorine anion and the oxygen anions. On the other hand dipolar aprotic solvents such as dimethyl sulfoxide and acetone are soft solvents with a preference for solvatating large anions and soft bases. - In coordination chemistry soft-soft and hard-hard interactions exist between ligands and metal centers. # Chemical hardness In 1983 Pearson together with Robert Parr extended the qualitative HSAB theory with quantitative chemical hardness (η) defined as : with I\, the ionization potential and A\, the electron affinity. (More recently Pearson recommends following modern usage and dropping the factor of 0.5.) When the electronegativity (χ) as the Mulliken scale: is the first derivative in a plot of energy E\, versus the amount of electrons N\, with fixed nuclear charge Z\, in an atom or molecule: then the chemical hardness is simply the second derivative: Hardness and electronegativity are related as: and in this sense hardness is a measure for resistance to deformation or change. Likewise a value of zero denotes maximum softness. (Softness is the reciprocal of hardness.) In a compilation of hardness values only that of the hydride anion deviates. Another discrepancy noted in the original 1983 article are the apparent higher hardness of Tl3+ compared to Tl+. # Kornblum's rule An application of HSAB theory is the so-called Kornblum's rule which states that in reactions with ambident nucleophiles, the more electronegative atom reacts when the reaction mechanism is SN1 and the less electronegative one in a SN2 reaction. This rule (established in 1954) actually predates HSAB theory but in HSAB terms its explanation is that in a SN1 reaction the carbocation (a hard acid) reacts with a hard base (high electronegativity) and that in a SN2 reaction tetravalent carbon (a soft acid) reacts with soft bases.	HSAB theory The HSAB concept is an acronym for 'hard and soft acids and bases'. Also known as the Pearson acid base concept, HSAB is widely used in chemistry for explaining stability of compounds, reaction mechanisms and pathways. It assigns the terms 'hard' or 'soft', and 'acid' or 'base' to chemical species. 'Hard' applies to species which are small, have high charge states (the charge criterion applies mainly to acids, to a lesser extent to bases), and are weakly polarizable. 'Soft' applies to species which are big, have low charge states and are strongly polarizable.[1] The theory is used in contexts where a qualitative, rather than quantitative description would help in understanding the predominant factors which drive chemical properties and reactions. This is especially so in transition metal chemistry, where numerous experiments have been done to determine the relative ordering of ligands and transition metal ions in terms of their hardness and softness. HSAB theory is also useful in predicting the products of metathesis reactions. Quite recently it has been shown that even the sensitivity and performance of explosive materials can be explained on basis of HSAB theory [2] Ralph Pearson introduced the HSAB principle in the early 1960s[3][4] as an attempt to unify inorganic and organic reaction chemistry.[5]. # Theory The gist of this theory is that soft acids react faster and form stronger bonds with soft bases, whereas hard acids react faster and form stronger bonds with hard bases, all other factors being equal.[6] The classification in the original work was mostly based on equilibrium constants for reaction of two Lewis bases competing for a Lewis acid. Hard acids and hard bases tend to have: - small atomic/ionic radius - high oxidation state - low polarizability - high electronegativity - energy low-lying HOMO (bases) or energy high-lying LUMO (acids).[6] Examples of hard acids are: H+, alkali ions, Ti4+, Cr3+, Cr6+, BF3. Examples of hard bases are: OH–, F–, Cl–, NH3, CH3COO–, CO32–. The affinity of hard acids and hard bases for each other is mainly ionic in nature. Soft acids and soft bases tend to have: - large atomic/ionic radius - low or zero oxidation state - high polarizability - low electronegativity - energy high-lying HOMO (bases) and energy-low lying LUMO (acids).[6] Examples of soft acids are: CH3Hg+, Pt4+, Pd2+, Ag+, Au+, Hg2+, Hg22+, Cd2+, BH3. Examples of soft bases are: H–, R3P, SCN–, I–. The affinity of soft acids and bases for each other is mainly covalent in nature. Borderline cases are also identified: borderline acids are trimethylborane, sulfur dioxide and ferrous Fe2+, cobalt Co2+ and lead Pb2+ cations. Borderline bases are: aniline, pyridine, nitrogen N2 and the azide, bromine, nitrate and sulfate anions. Generally speaking, acids and bases interact and the most stable interactions are hard-hard (ionogenic character) and soft-soft (covalent character). An attempt to quantify the 'softness' of a base consists in determining the equilibrium constant for the following equilibrium: Where CH3Hg+ (methylmercury ion) is a very soft acid and H+ (proton) is a hard acid, which compete for B (the base to be classified). Some examples illustrating the effectiveness of the theory: - Bulk metals are soft acids and are poisoned by soft bases such as phosphines and sulfides. - Hard solvents such as hydrogen fluoride, water and the protic solvents tend to solvatate strong solute bases such as the fluorine anion and the oxygen anions. On the other hand dipolar aprotic solvents such as dimethyl sulfoxide and acetone are soft solvents with a preference for solvatating large anions and soft bases. - In coordination chemistry soft-soft and hard-hard interactions exist between ligands and metal centers. # Chemical hardness In 1983 Pearson together with Robert Parr extended the qualitative HSAB theory with quantitative chemical hardness (η) defined as [7]: with <math>I\,</math> the ionization potential and <math>A\,</math> the electron affinity. (More recently Pearson recommends following modern usage and dropping the factor of 0.5[8].) When the electronegativity (χ) as the Mulliken scale: is the first derivative in a plot of energy <math>E\,</math> versus the amount of electrons <math>N\,</math> with fixed nuclear charge <math>Z\,</math> in an atom or molecule: then the chemical hardness is simply the second derivative: Hardness and electronegativity are related as: and in this sense hardness is a measure for resistance to deformation or change. Likewise a value of zero denotes maximum softness. (Softness is the reciprocal of hardness.) In a compilation of hardness values only that of the hydride anion deviates. Another discrepancy noted in the original 1983 article are the apparent higher hardness of Tl3+ compared to Tl+. # Kornblum's rule An application of HSAB theory is the so-called Kornblum's rule which states that in reactions with ambident nucleophiles, the more electronegative atom reacts when the reaction mechanism is SN1 and the less electronegative one in a SN2 reaction. This rule (established in 1954) [9] actually predates HSAB theory but in HSAB terms its explanation is that in a SN1 reaction the carbocation (a hard acid) reacts with a hard base (high electronegativity) and that in a SN2 reaction tetravalent carbon (a soft acid) reacts with soft bases.	https://www.wikidoc.org/index.php/HSAB_concept
40ad0185008e0a9d2cea484bc7c0790f69c8b6d6	wikidoc	Habana Leon	Habana Leon # History and Background The brand was created by José "Pepin" Garcia and is manufactured at the El Rey de los Habanos factory in the Little Havana section of Miami, Florida. One of Cuba's great baseball teams was the Club Habana team who played as the Habana Leones (Havana Lions). They were nicknamed los Rojos ("The Reds"), which was the team color. This brand commemorates and celebrates this great Cuban baseball team, and the color theme is carried over to the cigar band, which is red with gold lettering. The brand consists of a single range of seven vitolas. # Description This is a full-bodied cigar. The filler is 70% Nicaraguan ligero, with a Nicaraguan wrapper and a Nicaraguan-grown Corojo wrapper from the crop of 2000. # Models/Vitolas # Notes - ↑ Club Habana - ↑ Jump up to: 2.0 2.1 Catalogue blurb	Habana Leon # History and Background The brand was created by José "Pepin" Garcia and is manufactured at the El Rey de los Habanos factory in the Little Havana section of Miami, Florida. One of Cuba's great baseball teams was the Club Habana[1] team who played as the Habana Leones (Havana Lions). They were nicknamed los Rojos ("The Reds"), which was the team color. This brand commemorates and celebrates this great Cuban baseball team[2], and the color theme is carried over to the cigar band, which is red with gold lettering. The brand consists of a single range of seven vitolas. # Description This is a full-bodied cigar. The filler is 70% Nicaraguan ligero, with a Nicaraguan wrapper and a Nicaraguan-grown Corojo wrapper from the crop of 2000.[2] # Models/Vitolas # Notes - ↑ Club Habana - ↑ Jump up to: 2.0 2.1 Catalogue blurb Template:WikiDoc Sources	https://www.wikidoc.org/index.php/Habana_Leon
abcfc21727f1f7b9980f78bef92e3c8ad0bc58c6	wikidoc	Haemophilus	Haemophilus Haemophilus is a genus of Gram-negative, pleomorphic, coccobacilli bacteria. While Haemophilus bacteria are typically small coccobacilli, they are categorized as pleomorphic bacteria because of the wide range of shapes they occasionally assume. The genus includes commensal organisms along with some significant pathogenic strains such as H. influenzae—a cause of sepsis and bacterial meningitis in young children—and H. ducreyi, the causative agent of chancroid. All members are either aerobic or facultatively anaerobic. Haemophilus species are classified by characterization of their capsule: seven serogroups exist, a—f and e′. Capsule type b (Hib) is the most clinically significant because of its virulence. # Metabolism Members of the Haemophilus genus are typically cultured on blood agar plates as all species require at least one of the following blood factors for growth: hemin (factor X) and/or nicotinamide adenine dinucleotide (factor V). Chocolate agar is an excellent Haemophilus growth media as it allows for increased accessibility to these factors. Alternatively, Haemophilus is sometimes cultured using the "Staph streak" technique: both Staphylococcus and Haemophilus organisms are cultured together on a single blood agar plate. In this case, Haemophilus colonies will frequently grow in small "satellite" colonies around the larger Staphylococcus colonies because the metabolism of Staphylococcus produces the necessary blood factor by-products required for Haemophilus growth.	Haemophilus Haemophilus is a genus of Gram-negative, pleomorphic, coccobacilli bacteria.[1] While Haemophilus bacteria are typically small coccobacilli, they are categorized as pleomorphic bacteria because of the wide range of shapes they occasionally assume. The genus includes commensal organisms along with some significant pathogenic strains such as H. influenzae—a cause of sepsis and bacterial meningitis in young children—and H. ducreyi, the causative agent of chancroid. All members are either aerobic or facultatively anaerobic. Haemophilus species are classified by characterization of their capsule: seven serogroups exist, a—f and e′.[2] Capsule type b (Hib) is the most clinically significant because of its virulence. # Metabolism Members of the Haemophilus genus are typically cultured on blood agar plates as all species require at least one of the following blood factors for growth: hemin (factor X) and/or nicotinamide adenine dinucleotide (factor V). Chocolate agar is an excellent Haemophilus growth media as it allows for increased accessibility to these factors.[3] Alternatively, Haemophilus is sometimes cultured using the "Staph streak" technique: both Staphylococcus and Haemophilus organisms are cultured together on a single blood agar plate. In this case, Haemophilus colonies will frequently grow in small "satellite" colonies around the larger Staphylococcus colonies because the metabolism of Staphylococcus produces the necessary blood factor by-products required for Haemophilus growth.	https://www.wikidoc.org/index.php/Haemophilus
7a58ce1400913da76e620e06ea1b00032a1325fa	wikidoc	Hemosiderin	Hemosiderin Hemosiderin or haemosiderin is an abnormal microscopic pigment found in the human body. Hemosiderin is composed of iron oxide and can accumulate in different organs in various diseases. Iron is required by many of the chemical reactions in the body but is toxic when not properly contained. Thus, many methods of iron storage have developed. Humans typically store iron within a protein called ferritin. The form of iron in ferritin is Iron(III) oxide-hydroxide. By complexing with ferritin, the iron is made water soluble. Several diseases result in deposition of Iron(III) oxide-hydroxide in tissues in an insoluble form. These deposits of iron are called hemosiderin. Although these deposits often cause no symptoms, they can lead to organ damage. # Pathophysiology Hemosiderin often forms after bleeding (hemorrhage) into an organ. When blood leaves a ruptured blood vessel, the cell dies and the hemoglobin of the red blood cells is released into the intracellular space. White blood cells called macrophages engulf (phagocytose) the hemoglobin to degrade it, producing hemosiderin and porphyrin. # Diseases associated with hemosiderin deposition Hemosiderin deposition in the lungs is often seen after diffuse alveolar hemorrhage. Thus, diseases such as Goodpasture's syndrome, Wegener's granulomatosis, and idiopathic pulmonary hemosiderosis. Mitral stenosis can also lead to pulmonary hemosiderosis. Hemosiderin collects throughout the body in hemochromatosis. Hemosiderin deposition in the liver is a common feature of hemochromatosis and is the cause of liver failure in the disease. Deposition in the pancreas leads to diabetes and in the skin leads to hyperpigmentation. Hemosiderin deposition in the brain is seen after bleeds from any source, including chronic subdural hemorrhage, Cerebral arteriovenous malformations, cavernous hemangiomata. Hemosiderin collects in the skin and is slowly removed after bruising; hemosiderin may remain in some conditions such as stasis dermatitis. Hemosiderin may deposit in diseases associated with iron overload. These diseases are typically diseases in which chronic blood loss requires frequent blood transfusions, such as sickle cell anemia and thalassemia. # Treatment Treatment for hemosiderin focuses on limiting the effects of the underlying disease leading to continued deposition. In hemochromatosis, this entails frequent phlebotomy. In diseases such as Wegener's granulomatosis, immune suppression is required. Limiting blood transfusions and institution of iron chelation therapy when iron overload is detected are important when managing sickle-cell anemia and other chronic hemolytic anemias. de:Hämosiderin	Hemosiderin Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Hemosiderin or haemosiderin is an abnormal microscopic pigment found in the human body. Hemosiderin is composed of iron oxide and can accumulate in different organs in various diseases. Iron is required by many of the chemical reactions in the body but is toxic when not properly contained. Thus, many methods of iron storage have developed. Humans typically store iron within a protein called ferritin. The form of iron in ferritin is Iron(III) oxide-hydroxide. By complexing with ferritin, the iron is made water soluble. Several diseases result in deposition of Iron(III) oxide-hydroxide in tissues in an insoluble form. These deposits of iron are called hemosiderin. Although these deposits often cause no symptoms, they can lead to organ damage. # Pathophysiology Hemosiderin often forms after bleeding (hemorrhage) into an organ. When blood leaves a ruptured blood vessel, the cell dies and the hemoglobin of the red blood cells is released into the intracellular space. White blood cells called macrophages engulf (phagocytose) the hemoglobin to degrade it, producing hemosiderin and porphyrin. # Diseases associated with hemosiderin deposition Hemosiderin deposition in the lungs is often seen after diffuse alveolar hemorrhage. Thus, diseases such as Goodpasture's syndrome, Wegener's granulomatosis, and idiopathic pulmonary hemosiderosis. Mitral stenosis can also lead to pulmonary hemosiderosis. Hemosiderin collects throughout the body in hemochromatosis. Hemosiderin deposition in the liver is a common feature of hemochromatosis and is the cause of liver failure in the disease. Deposition in the pancreas leads to diabetes and in the skin leads to hyperpigmentation. Hemosiderin deposition in the brain is seen after bleeds from any source, including chronic subdural hemorrhage, Cerebral arteriovenous malformations, cavernous hemangiomata. Hemosiderin collects in the skin and is slowly removed after bruising; hemosiderin may remain in some conditions such as stasis dermatitis. Hemosiderin may deposit in diseases associated with iron overload. These diseases are typically diseases in which chronic blood loss requires frequent blood transfusions, such as sickle cell anemia and thalassemia. # Treatment Treatment for hemosiderin focuses on limiting the effects of the underlying disease leading to continued deposition. In hemochromatosis, this entails frequent phlebotomy. In diseases such as Wegener's granulomatosis, immune suppression is required. Limiting blood transfusions and institution of iron chelation therapy when iron overload is detected are important when managing sickle-cell anemia and other chronic hemolytic anemias. Template:Pathology de:Hämosiderin Template:WH Template:WikiDoc Sources	https://www.wikidoc.org/index.php/Haemosiderin
c178574227896022bd90c5151d158ed5b6308c52	wikidoc	Halcinonide	Halcinonide # Disclaimer WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here. # Overview Halcinonide is a topical corticosteroid that is FDA approved for the treatment of corticosteroid-responsive dermatoses. Common adverse reactions include Dry skin, Pruritus, Burning sensation, Irritation. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) ### Indications - HALOG (Halcinonide Cream, USP) 0.1% is indicated for the relief of the inflammatory and pruritic manifestations of corticosteroid-responsive dermatoses. ### Dosage - Apply the 0.1% HALOG (Halcinonide Cream, USP) to the affected area two to three times daily. Rub in gently. - Occlusive dressings may be used for the management of psoriasis or other recalcitrant conditions. Gently rub a small amount of cream into the lesion until it disappears. Reapply the preparation leaving a thin coating on the lesion, cover with a pliable nonporous film, and seal the edges. If needed, additional moisture may be provided by covering the lesion with a dampened clean cotton cloth before the nonporous film is applied or by briefly wetting the affected area with water immediately prior to applying the medication. The frequency of changing dressings is best determined on an individual basis. It may be convenient to apply HALOG under an occlusive dressing in the evening and to remove the dressing in the morning (i.e., 12-hour occlusion). When utilizing the 12-hour occlusion regimen, additional cream should be applied, without occlusion, during the day. Reapplication is essential at each dressing change. - If an infection develops, the use of occlusive dressings should be discontinued and appropriate antimicrobial therapy instituted. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Halcinonide in adult patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Halcinonide in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) There is limited information regarding FDA-Labeled Use of Halcinonide in pediatric patients. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Halcinonide in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Halcinonide in pediatric patients. # Contraindications - Topical corticosteroids are contraindicated in those patients with a history of hypersensitivity to any of the components of the preparations. # Warnings ### Precautions - Systemic absorption of topical corticosteroids has produced reversible hypothalamic-pituitary-adrenal (HPA) axis suppression, manifestations of Cushing’s syndrome, hyperglycemia, and glucosuria in some patients. - Conditions which augment systemic absorption include the application of the more potent steroids, use over large surface areas, prolonged use, and the addition of occlusive dressings. - Therefore, patients receiving a large dose of any potent topical steroid applied to a large surface area or under an occlusive dressing should be evaluated periodically for evidence of HPA axis suppression by using the urinary free cortisol and ACTH stimulation tests, and for impairment of thermal homeostasis. If HPA axis suppression or elevation of the body temperature occurs, an attempt should be made to withdraw the drug, to reduce the frequency of application, substitute a less potent steroid, or use a sequential approach when utilizing the occlusive technique. - Recovery of HPA axis function and thermal homeostasis are generally prompt and complete upon discontinuation of the drug. Infrequently, signs and symptoms of steroid withdrawal may occur, requiring supplemental systemic corticosteroids. Occasionally, a patient may develop a sensitivity reaction to a particular occlusive dressing material or adhesive and a substitute material may be necessary. - Children may absorb proportionally larger amounts of topical corticosteroids and thus be more susceptible to systemic toxicity. - If irritation develops, topical corticosteroids should be discontinued and appropriate therapy instituted. - In the presence of dermatological infections, the use of an appropriate antifungal or antibacterial agent should be instituted. If a favorable response does not occur promptly, the corticosteroid should be discontinued until the infection has been adequately controlled. - This preparation is not for ophthalmic, oral, or intravaginal use. - A urinary free cortisol test and ACTH stimulation test may be helpful in evaluating HPA axis suppression. # Adverse Reactions ## Clinical Trials Experience - The following local adverse reactions are reported infrequently with topical corticosteroids, but may occur more frequently with the use of occlusive dressings (reactions are listed in an approximate decreasing order of occurrence): burning, itching, irritation, dryness, folliculitis, hypertrichosis, acneiform eruptions, hypopigmentation, perioral dermatitis, Allergic contact dermatitis, maceration of the skin, Secondary infection, skin atrophy, striae, and miliaria. ## Postmarketing Experience There is limited information regarding Postmarketing Experience of Halcinonide in the drug label. # Drug Interactions There is limited information regarding Halcinonide Drug Interactions in the drug label. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): C - Corticosteroids are generally teratogenic in laboratory animals when administered systemically at relatively low dosage levels. The more potent corticosteroids have been shown to be teratogenic after dermal application in laboratory animals. There are no adequate and well-controlled studies in pregnant women on teratogenic effects from topically applied corticosteroids. Therefore, topical corticosteroids should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Drugs of this class should not be used extensively on pregnant patients, in large amounts, or for prolonged periods of time. Pregnancy Category (AUS): - Australian Drug Evaluation Committee (ADEC) Pregnancy Category There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Halcinonide in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Halcinonide during labor and delivery. ### Nursing Mothers - It is not known whether topical administration of corticosteroids could result in sufficient systemic absorption to produce detectable quantities in breast milk. Systemically administered corticosteroids are secreted into breast milk in quantities not likely to have a deleterious effect on the infant. Nevertheless, caution should be exercised when topical corticosteroids are administered to a nursing woman. ### Pediatric Use - Pediatric patients may demonstrate greater susceptibility to topical corticosteroid-induced HPA axis suppression and Cushing’s syndrome than mature patients because of a larger skin surface area to body weight ratio. - HPA axis suppression, Cushing’s syndrome, and intracranial hypertension have been reported in children receiving topical corticosteroids. Manifestations of adrenal suppression in children include linear Growth retardation, delayed weight gain, low plasma cortisol levels, and absence of response to ACTH stimulation. Manifestations of intracranial hypertension include bulging fontanelles, headaches, and bilateral papilledema. - Administration of topical corticosteroids to children should be limited to the least amount compatible with an effective therapeutic regimen. Chronic corticosteroid therapy may interfere with the growth and development of children. ### Geriatic Use - Of approximately 3000 patients included in clinical studies of 0.1% HALOG CREAM, 14% were 60 years or older, while 4% were 70 years or older. No overall differences in safety were observed between these patients and younger patients. Efficacy data have not been evaluated for differences between elderly and younger patients. Other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. ### Gender There is no FDA guidance on the use of Halcinonide with respect to specific gender populations. ### Race There is no FDA guidance on the use of Halcinonide with respect to specific racial populations. ### Renal Impairment There is no FDA guidance on the use of Halcinonide in patients with renal impairment. ### Hepatic Impairment There is no FDA guidance on the use of Halcinonide in patients with hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Halcinonide in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Halcinonide in patients who are immunocompromised. # Administration and Monitoring ### Administration - topical ### Monitoring - patients receiving a large dose of any potent topical steroid applied to a large surface area or under an occlusive dressing should be evaluated periodically for evidence of HPA axis suppression by using the urinary free cortisol and ACTH stimulation tests, and for impairment of thermal homeostasis. # IV Compatibility There is limited information regarding IV Compatibility of Halcinonide in the drug label. # Overdosage - Topically applied corticosteroids can be absorbed in sufficient amounts to produce systemic effects # Pharmacology ## Mechanism of Action - Topical corticosteroids share anti-inflammatory, antipruritic and vasoconstrictive actions. - The mechanism of anti-inflammatory activity of the topical corticosteroids is unclear. Various laboratory methods, including vasoconstrictor assays, are used to compare and predict potencies and/or clinical efficacies of the topical corticosteroids. There is some evidence to suggest that a recognizable correlation exists between vasoconstrictor potency and therapeutic efficacy in man. ## Structure - The topical corticosteroids constitute a class of primarily synthetic steroids used as anti-inflammatory and antipruritic agents. The steroids in this class include halcinonide. Halcinonide is designated chemically as 21-Chloro-9-fluoro-11β,16α, 17-trihydroxypregn-4-ene-3,20-dione cyclic 16,17-acetal with acetone. Graphic formula: - Each gram of 0.1% HALOG (Halcinonide Cream, USP) contains 1 mg halcinonide, USP in a specially formulated cream base consisting of cetyl alcohol, dimethicone 350, glyceryl monostearate , isopropyl palmitate, polysorbate 60, propylene glycol, purified water, and titanium dioxide. ## Pharmacodynamics There is limited information regarding Pharmacodynamics of Halcinonide in the drug label. ## Pharmacokinetics - The extent of percutaneous absorption of topical corticosteroids is determined by many factors including the vehicle, the integrity of the epidermal barrier, and the use of occlusive dressings. - Topical corticosteroids can be absorbed from normal intact skin. Inflammation and/or other disease processes in the skin increase percutaneous absorption. Occlusive dressings substantially increase the percutaneous absorption of topical corticosteroids. Thus, occlusive dressings may be a valuable therapeutic adjunct for treatment of resistant dermatoses. - Once absorbed through the skin, topical corticosteroids are handled through pharmacokinetic pathways similar to systemically administered corticosteroids. Corticosteroids are bound to plasma proteins in varying degrees. Corticosteroids are metabolized primarily in the liver and are then excreted by the kidneys. Some of the topical corticosteroids and their metabolites are also excreted into the bile. ## Nonclinical Toxicology - Long-term animal studies have not been performed to evaluate the carcinogenic potential or the effect on fertility of topical corticosteroids. - Studies to determine mutagenicity with prednisolone and hydrocortisone showed negative results. # Clinical Studies There is limited information regarding Clinical Studies of Halcinonide in the drug label. # How Supplied - HALOG ® (Halcinonide Cream, USP) 0.1% is smooth, soft homogeneous white to off-white cream, essentially free of foreign matter and is supplied as: ## Storage - Store at room temperature; avoid excessive heat (104° F). - To report SUSPECTED ADVERSE REACTIONS, contact the FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. # Images ## Drug Images ## Package and Label Display Panel ### PACKAGE LABEL.PRINCIPAL DISPLAY PANEL ### Ingredients and Appearance # Patient Counseling Information - Patients using topical corticosteroids should receive the following information and instructions: 1. This medication is to be used as directed by the physician. It is for dermatologic use only. Avoid contact with the eyes. 2. Patients should be advised not to use this medication for any disorder other than for which it was prescribed. 3. The treated skin area should not be bandaged or otherwise covered or wrapped as to be occlusive unless directed by the physician. 4. Patients should report any signs of local adverse reactions especially under occlusive dressing. 5. Parents of pediatric patients should be advised not to use tight-fitting diapers or plastic pants on a child being treated in the diaper area, as these garments may constitute occlusive dressings. # Precautions with Alcohol - Alcohol-Halcinonide interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - Halog® # Look-Alike Drug Names There is limited information regarding Halcinonide Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	Halcinonide Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Rabin Bista, M.B.B.S. [2] # Disclaimer WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here. # Overview Halcinonide is a topical corticosteroid that is FDA approved for the treatment of corticosteroid-responsive dermatoses. Common adverse reactions include Dry skin, Pruritus, Burning sensation, Irritation. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) ### Indications - HALOG (Halcinonide Cream, USP) 0.1% is indicated for the relief of the inflammatory and pruritic manifestations of corticosteroid-responsive dermatoses. ### Dosage - Apply the 0.1% HALOG (Halcinonide Cream, USP) to the affected area two to three times daily. Rub in gently. - Occlusive dressings may be used for the management of psoriasis or other recalcitrant conditions. Gently rub a small amount of cream into the lesion until it disappears. Reapply the preparation leaving a thin coating on the lesion, cover with a pliable nonporous film, and seal the edges. If needed, additional moisture may be provided by covering the lesion with a dampened clean cotton cloth before the nonporous film is applied or by briefly wetting the affected area with water immediately prior to applying the medication. The frequency of changing dressings is best determined on an individual basis. It may be convenient to apply HALOG under an occlusive dressing in the evening and to remove the dressing in the morning (i.e., 12-hour occlusion). When utilizing the 12-hour occlusion regimen, additional cream should be applied, without occlusion, during the day. Reapplication is essential at each dressing change. - If an infection develops, the use of occlusive dressings should be discontinued and appropriate antimicrobial therapy instituted. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Halcinonide in adult patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Halcinonide in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) There is limited information regarding FDA-Labeled Use of Halcinonide in pediatric patients. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Halcinonide in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Halcinonide in pediatric patients. # Contraindications - Topical corticosteroids are contraindicated in those patients with a history of hypersensitivity to any of the components of the preparations. # Warnings ### Precautions - Systemic absorption of topical corticosteroids has produced reversible hypothalamic-pituitary-adrenal (HPA) axis suppression, manifestations of Cushing’s syndrome, hyperglycemia, and glucosuria in some patients. - Conditions which augment systemic absorption include the application of the more potent steroids, use over large surface areas, prolonged use, and the addition of occlusive dressings. - Therefore, patients receiving a large dose of any potent topical steroid applied to a large surface area or under an occlusive dressing should be evaluated periodically for evidence of HPA axis suppression by using the urinary free cortisol and ACTH stimulation tests, and for impairment of thermal homeostasis. If HPA axis suppression or elevation of the body temperature occurs, an attempt should be made to withdraw the drug, to reduce the frequency of application, substitute a less potent steroid, or use a sequential approach when utilizing the occlusive technique. - Recovery of HPA axis function and thermal homeostasis are generally prompt and complete upon discontinuation of the drug. Infrequently, signs and symptoms of steroid withdrawal may occur, requiring supplemental systemic corticosteroids. Occasionally, a patient may develop a sensitivity reaction to a particular occlusive dressing material or adhesive and a substitute material may be necessary. - Children may absorb proportionally larger amounts of topical corticosteroids and thus be more susceptible to systemic toxicity. - If irritation develops, topical corticosteroids should be discontinued and appropriate therapy instituted. - In the presence of dermatological infections, the use of an appropriate antifungal or antibacterial agent should be instituted. If a favorable response does not occur promptly, the corticosteroid should be discontinued until the infection has been adequately controlled. - This preparation is not for ophthalmic, oral, or intravaginal use. - A urinary free cortisol test and ACTH stimulation test may be helpful in evaluating HPA axis suppression. # Adverse Reactions ## Clinical Trials Experience - The following local adverse reactions are reported infrequently with topical corticosteroids, but may occur more frequently with the use of occlusive dressings (reactions are listed in an approximate decreasing order of occurrence): burning, itching, irritation, dryness, folliculitis, hypertrichosis, acneiform eruptions, hypopigmentation, perioral dermatitis, Allergic contact dermatitis, maceration of the skin, Secondary infection, skin atrophy, striae, and miliaria. ## Postmarketing Experience There is limited information regarding Postmarketing Experience of Halcinonide in the drug label. # Drug Interactions There is limited information regarding Halcinonide Drug Interactions in the drug label. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): C - Corticosteroids are generally teratogenic in laboratory animals when administered systemically at relatively low dosage levels. The more potent corticosteroids have been shown to be teratogenic after dermal application in laboratory animals. There are no adequate and well-controlled studies in pregnant women on teratogenic effects from topically applied corticosteroids. Therefore, topical corticosteroids should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Drugs of this class should not be used extensively on pregnant patients, in large amounts, or for prolonged periods of time. Pregnancy Category (AUS): - Australian Drug Evaluation Committee (ADEC) Pregnancy Category There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Halcinonide in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Halcinonide during labor and delivery. ### Nursing Mothers - It is not known whether topical administration of corticosteroids could result in sufficient systemic absorption to produce detectable quantities in breast milk. Systemically administered corticosteroids are secreted into breast milk in quantities not likely to have a deleterious effect on the infant. Nevertheless, caution should be exercised when topical corticosteroids are administered to a nursing woman. ### Pediatric Use - Pediatric patients may demonstrate greater susceptibility to topical corticosteroid-induced HPA axis suppression and Cushing’s syndrome than mature patients because of a larger skin surface area to body weight ratio. - HPA axis suppression, Cushing’s syndrome, and intracranial hypertension have been reported in children receiving topical corticosteroids. Manifestations of adrenal suppression in children include linear Growth retardation, delayed weight gain, low plasma cortisol levels, and absence of response to ACTH stimulation. Manifestations of intracranial hypertension include bulging fontanelles, headaches, and bilateral papilledema. - Administration of topical corticosteroids to children should be limited to the least amount compatible with an effective therapeutic regimen. Chronic corticosteroid therapy may interfere with the growth and development of children. ### Geriatic Use - Of approximately 3000 patients included in clinical studies of 0.1% HALOG CREAM, 14% were 60 years or older, while 4% were 70 years or older. No overall differences in safety were observed between these patients and younger patients. Efficacy data have not been evaluated for differences between elderly and younger patients. Other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. ### Gender There is no FDA guidance on the use of Halcinonide with respect to specific gender populations. ### Race There is no FDA guidance on the use of Halcinonide with respect to specific racial populations. ### Renal Impairment There is no FDA guidance on the use of Halcinonide in patients with renal impairment. ### Hepatic Impairment There is no FDA guidance on the use of Halcinonide in patients with hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Halcinonide in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Halcinonide in patients who are immunocompromised. # Administration and Monitoring ### Administration - topical ### Monitoring - patients receiving a large dose of any potent topical steroid applied to a large surface area or under an occlusive dressing should be evaluated periodically for evidence of HPA axis suppression by using the urinary free cortisol and ACTH stimulation tests, and for impairment of thermal homeostasis. # IV Compatibility There is limited information regarding IV Compatibility of Halcinonide in the drug label. # Overdosage - Topically applied corticosteroids can be absorbed in sufficient amounts to produce systemic effects # Pharmacology ## Mechanism of Action - Topical corticosteroids share anti-inflammatory, antipruritic and vasoconstrictive actions. - The mechanism of anti-inflammatory activity of the topical corticosteroids is unclear. Various laboratory methods, including vasoconstrictor assays, are used to compare and predict potencies and/or clinical efficacies of the topical corticosteroids. There is some evidence to suggest that a recognizable correlation exists between vasoconstrictor potency and therapeutic efficacy in man. ## Structure - The topical corticosteroids constitute a class of primarily synthetic steroids used as anti-inflammatory and antipruritic agents. The steroids in this class include halcinonide. Halcinonide is designated chemically as 21-Chloro-9-fluoro-11β,16α, 17-trihydroxypregn-4-ene-3,20-dione cyclic 16,17-acetal with acetone. Graphic formula: - Each gram of 0.1% HALOG (Halcinonide Cream, USP) contains 1 mg halcinonide, USP in a specially formulated cream base consisting of cetyl alcohol, dimethicone 350, glyceryl monostearate , isopropyl palmitate, polysorbate 60, propylene glycol, purified water, and titanium dioxide. ## Pharmacodynamics There is limited information regarding Pharmacodynamics of Halcinonide in the drug label. ## Pharmacokinetics - The extent of percutaneous absorption of topical corticosteroids is determined by many factors including the vehicle, the integrity of the epidermal barrier, and the use of occlusive dressings. - Topical corticosteroids can be absorbed from normal intact skin. Inflammation and/or other disease processes in the skin increase percutaneous absorption. Occlusive dressings substantially increase the percutaneous absorption of topical corticosteroids. Thus, occlusive dressings may be a valuable therapeutic adjunct for treatment of resistant dermatoses. - Once absorbed through the skin, topical corticosteroids are handled through pharmacokinetic pathways similar to systemically administered corticosteroids. Corticosteroids are bound to plasma proteins in varying degrees. Corticosteroids are metabolized primarily in the liver and are then excreted by the kidneys. Some of the topical corticosteroids and their metabolites are also excreted into the bile. ## Nonclinical Toxicology - Long-term animal studies have not been performed to evaluate the carcinogenic potential or the effect on fertility of topical corticosteroids. - Studies to determine mutagenicity with prednisolone and hydrocortisone showed negative results. # Clinical Studies There is limited information regarding Clinical Studies of Halcinonide in the drug label. # How Supplied - HALOG ® (Halcinonide Cream, USP) 0.1% is smooth, soft homogeneous white to off-white cream, essentially free of foreign matter and is supplied as: ## Storage - Store at room temperature; avoid excessive heat (104° F). - To report SUSPECTED ADVERSE REACTIONS, contact the FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. # Images ## Drug Images ## Package and Label Display Panel ### PACKAGE LABEL.PRINCIPAL DISPLAY PANEL ### Ingredients and Appearance # Patient Counseling Information - Patients using topical corticosteroids should receive the following information and instructions: 1. This medication is to be used as directed by the physician. It is for dermatologic use only. Avoid contact with the eyes. 2. Patients should be advised not to use this medication for any disorder other than for which it was prescribed. 3. The treated skin area should not be bandaged or otherwise covered or wrapped as to be occlusive unless directed by the physician. 4. Patients should report any signs of local adverse reactions especially under occlusive dressing. 5. Parents of pediatric patients should be advised not to use tight-fitting diapers or plastic pants on a child being treated in the diaper area, as these garments may constitute occlusive dressings. # Precautions with Alcohol - Alcohol-Halcinonide interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - Halog®[1] # Look-Alike Drug Names There is limited information regarding Halcinonide Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	https://www.wikidoc.org/index.php/Halcinonide
ae77ea6b187ecb05d3706250d26a24d868c35c2b	wikidoc	Haloarchaea	Haloarchaea Haloarchaea are a member of the halophile community, in that they require high salt concentrations to grow. They are a distinct evolutionary branch of the Archaea, and are generally considered extremophiles, although not all members of this group can be considered as such. # Living environment Haloarchaea require salt concentrations in excess of 2 M (or about 10%) to grow, and optimal growth usually occurs at much higher concentrations, typically 20-25%. However, Haloarchaea can grow up to saturation (about 37% salts). Haloarchaea are found mainly in hypersaline lakes and solar salterns. Their high densities in the water often lead to pink or red colourations of the water (the cells possessing high levels of carotenoid pigments, presumably for UV protection). # Cellular shapes Haloarchaea are often considered pleomorphic, or able to take on a range of shapes - even within the one species. This makes identification by microscopic means difficult, and it is now more common to use gene sequencing techniques for identification instead. One of the more unusually shaped Haloarchaea is the "Square Haloarchaea of Walsby". This yet-to-be classified organism is square in shape and extremely thin (like a postage stamp). This shape is probably only permitted by the high osmolarity of the water, permitting cell shapes that would be difficult, if not impossible, under other conditions. # Haloarchaea as Exophiles Haloarchaea have been proposed as a kind of life that could live on Mars, since the martian atmosphere has a pressure below the triple point of water freshwater species would have no habitat.	Haloarchaea Haloarchaea are a member of the halophile community, in that they require high salt concentrations to grow. They are a distinct evolutionary branch of the Archaea, and are generally considered extremophiles, although not all members of this group can be considered as such. # Living environment Haloarchaea require salt concentrations in excess of 2 M (or about 10%) to grow, and optimal growth usually occurs at much higher concentrations, typically 20-25%. However, Haloarchaea can grow up to saturation (about 37% salts). Haloarchaea are found mainly in hypersaline lakes and solar salterns. Their high densities in the water often lead to pink or red colourations of the water (the cells possessing high levels of carotenoid pigments, presumably for UV protection). [1] # Cellular shapes Haloarchaea are often considered pleomorphic, or able to take on a range of shapes - even within the one species. This makes identification by microscopic means difficult, and it is now more common to use gene sequencing techniques for identification instead. One of the more unusually shaped Haloarchaea is the "Square Haloarchaea of Walsby". This yet-to-be classified organism is square in shape and extremely thin (like a postage stamp). This shape is probably only permitted by the high osmolarity of the water, permitting cell shapes that would be difficult, if not impossible, under other conditions. # Haloarchaea as Exophiles Haloarchaea have been proposed as a kind of life that could live on Mars, since the martian atmosphere has a pressure below the triple point of water freshwater species would have no habitat.[2]	https://www.wikidoc.org/index.php/Haloarchaea
64d8cd6eacfc9131ee190bf19b16df1d9fe3e656	wikidoc	Halobetasol	Halobetasol # Disclaimer WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here. # Overview Halobetasol is a corticosteroid that is FDA approved for the treatment of the inflammatory and pruritic manifestations of corticosteroid-responsive dermatoses. Common adverse reactions include itching, sensation of burning of skin, stinging of skin. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) - Halobetasol propionate cream, 0.05% is a super-high potency corticosteroid indictated for the relief of the inflammatory and pruritic manifestations of corticosteroid-responsive dermatoses. Treatment beyond two consecutive weeks is not recommended, and the total dosage should not exceed 50 g/week because of the potential for the drug to suppress the hypothalamic-pituitary-adrenal (HPA) axis. - Use in children under 12 years of age is not recommended. As with other highly active corticosteroid, therapy should be discontinued when control has been achieved. If no improvement is seen within 2 weeks, reassessment of the diagnosis may be necessary. - Apply a thin layer of halobetasol propionate cream, 0.05% to the affected skin once or twice daily, as directed by your physician, and rub in gently and completely. - Halobetasol propionate cream, 0.05% is a super-high potency topical corticosteroid; therefore, treatment should be limited to two weeks, and amounts greater than 50 g/wk should not be used. As with other corticosteroids, therapy should be discontinued when control is achieved. If no improvement is seen within 2 weeks, reassessment of diagnosis may be necessary. - Halobetasol propionate cream, 0.05% should not be used with occlusive dressings. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Halobetasol in adult patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Halobetasol in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) There is limited information regarding FDA-Labeled Use of Halobetasol in pediatric patients. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Halobetasol in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Halobetasol in pediatric patients. # Contraindications - Halobetasol propionate cream, 0.05% is contraindicated in those patients with a history of hypersensitivity to any of the components of the preparation. # Warnings ### Precautions - Systemic absorption of topical corticosteroids can produce reversible hypothalamic-pituitary-adrenal (HPA) axis suppression with the potential for glucocorticosteroid insufficiency after withdrawal of treatment. Manifestations of Cushing’s syndrome, hyperglycemia, and glucosuria can also be produced in some patients by systemic absorption of topical corticosteroids while on treatment. - Patients applying a topical steroid to a large surface area or to areas under occlusion should be evaluated periodically for evidence of HPA axis suppression. This may be done by using the ACTH stimulation, A.M. plasma cortisol, and urinary free-cortisol tests. Patients receiving super potent corticosteroids should not be treated for more than 2 weeks at a time and only small areas should be treated at any one time due to the increased risk of HPA suppression. - Halobetasol propionate cream, 0.05% produced HPA axis suppression when used in divided doses at 7 grams per day for one week in patients with psoriasis. These effects were reversible upon discontinuation of treatment. - If HPA axis suppression is noted, an attempt should be made to withdraw the drug, to reduce the frequency of application, or to substitute a less potent corticosteroid. Recovery of HPA axis function is generally prompt upon discontinuation of topical corticosteroids. Infrequently, signs and symptoms of glucocorticosteroid insufficiency may occur requiring supplemental systemic corticosteroids. For information on systemic supplementation, see prescribing information for those products. - Pediatric patients may be more susceptible to systemic toxicity from equivalent doses due to their larger skin surface to body mass ratios . - If irritation develops, halobetasol propionate cream, 0.05% should be discontinued and appropriate therapy instituted. Allergic contact dermatitis with corticosteroids is usually diagnosed by observing failure to heal rather than noting a clinical exacerbation as with most topical products not containing corticosteroids. Such an observation should be corroborated with appropriate diagnostic patch testing. - If concomitant skin infections are present or develop, an appropriate antifungal or antibacterial agent should be used. If a favorable response does not occur promptly, use of halobetasol propionate cream, 0.05% should be discontinued until the infection has been adequately controlled. - Halobetasol propionate cream, 0.05% should not be used in the treatment of rosacea or perioral dermatitis, and it should not be used on the face, groin, or in the axillae. # Adverse Reactions ## Clinical Trials Experience - In controlled clinical trials, the most frequent adverse events reported for halobetasol propionate cream, 0.05% included stinging, burning or itching in 4.4% of the patients. Less frequently reported adverse reactions were dry skin, erythema, skin atrophy, leukoderma, vesicles and rash. - The following additional local adverse reactions are reported infrequently with topical corticosteroids, and they may occur more frequently with high potency corticosteroids, such as halobetasol propionate cream, 0.05%. These reactions are listed in an approximate decreasing order of occurrence: folliculitis, hypertrichosis, acneiform eruptions, hypopigmentation, perioral dermatitis, allergic contact dermatitis, secondary infection, striae and miliaria. ## Postmarketing Experience There is limited information regarding Postmarketing Experience of Halobetasol in the drug label. # Drug Interactions There is limited information regarding Halobetasol Drug Interactions in the drug label. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): C - Corticosteroids have been shown to be teratogenic in laboratory animals when administered systemically at relatively low dosage levels. Some corticosteroids have been shown to be teratogenic after dermal application in laboratory animals. - Halobetasol propionate has been shown to be teratogenic in SPF rats and chinchilla-type rabbits when given systemically during gestation at doses of 0.04 to 0.1 mg/kg in rats and 0.01 mg/kg in rabbits. These doses are approximately 13, 33 and 3 times, respectively, the human topical dose of halobetasol propionate cream, 0.05%. Halobetasol propionate was embryotoxic in rabbits but not in rats. - Cleft palate was observed in both rats and rabbits. Omphalocele was seen in rats, but not in rabbits. - There are no adequate and well-controlled studies of teratogenic potential of halobetasol propionate in pregnant women. Halobetasol propionate cream, 0.05% should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Halobetasol in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Halobetasol during labor and delivery. ### Nursing Mothers - Systemically administered corticosteroids appear in human milk and could suppress growth, interfere with endogenous corticosteroid production, or cause other untoward effects. It is not known whether topical administration of corticosteroids could result in sufficient systemic absorption to produce detectable quantities in human milk. Because many drugs are excreted in human milk, caution should be exercised when halobetasol propionate cream, 0.05% is administered to a nursing woman. ### Pediatric Use - Safety and effectiveness of halobetasol propionate cream, 0.05% in pedriatric patients have not been established and use in pediatric patients under 12 is not recommended. Because of a higher ratio of skin surface area to body mass, pediatric patients are at a greater risk than adults of HPA suppression and Cushing’s syndrome when they are treated with topical corticosteroids. They are therefore also at greater risk of adrenal insufficiency during or after withdrawal of treatment. Adverse effects including striae have been reported with inappropriate use of topical corticosteroids in infants and children. HPA axis suppression, Cushing’s syndrome, linear growth retardation, delayed weight gain and intracranial hypertension have been reported in children receiving topical corticosteroids. Manifestations of adrenal suppression in children include low plasma cortisol levels and an absence of response to ACTH stimulation. Manifestations of intracranial hypertension include bulging fontanelles, headaches, and bilateral papilledema. ### Geriatic Use - Of approximately 400 patients treated with halobetasol propionate cream, 0.05% in clinical studies, 25% were 61 years and over and 6% were 71 years and over. No overall differences in safety or effectiveness were observed between these patients and younger patients; and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. ### Gender There is no FDA guidance on the use of Halobetasol with respect to specific gender populations. ### Race There is no FDA guidance on the use of Halobetasol with respect to specific racial populations. ### Renal Impairment There is no FDA guidance on the use of Halobetasol in patients with renal impairment. ### Hepatic Impairment There is no FDA guidance on the use of Halobetasol in patients with hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Halobetasol in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Halobetasol in patients who are immunocompromised. # Administration and Monitoring ### Administration - Topical ### Monitoring - The following tests may be helpful in evaluating patients for HPA axis suppression: ACTH-stimulation test; A.M. plasma-cortisol test; urinary free-cortisol test. # IV Compatibility There is limited information regarding IV Compatibility of Halobetasol in the drug label. # Overdosage - Topically applied halobetasol propionate cream, 0.05% can be absorbed in sufficient amounts to produce systemic effects # Pharmacology ## Mechanism of Action ## Structure - Halobetasol propionate cream, 0.05% contains halobetasol propionate, a synthetic corticosteroid for topical dermatological use. The corticosteroids constitute a class of primarily synthetic steroids used topically as an anti-inflammatory and antipruritic agent. - Chemically halobetasol propionate is 21-chloro-6α, 9-difluoro-11β, 17-dihydroxy-16β-methylpregna-1, 4-diene-3-20-dione, 17-propionate, C25H31CIF2O5. It has the following structural formula: - Halobetasol propionate has the molecular weight of 485. It is a white crystalline powder insoluble in water. - Each gram of halobetasol propionate cream, 0.05% contains 0.5 mg of halobetasol propionate in a cream base of cetyl alcohol, diazolidinyl urea, glycerin, isopropyl isostearate, isopropyl palmitate, methylchloroisothiazolinone, (and) methylisothiazolinone, steareth-21 and water. ## Pharmacodynamics There is limited information regarding Pharmacodynamics of Halobetasol in the drug label. ## Pharmacokinetics There is limited information regarding Pharmacokinetics of Halobetasol in the drug label. ## Nonclinical Toxicology - Long-term animal studies have not been performed to evaluate the carcinogenic potential of halobetasol propionate. - Positive mutagenicity effects were observed in two genotoxicity assays. Halobetasol propionate was positive in a Chinese hamster micronucleus test, and in a mouse lymphoma gene mutation assay in vitro. - Studies in the rat following oral administration at dose levels up to 50 μg/kg/day indicated no impairment of fertility or general reproductive performance. - In other genotoxicity testing, halobetasol propionate was not found to be genotoxic in the Ames/Salmonella assay, in the sister chromatid exchange test in somatic cells of the Chinese hamster, in chromosome aberration studies of germinal and somatic cells of rodents, and in a mammalian spot test to determine point mutations. # Clinical Studies There is limited information regarding Clinical Studies of Halobetasol in the drug label. # How Supplied - Halobetasol propionate cream, 0.05% is supplied in the following tube sizes: - 15 g (NDC 45802-129-35) - 50 g (NDC 45802-129-32) ## Storage - Store at 20 - 25°C (68 - 77°F) (See USP Controlled Room Temperature). # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information - Patients using topical corticosteroids should receive the following information and instructions:1. The medication is to be used as directed by the physician. It is for external use only. Avoid contact with the eyes. - The medication should not be used for any disorder other than that for which it was prescribed. - The treated skin area should not be bandaged, or otherwise covered or wrapped, so as to be occlusive unless directed by the physician. - Patients should report to their physician any signs of local adverse reactions. # Precautions with Alcohol - Alcohol-Halobetasol interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - Ultravate - Ultravate X # Look-Alike Drug Names There is limited information regarding Halobetasol Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	Halobetasol Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Aparna Vuppala, M.B.B.S. [2] # Disclaimer WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here. # Overview Halobetasol is a corticosteroid that is FDA approved for the treatment of the inflammatory and pruritic manifestations of corticosteroid-responsive dermatoses. Common adverse reactions include itching, sensation of burning of skin, stinging of skin. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) - Halobetasol propionate cream, 0.05% is a super-high potency corticosteroid indictated for the relief of the inflammatory and pruritic manifestations of corticosteroid-responsive dermatoses. Treatment beyond two consecutive weeks is not recommended, and the total dosage should not exceed 50 g/week because of the potential for the drug to suppress the hypothalamic-pituitary-adrenal (HPA) axis. - Use in children under 12 years of age is not recommended. As with other highly active corticosteroid, therapy should be discontinued when control has been achieved. If no improvement is seen within 2 weeks, reassessment of the diagnosis may be necessary. - Apply a thin layer of halobetasol propionate cream, 0.05% to the affected skin once or twice daily, as directed by your physician, and rub in gently and completely. - Halobetasol propionate cream, 0.05% is a super-high potency topical corticosteroid; therefore, treatment should be limited to two weeks, and amounts greater than 50 g/wk should not be used. As with other corticosteroids, therapy should be discontinued when control is achieved. If no improvement is seen within 2 weeks, reassessment of diagnosis may be necessary. - Halobetasol propionate cream, 0.05% should not be used with occlusive dressings. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Halobetasol in adult patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Halobetasol in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) There is limited information regarding FDA-Labeled Use of Halobetasol in pediatric patients. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Halobetasol in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Halobetasol in pediatric patients. # Contraindications - Halobetasol propionate cream, 0.05% is contraindicated in those patients with a history of hypersensitivity to any of the components of the preparation. # Warnings ### Precautions - Systemic absorption of topical corticosteroids can produce reversible hypothalamic-pituitary-adrenal (HPA) axis suppression with the potential for glucocorticosteroid insufficiency after withdrawal of treatment. Manifestations of Cushing’s syndrome, hyperglycemia, and glucosuria can also be produced in some patients by systemic absorption of topical corticosteroids while on treatment. - Patients applying a topical steroid to a large surface area or to areas under occlusion should be evaluated periodically for evidence of HPA axis suppression. This may be done by using the ACTH stimulation, A.M. plasma cortisol, and urinary free-cortisol tests. Patients receiving super potent corticosteroids should not be treated for more than 2 weeks at a time and only small areas should be treated at any one time due to the increased risk of HPA suppression. - Halobetasol propionate cream, 0.05% produced HPA axis suppression when used in divided doses at 7 grams per day for one week in patients with psoriasis. These effects were reversible upon discontinuation of treatment. - If HPA axis suppression is noted, an attempt should be made to withdraw the drug, to reduce the frequency of application, or to substitute a less potent corticosteroid. Recovery of HPA axis function is generally prompt upon discontinuation of topical corticosteroids. Infrequently, signs and symptoms of glucocorticosteroid insufficiency may occur requiring supplemental systemic corticosteroids. For information on systemic supplementation, see prescribing information for those products. - Pediatric patients may be more susceptible to systemic toxicity from equivalent doses due to their larger skin surface to body mass ratios . - If irritation develops, halobetasol propionate cream, 0.05% should be discontinued and appropriate therapy instituted. Allergic contact dermatitis with corticosteroids is usually diagnosed by observing failure to heal rather than noting a clinical exacerbation as with most topical products not containing corticosteroids. Such an observation should be corroborated with appropriate diagnostic patch testing. - If concomitant skin infections are present or develop, an appropriate antifungal or antibacterial agent should be used. If a favorable response does not occur promptly, use of halobetasol propionate cream, 0.05% should be discontinued until the infection has been adequately controlled. - Halobetasol propionate cream, 0.05% should not be used in the treatment of rosacea or perioral dermatitis, and it should not be used on the face, groin, or in the axillae. # Adverse Reactions ## Clinical Trials Experience - In controlled clinical trials, the most frequent adverse events reported for halobetasol propionate cream, 0.05% included stinging, burning or itching in 4.4% of the patients. Less frequently reported adverse reactions were dry skin, erythema, skin atrophy, leukoderma, vesicles and rash. - The following additional local adverse reactions are reported infrequently with topical corticosteroids, and they may occur more frequently with high potency corticosteroids, such as halobetasol propionate cream, 0.05%. These reactions are listed in an approximate decreasing order of occurrence: folliculitis, hypertrichosis, acneiform eruptions, hypopigmentation, perioral dermatitis, allergic contact dermatitis, secondary infection, striae and miliaria. ## Postmarketing Experience There is limited information regarding Postmarketing Experience of Halobetasol in the drug label. # Drug Interactions There is limited information regarding Halobetasol Drug Interactions in the drug label. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): C - Corticosteroids have been shown to be teratogenic in laboratory animals when administered systemically at relatively low dosage levels. Some corticosteroids have been shown to be teratogenic after dermal application in laboratory animals. - Halobetasol propionate has been shown to be teratogenic in SPF rats and chinchilla-type rabbits when given systemically during gestation at doses of 0.04 to 0.1 mg/kg in rats and 0.01 mg/kg in rabbits. These doses are approximately 13, 33 and 3 times, respectively, the human topical dose of halobetasol propionate cream, 0.05%. Halobetasol propionate was embryotoxic in rabbits but not in rats. - Cleft palate was observed in both rats and rabbits. Omphalocele was seen in rats, but not in rabbits. - There are no adequate and well-controlled studies of teratogenic potential of halobetasol propionate in pregnant women. Halobetasol propionate cream, 0.05% should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Halobetasol in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Halobetasol during labor and delivery. ### Nursing Mothers - Systemically administered corticosteroids appear in human milk and could suppress growth, interfere with endogenous corticosteroid production, or cause other untoward effects. It is not known whether topical administration of corticosteroids could result in sufficient systemic absorption to produce detectable quantities in human milk. Because many drugs are excreted in human milk, caution should be exercised when halobetasol propionate cream, 0.05% is administered to a nursing woman. ### Pediatric Use - Safety and effectiveness of halobetasol propionate cream, 0.05% in pedriatric patients have not been established and use in pediatric patients under 12 is not recommended. Because of a higher ratio of skin surface area to body mass, pediatric patients are at a greater risk than adults of HPA suppression and Cushing’s syndrome when they are treated with topical corticosteroids. They are therefore also at greater risk of adrenal insufficiency during or after withdrawal of treatment. Adverse effects including striae have been reported with inappropriate use of topical corticosteroids in infants and children. HPA axis suppression, Cushing’s syndrome, linear growth retardation, delayed weight gain and intracranial hypertension have been reported in children receiving topical corticosteroids. Manifestations of adrenal suppression in children include low plasma cortisol levels and an absence of response to ACTH stimulation. Manifestations of intracranial hypertension include bulging fontanelles, headaches, and bilateral papilledema. ### Geriatic Use - Of approximately 400 patients treated with halobetasol propionate cream, 0.05% in clinical studies, 25% were 61 years and over and 6% were 71 years and over. No overall differences in safety or effectiveness were observed between these patients and younger patients; and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. ### Gender There is no FDA guidance on the use of Halobetasol with respect to specific gender populations. ### Race There is no FDA guidance on the use of Halobetasol with respect to specific racial populations. ### Renal Impairment There is no FDA guidance on the use of Halobetasol in patients with renal impairment. ### Hepatic Impairment There is no FDA guidance on the use of Halobetasol in patients with hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Halobetasol in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Halobetasol in patients who are immunocompromised. # Administration and Monitoring ### Administration - Topical ### Monitoring - The following tests may be helpful in evaluating patients for HPA axis suppression: ACTH-stimulation test; A.M. plasma-cortisol test; urinary free-cortisol test. # IV Compatibility There is limited information regarding IV Compatibility of Halobetasol in the drug label. # Overdosage - Topically applied halobetasol propionate cream, 0.05% can be absorbed in sufficient amounts to produce systemic effects # Pharmacology ## Mechanism of Action - ## Structure - Halobetasol propionate cream, 0.05% contains halobetasol propionate, a synthetic corticosteroid for topical dermatological use. The corticosteroids constitute a class of primarily synthetic steroids used topically as an anti-inflammatory and antipruritic agent. - Chemically halobetasol propionate is 21-chloro-6α, 9-difluoro-11β, 17-dihydroxy-16β-methylpregna-1, 4-diene-3-20-dione, 17-propionate, C25H31CIF2O5. It has the following structural formula: - Halobetasol propionate has the molecular weight of 485. It is a white crystalline powder insoluble in water. - Each gram of halobetasol propionate cream, 0.05% contains 0.5 mg of halobetasol propionate in a cream base of cetyl alcohol, diazolidinyl urea, glycerin, isopropyl isostearate, isopropyl palmitate, methylchloroisothiazolinone, (and) methylisothiazolinone, steareth-21 and water. ## Pharmacodynamics There is limited information regarding Pharmacodynamics of Halobetasol in the drug label. ## Pharmacokinetics There is limited information regarding Pharmacokinetics of Halobetasol in the drug label. ## Nonclinical Toxicology - Long-term animal studies have not been performed to evaluate the carcinogenic potential of halobetasol propionate. - Positive mutagenicity effects were observed in two genotoxicity assays. Halobetasol propionate was positive in a Chinese hamster micronucleus test, and in a mouse lymphoma gene mutation assay in vitro. - Studies in the rat following oral administration at dose levels up to 50 μg/kg/day indicated no impairment of fertility or general reproductive performance. - In other genotoxicity testing, halobetasol propionate was not found to be genotoxic in the Ames/Salmonella assay, in the sister chromatid exchange test in somatic cells of the Chinese hamster, in chromosome aberration studies of germinal and somatic cells of rodents, and in a mammalian spot test to determine point mutations. # Clinical Studies There is limited information regarding Clinical Studies of Halobetasol in the drug label. # How Supplied - Halobetasol propionate cream, 0.05% is supplied in the following tube sizes: - 15 g (NDC 45802-129-35) - 50 g (NDC 45802-129-32) ## Storage - Store at 20 - 25°C (68 - 77°F) (See USP Controlled Room Temperature). # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information - Patients using topical corticosteroids should receive the following information and instructions:1. The medication is to be used as directed by the physician. It is for external use only. Avoid contact with the eyes. - The medication should not be used for any disorder other than that for which it was prescribed. - The treated skin area should not be bandaged, or otherwise covered or wrapped, so as to be occlusive unless directed by the physician. - Patients should report to their physician any signs of local adverse reactions. # Precautions with Alcohol - Alcohol-Halobetasol interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - Ultravate - Ultravate X # Look-Alike Drug Names There is limited information regarding Halobetasol Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	https://www.wikidoc.org/index.php/Halobetasol
0d99ef3a94764c6abc7942129d5428d531428a60	wikidoc	Hamate bone	Hamate bone The hamate bone (unciform bone) is a bone in the human hand that may be readily distinguished by its wedge-shaped form, and the hook-like process which projects from its volar surface. It is situated at the medial and lower angle of the carpus, with its base downward, resting on the fourth and fifth metacarpal bones, and its apex directed upward and lateralward. The etymology derives from the Latin hamatus "hooked," from hamus which means "hook." # Surfaces The superior surface, the apex of the wedge, is narrow, convex, smooth, and articulates with the lunate. The inferior surface articulates with the fourth and fifth metacarpal bones, by concave facets which are separated by a ridge. The dorsal surface is triangular and rough for ligamentous attachment. The volar surface presents, at its lower and ulnar side, a curved, hook-like process, the hamulus, directed forward and lateralward. The medial surface articulates with the triangular bone by an oblong facet, cut obliquely from above, downward and medialward. The lateral surface articulates with the capitate by its upper and posterior part, the remaining portion being rough, for the attachment of ligaments. # Clinical significance This is the bone most commonly fractured when an amateur golfer hits the ground hard with his/her golf club on his/her downswing. The fracture is usually a hairline fracture, commonly missed on normal X-Rays. Symptoms are pain aggravated by gripping, tenderness over the hamate and symptoms of irritation of the ulnar nerve. If the hamate bone is broken, it immobilizes your ring finger, pinky finger, and wrist until it is healed.	Hamate bone Template:Infobox Bone The hamate bone (unciform bone) is a bone in the human hand that may be readily distinguished by its wedge-shaped form, and the hook-like process which projects from its volar surface. It is situated at the medial and lower angle of the carpus, with its base downward, resting on the fourth and fifth metacarpal bones, and its apex directed upward and lateralward. The etymology derives from the Latin hamatus "hooked," from hamus which means "hook." # Surfaces The superior surface, the apex of the wedge, is narrow, convex, smooth, and articulates with the lunate. The inferior surface articulates with the fourth and fifth metacarpal bones, by concave facets which are separated by a ridge. The dorsal surface is triangular and rough for ligamentous attachment. The volar surface presents, at its lower and ulnar side, a curved, hook-like process, the hamulus, directed forward and lateralward. The medial surface articulates with the triangular bone by an oblong facet, cut obliquely from above, downward and medialward. The lateral surface articulates with the capitate by its upper and posterior part, the remaining portion being rough, for the attachment of ligaments. # Clinical significance This is the bone most commonly fractured when an amateur golfer hits the ground hard with his/her golf club on his/her downswing. The fracture is usually a hairline fracture, commonly missed on normal X-Rays. Symptoms are pain aggravated by gripping, tenderness over the hamate and symptoms of irritation of the ulnar nerve. If the hamate bone is broken, it immobilizes your ring finger, pinky finger, and wrist until it is healed.	https://www.wikidoc.org/index.php/Hamate
812ebcc81fe604b604486d3310fc0455e330ae50	wikidoc	Hans Chiari	Hans Chiari Hans Chiari (1851 − 1916) was an Austrian pathologist who practiced medicine in Vienna, Prague and Strasbourg. His primary duties were concerned with postmortem examinations, and most of his 177 published writings are the result of these autopsies. In 1891, he described a brain malformation that is characterized by abnormalities in the region where the brain and spinal cord meet, and it causes part of the cerebellum to protrude through the foramen magnum (bottom of the skull) into the spinal canal. This was to be called the Arnold-Chiari malformation, named after Chiari and another pathologist, Julius Arnold (1835 − 1915). The malformation was given its name in 1907 by two of Dr. Arnold's students. However, Arnold and Chiari were not the first to describe this condition; a Scottish physician named John Cleland (1835 − 1925) first described the malformation in 1883, and called it "basilar impression syndrome". Chiari has another eponymous medical term named after him; the Budd-Chiari syndrome, which is ascites and cirrhosis of the liver caused by an obstruction of the hepatic vein due to a blood clot. It was named in conjunction with British internist George Budd (1808 − 1882).	Hans Chiari Hans Chiari (1851 − 1916) was an Austrian pathologist who practiced medicine in Vienna, Prague and Strasbourg. His primary duties were concerned with postmortem examinations, and most of his 177 published writings are the result of these autopsies. In 1891, he described a brain malformation that is characterized by abnormalities in the region where the brain and spinal cord meet, and it causes part of the cerebellum to protrude through the foramen magnum (bottom of the skull) into the spinal canal. This was to be called the Arnold-Chiari malformation, named after Chiari and another pathologist, Julius Arnold (1835 − 1915). The malformation was given its name in 1907 by two of Dr. Arnold's students. However, Arnold and Chiari were not the first to describe this condition; a Scottish physician named John Cleland (1835 − 1925) first described the malformation in 1883, and called it "basilar impression syndrome". Chiari has another eponymous medical term named after him; the Budd-Chiari syndrome, which is ascites and cirrhosis of the liver caused by an obstruction of the hepatic vein due to a blood clot. It was named in conjunction with British internist George Budd (1808 − 1882). # External links - The Chiari Institute de:Hans von Chiari Template:WH Template:WikiDoc Sources	https://www.wikidoc.org/index.php/Hans_Chiari
c305fb0203548ec7991a493fd1e2e8c8805856e5	wikidoc	Haptocorrin	Haptocorrin Haptocorrin also known as transcobalamin-1 (TC-1) or cobalophilin is a transcobalamin protein that in humans is encoded by the TCN1 gene. The essential function of haptocorrin is protection of the acid-sensitive vitamin B12 while it moves through the stomach. # Function Haptocorrin (HC), also commonly known as the R-protein, or the R-factor, or previously referred to as transcobalamin I, is a unique glycoprotein produced by the salivary glands of the oral cavity, in response to ingestion of food. This protein binds strongly to vitamin B12 in what is an intricate and necessary mechanism to protect this vitamin from the acidic environment of the stomach.:44 Vitamin B12 is an essential water-soluble vitamin, the deficiency of which creates anemia (macrocytic anemia), decreased bone marrow cell production (anemia, pancytopenia), neurological problems, as well as metabolic issues (methylmalonyl-CoA acidosis).:50–51 Vitamin B12 is therefore an important vitamin for the body to absorb. Despite its vital role however, vitamin B12 is structurally very sensitive to the hydrochloric acid found in the stomach secretions, and easily denatures in that environment before it has a chance to be absorbed by the small intestine. Found in fresh animal products (such as liver), vitamin B12 attaches haptocorrin, which has a high affinity for its molecular structure. Coupled together vitamin B12 and haptocorrin create a complex. This Haptocorrin-B12 complex is impervious to the insult of the stomach acid, and passes on via the pylorus to the duodenum. In the duodenum pancreatic proteases (a component of pancreatic juice) cleave haptocorrin, releasing vitamin B12 in its free form. The same cells in the stomach that produce gastric hydrochloric acid, the parietal cells, also produce a molecule called the intrinsic factor (IF), which binds the B12 after its release from haptocorrin by digestion, and without which only 1% of vitamin B12 is absorbed. Intrinsic factor (IF) is a glycoprotein, with a molecular weight of 45 kDa. In the duodenum, the free vitamin B12 attaches to the intrinsic factor (IF) to create a vitamin B12-IF complex. This complex then travels through the small bowel and reaches the terminal tertiary portion of the small intestine, called the ileum. The ileum is the longest of all portions of the small intestine, and has on its surface specialized receptors called cubilin receptors, that identify the B12-IF complexes and take them up into the circulation via endocytosis mediated absorption. In short, the essential function of haptocorrin is protection of the acid-sensitive vitamin B12 while it moves through the stomach. Haptocorrin also circulates and binds approximately 80% of circulating B12, rendering it unavailable for cellular delivery by transcobalamin II.	Haptocorrin Haptocorrin also known as transcobalamin-1 (TC-1) or cobalophilin is a transcobalamin protein that in humans is encoded by the TCN1 gene.[1] The essential function of haptocorrin is protection of the acid-sensitive vitamin B12 while it moves through the stomach. # Function Haptocorrin (HC), also commonly known as the R-protein, or the R-factor, or previously referred to as transcobalamin I, is a unique glycoprotein produced by the salivary glands of the oral cavity, in response to ingestion of food. This protein binds strongly to vitamin B12 in what is an intricate and necessary mechanism to protect this vitamin from the acidic environment of the stomach.[2]:44 Vitamin B12 is an essential water-soluble vitamin, the deficiency of which creates anemia (macrocytic anemia), decreased bone marrow cell production (anemia, pancytopenia), neurological problems, as well as metabolic issues (methylmalonyl-CoA acidosis).[2]:50–51 Vitamin B12 is therefore an important vitamin for the body to absorb. Despite its vital role however, vitamin B12 is structurally very sensitive to the hydrochloric acid found in the stomach secretions, and easily denatures in that environment before it has a chance to be absorbed by the small intestine. Found in fresh animal products (such as liver), vitamin B12 attaches haptocorrin, which has a high affinity for its molecular structure.[3] Coupled together vitamin B12 and haptocorrin create a complex. This Haptocorrin-B12 complex is impervious to the insult of the stomach acid, and passes on via the pylorus to the duodenum. In the duodenum pancreatic proteases (a component of pancreatic juice) cleave haptocorrin, releasing vitamin B12 in its free form. The same cells in the stomach that produce gastric hydrochloric acid, the parietal cells, also produce a molecule called the intrinsic factor (IF), which binds the B12 after its release from haptocorrin by digestion, and without which only 1% of vitamin B12 is absorbed. Intrinsic factor (IF) is a glycoprotein, with a molecular weight of 45 kDa. In the duodenum, the free vitamin B12 attaches to the intrinsic factor (IF) to create a vitamin B12-IF complex. This complex then travels through the small bowel and reaches the terminal tertiary portion of the small intestine, called the ileum. The ileum is the longest of all portions of the small intestine, and has on its surface specialized receptors called cubilin receptors, that identify the B12-IF complexes and take them up into the circulation via endocytosis mediated absorption.[4] In short, the essential function of haptocorrin is protection of the acid-sensitive vitamin B12 while it moves through the stomach. Haptocorrin also circulates and binds approximately 80% of circulating B12, rendering it unavailable for cellular delivery by transcobalamin II.[5]	https://www.wikidoc.org/index.php/Haptocorrin
8cef0aaa7f6ddbda665202857ea943a432b757bc	wikidoc	Hard palate	Hard palate # Overview The hard palate is a thin horizontal bony plate of the skull, located in the roof of the mouth. It spans the arch formed by the upper teeth. It is formed by the palatine process of the maxilla and horizontal plate of palatine bone. It forms a partition between the nasal passages and the mouth. This partition is continued deeper into the mouth by a fleshy extension called the soft palate. # Function The interaction between the tongue and the hard palate is essential in the formation of certain speech sounds, notably. Also surrounds the teeth to protect them. # Cleft In the birth defect called cleft palate, the left and right portions of this plate are not joined, forming a gap between the mouth and nasal passage (a related defect affecting the face is cleft lip). Cleft palate has a severe impact upon the ability to nurse and speak but is now cured through reconstructive surgical procedures at an early age (where such procedures are available).	Hard palate Template:Infobox Anatomy Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview The hard palate is a thin horizontal bony plate of the skull, located in the roof of the mouth. It spans the arch formed by the upper teeth. It is formed by the palatine process of the maxilla and horizontal plate of palatine bone. It forms a partition between the nasal passages and the mouth. This partition is continued deeper into the mouth by a fleshy extension called the soft palate. # Function The interaction between the tongue and the hard palate is essential in the formation of certain speech sounds, notably. Also surrounds the teeth to protect them. # Cleft In the birth defect called cleft palate, the left and right portions of this plate are not joined, forming a gap between the mouth and nasal passage (a related defect affecting the face is cleft lip). Cleft palate has a severe impact upon the ability to nurse and speak but is now cured through reconstructive surgical procedures at an early age (where such procedures are available).	https://www.wikidoc.org/index.php/Hard_palate
00db8f52291c02285a0bb1502be722ddd65a621d	wikidoc	Harry Bisel	Harry Bisel # Overview Dr. Harry F. Bisel (1918 - 1994) was a pioneering American oncologist working in the field of medical oncology. Dr. Harry Bisel, along with Doctors Fred Ansfield, Herman Freckman, Arnoldus Goudsmit, Robert Talley, William Wilson, and Jane Wright, was one of the founding members of the American Society of Clinical Oncology (ASCO). This group of pioneering doctors, through the formation of ASCO, is largely credited with the development of modern American medical or clinical oncology. In 1964, Bisel was elected the first president of ASCO. He was active in the American Cancer Society and a consultant to the National Cancer Institute. Bisel was a founding member of American Society of Preventative Oncology as well as the American Association for Cancer Education. He was born on June 17, 1918 in Manor, Pennsylvania, USA. He attended Peabody High School and the University of Pittsburgh. There, he received the MD degree in 1942. Dr. Bisel did graduate work at the University of Pennsylvania and Harvard Medical School. He was one of the first trainees to graduate from Memorial Sloan-Kettering Medical Neoplasia program. In 1971, Dr. Bisel received the prestigious Hench Award from the School of Medicine at the University of Pittsburgh. He was in the United States Naval Reserve from 1942 to 1978, and on active duty from 1943 to 1947. During WW 2, he was flight surgeon and was awarded three battle stars for action in the Pacific. Dr. Bisel was the first formally trained oncologist hired by the Mayo Clinic. He was on staff from 1963 until he retired in 1983. He founded the Mayo Clinic Section of Medical Oncology, and was chairmen from 1963 to 1972. He also served as a faculty member of the Mayo Graduate School of Medicine and Mayo Medical School. He and his wife, Sara C. Bisel, had three children, Jane, Clark and Harold. # Review papers Bisel, H., Wroblewski, F., Ladue, J., "Incidents of Clinical Manifestations of Cardiac Metastases," J.A.M.A. 153:712-715, October 24, 1953 Bisel, H., "Clinical Aspects of the Cancer Chemotherapy Program," Current Res. Cancer Chemother., 5:6-14, June, 1956 Bisel, H., "The Incident and Clinical Aspects of Metastatic Heart Tumors," Acta Un. Int. Cancr., 12:28-34, 1956 Bisel, H., "Treatment of Advanced Breast Carcinoma with Delta 1-Testololactone," Acta Un. Int. Cancr., 20:429-431, 1964 Bisel, H., Ansfield, F., Mason, J., Wilson, W., "Clinical Studies with Tubercidin Administered by Direct Intravenous Injection," Cancer Res., 30:76-78, Jan., 1970 Bisel, H., Ahman, D., Hahn, R., "Chemotherapy for the Palliation of Disseminated Malignant Melanoma," Presented at XI Interbational Cancer Congress, Florence, Italy, Oct. 1974 Bisel, H., "Chemotherapy, Single and Multiple Agents in treatment of Locally Advanced, Recurrent and Disseminated Breast Cancer," The Breast, edited by Gallager, H., Leis, H., Synderman, R., and Urban, J., St. Louis, Missouri. C. V. Mosby Co. 1978 Bisel, H., Ahman, D., Edmonson, J., Hahn, R., O'Connell, M, "Treatment of Advanced Breast Carcinoma in Premenopausal Women," Prodeddings of the 12th International Cancer Congress. Buenos Aires, Oct. 1978 Bisel, H., "Management of Locally Advanced and Disseminated Breast Cancer - Chemotherapy" Cancer, Volume 46: Issue S4, Date: 15 August 1980, Pages: 1079-1083	Harry Bisel # Overview Dr. Harry F. Bisel (1918 - 1994) was a pioneering American oncologist working in the field of medical oncology. Dr. Harry Bisel, along with Doctors Fred Ansfield, Herman Freckman, Arnoldus Goudsmit, Robert Talley, William Wilson, and Jane Wright, was one of the founding members of the American Society of Clinical Oncology (ASCO). This group of pioneering doctors, through the formation of ASCO, is largely credited with the development of modern American medical or clinical oncology. In 1964, Bisel was elected the first president of ASCO. He was active in the American Cancer Society and a consultant to the National Cancer Institute. Bisel was a founding member of American Society of Preventative Oncology as well as the American Association for Cancer Education. He was born on June 17, 1918 in Manor, Pennsylvania, USA. He attended Peabody High School and the University of Pittsburgh. There, he received the MD degree in 1942. Dr. Bisel did graduate work at the University of Pennsylvania and Harvard Medical School. He was one of the first trainees to graduate from Memorial Sloan-Kettering Medical Neoplasia program. In 1971, Dr. Bisel received the prestigious Hench Award from the School of Medicine at the University of Pittsburgh. He was in the United States Naval Reserve from 1942 to 1978, and on active duty from 1943 to 1947. During WW 2, he was flight surgeon and was awarded three battle stars for action in the Pacific. Dr. Bisel was the first formally trained oncologist hired by the Mayo Clinic. He was on staff from 1963 until he retired in 1983. He founded the Mayo Clinic Section of Medical Oncology, and was chairmen from 1963 to 1972. He also served as a faculty member of the Mayo Graduate School of Medicine and Mayo Medical School. He and his wife, Sara C. Bisel, had three children, Jane, Clark and Harold. # Review papers Bisel, H., Wroblewski, F., Ladue, J., "Incidents of Clinical Manifestations of Cardiac Metastases," J.A.M.A. 153:712-715, October 24, 1953 Bisel, H., "Clinical Aspects of the Cancer Chemotherapy Program," Current Res. Cancer Chemother., 5:6-14, June, 1956 Bisel, H., "The Incident and Clinical Aspects of Metastatic Heart Tumors," Acta Un. Int. Cancr., 12:28-34, 1956 Bisel, H., "Treatment of Advanced Breast Carcinoma with Delta 1-Testololactone," Acta Un. Int. Cancr., 20:429-431, 1964 Bisel, H., Ansfield, F., Mason, J., Wilson, W., "Clinical Studies with Tubercidin Administered by Direct Intravenous Injection," Cancer Res., 30:76-78, Jan., 1970 Bisel, H., Ahman, D., Hahn, R., "Chemotherapy for the Palliation of Disseminated Malignant Melanoma," Presented at XI Interbational Cancer Congress, Florence, Italy, Oct. 1974 Bisel, H., "Chemotherapy, Single and Multiple Agents in treatment of Locally Advanced, Recurrent and Disseminated Breast Cancer," The Breast, edited by Gallager, H., Leis, H., Synderman, R., and Urban, J., St. Louis, Missouri. C. V. Mosby Co. 1978 Bisel, H., Ahman, D., Edmonson, J., Hahn, R., O'Connell, M, "Treatment of Advanced Breast Carcinoma in Premenopausal Women," Prodeddings of the 12th International Cancer Congress. Buenos Aires, Oct. 1978 Bisel, H., "Management of Locally Advanced and Disseminated Breast Cancer - Chemotherapy" Cancer, Volume 46: Issue S4, Date: 15 August 1980, Pages: 1079-1083 Template:WH Template:WikiDoc Sources	https://www.wikidoc.org/index.php/Harry_Bisel
cc04cc17a97a4b8a52c150f9aefe346301a6128c	wikidoc	Hazmat suit	Hazmat suit # Overview A hazmat suit is a garment worn as protection from hazardous materials or substances. A Hazmat suit is generally combined with breathing apparatus or protection and may be used by firefighters, emergency personnel responding to toxic spills, researchers, or specialists cleaning up contaminated facilities. It is sometimes confused with or referred to as an NBC (Nuclear, Biological, Chemical) suit, which is a military version intended to be usable in combat. # Capabilities ## Overview The United States Department of Homeland Security defines a hazmat suit as "an overall garment worn to protect people from hazardous materials or substances, including chemicals, biological agents, or radioactive materials." More generally, hazmat suits may provide protection from: - Chemical agents - through the use of appropriate barrier materials like teflon, heavy PVC or rubber and tyvek - Nuclear agents - possibly through radiation shielding in the lining, but more importantly by preventing direct contact with or inhalation of radioactive particles or gas - Biological agents - through fully sealed systems (often at overpressure to prevent contamination even if the suit is damaged) - Fire/high temperatures - usually by a combination of insulating and reflective materials which reduce or retard the effects Hazmat suits generally include breathing air supplies to provide clean, uncontaminated air for the wearer. In laboratory use, the external air may be provided via air hoses. Working in a hazmat suit is very strenuous, as the suits tend to be less flexible than conventional work garments, and are hot and poorly ventilated (if at all). Therefore use is usually limited to short durations of up to 2 hours, depending on the difficulty of the work. Level A (United States) suits for example are limited to around 15-20 minutes of very strenous work (such as a firefighting rescue in a building) by their air supply. ## Ratings ### In the United States Hazmat suits are considered to be Level A, B or C protective clothing. Level A suits are vapor-tight, providing total encapsulation and a high level of protection against direct and airborne chemical contact. They are typically worn with a self-contained breathing apparatus (SCBA) enclosed within the suit. Level B suits are not vapor-tight and thus provide a lesser level of protection. Level B suits are worn with an SCBA, which may be inside or outside of the suit, depending on the type of suit (encapsulating or non-encapsulating). Level C includes coveralls or splash suits providing a lesser level of protection than Level B and are typically worn with a respirator or gas mask only. Level D protection also exists, but does not include a 'hazmat suit', as it only requires specific work clothing and eye protection. # Types Hazmat suits come basically in two variations: splash protection and gastight suits. As the name implies the splash protection suits are designed to prevent the wearer from coming into contact with a fluid. These suits do not protect gainst gasses or dust. Gastight suits protect the wearer from basically any outside influence apart from heat and radiation. ## Gas / vapor protection Such suits (Level A in the US) are gas- or vapor-tight, providing total encapsulation and a high level of protection against direct and airborne chemical contact. They are typically worn with a self-contained breathing apparatus (SCBA) enclosed within the suit. These suits are typically constructed of several layers and, being airtight, include a release valve so the suit does not overinflate from exhaled air from the SCBA. The valve does retain some air to keep overpressure inside the suit. As noted, such suits are usually limited to around 15-20 minutes of use by their mobile air supply. ## Splash protection Such suits (Level B in the US) are not vapor-tight and thus provide a lesser level of protection. They are however worn with an SCBA, which may be located inside or outside of the suit, depending on the type of suit (encapsulating or non-encapsulating). They more closely resemble one-piece Tyvek coveralls used in construction, but may also be fully encapsulating suits which are simply not airtight. Lesser protection (Level C in the US) suits may be coveralls of treated material or multi-piece combinations sealed with tape. This kind of protection is still proof against many non-invasive substances, such as anthrax. # In fiction ## In movies Hazmat suits have long been an important device in fiction, especially science fiction, to accentuate the lethality of environments. Common dramatic situations usually involve a suit failure leading to rapid death in films such as The Andromeda Strain or Outbreak. Plot resolutions usually make the removal of a suit a pivotal moment, signifying the end of the threat. The anonymity provided by hazmat suits has often been used to accentuate sinister motives, the scientists in E.T. are a good example of this, as are the farcical squad of hazmat encased characters in the animation Monsters Inc. ## In television Hazmat suits are a favourite prop for MacGyver in MacGyver, which he wears when performing rescues in nuclear reactors. They are also frequently used in the science fiction television series Stargate SG-1 and its counterpart, Stargate Atlantis, in order to avoid alien pathogens. Employees of the Charles Montgomery Burns-owned Springfield Nuclear Power Plant, on the television show The Simpsons, are often shown wearing Hazmat suits. In season 17 of Law and Order in the episode 'Over Hear' doctors are seen wearing hazmat suits due to the poison Ricin. Hazmat suits are often seen in the TV series 24. They were used in Day 2 to deal with a radiation leak, in Day 3 during a biological threat, in Day 5 to deal with nerve gas, and in Day 6 after a nuclear bomb was detonated. ## In video games Gordon Freeman, the main protagonist of Half Life and Half Life 2 is famous for wearing his Hazardous Environment Suit (HEV Suit) throughout the game. This might however be more correctly tagged as an NBC suit (the military equivalent of a hazmat suit) and also functions as body- and power armour. The first-person shooter Doom features the 'Radiation Shielding Suit' which, while it lasts, renders the player immune to damage normally incurred from walking over toxic waste and lava. An advanced, disposable hazmat suit appears in the game Deus Ex, and can be used to temporarily ward off toxins and poisons when entering hazardous environments. In the game 007: Nightfire, during the mission 'Chain Reaction' in which James Bond infiltrates a nuclear power plant, enemies in the plant are seen wearing level A and B suits, although Bond himself does not wear a suit. In the game S.T.A.L.K.E.R., hazmat suits are almost essential to traversing the landscapes closer to the Chernobyl power plant. Early on the player gains access to civilian-grade hazmat suits, which offer little protection against conventional harm from bullets and wild animals. Armoured military-grade suits, and combat armour with some hazmat elements (such as a sealed helmet and air supply) become available later on. H.U.N.K., a character in Resident Evil 4 wears a black Class A Hazmat suit. He is generally agreed to be the most mysterious character in the game, and his face has never been shown in gameplay. The main characters in Area 51 also wear hazmat suits to protect themselves from infection from an alien disease.	Hazmat suit # Overview A hazmat suit is a garment worn as protection from hazardous materials or substances. A Hazmat suit is generally combined with breathing apparatus or protection and may be used by firefighters, emergency personnel responding to toxic spills, researchers, or specialists cleaning up contaminated facilities. It is sometimes confused with or referred to as an NBC (Nuclear, Biological, Chemical) suit, which is a military version intended to be usable in combat. # Capabilities ## Overview The United States Department of Homeland Security defines a hazmat suit as "an overall garment worn to protect people from hazardous materials or substances, including chemicals, biological agents, or radioactive materials."[1] More generally, hazmat suits may provide protection from: - Chemical agents - through the use of appropriate barrier materials like teflon, heavy PVC or rubber and tyvek[citation needed] - Nuclear agents - possibly through radiation shielding in the lining, but more importantly by preventing direct contact with or inhalation of radioactive particles or gas - Biological agents - through fully sealed systems (often at overpressure to prevent contamination even if the suit is damaged) - Fire/high temperatures - usually by a combination of insulating and reflective materials which reduce or retard the effects Hazmat suits generally include breathing air supplies to provide clean, uncontaminated air for the wearer. In laboratory use, the external air may be provided via air hoses. Working in a hazmat suit is very strenuous, as the suits tend to be less flexible than conventional work garments, and are hot and poorly ventilated (if at all). Therefore use is usually limited to short durations of up to 2 hours, depending on the difficulty of the work. Level A (United States) suits for example are limited to around 15-20 minutes of very strenous work (such as a firefighting rescue in a building) by their air supply.[2] ## Ratings ### In the United States Hazmat suits are considered to be Level A, B or C protective clothing.[3] Level A suits are vapor-tight, providing total encapsulation and a high level of protection against direct and airborne chemical contact. They are typically worn with a self-contained breathing apparatus (SCBA) enclosed within the suit. Level B suits are not vapor-tight and thus provide a lesser level of protection. Level B suits are worn with an SCBA, which may be inside or outside of the suit, depending on the type of suit (encapsulating or non-encapsulating). Level C includes coveralls or splash suits providing a lesser level of protection than Level B and are typically worn with a respirator or gas mask only. Level D protection also exists, but does not include a 'hazmat suit', as it only requires specific work clothing and eye protection. # Types Hazmat suits come basically in two variations: splash protection and gastight suits. As the name implies the splash protection suits are designed to prevent the wearer from coming into contact with a fluid. These suits do not protect gainst gasses or dust. Gastight suits protect the wearer from basically any outside influence apart from heat and radiation. ## Gas / vapor protection Such suits (Level A in the US) are gas- or vapor-tight, providing total encapsulation and a high level of protection against direct and airborne chemical contact. They are typically worn with a self-contained breathing apparatus (SCBA) enclosed within the suit. These suits are typically constructed of several layers and, being airtight, include a release valve so the suit does not overinflate from exhaled air from the SCBA. The valve does retain some air to keep overpressure inside the suit. As noted, such suits are usually limited to around 15-20 minutes of use by their mobile air supply.[2] ## Splash protection Such suits (Level B in the US) are not vapor-tight and thus provide a lesser level of protection. They are however worn with an SCBA, which may be located inside or outside of the suit, depending on the type of suit (encapsulating or non-encapsulating). They more closely resemble one-piece Tyvek coveralls used in construction, but may also be fully encapsulating suits which are simply not airtight. Lesser protection (Level C in the US) suits may be coveralls of treated material or multi-piece combinations sealed with tape. This kind of protection is still proof against many non-invasive substances, such as anthrax.[2] # In fiction ## In movies Hazmat suits have long been an important device in fiction, especially science fiction, to accentuate the lethality of environments. Common dramatic situations usually involve a suit failure leading to rapid death in films such as The Andromeda Strain or Outbreak. Plot resolutions usually make the removal of a suit a pivotal moment, signifying the end of the threat. The anonymity provided by hazmat suits has often been used to accentuate sinister motives, the scientists in E.T. are a good example of this, as are the farcical squad of hazmat encased characters in the animation Monsters Inc. ## In television Hazmat suits are a favourite prop for MacGyver in MacGyver, which he wears when performing rescues in nuclear reactors. They are also frequently used in the science fiction television series Stargate SG-1 and its counterpart, Stargate Atlantis, in order to avoid alien pathogens. Employees of the Charles Montgomery Burns-owned Springfield Nuclear Power Plant, on the television show The Simpsons, are often shown wearing Hazmat suits. In season 17 of Law and Order in the episode 'Over Hear' doctors are seen wearing hazmat suits due to the poison Ricin. Hazmat suits are often seen in the TV series 24. They were used in Day 2 to deal with a radiation leak, in Day 3 during a biological threat, in Day 5 to deal with nerve gas, and in Day 6 after a nuclear bomb was detonated. ## In video games Gordon Freeman, the main protagonist of Half Life and Half Life 2 is famous for wearing his Hazardous Environment Suit (HEV Suit) throughout the game. This might however be more correctly tagged as an NBC suit (the military equivalent of a hazmat suit) and also functions as body- and power armour. The first-person shooter Doom features the 'Radiation Shielding Suit' which, while it lasts, renders the player immune to damage normally incurred from walking over toxic waste and lava. An advanced, disposable hazmat suit appears in the game Deus Ex, and can be used to temporarily ward off toxins and poisons when entering hazardous environments. In the game 007: Nightfire, during the mission 'Chain Reaction' in which James Bond infiltrates a nuclear power plant, enemies in the plant are seen wearing level A and B suits, although Bond himself does not wear a suit. In the game S.T.A.L.K.E.R., hazmat suits are almost essential to traversing the landscapes closer to the Chernobyl power plant. Early on the player gains access to civilian-grade hazmat suits, which offer little protection against conventional harm from bullets and wild animals. Armoured military-grade suits, and combat armour with some hazmat elements (such as a sealed helmet and air supply) become available later on. H.U.N.K., a character in Resident Evil 4 wears a black Class A Hazmat suit. He is generally agreed to be the most mysterious character in the game, and his face has never been shown in gameplay.[citation needed] The main characters in Area 51 also wear hazmat suits to protect themselves from infection from an alien disease.	https://www.wikidoc.org/index.php/Hazmat_suit
58e7383a5daa52cb9d3cf9f41287d1759121434d	wikidoc	Health care	Health care # Overview Health care, or healthcare, is the prevention, treatment, and management of illness and the preservation of mental and physical well being through the services offered by the medical, nursing, and allied health professions. Health care embraces all the goods and services designed to promote health, including “preventive, curative and palliative interventions, whether directed to individuals or to populations”. The organised provision of such services may constitute a health care system. This can include specific governmental organizations such as, in the UK, the National Health Service or a cooperation across the National Health Service and Social Services as in Shared Care. Before the term "health care" became popular, English-speakers referred to medicine or to the health sector and spoke of the treatment and prevention of illness and disease. In most developed countries and many developing countries health care is provided to everyone regardless of their ability to pay. The National Health Service, established in 1948 by Clement Atlee's Labour government in the United Kingdom, were the world's first universal health care system provided by government and paid for from general taxation. Alternatively, compulsory government funded health insurance with nominal fees can be provided, as in Italy. Other examples are Medicare in Australia, established in the 1970s by the Labor government, and by the same name Medicare was established in Canada between 1966 and 1984. Universal health care contrasts to the systems like health care in the United States or South Africa, though South Africa is one of the many countries attempting health care reform. The United States is the only wealthy, industrialized nation that does not provide universal health care. # Industry The health care industry is considered an industry or profession which includes peoples' exercise of skill or judgment or the providing of a service related to the preservation or improvement of the health of individuals or the treatment or care of individuals who are injured, sick, disabled, or infirm. The delivery of modern health care depends on an expanding group of trained professionals coming together as an interdisciplinary team. Consuming over 10 percent of gross domestic product of most developed nations, health care can form an enormous part of a country's economy. In 2003, health care costs paid to hospitals, physicians, nursing homes, diagnostic laboratories, pharmacies, medical device manufacturers and other components of the health care system, consumed 16.3 percent of the GDP of the United States, the largest of any country in the world. For the United States, the health share of gross domestic product (GDP) is expected to hold steady in 2006 before resuming its historical upward trend, reaching 19.5 percent of GDP by 2016. In 2001, for the OECD countries the average was 8.4 percent with the United States (13.9%), Switzerland (10.9%), and Germany (10.7%) being the top three. # Systems Purely private enterprise health care systems are comparatively rare. Where they exist, it is usually for a comparatively well-off subpopulation in a poorer country with a poorer standard of health care–for instance, private clinics for a small, wealthy expatriate population in an otherwise poor country. But there are countries with a majority-private health care system with residual public service (see Medicare, Medicaid). The other major models are public insurance systems. A Social security health care model is where workers and their families are insured by the State. A publicly funded health care model is where the residents of the country are insured by the State. Within this branch is Single-payer health care, which describes a type of financing system in which a single entity, typically a government run organisation, acts as the administrator (or "payer") to collect all health care fees, and pay out all health care costs. Some advocates of universal health care assert that single-payer systems save money that could be used directly towards health care by reducing administrative waste. In practice this means that the government collects taxes from the public, businesses, etc., creates an entity to administer the supply of health care and then pays health care professionals. A single-payer universal health care system will actually save money through reduced bureaucratic administration costs. Social health insurance is where the whole population or most of the population is a member of a sickness insurance company. Most health services are provided by private enterprises which act as contractors, billing the government for patient care. In almost every country with a government health care system a parallel private system is allowed to operate. This is sometimes referred to as two-tier health care. The scale, extent, and funding of these private systems is very variable. A traditional view is that improvements in health result from advancements in medical science. The medical model of health focuses on the eradication of illness through diagnosis and effective treatment. In contrast, the social model of health places emphasis on changes that can be made in society and in people's own lifestyles to make the population healthier. It defines illness from the point of view of the individual's functioning within their society rather than by monitoring for changes in biological or physiological signs. # World Health Organization The World Health Organization (WHO) is a specialised United Nations agency which acts as a coordinator and researcher for public health around the world. Established on 7 April 1948, and headquartered in Geneva, Switzerland, the agency inherited the mandate and resources of its predecessor, the Health Organization, which had been an agency of the League of Nations. The WHO's constitution states that its mission "is the attainment by all peoples of the highest possible level of health." Its major task is to combat disease, especially key infectious diseases, and to promote the general health of the peoples of the world. Examples of its work include years of fighting smallpox. In 1979 the WHO declared that the disease had been eradicated - the first disease in history to be completely eliminated by deliberate human design. The WHO is nearing success in developing vaccines against malaria and schistosomiasis and aims to eradicate polio within the next few years. The organization has already endorsed the world's first official HIV/AIDS Toolkit for Zimbabwe from October 3 2006, making it an international standard. The WHO is financed by contributions from member states and from donors. In recent years the WHO's work has involved more collaboration, currently around 80 such partnerships, with NGOs and the pharmaceutical industry, as well as with foundations such as the Bill and Melinda Gates Foundation and the Rockefeller Foundation. Voluntary contributions to the WHO from national and local governments, foundations and NGOs, other UN organizations, and the private sector (including pharmaceutical companies), now exceed that of assessed contributions (dues) from its 193 member nations. # Regions ## Oceania Australia and New Zealand both have publicly funded universal health care systems, alongside ancillary private health care and insurance. ### Australia Medicare was introduced by the Whitlam Labor Government on 1 July 1975 through the Health Insurance Act 1973. The Australian Senate rejected the changes multiple times and they were passed only after a joint sitting after the 1974 double dissolution election. Yet Medicare has been supported by subsequent governments and became a key feature of Australia’s public policy landscape. The exact structure of Medicare, in terms of the size of the rebate to doctors and hospitals and the way it has administered, has varied over the years. The original Medicare program proposed a 1.35% levy (with low income exemptions) but these bills were rejected by the Senate, and so Medicare was originally funded from general taxation. In October 1976, the Fraser Government introduced a 2.5% levy. The program is now nominally funded by an income tax surcharge known as the Medicare levy, which is currently set at 1.5% with exemptions for low income earners. In practice the levy raises only a fraction of the money required to pay for the scheme. If the levy was to fully pay for the services provided under the medicare banner then it would need to be set at about 8%. There is an additional levy of 1.0%, known as the Medicare Levy Surcharge, for those on high annual incomes ($50,000) who do not have private patient hospital coverage. This policy was instituted by the former Coalition Federal Government in an attempt to encourage people to take up private health insurance. ## Europe All of Europe has publicly sponsored and regulated health care. Countries include Austria, Belgium, Czech Republic, Denmark, Finland, France, Germany, Greece, Hungary, Ireland, Italy, Slovakia, Slovenia, the Netherlands, Norway, Poland, Portugal, Romania, Russia, Spain, Sweden and the United Kingdom. ### Ireland The Irish health care system is a socialized, universal, public health care system and is governed by the Health Act 2004, which established a new body to be responsible for providing health and personal social services to everyone living in Ireland - the Health Service Executive. The new national health service came into being officially on 1 January, 2005; however the new structures are currently in the process of being established as the reform programme continues. ### Slovenia The Health Insurance Institute of Slovenia (the Institute) was founded on March 1, 1992, according to the Law on health care and health insurance, after declaring independence from Yugoslavia. The Institute conducts its business as a public institute, bound by statute to provide compulsory health insurance. In the field of compulsory health insurance, the Institute's principal task is to provide effective collection (mobilisation) and distribution (allocation) of public funds, in order to ensure the insured persons quality rights arising from the said funds. The rights arising from compulsory health insurance, furnished by the funds collected by means of compulsory insurance contributions, comprise the rights to health care services and rights to several financial benefits (sick leave pay, reimbursement of travel costs and funeral costs, and insurance money paid in case of death). The Institute comprises 10 regional units and 45 branch offices distributed around the territory of Slovenia. The functional unit the Information Centre and the Directorate complete the Institute structure. At the end of 2005, the Institute staff numbered regular 929 employees. The Institute is governed by an Assembly, whose members are the (elected) representatives of employers (including the representatives of the Government of the Republic of Slovenia) and employees. The executive body of the Assembly is the Institute Board of Directors. The Slovene health insurance card system was introduced, at the national scale, in the year 1999. The system provided the insured persons with a smart card and set up data links between the health care service providers and health insurance providers (the Health Insurance Institute and the two voluntary health insurance providers). ### Switzerland Healthcare in Switzerland is regulated by the Federal Health Insurance Act. Health insurance is compulsory for all persons resident in Switzerland (within three months of taking up residence or being born in the country). International civil servants, members of permanent missions and their familiy members are exempted from compulsory health insurance. They can, however, apply to join the Swiss health insurance system, within six months of taking up residence in the country. Health insurance covers the costs of medical treatment and hospitalisation of the insured. However, the insured person pays part of the cost of treatment. This is done (a) by means of an annual excess (or deductible, called the franchise), which ranges from CHF 300 to a maximum of CHF 2,500 as chosen by the insured person (premiums are adjusted accordingly) and (b) by a charge of 10% of the costs over and above the excess. ### United Kingdom Each of the countries of the United Kingdom has a public health service that provides healthcare to all UK permanent residents that is free at the point of need and paid for from general taxation. However, since Health is a devolved matter, considerable differences are developing between the systems in the different countries. Though commonly referred to as the NHS across the UK, in fact the National Health Service just covers England with separate 'National Health Services' in the other parts of the UK. For details of public healthcare in each country, see: The NHS provides the majority of healthcare in England, including primary care, in-patient care, long-term healthcare, ophthalmology and dentistry. The National Health Service Act 1946 came into effect on 5 July 1948. Private health care has continued parallel to the NHS, paid for largely by private insurance, but it is used by less than 8% of the population, and generally as a top-up to NHS services. NHS Scotland was founded by the National Health Service (Scotland) Act 1947 (since repealed by the National Health Service (Scotland) Act 1978) which came into effect on the same day as the NHS in England and Wales but has always been a separate organisation. NHS Wales was originally formed as part of the same NHS structure created by the National Health Service Act 1946 but powers over the NHS in Wales came under the Secretary of State for Wales in 1969. ## Latin America Most countries in Latin America have public health care provided. Mexico is planning to launch its own universal health care network though at the moment the standards of health care in Mexico are seriously lacking with large divides between rich and poor. Puerto Rico is planning its own health reform for the poorest of the population. Health care in Venezuela is probably the most extensive and given the country's fortunes in oil wealth, expenditure has recently increased greatly, starting with mass vaccinations under the Plan Bolivar 2000. Trinidad and Tobago has universal healthcare, but there are shortages of equipment, supplies, space and staff. ### Cuba The Cuban government operates a national health system and assumes fiscal and administrative responsibility for the health care of its citizens. Following the Revolution, the new Cuban government asserted that universal healthcare was to become a priority of state planning. In 1960 revolutionary and physician Che Guevara outlined his aims for the future of Cuban healthcare in an essay entitled "On Revolutionary Medicine", stating: "The work that today is entrusted to the Ministry of Health and similar organizations is to provide public health services for the greatest possible number of persons, institute a program of preventive medicine, and orient the public to the performance of hygienic practices." These aims were hampered almost immediately by an exodus of almost half of Cuba’s physicians to the United States, leaving the country with only 3,000 doctors and 16 professors in University of Havana’s medical college. Beginning in 1960, the Ministry of Public Health began a program of nationalization and regionalization of medical services. In 1976, Cuba's healthcare program was enshrined in Article 50 of the revised Cuban constitution which states "Everyone has the right to health protection and care. The state guarantees this right by providing free medical and hospital care by means of the installations of the rural medical service network, polyclinics, hospitals, preventative and specialized treatment centers; by providing free dental care; by promoting the health publicity campaigns, health education, regular medical examinations, general vaccinations and other measures to prevent the outbreak of disease. All the population cooperates in these activities and plans through the social and mass organizations." Like the rest of the Cuban economy, Cuban medical care has suffered from severe material shortages following the end of Soviet subsidies and the ongoing United States embargo against Cuba that began after the Cuban Missile Crisis. Data for 2004 show that Cuba has one of the highest life expectancy rates in Latin America. Costa Rica, Chile, Virgin Islands, Guadeloupe, and Martinique now have a higher life expectancy for combined sexes from birth. ## North America ### Canada The federal government of Lester B. Pearson, pressured by the New Democratic Party (NDP) who held the balance of power, introduced the Medical Care Act in 1966 that extended the HIDS Act cost-sharing to allow each province to establish a universal health care plan. It also set up the Medicare system. In 1984, the Canada Health Act was passed, which prohibited user fees and extra billing by doctors. In 1999, the prime minister and most premiers reaffirmed in the Social Union Framework Agreement that they are committed to health care that has "comprehensiveness, universality, portability, public administration and accessibility." The Canadian system is for the most part publicly funded, yet most of the services are provided by private enterprises, private corporations. Most of all doctors do not receive an annual salary, but receive a fee per visit or service. About 30% of Canadians' health care is paid for through the private sector. This mostly goes towards services not covered or only partially covered by Medicare such as prescription drugs, dentistry and optometry. Many Canadians have private health insurance, often through their employers, that cover these expenses. In Canada, some services are permitted and some are not. The Supreme Court of Quebec ruled, in Chaoulli v. Quebec, that private services must be allowed to compete with the public program, thus opening the door to a dual system of private and public healthcare. Quebec has been the fastest to adopt this system and has the most private healthcare available of all the Canadian provinces. ### United States In the United States, certain publicly funded health care programs help to provide for the elderly, disabled, military service families and veterans, children, and the poor, and federal law ensures public access to emergency services regardless of ability to pay; however, a system of universal health care has not been implemented. The Commonwealth of Massachusetts is attempting to implement a near-universal health care system by mandating that residents purchase health insurance by July 1, 2007. California, Maine, Pennsylvania, and Vermont also are attempting universal systems at the state level, with some smaller locations such as San Francisco also attempting this at the citywide level. Some government health care systems allow private practitioners to provide services, and some do not. ## Asia Israel, South Korea, Seychelles and Taiwan have universal health care. Thailand plans to. Health care in India is guaranteed to "improve" for all under the constitution, although the reality does not live up to the vague wording of the article. In Sri Lanka, drugs are provided by a government owned drug manufacturer called the State Pharmaceuticals Corporation of Sri Lanka. In the Philippines, the Department of Health (Philippines) organises public health for the country, and was established at the initiative of the American governors, before independence. Saudi Arabia has a publicly funded health system, although its levels are lower than the regional average. ### China Since the founding of the People's Republic of China, the goal of healthcare programs has been to provide care to every member of the population and to make maximum use of limited health-care personnel, equipment, and financial resources. The current health insurance system in China provides virtually free coverage for people employed in urban state enterprises and relatively inexpensive coverage for their families. The situation for workers in the rural areas or in urban employment outside the state sector is far more varied. There are some cooperative health care programs, but their voluntary nature produced a decline in membership from the late 1970s. The severest limitation on the availability of health services, however, appears to be the serious lack of resources, rather than discrimination in access on the basis of the ability of individuals to pay. An extensive system of paramedical care has been fostered as the major medical resource available to most of the rural population, but the care has been of uneven quality. The paramedical system feeds patients into the more sophisticated commune-level and county-level hospitals when they are available. China is undertaking a reform on its universal health care system. The New Rural Co-operative Medical Care System (NRCMCS) is a new 2005 initiative to overhaul the healthcare system, particularly intended to make it more affordable for the rural poor. Under the NRCMCS, the annual cost of medical cover is 50 yuan (US$7) per person. Of that, 20 yuan is paid in by the central government, 20 yuan by the provincial government and a contribution of 10 yuan is made by the patient. As of September 2007, around 80% of the whole rural population of China had signed up (about 685 million people). The system is tiered, depending on the location. If patients go to a small hospital or clinic in their local town, the scheme will cover from 70-80% of their bill. If they go to a county one, the percentage of the cost being covered falls to about 60%. And if they need specialist help in a large modern city hospital, they have to bear most of the cost themselves, the scheme would cover about 30% of the bill. ### Japan In Japan, payment for personal medical services is offered through a universal insurance system that provides relative equality of access, with fees set by a government committee. People without insurance through employers can participate in a national health insurance program administered by local governments. Since 1973, all elderly persons have been covered by government-sponsored insurance. Patients are free to select physicians or facilities of their choice. In the early 1990s, there were more than 1,000 mental hospitals, 8,700 general hospitals, and 1,000 comprehensive hospitals with a total capacity of 1.5 million beds. Hospitals provided both out-patient and in-patient care. In addition, 79,000 clinics offered primarily out-patient services, and there were 48,000 dental clinics. Most hospitals sell medicine directly to patients, but there are 36,000 pharmacies where patients could purchase synthetic or herbal medication. National health expenditures rose from about 1 trillion Yen in 1965 to nearly 20 trillion Yen in 1989, or from slightly more than 5% to more than 6% of Japan's national income. However, this rise was in accordance with Japan's post-war economic boom (GDP had increased four times between 1965 and 1989). In addition to cost-control problems, the system was troubled with excessive paperwork, long waits to see physicians, assembly-line care for out-patients (because few facilities made appointments), over medication, and abuse of the system because of low out-of-pocket costs to patients. Another problem is an uneven distribution of health personnel, with cities favored over rural areas. ## Africa Health care in Africa is usually non existent or highly limited and under resourced. The outbreak and spread of HIV/AIDS in Africa has crippled many populations and sent life expectancies plummeting. However, some countries have been able to tackle the challenges, for instance health care in Uganda as well as education has reduced HIV/AIDS infections from 13% to 4.1% from 1990 to 2003. This contrasts to some governments' approach, especially that of the South African Health Ministry who until recently denied the link between HIV/AIDS. ### Nigeria Health care provision in Nigeria is a concurrent responsibility of the three tiers of government in the country. However, because Nigeria operates a mixed economy, private providers of health care have a visible role to play in health care delivery. The federal government's role is mostly limited to coordinating the affairs of the university teaching hospitals, while the state government manages the various general hospitals and the local government focus on dispensaries. The total expenditure on health care as % of GDP is 4.6, while the percentage of federal government expenditure on health care is about 1.5%. A long run indicator of the ability of the country to provide food sustenance and avoid malnutrition is the rate of growth of per capita food production; from 1970-1990, the rate for Nigeria was 0.25%. Though small, the positive rate of per capita may be due to Nigeria's importation of food products. Historically, health insurance in Nigeria can be applied to a few instances: free health care provided and financed for all citizens, health care provided by government through a special health insurance scheme for government employees and private firms entering contracts with private health care providers. However, there are few people who fall within the three instances. In May 1999, the government created the National Health Insurance Scheme, the scheme encompasses government employees, the organized private sector and the informal sector. Legislative wise, the scheme also covers children under five, permanently disabled persons and prison inmates. In 2004, the administration of Obasanjo further gave more legislative powers to the scheme with positive amendments to the original 1999 legislative act. ## Countries # Economics Health care economics consists of a complicated relationship between a number of participants; the consumer, insurance companies, employers, medical professionals, and various government entities. An essential feature of health care economics is the spreading of risk, since the cost of health care for catastrophic illness can be prohibitive. This risk may be spread by private insurance companies, or by government involvement in the health care market. The health care market can suffer from a number of problems which are so severe as to be characterized by some as market failure - Adverse selection in insurance markets occurs because those providing insurance have limited information with which to estimate the risks their clients wish to insure against. In simple terms, those with poor health will apply for insurance, raising the cost of providing insurance; those with good health will find the cost of insurance too expensive, raising costs further. Private insurers are economically incentivized to spend substantial sums on investigating the health history of prospective clients, charging higher premiums for unhealthy individuals, which they may not be able to afford. - Moral hazard in insurance markets occurs when the insured behave in a riskier manner than they would if they were not insured. This problem is made worse when the individual is paying only a fraction of the true cost of coverage. Among the potential solutions posited by economists are: - Various forms of universal health insurance, such as requiring all citizens to purchase insurance, limiting the ability of insurance companies to deny insurance to individuals or vary price between individuals. Compulsory universal health insurance is a common thread, although there is no requirement that the insurance or medical services be provided by government. - Decreased government regulation: Conservative Republican US Senator Bill Frist argued that the free market will keep costs down, because individuals who have to pay for their own health care will make wiser decisions and not spend money on unneeded or inefficient care. A deregulated free market, Frist argues, will also encourage efficiency and innovation. The US currently (2007) has the most expensive health care of any OECD country and also has the highest percentage of costs paid privately. Most European systems are financed through a mix of public and private contributions. The majority of universal health care systems are funded primarily by tax revenue (e.g. Portugal). Some nations, such as Germany, France and Japan employ a multi-payer system in which health care is funded by private and public contributions. In 2001 Canadians paid $2,163 per capita versus $4,887 U.S., according to the Los Angeles Times (also, see table above). According to Dr. Stephen Bezruchka, a senior lecturer in the School of Public Health at the University of Washington in Seattle, Canadians do better by every health care measure. According to a World Health Organization report published in 2003, life expectancy at birth in Canada is 79.8 years, versus 77.3 in the U.S. A distinction is also made between municipal and national healthcare funding. For example, one model is that the bulk of the healthcare is funded by the municipality, speciality healthcare is provided and possibly funded by a larger entity, such as a municipal co-operation board or the state, and the medications are paid by a state agency. No entirely private health care system exists, although the reform bill in Massachusetts attempts to make private health care more affordable. # Politics The politics of health care depends largely on which country one is in. Current concerns in England, for instance, revolve around the use of private finance initiatives to build hospitals or the excessive use of targets in cutting waiting lists. In Germany and France, concerns are more based on the rising cost of drugs to the governments. In Brazil, an important political issue is the breach of intellectual property rights, or patents, for the domestic manufacture of antiretroviral drugs used in the treatment of HIV/AIDS. The South African government, whose population sets the record for HIV infections, came under pressure for its refusal to admit there is any connection with AIDS because of the cost it would have involved. In the United States, which has some of the most sophisticated, technologically advanced health care in the world, 12% to 16% of the citizens are still unable to afford complete health insurance. Opponents of universal health care in the United States often argue that it will require higher taxes and a great likelihood of poorly performing health care facilities and physicians. The absence of a market mechanism may slow innovation in treatment and research leading to rationing of care through waiting lists. A statistical comparison shows that it is not universal health care that leads to a doctor shortage, but the payment system to doctors that causes a doctors shortage. In Italy, doctors are paid a fee per patient per year, a per capita salary, and Italy does not have a doctor shortage but has one of the highest doctor per patient ratios, 5.8 doctors per 1,000 patients. In Italy though, it should be noted that most physicians subsequently have very limited hours; many only maintaining patient hours 2 days per week. Canada, whose universal health care system pays its doctors a "fee per visit", creates a real market condition, where doctors' salaries are protected, and even increased, by decreasing the supply of doctors. Canada has a low doctor per patient ratio of 2.1 doctors per 1,000 patients. A comparative analysis shows that a salaried doctor system, while not perfect, results in more doctors; however, they work substantially fewer hours, while the fee per visit system creates economic pressures to reduce the number of doctors, who subsequently work more hours. # Providers A health care provider or health professional is an organization or person who delivers proper health care in a systematic way professionally to any individual in need of health care services. A health care provider could be a government, Health care industry, health care equipment, institution such as a hospital or medical laboratory, physicians, support staff, nurses, therapists, psychologists, chiropractors, veterinarians, dentists, optometrists, paramedics, pharmacists, or even a health insurance company. # Further reading - Journal of Health Care for the Poor and Underserved	Health care Editor-In-Chief: C. Michael Gibson, M.S., M.D. [2] # Overview Health care, or healthcare, is the prevention, treatment, and management of illness and the preservation of mental and physical well being through the services offered by the medical, nursing, and allied health professions. Health care embraces all the goods and services designed to promote health, including “preventive, curative and palliative interventions, whether directed to individuals or to populations”.[1] The organised provision of such services may constitute a health care system. This can include specific governmental organizations such as, in the UK, the National Health Service or a cooperation across the National Health Service and Social Services as in Shared Care. Before the term "health care" became popular, English-speakers referred to medicine or to the health sector and spoke of the treatment and prevention of illness and disease. In most developed countries and many developing countries health care is provided to everyone regardless of their ability to pay. The National Health Service, established in 1948 by Clement Atlee's Labour government in the United Kingdom, were the world's first universal health care system provided by government and paid for from general taxation. Alternatively, compulsory government funded health insurance with nominal fees can be provided, as in Italy. Other examples are Medicare in Australia, established in the 1970s by the Labor government, and by the same name Medicare was established in Canada between 1966 and 1984. Universal health care contrasts to the systems like health care in the United States or South Africa, though South Africa is one of the many countries attempting health care reform.[2] The United States is the only wealthy, industrialized nation that does not provide universal health care.[3][4] # Industry The health care industry is considered an industry or profession which includes peoples' exercise of skill or judgment or the providing of a service related to the preservation or improvement of the health of individuals or the treatment or care of individuals who are injured, sick, disabled, or infirm. The delivery of modern health care depends on an expanding group of trained professionals coming together as an interdisciplinary team.[5][6] Consuming over 10 percent of gross domestic product of most developed nations, health care can form an enormous part of a country's economy. In 2003, health care costs paid to hospitals, physicians, nursing homes, diagnostic laboratories, pharmacies, medical device manufacturers and other components of the health care system, consumed 16.3 percent[7] of the GDP of the United States, the largest of any country in the world. For the United States, the health share of gross domestic product (GDP) is expected to hold steady in 2006 before resuming its historical upward trend, reaching 19.5 percent of GDP by 2016.[8] In 2001, for the OECD countries the average was 8.4 percent[9] with the United States (13.9%), Switzerland (10.9%), and Germany (10.7%) being the top three. # Systems Purely private enterprise health care systems are comparatively rare. Where they exist, it is usually for a comparatively well-off subpopulation in a poorer country with a poorer standard of health care–for instance, private clinics for a small, wealthy expatriate population in an otherwise poor country. But there are countries with a majority-private health care system with residual public service (see Medicare, Medicaid). The other major models are public insurance systems. A Social security health care model is where workers and their families are insured by the State. A publicly funded health care model is where the residents of the country are insured by the State. Within this branch is Single-payer health care, which describes a type of financing system in which a single entity, typically a government run organisation, acts as the administrator (or "payer") to collect all health care fees, and pay out all health care costs.[10] Some advocates of universal health care assert that single-payer systems save money that could be used directly towards health care by reducing administrative waste.[10] In practice this means that the government collects taxes from the public, businesses, etc., creates an entity to administer the supply of health care and then pays health care professionals. A single-payer universal health care system will actually save money through reduced bureaucratic administration costs.[11] Social health insurance is where the whole population or most of the population is a member of a sickness insurance company. Most health services are provided by private enterprises which act as contractors, billing the government for patient care.[12] In almost every country with a government health care system a parallel private system is allowed to operate. This is sometimes referred to as two-tier health care. The scale, extent, and funding of these private systems is very variable. A traditional view is that improvements in health result from advancements in medical science. The medical model of health focuses on the eradication of illness through diagnosis and effective treatment. In contrast, the social model of health places emphasis on changes that can be made in society and in people's own lifestyles to make the population healthier. It defines illness from the point of view of the individual's functioning within their society rather than by monitoring for changes in biological or physiological signs.[13] # World Health Organization Template:Seealso The World Health Organization (WHO) is a specialised United Nations agency which acts as a coordinator and researcher for public health around the world. Established on 7 April 1948, and headquartered in Geneva, Switzerland, the agency inherited the mandate and resources of its predecessor, the Health Organization, which had been an agency of the League of Nations. The WHO's constitution states that its mission "is the attainment by all peoples of the highest possible level of health." Its major task is to combat disease, especially key infectious diseases, and to promote the general health of the peoples of the world. Examples of its work include years of fighting smallpox. In 1979 the WHO declared that the disease had been eradicated - the first disease in history to be completely eliminated by deliberate human design. The WHO is nearing success in developing vaccines against malaria and schistosomiasis and aims to eradicate polio within the next few years. The organization has already endorsed the world's first official HIV/AIDS Toolkit for Zimbabwe from October 3 2006, making it an international standard.[14] The WHO is financed by contributions from member states and from donors. In recent years the WHO's work has involved more collaboration, currently around 80 such partnerships, with NGOs and the pharmaceutical industry, as well as with foundations such as the Bill and Melinda Gates Foundation and the Rockefeller Foundation. Voluntary contributions to the WHO from national and local governments, foundations and NGOs, other UN organizations, and the private sector (including pharmaceutical companies), now exceed that of assessed contributions (dues) from its 193 member nations.[15] # Regions Template:Seealso ## Oceania Australia and New Zealand both have publicly funded universal health care systems, alongside ancillary private health care and insurance. ### Australia Medicare was introduced by the Whitlam Labor Government on 1 July 1975 through the Health Insurance Act 1973. The Australian Senate rejected the changes multiple times and they were passed only after a joint sitting after the 1974 double dissolution election. Yet Medicare has been supported by subsequent governments and became a key feature of Australia’s public policy landscape. The exact structure of Medicare, in terms of the size of the rebate to doctors and hospitals and the way it has administered, has varied over the years. The original Medicare program proposed a 1.35% levy (with low income exemptions) but these bills were rejected by the Senate, and so Medicare was originally funded from general taxation. In October 1976, the Fraser Government introduced a 2.5% levy. The program is now nominally funded by an income tax surcharge known as the Medicare levy, which is currently set at 1.5% with exemptions for low income earners. In practice the levy raises only a fraction of the money required to pay for the scheme. If the levy was to fully pay for the services provided under the medicare banner then it would need to be set at about 8%. There is an additional levy of 1.0%, known as the Medicare Levy Surcharge, for those on high annual incomes ($50,000) who do not have private patient hospital coverage. This policy was instituted by the former Coalition Federal Government in an attempt to encourage people to take up private health insurance. ## Europe Template:Seealso All of Europe has publicly sponsored and regulated health care. Countries include Austria, Belgium, Czech Republic, Denmark, Finland, France, Germany, Greece, Hungary, Ireland, Italy, Slovakia, Slovenia, the Netherlands, Norway, Poland, Portugal,[16] Romania, Russia, Spain, Sweden and the United Kingdom.[17] ### Ireland The Irish health care system is a socialized, universal, public health care system and is governed by the Health Act 2004, which established a new body to be responsible for providing health and personal social services to everyone living in Ireland - the Health Service Executive. The new national health service came into being officially on 1 January, 2005; however the new structures are currently in the process of being established as the reform programme continues. ### Slovenia The Health Insurance Institute of Slovenia (the Institute) was founded on March 1, 1992, according to the Law on health care and health insurance, after declaring independence from Yugoslavia. The Institute conducts its business as a public institute, bound by statute to provide compulsory health insurance. In the field of compulsory health insurance, the Institute's principal task is to provide effective collection (mobilisation) and distribution (allocation) of public funds, in order to ensure the insured persons quality rights arising from the said funds. The rights arising from compulsory health insurance, furnished by the funds collected by means of compulsory insurance contributions, comprise the rights to health care services and rights to several financial benefits (sick leave pay, reimbursement of travel costs and funeral costs, and insurance money paid in case of death). The Institute comprises 10 regional units and 45 branch offices distributed around the territory of Slovenia. The functional unit the Information Centre and the Directorate complete the Institute structure. At the end of 2005, the Institute staff numbered regular 929 employees. The Institute is governed by an Assembly, whose members are the (elected) representatives of employers (including the representatives of the Government of the Republic of Slovenia) and employees. The executive body of the Assembly is the Institute Board of Directors. The Slovene health insurance card system was introduced, at the national scale, in the year 1999. The system provided the insured persons with a smart card and set up data links between the health care service providers and health insurance providers (the Health Insurance Institute and the two voluntary health insurance providers). ### Switzerland Healthcare in Switzerland is regulated by the Federal Health Insurance Act. Health insurance is compulsory for all persons resident in Switzerland (within three months of taking up residence or being born in the country). International civil servants, members of permanent missions and their familiy members are exempted from compulsory health insurance. They can, however, apply to join the Swiss health insurance system, within six months of taking up residence in the country. Health insurance covers the costs of medical treatment and hospitalisation of the insured. However, the insured person pays part of the cost of treatment. This is done (a) by means of an annual excess (or deductible, called the franchise), which ranges from CHF 300 to a maximum of CHF 2,500 as chosen by the insured person (premiums are adjusted accordingly) and (b) by a charge of 10% of the costs over and above the excess. ### United Kingdom Each of the countries of the United Kingdom has a public health service that provides healthcare to all UK permanent residents that is free at the point of need and paid for from general taxation. However, since Health is a devolved matter, considerable differences are developing between the systems in the different countries.[18] Though commonly referred to as the NHS across the UK, in fact the National Health Service just covers England with separate 'National Health Services' in the other parts of the UK. For details of public healthcare in each country, see: The NHS provides the majority of healthcare in England, including primary care, in-patient care, long-term healthcare, ophthalmology and dentistry. The National Health Service Act 1946 came into effect on 5 July 1948. Private health care has continued parallel to the NHS, paid for largely by private insurance, but it is used by less than 8% of the population, and generally as a top-up to NHS services. NHS Scotland was founded by the National Health Service (Scotland) Act 1947 (since repealed by the National Health Service (Scotland) Act 1978) which came into effect on the same day as the NHS in England and Wales but has always been a separate organisation. NHS Wales was originally formed as part of the same NHS structure created by the National Health Service Act 1946 but powers over the NHS in Wales came under the Secretary of State for Wales in 1969[19]. ## Latin America Most countries in Latin America have public health care provided. Mexico is planning to launch its own universal health care network[20] though at the moment the standards of health care in Mexico are seriously lacking with large divides between rich and poor. Puerto Rico is planning its own health reform for the poorest of the population. Health care in Venezuela is probably the most extensive and given the country's fortunes in oil wealth, expenditure has recently increased greatly, starting with mass vaccinations under the Plan Bolivar 2000. Trinidad and Tobago has universal healthcare, but there are shortages of equipment, supplies, space and staff. ### Cuba The Cuban government operates a national health system and assumes fiscal and administrative responsibility for the health care of its citizens.[21] Following the Revolution, the new Cuban government asserted that universal healthcare was to become a priority of state planning. In 1960 revolutionary and physician Che Guevara outlined his aims for the future of Cuban healthcare in an essay entitled "On Revolutionary Medicine", stating: "The work that today is entrusted to the Ministry of Health and similar organizations is to provide public health services for the greatest possible number of persons, institute a program of preventive medicine, and orient the public to the performance of hygienic practices."[22] These aims were hampered almost immediately by an exodus of almost half of Cuba’s physicians to the United States, leaving the country with only 3,000 doctors and 16 professors in University of Havana’s medical college.[23] Beginning in 1960, the Ministry of Public Health began a program of nationalization and regionalization of medical services.[23] In 1976, Cuba's healthcare program was enshrined in Article 50 of the revised Cuban constitution which states "Everyone has the right to health protection and care. The state guarantees this right by providing free medical and hospital care by means of the installations of the rural medical service network, polyclinics, hospitals, preventative and specialized treatment centers; by providing free dental care; by promoting the health publicity campaigns, health education, regular medical examinations, general vaccinations and other measures to prevent the outbreak of disease. All the population cooperates in these activities and plans through the social and mass organizations."[24] Like the rest of the Cuban economy, Cuban medical care has suffered from severe material shortages following the end of Soviet subsidies and the ongoing United States embargo against Cuba that began after the Cuban Missile Crisis.[25] Data for 2004 show that Cuba has one of the highest life expectancy rates in Latin America. Costa Rica, Chile, Virgin Islands, Guadeloupe, and Martinique now have a higher life expectancy for combined sexes from birth.[26] ## North America ### Canada The federal government of Lester B. Pearson, pressured by the New Democratic Party (NDP) who held the balance of power, introduced the Medical Care Act in 1966 that extended the HIDS Act cost-sharing to allow each province to establish a universal health care plan. It also set up the Medicare system. In 1984, the Canada Health Act was passed, which prohibited user fees and extra billing by doctors. In 1999, the prime minister and most premiers reaffirmed in the Social Union Framework Agreement that they are committed to health care that has "comprehensiveness, universality, portability, public administration and accessibility."[27] The Canadian system is for the most part publicly funded, yet most of the services are provided by private enterprises, private corporations. Most of all doctors do not receive an annual salary, but receive a fee per visit or service. About 30% of Canadians' health care is paid for through the private sector. This mostly goes towards services not covered or only partially covered by Medicare such as prescription drugs, dentistry and optometry. Many Canadians have private health insurance, often through their employers, that cover these expenses. In Canada, some services are permitted and some are not. The Supreme Court of Quebec ruled, in Chaoulli v. Quebec, that private services must be allowed to compete with the public program,[28] thus opening the door to a dual system of private and public healthcare. Quebec has been the fastest to adopt this system and has the most private healthcare available of all the Canadian provinces. ### United States In the United States, certain publicly funded health care programs help to provide for the elderly, disabled, military service families and veterans, children, and the poor,[29] and federal law ensures public access to emergency services regardless of ability to pay;[30] however, a system of universal health care has not been implemented. The Commonwealth of Massachusetts is attempting to implement a near-universal health care system by mandating that residents purchase health insurance by July 1, 2007.[31] California, Maine, Pennsylvania, and Vermont also are attempting universal systems at the state level, with some smaller locations such as San Francisco also attempting this at the citywide level.[32] Some government health care systems allow private practitioners to provide services, and some do not. ## Asia Israel,[33] South Korea, Seychelles and Taiwan have universal health care. Thailand[34] plans to.[20] Health care in India is guaranteed to "improve" for all under the constitution, although the reality does not live up to the vague wording of the article. In Sri Lanka, drugs are provided by a government owned drug manufacturer called the State Pharmaceuticals Corporation of Sri Lanka. In the Philippines, the Department of Health (Philippines) organises public health for the country, and was established at the initiative of the American governors, before independence. Saudi Arabia has a publicly funded health system, although its levels are lower than the regional average. ### China Since the founding of the People's Republic of China, the goal of healthcare programs has been to provide care to every member of the population and to make maximum use of limited health-care personnel, equipment, and financial resources. The current health insurance system in China provides virtually free coverage for people employed in urban state enterprises and relatively inexpensive coverage for their families. The situation for workers in the rural areas or in urban employment outside the state sector is far more varied. There are some cooperative health care programs, but their voluntary nature produced a decline in membership from the late 1970s. The severest limitation on the availability of health services, however, appears to be the serious lack of resources, rather than discrimination in access on the basis of the ability of individuals to pay. An extensive system of paramedical care has been fostered as the major medical resource available to most of the rural population, but the care has been of uneven quality. The paramedical system feeds patients into the more sophisticated commune-level and county-level hospitals when they are available. China is undertaking a reform on its universal health care system. The New Rural Co-operative Medical Care System (NRCMCS) is a new 2005 initiative to overhaul the healthcare system, particularly intended to make it more affordable for the rural poor. Under the NRCMCS, the annual cost of medical cover is 50 yuan (US$7) per person. Of that, 20 yuan is paid in by the central government, 20 yuan by the provincial government and a contribution of 10 yuan is made by the patient. As of September 2007, around 80% of the whole rural population of China had signed up (about 685 million people). The system is tiered, depending on the location. If patients go to a small hospital or clinic in their local town, the scheme will cover from 70-80% of their bill. If they go to a county one, the percentage of the cost being covered falls to about 60%. And if they need specialist help in a large modern city hospital, they have to bear most of the cost themselves, the scheme would cover about 30% of the bill.[35] ### Japan In Japan, payment for personal medical services is offered through a universal insurance system that provides relative equality of access, with fees set by a government committee. People without insurance through employers can participate in a national health insurance program administered by local governments. Since 1973, all elderly persons have been covered by government-sponsored insurance. Patients are free to select physicians or facilities of their choice. In the early 1990s, there were more than 1,000 mental hospitals, 8,700 general hospitals, and 1,000 comprehensive hospitals with a total capacity of 1.5 million beds. Hospitals provided both out-patient and in-patient care. In addition, 79,000 clinics offered primarily out-patient services, and there were 48,000 dental clinics. Most hospitals sell medicine directly to patients, but there are 36,000 pharmacies where patients could purchase synthetic or herbal medication. National health expenditures rose from about 1 trillion Yen in 1965 to nearly 20 trillion Yen in 1989, or from slightly more than 5% to more than 6% of Japan's national income. However, this rise was in accordance with Japan's post-war economic boom (GDP had increased four times between 1965 and 1989[36]). In addition to cost-control problems, the system was troubled with excessive paperwork, long waits to see physicians, assembly-line care for out-patients (because few facilities made appointments), over medication, and abuse of the system because of low out-of-pocket costs to patients. Another problem is an uneven distribution of health personnel, with cities favored over rural areas. ## Africa Health care in Africa is usually non existent or highly limited and under resourced. The outbreak and spread of HIV/AIDS in Africa has crippled many populations and sent life expectancies plummeting. However, some countries have been able to tackle the challenges, for instance health care in Uganda as well as education has reduced HIV/AIDS infections from 13% to 4.1% from 1990 to 2003. This contrasts to some governments' approach, especially that of the South African Health Ministry who until recently denied the link between HIV/AIDS. ### Nigeria Health care provision in Nigeria is a concurrent responsibility of the three tiers of government in the country.[37] However, because Nigeria operates a mixed economy, private providers of health care have a visible role to play in health care delivery. The federal government's role is mostly limited to coordinating the affairs of the university teaching hospitals, while the state government manages the various general hospitals and the local government focus on dispensaries. The total expenditure on health care as % of GDP is 4.6, while the percentage of federal government expenditure on health care is about 1.5%.[38] A long run indicator of the ability of the country to provide food sustenance and avoid malnutrition is the rate of growth of per capita food production; from 1970-1990, the rate for Nigeria was 0.25%.[39] Though small, the positive rate of per capita may be due to Nigeria's importation of food products. Historically, health insurance in Nigeria can be applied to a few instances: free health care provided and financed for all citizens, health care provided by government through a special health insurance scheme for government employees and private firms entering contracts with private health care providers.[40] However, there are few people who fall within the three instances. In May 1999, the government created the National Health Insurance Scheme, the scheme encompasses government employees, the organized private sector and the informal sector. Legislative wise, the scheme also covers children under five, permanently disabled persons and prison inmates. In 2004, the administration of Obasanjo further gave more legislative powers to the scheme with positive amendments to the original 1999 legislative act.[41] ## Countries # Economics Health care economics consists of a complicated relationship between a number of participants; the consumer, insurance companies, employers, medical professionals, and various government entities. An essential feature of health care economics is the spreading of risk, since the cost of health care for catastrophic illness can be prohibitive. This risk may be spread by private insurance companies, or by government involvement in the health care market. The health care market can suffer from a number of problems which are so severe as to be characterized by some as market failure - Adverse selection in insurance markets occurs because those providing insurance have limited information with which to estimate the risks their clients wish to insure against. In simple terms, those with poor health will apply for insurance, raising the cost of providing insurance; those with good health will find the cost of insurance too expensive, raising costs further. Private insurers are economically incentivized to spend substantial sums on investigating the health history of prospective clients, charging higher premiums for unhealthy individuals, which they may not be able to afford. [42][43] - Moral hazard in insurance markets occurs when the insured behave in a riskier manner than they would if they were not insured. This problem is made worse when the individual is paying only a fraction of the true cost of coverage. Among the potential solutions posited by economists are: - Various forms of universal health insurance, such as requiring all citizens to purchase insurance, limiting the ability of insurance companies to deny insurance to individuals or vary price between individuals. Compulsory universal health insurance is a common thread, although there is no requirement that the insurance or medical services be provided by government. - Decreased government regulation: Conservative Republican US Senator Bill Frist argued[44] that the free market will keep costs down, because individuals who have to pay for their own health care will make wiser decisions and not spend money on unneeded or inefficient care. A deregulated free market, Frist argues, will also encourage efficiency and innovation. The US currently (2007) has the most expensive health care of any OECD country and also has the highest percentage of costs paid privately.[45] Most European systems are financed through a mix of public and private contributions.[47] The majority of universal health care systems are funded primarily by tax revenue (e.g. Portugal[47]). Some nations, such as Germany, France[48] and Japan[49] employ a multi-payer system in which health care is funded by private and public contributions. In 2001 Canadians paid $2,163 per capita versus $4,887 U.S., according to the Los Angeles Times (also, see table above). According to Dr. Stephen Bezruchka, a senior lecturer in the School of Public Health at the University of Washington in Seattle, Canadians do better by every health care measure. According to a World Health Organization report published in 2003, life expectancy at birth in Canada is 79.8 years, versus 77.3 in the U.S.[50] A distinction is also made between municipal and national healthcare funding. For example, one model is that the bulk of the healthcare is funded by the municipality, speciality healthcare is provided and possibly funded by a larger entity, such as a municipal co-operation board or the state, and the medications are paid by a state agency. No entirely private health care system exists, although the reform bill in Massachusetts attempts to make private health care more affordable. # Politics The politics of health care depends largely on which country one is in. Current concerns in England, for instance, revolve around the use of private finance initiatives to build hospitals or the excessive use of targets in cutting waiting lists. In Germany and France, concerns are more based on the rising cost of drugs to the governments. In Brazil, an important political issue is the breach of intellectual property rights, or patents, for the domestic manufacture of antiretroviral drugs used in the treatment of HIV/AIDS. The South African government, whose population sets the record for HIV infections, came under pressure for its refusal to admit there is any connection with AIDS[51] because of the cost it would have involved. In the United States, which has some of the most sophisticated, technologically advanced health care in the world, 12% to 16% of the citizens are still unable to afford complete health insurance. Opponents of universal health care in the United States often argue that it will require higher taxes and a great likelihood of poorly performing health care facilities and physicians.[52] The absence of a market mechanism may slow innovation in treatment and research leading to rationing of care through waiting lists. A statistical comparison shows that it is not universal health care that leads to a doctor shortage, but the payment system to doctors that causes a doctors shortage. In Italy,[53] doctors are paid a fee per patient per year, a per capita salary, and Italy does not have a doctor shortage but has one of the highest doctor per patient ratios, 5.8 doctors per 1,000 patients. In Italy though, it should be noted that most physicians subsequently have very limited hours; many only maintaining patient hours 2 days per week. Canada, whose universal health care system pays its doctors a "fee per visit", creates a real market condition, where doctors' salaries are protected, and even increased, by decreasing the supply of doctors. Canada has a low doctor per patient ratio of 2.1 doctors per 1,000 patients. A comparative analysis shows that a salaried doctor system, while not perfect, results in more doctors; however, they work substantially fewer hours, while the fee per visit system creates economic pressures to reduce the number of doctors, who subsequently work more hours. # Providers A health care provider or health professional is an organization or person who delivers proper health care in a systematic way professionally to any individual in need of health care services. A health care provider could be a government, Health care industry, health care equipment, institution such as a hospital or medical laboratory, physicians, support staff, nurses, therapists, psychologists, chiropractors, veterinarians, dentists, optometrists, paramedics, pharmacists, or even a health insurance company. # Further reading - Journal of Health Care for the Poor and Underserved	https://www.wikidoc.org/index.php/Health_Care
79d1df51cc9a85f021c6c43cfcef1b349fd3b5b1	wikidoc	Ototoxicity	Ototoxicity Synonyms and keywords: Vestibulotoxicity; hearing toxicity # Overview Ototoxicity is damage to the ear (oto-), specifically the cochlea or auditory nerve and sometimes the vestibular system, by a toxin. It is commonly medication-induced; ototoxic drugs include antibiotics such as the aminoglycoside gentamicin, loop diuretics such as furosemide, and platinum-based chemotherapy agents such as cisplatin. A number of nonsteroidal anti-inflammatory drugs (NSAIDS) have also been shown to be ototoxic. This can result in sensorineural hearing loss, dysequilibrium, or both. Either may be reversible and temporary, or irreversible and permanent. # Ototoxic Agents ## Antibiotics - Amikacin sulfate - Azithromycin - Capreomycin - Chloramphenicol - Clarithromycin - Dibekacin - Dihydrostreptomycin - Erythromycin - Gentamicin - Kanamyycin - Metronidazole - Neomycin - Netilmicin - Polymyxin B - Streptomycin - Tobramycin - Tetracycline - Vancomycin - Gentamicin Antibiotics in the aminoglycoside class, such as gentamicin and tobramycin, may produce cochleotoxicity through a poorly understood mechanism. It may result from antibiotic binding to NMDA receptors in the cochlea and damaging neurons through excitotoxicity. Aminoglycoside-induced production of reactive oxygen species may also injure cells of the cochlea. Once-daily dosing and co-administration of N-acetylcysteine may protect against aminoglycoside-induced ototoxicity. The ototoxicity of gentamicin can be exploited to treat some individuals with Ménière's disease by destroying the inner ear, which stops the vertigo attacks but causes permanent deafness. Macrolide antibiotics, including erythromycin, are associated with reversible ototoxic effects. The underlying mechanism of ototoxicity may be impairment of ion transport in the stria vascularis. Predisposing factors include renal impairment, hepatic impairment, and recent organ transplantation. ## Loop Diuretics - Lasix (furosemide) - Bumex (bumetanide) - Edecrin (ethacrynic acid) - Piretamide The loop diuretic furosemide is associated with ototoxicity, particularly when doses exceed 240 mg per hour. The related compound ethacrynic acid has a higher association with ototoxicity, therefore it is only preferred in patients with sulfur allergies. Bumetanide confers a decreased risk of ototoxicity compared to furosemide. ## Chemotherapeutic Agents - Bleomycin - Carboplatin - Cisplatin - Interferon - Mechlorethamine - Methotrexate - Pegylated interferon-alpha-2b - Nitrogen mustard - Vincristine Platinum-containing chemotherapeutic agents, including cisplatin and carboplatin, are associated with cochleotoxicity characterized by high-frequency hearing loss and tinnitus (ringing in the ears). Ototoxicity is less frequently seen with the related compound oxaliplatin. Cisplatin-induced ototoxicity is dose-dependent, typically occurring with doses greater than 60 mg/m2, and tend to occur when chemotherapy is given every two weeks compared to every one week. Cisplatin and related agents are absorbed by the cochlear hair cells and result in ototoxicity through the production of reactive oxygen species. The decreased incidence of oxaliplatin ototoxicity has been attributed to decreased uptake of the drug by cells of the cochlea. Administration of amifostine has been used in attempts to prevent cisplatin-induced ototoxicity, but the American Society of Clinical Oncology recommends against its routine use. The vinca alkaloids, including vincristine, are also associated with reversible ototoxicity. ## Others ### Quinidine Derivatives - Quinidex - Atabrine - Plaquenil - Quinine Sulfate - Mefloquine (Lariam) - Hydroxychloroquine - Chloroquine (Malaquin) ### Analgesics - Aspirin - Nonsteroidal anti-inflammatory drugs ### Heavy Metals - Mercury - Lead Ototoxic effects are also seen with quinine and heavy metals such as mercury and lead. At high doses, aspirin and other salicylates may also cause high-pitch tinnitus and hearing loss in both ears, typically reversible upon discontinuation of the drug. The erectile dysfunction medications Viagra, Levitra, and Cialis have also been reported to cause hearing loss. ## Mixed Exposures Ototoxic chemicals interact with mechanical stresses on the hair cells of the cochlea in different ways. For organic solvents such as Toluene, styrene or xylene, the combined exposure with noise increases the risk of hearing loss in a synergistic manner Heavy metals, asphyxiants and endocrine disruptors have a variety of interactions as well. Specific toxicity limits for combined exposures are not well established. However, given the potential for enhanced risk of hearing loss, the noise exposures should be kept below 85 decibels and the chemical exposures should be below the recommended exposure limits given by agencies such as OSHA, NIOSH, or ACGIH. # Symptoms Symptoms of ototoxicity include partial or profound hearing loss, vertigo, and tinnitus. Ototoxicity is the result of the inner ear being poisoned by a medication which subsequently causes damage to the cochlea, vestibule, semi-circular canals, or auditory/ vestibulocochlear nerve. The structure afflicted with Ototoxicity also affects the symptoms the patient presents with. The cochlea is primarily a hearing structure. Within the inner ear, it is the snail shaped shell that contains several nerve endings and makes hearing possible. When a patient develops ototoxicity in the cochlea, they experience hearing loss that can range from loss of the high frequency pitch ranges to complete deafness. Ototoxicity most commonly presents itself with bilaterally symmetrical symptoms, but if the symptoms do present asymmetrically, it is possible the other ear will develop the condition at a later time. The time frame in which the patient experiences hearing loss remains debatable as the symptoms which patients suffer vary greatly. In many instances, symptoms are temporary; however, there are many cases in which the hearing loss is permanent. The cochlea can also develop tinnitus from ototoxicity, causing a ringing sound in the ears which only the patient can hear. The vestibule and semi-circular canal are inner-ear components which comprise the vestibular system, another area of the ear affected by ototoxicity. Due to the difference in the function of these structures, ototoxic poisoning affects the patient differently than in the case of cochlear damage. The vestibule is where the two types of otolith organs are housed: the saccule, which points vertically and detects vertical acceleration, and the utricle, which points horizontally and detects horizontal acceleration. The otolith organs detect the head’s position with respect to gravity when the body is static, the head’s movement in an angular or tilted direction, and pitch changes during any linear motion of the head. The saccule and utricle work together to detect different motions that the brain later integrates to correctly determine exactly where the head is and how and where it is moving. The vestibule and the semi-circular canals work together to detect all forms of head movement. The semi-circular canals are three bony structures that are filled with fluid. Just as the vestibule, the primary purpose of the canals is to detect movement. Each canal is oriented independently at right angles from the others, enabling detection of movement in any plane. The posterior canal detects rolling motion, or motion about the X axis; the anterior canal detects pitch, or motion about the Y axis; the horizontal canal detects yaw motion, or motion about the Z axis. When a medication causes an ototoxic reaction in either the vestibule or semi-circular canals, the patient suffers from problems in balance and orientation rather than hearing issues. Symptoms in these organs present as vertigo, difficulties walking at night, and disequilibrium, oscillopsia among other balance related problems. Each of these problems is directly related to balance and the mind being confused with the direction of motion or lack of motion. Because both the vestibule and semi-circular canals transmit information to the brain about movement, when these are poisoned, they are unable to function properly which results in miscommunication with the brain. When the vestibule and/or semi-circular canals are affected by ototoxicity, the eye can also be affected. Nystagmus and oscillopsia are two conditions that overlap the vestibular and ocular systems. These symptoms cause the patient to have difficulties with seeing and processing images. The body subconsciously tries to compensate for the imbalance signals being sent to the brain by trying to obtain visual cues to support the information it is receiving. This results in that dizziness and “woozy” feeling patients use to describe conditions such as oscillopsia and vertigo. The auditory/vestibulocochlear nerve, or cranial nerve VIII, is the least afflicted component of the ear when ototoxicity arises, but if the nerve is affected, the damage is most often permanent. Cranial nerve VIII “has a vestibular part which functions in balance, equilibrium, and orientation in three-dimensional space, and a cochlear part which functions in hearing." Despite the vestibular or cochlear structures functioning normally, affliction of the nerve effectively arrests communication between these structures and the brain. Symptoms present similar to those resulting from vestibular and cochlear damage, including tinnitus, ringing of the ears, difficultly walking, deafness, and balance and orientation issues. # Treatment No specific treatment is available, but immediate withdrawal of the drug may be warranted in cases where the consequences of doing so are less severe than the consequences of the ototoxicity. It is difficult to distinguish between nerve damage and structural damage due to similarity of the symptoms. Often ototoxicity diagnoses result from ruling out all other possible sources of hearing loss and is the catchall explanation for the sudden problem. Treatment options vary depending on the patient and the diagnosis. Some patients only experience temporary symptoms, which do not require drastic treatment while other patients can be treated with medication. Physical therapy remains particularly useful with regaining balance and walking abilities. Cochlear implants are sometimes an option as well to restore hearing. However, these treatments are more often made in an effort to make the patient as comfortable as possible and to help them cope with the symptoms, not to cure them of the disease or damage caused by ototoxicity. There is no cure or restoration capability if the damage becomes permanent.	Ototoxicity Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Sapan Patel M.B.B.S Synonyms and keywords: Vestibulotoxicity; hearing toxicity # Overview Ototoxicity is damage to the ear (oto-), specifically the cochlea or auditory nerve and sometimes the vestibular system, by a toxin. It is commonly medication-induced; ototoxic drugs include antibiotics such as the aminoglycoside gentamicin, loop diuretics such as furosemide, and platinum-based chemotherapy agents such as cisplatin. A number of nonsteroidal anti-inflammatory drugs (NSAIDS) have also been shown to be ototoxic. This can result in sensorineural hearing loss, dysequilibrium, or both. Either may be reversible and temporary, or irreversible and permanent. # Ototoxic Agents ## Antibiotics - Amikacin sulfate - Azithromycin - Capreomycin - Chloramphenicol - Clarithromycin - Dibekacin - Dihydrostreptomycin - Erythromycin - Gentamicin - Kanamyycin - Metronidazole - Neomycin - Netilmicin - Polymyxin B - Streptomycin - Tobramycin - Tetracycline - Vancomycin - Gentamicin Antibiotics in the aminoglycoside class, such as gentamicin and tobramycin, may produce cochleotoxicity through a poorly understood mechanism.[1] It may result from antibiotic binding to NMDA receptors in the cochlea and damaging neurons through excitotoxicity.[2] Aminoglycoside-induced production of reactive oxygen species may also injure cells of the cochlea.[3] Once-daily dosing[4] and co-administration of N-acetylcysteine[5] may protect against aminoglycoside-induced ototoxicity. The ototoxicity of gentamicin can be exploited to treat some individuals with Ménière's disease by destroying the inner ear, which stops the vertigo attacks but causes permanent deafness.[6] Macrolide antibiotics, including erythromycin, are associated with reversible ototoxic effects.[7] The underlying mechanism of ototoxicity may be impairment of ion transport in the stria vascularis.[7] Predisposing factors include renal impairment, hepatic impairment, and recent organ transplantation.[7] ## Loop Diuretics - Lasix (furosemide) - Bumex (bumetanide) - Edecrin (ethacrynic acid) - Piretamide The loop diuretic furosemide is associated with ototoxicity, particularly when doses exceed 240 mg per hour.[8] The related compound ethacrynic acid has a higher association with ototoxicity, therefore it is only preferred in patients with sulfur allergies.[9] Bumetanide confers a decreased risk of ototoxicity compared to furosemide.[7] ## Chemotherapeutic Agents - Bleomycin - Carboplatin - Cisplatin - Interferon - Mechlorethamine - Methotrexate - Pegylated interferon-alpha-2b - Nitrogen mustard - Vincristine Platinum-containing chemotherapeutic agents, including cisplatin and carboplatin, are associated with cochleotoxicity characterized by high-frequency hearing loss and tinnitus (ringing in the ears).[10] Ototoxicity is less frequently seen with the related compound oxaliplatin.[11] Cisplatin-induced ototoxicity is dose-dependent, typically occurring with doses greater than 60 mg/m2, and tend to occur when chemotherapy is given every two weeks compared to every one week.[10] Cisplatin and related agents are absorbed by the cochlear hair cells and result in ototoxicity through the production of reactive oxygen species.[12] The decreased incidence of oxaliplatin ototoxicity has been attributed to decreased uptake of the drug by cells of the cochlea.[11] Administration of amifostine has been used in attempts to prevent cisplatin-induced ototoxicity, but the American Society of Clinical Oncology recommends against its routine use.[13] The vinca alkaloids, including vincristine, are also associated with reversible ototoxicity.[7] ## Others ### Quinidine Derivatives - Quinidex - Atabrine - Plaquenil - Quinine Sulfate - Mefloquine (Lariam) - Hydroxychloroquine - Chloroquine (Malaquin) ### Analgesics - Aspirin - Nonsteroidal anti-inflammatory drugs ### Heavy Metals - Mercury - Lead Ototoxic effects are also seen with quinine and heavy metals such as mercury and lead.[7] At high doses, aspirin and other salicylates may also cause high-pitch tinnitus and hearing loss in both ears, typically reversible upon discontinuation of the drug.[7] The erectile dysfunction medications Viagra, Levitra, and Cialis have also been reported to cause hearing loss.[14] ## Mixed Exposures Ototoxic chemicals interact with mechanical stresses on the hair cells of the cochlea in different ways. For organic solvents such as Toluene, styrene or xylene, the combined exposure with noise increases the risk of hearing loss in a synergistic manner [15] Heavy metals, asphyxiants and endocrine disruptors have a variety of interactions as well. Specific toxicity limits for combined exposures are not well established. However, given the potential for enhanced risk of hearing loss, the noise exposures should be kept below 85 decibels and the chemical exposures should be below the recommended exposure limits given by agencies such as OSHA, NIOSH, or ACGIH. # Symptoms Symptoms of ototoxicity include partial or profound hearing loss, vertigo, and tinnitus.[7] Ototoxicity is the result of the inner ear being poisoned by a medication which subsequently causes damage to the cochlea, vestibule, semi-circular canals, or auditory/ vestibulocochlear nerve. The structure afflicted with Ototoxicity also affects the symptoms the patient presents with. The cochlea is primarily a hearing structure. Within the inner ear, it is the snail shaped shell that contains several nerve endings and makes hearing possible.[16] When a patient develops ototoxicity in the cochlea, they experience hearing loss that can range from loss of the high frequency pitch ranges to complete deafness.[17] Ototoxicity most commonly presents itself with bilaterally symmetrical symptoms, but if the symptoms do present asymmetrically, it is possible the other ear will develop the condition at a later time.[17] The time frame in which the patient experiences hearing loss remains debatable as the symptoms which patients suffer vary greatly. In many instances, symptoms are temporary; however, there are many cases in which the hearing loss is permanent.[16] The cochlea can also develop tinnitus from ototoxicity, causing a ringing sound in the ears which only the patient can hear. The vestibule and semi-circular canal are inner-ear components which comprise the vestibular system, another area of the ear affected by ototoxicity. Due to the difference in the function of these structures, ototoxic poisoning affects the patient differently than in the case of cochlear damage. The vestibule is where the two types of otolith organs are housed: the saccule, which points vertically and detects vertical acceleration, and the utricle, which points horizontally and detects horizontal acceleration. The otolith organs detect the head’s position with respect to gravity when the body is static, the head’s movement in an angular or tilted direction, and pitch changes during any linear motion of the head. The saccule and utricle work together to detect different motions that the brain later integrates to correctly determine exactly where the head is and how and where it is moving. The vestibule and the semi-circular canals work together to detect all forms of head movement. The semi-circular canals are three bony structures that are filled with fluid. Just as the vestibule, the primary purpose of the canals is to detect movement. Each canal is oriented independently at right angles from the others, enabling detection of movement in any plane. The posterior canal detects rolling motion, or motion about the X axis; the anterior canal detects pitch, or motion about the Y axis; the horizontal canal detects yaw motion, or motion about the Z axis. When a medication causes an ototoxic reaction in either the vestibule or semi-circular canals, the patient suffers from problems in balance and orientation rather than hearing issues. Symptoms in these organs present as vertigo, difficulties walking at night, and disequilibrium, oscillopsia among other balance related problems.[17] Each of these problems is directly related to balance and the mind being confused with the direction of motion or lack of motion. Because both the vestibule and semi-circular canals transmit information to the brain about movement, when these are poisoned, they are unable to function properly which results in miscommunication with the brain. When the vestibule and/or semi-circular canals are affected by ototoxicity, the eye can also be affected. Nystagmus and oscillopsia are two conditions that overlap the vestibular and ocular systems. These symptoms cause the patient to have difficulties with seeing and processing images. The body subconsciously tries to compensate for the imbalance signals being sent to the brain by trying to obtain visual cues to support the information it is receiving. This results in that dizziness and “woozy” feeling patients use to describe conditions such as oscillopsia and vertigo.[17] The auditory/vestibulocochlear nerve, or cranial nerve VIII, is the least afflicted component of the ear when ototoxicity arises, but if the nerve is affected, the damage is most often permanent. Cranial nerve VIII “has a vestibular part which functions in balance, equilibrium, and orientation in three-dimensional space, and a cochlear part which functions in hearing."[18] Despite the vestibular or cochlear structures functioning normally, affliction of the nerve effectively arrests communication between these structures and the brain. Symptoms present similar to those resulting from vestibular and cochlear damage, including tinnitus, ringing of the ears, difficultly walking, deafness, and balance and orientation issues.[18] # Treatment No specific treatment is available, but immediate withdrawal of the drug may be warranted in cases where the consequences of doing so are less severe than the consequences of the ototoxicity.[7] It is difficult to distinguish between nerve damage and structural damage due to similarity of the symptoms. Often ototoxicity diagnoses result from ruling out all other possible sources of hearing loss and is the catchall explanation for the sudden problem. Treatment options vary depending on the patient and the diagnosis. Some patients only experience temporary symptoms, which do not require drastic treatment while other patients can be treated with medication. Physical therapy remains particularly useful with regaining balance and walking abilities. Cochlear implants are sometimes an option as well to restore hearing. However, these treatments are more often made in an effort to make the patient as comfortable as possible and to help them cope with the symptoms, not to cure them of the disease or damage caused by ototoxicity. There is no cure or restoration capability if the damage becomes permanent.[19][20] # External links - Ototoxic Medications Template:Diseases of the ear and mastoid process	https://www.wikidoc.org/index.php/Hearing_toxicity
078cfd6f797b16b74a6bf511c7df8b9cbb4a0023	wikidoc	Heavy water	Heavy water Heavy water is water which contains a higher proportion than normal of the isotope deuterium, as deuterium oxide, D2O or ²H2O, or as deuterium protium oxide, HDO or ¹H²HO. Its physical and chemical properties are somewhat similar to those of water, H2O. Heavy water may contain as much as 100% D2O, and usually the term refers to water which is highly enriched in deuterium. The isotopic substitution with deuterium alters the bond energy of the hydrogen-oxygen bond in water, altering the physical, chemical, and especially biological properties of the pure or highly-enriched substance to a larger degree than is found in most isotope-substituted chemical compounds. Heavy water should not be confused with hard water or with tritiated water. # Other meanings ## Semiheavy water Semiheavy water, HDO, exists whenever there is water with hydrogen-1 (or protium) and deuterium present in the mixture. This is because hydrogen atoms (hydrogen-1 and deuterium) are rapidly exchanged between water molecules. Water containing 50% H and 50% D in its hydrogen actually contains about 50% HDO and 25% each of H2O and D2O, in dynamic equilibrium. Semiheavy water, HDO, occurs naturally in regular water at a proportion of about 1 molecule in 3,200 (each hydrogen has a probability of 1 in 6,400 of being D). Heavy water, D2O, by comparison, occurs naturally at a proportion of about 1 molecule in 41 million (i.e., 1 in 6,4002). This makes semiheavy water actually far more prevalent than 'normal' heavy water. ## Heavy-oxygen water A common type of heavy-oxygen water H218O is available commercially for use as a non-radioactive isotopic tracer (see doubly-labeled water for discussion), and qualifies as "heavy water" insofar as having a higher density than normal water (in this case, similar density to deuterium oxide). At higher expense (due to the greater difficulty in separation of O-17, a less common heavy isotope of oxygen), water is available in which the oxygen is enriched to varying degrees with 17O. However, these types of heavy-isotope water are rarely referred to as "heavy water", as they do not contain the deuterium which gives D2O its characteristically different nuclear and biological properties. Heavy-oxygen waters with normal hydrogen, for example, would not be expected to show any toxicity whatsoever (see discussion of toxicity below). # Physical properties (with comparison to light water) No physical properties are listed for "pure" semi-heavy water, because it cannot be isolated in bulk quantities. In the liquid state, a few water molecules are always in an ionised state, which means the hydrogen atoms can exchange among different oxygen atoms. A sample of hypothetical "pure" semi-heavy water would rapidly transform into a dynamic mixture of 25% light water, 25% heavy water, and 50% semi-heavy water. Physical properties obvious by inspection: Heavy water is 10.6% more dense than ordinary water, a difference which is nearly impossible to notice in a sample of it (which otherwise looks and tastes exactly like normal water). One of the few ways to demonstrate heavy water's physically different properties without equipment, is to freeze a sample and drop it into normal water. Ice made from heavy water sinks in normal water. If the normal water is ice-cold this phenomenon may be observed long enough for a good demonstration, since heavy-water ice has a slightly higher melting-temperature (3.8 °C) than normal ice, and thus holds up very well in ice-cold normal water. # History Harold Urey discovered the isotope deuterium in 1931 and was later able to concentrate it in water. Urey's mentor Gilbert Newton Lewis isolated the first sample of pure heavy water by electrolysis in 1933. George de Hevesy and Hoffer used heavy water in 1934 in one of the first biological tracer experiments, to estimate the rate of turnover of water in the human body. The history of large-quantity production and use of heavy water in early nuclear experiments is given below. # Effect on biological systems Heavy isotopes of chemical elements have very slightly different chemical behaviors, but for most elements the differences in chemical behavior between isotopes are far too small to use, or even detect. For hydrogen, however, this is not true. The larger chemical isotope-effects seen with deuterium and tritium manifest because bond energies in chemistry are determined in quantum mechanics by equations in which the quantity of reduced mass of the nucleus and electrons appears. This quantity is altered in heavy-hydrogen compounds (of which deuterium oxide is the most common and familiar) far more than for heavy-isotope substitution in other chemical elements. This isotope effect of heavy hydrogen is magnified further in biological systems, which are very sensitive to small changes in the solvent properties of water. Heavy water is the only known chemical substance which affects the period of circadian oscillations, consistently increasing them. The effect is seen in unicellular organisms, green plants, isopods, insects, birds, mice, and hamsters. The mechanism is unknown. To perform their tasks, enzymes rely on their finely tuned networks of hydrogen bonds, both in the active center with their substrates, and outside the active center, to stabilize their tertiary structures. As a hydrogen bond with deuterium is slightly stronger than one involving ordinary hydrogen, in a highly deuterated environment, some normal reactions in cells are disrupted. Particularly hard-hit by heavy water are the delicate assemblies of mitotic spindle formation necessary for cell division in eukaryotes. Plants stop growing and seeds do not germinate when given only heavy water, because heavy water stops eukaryotic cell division. # Effect on animals Experiments in mice, rats, and dogs have shown that a degree of 25% deuteration causes (sometimes irreversible) sterility, because neither gametes nor zygotes can develop. High concentrations of heavy water (90%) rapidly kills fish, tadpoles, flatworms, and drosophila. Mammals such as rats given heavy water to drink die after a week, at a time when their body water approaches about 50% deuteration. The mode of death appears to be the same as that in cytotoxic poisoning (such as chemotherapy) or in acute radiation syndrome (though deuterium is not radioactive), and is due to deuterium's action in generally inhibiting cell division. Deuterium oxide is used to enhance boron neutron capture therapy. It is more toxic to malignant cells than normal cells but the concentrations needed are too high for regular use. As in chemotherapy, deuterium-poisoned mammals die of a failure of bone marrow (bleeding and infection) and intestinal-barrier functions (diarrhea and fluid loss). Notwithstanding the problems of plants and animals in living with too much deuterium, prokaryotic organisms such as bacteria (which do not have the mitotic problems induced by deuterium) may be grown and propagated in fully deuterated conditions, resulting in replacement of all hydrogen atoms in the bacterial proteins and DNA with the deuterium isotope. Full replacement with heavy atom isotopes can be accomplished in higher organisms with other non-radioactive heavy isotopes (such as carbon-13, nitrogen-15, and oxygen-18), but this cannot be done for the stable heavy isotope of hydrogen. # Toxicity in humans Because it would take a very great deal of heavy water to replace 25% to 50% of a human being's body water (which in turn is 70% of body weight) with heavy water, accidental or intentional poisoning with heavy water is unlikely to the point of practical disregard. For a poisoning, large amounts of heavy water would need to be ingested without significant normal water intake for many days to produce any noticeable toxic effects (although in a few tests, volunteers drinking large amounts of heavy water have reported dizziness, a possible effect of density changes in the fluid in the inner ear). For example, a 70 kg human containing 50 kg of water and drinking 3 liters of pure heavy water per day, would need to do this for almost 5 days to reach 25% deuteration, and for about 11 days to approach 50% deuteration. Thus, it would take a week of drinking nothing but pure heavy water for a human to begin to feel ill, and 10 days to 2 weeks (depending on water intake) for severe poisoning and death. In the highly unlikely event that a human were to receive a toxic dose of heavy water, the treatment would involve the use of intravenous water replacement (due to possible intestinal dysfunction and problems with absorption of fluids). This would be done via 0.9% (normal physiologic) saline solution with other salts as needed, perhaps in conjunction with diuretics. Oral doses of heavy water in the multi-gram range, along with heavy oxygen 18O, are routinely used in human metabolic experiments. See doubly-labeled water testing. Since 1 in every 6400 hydrogen atoms is deuterium, a 50 kg human containing 32 kg of body water would normally contain enough deuterium (about 1.1 gram) to make 5.5 grams of pure heavy water, so roughly this dose is required to double the amount of deuterium in the body. # Confused report of a "heavy water" contamination incident In 1990, a disgruntled employee at the Point Lepreau Nuclear Generating Station in Canada obtained a sample (estimated as about a "half cup") of heavy water from the primary heat transport loop of the nuclear reactor, and loaded it into the employee water cooler. Eight employees drank some of the contaminated water. The incident was discovered when employees began leaving bioassay urine samples with elevated tritium levels. The quantity of heavy water involved was far below levels which could induce heavy water toxicity per se, but several employees received elevated radiation doses from tritium and neutron-activated chemicals in the water. This was not an incident of heavy water poisoning, but rather radiation poisoning from other isotopes in the heavy water. Some news services were not careful to distinguish these points, and some of the public was left with the impression that heavy water is normally radioactive and more severely toxic than it is. Even if pure heavy water had been used in the water cooler indefinitely, it is not likely the incident would have been detected or caused harm, since no employees would be expected to get as much as 25% of their daily drinking water from such a source. # Production On Earth, semiheavy water, HDO, occurs naturally in regular water at a proportion of about 1 molecule in 3200. This means that 1 in 6400 hydrogen atoms is deuterium, which is 1 part in 3200 by weight (hydrogen weight). The HDO may be separated from regular water by distillation or electrolysis and also by various chemical exchange processes, all of which exploit a kinetic isotope effect. (For more information about the isotopic distribution of deuterium in water, see Vienna Standard Mean Ocean Water.) The difference in mass between the two hydrogen isotopes translates into a difference in the zero-point energy and thus into a slight difference in the speed at which the reaction proceeds. Once HDO becomes a significant fraction of the water, heavy water will become more prevalent as water molecules trade hydrogen atoms very frequently. To produce pure heavy water by distillation or electrolysis requires a large cascade of stills or electrolysis chambers, and consumes large amounts of power, so the chemical methods are generally preferred. The most important chemical method is the Girdler sulfide process. ## United States In 1953, the United States began using heavy water in plutonium production reactors at the Savannah River Site. The first of the five heavy water reactors came online in 1953, and the last was placed in cold shutdown in 1996. The SRS reactors were heavy water reactors so that they could produce both plutonium and tritium for the US nuclear weapons program. The U.S. developed the Girdler Sulfide chemical exchange production process which was first demonstrated on a large scale at the Dana, Indiana plant in 1945 and at the Savannah River Plant, South Carolina in 1952. The SRP was operated by DuPont for the USDOE until April 1, 1989 at which time the operation was taken over by Westinghouse. In 1934, Norsk Hydro built the first commercial heavy water plant at Vemork, Tinn, with a capacity of 12 tonnes per year. From 1940 and throughout World War II, the plant was under German control and the allies decided to destroy the plant and its heavy water to inhibit German development of nuclear weapons. In late 1942, a raid by British paratroopers failed when the gliders they were in crashed. All the raiders were killed in the crash or shot by German army troops. But in the night of 27 February 1943 Operation Gunnerside succeeded. Norwegian commandos managed to demolish small but key bits of the electrolytic cells, dumping the accumulated heavy water down the factory drains. ArguablyTemplate:Clarifyme (see below) this prevented Germany from building a nuclear reactor (German nuclear weapons would not have automatically followed the reactor for many reasonsTemplate:Clarifyme). The Norsk Hydro operation is one of the great commando/sabotage operations of the war. On 16 November 1943, the allied air forces dropped more than 400 bombs on the site. The allied air raid prompted the Nazi government to move all available heavy water to Germany for safekeeping. On 20 February 1944, a Norwegian partisan sank the ferry M/F Hydro carrying the heavy water across Lake Tinn, at the cost of 14 Norwegian civilians, and most of the heavy water was presumably lost. A few of the barrels were only half full, and therefore could float, and may have been salvaged and transported to Germany. (These events were dramatized in the 1965 movie, The Heroes of Telemark.) However, recent investigation of production records at Norsk Hydro and analysis of an intact barrel that was salvaged in 2004 revealed that although the barrels in this shipment contained water of pH 14 — indicative of the alkaline electrolytic refinement process — they did not contain high concentrations of D2O. Despite the apparent size of shipment, the total quantity of pure heavy water was quite small, most barrels only containing between 1/2–1% pure heavy water. The Germans would have needed a total of about 5 tons of heavy water to get a nuclear reactor running. The manifest clearly indicated that there was only half a ton of heavy water being transported to Germany. The Hydro was carrying far too little heavy water for even one reactor, let alone the 10 or more tons needed to make enough plutonium for a nuclear weapon. The Hydro shipment on 20 February 1944 was probably destined for an experimental reactor project. ## Canada As part of its contribution to the Manhattan Project, Canada built and operated a 6 tonnes per year electrolytic heavy water plant at Trail, BC, which started operation in 1943. The Atomic Energy of Canada Limited (AECL) design of power reactor requires large quantities of heavy water to act as a neutron moderator and coolant. AECL ordered two heavy water plants which were built and operated in Atlantic Canada at Glace Bay (by Deuterium of Canada Limited) and Port Hawkesbury, Nova Scotia (by General Electric Canada). These plants proved to have significant design, construction and production problems and so AECL built the Bruce Heavy Water Plant, which it later sold to Ontario Hydro, to ensure a reliable supply of heavy water for future power plants. The two Nova Scotia plants were shut down in 1985 when their production proved to be unnecessary. The Bruce Heavy Water Plant in Ontario was the world's largest heavy water production plant with a capacity of 700 tonnes per year. It used the Girdler sulfide process to produce heavy water, and required 340,000 tonnes of feed water to produce one tonne of heavy water. It was part of a complex that included 8 CANDU reactors which provided heat and power for the heavy water plant. The site was located at Douglas Point in Bruce County on Lake Huron where it had access to the waters of the Great Lakes. The Bruce plant was commissioned in 1979 to provide heavy water for a large increase in Ontario's nuclear power generation. The plants proved to be significantly more efficient than planned and only three of the planned four units were eventually commissioned. In addition, the nuclear power programme was slowed down and effectively stopped due to a perceived oversupply of electricity, later shown to be temporary, in 1993. Improved efficiency in the use and recycling of heavy water plus the over-production at Bruce left Canada with enough heavy water for its anticipated future needs. Also, the Girdler process involves large amounts of hydrogen sulfide, raising environmental concerns if there should be a release. The Bruce heavy-water plant was shut down in 1997, after which the plant was gradually dismantled and the site cleared. Atomic Energy of Canada Limited (AECL) is currently researching other more efficient and environmentally benign processes for creating heavy water. This is essential for the future of the CANDU reactors since heavy water represents about 20% of the capital cost of each reactor. India is the world's second largest producer of heavy water through its Heavy Water Board. On August 26, 2006, Iranian President Ahmadinejad inaugurated an expansion of the country's heavy-water plant near Arak. Iran has indicated that the heavy-water production facility will operate in tandem with a 40 MW research reactor that has a scheduled completion date in 2009. In an interview which aired on the Iranian News Channel (IRINN) on August 27, 2006, Iranian Nuclear Chief Mohammad Sa'idi claimed that heavy water could be used to treat AIDS and cancer. Daily consumption was recommended. ## Other countries Roghayeh Marandi, M.D. also produces heavy water at the Drobeta Girdler Sulfide plant and has exported from time to time. # Applications ## Nuclear magnetic resonance Deuterium oxide is used in nuclear magnetic resonance spectroscopy when the solvent of interest is water and the nuclide of interest is hydrogen. This is because the signal from the water solvent would interfere with the signal from the molecule of interest. Deuterium has a different magnetic moment from hydrogen and therefore does not contribute to the NMR signal at the hydrogen resonance frequency. ## Neutron moderator Heavy water is used in certain types of nuclear reactors where it acts as a neutron moderator to slow down neutrons so that they can react with the uranium in the reactor. The CANDU reactor uses this design. Light water also acts as a moderator but because light water absorbs more neutrons than heavy water, reactors using light water must use enriched uranium rather than natural uranium, otherwise criticality is impossible. The use of heavy water essentially increases the efficiency of the nuclear reaction. Because of this, heavy water reactors will be more efficient at breeding plutonium (from uranium-238) or uranium-233 (from thorium-232) than a comparable light-water reactor, leading them to be of greater concern in regards to nuclear proliferation. The breeding and extraction of plutonium can be a relatively rapid and cheap route to building a nuclear weapon, as chemical separation of plutonium from fuel is easier than isotopic separation of U-235 from natural uranium. Heavy water moderated research reactors or specifically-built plutonium breeder reactors have been used for this purpose by most, if not all, states which possess nuclear weapons, although historically the first nuclear weapons were produced without it. (Pure carbon may be used as a moderator, even in unenriched uranium nuclear reactors. Thus, in the U.S., the first experimental atomic reactor (1942), as well as the Manhattan Project Hanford production reactors which produced the plutonium for the Trinity test and Fat Man bombs, all used pure carbon neutron moderators and functioned with neither enriched uranium nor heavy water). There is no evidence that civilian heavy water power reactors, such as the CANDU or Atucha designs, have been used for military production of fissile materials. In states which do not already possess nuclear weapons, the nuclear material at these facilities is under IAEA safeguards to discourage any such diversion. Due to its potential for use in nuclear weapons programs, the possession or import/export of large industrial quantities of heavy water are subject to government control in several countries. Suppliers of heavy water and heavy water production technology typically apply IAEA (International Atomic Energy Agency) administered safeguards and material accounting to heavy water. (In Australia, the Nuclear Non-Proliferation (Safeguards) Act 1987.) In the U.S. and Canada, non-industrial quantities of heavy water (i.e., in the gram to kg range) are routinely available through chemical supply dealers, and directly commercial companies such as the world's former major producer Ontario Hydro, without special license. Current (2006) cost of a kilogram of 99.98% reactor-purity heavy water, is about $600 to $700. Smaller quantities of reasonable purity (99.9%) may be purchased from chemical supply houses at prices of roughly $1 per gram. ## Neutrino detector The Sudbury Neutrino Observatory (SNO) in Sudbury, Ontario uses 1000 tonnes of heavy water on loan from Atomic Energy of Canada Limited. The neutrino detector is 6800 feet underground in a deep mine, in order to shield it from muons produced by cosmic rays. SNO was built to answer the question of whether or not electron-type neutrinos produced by fusion in the Sun (the only type the Sun should be producing directly, according to theory) might be able to turn into other types of neutrinos on the way to Earth. SNO detects the Čerenkov radiation in the water from high-energy electrons produced from electron-type neutrinos as they undergo reactions with neutrons in deuterium, turning them into protons and electrons (only the electrons move fast enough to be detected in this manner). SNO also detects the same radiation from neutrino↔electron scattering events, which again produces high energy electrons. These two reactions are produced only by electron-type neutrinos. The use of deuterium is critical to the SNO function, because all three "flavours" (types) of neutrinos may be detected in a third type of reaction, neutrino-disintegration, in which a neutrino of any type (electron, muon, or tau) scatters from a deuterium nucleus (deuteron), transferring enough energy to break up the loosely-bound deuteron into a free neutron and proton. This event is detected when the free neutron is absorbed by 35Cl− present from NaCl which has been deliberately dissolved in the heavy water, causing emission of characteristic capture gamma rays. Thus, in this experiment, heavy water not only provides the transparent medium necessary to produce and visualize Čerenkov radiation, but it also provides deuterium to detect exotic mu type (μ) and tau (τ) neutrinos, as well as a non-absorbent moderator medium to preserve free neutrons from this reaction, until they can be absorbed by an easily-detected neutron-activated isotope. ## Metabolic rate testing in physiology/biology Heavy water is employed as part of a mixture with H218O for a common and safe test of mean metabolic rate in humans and animals undergoing their normal activities. This metabolic test is usually called the doubly-labeled water test. ## Space-based non-toxic cooling systems Heavy water (D2O) has a similar high heat of fusion to regular water, but freezes at a slightly higher temperature. It has been proposed as a non-toxic heatsink for space based cooling applications, where D2O ice acts as a heatsink to remove water vapor in air, but without danger that the water vapor will freeze to water-ice, because D2O ice maintains temperatures too high for this to occur. See U.S. Patent 5,246,061. Such a system has not yet been tested. ## Tritium production Tritium is an important material in nuclear weapon design for boosted fission weapons and initiators, and also has civilian industrial applications. Some is created in heavy water moderated reactors when deuterium captures a neutron. This reaction has a small cross-section and produces only small amounts of tritium, although enough so that cleaning tritium from the moderator may be desirable after several years to reduce the risk of tritium escape and radiation exposure. Production of large amounts of tritium in this way would require reactors with very high neutron fluxes, or with a very high proportion of heavy water to nuclear fuel and very low neutron absorption by other reactor material. The tritium would then have to be recovered by isotope separation from a much larger quantity of deuterium, unlike tritium production from lithium-6 (the present method of tritium production), where only chemical separation is needed. Deuterium's absorption cross section for thermal neutrons is .52 millibarns, while oxygen-16's is .19 millibarns and oxygen-17's is .24 barn. 17O makes up .038% of natural oxygen, which has an overall absorption cross section of .28 millibarns. Therefore in D2O with natural oxygen, 21% of neutron captures are on oxygen, a proportion that may rise further as 17O accumulates from neutron capture on 16O. Also, 17O emits an alpha particle on capture, producing radioactive carbon-14.	Heavy water Template:Chembox new Heavy water is water which contains a higher proportion than normal of the isotope deuterium, as deuterium oxide, D2O or ²H2O, or as deuterium protium oxide, HDO or ¹H²HO.[1] Its physical and chemical properties are somewhat similar to those of water, H2O. Heavy water may contain as much as 100% D2O, and usually the term refers to water which is highly enriched in deuterium. The isotopic substitution with deuterium alters the bond energy of the hydrogen-oxygen bond in water, altering the physical, chemical, and especially biological properties of the pure or highly-enriched substance to a larger degree than is found in most isotope-substituted chemical compounds. Heavy water should not be confused with hard water or with tritiated water. # Other meanings ## Semiheavy water Semiheavy water, HDO, exists whenever there is water with hydrogen-1 (or protium) and deuterium present in the mixture. This is because hydrogen atoms (hydrogen-1 and deuterium) are rapidly exchanged between water molecules. Water containing 50% H and 50% D in its hydrogen actually contains about 50% HDO and 25% each of H2O and D2O, in dynamic equilibrium. Semiheavy water, HDO, occurs naturally in regular water at a proportion of about 1 molecule in 3,200 (each hydrogen has a probability of 1 in 6,400 of being D). Heavy water, D2O, by comparison, occurs naturally at a proportion of about 1 molecule in 41 million (i.e., 1 in 6,4002). This makes semiheavy water actually far more prevalent than 'normal' heavy water. ## Heavy-oxygen water A common type of heavy-oxygen water H218O is available commercially for use as a non-radioactive isotopic tracer (see doubly-labeled water for discussion), and qualifies as "heavy water" insofar as having a higher density than normal water (in this case, similar density to deuterium oxide). At higher expense (due to the greater difficulty in separation of O-17, a less common heavy isotope of oxygen), water is available in which the oxygen is enriched to varying degrees with 17O. However, these types of heavy-isotope water are rarely referred to as "heavy water", as they do not contain the deuterium which gives D2O its characteristically different nuclear and biological properties. Heavy-oxygen waters with normal hydrogen, for example, would not be expected to show any toxicity whatsoever (see discussion of toxicity below). # Physical properties (with comparison to light water) No physical properties are listed for "pure" semi-heavy water, because it cannot be isolated in bulk quantities. In the liquid state, a few water molecules are always in an ionised state, which means the hydrogen atoms can exchange among different oxygen atoms. A sample of hypothetical "pure" semi-heavy water would rapidly transform into a dynamic mixture of 25% light water, 25% heavy water, and 50% semi-heavy water. Physical properties obvious by inspection: Heavy water is 10.6% more dense than ordinary water, a difference which is nearly impossible to notice in a sample of it (which otherwise looks and tastes exactly like normal water). One of the few ways to demonstrate heavy water's physically different properties without equipment, is to freeze a sample and drop it into normal water. Ice made from heavy water sinks in normal water. If the normal water is ice-cold this phenomenon may be observed long enough for a good demonstration, since heavy-water ice has a slightly higher melting-temperature (3.8 °C) than normal ice, and thus holds up very well in ice-cold normal water. [2] # History Harold Urey discovered the isotope deuterium in 1931 and was later able to concentrate it in water.[3] Urey's mentor Gilbert Newton Lewis isolated the first sample of pure heavy water by electrolysis in 1933. George de Hevesy and Hoffer used heavy water in 1934 in one of the first biological tracer experiments, to estimate the rate of turnover of water in the human body. The history of large-quantity production and use of heavy water in early nuclear experiments is given below.[4] # Effect on biological systems Heavy isotopes of chemical elements have very slightly different chemical behaviors, but for most elements the differences in chemical behavior between isotopes are far too small to use, or even detect. For hydrogen, however, this is not true. The larger chemical isotope-effects seen with deuterium and tritium manifest because bond energies in chemistry are determined in quantum mechanics by equations in which the quantity of reduced mass of the nucleus and electrons appears. This quantity is altered in heavy-hydrogen compounds (of which deuterium oxide is the most common and familiar) far more than for heavy-isotope substitution in other chemical elements. This isotope effect of heavy hydrogen is magnified further in biological systems, which are very sensitive to small changes in the solvent properties of water. Heavy water is the only known chemical substance which affects the period of circadian oscillations, consistently increasing them. The effect is seen in unicellular organisms, green plants, isopods, insects, birds, mice, and hamsters. The mechanism is unknown.[5] To perform their tasks, enzymes rely on their finely tuned networks of hydrogen bonds, both in the active center with their substrates, and outside the active center, to stabilize their tertiary structures. As a hydrogen bond with deuterium is slightly stronger than one involving ordinary hydrogen, in a highly deuterated environment, some normal reactions in cells are disrupted. Particularly hard-hit by heavy water are the delicate assemblies of mitotic spindle formation necessary for cell division in eukaryotes. Plants stop growing and seeds do not germinate when given only heavy water, because heavy water stops eukaryotic cell division. # Effect on animals Experiments in mice, rats, and dogs[6] have shown that a degree of 25% deuteration causes (sometimes irreversible) sterility, because neither gametes nor zygotes can develop. High concentrations of heavy water (90%) rapidly kills fish, tadpoles, flatworms, and drosophila. Mammals such as rats given heavy water to drink die after a week, at a time when their body water approaches about 50% deuteration. The mode of death appears to be the same as that in cytotoxic poisoning (such as chemotherapy) or in acute radiation syndrome (though deuterium is not radioactive), and is due to deuterium's action in generally inhibiting cell division. Deuterium oxide is used to enhance boron neutron capture therapy.[6] It is more toxic to malignant cells than normal cells but the concentrations needed are too high for regular use.[6] As in chemotherapy, deuterium-poisoned mammals die of a failure of bone marrow (bleeding and infection) and intestinal-barrier functions (diarrhea and fluid loss). Notwithstanding the problems of plants and animals in living with too much deuterium, prokaryotic organisms such as bacteria (which do not have the mitotic problems induced by deuterium) may be grown and propagated in fully deuterated conditions, resulting in replacement of all hydrogen atoms in the bacterial proteins and DNA with the deuterium isotope.[6] Full replacement with heavy atom isotopes can be accomplished in higher organisms with other non-radioactive heavy isotopes (such as carbon-13, nitrogen-15, and oxygen-18), but this cannot be done for the stable heavy isotope of hydrogen. # Toxicity in humans Because it would take a very great deal of heavy water to replace 25% to 50% of a human being's body water (which in turn is 70% of body weight) with heavy water, accidental or intentional poisoning with heavy water is unlikely to the point of practical disregard. For a poisoning, large amounts of heavy water would need to be ingested without significant normal water intake for many days to produce any noticeable toxic effects (although in a few tests, volunteers drinking large amounts of heavy water have reported dizziness, a possible effect of density changes in the fluid in the inner ear). For example, a 70 kg human containing 50 kg of water and drinking 3 liters of pure heavy water per day, would need to do this for almost 5 days to reach 25% deuteration, and for about 11 days to approach 50% deuteration. Thus, it would take a week of drinking nothing but pure heavy water for a human to begin to feel ill, and 10 days to 2 weeks (depending on water intake) for severe poisoning and death. In the highly unlikely event that a human were to receive a toxic dose of heavy water, the treatment would involve the use of intravenous water replacement (due to possible intestinal dysfunction and problems with absorption of fluids). This would be done via 0.9% (normal physiologic) saline solution with other salts as needed, perhaps in conjunction with diuretics. Oral doses of heavy water in the multi-gram range, along with heavy oxygen 18O, are routinely used in human metabolic experiments. See doubly-labeled water testing. Since 1 in every 6400 hydrogen atoms is deuterium, a 50 kg human containing 32 kg of body water would normally contain enough deuterium (about 1.1 gram) to make 5.5 grams of pure heavy water, so roughly this dose is required to double the amount of deuterium in the body. # Confused report of a "heavy water" contamination incident In 1990, a disgruntled employee at the Point Lepreau Nuclear Generating Station in Canada obtained a sample (estimated as about a "half cup") of heavy water from the primary heat transport loop of the nuclear reactor, and loaded it into the employee water cooler. Eight employees drank some of the contaminated water. The incident was discovered when employees began leaving bioassay urine samples with elevated tritium levels. The quantity of heavy water involved was far below levels which could induce heavy water toxicity per se, but several employees received elevated radiation doses from tritium and neutron-activated chemicals in the water.[7] This was not an incident of heavy water poisoning, but rather radiation poisoning from other isotopes in the heavy water. Some news services were not careful to distinguish these points, and some of the public was left with the impression that heavy water is normally radioactive and more severely toxic than it is. Even if pure heavy water had been used in the water cooler indefinitely, it is not likely the incident would have been detected or caused harm, since no employees would be expected to get as much as 25% of their daily drinking water from such a source.[8] # Production On Earth, semiheavy water, HDO, occurs naturally in regular water at a proportion of about 1 molecule in 3200. This means that 1 in 6400 hydrogen atoms is deuterium, which is 1 part in 3200 by weight (hydrogen weight). The HDO may be separated from regular water by distillation or electrolysis and also by various chemical exchange processes, all of which exploit a kinetic isotope effect. (For more information about the isotopic distribution of deuterium in water, see Vienna Standard Mean Ocean Water.) The difference in mass between the two hydrogen isotopes translates into a difference in the zero-point energy and thus into a slight difference in the speed at which the reaction proceeds. Once HDO becomes a significant fraction of the water, heavy water will become more prevalent as water molecules trade hydrogen atoms very frequently. To produce pure heavy water by distillation or electrolysis requires a large cascade of stills or electrolysis chambers, and consumes large amounts of power, so the chemical methods are generally preferred. The most important chemical method is the Girdler sulfide process. ## United States In 1953, the United States began using heavy water in plutonium production reactors at the Savannah River Site. The first of the five heavy water reactors came online in 1953, and the last was placed in cold shutdown in 1996. The SRS reactors were heavy water reactors so that they could produce both plutonium and tritium for the US nuclear weapons program. The U.S. developed the Girdler Sulfide chemical exchange production process which was first demonstrated on a large scale at the Dana, Indiana plant in 1945 and at the Savannah River Plant, South Carolina in 1952. The SRP was operated by DuPont for the USDOE until April 1, 1989 at which time the operation was taken over by Westinghouse. ## Template:NOR In 1934, Norsk Hydro built the first commercial heavy water plant at Vemork, Tinn, with a capacity of 12 tonnes per year. From 1940 and throughout World War II, the plant was under German control and the allies decided to destroy the plant and its heavy water to inhibit German development of nuclear weapons. In late 1942, a raid by British paratroopers failed when the gliders they were in crashed. All the raiders were killed in the crash or shot by German army troops. But in the night of 27 February 1943 Operation Gunnerside succeeded. Norwegian commandos managed to demolish small but key bits of the electrolytic cells, dumping the accumulated heavy water down the factory drains. ArguablyTemplate:Clarifyme (see below) this prevented Germany from building a nuclear reactor (German nuclear weapons would not have automatically followed the reactor for many reasonsTemplate:Clarifyme). The Norsk Hydro operation is one of the great commando/sabotage operations of the war. On 16 November 1943, the allied air forces dropped more than 400 bombs on the site. The allied air raid prompted the Nazi government to move all available heavy water to Germany for safekeeping. On 20 February 1944, a Norwegian partisan sank the ferry M/F Hydro carrying the heavy water across Lake Tinn, at the cost of 14 Norwegian civilians, and most of the heavy water was presumably lost. A few of the barrels were only half full, and therefore could float, and may have been salvaged and transported to Germany. (These events were dramatized in the 1965 movie, The Heroes of Telemark.) However, recent investigation of production records at Norsk Hydro and analysis of an intact barrel that was salvaged in 2004 revealed that although the barrels in this shipment contained water of pH 14 — indicative of the alkaline electrolytic refinement process — they did not contain high concentrations of D2O. Despite the apparent size of shipment, the total quantity of pure heavy water was quite small, most barrels only containing between 1/2–1% pure heavy water. The Germans would have needed a total of about 5 tons of heavy water to get a nuclear reactor running. The manifest clearly indicated that there was only half a ton of heavy water being transported to Germany. The Hydro was carrying far too little heavy water for even one reactor, let alone the 10 or more tons needed to make enough plutonium for a nuclear weapon. The Hydro shipment on 20 February 1944 was probably destined for an experimental reactor project. ## Canada As part of its contribution to the Manhattan Project, Canada built and operated a 6 tonnes per year electrolytic heavy water plant at Trail, BC, which started operation in 1943. The Atomic Energy of Canada Limited (AECL) design of power reactor requires large quantities of heavy water to act as a neutron moderator and coolant. AECL ordered two heavy water plants which were built and operated in Atlantic Canada at Glace Bay (by Deuterium of Canada Limited) and Port Hawkesbury, Nova Scotia (by General Electric Canada). These plants proved to have significant design, construction and production problems and so AECL built the Bruce Heavy Water Plant, which it later sold to Ontario Hydro, to ensure a reliable supply of heavy water for future power plants. The two Nova Scotia plants were shut down in 1985 when their production proved to be unnecessary. The Bruce Heavy Water Plant in Ontario was the world's largest heavy water production plant with a capacity of 700 tonnes per year. It used the Girdler sulfide process to produce heavy water, and required 340,000 tonnes of feed water to produce one tonne of heavy water. It was part of a complex that included 8 CANDU reactors which provided heat and power for the heavy water plant. The site was located at Douglas Point in Bruce County on Lake Huron where it had access to the waters of the Great Lakes. The Bruce plant was commissioned in 1979 to provide heavy water for a large increase in Ontario's nuclear power generation. The plants proved to be significantly more efficient than planned and only three of the planned four units were eventually commissioned. In addition, the nuclear power programme was slowed down and effectively stopped due to a perceived oversupply of electricity, later shown to be temporary, in 1993. Improved efficiency in the use and recycling of heavy water plus the over-production at Bruce left Canada with enough heavy water for its anticipated future needs. Also, the Girdler process involves large amounts of hydrogen sulfide, raising environmental concerns if there should be a release. The Bruce heavy-water plant was shut down in 1997, after which the plant was gradually dismantled and the site cleared. Atomic Energy of Canada Limited (AECL) is currently researching other more efficient and environmentally benign processes for creating heavy water. This is essential for the future of the CANDU reactors since heavy water represents about 20% of the capital cost of each reactor. # == India is the world's second largest producer of heavy water through its Heavy Water Board. ## Template:IRN On August 26, 2006, Iranian President Ahmadinejad inaugurated an expansion of the country's heavy-water plant near Arak. Iran has indicated that the heavy-water production facility will operate in tandem with a 40 MW research reactor that has a scheduled completion date in 2009.[9] In an interview which aired on the Iranian News Channel (IRINN) on August 27, 2006, Iranian Nuclear Chief Mohammad Sa'idi claimed that heavy water could be used to treat AIDS and cancer. Daily consumption was recommended.[10] ## Other countries Template:ARG is another declared producer of heavy water, using an ammonia/hydrogen exchange based plant supplied by Switzerland's Sulzer company. Roghayeh Marandi, M.D.[1] also produces heavy water at the Drobeta Girdler Sulfide plant and has exported from time to time. Template:UK The Department of Atomic Energy built a station at Loch Morar in 1947, possibly investigating using the loch as a source of heavy water.[11] # Applications ## Nuclear magnetic resonance Deuterium oxide is used in nuclear magnetic resonance spectroscopy when the solvent of interest is water and the nuclide of interest is hydrogen. This is because the signal from the water solvent would interfere with the signal from the molecule of interest. Deuterium has a different magnetic moment from hydrogen and therefore does not contribute to the NMR signal at the hydrogen resonance frequency. ## Neutron moderator Heavy water is used in certain types of nuclear reactors where it acts as a neutron moderator to slow down neutrons so that they can react with the uranium in the reactor. The CANDU reactor uses this design. Light water also acts as a moderator but because light water absorbs more neutrons than heavy water, reactors using light water must use enriched uranium rather than natural uranium, otherwise criticality is impossible. The use of heavy water essentially increases the efficiency of the nuclear reaction. Because of this, heavy water reactors will be more efficient at breeding plutonium (from uranium-238) or uranium-233 (from thorium-232) than a comparable light-water reactor, leading them to be of greater concern in regards to nuclear proliferation. The breeding and extraction of plutonium can be a relatively rapid and cheap route to building a nuclear weapon, as chemical separation of plutonium from fuel is easier than isotopic separation of U-235 from natural uranium. Heavy water moderated research reactors or specifically-built plutonium breeder reactors have been used for this purpose by most, if not all, states which possess nuclear weapons, although historically the first nuclear weapons were produced without it. (Pure carbon may be used as a moderator, even in unenriched uranium nuclear reactors. Thus, in the U.S., the first experimental atomic reactor (1942), as well as the Manhattan Project Hanford production reactors which produced the plutonium for the Trinity test and Fat Man bombs, all used pure carbon neutron moderators and functioned with neither enriched uranium nor heavy water). There is no evidence that civilian heavy water power reactors, such as the CANDU or Atucha designs, have been used for military production of fissile materials. In states which do not already possess nuclear weapons, the nuclear material at these facilities is under IAEA safeguards to discourage any such diversion. Due to its potential for use in nuclear weapons programs, the possession or import/export of large industrial quantities of heavy water are subject to government control in several countries. Suppliers of heavy water and heavy water production technology typically apply IAEA (International Atomic Energy Agency) administered safeguards and material accounting to heavy water. (In Australia, the Nuclear Non-Proliferation (Safeguards) Act 1987.) In the U.S. and Canada, non-industrial quantities of heavy water (i.e., in the gram to kg range) are routinely available through chemical supply dealers, and directly commercial companies such as the world's former major producer Ontario Hydro, without special license. Current (2006) cost of a kilogram of 99.98% reactor-purity heavy water, is about $600 to $700. Smaller quantities of reasonable purity (99.9%) may be purchased from chemical supply houses at prices of roughly $1 per gram. ## Neutrino detector The Sudbury Neutrino Observatory (SNO) in Sudbury, Ontario uses 1000 tonnes of heavy water on loan from Atomic Energy of Canada Limited. The neutrino detector is 6800 feet underground in a deep mine, in order to shield it from muons produced by cosmic rays. SNO was built to answer the question of whether or not electron-type neutrinos produced by fusion in the Sun (the only type the Sun should be producing directly, according to theory) might be able to turn into other types of neutrinos on the way to Earth. SNO detects the Čerenkov radiation in the water from high-energy electrons produced from electron-type neutrinos as they undergo reactions with neutrons in deuterium, turning them into protons and electrons (only the electrons move fast enough to be detected in this manner). SNO also detects the same radiation from neutrino↔electron scattering events, which again produces high energy electrons. These two reactions are produced only by electron-type neutrinos. The use of deuterium is critical to the SNO function, because all three "flavours" (types) of neutrinos[12] may be detected in a third type of reaction, neutrino-disintegration, in which a neutrino of any type (electron, muon, or tau) scatters from a deuterium nucleus (deuteron), transferring enough energy to break up the loosely-bound deuteron into a free neutron and proton. This event is detected when the free neutron is absorbed by 35Cl− present from NaCl which has been deliberately dissolved in the heavy water, causing emission of characteristic capture gamma rays. Thus, in this experiment, heavy water not only provides the transparent medium necessary to produce and visualize Čerenkov radiation, but it also provides deuterium to detect exotic mu type (μ) and tau (τ) neutrinos, as well as a non-absorbent moderator medium to preserve free neutrons from this reaction, until they can be absorbed by an easily-detected neutron-activated isotope. ## Metabolic rate testing in physiology/biology Heavy water is employed as part of a mixture with H218O for a common and safe test of mean metabolic rate in humans and animals undergoing their normal activities. This metabolic test is usually called the doubly-labeled water test. ## Space-based non-toxic cooling systems Heavy water (D2O) has a similar high heat of fusion to regular water, but freezes at a slightly higher temperature. It has been proposed as a non-toxic heatsink for space based cooling applications, where D2O ice acts as a heatsink to remove water vapor in air, but without danger that the water vapor will freeze to water-ice, because D2O ice maintains temperatures too high for this to occur. See U.S. Patent 5,246,061. Such a system has not yet been tested. ## Tritium production Tritium is an important material in nuclear weapon design for boosted fission weapons and initiators, and also has civilian industrial applications. Some is created in heavy water moderated reactors when deuterium captures a neutron. This reaction has a small cross-section and produces only small amounts of tritium, although enough so that cleaning tritium from the moderator may be desirable after several years to reduce the risk of tritium escape and radiation exposure. Production of large amounts of tritium in this way would require reactors with very high neutron fluxes, or with a very high proportion of heavy water to nuclear fuel and very low neutron absorption by other reactor material. The tritium would then have to be recovered by isotope separation from a much larger quantity of deuterium, unlike tritium production from lithium-6 (the present method of tritium production), where only chemical separation is needed. Deuterium's absorption cross section for thermal neutrons is .52 millibarns, while oxygen-16's is .19 millibarns and oxygen-17's is .24 barn. 17O makes up .038% of natural oxygen, which has an overall absorption cross section of .28 millibarns. Therefore in D2O with natural oxygen, 21% of neutron captures are on oxygen, a proportion that may rise further as 17O accumulates from neutron capture on 16O. Also, 17O emits an alpha particle on capture, producing radioactive carbon-14.	https://www.wikidoc.org/index.php/Heavy_water
01e536e9b2e666811a3d3d20be51982ed9cc31c0	wikidoc	Heliophobia	Heliophobia # Overview Heliophobia has two meanings: - a specific phobia: dread or avoidance of sunlight - excessive sensitiveness to sunlight. # Causes Heliophobia is a problem that afflicts hundreds of Americans, but one that suffers from a lack of true research. The Pacific Health Center suggested that many people have been staying away from the sun because of growing fears about skin cancer. This is not technically heliophobia, simply an unfounded and illogical solution. Medical conditions such as keratoconus, which is an eye disorder that results in extreme optic sensitivity to sunlight and bright lights, and porphyria cutanea tarda, which causes the skin to be overly sensitive to sunlight to the point of causing blisters, can result in heliophobia. Since heliophobia forces its victims indoors, heliophobia causes a Vitamin D deficiency problem. This can be corrected by taking Vitamin D supplements or drinking Vitamin D fortified milk. # Hypersensitivity In chemistry or biology the terms heliophobic/heliophobe refers to an organism or substance that is sunlight-sensitive or has an aversion to sunlight. Heliophobous plants are commonly known as "shade-tolerant". # In culture The classic history of heliophobia can be seen easily in most modern vampire stories (Nosferatu was the first to claim heliophobia as an attribute of vampires), in which it was shown that vampires had a total aversion to the sun. This heliophobia was considered a "telltale sign" of witches, vampires, and demons. There was a short-lived magazine Heliophobe (3 issues, 1994-1996), described as "a not-so-sexual fetish magazine exclusively devoted to pale-skinned women". Heliophobe is a 1997 album by a German rock band Scumbucket	Heliophobia Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview Heliophobia has two meanings: - a specific phobia: dread or avoidance of sunlight - excessive sensitiveness to sunlight. # Causes Heliophobia is a problem that afflicts hundreds of Americans, but one that suffers from a lack of true research. The Pacific Health Center suggested that many people have been staying away from the sun because of growing fears about skin cancer. This is not technically heliophobia, simply an unfounded and illogical solution. Medical conditions such as keratoconus, which is an eye disorder that results in extreme optic sensitivity to sunlight and bright lights, and porphyria cutanea tarda, which causes the skin to be overly sensitive to sunlight to the point of causing blisters, can result in heliophobia. Since heliophobia forces its victims indoors, heliophobia causes a Vitamin D deficiency problem. This can be corrected by taking Vitamin D supplements or drinking Vitamin D fortified milk. # Hypersensitivity In chemistry or biology the terms heliophobic/heliophobe refers to an organism or substance that is sunlight-sensitive or has an aversion to sunlight. Heliophobous plants are commonly known as "shade-tolerant". # In culture The classic history of heliophobia can be seen easily in most modern vampire stories (Nosferatu was the first to claim heliophobia as an attribute of vampires[citation needed]), in which it was shown that vampires had a total aversion to the sun. This heliophobia was considered a "telltale sign" of witches, vampires, and demons. There was a short-lived magazine Heliophobe (3 issues, 1994-1996), described as "a not-so-sexual fetish magazine exclusively devoted to pale-skinned women". [1] Heliophobe is a 1997 album by a German rock band Scumbucket [2]	https://www.wikidoc.org/index.php/Heliophobia
f9e45833de3275330452aa20880c9f9ea83cdc3f	wikidoc	Hematoxylin	Hematoxylin # Overview Haematoxylin, hematoxylin, Natural Black 1, or C.I. 75290 is extracted from the wood of the logwood tree. When oxidised it forms haematein, a compound with rich blue-purple colour, and is used, together with a suitable mordant (most commonly Fe(III) or Al(III) salts), to stain cell nuclei prior to examination under a microscope. Structures that stain with haematoxylin are called basophilic. Haematoxylin and eosin stain is one of the most commonly used stains in histology. It is a permanent stain as opposed to temporary stains (e.g. iodine solution in KI). Other common stain is phosphotungstic acid haematoxylin, a mix of haematoxylin with phosphotungstic acid. In 1970's, due to clear felling of forests in Brazil and Central America, there was a shortage of logwood and therefore of haematoxylin. Its price went to record heights, which affected the cost of diagnostic histopathology, and prompted a search for alternative nuclear stains. Before the use of any alternatives became firmly established, hematoxylin returned to the market, though at a higher price, and resumed its place in histopathology. There were several dyes recommended as replacements: Celestine blue B (CI 51050), Gallocyanin (CI 51030), Gallein (CI 45445) and Solochrome cyanin (CI 43820). All four used Fe(III) as the mordant. Another alternative is the red dye brazilin, which differs from hematoxylin by only one hydroxyl group. # Hematoxylin Staining Solutions These stains are commonly employed for histologic studies. The mordants used to demonstrate nuclear and cytoplasmic structures are Alum and Iron, forming lakes or colored complexes (dye-mordant-tissue complexes), the color of which will depend on the salt used. Aluminum salt lakes are usually colored blue white while Ferric salt lakes are colored blue-black. ## Aluminum Hematoxylin Solutions The two main Alum Hematoxylin solutions employed are Ehrlich's Hematoxylin and Harris Hematoxylin. Alum Hematoxylin solutions impart on the nucleus a light transparent blue stain which rapidly turns red in the presence of an acid. Alum or Potassium Aluminum Sulfate used as the mordant usually dissociates in an alkaline solution, combining with -OH of water to form insoluble Aluminum Hydroxide. In the presence of excess acid, Aluminum Hydroxide cannot be formed thus failure of Aluminum Hematoxylin dye-lake to form, due to lack of –OH ions. Hence, acid solutions of Alum Hematoxylin become red. During staining Alum Hematoxylin stained sections are usually passed on to an alkaline solution (e.g. 1% Hydroxide) in order to neutralize the acid and free the OH group, to form an insoluble blue Aluminum Hematin-Tissue Lake. Such procedure is known as Blueing. When tap water is not sufficiently alkaline, or is even acid and is unsatisfactory for Blueing Hematoxylin, Tap Water Substitute consisting of 33.5 g NaHCO4 and 20 grams MgSO4 in 1000 cc of water, with Thymol (to inhibit formation of molds), is used to accelerate blueing of thin paraffin sections. Use of very cold water slows down the process while warming accelerates it. In fact, the use of very cold water below 10°C for blueing sections may even produce pink artifact discolorations on the tissue. ### Ehrlich’s Hematoxylin Formula: - 1 g Hematoxylin - 100 ml Absolute Ethanol - 60 g Potassium Alum (Aluminum Potassium Sulfate) - 100 ml Glycerin - 100 ml Distilled water - 10 ml Glacial Acetic Acid (HOAc) First, Dissolve 1 g Hematoxylin in 100 ml of Absolute Ethanol with gentle heat. Second, dissolve the 60 g of Potassium Alum (Aluminum Potassium Sulfate) in 100 ml Distilled water with 100 ml Glycerin with gentle heating and agitation. Third, mix the two solutions and add 10 ml Glacial HOAc. Then Expose to the air and sunlight for several weeks or months in a flask lightly plugged with cotton. Shake the solution daily. Finally, transfer the solution in a well-stoppered bottle and store in a warm place. Hematoxylin may be partially oxidized and the stain may be used by addition of 0.3 g Sodium Iodate. As Hematoxylin solutions becomes oxidized, the color of the solution will change from purplish to deep red, while the pungent odor of HOAc will be replaced by a pleasant vineous aroma. Glycerin acts as a stabilizer and retards evaporation of the solution. However, glycerin appears to slow down ripening and hence may be added 4 to 6 weeks after the initial preparation. Ehrlich's Hematoxylin is generally used for regressive staining, differentiated with 1% HCl in 70% Acid-Alcohol until the nucleus is selectively stained. Mucopolysaccharide substance such as cartilage and cement lines of bones are also stained intensely blue. Staining time is usually 15 to 40 minutes. ### Harris Hematoxylin Formula: - 1 g Hematoxylin - 10 ml Absolute Ethanol - 20 g Ammonium/Potassium Alum - 190 ml Distilled water - 0.5 g Mercuric Oxide (Red) - 10 ml Glacial Acetic Acid (HOAc) First, dissolve 1 g Hematoxylin in 10 ml of Absolute Ethanol with gentle heating. Second, dissolve 20 g of Ammonium or Potassium Alum in 190 ml Distilled water inside a 500 ml flask or beaker. Third, add Mercuric Oxide and plunge immediately into cold water for rapid cooling. Using a wide-mouth container or flask will prevent a violent explosion due to the liberation of Oxygen upon addition of Mercuric Oxide to the solution. The solution should assume a dark purple color upon addition of Mercuric Oxide. The addition of 4% Glacial HOAc will give a more precise nuclear staining. Finally, the solution is then filtered and transferred into a well-stoppered bottle, and may be used off-hand or stored since it remains stable for a long time. Harris Hematoxylin is widely used for routine nuclear staining in Exfoliative Cytology and for staining of sex chromosomes. The usual staining time is 5 to 20 minutes. ### Cole’s Hematoxylin Cole's Hematoxylin is another Alum Hematoxylin solution recommended for routine purposes, especially used in sequence with Celestine Blue. Formula: - 1.5 g Hematoxylin - 50 ml of 1% Iodine in 95% Alcohol - 700 ml of Saturated Aq. Ammonium Alum - 250 ml Distilled water Dissolve 1.5 g Hematoxylin in warm 250 ml Distilled water, and mix with 50 ml Iodine solution. Add 700 ml Saturated Aq. Ammonium Alum then boil. Finally, cool and filter before use. Staining time is 10 minutes. ### Mayer’s Hematoxylin Mayer's Hematoxylin is more vigorous in action than Ehrlich's Solution, giving little or no staining of Mucopolysaccharides. It is used in Celestine Blue Hemalum method of Nuclear Staining. Formula: - 1 g Hematoxylin - 0.2 g Sodium Iodate - 50 g Potassium Alum - 1 g Citric Acid - 50 g Chloral Hydrate - 1000 ml Distilled water Allow Hematoxylin, Alum, Sodium iodate to dissolve in water overnight. Then add Chloral Hydrate and Citric Acid. Boil for 5 minutes and cool. ## Iron Hematoxylin Solutions Two main Iron Hematoxylin solutions are employed for routine work in the laboratory: Weigert's Solution, using Ferric Ammonium Chloride, and Heidenhain's Solution, using Ferric Ammonium Sulfate (Iron Alum) as mordants. Both are active oxidizing agents; hence, do not prolong in storage as a prepared fixative. They can be applied to tissues fixed in virtually all fixatives, producing permanent stains, provided all Iron mordants have been wiped out. Tissues that have been stored in alcohol for years and which would ordinarily fail to stain, will normally take Iron Hematoxylin. Tissue structures are stained blackish or grayish, according to the extent of differentiation, producing minimal eyestrain; hence, making it useful for photomicrography. ### Weigert's Hematoxylin Weigert's Solution is the standard Iron Hematoxylin used in the laboratory, especially for demonstrating muscle fibers and connective tissues. It is particularly recommended when the preceding stains contain acid (e.g. Van Gieson's Stain containing Picric Acid) which decolorizes nuclei stained with Alum Hematoxylin. Formula - Solution A: - Solution B: Hematoxylin is dissolved in Alcohol with gentle heating, while FeCl3, HCl and Water are mixed in a different container. Both solutions are stable and may be stored 6 weeks before use. Ferric Chloride is usually added to the staining solution just before use, by mixing equal parts of the two solutions, producing a deep black mixture. The working solution will remain active for 1 to 2 days. ### Heidenhain’s Hematoxylin Heidanhain's solution is a cytological stain recommended for regressive staining of thin sections. It is utilized for the demonsrtation of both nuclear and cytoplasmic inclusions such as chromatin, chromosomes and mitochondria. Voluntary muscle striations and myelin are also well stained. Formula - Mordant Differentiator: - Hematoxylin Stain: Clear violet crystal of Alum are used and dissolved in distilled water. Then, Hematoxylin is dissolved in Ethanol with water in another container. Allow to ripen for 4 to 5 weeks, and store in tightly stoppered bottles. The Mordant Differentiator is used separately during the process of staining, instead of being added to the solution. ### Phosphotungstic Acid Hematoxylin (PTAH) PTAH usually demonstrates structures in paraffin as well as celloidin and frozen sections. Staining time is usually 12 to 24 hours. Formula - 1 g Hematoxylin - 20 g Phosphotungstic Acid - 1000 ml Distilled water Completely dissolve the solids in separate portions of distilled water. Then, add together and stand under the light to ripen for several weeks. Immediate ripening may be obtained by adding 0.177 g Potassium. The color of the solution ranges from reddish-brown to purple, although this is not a reliable guide for the study of stained tissues. Nuclei, fibrin, muscle striations, myofibrils and fibroglia are colored blue while collagen, bone and cartilage take an orange-red or brownish red to deep brick-red stain. Staining is usually progressive, hence, microscopic examination of the materials every hour is recommended. 95% Alcohol usually removes the red component of the stain, so that dehydration and rinsing of sections should be brief.	Hematoxylin Template:Chembox new # Overview Haematoxylin, hematoxylin, Natural Black 1, or C.I. 75290 is extracted from the wood of the logwood tree. When oxidised it forms haematein, a compound with rich blue-purple colour, and is used, together with a suitable mordant (most commonly Fe(III) or Al(III) salts), to stain cell nuclei prior to examination under a microscope. Structures that stain with haematoxylin are called basophilic. Template:SMILESCAS Haematoxylin and eosin stain is one of the most commonly used stains in histology. It is a permanent stain as opposed to temporary stains (e.g. iodine solution in KI). Other common stain is phosphotungstic acid haematoxylin, a mix of haematoxylin with phosphotungstic acid. In 1970's, due to clear felling of forests in Brazil and Central America, there was a shortage of logwood and therefore of haematoxylin. Its price went to record heights, which affected the cost of diagnostic histopathology, and prompted a search for alternative nuclear stains. Before the use of any alternatives became firmly established, hematoxylin returned to the market, though at a higher price, and resumed its place in histopathology. There were several dyes recommended as replacements: Celestine blue B (CI 51050), Gallocyanin (CI 51030), Gallein (CI 45445) and Solochrome cyanin (CI 43820). All four used Fe(III) as the mordant. Another alternative is the red dye brazilin, which differs from hematoxylin by only one hydroxyl group. # Hematoxylin Staining Solutions These stains are commonly employed for histologic studies. The mordants used to demonstrate nuclear and cytoplasmic structures are Alum and Iron, forming lakes or colored complexes (dye-mordant-tissue complexes), the color of which will depend on the salt used. Aluminum salt lakes are usually colored blue white while Ferric salt lakes are colored blue-black. ## Aluminum Hematoxylin Solutions The two main Alum Hematoxylin solutions employed are Ehrlich's Hematoxylin and Harris Hematoxylin. Alum Hematoxylin solutions impart on the nucleus a light transparent blue stain which rapidly turns red in the presence of an acid. Alum or Potassium Aluminum Sulfate used as the mordant usually dissociates in an alkaline solution, combining with -OH of water to form insoluble Aluminum Hydroxide. In the presence of excess acid, Aluminum Hydroxide cannot be formed thus failure of Aluminum Hematoxylin dye-lake to form, due to lack of –OH ions. Hence, acid solutions of Alum Hematoxylin become red. During staining Alum Hematoxylin stained sections are usually passed on to an alkaline solution (e.g. 1% Hydroxide) in order to neutralize the acid and free the OH group, to form an insoluble blue Aluminum Hematin-Tissue Lake. Such procedure is known as Blueing. When tap water is not sufficiently alkaline, or is even acid and is unsatisfactory for Blueing Hematoxylin, Tap Water Substitute consisting of 33.5 g NaHCO4 and 20 grams MgSO4 in 1000 cc of water, with Thymol (to inhibit formation of molds), is used to accelerate blueing of thin paraffin sections. Use of very cold water slows down the process while warming accelerates it. In fact, the use of very cold water below 10°C for blueing sections may even produce pink artifact discolorations on the tissue. ### Ehrlich’s Hematoxylin Formula: - 1 g Hematoxylin - 100 ml Absolute Ethanol - 60 g Potassium Alum (Aluminum Potassium Sulfate) - 100 ml Glycerin - 100 ml Distilled water - 10 ml Glacial Acetic Acid (HOAc) First, Dissolve 1 g Hematoxylin in 100 ml of Absolute Ethanol with gentle heat. Second, dissolve the 60 g of Potassium Alum (Aluminum Potassium Sulfate) in 100 ml Distilled water with 100 ml Glycerin with gentle heating and agitation. Third, mix the two solutions and add 10 ml Glacial HOAc. Then Expose to the air and sunlight for several weeks or months in a flask lightly plugged with cotton. Shake the solution daily. Finally, transfer the solution in a well-stoppered bottle and store in a warm place. Hematoxylin may be partially oxidized and the stain may be used by addition of 0.3 g Sodium Iodate. As Hematoxylin solutions becomes oxidized, the color of the solution will change from purplish to deep red, while the pungent odor of HOAc will be replaced by a pleasant vineous aroma. Glycerin acts as a stabilizer and retards evaporation of the solution. However, glycerin appears to slow down ripening and hence may be added 4 to 6 weeks after the initial preparation. Ehrlich's Hematoxylin is generally used for regressive staining, differentiated with 1% HCl in 70% Acid-Alcohol until the nucleus is selectively stained. Mucopolysaccharide substance such as cartilage and cement lines of bones are also stained intensely blue. Staining time is usually 15 to 40 minutes. ### Harris Hematoxylin Formula: - 1 g Hematoxylin - 10 ml Absolute Ethanol - 20 g Ammonium/Potassium Alum - 190 ml Distilled water - 0.5 g Mercuric Oxide (Red) - 10 ml Glacial Acetic Acid (HOAc) First, dissolve 1 g Hematoxylin in 10 ml of Absolute Ethanol with gentle heating. Second, dissolve 20 g of Ammonium or Potassium Alum in 190 ml Distilled water inside a 500 ml flask or beaker. Third, add Mercuric Oxide and plunge immediately into cold water for rapid cooling. Using a wide-mouth container or flask will prevent a violent explosion due to the liberation of Oxygen upon addition of Mercuric Oxide to the solution. The solution should assume a dark purple color upon addition of Mercuric Oxide. The addition of 4% Glacial HOAc will give a more precise nuclear staining. Finally, the solution is then filtered and transferred into a well-stoppered bottle, and may be used off-hand or stored since it remains stable for a long time. Harris Hematoxylin is widely used for routine nuclear staining in Exfoliative Cytology and for staining of sex chromosomes. The usual staining time is 5 to 20 minutes. ### Cole’s Hematoxylin Cole's Hematoxylin is another Alum Hematoxylin solution recommended for routine purposes, especially used in sequence with Celestine Blue. Formula: - 1.5 g Hematoxylin - 50 ml of 1% Iodine in 95% Alcohol - 700 ml of Saturated Aq. Ammonium Alum - 250 ml Distilled water Dissolve 1.5 g Hematoxylin in warm 250 ml Distilled water, and mix with 50 ml Iodine solution. Add 700 ml Saturated Aq. Ammonium Alum then boil. Finally, cool and filter before use. Staining time is 10 minutes. ### Mayer’s Hematoxylin Mayer's Hematoxylin is more vigorous in action than Ehrlich's Solution, giving little or no staining of Mucopolysaccharides. It is used in Celestine Blue Hemalum method of Nuclear Staining. Formula: - 1 g Hematoxylin - 0.2 g Sodium Iodate - 50 g Potassium Alum - 1 g Citric Acid - 50 g Chloral Hydrate - 1000 ml Distilled water Allow Hematoxylin, Alum, Sodium iodate to dissolve in water overnight. Then add Chloral Hydrate and Citric Acid. Boil for 5 minutes and cool. ## Iron Hematoxylin Solutions Two main Iron Hematoxylin solutions are employed for routine work in the laboratory: Weigert's Solution, using Ferric Ammonium Chloride, and Heidenhain's Solution, using Ferric Ammonium Sulfate (Iron Alum) as mordants. Both are active oxidizing agents; hence, do not prolong in storage as a prepared fixative. They can be applied to tissues fixed in virtually all fixatives, producing permanent stains, provided all Iron mordants have been wiped out. Tissues that have been stored in alcohol for years and which would ordinarily fail to stain, will normally take Iron Hematoxylin. Tissue structures are stained blackish or grayish, according to the extent of differentiation, producing minimal eyestrain; hence, making it useful for photomicrography. ### Weigert's Hematoxylin Weigert's Solution is the standard Iron Hematoxylin used in the laboratory, especially for demonstrating muscle fibers and connective tissues. It is particularly recommended when the preceding stains contain acid (e.g. Van Gieson's Stain containing Picric Acid) which decolorizes nuclei stained with Alum Hematoxylin. Formula - Solution A: - Solution B: Hematoxylin is dissolved in Alcohol with gentle heating, while FeCl3, HCl and Water are mixed in a different container. Both solutions are stable and may be stored 6 weeks before use. Ferric Chloride is usually added to the staining solution just before use, by mixing equal parts of the two solutions, producing a deep black mixture. The working solution will remain active for 1 to 2 days. ### Heidenhain’s Hematoxylin Heidanhain's solution is a cytological stain recommended for regressive staining of thin sections. It is utilized for the demonsrtation of both nuclear and cytoplasmic inclusions such as chromatin, chromosomes and mitochondria. Voluntary muscle striations and myelin are also well stained. Formula - Mordant Differentiator: - Hematoxylin Stain: Clear violet crystal of Alum are used and dissolved in distilled water. Then, Hematoxylin is dissolved in Ethanol with water in another container. Allow to ripen for 4 to 5 weeks, and store in tightly stoppered bottles. The Mordant Differentiator is used separately during the process of staining, instead of being added to the solution. ### Phosphotungstic Acid Hematoxylin (PTAH) PTAH usually demonstrates structures in paraffin as well as celloidin and frozen sections. Staining time is usually 12 to 24 hours. Formula - 1 g Hematoxylin - 20 g Phosphotungstic Acid - 1000 ml Distilled water Completely dissolve the solids in separate portions of distilled water. Then, add together and stand under the light to ripen for several weeks. Immediate ripening may be obtained by adding 0.177 g Potassium. The color of the solution ranges from reddish-brown to purple, although this is not a reliable guide for the study of stained tissues. Nuclei, fibrin, muscle striations, myofibrils and fibroglia are colored blue while collagen, bone and cartilage take an orange-red or brownish red to deep brick-red stain. Staining is usually progressive, hence, microscopic examination of the materials every hour is recommended. 95% Alcohol usually removes the red component of the stain, so that dehydration and rinsing of sections should be brief. # External links - Stainsfile - Mayer's Hematoxylin Preparation	https://www.wikidoc.org/index.php/Hematoxylin
3aa5362ed9c66af38f2d72b9aa0c87e3eaa34f5a	wikidoc	Hemiparesis	Hemiparesis Hemiparesis is the partial paralysis of one side of the body. It is generally caused by the lesions of the corticospinal tract, which runs down from the cortical neurons of the frontal lobe to the motor neurons of the spinal cord (see the second paragraph of Amyotrophic lateral sclerosis) and is responsible for the movements of the muscles of the body and its limbs. On its way the tract passes through several parts of the brain stem; namely the midbrain, pons and medulla, respectively. The tract crosses to the opposite side (or decussates) on the lowest portion of the medulla (forming an anatomical structure named as the pyramids) and goes down along the opposite side of the spinal cord to meet the contralateral motor neurons. For this reason, one side of the brain controls the muscle movements of the opposite side of the body, and thus the disruption of the right corticospinal tract on brain stem or upper brain structures causes a hemiparesis on the left side of the body and vice versa. On the other hand, the lesions of the tract on the spinal cord lead to a hemiparesis on the same side of the body. The facial muscles are also controlled by the same tract. The tract activates the facial nuclei (see ganglion) and the facial nerve emerging from these nuclei activate the facial muscles during voluntary facial muscle contraction. Since the facial nuclei are located in the pons above the decussation, the lesions of the tract on the pons or upper structures give rise to a hemiparesis on the opposite side of the body and a paresis on the same side of the face and that is called a crossed hemiparesis. If the patient's face is not involved, this is highly suggestive of a lesion of the tract on lower parts of the brain stem or spinal cord. Since the spinal cord is a very small structure, it is very unusual for only one side to be affected by a lesion and usually both tracts are affected. Therefore, the spinal cord lesions usually present with the paralysis of both arms and legs (quadriparesis) or both legs (paraparesis). # Causes - Drug side effects - Temozolomide Hemiplegia is similar to hemiparesis, but hemiparesis is considered less severe.	Hemiparesis Template:DiseaseDisorder infobox Hemiparesis is the partial paralysis of one side of the body. It is generally caused by the lesions of the corticospinal tract, which runs down from the cortical neurons of the frontal lobe to the motor neurons of the spinal cord (see the second paragraph of Amyotrophic lateral sclerosis) and is responsible for the movements of the muscles of the body and its limbs. On its way the tract passes through several parts of the brain stem; namely the midbrain, pons and medulla, respectively. The tract crosses to the opposite side (or decussates) on the lowest portion of the medulla (forming an anatomical structure named as the pyramids) and goes down along the opposite side of the spinal cord to meet the contralateral motor neurons. For this reason, one side of the brain controls the muscle movements of the opposite side of the body, and thus the disruption of the right corticospinal tract on brain stem or upper brain structures causes a hemiparesis on the left side of the body and vice versa. On the other hand, the lesions of the tract on the spinal cord lead to a hemiparesis on the same side of the body. The facial muscles are also controlled by the same tract. The tract activates the facial nuclei (see ganglion) and the facial nerve emerging from these nuclei activate the facial muscles during voluntary facial muscle contraction. Since the facial nuclei are located in the pons above the decussation, the lesions of the tract on the pons or upper structures give rise to a hemiparesis on the opposite side of the body and a paresis on the same side of the face and that is called a crossed hemiparesis. If the patient's face is not involved, this is highly suggestive of a lesion of the tract on lower parts of the brain stem or spinal cord. Since the spinal cord is a very small structure, it is very unusual for only one side to be affected by a lesion and usually both tracts are affected. Therefore, the spinal cord lesions usually present with the paralysis of both arms and legs (quadriparesis) or both legs (paraparesis). ### Causes - Drug side effects - Temozolomide Hemiplegia is similar to hemiparesis, but hemiparesis is considered less severe. [1]	https://www.wikidoc.org/index.php/Hemiparesis
d72ca1e9487a0822ebcf42425c67471a3e58011f	wikidoc	Hemojuvelin	Hemojuvelin Hemojuvelin (HJV), also known as repulsive guidance molecule C (RGMc) or hemochromatosis type 2 protein (HFE2), is a membrane-bound and soluble protein in mammals that is responsible for the iron overload condition known as juvenile hemochromatosis in humans, a severe form of hemochromatosis. In humans, the hemojuvelin protein is encoded by the HFE2 gene. Hemojuvelin is a member of the repulsive guidance molecule family of proteins. Both RGMa and RGMb are found in the nervous system, while hemojuvelin is found in skeletal muscle and the liver. # Function For many years the signal transduction pathways that regulate systemic iron homeostasis have been unknown. However it has been demonstrated that hemojuvelin interacts with bone morphogenetic protein (BMP), possibly as a co-receptor, and may signal via the SMAD pathway to regulate hepcidin expression. Associations with BMP2 and BMP4 have been described. Mouse HJV knock-out models confirmed that HJV is the gene responsible for juvenile hemochromatosis. Hepcidin levels in the liver are dramatically depressed in these knockout animals. A soluble form of HJV may be a molecule that suppresses hepcidin expression. RGMs may play inhibitory roles in prostate cancer by suppressing cell growth, adhesion, migration and invasion. RGMs can coordinate Smad-dependent and Smad-independent signalling of BMPs in prostate cancer and breast cancer cells. Furthermore, aberrant expression of RGMs was indicated in breast cancer. The perturbed expression was associated with disease progression and poor prognosis. # Related gene problems - TAR syndrome - 1q21.1 deletion syndrome - 1q21.1 duplication syndrome # Gene structure and transcription RGMc/HJV is a 4-exon gene in mammals that undergoes alternative RNA splicing to yield 3 mRNAs with different 5’ untranslated regions (5’UTRs). Gene transcription is induced during myoblast differentiation, producing all 3 mRNAs. There are three critical promoter elements responsible for transcriptional activation in skeletal muscle (the tissue that has the highest level of RGMc expressesion per weight), comprising paired E-boxes, a putative Stat and/or Ets element, and a MEF2 site, and muscle transcription factors myogenin and MEF2C stimulate RGMc promoter function in non-muscle cells. As these elements are conserved in RGMc genes from multiple species, these results suggest that RGMc has been a muscle-enriched gene throughout its evolutionary history. RGMc/HJV, is transcriptionally regulated during muscle differentiation. # Isoforms Two classes of GPI-anchored and glycosylated HJV molecules are targeted to the membrane and undergo distinct fates. - Full-length HJV is released from the cell surface and accumulates in extracellular fluid, where its half-life exceeds 24 hours. There appears to be two potential soluble isoforms and two membrane-associated isoforms. - The predominant membrane-associated isoform, a disulfide-linked two-chain form composed of N- and C-terminal fragments, is not found in the extracellular fluid, and is short-lived, as it disappears from the cell surface with a half-life of < 3 hours after interruption of protein synthesis. RGMc appears to undergo a complex processing that generates 2 soluble, single-chain forms, and two membrane-bound forms found as a (i) single-chain, and (ii) two-chain species which appears to be cleaved at a site within a partial von Willebrand factor domain. Using a combination of biochemical and cell-based approaches, it has demonstrated that BMP-2 could interact in biochemical assays with the single-chain HJV species, and also could bind to cell-associated HJV. Two mouse HJV amino acid substitution mutants, D165E and G313V (corresponding to human D172E and G320V), also could bind BMP-2, but less effectively than wild-type HJV, while G92V (human G99V) could not. In contrast, the membrane-spanning protein, neogenin, a receptor for the related molecule, RGMa, preferentially bound membrane-associated heterodimeric RGMc and was able to interact on cells only with wild-type RGMc and G92V. These results show that different isoforms of RGMc/HJV may play unique physiological roles through defined interactions with distinct signaling proteins and demonstrate that, in some disease-linked HJV mutants, these interactions are defective. # Structure In 2009, the Rosetta ab initio protein structure prediction software has been used to create a three-dimensional model of the RGM family of proteins., In 2011, a crystal structure of a fragment of hemojuvelin binding to neogenin was completed showing similar structures to the ab initio model and further informing the view of the RGM family of proteins. # Mechanism of action Furin-like proprotein convertases (PPC) are responsible for conversion of 50 kDa HJV to a 40 kDa protein with a truncated COOH-terminus, at a conserved polybasic RNRR site. This suggests a potential mechanism to generate the soluble forms of HJV/hemojuvelin (s-hemojuvelin) found in the blood of rodents and humans. # Clinical significance Mutations in HJV are responsible for the vast majority of juvenile hemochromatosis patients. A small number of patients have mutations in the hepcidin (HAMP) gene. The gene was positionally cloned. Hemojuvelin is highly expressed in skeletal muscle and heart, and to a lesser extent in the liver. One insight into the pathogenesis of juvenile hemochromatosis is that patients have low to undetectable urinary hepcidin levels, suggesting that hemojuvelin is a positive regulator of hepcidin, the central iron regulatory hormone. As a result, low hepcidin levels would result in increased intestinal iron absorption. Thus, HJV/RGMc appears to play a critical role in iron metabolism.	Hemojuvelin Hemojuvelin (HJV), also known as repulsive guidance molecule C (RGMc) or hemochromatosis type 2 protein (HFE2), is a membrane-bound and soluble protein in mammals that is responsible for the iron overload condition known as juvenile hemochromatosis in humans, a severe form of hemochromatosis. In humans, the hemojuvelin protein is encoded by the HFE2 gene.[1][2] Hemojuvelin is a member of the repulsive guidance molecule family of proteins.[3][4] Both RGMa and RGMb are found in the nervous system,[5][6] while hemojuvelin is found in skeletal muscle and the liver.[6][7] # Function For many years the signal transduction pathways that regulate systemic iron homeostasis have been unknown. However it has been demonstrated that hemojuvelin interacts with bone morphogenetic protein (BMP), possibly as a co-receptor, and may signal via the SMAD pathway to regulate hepcidin expression.[8] Associations with BMP2 and BMP4 have been described.[9] Mouse HJV knock-out models confirmed that HJV is the gene responsible for juvenile hemochromatosis. Hepcidin levels in the liver are dramatically depressed in these knockout animals.[10][11] A soluble form of HJV may be a molecule that suppresses hepcidin expression.[12] RGMs may play inhibitory roles in prostate cancer by suppressing cell growth, adhesion, migration and invasion. RGMs can coordinate Smad-dependent and Smad-independent signalling of BMPs in prostate cancer and breast cancer cells.[13][14] Furthermore, aberrant expression of RGMs was indicated in breast cancer. The perturbed expression was associated with disease progression and poor prognosis.[15] # Related gene problems - TAR syndrome - 1q21.1 deletion syndrome - 1q21.1 duplication syndrome # Gene structure and transcription RGMc/HJV is a 4-exon gene in mammals that undergoes alternative RNA splicing to yield 3 mRNAs with different 5’ untranslated regions (5’UTRs).[7] Gene transcription is induced during myoblast differentiation, producing all 3 mRNAs. There are three critical promoter elements responsible for transcriptional activation in skeletal muscle (the tissue that has the highest level of RGMc expressesion per weight), comprising paired E-boxes, a putative Stat and/or Ets element, and a MEF2 site, and muscle transcription factors myogenin and MEF2C stimulate RGMc promoter function in non-muscle cells. As these elements are conserved in RGMc genes from multiple species, these results suggest that RGMc has been a muscle-enriched gene throughout its evolutionary history.[7] RGMc/HJV, is transcriptionally regulated during muscle differentiation.[7] # Isoforms Two classes of GPI-anchored and glycosylated HJV molecules are targeted to the membrane and undergo distinct fates.[16] - Full-length HJV is released from the cell surface and accumulates in extracellular fluid, where its half-life exceeds 24 hours. There appears to be two potential soluble isoforms and two membrane-associated isoforms.[16] - The predominant membrane-associated isoform, a disulfide-linked two-chain form composed of N- and C-terminal fragments, is not found in the extracellular fluid, and is short-lived, as it disappears from the cell surface with a half-life of < 3 hours after interruption of protein synthesis.[16] RGMc appears to undergo a complex processing that generates 2 soluble, single-chain forms, and two membrane-bound forms found as a (i) single-chain, and (ii) two-chain species which appears to be cleaved at a site within a partial von Willebrand factor domain.[16] Using a combination of biochemical and cell-based approaches, it has demonstrated that BMP-2 could interact in biochemical assays with the single-chain HJV species, and also could bind to cell-associated HJV. Two mouse HJV amino acid substitution mutants, D165E and G313V (corresponding to human D172E and G320V), also could bind BMP-2, but less effectively than wild-type HJV, while G92V (human G99V) could not. In contrast, the membrane-spanning protein, neogenin, a receptor for the related molecule, RGMa, preferentially bound membrane-associated heterodimeric RGMc and was able to interact on cells only with wild-type RGMc and G92V. These results show that different isoforms of RGMc/HJV may play unique physiological roles through defined interactions with distinct signaling proteins and demonstrate that, in some disease-linked HJV mutants, these interactions are defective.[17] # Structure In 2009, the Rosetta ab initio protein structure prediction software has been used to create a three-dimensional model of the RGM family of proteins.,[4] In 2011, a crystal structure of a fragment of hemojuvelin binding to neogenin was completed [18] showing similar structures to the ab initio model and further informing the view of the RGM family of proteins. # Mechanism of action Furin-like proprotein convertases (PPC) are responsible for conversion of 50 kDa HJV to a 40 kDa protein with a truncated COOH-terminus, at a conserved polybasic RNRR site. This suggests a potential mechanism to generate the soluble forms of HJV/hemojuvelin (s-hemojuvelin) found in the blood of rodents and humans.[19][20] # Clinical significance Mutations in HJV are responsible for the vast majority of juvenile hemochromatosis patients. A small number of patients have mutations in the hepcidin (HAMP) gene. The gene was positionally cloned.[2] Hemojuvelin is highly expressed in skeletal muscle and heart, and to a lesser extent in the liver. One insight into the pathogenesis of juvenile hemochromatosis is that patients have low to undetectable urinary hepcidin levels, suggesting that hemojuvelin is a positive regulator of hepcidin, the central iron regulatory hormone. As a result, low hepcidin levels would result in increased intestinal iron absorption. Thus, HJV/RGMc appears to play a critical role in iron metabolism.[citation needed]	https://www.wikidoc.org/index.php/Hemojuvelin
6ca375ffaaae24a2399a076edb61a1ffe7c1e273	wikidoc	Hepatectomy	Hepatectomy # Overview Hepatectomy consists on the surgical resection of the liver. While the term is often employed for the removal of the liver from a liver transplant recipient, this article will focus on partial resections of hepatic tissue. # History The first successful anatomic hepatectomy was reported by Jean-Louis Lortat-Jacob in 1952, the patient being a 58-year-old woman diagnosed with colorectal cancer metastatic to the liver. # Indications Most hepatectomies are performed for the treatment of hepatic neoplasms, both benign or malignant. Benign neoplasms include hepatocellular adenoma, hepatic hemangioma and focal nodular hyperplasia. The most common malignant neoplasms (cancers) of the liver are metastases; those arising from colorectal cancer are among the most common, and the most amenable to surgical resection. The most common primary malignant tumour of the liver is the hepatocellular carcinoma. Hepatectomy may also be the procedure of choice to treat intrahepatic gallstones or parasitic cysts of the liver. # Technique Access is accomplished by laparotomy, typically by a bilateral subcostal ("chevron") incision, possibly with midline extension (Calne or "Mercedes-Benz" incision). Hepatectomies may be anatomic, i.e. the lines of resection match the limits of one or more functional segments of the liver as defined by the Couinaud classification (cf. liver#Functional anatomy); or they may be non-anatomic, irregular or "wedge" hepatectomies. Anatomic resections are generally preferred because of the smaller risk of bleeding and biliary fistula; however, non-anatomic resections can be performed safely as well in selected cases. For details on the variety of anatomic hepatectomies and the specific nomenclature, cf. the International Hepato-Pancreatico-Biliary Association (IHPBA) Terminology for Liver Resections # Complications Bleeding is the most feared technical complication and may be grounds for urgent reoperation. Biliary fistula is also a possible complication, albeit one more amenable to nonsurgical management. Pulmonary complications such as atelectasis and pleural effusion are commonplace, and dangerous in patients with underlying lung disease. Infection is relatively rare. Liver failure poses a significant hazard to patients with underlying hepatic disease; this is a major deterrent in the surgical resection of hepatocellular carcinoma in patients with cirrhosis. It is also a problem, to a lesser degree, in patients with previous hepatectomies (e.g. repeat resections for reincident colorectal cancer metastases). # Results Liver surgery is safe when performed by experienced surgeons with appropriate technological and institutional support. As with most major surgical procedures, there is a marked tendency towards optimal results at the hands of surgeons with high caseloads in selected centres (typically cancer centres and transplantation centres). For optimal results, combination treatment with systemic or regionally infused chemo or biological therapy should be considered. Prior to surgery, cytotoxic agents such as oxaliplatin given systemically for colorectal metastasis, or chemoembolization for hepatocellular carcinoma can significantly decrease the size of the tumor bulk, allowing then for resections which would remove a segment or wedge portion of the liver only. These procedures can also be aided by application of liver clamp (Lin or Chu liver clamp; Pilling no.604113-61995) in order to minimize blood loss.	Hepatectomy Template:Interventions infobox Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview Hepatectomy consists on the surgical resection of the liver. While the term is often employed for the removal of the liver from a liver transplant recipient, this article will focus on partial resections of hepatic tissue. # History The first successful anatomic hepatectomy was reported by Jean-Louis Lortat-Jacob in 1952, the patient being a 58-year-old woman diagnosed with colorectal cancer metastatic to the liver. # Indications Most hepatectomies are performed for the treatment of hepatic neoplasms, both benign or malignant. Benign neoplasms include hepatocellular adenoma, hepatic hemangioma and focal nodular hyperplasia. The most common malignant neoplasms (cancers) of the liver are metastases; those arising from colorectal cancer are among the most common, and the most amenable to surgical resection. The most common primary malignant tumour of the liver is the hepatocellular carcinoma. Hepatectomy may also be the procedure of choice to treat intrahepatic gallstones or parasitic cysts of the liver. # Technique Access is accomplished by laparotomy, typically by a bilateral subcostal ("chevron") incision, possibly with midline extension (Calne or "Mercedes-Benz" incision). Hepatectomies may be anatomic, i.e. the lines of resection match the limits of one or more functional segments of the liver as defined by the Couinaud classification (cf. liver#Functional anatomy); or they may be non-anatomic, irregular or "wedge" hepatectomies. Anatomic resections are generally preferred because of the smaller risk of bleeding and biliary fistula; however, non-anatomic resections can be performed safely as well in selected cases. For details on the variety of anatomic hepatectomies and the specific nomenclature, cf. the International Hepato-Pancreatico-Biliary Association (IHPBA) Terminology for Liver Resections # Complications Bleeding is the most feared technical complication and may be grounds for urgent reoperation. Biliary fistula is also a possible complication, albeit one more amenable to nonsurgical management. Pulmonary complications such as atelectasis and pleural effusion are commonplace, and dangerous in patients with underlying lung disease. Infection is relatively rare. Liver failure poses a significant hazard to patients with underlying hepatic disease; this is a major deterrent in the surgical resection of hepatocellular carcinoma in patients with cirrhosis. It is also a problem, to a lesser degree, in patients with previous hepatectomies (e.g. repeat resections for reincident colorectal cancer metastases). # Results Liver surgery is safe when performed by experienced surgeons with appropriate technological and institutional support. As with most major surgical procedures, there is a marked tendency towards optimal results at the hands of surgeons with high caseloads in selected centres (typically cancer centres and transplantation centres). For optimal results, combination treatment with systemic or regionally infused chemo or biological therapy should be considered. Prior to surgery, cytotoxic agents such as oxaliplatin given systemically for colorectal metastasis, or chemoembolization for hepatocellular carcinoma can significantly decrease the size of the tumor bulk, allowing then for resections which would remove a segment or wedge portion of the liver only. These procedures can also be aided by application of liver clamp (Lin or Chu liver clamp; Pilling no.604113-61995) in order to minimize blood loss.	https://www.wikidoc.org/index.php/Hepatectomy
36bb801bd1a9296c5e1ff23bdcfe0ef807808e58	wikidoc	Tyrosinemia	Tyrosinemia Please help WikiDoc by adding content here. It's easy! Click here to learn about editing. # Overview Tyrosinemia (or "Tyrosinaemia") is an error of metabolism, usually inborn, in which the body cannot effectively break down the amino acid tyrosine. Symptoms include liver and kidney disturbances and mental retardation. Most inborn forms of tyrosinemia produce hypertyrosinemia (high levels of tyrosine). # Historical Perspective # Classification File:Autorecessive.svg There are three types of tyrosinemia, each with distinctive symptoms and caused by the deficiency of a different enzyme. - Type I tyrosinemia - Type II tyrosinemia - Type III tyrosinemia # Pathophysiology # Causes # Differentiating Tyrosinemia from Other Diseases # Epidemiology and Demographics # Risk Factors # Screening # Natural History, Complications, and Prognosis # Diagnosis ## Diagnostic Criteria ## History and Symptoms ## Physical Examination ## Laboratory Findings ## Imaging Findings ## Other Diagnostic Studies # Treatment Treatment varies depending on the specific type. A low protein diet may be required in the management of tyrosinemia. Recent experience with NTBC has shown to be very effective. The most effective treatment in patients with tyrosinemia type I seems to be full or partial liver transplant. ## Medical Therapy ## Surgery ## Prevention	Tyrosinemia Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Please help WikiDoc by adding content here. It's easy! Click here to learn about editing. # Overview Tyrosinemia (or "Tyrosinaemia") is an error of metabolism, usually inborn, in which the body cannot effectively break down the amino acid tyrosine. Symptoms include liver and kidney disturbances and mental retardation. Most inborn forms of tyrosinemia produce hypertyrosinemia (high levels of tyrosine).[1] # Historical Perspective # Classification File:Autorecessive.svg There are three types of tyrosinemia, each with distinctive symptoms and caused by the deficiency of a different enzyme. - Type I tyrosinemia - Type II tyrosinemia - Type III tyrosinemia # Pathophysiology # Causes # Differentiating Tyrosinemia from Other Diseases # Epidemiology and Demographics # Risk Factors # Screening # Natural History, Complications, and Prognosis # Diagnosis ## Diagnostic Criteria ## History and Symptoms ## Physical Examination ## Laboratory Findings ## Imaging Findings ## Other Diagnostic Studies # Treatment Treatment varies depending on the specific type. A low protein diet may be required in the management of tyrosinemia. Recent experience with NTBC has shown to be very effective. The most effective treatment in patients with tyrosinemia type I seems to be full or partial liver transplant. ## Medical Therapy ## Surgery ## Prevention	https://www.wikidoc.org/index.php/Hepatorenal_tyrosinemia
91766b432a1cb725f5b8f2c30545870c0254c064	wikidoc	Herapathite	Herapathite Herapathite, or iodoquinine sulphate, is a chemical compound whose crystals are dichroic and thus can be used for polarizing light. According to Edwin H. Land, it was discovered in 1852 by William Herapath, a doctor in Bristol. One of his pupils found that adding iodine to the urine of a dog that had been fed quinine produced unusual green crystals. Herapath noticed while studying the crystals under a microscope that they appeared to polarize light. Herapathite's dichroic properties came to the attention of Sir David Brewster, and were later used by Land in 1929 to construct the first type of Polaroid sheet polarizer.	Herapathite Herapathite, or iodoquinine sulphate, is a chemical compound whose crystals are dichroic and thus can be used for polarizing light. According to Edwin H. Land, it was discovered in 1852 by William Herapath, a doctor in Bristol. One of his pupils found that adding iodine to the urine of a dog that had been fed quinine produced unusual green crystals. Herapath noticed while studying the crystals under a microscope that they appeared to polarize light. Herapathite's dichroic properties came to the attention of Sir David Brewster, and were later used by Land in 1929 to construct the first type of Polaroid sheet polarizer.	https://www.wikidoc.org/index.php/Herapathite
e0cf4d5926bdd9069a5d938dbc43d5686f44e513	wikidoc	Trastuzumab	Trastuzumab # Disclaimer WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here. # Black Box Warning # Overview Trastuzumab is a Monoclonal antibodies that is FDA approved for the treatment of Adjuvant Breast Cancer, Metastatic Breast Cancer, Metastatic Gastric Cancer. There is a Black Box Warning for this drug as shown here. Common adverse reactions include edema， peripheral edema，tachycardia, rash, weight decreased, abdominal pain，diarrhea，loss of appetite, nausea, stomatitis, vomiting, anemia, neutropenia, thrombocytopenia, infectious disease, breast cancer, arthralgia, backache, myalgia, asthenia, dizziness, headache, insomnia, renal impairment, cough, dyspnea, nasopharyngitis, pharyngitis, rhinitis, upper respiratory infection, fatigue, fever, inflammatory disease of mucous membrane, shivering. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) - Do not administer as an intravenous push or bolus. Do not mix Trastuzumab with other drugs. - Do not substitute Trastuzumab for or with ado-trastuzumab emtansine. - Dosing information - Administer according to one of the following doses and schedules for a total of 52 weeks of Trastuzumab therapy: - During and following paclitaxel, docetaxel, or docetaxel/carboplatin: - Initial dosage: 4 mg/kg as an intravenous infusion over 90 minutes then at 2 mg/kg as an intravenous infusion over 30 minutes weekly during chemotherapy for the first 12 weeks (paclitaxel or docetaxel) or 18 weeks (docetaxel/carboplatin). - One week following the last weekly dose of Trastuzumab, administer Trastuzumab at 6 mg/kg as an intravenous infusion over 30–90 minutes every three weeks. - As a single agent within three weeks following completion of multi-modality, anthracycline-based chemotherapy regimens: - Extending adjuvant treatment beyond one year is not recommended. - Dosing information - Initial dosage: 8 mg/kg as a 90 minute intravenous infusion - Subsequent dosage: 6 mg/kg as an intravenous infusion over 30-90 minutes every three weeks until disease progression ## Dose Modifications - Decrease the rate of infusion for mild or moderate infusion reactions - Interrupt the infusion in patients with dyspnea or clinically significant hypotension - Discontinue Trastuzumab for severe or life-threatening infusion reactions. - Assess left ventricular ejection fraction (LVEF) prior to initiation of Trastuzumab and at regular intervals during treatment. Withhold Trastuzumab dosing for at least 4 weeks for either of the following: - ≥ 16% absolute decrease in LVEF from pre-treatment values - LVEF below institutional limits of normal and ≥ 10% absolute decrease in LVEF from pretreatment values. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Trastuzumab in adult patients. ### Non–Guideline-Supported Use - Dosing information - ‘’‘(4 mg/kg) IV on day 1 of cycle 1, then 2 mg/kg IV on days 2, 9, and 16’‘ - Dosing information - individual doses ranged from 4 to 150 mg - Dosing information - 4 mg/kg is administered IV on day 1, then 2 mg/kg IV weekly thereafter # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) The safety and effectiveness of Trastuzumab in pediatric patients has not been established. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Trastuzumab in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Trastuzumab in pediatric patients. # Contraindications None. # Warnings There is limited information regarding Trastuzumab Warnings' in the drug label. # Adverse Reactions ## Clinical Trials Experience - The most common adverse reactions in patients receiving Trastuzumab in the adjuvant and metastatic breast cancer setting are fever, nausea, vomiting, infusion reactions, diarrhea, infections, increased cough, headache, fatigue, dyspnea, rash, neutropenia, anemia, and myalgia. Adverse reactions requiring interruption or discontinuation of Trastuzumab treatment include CHF, significant decline in left ventricular cardiac function, severe infusion reactions, and pulmonary toxicity. - In the metastatic gastric cancer setting, the most common adverse reactions (≥ 10%) that were increased (≥ 5% difference) in the Trastuzumab arm as compared to the chemotherapy alone arm were neutropenia, diarrhea, fatigue, anemia, stomatitis, weight loss, upper respiratory tract infections, fever, thrombocytopenia, mucosal inflammation, nasopharyngitis, and dysgeusia. The most common adverse reactions which resulted in discontinuation of treatment on the Trastuzumab-containing arm in the absence of disease progression were infection, diarrhea, and febrile neutropenia. - Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Adjuvant Breast Cancer Studies - The data below reflect exposure to one-year Trastuzumab therapy across three randomized, open-label studies, Studies 1, 2, and 3, with (n=3678) or without (n= 3363) trastuzumab in the adjuvant treatment of breast cancer. The data summarized in Table 3 below, from Study 3, reflect exposure to Trastuzumab in 1678 patients; the median treatment duration was 51 weeks and median number of infusions was 18. Among the 3386 patients enrolled in the observation and one-year Trastuzumab arms of Study 3 at a median duration of follow-up of 12.6 months in the Trastuzumab arm, the median age was 49 years (range: 21 to 80 years), 83% of patients were Caucasian, and 13% were Asian. In Study 3, a comparison of 3-weekly Trastuzumab treatment for two years versus one year was also performed. The rate of asymptomatic cardiac dysfunction was increased in the 2-year Trastuzumab treatment arm (8.1% versus 4.6% in the one-year Trastuzumab treatment arm). More patients experienced at least one adverse reaction of grade 3 or higher in the 2-year Trastuzumab treatment arm (20.4%) compared with the one-year Trastuzumab treatment arm (16.3%). The safety data from Studies 1 and 2 were obtained from 3655 patients, of whom 2000 received Trastuzumab; the median treatment duration was 51 weeks. The median age was 49 years (range: 24–80); 84% of patients were White, 7% Black, 4% Hispanic, and 3% Asian. In Study 1, only Grade 3–5 adverse events, treatment-related Grade 2 events, and Grade 2–5 dyspnea were collected during and for up to 3 months following protocol-specified treatment. The following non-cardiac adverse reactions of Grade 2–5 occurred at an incidence of at least 2% greater among patients receiving Trastuzumab plus chemotherapy as compared to chemotherapy alone: fatigue (29.5% vs. 22.4%), infection (24.0% vs. 12.8%), hot flashes (17.1% vs. 15.0%), anemia (12.3% vs. 6.7%), dyspnea (11.8% vs. 4.6%), rash/desquamation (10.9% vs. 7.6%), leukopenia (10.5% vs. 8.4%), neutropenia (6.4% vs. 4.3%), headache (6.2% vs. 3.8%), pain (5.5% vs. 3.0%), edema (4.7% vs. 2.7%) and insomnia (4.3% vs. 1.5%). The majority of these events were Grade 2 in severity. In Study 2, data collection was limited to the following investigator-attributed treatment-related adverse reactions: NCI-CTC Grade 4 and 5 hematologic toxicities, Grade 3–5 non-hematologic toxicities, selected Grade 2–5 toxicities associated with taxanes (myalgia, arthralgias, nail changes, motor neuropathy, sensory neuropathy) and Grade 1–5 cardiac toxicities occurring during chemotherapy and/or Trastuzumab treatment. The following non-cardiac adverse reactions of Grade 2–5 occurred at an incidence of at least 2% greater among patients receiving Trastuzumab plus chemotherapy as compared to chemotherapy alone: arthralgia (12.2% vs. 9.1%), nail changes (11.5% vs.6.8%), dyspnea (2.4% vs. 0.2%), and diarrhea (2.2% vs. 0%). The majority of these events were Grade 2 in severity. Safety data from Study 4 reflect exposure to Trastuzumab as part of an adjuvant treatment regimen from 2124 patients receiving at least one dose of study treatment . The overall median treatment duration was 54 weeks in both the AC-TH and TCH arms. The median number of infusions was 26 in the AC-TH arm and 30 in the TCH arm, including weekly infusions during the chemotherapy phase and every three week dosing in the monotherapy period. Among these patients, the median age was 49 years (range 22 to 74 years). In Study 4, the toxicity profile was similar to that reported in Studies 1, 2, and 3 with the exception of a low incidence of CHF in the TCH arm. Metastatic Breast Cancer Studies The data below reflect exposure to Trastuzumab in one randomized, open-label study, Study 5, of chemotherapy with (n=235) or without (n=234) trastuzumab in patients with metastatic breast cancer, and one single-arm study (Study 6; n=222) in patients with metastatic breast cancer. Data in Table 4 are based on Studies 5 and 6. Among the 464 patients treated in Study 5, the median age was 52 years (range: 25–77 years). Eighty-nine percent were White, 5% Black, 1% Asian and 5% other racial/ethnic groups. All patients received 4 mg/kg initial dose of Trastuzumab followed by 2 mg/kg weekly. The percentages of patients who received Trastuzumab treatment for ≥ 6 months and ≥ 12 months were 58% and 9%, respectively. Among the 352 patients treated in single agent studies (213 patients from Study 6), the median age was 50 years (range 28–86 years), 86% were White, 3% were Black, 3% were Asian, and 8% in other racial/ethnic groups. Most of the patients received 4 mg/kg initial dose of Trastuzumab followed by 2 mg/kg weekly. The percentages of patients who received Trastuzumab treatment for ≥ 6 months and ≥ 12 months were 31% and 16%, respectively. Metastatic Gastric Cancer The data below are based on the exposure of 294 patients to Trastuzumab in combination with a fluoropyrimidine (capecitabine or 5-FU) and cisplatin (Study 7). In the Trastuzumab plus chemotherapy arm, the initial dose of Trastuzumab 8 mg/kg was administered on Day 1 (prior to chemotherapy) followed by 6 mg/kg every 21 days until disease progression. Cisplatin was administered at 80 mg/m2 on Day 1 and the fluoropyrimidine was administered as either capecitabine 1000 mg/m2 orally twice a day on Days 1-14 or 5-fluorouracil 800 mg/m2/day as a continuous intravenous infusion Days 1 through 5. Chemotherapy was administered for six 21-day cycles. Median duration of Trastuzumab treatment was 21 weeks; median number of Trastuzumab infusions administered was eight. The following subsections provide additional detail regarding adverse reactions observed in clinical trials of adjuvant breast, metastatic breast cancer, metastatic gastric cancer, or post-marketing experience. Cardiomyopathy Serial measurement of cardiac function (LVEF) was obtained in clinical trials in the adjuvant treatment of breast cancer. In Study 3, the median duration of follow-up was 12.6 months (12.4 months in the observation arm; 12.6 months in the 1-year Trastuzumab arm); and in Studies 1 and 2, 7.9 years in the AC-T arm, 8.3 years in the AC-TH arm. In Studies 1 and 2, 6% of all randomized patients with post-AC LVEF evaluation were not permitted to initiate Trastuzumab following completion of AC chemotherapy due to cardiac dysfunction (LVEF < LLN or ≥ 16 point decline in LVEF from baseline to end of AC). Following initiation of Trastuzumab therapy, the incidence of new-onset dose-limiting myocardial dysfunction was higher among patients receiving Trastuzumab and paclitaxel as compared to those receiving paclitaxel alone in Studies 1 and 2, and in patients receiving one-year Trastuzumab monotherapy compared to observation in Study 3 (see Table 6, Figures 1 and 2). The per-patient incidence of new-onset cardiac dysfunction, as measured by LVEF, remained similar when compared to the analysis performed at a median follow-up of 2.0 years in the AC-TH arm. This analysis also showed evidence of reversibility of left ventricular dysfunction, with 64.5% of patients who experienced symptomatic CHF in the AC-TH group being asymptomatic at latest follow-up, and 90.3% having full or partial LVEF recovery. Figure 1 Studies 1 and 2: Cumulative Incidence of Time to First LVEF Decline of ≥ 10 Percentage Points from Baseline and to Below 50% with Death as a Competing Risk Event Time 0 is initiation of paclitaxel or Trastuzumab + paclitaxel therapy. Figure 2 Study 3: Cumulative Incidence of Time to First LVEF Decline of ≥ 10 Percentage Points from Baseline and to Below 50% with Death as a Competing Risk Event Time 0 is the date of randomization. Figure 3 Study 4: Cumulative Incidence of Time to First LVEF Decline of ≥10 Percentage Points from Baseline and to Below 50% with Death as a Competing Risk Event Time 0 is the date of randomization. The incidence of treatment emergent congestive heart failure among patients in the metastatic breast cancer trials was classified for severity using the New York Heart Association classification system (I–IV, where IV is the most severe level of cardiac failure) (see Table 2). In the metastatic breast cancer trials the probability of cardiac dysfunction was highest in patients who received Trastuzumab concurrently with anthracyclines. In Study 7, 5.0% of patients in the Trastuzumab plus chemotherapy arm compared to 1.1% of patients in the chemotherapy alone arm had LVEF value below 50% with a ≥ 10% absolute decrease in LVEF from pretreatment values. Infusion Reactions During the first infusion with Trastuzumab, the symptoms most commonly reported were chills and fever, occurring in approximately 40% of patients in clinical trials. Symptoms were treated with acetaminophen, diphenhydramine, and meperidine (with or without reduction in the rate of Trastuzumab infusion); permanent discontinuation of Trastuzumab for infusional toxicity was required in < 1% of patients. Other signs and/or symptoms may include nausea, vomiting, pain (in some cases at tumor sites), rigors, headache, dizziness, dyspnea, hypotension, elevated blood pressure, rash, and asthenia. Infusional toxicity occurred in 21% and 35% of patients, and was severe in 1.4% and 9% of patients, on second or subsequent Trastuzumab infusions administered as monotherapy or in combination with chemotherapy, respectively. In the post-marketing setting, severe infusion reactions, including hypersensitivity, anaphylaxis, and angioedema have been reported. Anemia In randomized controlled clinical trials, the overall incidence of anemia (30% vs. 21% ), of selected NCI-CTC Grade 2–5 anemia (12.3% vs. 6.7% ), and of anemia requiring transfusions (0.1% vs. 0 patients ) were increased in patients receiving Trastuzumab and chemotherapy compared with those receiving chemotherapy alone. Following the administration of Trastuzumab as a single agent (Study 6), the incidence of NCI-CTC Grade 3 anemia was < 1%. In Study 7 (metastatic gastric cancer) on the Trastuzumab containing arm as compared to the chemotherapy alone arm the overall incidence of anemia was 28% compared 21% and of NCI CTC Grade 3/4 anemia was 12.2% compared to 10.3%. Neutropenia In randomized controlled clinical trials in the adjuvant setting, the incidence of selected NCI-CTC Grade 4–5 neutropenia (1.7% vs. 0.8% ) and of selected Grade 2–5 neutropenia (6.4% vs. 4.3% ) were increased in patients receiving Trastuzumab and chemotherapy compared with those receiving chemotherapy alone. In a randomized, controlled trial in patients with metastatic breast cancer, the incidences of NCI-CTC Grade 3/4 neutropenia (32% vs. 22%) and of febrile neutropenia (23% vs. 17%) were also increased in patients randomized to Trastuzumab in combination with myelosuppressive chemotherapy as compared to chemotherapy alone. In Study 7 (metastatic gastric cancer) on the Trastuzumab containing arm as compared to the chemotherapy alone arm, the incidence of NCI CTC Grade 3/4 neutropenia was 36.8% compared to 28.9%; febrile neutropenia 5.1% compared to 2.8%. Infection The overall incidences of infection (46% vs. 30% ), of selected NCI-CTC Grade 2–5 infection/febrile neutropenia (24.3% vs. 13.4% ) and of selected Grade 3–5 infection/febrile neutropenia (2.9% vs. 1.4%) ), were higher in patients receiving Trastuzumab and chemotherapy compared with those receiving chemotherapy alone. The most common site of infections in the adjuvant setting involved the upper respiratory tract, skin, and urinary tract. In Study 4, the overall incidence of infection was higher with the addition of Trastuzumab to AC-T but not to TCH . The incidences of NCI-CTC Grade 3-4 infection were similar across the three arms. In a randomized, controlled trial in treatment of metastatic breast cancer, the reported incidence of febrile neutropenia was higher (23% vs. 17%) in patients receiving Trastuzumab in combination with myelosuppressive chemotherapy as compared to chemotherapy alone. Pulmonary Toxicity Adjuvant Breast Cancer Among women receiving adjuvant therapy for breast cancer, the incidence of selected NCI-CTC Grade 2–5 pulmonary toxicity (14.3% vs. 5.4% ) and of selected NCI-CTC Grade 3–5 pulmonary toxicity and spontaneous reported Grade 2 dyspnea (3.4% vs. 0.9% ) was higher in patients receiving Trastuzumab and chemotherapy compared with chemotherapy alone. The most common pulmonary toxicity was dyspnea (NCI-CTC Grade 2–5: 11.8% vs. 4.6% ; NCI-CTC Grade 2–5: 2.4% vs. 0.2% ). Pneumonitis/pulmonary infiltrates occurred in 0.7% of patients receiving Trastuzumab compared with 0.3% of those receiving chemotherapy alone. Fatal respiratory failure occurred in 3 patients receiving Trastuzumab, one as a component of multi-organ system failure, as compared to 1 patient receiving chemotherapy alone. In Study 3, there were 4 cases of interstitial pneumonitis in the one-year Trastuzumab treatment arm compared to none in the observation arm at a median follow-up duration of 12.6 months. Metastatic Breast Cancer Among women receiving Trastuzumab for treatment of metastatic breast cancer, the incidence of pulmonary toxicity was also increased. Pulmonary adverse events have been reported in the post-marketing experience as part of the symptom complex of infusion reactions. Pulmonary events include bronchospasm, hypoxia, dyspnea, pulmonary infiltrates, pleural effusions, non-cardiogenic pulmonary edema, and acute respiratory distress syndrome. Thrombosis/Embolism In 4 randomized, controlled clinical trials, the incidence of thrombotic adverse events was higher in patients receiving Trastuzumab and chemotherapy compared to chemotherapy alone in three studies (2.6% vs. 1.5% , 2.5% and 3.7% vs. 2.2% and 2.1% vs. 0% ). Diarrhea Among women receiving adjuvant therapy for breast cancer, the incidence of NCI-CTC Grade 2–5 diarrhea (6.7% vs. 5.4% ) and of NCI-CTC Grade 3–5 diarrhea (2.2% vs. 0% ), and of Grade 1–4 diarrhea (7% vs. 1% ) were higher in patients receiving Trastuzumab as compared to controls. In Study 4, the incidence of Grade 3–4 diarrhea was higher and of Grade 1–4 was higher among women receiving Trastuzumab. Of patients receiving Trastuzumab as a single agent for the treatment of metastatic breast cancer, 25% experienced diarrhea. An increased incidence of diarrhea was observed in patients receiving Trastuzumab in combination with chemotherapy for treatment of metastatic breast cancer. Renal Toxicity In Study 7 (metastatic gastric cancer) on the Trastuzumab-containing arm as compared to the chemotherapy alone arm the incidence of renal impairment was 18% compared to 14.5%. Severe (Grade 3/4) renal failure was 2.7% on the Trastuzumab-containing arm compared to 1.7% on the chemotherapy only arm. Treatment discontinuation for renal insufficiency/failure was 2% on the Trastuzumab-containing arm and 0.3% on the chemotherapy only arm. In the postmarketing setting, rare cases of nephrotic syndrome with pathologic evidence of glomerulopathy have been reported. The time to onset ranged from 4 months to approximately 18 months from initiation of Trastuzumab therapy. Pathologic findings included membranous glomerulonephritis, focal glomerulosclerosis, and fibrillary glomerulonephritis. Complications included volume overload and congestive heart failure. ## Immunogenicity As with all therapeutic proteins, there is a potential for immunogenicity. Among 903 women with metastatic breast cancer, human anti-human antibody (HAHA) to Trastuzumab was detected in one patient using an enzyme-linked immunosorbent assay (ELISA). This patient did not experience an allergic reaction. Samples for assessment of HAHA were not collected in studies of adjuvant breast cancer. The incidence of antibody formation is highly dependent on the sensitivity and the specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to Trastuzumab with the incidence of antibodies to other products may be misleading. ## Postmarketing Experience The following adverse reactions have been identified during post approval use of Trastuzumab. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. - Infusion reaction - Oligohydramnios or oligohydramnios sequence, including pulmonary hypoplasia, skeletal abnormalities, and neonatal death - Glomerulopathy # Drug Interactions In Study 5, the mean serum trough concentration of trastuzumab was consistently elevated approximately 1.5–fold, when administered in combination with paclitaxel as compared to trough concentrations of trastuzumab when administered in combination with an anthracycline and cyclophosphamide. In other pharmacokinetic studies, where Trastuzumab was administered in combination with paclitaxel, docetaxel, carboplatin, or doxorubicin, Trastuzumab did not alter the plasma concentrations of these chemotherapeutic agents, or the metabolites that were analyzed. In a drug interaction substudy conducted in patients in Study 7, the pharmacokinetics of cisplatin, capecitabine and their metabolites were not altered when administered in combination with Trastuzumab. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): D Trastuzumab can cause fetal harm when administered to a pregnant woman. In post-marketing reports use of Trastuzumab during pregnancy resulted in cases of oligohydramnios and of oligohydramnios sequence, manifesting as pulmonary hypoplasia, skeletal abnormalities, and neonatal death. These case reports described oligohydramnios in pregnant women who received Trastuzumab either alone or in combination with chemotherapy. In some case reports, amniotic fluid index increased after Trastuzumab was stopped. In one case, Trastuzumab therapy resumed after the amniotic fluid index improved, and oligohydramnios recurred. Monitor women exposed to Trastuzumab during pregnancy for oligohydramnios. If oligohydramnios occurs, perform fetal testing that is appropriate for gestational age and consistent with community standards of care. The efficacy of IV hydration in management of oligohydramnios due to Trastuzumab exposure is not known. Advise women of the potential hazard to the fetus resulting from Trastuzumab exposure during pregnancy. Encourage pregnant women with breast cancer who are using Trastuzumab to enroll in MotHER the Trastuzumab Pregnancy Registry: phone 1 800 690 6720. No teratogenic effects were observed in offspring from reproduction studies in cynomolgus monkeys at doses up to 25 times the recommended weekly human dose of 2 mg/kg trastuzumab. In mutant mice lacking HER2, embryos died in early gestation. Trastuzumab exposure was reported at delivery in offspring of cynomolgus monkeys treated during the early (Days 20–50 of gestation) or late (Days 120–150 of gestation) fetal development periods, at levels of 15 to 28% of the maternal blood levels. Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Trastuzumab in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Trastuzumab during labor and delivery. ### Nursing Mothers It is not known whether Trastuzumab is excreted in human milk, but human IgG is excreted in human milk. Published data suggest that breast milk antibodies do not enter the neonatal and infant circulation in substantial amounts. Trastuzumab was present in the breast milk of lactating cynomolgus monkeys given 12.5 times the recommended weekly human dose of 2 mg/kg of Trastuzumab. Infant monkeys with detectable serum levels of trastuzumab did not have any adverse effects on growth or development from birth to 3 months of age; however, trastuzumab levels in animal breast milk may not accurately reflect human breast milk levels. Because many drugs are secreted in human milk and because of the potential for serious adverse reactions in nursing infants from Trastuzumab, a decision should be made whether to discontinue nursing, or discontinue drug, taking into account the elimination half-life of trastuzumab and the importance of the drug to the mother. ### Pediatric Use The safety and effectiveness of Trastuzumab in pediatric patients has not been established. ### Geriatic Use Trastuzumab has been administered to 386 patients who were 65 years of age or over (253 in the adjuvant treatment and 133 in metastatic breast cancer treatment settings). The risk of cardiac dysfunction was increased in geriatric patients as compared to younger patients in both those receiving treatment for metastatic disease in Studies 5 and 6, or adjuvant therapy in Studies 1 and 2. Limitations in data collection and differences in study design of the 4 studies of Trastuzumab in adjuvant treatment of breast cancer preclude a determination of whether the toxicity profile of Trastuzumab in older patients is different from younger patients. The reported clinical experience is not adequate to determine whether the efficacy improvements (ORR, TTP, OS, DFS) of Trastuzumab treatment in older patients is different from that observed in patients <65 years of age for metastatic disease and adjuvant treatment. In Study 7 (metastatic gastric cancer), of the 294 patients treated with Trastuzumab 108 (37%) were 65 years of age or older, while 13 (4.4%) were 75 and over. No overall differences in safety or effectiveness were observed. ### Gender There is no FDA guidance on the use of Trastuzumab with respect to specific gender populations. ### Race There is no FDA guidance on the use of Trastuzumab with respect to specific racial populations. ### Renal Impairment There is no FDA guidance on the use of Trastuzumab in patients with renal impairment. ### Hepatic Impairment There is no FDA guidance on the use of Trastuzumab in patients with hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Trastuzumab in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Trastuzumab in patients who are immunocompromised. # Administration and Monitoring ### Administration To prevent medication errors, it is important to check the vial labels to ensure that the drug being prepared and administered is Trastuzumab and not ado-trastuzumab emtansine. Reconstitution Reconstitute each 440 mg vial of Trastuzumab with 20 mL of Bacteriostatic Water for Injection (BWFI), USP, containing 1.1% benzyl alcohol as a preservative to yield a multi-dose solution containing 21 mg/mL trastuzumab. In patients with known hypersensitivity to benzyl alcohol, reconstitute with 20 mL of Sterile Water for Injection (SWFI) without preservative to yield a single use solution. Use appropriate aseptic technique when performing the following reconstitution steps: - Using a sterile syringe, slowly inject the 20 mL of diluent into the vial containing the lyophilized cake of Trastuzumab. The stream of diluent should be directed into the lyophilized cake. - Swirl the vial gently to aid reconstitution. DO NOT SHAKE. - Slight foaming of the product may be present upon reconstitution. Allow the vial to stand undisturbed for approximately 5 minutes. - Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Inspect visually for particulates and discoloration. The solution should be free of visible particulates, clear to slightly opalescent and colorless to pale yellow. - Store reconstituted Trastuzumab at 2–8° C; discard unused Trastuzumab after 28 days. If Trastuzumab is reconstituted with SWFI without preservative, use immediately and discard any unused portion. Dilution - Determine the dose (mg) of Trastuzumab. Calculate the volume of the 21 mg/mL reconstituted Trastuzumab solution needed, withdraw this amount from the vial and add it to an infusion bag containing 250 mL of 0.9% Sodium Chloride Injection, USP. DO NOT USE DEXTROSE (5%) SOLUTION. - Gently invert the bag to mix the solution. ### Monitoring FDA Package Insert for Trastuzumab contains no information regarding drug monitoring. # IV Compatibility There is limited information about the IV Compatibility. # Overdosage There is no experience with overdosage in human clinical trials. Single doses higher than 8 mg/kg have not been tested. # Pharmacology ## Mechanism of Action The HER2 (or c-erbB2) proto-oncogene encodes a transmembrane receptor protein of 185 kDa, which is structurally related to the epidermal growth factor receptor. Trastuzumab has been shown, in both in vitro assays and in animals, to inhibit the proliferation of human tumor cells that overexpress HER2. Trastuzumab is a mediator of antibody-dependent cellular cytotoxicity (ADCC). In vitro, Trastuzumab-mediated ADCC has been shown to be preferentially exerted on HER2 overexpressing cancer cells compared with cancer cells that do not overexpress HER2. ## Structure Trastuzumab is a humanized IgG1 kappa monoclonal antibody that selectively binds with high affinity to the extracellular domain of the human epidermal growth factor receptor 2 protein, HER2. Trastuzumab is produced by recombinant DNA technology in a mammalian cell (Chinese Hamster Ovary) culture containing the antibiotic gentamicin. Gentamicin is not detectable in the final product. Trastuzumab is a sterile, white to pale yellow, preservative-free lyophilized powder for intravenous administration. Each multi-use vial of Trastuzumab contains 440 mg trastuzumab, 400 mg α,α-trehalose dihydrate, 9.9 mg L-histidine HCl, 6.4 mg L-histidine, and 1.8 mg polysorbate 20, USP. Reconstitution with 20 mL of the appropriate diluent (BWFI or SWFI) yields a solution containing 21 mg/mL trastuzumab, at a pH of approximately 6. ## Pharmacodynamics FDA Package Insert for Trastuzumab contains no information regarding Pharmacokinetics. ## Pharmacokinetics The pharmacokinetics of trastuzumab were studied in women with metastatic breast cancer. Short duration intravenous infusions of 10 to 500 mg Trastuzumab once weekly demonstrated dose-dependent pharmacokinetics. Mean half-life increased and clearance decreased with increasing dose level. The half-life averaged 2 and 12 days at the 10 and 500 mg dose levels, respectively. The volume of distribution of trastuzumab was approximately that of serum volume (44 mL/kg). At the highest weekly dose studied (500 mg), mean peak serum concentrations were 377 mcg/mL. In studies using an initial dose of 4 mg/kg followed by a weekly dose of 2 mg/kg, a mean half-life of 6 days (range 1–32 days) was observed. Between weeks 16 and 32, trastuzumab serum concentrations reached a steady state with mean trough and peak concentrations of approximately 79 mcg/mL and 123 mcg/mL, respectively. In a study of women receiving adjuvant therapy for breast cancer, a mean half-life of trastuzumab of 16 days (range: 11–23 days) was observed after an initial dose of 8 mg/kg followed by a dose of 6 mg/kg every three weeks. Between weeks 6 and 37, trastuzumab serum concentrations reached a steady-state with mean trough and peak concentrations of 63 mcg/mL and 216 mcg/mL, respectively. In patients with metastatic gastric cancer (Study 7), mean serum trastuzumab trough concentrations at steady state were 24 to 63% lower as compared to the concentrations observed in patients with breast cancer receiving treatment for metastatic disease in combination with paclitaxel, as monotherapy for metastatic disease, or as adjuvant monotherapy. Sixty-four percent (286/447) of women with metastatic breast cancer had detectable circulating extracellular domain of the HER2 receptor (shed antigen), which ranged as high as 1880 ng/mL (median 11 ng/mL). Patients with higher baseline shed antigen levels were more likely to have lower serum trough concentrations. Data suggest that the disposition of trastuzumab is not altered based on age or serum creatinine (≤2.0 mg creatinine/dL). ## Nonclinical Toxicology ## Carcinogenesis, Mutagenesis, Impairment of Fertility Trastuzumab has not been tested for carcinogenic potential. No evidence of mutagenic activity was observed when trastuzumab was tested in the standard Ames bacterial and human peripheral blood lymphocyte mutagenicity assays, at concentrations of up to 5000 mcg/mL. In an in vivo micronucleus assay, no evidence of chromosomal damage to mouse bone marrow cells was observed following bolus intravenous doses of up to 118 mg/kg Trastuzumab. A fertility study conducted in female cynomolgus monkeys at doses up to 25 times the weekly recommended human dose of 2 mg/kg trastuzumab and has revealed no evidence of impaired fertility, as measured by menstrual cycle duration and female sex hormone levels. Studies to evaluate the effects of trastuzumab on male fertility have not been conducted. ## Animal Toxicology and/or Pharmacology Reproductive Toxicology Studies Reproductive toxicology studies have been conducted in cynomolgus monkeys at doses up to 25 times the weekly recommended human dose of 2 mg/kg Trastuzumab and have revealed no evidence of impaired fertility or harm to the fetus. However, HER2 protein expression is high in many embryonic tissues including cardiac and neural tissues; in mutant mice lacking HER2, embryos died in early gestation. Placental transfer of trastuzumab was detected at Caesarean section in offspring from pregnant cynomolgus monkeys dosed during the early (Days 20–50 of gestation) or late (Days 120–150 of gestation) fetal development periods. # Clinical Studies ## Adjuvant Breast Cancer The safety and efficacy of Trastuzumab in women receiving adjuvant chemotherapy for HER2 overexpressing breast cancer, were evaluated in an integrated analysis of two randomized, open-label, clinical trials (Studies 1 and 2) with a total of 4063 women at the protocol-specified final overall survival analysis, a third randomized, open-label, clinical trial (Study 3) with a total of 3386 women at definitive Disease Free Survival analysis for one-year Trastuzumab treatment versus observation, and a fourth randomized, open-label clinical trial with a total of 3222 patients (Study 4). Studies 1 and 2 In Studies 1 and 2, breast tumor specimens were required to show HER2 overexpression (3+ by IHC) or gene amplification (by FISH). HER2 testing was verified by a central laboratory prior to randomization (Study 2) or was required to be performed at a reference laboratory (Study 1). Patients with a history of active cardiac disease based on symptoms, abnormal electrocardiographic, radiologic, or left ventricular ejection fraction findings or uncontrolled hypertension (diastolic > 100 mmHg or systolic > 200 mmHg) were not eligible. Patients were randomized (1:1) to receive doxorubicin and cyclophosphamide followed by paclitaxel (AC→paclitaxel) alone or paclitaxel plus Trastuzumab (AC→paclitaxel + Trastuzumab). In both trials, patients received four 21-day cycles of doxorubicin 60 mg/m2 and cyclophosphamide 600 mg/m2. Paclitaxel was administered either weekly (80 mg/m2) or every 3 weeks (175 mg/m2) for a total of 12 weeks in Study 1; paclitaxel was administered only by the weekly schedule in Study 2. Trastuzumab was administered at 4 mg/kg on the day of initiation of paclitaxel and then at a dose of 2 mg/kg weekly for a total of 52 weeks. Trastuzumab treatment was permanently discontinued in patients who developed congestive heart failure, or persistent/recurrent LVEF decline. Radiation therapy, if administered, was initiated after the completion of chemotherapy. Patients with ER+ and/or PR+ tumors received hormonal therapy. The primary endpoint of the combined efficacy analysis was Disease-free survival (DFS), defined as the time from randomization to recurrence, occurrence of contralateral breast cancer, other second primary cancer, or death. The secondary endpoint was overall survival (OS). A total of 3752 patients were included in the joint efficacy analysis of the primary endpoint of DFS following a median follow-up of 2.0 years in the AC→paclitaxel + Trastuzumab arm. The pre-planned final OS analysis from the joint analysis included 4063 patients and was performed when 707 deaths had occurred after a median follow-up of 8.3 years in the AC→paclitaxel + Trastuzumab arm. The data from both arms in Study 1 and two of the three study arms in Study 2 were pooled for efficacy analyses. The patients included in the primary DFS analysis had a median age of 49 years (range, 22–80 years; 6% > 65 years), 84% were white, 7% black, 4% Hispanic, and 4% Asian/Pacific Islander. Disease characteristics included 90% infiltrating ductal histology, 38% T1, 91% nodal involvement, 27% intermediate and 66% high grade pathology, and 53% ER+ and/or PR+ tumors. Similar demographic and baseline characteristics were reported for the efficacy evaluable population, after 8.3 years of median follow-up in the AC→paclitaxel + Trastuzumab arm. Study 3 In Study 3, breast tumor specimens were required to show HER2 overexpression (3+ by IHC) or gene amplification (by FISH) as determined at a central laboratory. Patients with node-negative disease were required to have ≥ T1c primary tumor. Patients with a history of congestive heart failure or LVEF 180 mm Hg or diastolic > 100 mm Hg) were not eligible. Study 3 was designed to compare one and two years of three-weekly Trastuzumab treatment versus observation in patients with HER2 positive EBC following surgery, established chemotherapy and radiotherapy (if applicable). Patients were randomized (1:1:1) upon completion of definitive surgery, and at least four cycles of chemotherapy to receive no additional treatment, or one year of Trastuzumab treatment or two years of Trastuzumab treatment. Patients undergoing a lumpectomy had also completed standard radiotherapy. Patients with ER+ and/or PgR+ disease received systemic adjuvant hormonal therapy at investigator discretion. Trastuzumab was administered with an initial dose of 8 mg/kg followed by subsequent doses of 6 mg/kg once every three weeks. The main outcome measure was disease-free survival (DFS), defined as in Studies 1 and 2. A protocol specified interim efficacy analysis comparing one-year Trastuzumab treatment to observation was performed at a median follow-up duration of 12.6 months in the Trastuzumab arm and formed the basis for the definitive DFS results from this study. Among the 3386 patients randomized to the observation (n =1693) and Trastuzumab one-year (n= 1693) treatment arms, the median age was 49 years (range 21–80), 83% were Caucasian, and 13% were Asian. Disease characteristics: 94% infiltrating ductal carcinoma, 50% ER+ and/or PgR+, 57% node positive, 32% node negative, and in 11% of patients, nodal status was not assessable due to prior neo-adjuvant chemotherapy. Ninety-six percent (1055/1098) of patients with node-negative disease had high risk features: among the 1098 patients with node-negative disease, 49% (543) were ER− and PgR−, and 47% (512) were ER and/or PgR + and had at least one of the following high risk features: pathological tumor size greater than 2 cm, Grade 2–3, or age < 35 years. Prior to randomization, 94% of patients had received anthracycline-based chemotherapy regimens. After the definitive DFS results comparing observation to one-year Trastuzumab treatment were disclosed, a prospectively planned analysis that included comparison of one year versus two years of Trastuzumab treatment at a median follow-up duration of 8 years was performed. Based on this analysis, extending Trastuzumab treatment for a duration of two years did not show additional benefit over treatment for one year . Study 4 In Study 4, breast tumor specimens were required to show HER2 gene amplification (FISH+ only) as determined at a central laboratory. Patients were required to have either node-positive disease, or node-negative disease with at least one of the following high-risk features: ER/PR-negative, tumor size > 2 cm, age 100 mmHg), any T4 or N2 or known N3 or M1 breast cancer were not eligible. Patients were randomized (1:1:1) to receive doxorubicin and cyclophosphamide followed by docetaxel (AC-T), doxorubicin and cyclophosphamide followed by docetaxel plus Trastuzumab (AC-TH), or docetaxel and carboplatin plus Trastuzumab (TCH). In both the AC-T and AC-TH arms, doxorubicin 60 mg/m2 and cyclophosphamide 600 mg/m2 were administered every 3 weeks for four cycles; docetaxel 100 mg/m 2 was administered every 3 weeks for four cycles. In the TCH arm, docetaxel 75 mg/m2 and carboplatin (at a target AUC of 6 mg/mL/min as a 30- to 60-minute infusion) were administered every 3 weeks for six cycles. Trastuzumab was administered weekly (initial dose of 4 mg/kg followed by weekly dose of 2 mg/kg) concurrently with either T or TC, and then every 3 weeks (6 mg/kg) as monotherapy for a total of 52 weeks. Radiation therapy, if administered, was initiated after completion of chemotherapy. Patients with ER+ and/or PR+ tumors received hormonal therapy. Disease-free survival (DFS) was the main outcome measure. Among the 3222 patients randomized, the median age was 49 (range 22 to 74 years; 6% ≥ 65 years). Disease characteristics included 54% ER+ and/or PR+ and 71% node positive. Prior to randomization, all patients underwent primary surgery for breast cancer. The results for DFS for the integrated analysis of Studies 1 and 2, Study 3, and Study 4 and OS results for the integrated analysis of Studies 1 and 2, and Study 3 are presented in Table 7. For Studies 1 and 2, the duration of DFS following a median follow-up of 2.0 years in the AC→TH arm, is presented in Figure 4, and the duration of OS after a median follow-up of 8.3 years in the AC→TH arm is presented in Figure 5. The duration of DFS for Study 4 is presented in Figure 6. Across all four studies, at the time of definitive DFS analysis, there were insufficient numbers of patients within each of the following subgroups to determine if the treatment effect was different from that of the overall patient population: patients with low tumor grade, patients within specific ethnic/racial subgroups (Black, Hispanic, Asian/Pacific Islander patients), and patients > 65 years of age. For Studies 1 and 2, the OS hazard ratio was 0.64 (95% CI: 0.55, 0.74). At 8.3 years of median follow up , the survival rate was estimated to be 86.9% in the AC→TH arm and 79.4% in the AC→T arm. The final OS analysis results from Studies 1 and 2 indicate that OS benefit by age, hormone receptor status, number of positive lymph nodes, tumor size and grade, and surgery/radiation therapy, was consistent with the treatment effect in the overall population. In patients ≤ 50 years of age (n=2197), the OS hazard ratio was 0.65 (95% CI: 0.52, 0.81) and in patients > 50 years of age (n=1866), the OS hazard ratio was 0.63 (95% CI: 0.51, 0.78). In the subgroup of patients with hormone receptor-positive disease (ER-positive and/or PR-positive) (n=2223), the hazard ratio for OS was 0.63 (95% CI: 0.51, 0.78). In the subgroup of patients with hormone receptor-negative disease (ER-negative and PR-negative) (n=1830), the hazard ratio for OS was 0.64 (95% CI: 0.52, 0.80). In the subgroup of patients with tumor size ≤2 cm (n=1604), the hazard ratio for OS was 0.52 (95% CI: 0.39, 0.71). In the subgroup of patients with tumor size >2 cm (n=2448), the hazard ratio for OS was 0.67 (95% CI: 0.56, 0.80). Figure 4 Duration of Disease-Free Survival in Patients with Adjuvant Treatment of Breast Cancer (Studies 1 and 2) Exploratory analyses of DFS as a function of HER2 overexpression or gene amplification were conducted for patients in Studies 2 and 3, where central laboratory testing data were available. The results are shown in Table 8. The number of events in Study 2 was small with the exception of the IHC 3+/FISH+ subgroup, which constituted 81% of those with data. Definitive conclusions cannot be drawn regarding efficacy within other subgroups due to the small number of events. The number of events in Study 3 was adequate to demonstrate significant effects on DFS in the IHC 3+/FISH unknown and the FISH +/IHC unknown subgroups. ## Metastatic Breast Cancer The safety and efficacy of Trastuzumab in treatment of women with metastatic breast cancer were studied in a randomized, controlled clinical trial in combination with chemotherapy (Study 5, n=469 patients) and an open-label single agent clinical trial (Study 6, n=222 patients). Both trials studied patients with metastatic breast cancer whose tumors overexpress the HER2 protein. Patients were eligible if they had 2 or 3 levels of overexpression (based on a 0 to 3 scale) by immunohistochemical assessment of tumor tissue performed by a central testing lab. Previously Untreated Metastatic Breast Cancer (Study 5) Study 5 was a multicenter, randomized, open-label clinical trial conducted in 469 women with metastatic breast cancer who had not been previously treated with chemotherapy for metastatic disease. Tumor specimens were tested by IHC (Clinical Trial Assay, CTA) and scored as 0, 1+, 2+, or 3+, with 3+ indicating the strongest positivity. Only patients with 2+ or 3+ positive tumors were eligible (about 33% of those screened). Patients were randomized to receive chemotherapy alone or in combination with Trastuzumab given intravenously as a 4 mg/kg loading dose followed by weekly doses of Trastuzumab at 2 mg/kg. For those who had received prior anthracycline therapy in the adjuvant setting, chemotherapy consisted of paclitaxel (175 mg/m2 over 3 hours every 21 days for at least six cycles); for all other patients, chemotherapy consisted of anthracycline plus cyclophosphamide (AC: doxorubicin 60 mg/m2 or epirubicin 75 mg/m2 plus 600 mg/m2 cyclophosphamide every 21 days for six cycles). Sixty-five percent of patients randomized to receive chemotherapy alone in this study received Trastuzumab at the time of disease progression as part of a separate extension study. Based upon the determination by an independent response evaluation committee the patients randomized to Trastuzumab and chemotherapy experienced a significantly longer median time to disease progression, a higher overall response rate (ORR), and a longer median duration of response, as compared with patients randomized to chemotherapy alone. Patients randomized to Trastuzumab and chemotherapy also had a longer median survival (see Table 9). These treatment effects were observed both in patients who received Trastuzumab plus paclitaxel and in those who received Trastuzumab plus AC; however the magnitude of the effects was greater in the paclitaxel subgroup. Data from Study 5 suggest that the beneficial treatment effects were largely limited to patients with the highest level of HER2 protein overexpression (3+) . Previously Treated Metastatic Breast Cancer (Study 6) Trastuzumab was studied as a single agent in a multicenter, open-label, single-arm clinical trial (Study 6) in patients with HER2 overexpressing metastatic breast cancer who had relapsed following one or two prior chemotherapy regimens for metastatic disease. Of 222 patients enrolled, 66% had received prior adjuvant chemotherapy, 68% had received two prior chemotherapy regimens for metastatic disease, and 25% had received prior myeloablative treatment with hematopoietic rescue. Patients were treated with a loading dose of 4 mg/kg IV followed by weekly doses of Trastuzumab at 2 mg/kg IV. The ORR (complete response+partial response), as determined by an independent Response Evaluation Committee, was 14%, with a 2% complete response rate and a 12% partial response rate. Complete responses were observed only in patients with disease limited to skin and lymph nodes. The overall response rate in patients whose tumors tested as CTA 3+ was 18% while in those that tested as CTA 2+, it was 6%. ## Metastatic Gastric Cancer The safety and efficacy of Trastuzumab in combination with cisplatin and a fluoropyrimidine (capecitabine or 5-fluorouracil) were studied in patients previously untreated for metastatic gastric or gastroesophageal junction adenocarcinoma (Study 7). In this open-label, multi-center trial, 594 patients were randomized 1:1 to Trastuzumab in combination with cisplatin and a fluoropyrimidine (FC+H) or chemotherapy alone (FC). Randomization was stratified by extent of disease (metastatic vs. locally advanced), primary site (gastric vs. gastroesophageal junction), tumor measurability (yes vs. no), ECOG performance status (0,1 vs. 2), and fluoropyrimidine (capecitabine vs. 5-fluorouracil). All patients were either HER2 gene amplified (FISH+) or HER2 overexpressing (IHC 3+). Patients were also required to have adequate cardiac function (e.g., LVEF > 50%). On the Trastuzumab-containing arm, Trastuzumab was administered as an IV infusion at an initial dose of 8 mg/kg followed by 6 mg/kg every 3 weeks until disease progression. On both study arms cisplatin was administered at a dose of 80 mg/m2 Day 1 every 3 weeks for 6 cycles as a 2 hour IV infusion. On both study arms capecitabine was administered at 1000 mg/m2 dose orally twice daily (total daily dose 2000 mg/m2) for 14 days of each 21 day cycle for 6 cycles. Alternatively continuous intravenous infusion (CIV) 5-fluorouracil was administered at a dose of 800 mg/m2/day from Day 1 through Day 5 every three weeks for 6 cycles. The median age of the study population was 60 years (range: 21-83); 76% were male; 53% were Asian, 38% Caucasian, 5% Hispanic, 5% other racial/ethnic groups; 91% had ECOG PS of 0 or 1; 82% had primary gastric cancer and 18% had primary gastroesophageal adenocarcinoma. Of these patients, 23% had undergone prior gastrectomy, 7% had received prior neoadjuvant and/or adjuvant therapy, and 2% had received prior radiotherapy. The main outcome measure of Study 7 was overall survival (OS), analyzed by the unstratified log-rank test. The final OS analysis based on 351 deaths was statistically significant (nominal significance level of 0.0193). An updated OS analysis was conducted at one year after the final analysis. The efficacy results of both the final and the updated analyses are summarized in Table 11 and Figure 7. An exploratory analysis of OS in patients based on HER2 gene amplification (FISH) and protein overexpression (IHC) testing is summarized in Table 12. # How Supplied Trastuzumab is supplied in a multi-use vial containing 440 mg trastuzumab as a lyophilized sterile powder, under vacuum. Each carton contains one vial Trastuzumab® and one vial (20 mL) of Bacteriostatic Water for Injection (BWFI), USP, containing 1.1% benzyl alcohol as a preservative. NDC 50242-134-68. ## Storage Vials of Trastuzumab are stable at 2–8°C (36–46°F) prior to reconstitution. Do not use beyond the expiration date stamped on the vial. A vial of Trastuzumab reconstituted with BWFI, as supplied, is stable for 28 days after reconstitution when stored refrigerated at 2–8°C (36–46°F). Discard any remaining multi-dose reconstituted solution after 28 days. A vial of Trastuzumab reconstituted with unpreserved SWFI (not supplied) should be used immediately and any unused portion discarded. Do Not Freeze Trastuzumab following reconstitution or dilution. The solution of Trastuzumab for infusion diluted in polyvinylchloride or polyethylene bags containing 0.9% Sodium Chloride Injection, USP, should be stored at 2–8°C (36–46°F) for no more than 24 hours prior to use. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information - Advise patients to contact a health care professional immediately for any of the following: new onset or worsening shortness of breath, cough, swelling of the ankles/legs, swelling of the face, palpitations, weight gain of more than 5 pounds in 24 hours, dizziness or loss of consciousness - Advise pregnant women and women of childbearing potential that Trastuzumab exposure can result in fetal harm - Advise women of childbearing potential to use effective contraceptive methods during treatment and for a minimum of six months following Trastuzumab - Advise nursing mothers treated with Trastuzumab to discontinue nursing or discontinue Trastuzumab, taking into account the importance of the drug to the mother - Encourage women who are exposed to Trastuzumab during pregnancy to enroll in MotHER the Trastuzumab Pregnancy Registry (1-800-690-6720) # Precautions with Alcohol Alcohol-Trastuzumab interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - Herceptin # Look-Alike Drug Names Trastuzumab - Kadcyla # Drug Shortage Status # Price	Trastuzumab Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Sheng Shi, M.D. [2]; Aparna Vuppala, M.B.B.S. [3] # Disclaimer WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here. # Black Box Warning # Overview Trastuzumab is a Monoclonal antibodies that is FDA approved for the treatment of Adjuvant Breast Cancer, Metastatic Breast Cancer, Metastatic Gastric Cancer. There is a Black Box Warning for this drug as shown here. Common adverse reactions include edema， peripheral edema，tachycardia, rash, weight decreased, abdominal pain，diarrhea，loss of appetite, nausea, stomatitis, vomiting, anemia, neutropenia, thrombocytopenia, infectious disease, breast cancer, arthralgia, backache, myalgia, asthenia, dizziness, headache, insomnia, renal impairment, cough, dyspnea, nasopharyngitis, pharyngitis, rhinitis, upper respiratory infection, fatigue, fever, inflammatory disease of mucous membrane, shivering. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) - Do not administer as an intravenous push or bolus. Do not mix Trastuzumab with other drugs. - Do not substitute Trastuzumab for or with ado-trastuzumab emtansine. - Dosing information - Administer according to one of the following doses and schedules for a total of 52 weeks of Trastuzumab therapy: - During and following paclitaxel, docetaxel, or docetaxel/carboplatin: - Initial dosage: 4 mg/kg as an intravenous infusion over 90 minutes then at 2 mg/kg as an intravenous infusion over 30 minutes weekly during chemotherapy for the first 12 weeks (paclitaxel or docetaxel) or 18 weeks (docetaxel/carboplatin). - One week following the last weekly dose of Trastuzumab, administer Trastuzumab at 6 mg/kg as an intravenous infusion over 30–90 minutes every three weeks. - As a single agent within three weeks following completion of multi-modality, anthracycline-based chemotherapy regimens: - Extending adjuvant treatment beyond one year is not recommended. - Dosing information - Initial dosage: 8 mg/kg as a 90 minute intravenous infusion - Subsequent dosage: 6 mg/kg as an intravenous infusion over 30-90 minutes every three weeks until disease progression ## Dose Modifications - Decrease the rate of infusion for mild or moderate infusion reactions - Interrupt the infusion in patients with dyspnea or clinically significant hypotension - Discontinue Trastuzumab for severe or life-threatening infusion reactions. - Assess left ventricular ejection fraction (LVEF) prior to initiation of Trastuzumab and at regular intervals during treatment. Withhold Trastuzumab dosing for at least 4 weeks for either of the following: - ≥ 16% absolute decrease in LVEF from pre-treatment values - LVEF below institutional limits of normal and ≥ 10% absolute decrease in LVEF from pretreatment values. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Trastuzumab in adult patients. ### Non–Guideline-Supported Use - Dosing information - ‘’‘(4 mg/kg) IV on day 1 of cycle 1, then 2 mg/kg IV on days 2, 9, and 16’‘[1] - Dosing information - individual doses ranged from 4 to 150 mg [2] - Dosing information - 4 mg/kg is administered IV on day 1, then 2 mg/kg IV weekly thereafter[3] # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) The safety and effectiveness of Trastuzumab in pediatric patients has not been established. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Trastuzumab in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Trastuzumab in pediatric patients. # Contraindications None. # Warnings There is limited information regarding Trastuzumab Warnings' in the drug label. # Adverse Reactions ## Clinical Trials Experience - The most common adverse reactions in patients receiving Trastuzumab in the adjuvant and metastatic breast cancer setting are fever, nausea, vomiting, infusion reactions, diarrhea, infections, increased cough, headache, fatigue, dyspnea, rash, neutropenia, anemia, and myalgia. Adverse reactions requiring interruption or discontinuation of Trastuzumab treatment include CHF, significant decline in left ventricular cardiac function, severe infusion reactions, and pulmonary toxicity. - In the metastatic gastric cancer setting, the most common adverse reactions (≥ 10%) that were increased (≥ 5% difference) in the Trastuzumab arm as compared to the chemotherapy alone arm were neutropenia, diarrhea, fatigue, anemia, stomatitis, weight loss, upper respiratory tract infections, fever, thrombocytopenia, mucosal inflammation, nasopharyngitis, and dysgeusia. The most common adverse reactions which resulted in discontinuation of treatment on the Trastuzumab-containing arm in the absence of disease progression were infection, diarrhea, and febrile neutropenia. - Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Adjuvant Breast Cancer Studies - The data below reflect exposure to one-year Trastuzumab therapy across three randomized, open-label studies, Studies 1, 2, and 3, with (n=3678) or without (n= 3363) trastuzumab in the adjuvant treatment of breast cancer. The data summarized in Table 3 below, from Study 3, reflect exposure to Trastuzumab in 1678 patients; the median treatment duration was 51 weeks and median number of infusions was 18. Among the 3386 patients enrolled in the observation and one-year Trastuzumab arms of Study 3 at a median duration of follow-up of 12.6 months in the Trastuzumab arm, the median age was 49 years (range: 21 to 80 years), 83% of patients were Caucasian, and 13% were Asian. In Study 3, a comparison of 3-weekly Trastuzumab treatment for two years versus one year was also performed. The rate of asymptomatic cardiac dysfunction was increased in the 2-year Trastuzumab treatment arm (8.1% versus 4.6% in the one-year Trastuzumab treatment arm). More patients experienced at least one adverse reaction of grade 3 or higher in the 2-year Trastuzumab treatment arm (20.4%) compared with the one-year Trastuzumab treatment arm (16.3%). The safety data from Studies 1 and 2 were obtained from 3655 patients, of whom 2000 received Trastuzumab; the median treatment duration was 51 weeks. The median age was 49 years (range: 24–80); 84% of patients were White, 7% Black, 4% Hispanic, and 3% Asian. In Study 1, only Grade 3–5 adverse events, treatment-related Grade 2 events, and Grade 2–5 dyspnea were collected during and for up to 3 months following protocol-specified treatment. The following non-cardiac adverse reactions of Grade 2–5 occurred at an incidence of at least 2% greater among patients receiving Trastuzumab plus chemotherapy as compared to chemotherapy alone: fatigue (29.5% vs. 22.4%), infection (24.0% vs. 12.8%), hot flashes (17.1% vs. 15.0%), anemia (12.3% vs. 6.7%), dyspnea (11.8% vs. 4.6%), rash/desquamation (10.9% vs. 7.6%), leukopenia (10.5% vs. 8.4%), neutropenia (6.4% vs. 4.3%), headache (6.2% vs. 3.8%), pain (5.5% vs. 3.0%), edema (4.7% vs. 2.7%) and insomnia (4.3% vs. 1.5%). The majority of these events were Grade 2 in severity. In Study 2, data collection was limited to the following investigator-attributed treatment-related adverse reactions: NCI-CTC Grade 4 and 5 hematologic toxicities, Grade 3–5 non-hematologic toxicities, selected Grade 2–5 toxicities associated with taxanes (myalgia, arthralgias, nail changes, motor neuropathy, sensory neuropathy) and Grade 1–5 cardiac toxicities occurring during chemotherapy and/or Trastuzumab treatment. The following non-cardiac adverse reactions of Grade 2–5 occurred at an incidence of at least 2% greater among patients receiving Trastuzumab plus chemotherapy as compared to chemotherapy alone: arthralgia (12.2% vs. 9.1%), nail changes (11.5% vs.6.8%), dyspnea (2.4% vs. 0.2%), and diarrhea (2.2% vs. 0%). The majority of these events were Grade 2 in severity. Safety data from Study 4 reflect exposure to Trastuzumab as part of an adjuvant treatment regimen from 2124 patients receiving at least one dose of study treatment [AC-TH: n = 1068; TCH: n = 1056]. The overall median treatment duration was 54 weeks in both the AC-TH and TCH arms. The median number of infusions was 26 in the AC-TH arm and 30 in the TCH arm, including weekly infusions during the chemotherapy phase and every three week dosing in the monotherapy period. Among these patients, the median age was 49 years (range 22 to 74 years). In Study 4, the toxicity profile was similar to that reported in Studies 1, 2, and 3 with the exception of a low incidence of CHF in the TCH arm. Metastatic Breast Cancer Studies The data below reflect exposure to Trastuzumab in one randomized, open-label study, Study 5, of chemotherapy with (n=235) or without (n=234) trastuzumab in patients with metastatic breast cancer, and one single-arm study (Study 6; n=222) in patients with metastatic breast cancer. Data in Table 4 are based on Studies 5 and 6. Among the 464 patients treated in Study 5, the median age was 52 years (range: 25–77 years). Eighty-nine percent were White, 5% Black, 1% Asian and 5% other racial/ethnic groups. All patients received 4 mg/kg initial dose of Trastuzumab followed by 2 mg/kg weekly. The percentages of patients who received Trastuzumab treatment for ≥ 6 months and ≥ 12 months were 58% and 9%, respectively. Among the 352 patients treated in single agent studies (213 patients from Study 6), the median age was 50 years (range 28–86 years), 86% were White, 3% were Black, 3% were Asian, and 8% in other racial/ethnic groups. Most of the patients received 4 mg/kg initial dose of Trastuzumab followed by 2 mg/kg weekly. The percentages of patients who received Trastuzumab treatment for ≥ 6 months and ≥ 12 months were 31% and 16%, respectively. Metastatic Gastric Cancer The data below are based on the exposure of 294 patients to Trastuzumab in combination with a fluoropyrimidine (capecitabine or 5-FU) and cisplatin (Study 7). In the Trastuzumab plus chemotherapy arm, the initial dose of Trastuzumab 8 mg/kg was administered on Day 1 (prior to chemotherapy) followed by 6 mg/kg every 21 days until disease progression. Cisplatin was administered at 80 mg/m2 on Day 1 and the fluoropyrimidine was administered as either capecitabine 1000 mg/m2 orally twice a day on Days 1-14 or 5-fluorouracil 800 mg/m2/day as a continuous intravenous infusion Days 1 through 5. Chemotherapy was administered for six 21-day cycles. Median duration of Trastuzumab treatment was 21 weeks; median number of Trastuzumab infusions administered was eight. The following subsections provide additional detail regarding adverse reactions observed in clinical trials of adjuvant breast, metastatic breast cancer, metastatic gastric cancer, or post-marketing experience. Cardiomyopathy Serial measurement of cardiac function (LVEF) was obtained in clinical trials in the adjuvant treatment of breast cancer. In Study 3, the median duration of follow-up was 12.6 months (12.4 months in the observation arm; 12.6 months in the 1-year Trastuzumab arm); and in Studies 1 and 2, 7.9 years in the AC-T arm, 8.3 years in the AC-TH arm. In Studies 1 and 2, 6% of all randomized patients with post-AC LVEF evaluation were not permitted to initiate Trastuzumab following completion of AC chemotherapy due to cardiac dysfunction (LVEF < LLN or ≥ 16 point decline in LVEF from baseline to end of AC). Following initiation of Trastuzumab therapy, the incidence of new-onset dose-limiting myocardial dysfunction was higher among patients receiving Trastuzumab and paclitaxel as compared to those receiving paclitaxel alone in Studies 1 and 2, and in patients receiving one-year Trastuzumab monotherapy compared to observation in Study 3 (see Table 6, Figures 1 and 2). The per-patient incidence of new-onset cardiac dysfunction, as measured by LVEF, remained similar when compared to the analysis performed at a median follow-up of 2.0 years in the AC-TH arm. This analysis also showed evidence of reversibility of left ventricular dysfunction, with 64.5% of patients who experienced symptomatic CHF in the AC-TH group being asymptomatic at latest follow-up, and 90.3% having full or partial LVEF recovery. Figure 1 Studies 1 and 2: Cumulative Incidence of Time to First LVEF Decline of ≥ 10 Percentage Points from Baseline and to Below 50% with Death as a Competing Risk Event Time 0 is initiation of paclitaxel or Trastuzumab + paclitaxel therapy. Figure 2 Study 3: Cumulative Incidence of Time to First LVEF Decline of ≥ 10 Percentage Points from Baseline and to Below 50% with Death as a Competing Risk Event Time 0 is the date of randomization. Figure 3 Study 4: Cumulative Incidence of Time to First LVEF Decline of ≥10 Percentage Points from Baseline and to Below 50% with Death as a Competing Risk Event Time 0 is the date of randomization. The incidence of treatment emergent congestive heart failure among patients in the metastatic breast cancer trials was classified for severity using the New York Heart Association classification system (I–IV, where IV is the most severe level of cardiac failure) (see Table 2). In the metastatic breast cancer trials the probability of cardiac dysfunction was highest in patients who received Trastuzumab concurrently with anthracyclines. In Study 7, 5.0% of patients in the Trastuzumab plus chemotherapy arm compared to 1.1% of patients in the chemotherapy alone arm had LVEF value below 50% with a ≥ 10% absolute decrease in LVEF from pretreatment values. Infusion Reactions During the first infusion with Trastuzumab, the symptoms most commonly reported were chills and fever, occurring in approximately 40% of patients in clinical trials. Symptoms were treated with acetaminophen, diphenhydramine, and meperidine (with or without reduction in the rate of Trastuzumab infusion); permanent discontinuation of Trastuzumab for infusional toxicity was required in < 1% of patients. Other signs and/or symptoms may include nausea, vomiting, pain (in some cases at tumor sites), rigors, headache, dizziness, dyspnea, hypotension, elevated blood pressure, rash, and asthenia. Infusional toxicity occurred in 21% and 35% of patients, and was severe in 1.4% and 9% of patients, on second or subsequent Trastuzumab infusions administered as monotherapy or in combination with chemotherapy, respectively. In the post-marketing setting, severe infusion reactions, including hypersensitivity, anaphylaxis, and angioedema have been reported. Anemia In randomized controlled clinical trials, the overall incidence of anemia (30% vs. 21% [Study 5]), of selected NCI-CTC Grade 2–5 anemia (12.3% vs. 6.7% [Study 1]), and of anemia requiring transfusions (0.1% vs. 0 patients [Study 2]) were increased in patients receiving Trastuzumab and chemotherapy compared with those receiving chemotherapy alone. Following the administration of Trastuzumab as a single agent (Study 6), the incidence of NCI-CTC Grade 3 anemia was < 1%. In Study 7 (metastatic gastric cancer) on the Trastuzumab containing arm as compared to the chemotherapy alone arm the overall incidence of anemia was 28% compared 21% and of NCI CTC Grade 3/4 anemia was 12.2% compared to 10.3%. Neutropenia In randomized controlled clinical trials in the adjuvant setting, the incidence of selected NCI-CTC Grade 4–5 neutropenia (1.7% vs. 0.8% [Study 2]) and of selected Grade 2–5 neutropenia (6.4% vs. 4.3% [Study 1]) were increased in patients receiving Trastuzumab and chemotherapy compared with those receiving chemotherapy alone. In a randomized, controlled trial in patients with metastatic breast cancer, the incidences of NCI-CTC Grade 3/4 neutropenia (32% vs. 22%) and of febrile neutropenia (23% vs. 17%) were also increased in patients randomized to Trastuzumab in combination with myelosuppressive chemotherapy as compared to chemotherapy alone. In Study 7 (metastatic gastric cancer) on the Trastuzumab containing arm as compared to the chemotherapy alone arm, the incidence of NCI CTC Grade 3/4 neutropenia was 36.8% compared to 28.9%; febrile neutropenia 5.1% compared to 2.8%. Infection The overall incidences of infection (46% vs. 30% [Study 5]), of selected NCI-CTC Grade 2–5 infection/febrile neutropenia (24.3% vs. 13.4% [Study 1]) and of selected Grade 3–5 infection/febrile neutropenia (2.9% vs. 1.4%) [Study 2]), were higher in patients receiving Trastuzumab and chemotherapy compared with those receiving chemotherapy alone. The most common site of infections in the adjuvant setting involved the upper respiratory tract, skin, and urinary tract. In Study 4, the overall incidence of infection was higher with the addition of Trastuzumab to AC-T but not to TCH [44% (AC-TH), 37% (TCH), 38% (AC-T)]. The incidences of NCI-CTC Grade 3-4 infection were similar [25% (AC-TH), 21% (TCH), 23% (AC-T)] across the three arms. In a randomized, controlled trial in treatment of metastatic breast cancer, the reported incidence of febrile neutropenia was higher (23% vs. 17%) in patients receiving Trastuzumab in combination with myelosuppressive chemotherapy as compared to chemotherapy alone. Pulmonary Toxicity Adjuvant Breast Cancer Among women receiving adjuvant therapy for breast cancer, the incidence of selected NCI-CTC Grade 2–5 pulmonary toxicity (14.3% vs. 5.4% [Study 1]) and of selected NCI-CTC Grade 3–5 pulmonary toxicity and spontaneous reported Grade 2 dyspnea (3.4% vs. 0.9% [Study 2]) was higher in patients receiving Trastuzumab and chemotherapy compared with chemotherapy alone. The most common pulmonary toxicity was dyspnea (NCI-CTC Grade 2–5: 11.8% vs. 4.6% [Study 1]; NCI-CTC Grade 2–5: 2.4% vs. 0.2% [Study 2]). Pneumonitis/pulmonary infiltrates occurred in 0.7% of patients receiving Trastuzumab compared with 0.3% of those receiving chemotherapy alone. Fatal respiratory failure occurred in 3 patients receiving Trastuzumab, one as a component of multi-organ system failure, as compared to 1 patient receiving chemotherapy alone. In Study 3, there were 4 cases of interstitial pneumonitis in the one-year Trastuzumab treatment arm compared to none in the observation arm at a median follow-up duration of 12.6 months. Metastatic Breast Cancer Among women receiving Trastuzumab for treatment of metastatic breast cancer, the incidence of pulmonary toxicity was also increased. Pulmonary adverse events have been reported in the post-marketing experience as part of the symptom complex of infusion reactions. Pulmonary events include bronchospasm, hypoxia, dyspnea, pulmonary infiltrates, pleural effusions, non-cardiogenic pulmonary edema, and acute respiratory distress syndrome. Thrombosis/Embolism In 4 randomized, controlled clinical trials, the incidence of thrombotic adverse events was higher in patients receiving Trastuzumab and chemotherapy compared to chemotherapy alone in three studies (2.6% vs. 1.5% [Study 1], 2.5% and 3.7% vs. 2.2% [Study 4] and 2.1% vs. 0% [Study 5]). Diarrhea Among women receiving adjuvant therapy for breast cancer, the incidence of NCI-CTC Grade 2–5 diarrhea (6.7% vs. 5.4% [Study 1]) and of NCI-CTC Grade 3–5 diarrhea (2.2% vs. 0% [Study 2]), and of Grade 1–4 diarrhea (7% vs. 1% [Study 3; one-year Trastuzumab treatment at 12.6 months median duration of follow-up]) were higher in patients receiving Trastuzumab as compared to controls. In Study 4, the incidence of Grade 3–4 diarrhea was higher [5.7% AC-TH, 5.5% TCH vs. 3.0% AC-T] and of Grade 1–4 was higher [51% AC-TH, 63% TCH vs. 43% AC-T] among women receiving Trastuzumab. Of patients receiving Trastuzumab as a single agent for the treatment of metastatic breast cancer, 25% experienced diarrhea. An increased incidence of diarrhea was observed in patients receiving Trastuzumab in combination with chemotherapy for treatment of metastatic breast cancer. Renal Toxicity In Study 7 (metastatic gastric cancer) on the Trastuzumab-containing arm as compared to the chemotherapy alone arm the incidence of renal impairment was 18% compared to 14.5%. Severe (Grade 3/4) renal failure was 2.7% on the Trastuzumab-containing arm compared to 1.7% on the chemotherapy only arm. Treatment discontinuation for renal insufficiency/failure was 2% on the Trastuzumab-containing arm and 0.3% on the chemotherapy only arm. In the postmarketing setting, rare cases of nephrotic syndrome with pathologic evidence of glomerulopathy have been reported. The time to onset ranged from 4 months to approximately 18 months from initiation of Trastuzumab therapy. Pathologic findings included membranous glomerulonephritis, focal glomerulosclerosis, and fibrillary glomerulonephritis. Complications included volume overload and congestive heart failure. ## Immunogenicity As with all therapeutic proteins, there is a potential for immunogenicity. Among 903 women with metastatic breast cancer, human anti-human antibody (HAHA) to Trastuzumab was detected in one patient using an enzyme-linked immunosorbent assay (ELISA). This patient did not experience an allergic reaction. Samples for assessment of HAHA were not collected in studies of adjuvant breast cancer. The incidence of antibody formation is highly dependent on the sensitivity and the specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to Trastuzumab with the incidence of antibodies to other products may be misleading. ## Postmarketing Experience The following adverse reactions have been identified during post approval use of Trastuzumab. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. - Infusion reaction - Oligohydramnios or oligohydramnios sequence, including pulmonary hypoplasia, skeletal abnormalities, and neonatal death - Glomerulopathy # Drug Interactions In Study 5, the mean serum trough concentration of trastuzumab was consistently elevated approximately 1.5–fold, when administered in combination with paclitaxel as compared to trough concentrations of trastuzumab when administered in combination with an anthracycline and cyclophosphamide. In other pharmacokinetic studies, where Trastuzumab was administered in combination with paclitaxel, docetaxel, carboplatin, or doxorubicin, Trastuzumab did not alter the plasma concentrations of these chemotherapeutic agents, or the metabolites that were analyzed. In a drug interaction substudy conducted in patients in Study 7, the pharmacokinetics of cisplatin, capecitabine and their metabolites were not altered when administered in combination with Trastuzumab. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): D Trastuzumab can cause fetal harm when administered to a pregnant woman. In post-marketing reports use of Trastuzumab during pregnancy resulted in cases of oligohydramnios and of oligohydramnios sequence, manifesting as pulmonary hypoplasia, skeletal abnormalities, and neonatal death. These case reports described oligohydramnios in pregnant women who received Trastuzumab either alone or in combination with chemotherapy. In some case reports, amniotic fluid index increased after Trastuzumab was stopped. In one case, Trastuzumab therapy resumed after the amniotic fluid index improved, and oligohydramnios recurred. Monitor women exposed to Trastuzumab during pregnancy for oligohydramnios. If oligohydramnios occurs, perform fetal testing that is appropriate for gestational age and consistent with community standards of care. The efficacy of IV hydration in management of oligohydramnios due to Trastuzumab exposure is not known. Advise women of the potential hazard to the fetus resulting from Trastuzumab exposure during pregnancy. Encourage pregnant women with breast cancer who are using Trastuzumab to enroll in MotHER the Trastuzumab Pregnancy Registry: phone 1 800 690 6720. No teratogenic effects were observed in offspring from reproduction studies in cynomolgus monkeys at doses up to 25 times the recommended weekly human dose of 2 mg/kg trastuzumab. In mutant mice lacking HER2, embryos died in early gestation. Trastuzumab exposure was reported at delivery in offspring of cynomolgus monkeys treated during the early (Days 20–50 of gestation) or late (Days 120–150 of gestation) fetal development periods, at levels of 15 to 28% of the maternal blood levels. Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Trastuzumab in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Trastuzumab during labor and delivery. ### Nursing Mothers It is not known whether Trastuzumab is excreted in human milk, but human IgG is excreted in human milk. Published data suggest that breast milk antibodies do not enter the neonatal and infant circulation in substantial amounts. Trastuzumab was present in the breast milk of lactating cynomolgus monkeys given 12.5 times the recommended weekly human dose of 2 mg/kg of Trastuzumab. Infant monkeys with detectable serum levels of trastuzumab did not have any adverse effects on growth or development from birth to 3 months of age; however, trastuzumab levels in animal breast milk may not accurately reflect human breast milk levels. Because many drugs are secreted in human milk and because of the potential for serious adverse reactions in nursing infants from Trastuzumab, a decision should be made whether to discontinue nursing, or discontinue drug, taking into account the elimination half-life of trastuzumab and the importance of the drug to the mother. ### Pediatric Use The safety and effectiveness of Trastuzumab in pediatric patients has not been established. ### Geriatic Use Trastuzumab has been administered to 386 patients who were 65 years of age or over (253 in the adjuvant treatment and 133 in metastatic breast cancer treatment settings). The risk of cardiac dysfunction was increased in geriatric patients as compared to younger patients in both those receiving treatment for metastatic disease in Studies 5 and 6, or adjuvant therapy in Studies 1 and 2. Limitations in data collection and differences in study design of the 4 studies of Trastuzumab in adjuvant treatment of breast cancer preclude a determination of whether the toxicity profile of Trastuzumab in older patients is different from younger patients. The reported clinical experience is not adequate to determine whether the efficacy improvements (ORR, TTP, OS, DFS) of Trastuzumab treatment in older patients is different from that observed in patients <65 years of age for metastatic disease and adjuvant treatment. In Study 7 (metastatic gastric cancer), of the 294 patients treated with Trastuzumab 108 (37%) were 65 years of age or older, while 13 (4.4%) were 75 and over. No overall differences in safety or effectiveness were observed. ### Gender There is no FDA guidance on the use of Trastuzumab with respect to specific gender populations. ### Race There is no FDA guidance on the use of Trastuzumab with respect to specific racial populations. ### Renal Impairment There is no FDA guidance on the use of Trastuzumab in patients with renal impairment. ### Hepatic Impairment There is no FDA guidance on the use of Trastuzumab in patients with hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Trastuzumab in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Trastuzumab in patients who are immunocompromised. # Administration and Monitoring ### Administration To prevent medication errors, it is important to check the vial labels to ensure that the drug being prepared and administered is Trastuzumab and not ado-trastuzumab emtansine. Reconstitution Reconstitute each 440 mg vial of Trastuzumab with 20 mL of Bacteriostatic Water for Injection (BWFI), USP, containing 1.1% benzyl alcohol as a preservative to yield a multi-dose solution containing 21 mg/mL trastuzumab. In patients with known hypersensitivity to benzyl alcohol, reconstitute with 20 mL of Sterile Water for Injection (SWFI) without preservative to yield a single use solution. Use appropriate aseptic technique when performing the following reconstitution steps: - Using a sterile syringe, slowly inject the 20 mL of diluent into the vial containing the lyophilized cake of Trastuzumab. The stream of diluent should be directed into the lyophilized cake. - Swirl the vial gently to aid reconstitution. DO NOT SHAKE. - Slight foaming of the product may be present upon reconstitution. Allow the vial to stand undisturbed for approximately 5 minutes. - Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Inspect visually for particulates and discoloration. The solution should be free of visible particulates, clear to slightly opalescent and colorless to pale yellow. - Store reconstituted Trastuzumab at 2–8° C; discard unused Trastuzumab after 28 days. If Trastuzumab is reconstituted with SWFI without preservative, use immediately and discard any unused portion. Dilution - Determine the dose (mg) of Trastuzumab. Calculate the volume of the 21 mg/mL reconstituted Trastuzumab solution needed, withdraw this amount from the vial and add it to an infusion bag containing 250 mL of 0.9% Sodium Chloride Injection, USP. DO NOT USE DEXTROSE (5%) SOLUTION. - Gently invert the bag to mix the solution. ### Monitoring FDA Package Insert for Trastuzumab contains no information regarding drug monitoring. # IV Compatibility There is limited information about the IV Compatibility. # Overdosage There is no experience with overdosage in human clinical trials. Single doses higher than 8 mg/kg have not been tested. # Pharmacology ## Mechanism of Action The HER2 (or c-erbB2) proto-oncogene encodes a transmembrane receptor protein of 185 kDa, which is structurally related to the epidermal growth factor receptor. Trastuzumab has been shown, in both in vitro assays and in animals, to inhibit the proliferation of human tumor cells that overexpress HER2. Trastuzumab is a mediator of antibody-dependent cellular cytotoxicity (ADCC). In vitro, Trastuzumab-mediated ADCC has been shown to be preferentially exerted on HER2 overexpressing cancer cells compared with cancer cells that do not overexpress HER2. ## Structure Trastuzumab is a humanized IgG1 kappa monoclonal antibody that selectively binds with high affinity to the extracellular domain of the human epidermal growth factor receptor 2 protein, HER2. Trastuzumab is produced by recombinant DNA technology in a mammalian cell (Chinese Hamster Ovary) culture containing the antibiotic gentamicin. Gentamicin is not detectable in the final product. Trastuzumab is a sterile, white to pale yellow, preservative-free lyophilized powder for intravenous administration. Each multi-use vial of Trastuzumab contains 440 mg trastuzumab, 400 mg α,α-trehalose dihydrate, 9.9 mg L-histidine HCl, 6.4 mg L-histidine, and 1.8 mg polysorbate 20, USP. Reconstitution with 20 mL of the appropriate diluent (BWFI or SWFI) yields a solution containing 21 mg/mL trastuzumab, at a pH of approximately 6. ## Pharmacodynamics FDA Package Insert for Trastuzumab contains no information regarding Pharmacokinetics. ## Pharmacokinetics The pharmacokinetics of trastuzumab were studied in women with metastatic breast cancer. Short duration intravenous infusions of 10 to 500 mg Trastuzumab once weekly demonstrated dose-dependent pharmacokinetics. Mean half-life increased and clearance decreased with increasing dose level. The half-life averaged 2 and 12 days at the 10 and 500 mg dose levels, respectively. The volume of distribution of trastuzumab was approximately that of serum volume (44 mL/kg). At the highest weekly dose studied (500 mg), mean peak serum concentrations were 377 mcg/mL. In studies using an initial dose of 4 mg/kg followed by a weekly dose of 2 mg/kg, a mean half-life of 6 days (range 1–32 days) was observed. Between weeks 16 and 32, trastuzumab serum concentrations reached a steady state with mean trough and peak concentrations of approximately 79 mcg/mL and 123 mcg/mL, respectively. In a study of women receiving adjuvant therapy for breast cancer, a mean half-life of trastuzumab of 16 days (range: 11–23 days) was observed after an initial dose of 8 mg/kg followed by a dose of 6 mg/kg every three weeks. Between weeks 6 and 37, trastuzumab serum concentrations reached a steady-state with mean trough and peak concentrations of 63 mcg/mL and 216 mcg/mL, respectively. In patients with metastatic gastric cancer (Study 7), mean serum trastuzumab trough concentrations at steady state were 24 to 63% lower as compared to the concentrations observed in patients with breast cancer receiving treatment for metastatic disease in combination with paclitaxel, as monotherapy for metastatic disease, or as adjuvant monotherapy. Sixty-four percent (286/447) of women with metastatic breast cancer had detectable circulating extracellular domain of the HER2 receptor (shed antigen), which ranged as high as 1880 ng/mL (median 11 ng/mL). Patients with higher baseline shed antigen levels were more likely to have lower serum trough concentrations. Data suggest that the disposition of trastuzumab is not altered based on age or serum creatinine (≤2.0 mg creatinine/dL). ## Nonclinical Toxicology ## Carcinogenesis, Mutagenesis, Impairment of Fertility Trastuzumab has not been tested for carcinogenic potential. No evidence of mutagenic activity was observed when trastuzumab was tested in the standard Ames bacterial and human peripheral blood lymphocyte mutagenicity assays, at concentrations of up to 5000 mcg/mL. In an in vivo micronucleus assay, no evidence of chromosomal damage to mouse bone marrow cells was observed following bolus intravenous doses of up to 118 mg/kg Trastuzumab. A fertility study conducted in female cynomolgus monkeys at doses up to 25 times the weekly recommended human dose of 2 mg/kg trastuzumab and has revealed no evidence of impaired fertility, as measured by menstrual cycle duration and female sex hormone levels. Studies to evaluate the effects of trastuzumab on male fertility have not been conducted. ## Animal Toxicology and/or Pharmacology Reproductive Toxicology Studies Reproductive toxicology studies have been conducted in cynomolgus monkeys at doses up to 25 times the weekly recommended human dose of 2 mg/kg Trastuzumab and have revealed no evidence of impaired fertility or harm to the fetus. However, HER2 protein expression is high in many embryonic tissues including cardiac and neural tissues; in mutant mice lacking HER2, embryos died in early gestation. Placental transfer of trastuzumab was detected at Caesarean section in offspring from pregnant cynomolgus monkeys dosed during the early (Days 20–50 of gestation) or late (Days 120–150 of gestation) fetal development periods. # Clinical Studies ## Adjuvant Breast Cancer The safety and efficacy of Trastuzumab in women receiving adjuvant chemotherapy for HER2 overexpressing breast cancer, were evaluated in an integrated analysis of two randomized, open-label, clinical trials (Studies 1 and 2) with a total of 4063 women at the protocol-specified final overall survival analysis, a third randomized, open-label, clinical trial (Study 3) with a total of 3386 women at definitive Disease Free Survival analysis for one-year Trastuzumab treatment versus observation, and a fourth randomized, open-label clinical trial with a total of 3222 patients (Study 4). Studies 1 and 2 In Studies 1 and 2, breast tumor specimens were required to show HER2 overexpression (3+ by IHC) or gene amplification (by FISH). HER2 testing was verified by a central laboratory prior to randomization (Study 2) or was required to be performed at a reference laboratory (Study 1). Patients with a history of active cardiac disease based on symptoms, abnormal electrocardiographic, radiologic, or left ventricular ejection fraction findings or uncontrolled hypertension (diastolic > 100 mmHg or systolic > 200 mmHg) were not eligible. Patients were randomized (1:1) to receive doxorubicin and cyclophosphamide followed by paclitaxel (AC→paclitaxel) alone or paclitaxel plus Trastuzumab (AC→paclitaxel + Trastuzumab). In both trials, patients received four 21-day cycles of doxorubicin 60 mg/m2 and cyclophosphamide 600 mg/m2. Paclitaxel was administered either weekly (80 mg/m2) or every 3 weeks (175 mg/m2) for a total of 12 weeks in Study 1; paclitaxel was administered only by the weekly schedule in Study 2. Trastuzumab was administered at 4 mg/kg on the day of initiation of paclitaxel and then at a dose of 2 mg/kg weekly for a total of 52 weeks. Trastuzumab treatment was permanently discontinued in patients who developed congestive heart failure, or persistent/recurrent LVEF decline. Radiation therapy, if administered, was initiated after the completion of chemotherapy. Patients with ER+ and/or PR+ tumors received hormonal therapy. The primary endpoint of the combined efficacy analysis was Disease-free survival (DFS), defined as the time from randomization to recurrence, occurrence of contralateral breast cancer, other second primary cancer, or death. The secondary endpoint was overall survival (OS). A total of 3752 patients were included in the joint efficacy analysis of the primary endpoint of DFS following a median follow-up of 2.0 years in the AC→paclitaxel + Trastuzumab arm. The pre-planned final OS analysis from the joint analysis included 4063 patients and was performed when 707 deaths had occurred after a median follow-up of 8.3 years in the AC→paclitaxel + Trastuzumab arm. The data from both arms in Study 1 and two of the three study arms in Study 2 were pooled for efficacy analyses. The patients included in the primary DFS analysis had a median age of 49 years (range, 22–80 years; 6% > 65 years), 84% were white, 7% black, 4% Hispanic, and 4% Asian/Pacific Islander. Disease characteristics included 90% infiltrating ductal histology, 38% T1, 91% nodal involvement, 27% intermediate and 66% high grade pathology, and 53% ER+ and/or PR+ tumors. Similar demographic and baseline characteristics were reported for the efficacy evaluable population, after 8.3 years of median follow-up in the AC→paclitaxel + Trastuzumab arm. Study 3 In Study 3, breast tumor specimens were required to show HER2 overexpression (3+ by IHC) or gene amplification (by FISH) as determined at a central laboratory. Patients with node-negative disease were required to have ≥ T1c primary tumor. Patients with a history of congestive heart failure or LVEF <55%, uncontrolled arrhythmias, angina requiring medication, clinically significant valvular heart disease, evidence of transmural infarction on ECG, poorly controlled hypertension (systolic > 180 mm Hg or diastolic > 100 mm Hg) were not eligible. Study 3 was designed to compare one and two years of three-weekly Trastuzumab treatment versus observation in patients with HER2 positive EBC following surgery, established chemotherapy and radiotherapy (if applicable). Patients were randomized (1:1:1) upon completion of definitive surgery, and at least four cycles of chemotherapy to receive no additional treatment, or one year of Trastuzumab treatment or two years of Trastuzumab treatment. Patients undergoing a lumpectomy had also completed standard radiotherapy. Patients with ER+ and/or PgR+ disease received systemic adjuvant hormonal therapy at investigator discretion. Trastuzumab was administered with an initial dose of 8 mg/kg followed by subsequent doses of 6 mg/kg once every three weeks. The main outcome measure was disease-free survival (DFS), defined as in Studies 1 and 2. A protocol specified interim efficacy analysis comparing one-year Trastuzumab treatment to observation was performed at a median follow-up duration of 12.6 months in the Trastuzumab arm and formed the basis for the definitive DFS results from this study. Among the 3386 patients randomized to the observation (n =1693) and Trastuzumab one-year (n= 1693) treatment arms, the median age was 49 years (range 21–80), 83% were Caucasian, and 13% were Asian. Disease characteristics: 94% infiltrating ductal carcinoma, 50% ER+ and/or PgR+, 57% node positive, 32% node negative, and in 11% of patients, nodal status was not assessable due to prior neo-adjuvant chemotherapy. Ninety-six percent (1055/1098) of patients with node-negative disease had high risk features: among the 1098 patients with node-negative disease, 49% (543) were ER− and PgR−, and 47% (512) were ER and/or PgR + and had at least one of the following high risk features: pathological tumor size greater than 2 cm, Grade 2–3, or age < 35 years. Prior to randomization, 94% of patients had received anthracycline-based chemotherapy regimens. After the definitive DFS results comparing observation to one-year Trastuzumab treatment were disclosed, a prospectively planned analysis that included comparison of one year versus two years of Trastuzumab treatment at a median follow-up duration of 8 years was performed. Based on this analysis, extending Trastuzumab treatment for a duration of two years did not show additional benefit over treatment for one year [Hazard Ratios of two-years Trastuzumab versus one-year Trastuzumab treatment in the intent to treat (ITT) population for Disease Free Survival (DFS) = 0.99 (95% CI: 0.87, 1.13), p-value = 0.90 and Overall Survival (OS) = 0.98 (0.83, 1.15); p-value= 0.78]. Study 4 In Study 4, breast tumor specimens were required to show HER2 gene amplification (FISH+ only) as determined at a central laboratory. Patients were required to have either node-positive disease, or node-negative disease with at least one of the following high-risk features: ER/PR-negative, tumor size > 2 cm, age < 35 years, or histologic and/or nuclear Grade 2 or 3. Patients with a history of CHF, myocardial infarction, Grade 3 or 4 cardiac arrhythmia, angina requiring medication, clinically significant valvular heart disease, poorly controlled hypertension (diastolic > 100 mmHg), any T4 or N2 or known N3 or M1 breast cancer were not eligible. Patients were randomized (1:1:1) to receive doxorubicin and cyclophosphamide followed by docetaxel (AC-T), doxorubicin and cyclophosphamide followed by docetaxel plus Trastuzumab (AC-TH), or docetaxel and carboplatin plus Trastuzumab (TCH). In both the AC-T and AC-TH arms, doxorubicin 60 mg/m2 and cyclophosphamide 600 mg/m2 were administered every 3 weeks for four cycles; docetaxel 100 mg/m 2 was administered every 3 weeks for four cycles. In the TCH arm, docetaxel 75 mg/m2 and carboplatin (at a target AUC of 6 mg/mL/min as a 30- to 60-minute infusion) were administered every 3 weeks for six cycles. Trastuzumab was administered weekly (initial dose of 4 mg/kg followed by weekly dose of 2 mg/kg) concurrently with either T or TC, and then every 3 weeks (6 mg/kg) as monotherapy for a total of 52 weeks. Radiation therapy, if administered, was initiated after completion of chemotherapy. Patients with ER+ and/or PR+ tumors received hormonal therapy. Disease-free survival (DFS) was the main outcome measure. Among the 3222 patients randomized, the median age was 49 (range 22 to 74 years; 6% ≥ 65 years). Disease characteristics included 54% ER+ and/or PR+ and 71% node positive. Prior to randomization, all patients underwent primary surgery for breast cancer. The results for DFS for the integrated analysis of Studies 1 and 2, Study 3, and Study 4 and OS results for the integrated analysis of Studies 1 and 2, and Study 3 are presented in Table 7. For Studies 1 and 2, the duration of DFS following a median follow-up of 2.0 years in the AC→TH arm, is presented in Figure 4, and the duration of OS after a median follow-up of 8.3 years in the AC→TH arm is presented in Figure 5. The duration of DFS for Study 4 is presented in Figure 6. Across all four studies, at the time of definitive DFS analysis, there were insufficient numbers of patients within each of the following subgroups to determine if the treatment effect was different from that of the overall patient population: patients with low tumor grade, patients within specific ethnic/racial subgroups (Black, Hispanic, Asian/Pacific Islander patients), and patients > 65 years of age. For Studies 1 and 2, the OS hazard ratio was 0.64 (95% CI: 0.55, 0.74). At 8.3 years of median follow up [AC→TH], the survival rate was estimated to be 86.9% in the AC→TH arm and 79.4% in the AC→T arm. The final OS analysis results from Studies 1 and 2 indicate that OS benefit by age, hormone receptor status, number of positive lymph nodes, tumor size and grade, and surgery/radiation therapy, was consistent with the treatment effect in the overall population. In patients ≤ 50 years of age (n=2197), the OS hazard ratio was 0.65 (95% CI: 0.52, 0.81) and in patients > 50 years of age (n=1866), the OS hazard ratio was 0.63 (95% CI: 0.51, 0.78). In the subgroup of patients with hormone receptor-positive disease (ER-positive and/or PR-positive) (n=2223), the hazard ratio for OS was 0.63 (95% CI: 0.51, 0.78). In the subgroup of patients with hormone receptor-negative disease (ER-negative and PR-negative) (n=1830), the hazard ratio for OS was 0.64 (95% CI: 0.52, 0.80). In the subgroup of patients with tumor size ≤2 cm (n=1604), the hazard ratio for OS was 0.52 (95% CI: 0.39, 0.71). In the subgroup of patients with tumor size >2 cm (n=2448), the hazard ratio for OS was 0.67 (95% CI: 0.56, 0.80). Figure 4 Duration of Disease-Free Survival in Patients with Adjuvant Treatment of Breast Cancer (Studies 1 and 2) Exploratory analyses of DFS as a function of HER2 overexpression or gene amplification were conducted for patients in Studies 2 and 3, where central laboratory testing data were available. The results are shown in Table 8. The number of events in Study 2 was small with the exception of the IHC 3+/FISH+ subgroup, which constituted 81% of those with data. Definitive conclusions cannot be drawn regarding efficacy within other subgroups due to the small number of events. The number of events in Study 3 was adequate to demonstrate significant effects on DFS in the IHC 3+/FISH unknown and the FISH +/IHC unknown subgroups. ## Metastatic Breast Cancer The safety and efficacy of Trastuzumab in treatment of women with metastatic breast cancer were studied in a randomized, controlled clinical trial in combination with chemotherapy (Study 5, n=469 patients) and an open-label single agent clinical trial (Study 6, n=222 patients). Both trials studied patients with metastatic breast cancer whose tumors overexpress the HER2 protein. Patients were eligible if they had 2 or 3 levels of overexpression (based on a 0 to 3 scale) by immunohistochemical assessment of tumor tissue performed by a central testing lab. Previously Untreated Metastatic Breast Cancer (Study 5) Study 5 was a multicenter, randomized, open-label clinical trial conducted in 469 women with metastatic breast cancer who had not been previously treated with chemotherapy for metastatic disease. Tumor specimens were tested by IHC (Clinical Trial Assay, CTA) and scored as 0, 1+, 2+, or 3+, with 3+ indicating the strongest positivity. Only patients with 2+ or 3+ positive tumors were eligible (about 33% of those screened). Patients were randomized to receive chemotherapy alone or in combination with Trastuzumab given intravenously as a 4 mg/kg loading dose followed by weekly doses of Trastuzumab at 2 mg/kg. For those who had received prior anthracycline therapy in the adjuvant setting, chemotherapy consisted of paclitaxel (175 mg/m2 over 3 hours every 21 days for at least six cycles); for all other patients, chemotherapy consisted of anthracycline plus cyclophosphamide (AC: doxorubicin 60 mg/m2 or epirubicin 75 mg/m2 plus 600 mg/m2 cyclophosphamide every 21 days for six cycles). Sixty-five percent of patients randomized to receive chemotherapy alone in this study received Trastuzumab at the time of disease progression as part of a separate extension study. Based upon the determination by an independent response evaluation committee the patients randomized to Trastuzumab and chemotherapy experienced a significantly longer median time to disease progression, a higher overall response rate (ORR), and a longer median duration of response, as compared with patients randomized to chemotherapy alone. Patients randomized to Trastuzumab and chemotherapy also had a longer median survival (see Table 9). These treatment effects were observed both in patients who received Trastuzumab plus paclitaxel and in those who received Trastuzumab plus AC; however the magnitude of the effects was greater in the paclitaxel subgroup. Data from Study 5 suggest that the beneficial treatment effects were largely limited to patients with the highest level of HER2 protein overexpression (3+) . Previously Treated Metastatic Breast Cancer (Study 6) Trastuzumab was studied as a single agent in a multicenter, open-label, single-arm clinical trial (Study 6) in patients with HER2 overexpressing metastatic breast cancer who had relapsed following one or two prior chemotherapy regimens for metastatic disease. Of 222 patients enrolled, 66% had received prior adjuvant chemotherapy, 68% had received two prior chemotherapy regimens for metastatic disease, and 25% had received prior myeloablative treatment with hematopoietic rescue. Patients were treated with a loading dose of 4 mg/kg IV followed by weekly doses of Trastuzumab at 2 mg/kg IV. The ORR (complete response+partial response), as determined by an independent Response Evaluation Committee, was 14%, with a 2% complete response rate and a 12% partial response rate. Complete responses were observed only in patients with disease limited to skin and lymph nodes. The overall response rate in patients whose tumors tested as CTA 3+ was 18% while in those that tested as CTA 2+, it was 6%. ## Metastatic Gastric Cancer The safety and efficacy of Trastuzumab in combination with cisplatin and a fluoropyrimidine (capecitabine or 5-fluorouracil) were studied in patients previously untreated for metastatic gastric or gastroesophageal junction adenocarcinoma (Study 7). In this open-label, multi-center trial, 594 patients were randomized 1:1 to Trastuzumab in combination with cisplatin and a fluoropyrimidine (FC+H) or chemotherapy alone (FC). Randomization was stratified by extent of disease (metastatic vs. locally advanced), primary site (gastric vs. gastroesophageal junction), tumor measurability (yes vs. no), ECOG performance status (0,1 vs. 2), and fluoropyrimidine (capecitabine vs. 5-fluorouracil). All patients were either HER2 gene amplified (FISH+) or HER2 overexpressing (IHC 3+). Patients were also required to have adequate cardiac function (e.g., LVEF > 50%). On the Trastuzumab-containing arm, Trastuzumab was administered as an IV infusion at an initial dose of 8 mg/kg followed by 6 mg/kg every 3 weeks until disease progression. On both study arms cisplatin was administered at a dose of 80 mg/m2 Day 1 every 3 weeks for 6 cycles as a 2 hour IV infusion. On both study arms capecitabine was administered at 1000 mg/m2 dose orally twice daily (total daily dose 2000 mg/m2) for 14 days of each 21 day cycle for 6 cycles. Alternatively continuous intravenous infusion (CIV) 5-fluorouracil was administered at a dose of 800 mg/m2/day from Day 1 through Day 5 every three weeks for 6 cycles. The median age of the study population was 60 years (range: 21-83); 76% were male; 53% were Asian, 38% Caucasian, 5% Hispanic, 5% other racial/ethnic groups; 91% had ECOG PS of 0 or 1; 82% had primary gastric cancer and 18% had primary gastroesophageal adenocarcinoma. Of these patients, 23% had undergone prior gastrectomy, 7% had received prior neoadjuvant and/or adjuvant therapy, and 2% had received prior radiotherapy. The main outcome measure of Study 7 was overall survival (OS), analyzed by the unstratified log-rank test. The final OS analysis based on 351 deaths was statistically significant (nominal significance level of 0.0193). An updated OS analysis was conducted at one year after the final analysis. The efficacy results of both the final and the updated analyses are summarized in Table 11 and Figure 7. An exploratory analysis of OS in patients based on HER2 gene amplification (FISH) and protein overexpression (IHC) testing is summarized in Table 12. # How Supplied Trastuzumab is supplied in a multi-use vial containing 440 mg trastuzumab as a lyophilized sterile powder, under vacuum. Each carton contains one vial Trastuzumab® and one vial (20 mL) of Bacteriostatic Water for Injection (BWFI), USP, containing 1.1% benzyl alcohol as a preservative. NDC 50242-134-68. ## Storage Vials of Trastuzumab are stable at 2–8°C (36–46°F) prior to reconstitution. Do not use beyond the expiration date stamped on the vial. A vial of Trastuzumab reconstituted with BWFI, as supplied, is stable for 28 days after reconstitution when stored refrigerated at 2–8°C (36–46°F). Discard any remaining multi-dose reconstituted solution after 28 days. A vial of Trastuzumab reconstituted with unpreserved SWFI (not supplied) should be used immediately and any unused portion discarded. Do Not Freeze Trastuzumab following reconstitution or dilution. The solution of Trastuzumab for infusion diluted in polyvinylchloride or polyethylene bags containing 0.9% Sodium Chloride Injection, USP, should be stored at 2–8°C (36–46°F) for no more than 24 hours prior to use. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information - Advise patients to contact a health care professional immediately for any of the following: new onset or worsening shortness of breath, cough, swelling of the ankles/legs, swelling of the face, palpitations, weight gain of more than 5 pounds in 24 hours, dizziness or loss of consciousness - Advise pregnant women and women of childbearing potential that Trastuzumab exposure can result in fetal harm - Advise women of childbearing potential to use effective contraceptive methods during treatment and for a minimum of six months following Trastuzumab - Advise nursing mothers treated with Trastuzumab to discontinue nursing or discontinue Trastuzumab, taking into account the importance of the drug to the mother - Encourage women who are exposed to Trastuzumab during pregnancy to enroll in MotHER the Trastuzumab Pregnancy Registry (1-800-690-6720) # Precautions with Alcohol Alcohol-Trastuzumab interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - Herceptin # Look-Alike Drug Names Trastuzumab - Kadcyla[4] # Drug Shortage Status # Price	https://www.wikidoc.org/index.php/Herceptin
01e5164a709c4cf5bfe3e907cb53f7cc83bba721	wikidoc	Heterocysts	Heterocysts Heterocysts are specialized nitrogen-fixing cells formed by some filamentous cyanobacteria, such as Nostoc punctiforme, Cylindrospermum stagnale and Anabaena sperica, during nitrogen starvation. They fix nitrogen from dinitrogen (N2) in the air using the enzyme nitrogenase, in order to provide the cells in the filament with nitrogen for biosynthesis. Nitrogenase is inactivated by oxygen, so the heterocyst must create a microanaerobic environment. The heterocysts' unique structure and physiology requires a global change in gene expression. For example, heterocysts: - produce three additional cell walls, including one of glycolipid that forms a hydrophobic barrier to oxygen - produce nitrogenase and other proteins involved in nitrogen fixation - degrade photosystem II, which produces oxygen - up-regulate glycolytic enzymes - produce proteins that scavenge any remaining oxygen Cyanobacteria usually obtain a fixed carbon (carbohydrate) by photosynthesis. The lack of photosystem II prevents heterocysts from photosynthesising, so the vegetative cells provide them with carbohydrates, which is thought to be sucrose. The fixed carbon and nitrogen sources are exchanged though channels between the cells in the filament. Heterocysts maintain photosystem I, allowing them to generate ATP by cyclic photophosphorylation. Single heterocysts develop about every 9-15 cells, producing a one-dimensional pattern along the filament. The interval between heterocysts remains approximately constant even though the cells in the filament are dividing. The bacterial filament can be seen as a multicellular organism with two distinct yet interdependent cell types. Such behaviour is highly unusual in prokaryotes and may have been the first example of multicellular patterning in evolution. Once a heterocyst has formed, it cannot revert to a vegetative cell, so this differentiation can be seen as a form of apoptosis. Certain heterocyst-forming bacteria can differentiate into spore-like cells called akinetes or motile cells called hormogonia, making them the most phenotyptically versatile of all prokaryotes. The mechanism of controlling heterocysts is thought to involve the diffusion of an inhibitor of differentiation called patS. Heterocyst formation is inhibited in the presence of a fixed nitrogen source, such as ammonium or nitrate. Heterocyst maintenance is dependent on an enzyme called hetN. The bacteria may also enter a symbiotic relationship with certain plants. In such a relationship, the bacteria do not respond to the availability of nitrogen, but to signals produced by the plant. Up to 60% of the cells can become heterocysts, providing fixed nitrogen to the plant in return for fixed carbon. The cyanobacteria that form heterocysts are divided into the orders Nostocales and Stigonematales, which form simple and branching filaments respectively. Together they form a monophyletic group, with very low genetic variability. cs:Heterocyt de:Heterozyste sv:Heterocyst uk:Гетероцисти	Heterocysts Heterocysts are specialized nitrogen-fixing cells formed by some filamentous cyanobacteria, such as Nostoc punctiforme, Cylindrospermum stagnale and Anabaena sperica, during nitrogen starvation. They fix nitrogen from dinitrogen (N2) in the air using the enzyme nitrogenase, in order to provide the cells in the filament with nitrogen for biosynthesis. Nitrogenase is inactivated by oxygen, so the heterocyst must create a microanaerobic environment. The heterocysts' unique structure and physiology requires a global change in gene expression. For example, heterocysts: - produce three additional cell walls, including one of glycolipid that forms a hydrophobic barrier to oxygen - produce nitrogenase and other proteins involved in nitrogen fixation - degrade photosystem II, which produces oxygen - up-regulate glycolytic enzymes - produce proteins that scavenge any remaining oxygen Cyanobacteria usually obtain a fixed carbon (carbohydrate) by photosynthesis. The lack of photosystem II prevents heterocysts from photosynthesising, so the vegetative cells provide them with carbohydrates, which is thought to be sucrose. The fixed carbon and nitrogen sources are exchanged though channels between the cells in the filament. Heterocysts maintain photosystem I, allowing them to generate ATP by cyclic photophosphorylation. Single heterocysts develop about every 9-15 cells, producing a one-dimensional pattern along the filament. The interval between heterocysts remains approximately constant even though the cells in the filament are dividing. The bacterial filament can be seen as a multicellular organism with two distinct yet interdependent cell types. Such behaviour is highly unusual in prokaryotes and may have been the first example of multicellular patterning in evolution. Once a heterocyst has formed, it cannot revert to a vegetative cell, so this differentiation can be seen as a form of apoptosis. Certain heterocyst-forming bacteria can differentiate into spore-like cells called akinetes or motile cells called hormogonia, making them the most phenotyptically versatile of all prokaryotes. The mechanism of controlling heterocysts is thought to involve the diffusion of an inhibitor of differentiation called patS. Heterocyst formation is inhibited in the presence of a fixed nitrogen source, such as ammonium or nitrate. Heterocyst maintenance is dependent on an enzyme called hetN. The bacteria may also enter a symbiotic relationship with certain plants. In such a relationship, the bacteria do not respond to the availability of nitrogen, but to signals produced by the plant. Up to 60% of the cells can become heterocysts, providing fixed nitrogen to the plant in return for fixed carbon. The cyanobacteria that form heterocysts are divided into the orders Nostocales and Stigonematales, which form simple and branching filaments respectively. Together they form a monophyletic group, with very low genetic variability. cs:Heterocyt de:Heterozyste sv:Heterocyst uk:Гетероцисти Template:WH Template:WS	https://www.wikidoc.org/index.php/Heterocysts
09e5734166c192fcdeba1004a3294f4d2674467a	wikidoc	Heterolysis	Heterolysis # Overview In chemistry, heterolysis or heterolytic fission (from Greek ἑτερος, heteros, "different," and λυσις, lusis, "loosening") is chemical bond cleavage of a neutral molecule generating a cation and an anion. In this process the two electrons that make up the bond are assigned to the same fragment. The energy involved in this process is called heterolytic bond dissociation energy. Bond cleavage is also possible by a process called homolysis. In heterolysis additional energy is required to separate the ion pair. An ionising solvent helps reduce this energy. In biology, heterolysis refers to necrosis induced by hydrolytic enzymes from surrounding (usually inflammatory) cells. Autolysis is necrosis of a cell by its own enzymes.	Heterolysis # Overview In chemistry, heterolysis or heterolytic fission (from Greek ἑτερος, heteros, "different," and λυσις, lusis, "loosening") is chemical bond cleavage of a neutral molecule generating a cation and an anion.[1] In this process the two electrons that make up the bond are assigned to the same fragment. The energy involved in this process is called heterolytic bond dissociation energy. Bond cleavage is also possible by a process called homolysis. In heterolysis additional energy is required to separate the ion pair. An ionising solvent helps reduce this energy. In biology, heterolysis refers to necrosis induced by hydrolytic enzymes from surrounding (usually inflammatory) cells. Autolysis is necrosis of a cell by its own enzymes.	https://www.wikidoc.org/index.php/Heterolysis
f831c956310a221960dba42b858ff73240d0c496	wikidoc	Hippocalcin	Hippocalcin Hippocalcin is a protein that in humans is encoded by the HPCA gene. Hippocalcin is a calcium-binding protein that belongs to the neuronal calcium sensor (NCS) family of proteins. It is expressed in mammalian brains especially in the hippocampus. It possesses a Ca2+/myristoyl switch. # Processes Hippocalcin takes part in the following processes: - Activation of PLD1 and PLD2 expression - Inhibition of apoptosis - MAP kinase signalling - Involved in long term depression in hippocampal neuron - Required for normal spatial learning # Interactions Hippocalcin interacts with following proteins: - Neuronal apoptosis inhibitory protein (NAIP) - Mixed lineage kinase 2 (MLK2) – MLK2 is myosin light chain kinase 2 - The b2 adaptin of the AP2 complex - Calcium-dependent activator protein for secretion (CADPS)	Hippocalcin Hippocalcin is a protein that in humans is encoded by the HPCA gene.[1][2] Hippocalcin is a calcium-binding protein that belongs to the neuronal calcium sensor (NCS) family of proteins.[3][4] It is expressed in mammalian brains especially in the hippocampus. It possesses a Ca2+/myristoyl switch.[5] # Processes Hippocalcin takes part in the following processes: - Activation of PLD1 and PLD2 expression - Inhibition of apoptosis - MAP kinase signalling - Involved in long term depression in hippocampal neuron - Required for normal spatial learning # Interactions Hippocalcin interacts with following proteins: - Neuronal apoptosis inhibitory protein (NAIP) - Mixed lineage kinase 2 (MLK2) – MLK2 is myosin light chain kinase 2 - The b2 adaptin of the AP2 complex - Calcium-dependent activator protein for secretion (CADPS)	https://www.wikidoc.org/index.php/Hippocalcin

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