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a9583126c1d9246c11b7c40f156c32d341977866	wikidoc	Laminopathy	Laminopathy Laminopathies are a group of rare genetic disorders caused by mutations in genes encoding proteins of the nuclear lamina. They are included in the more generic term nuclear envelopathies that was coined in 2000 for diseases associated with defects of the nuclear envelope. Since the first reports of laminopathies in the late 1990s, increased research efforts have started to uncover the vital role of nuclear envelope proteins in cell and tissue integrity in animals. # Symptoms Laminopathies and other nuclear envelopathies have a large variety of clinical symptoms including skeletal and/or cardiac muscular dystrophy, lipodystrophy and diabetes, dysplasia, dermo- or neuropathy, leukodystrophy, and progeria (premature aging). Most of these symptoms develop after birth, typically during childhood or adolescence. Some laminopathies however may lead to an early death, and mutations of lamin B (LMNB1 gene) may be lethal before or at birth. # Genetics Patients with classical laminopathy have mutations in the gene coding for lamin A/C (LMNA gene). More recently, mutations in lamin B (LMNB2 gene) or genetic defects leading to changes in lamin B abundance were identified as cause for laminopathies. Mutations implicated in other nuclear envelopathies were found in genes coding for lamin-binding proteins such as lamin B receptor (LBR gene), emerin (EMD gene) and LEM domain-containing protein 3 (LEMD3 gene) and prelamin-processing enzymes such as the zinc metalloproteinase STE24 (ZMPSTE24 gene). Mutations causing laminopathies include recessive as well as dominant alleles with rare de novo mutations creating dominant alleles that do not allow their carriers to reproduce before death. The nuclear envelopathy with the highest frequency in human populations is Emery-Dreifuss muscular dystrophy caused by an X-linked mutation in the EMD gene coding for emerin and affecting an estimated 1 in 100,000 people. # Molecular action Lamins are intermediate filament proteins that form the nuclear lamina scaffold underneath the nuclear envelope in animal cells. They are attached to the nuclear envelope membrane via farnesyl anchors and interaction with inner nuclear membrane proteins such as lamin B receptor and emerin. The nuclear lamina appears to be an adaptation to mobility in animals as sessile organisms such as plants or fungi do not have lamins and the symptoms of many laminopathies include muscle defects. Mutations in these genes might lead to defects in filament assembly and/or attachment to the nuclear envelope and thus jeopardize nuclear envelope stability in physically stressed tissues such as muscle fibers, bone, skin and connective tissue. Messenger RNA produced from the LMNA gene undergoes alternative splicing and is translated into lamins A and C. Lamin A undergoes farnesylation to attach a membrane anchor to the protein. This version of the protein is also referred to as prelamin A. Farnesylated prelamin A is further processed into mature lamin A by a metalloproteinase removing the last 15 amino acids and its farnesylated cysteine. This allows lamin A to dissociate from the nuclear envelope membrane and fulfill nuclear functions. Mutations causing laminopathies interfere with these processes on different levels. ## Nonsense and missense mutations Missense mutations in the lamin A/C rod and tail domains are the cause for a wide array of genetic disorders, suggesting that lamin A/C protein contains distinct functional domains that are essential for the maintenance and integrity of different cell lineages. Interaction between lamin A and the nuclear envelope protein emerin appears to be crucial in muscle cells, with certain mutations in lamin mimicking mutations in emerin and causing Emery-Dreifuss muscular dystrophy. Different mutations lead to dominant-negative and recessive alleles. Mutations in the lamin rod domain leading to mislocalization of both lamin A and emerin occur in patients with autosomal dominant forms of muscular dystrophy and cardiomyopathy. Most lamin B mutations appear to be lethal with mutations in lamin B1 causing death at birth in mice. In 2006, lamin B2 missense mutations were identified in patients with acquired partial lipodystrophy. ## Splicing defects Mutations causing progeria are defective in splicing LMNA mRNA, therefore producing abnormal lamin A protein, also known as progerin. The mutations activate a cryptic splice site within exon 11 of the gene, thereby causing the deletion of the processing site on prelamin A. This results in an accumulation of progerin that is unable to mature into lamin A, leading to misshapen nuclei. Missplicing also leads to the complete or partial loss of exon 11 and results in a truncated prelamin A protein in the neonatal lethal tight skin contracture syndrome. ## Processing defects Since the metalloproteinase STE24 is required to process prelamin A into mature lamin A, mutations in this gene abolishing protease activity cause defects similar to laminopathies caused by prelamin A with truncated processing sites. Symptoms in patients with ZMPSTE24 mutation range from mandibuloacral dysplasia, progeroid appearance, and generalized lipodystrophy to infant-lethal restrictive dermopathy. ## Gene dosage effects In the case of autosomal dominant leukodystrophy, the disease is associated with a duplication of the lamin B gene LMNB1. The exact dosage of lamin B in cells appears to be crucial for nuclear integrity as increased expression of lamin B causes a degenerative phenotype in fruit flies and leads to abnormal nuclear morphology. ## Autoimmune antibodies Antibodies against lamin B have been implicated in autoimmune diseases and are possibly involved in multiple sclerosis. # Treatment and drug development Currently, there is no cure for laminopathies and treatment is largely symptomatic and supportive. Physical therapy and/or corrective orthopedic surgery may be helpful for patients with muscular dystrophies. Cardiac problems that occur with some laminopathies may require a pacemaker. Treatment for neuropathies may include medication for seizures and spasticity. The recent progress in uncovering the molecular mechanisms of toxic progerin formation in laminopathies leading to premature aging has opened up the potential for the development of targeted treatment. The farnesylation of prelamin A and its pathological form progerin is carried out by the enzyme farnesyl transferase. Farnesyl transferase inhibitors (FTIs) can be used effectively to reduce symptoms in two mouse model systems for progeria and to revert the abnormal nuclear morphology in progeroid cell cultures. Two oral FTIs, lonafarnib and tipifarnib, are already in use as anti-tumor medication in humans and may become avenues of treatment for children suffering from laminopathic progeria. Nitrogen-containing bisphosphate drugs used in the treatment of osteoporosis reduce farnesyldiphosphate production and thus prelamin A farnesylation. Testing of these drugs may prove them to be useful in treating progeria as well. The use of antisense oligonucleotides to inhibit progerin synthesis in affected cells is another avenue of current research into the development of anti-progerin drugs. # List of known laminopathies and other nuclear envelopathies	Laminopathy Laminopathies are a group of rare genetic disorders caused by mutations in genes encoding proteins of the nuclear lamina. They are included in the more generic term nuclear envelopathies that was coined in 2000 for diseases associated with defects of the nuclear envelope.[1] Since the first reports of laminopathies in the late 1990s, increased research efforts have started to uncover the vital role of nuclear envelope proteins in cell and tissue integrity in animals. # Symptoms Laminopathies and other nuclear envelopathies have a large variety of clinical symptoms including skeletal and/or cardiac muscular dystrophy, lipodystrophy and diabetes, dysplasia, dermo- or neuropathy, leukodystrophy, and progeria (premature aging). Most of these symptoms develop after birth, typically during childhood or adolescence. Some laminopathies however may lead to an early death, and mutations of lamin B (LMNB1 gene) may be lethal before or at birth.[3] # Genetics Patients with classical laminopathy have mutations in the gene coding for lamin A/C (LMNA gene). More recently, mutations in lamin B (LMNB2 gene) or genetic defects leading to changes in lamin B abundance were identified as cause for laminopathies. Mutations implicated in other nuclear envelopathies were found in genes coding for lamin-binding proteins such as lamin B receptor (LBR gene), emerin (EMD gene) and LEM domain-containing protein 3 (LEMD3 gene) and prelamin-processing enzymes such as the zinc metalloproteinase STE24 (ZMPSTE24 gene). Mutations causing laminopathies include recessive as well as dominant alleles with rare de novo mutations creating dominant alleles that do not allow their carriers to reproduce before death. The nuclear envelopathy with the highest frequency in human populations is Emery-Dreifuss muscular dystrophy caused by an X-linked mutation in the EMD gene coding for emerin and affecting an estimated 1 in 100,000 people. # Molecular action Lamins are intermediate filament proteins that form the nuclear lamina scaffold underneath the nuclear envelope in animal cells. They are attached to the nuclear envelope membrane via farnesyl anchors and interaction with inner nuclear membrane proteins such as lamin B receptor and emerin. The nuclear lamina appears to be an adaptation to mobility in animals as sessile organisms such as plants or fungi do not have lamins[4] and the symptoms of many laminopathies include muscle defects. Mutations in these genes might lead to defects in filament assembly and/or attachment to the nuclear envelope and thus jeopardize nuclear envelope stability in physically stressed tissues such as muscle fibers, bone, skin and connective tissue.[5] Messenger RNA produced from the LMNA gene undergoes alternative splicing and is translated into lamins A and C. Lamin A undergoes farnesylation to attach a membrane anchor to the protein. This version of the protein is also referred to as prelamin A. Farnesylated prelamin A is further processed into mature lamin A by a metalloproteinase removing the last 15 amino acids and its farnesylated cysteine. This allows lamin A to dissociate from the nuclear envelope membrane and fulfill nuclear functions. Mutations causing laminopathies interfere with these processes on different levels. ## Nonsense and missense mutations Missense mutations in the lamin A/C rod and tail domains are the cause for a wide array of genetic disorders, suggesting that lamin A/C protein contains distinct functional domains that are essential for the maintenance and integrity of different cell lineages. Interaction between lamin A and the nuclear envelope protein emerin appears to be crucial in muscle cells, with certain mutations in lamin mimicking mutations in emerin and causing Emery-Dreifuss muscular dystrophy. Different mutations lead to dominant-negative and recessive alleles. Mutations in the lamin rod domain leading to mislocalization of both lamin A and emerin occur in patients with autosomal dominant forms of muscular dystrophy and cardiomyopathy. Most lamin B mutations appear to be lethal with mutations in lamin B1 causing death at birth in mice.[3] In 2006, lamin B2 missense mutations were identified in patients with acquired partial lipodystrophy.[6] ## Splicing defects Mutations causing progeria are defective in splicing LMNA mRNA, therefore producing abnormal lamin A protein, also known as progerin. The mutations activate a cryptic splice site within exon 11 of the gene, thereby causing the deletion of the processing site on prelamin A.[7] This results in an accumulation of progerin that is unable to mature into lamin A, leading to misshapen nuclei. Missplicing also leads to the complete or partial loss of exon 11 and results in a truncated prelamin A protein in the neonatal lethal tight skin contracture syndrome.[8] ## Processing defects Since the metalloproteinase STE24 is required to process prelamin A into mature lamin A, mutations in this gene abolishing protease activity cause defects similar to laminopathies caused by prelamin A with truncated processing sites. Symptoms in patients with ZMPSTE24 mutation range from mandibuloacral dysplasia, progeroid appearance, and generalized lipodystrophy to infant-lethal restrictive dermopathy. ## Gene dosage effects In the case of autosomal dominant leukodystrophy, the disease is associated with a duplication of the lamin B gene LMNB1. The exact dosage of lamin B in cells appears to be crucial for nuclear integrity as increased expression of lamin B causes a degenerative phenotype in fruit flies and leads to abnormal nuclear morphology.[9] ## Autoimmune antibodies Antibodies against lamin B have been implicated in autoimmune diseases and are possibly involved in multiple sclerosis.[9] # Treatment and drug development Currently, there is no cure for laminopathies and treatment is largely symptomatic and supportive. Physical therapy and/or corrective orthopedic surgery may be helpful for patients with muscular dystrophies. Cardiac problems that occur with some laminopathies may require a pacemaker. Treatment for neuropathies may include medication for seizures and spasticity. The recent progress in uncovering the molecular mechanisms of toxic progerin formation in laminopathies leading to premature aging has opened up the potential for the development of targeted treatment. The farnesylation of prelamin A and its pathological form progerin is carried out by the enzyme farnesyl transferase. Farnesyl transferase inhibitors (FTIs) can be used effectively to reduce symptoms in two mouse model systems for progeria and to revert the abnormal nuclear morphology in progeroid cell cultures. Two oral FTIs, lonafarnib and tipifarnib, are already in use as anti-tumor medication in humans and may become avenues of treatment for children suffering from laminopathic progeria. Nitrogen-containing bisphosphate drugs used in the treatment of osteoporosis reduce farnesyldiphosphate production and thus prelamin A farnesylation. Testing of these drugs may prove them to be useful in treating progeria as well. The use of antisense oligonucleotides to inhibit progerin synthesis in affected cells is another avenue of current research into the development of anti-progerin drugs.[10][11] # List of known laminopathies and other nuclear envelopathies	https://www.wikidoc.org/index.php/Laminopathies
e0c827ada5662d654dc27f77fd8f6c60c5279f1e	wikidoc	Lanadelumab	Lanadelumab # 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 Lanadelumab is a plasma kallikrein inhibitor (monoclonal antibody) that is FDA approved for the prophylaxis to prevent attacks of hereditary angioedema (HAE) in patients 12 years and older. Common adverse reactions include injection site reactions, upper respiratory infections, headache, rash, myalgia, dizziness, and diarrhea. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) Indication - Lanadelumab is indicated for prophylaxis to prevent attacks of hereditary angioedema (HAE) in patients 12 years and older. Dosage - The recommended starting dose is 300 mg every 2 weeks. A dosing interval of 300 mg every 4 weeks is also effective and may be considered if the patient is well-controlled (e.g., attack free) for more than 6 months. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding lanadelumab Off-Label Guideline-Supported Use and Dosage (Adult) in the drug label. ### Non–Guideline-Supported Use There is limited information regarding lanadelumab Off-Label Non-Guideline-Supported Use and Dosage (Adult) in the drug label. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) Indication - Lanadelumab is indicated for prophylaxis to prevent attacks of hereditary angioedema (HAE) in patients 12 years and older. - The safety and efficacy of lanadelumab in pediatric patients < 12 years of age have not been established. Dosage - The recommended starting dose for pediatric patients 12 years or older is 300 mg every 2 weeks. A dosing interval of 300 mg every 4 weeks is also effective and may be considered if the patient is well-controlled (e.g., attack free) for more than 6 months. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding lanadelumab Off-Label Guideline-Supported Use and Dosage (Pediatric) in the drug label. ### Non–Guideline-Supported Use There is limited information regarding lanadelumab Off-Label Non-Guideline-Supported Use and Dosage (Pediatric) in the drug label. # Contraindications None. # Warnings - Hypersensitivity reactions have been observed. In case of a severe hypersensitivity reaction, discontinue lanadelumab administration and institute appropriate treatment. # 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 practice. - The safety of lanadelumab is primarily based on a 26-week, randomized, double-blind, parallel-group and placebo-controlled study (Trial 1) in 125 patients with Type I or II HAE. Eligible patients were also able to participate in an open-label extension study (Trial 2) up to 130 weeks. In Trial 1, a total of 84 patients with HAE aged 12 years and older received at least one dose of lanadelumab. Overall, 70% of patients were female and 90% of patients were Caucasian with a mean age of 41 years. The proportion of patients who discontinued study drug prematurely due to adverse events was 1.2% for lanadelumab-treated patients and 4.9% for placebo-treated patients. No deaths occurred in the trial. - The safety profile of lanadelumab was generally similar across all subgroups of patients, including analysis by age, sex, and geographic region. - Table 1 shows adverse reactions occurring in ≥10% of patients in any lanadelumab treatment group that also occurred at a higher rate than in the placebo treatment group in Trial 1. - Injection site reactions primarily consisted mainly of pain, erythema, and bruising at the injection site. There was no meaningful difference in injection site reactions with self-administration. Less Common Adverse Reactions - Other adverse reactions that occurred at a higher incidence in lanadelumab-treated patients compared to placebo include hypersensitivity (1% vs 0%), increased aspartate transaminase (2% vs 0%), and increased alanine transaminase (2% vs 0%). - Safety data from the ongoing open-label extension study, consisting of 109 rollover patients from Trial 1 and 103 non-rollover HAE patients, is consistent with controlled safety data from Trial 1. Laboratory Abnormalities Transaminase elevations - During the placebo-controlled treatment period in Trial 1, the number of lanadelumab-treated patients with maximum transaminase (ALT or AST) levels >8, >5, or >3 times the upper limit of normal (ULN) was 1 (1.2%), 0 (0%), or 3 (3.6%) respectively, compared to 0 in the placebo-treated patients. These transaminase elevations were asymptomatic and transient. No patients had elevated total bilirubin >2× ULN. One lanadelumab-treated patient permanently discontinued treatment due to elevated transaminases (4.1× ULN AST). None of the patients were reported to have serious adverse reactions of elevated transaminases. ## Immunogenicity - As with all therapeutic proteins, there is a potential for immunogenicity. The detection of antibody formation is highly dependent on the sensitivity and 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 lanadelumab-flyo in the study described below with the incidence of antibodies in other studies or to other products may be misleading. - In Trial 1, 10 (12%) lanadelumab-flyo-treated and 2 (5%) placebo-treated patients had at least 1 anti-drug antibody (ADA)-positive sample during the treatment period; antibody titers were low (range: 20 to 1280). The ADA response observed was transient in 2/10 lanadelumab-flyo and 1/2 placebo-treated patients. Pre-existing low titer antibodies were observed in 3 lanadelumab-flyo-treated patients and 1 placebo-treated patient with ADAs. Two patients receiving 150 mg q4wks had low titer antibodies classified as neutralizing. - The development of ADA including neutralizing antibodies against lanadelumab-flyo did not appear to adversely affect pharmacokinetics (PK), pharmacodynamics (PD), safety or clinical response. ## Postmarketing Experience There is limited information regarding Lanadelumab Postmarketing Experience in the drug label. # Drug Interactions - No dedicated drug interaction studies have been conducted. Coagulation tests - Lanadelumab can increase activated partial thromboplastin time (aPTT) due to an interaction of lanadelumab with the aPTT assay. The reagents used in the aPTT laboratory test initiate intrinsic coagulation through the activation of plasma kallikrein in the contact system. Inhibition of plasma kallikrein by lanadelumab can increase aPTT in this assay. In Trial 1, prolongation of aPTT (>1× ULN) was observed at one or more time points in 3, 9, and 11 patients treated with lanadelumab 150 mg q4 wks, 300 mg q4 wks, and 300 mg q2 wks, respectively, compared to 5 placebo-treated patients. Only one patient in the 300 mg q2 wks treatment group experienced transient aPTT prolongation ≥1.5× ULN which was confounded by ongoing heparin therapy. None of the increases in aPTT in patients treated with lanadelumab were associated with abnormal bleeding adverse events. There were no differences in INR values between treatment groups. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): Risk Summary - There are no available data on lanadelumab use in pregnant women to inform any drug associated risks. Monoclonal antibodies such as lanadelumab-flyo are transported across the placenta during the third trimester of pregnancy; therefore, potential effects on a fetus are likely to be greater during the third trimester of pregnancy. An enhanced pre-and postnatal development (ePPND) study conducted in pregnant monkeys at doses resulting in exposures of up to 33 times the exposure achieved (on an AUC basis) at the maximum recommended human dose (MRHD) revealed no evidence of harm to the developing fetus. - The background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. Animal Data - In the ePPND study, pregnant cynomolgus monkeys were administered lanadelumab-flyo once weekly at subcutaneous doses resulting in up to 33 times the exposure at the MRHD (on an AUC basis with maternal subcutaneous doses up to 50 mg/kg/week) from gestation day 20, at the beginning of organogenesis, through to parturition. There were no lanadelumab-flyo-related effects on maintenance of pregnancy or parturition. Maternal lanadelumab-flyo treatment had no effects on embryo-fetal development, survival, growth, or postnatal development of offspring through 3 months of age. Lanadelumab-flyo crossed the placenta in monkeys. Offspring were exposed to lanadelumab-flyo at approximately 50% of the maternal plasma concentration out to postnatal day 21 (PND 21). Lanadelumab-flyo concentrations were approximately equivalent in maternal and offspring plasma at PND 90. Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Lanadelumab in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Lanadelumab during labor and delivery. ### Nursing Mothers Risk Summary - There are no data on the presence of lanadelumab-flyo in human milk, its effects on the breastfed infant, or its effects on milk production. Lanadelumab-flyo was detected in the milk of lactating cynomolgus monkeys at approximately 0.2% of the maternal plasma concentration. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for lanadelumab and any potential adverse effects on the breastfed infant from lanadelumab or from the underlying maternal condition. Animal Data - Available pharmacokinetic data in cynomolgus monkeys have shown excretion of lanadelumab-flyo in milk at approximately 0.2% of the maternal plasma level. ### Pediatric Use - The safety and efficacy of lanadelumab were evaluated in a subgroup of patients (N=10) aged 12 to <18 years in Trial 1. Results of the subgroup analysis by age were consistent with overall study results. An additional 13 adolescent patients aged 12 to <18 years were enrolled in the open-label extension study. - The safety and efficacy of lanadelumab in pediatric patients < 12 years of age have not been established. ### Geriatic Use - The safety and efficacy of lanadelumab were evaluated in a subgroup of patients (N=5) aged ≥65 years in Trial 1. Results of the subgroup analysis by age were consistent with overall study results. ### Gender There is no FDA guidance on the use of Lanadelumab with respect to specific gender populations. ### Race There is no FDA guidance on the use of Lanadelumab with respect to specific racial populations. ### Renal Impairment There is no FDA guidance on the use of Lanadelumab in patients with renal impairment. ### Hepatic Impairment There is no FDA guidance on the use of Lanadelumab in patients with hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Lanadelumab in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Lanadelumab in patients who are immunocompromised. # Administration and Monitoring ### Administration - The recommended starting dose is 300 mg every 2 weeks. A dosing interval of 300 mg every 4 weeks is also effective and may be considered if the patient is well-controlled (e.g., attack free) for more than 6 months. - Lanadelumab is administered subcutaneously only. - Lanadelumab is provided as a ready-to-use solution in a single-dose vial that does not require additional reconstitution or dilution for administration. Lanadelumab is supplied as a clear to slightly opalescent, colorless to slightly yellow solution. Do not use the vial if it appears discolored or contains visible particles. Avoid vigorous agitation of the vial. - Lanadelumab is intended for self-administration or administration by a caregiver. The patient or caregiver should be trained by a healthcare professional. - Take the lanadelumab vial out of the refrigerator 15 minutes before injecting to allow it to equilibrate to room temperature. - Using aseptic technique, withdraw the prescribed dose of lanadelumab from the vial using an 18-gauge needle. Change the needle on the syringe to a 27-gauge, ½-inch needle or other needle suitable for subcutaneous injection. Inject lanadelumab subcutaneously into the abdomen, thigh, or upper arm. Patients should inject the complete dose as prescribed by their physician. In clinical studies, the majority of patients self-administered lanadelumab over 10 to 60 seconds. - Lanadelumab should be administered within 2 hours of preparing the dosing syringe. After the dosing syringe is prepared, it can be refrigerated at 36ºF to 46ºF (2°C to 8°C) and must be used within 8 hours. - Discard any unused portions of drug remaining in the vial and syringe. - For detailed instructions on the preparation and administration of lanadelumab see INSTRUCTIONS FOR USE. ### Monitoring There is limited information regarding Lanadelumab Monitoring in the drug label. # IV Compatibility There is limited information regarding the compatibility of Lanadelumab and IV administrations. # Overdosage - There is no clinical experience with overdosage of lanadelumab. # Pharmacology ## Mechanism of Action - Lanadelumab-flyo is a fully human monoclonal antibody (IgG1/κ-light chain) that binds plasma kallikrein and inhibits its proteolytic activity. Plasma kallikrein is a protease that cleaves high-molecular-weight-kininogen (HMWK) to generate cleaved HMWK (cHMWK) and bradykinin, a potent vasodilator that increases vascular permeability resulting in swelling and pain associated with HAE. In patients with HAE due to C1-inhibitor (C1-INH) deficiency or dysfunction, normal regulation of plasma kallikrein activity is not present, which leads to uncontrolled increases in plasma kallikrein activity and results in angioedema attacks. Lanadelumab-flyo decreases plasma kallikrein activity to control excess bradykinin generation in patients with HAE. ## Structure There is limited information regarding Lanadelumab Structure in the drug label. ## Pharmacodynamics - Concentration-dependent inhibition of plasma kallikrein, measured as reduction of cHMWK levels, was demonstrated after subcutaneous administration of lanadelumab 150 mg q4wks, 300 mg q4wks or 300 mg q2wks in patients with HAE. - Lanadelumab did not prolong the QT/QTc interval. ## Pharmacokinetics - Following subcutaneous administration, the pharmacokinetics of lanadelumab-flyo was approximately dose-proportional in the therapeutic dose range in patients with HAE (Table 2). The pharmacokinetic properties and exposure (steady state) of lanadelumab-flyo in HAE patients, following subcutaneous administration of 150 mg q4wks, 300 mg q4wks and 300 mg q2wks, are provided in Table 2. Following subcutaneous administration of lanadelumab, peak plasma concentrations are reached within 5 days, and terminal elimination half-life is ~2 weeks. The anticipated time to reach steady state concentration was approximately 70 days. At steady-state, the mean accumulation ratio is approximately 1.44, 1.42, and 2.43 for dosing regimen of 150 mg q4wks, 300 mg q4wks and 300 mg q2wks, respectively. Specific Populations - Population pharmacokinetic analyses showed that age, gender and race did not meaningfully influence the pharmacokinetics of lanadelumab-flyo after correcting for body weight. Body weight was identified as an important covariate describing the variability of clearance and volume of distribution, resulting in higher exposure (AUC and Cmax) in lighter patients. However, this difference is not considered to be clinically relevant and no dose adjustments are recommended for any of these demographics. Pediatric Population - Based on population pharmacokinetics (PK) analyses, the mean lanadelumab-flyo (±SD) AUCss was 629 (204) µgday/mL following SC administration of lanadelumab 300 mg every 2 weeks in pediatric patients 12 to less than 18 years of age. This is approximately 37% higher than the mean AUCss in adult patients (460 μgday/mL) under the same dosing regimen, due to lower body weight in pediatric patients. Renal Impairment - No dedicated studies have been conducted to evaluate the PK of lanadelumab-flyo in renal impairment patients. Based on population pharmacokinetic analysis, renal impairment (estimated GFR: 60 to 89 mL/min/1.73m2, and 30 to 59 mL/min/1.73m2, ) had no effect on the clearance or volume of distribution of lanadelumab-flyo. Concomitant medications - The use of analgesic, antibacterial, antihistamine, anti-inflammatory and antirheumatic medications had no effect on clearance and volume of distribution of lanadelumab-flyo. - For breakthrough HAE attacks, use of rescue medications such as plasma-derived and recombinant C1-INH, icatibant or ecallantide had no effects on clearance and volume of distribution of lanadelumab-flyo. ## Nonclinical Toxicology - Animal studies have not been conducted to evaluate the carcinogenic potential of lanadelumab-flyo. Published literature supports bradykinin, which is elevated in HAE, as a pro-tumorigenic molecule. However, the malignancy risk in humans from an antibody that inhibits plasma kallikrein activity, such as lanadelumab-flyo, which lowers bradykinin levels, is currently unknown. - Male and female fertility were unaffected based upon no observed adverse histopathological findings in the reproductive organs from sexually mature cynomolgus monkeys that received lanadelumab-flyo for 13 weeks at subcutaneous doses up to 50 mg/kg/week (resulting in approximately 22 times the exposure at the MRHD on an AUC basis). # Clinical Studies Trial 1 (NCT02586805) - The efficacy of lanadelumab for the prevention of angioedema attacks in patients 12 years of age and older with Type I or II HAE was demonstrated in a multicenter, randomized, double-blind, placebo-controlled parallel-group study (Trial 1). - The study included 125 adult and adolescent patients with Type I or II HAE who experienced at least one investigator-confirmed attack per 4 weeks during the run-in period. Patients were randomized into 1 of 4 parallel treatment arms, stratified by baseline attack rate, in a 3:2:2:2 ratio (placebo, lanadelumab-flyo 150 mg q4wks, lanadelumab-flyo 300 mg q4wks, or lanadelumab-flyo 300 mg q2wks by subcutaneous injection) for the 26-week treatment period. Patients ≥18 years of age were required to discontinue other prophylactic HAE medications prior to entering the study; however, all patients were allowed to use rescue medications for treatment of breakthrough HAE attacks. - Overall, 90% of patients had Type I HAE. A history of laryngeal angioedema attacks was reported in 65% of patients and 56% were on prior long-term prophylaxis. During the study run-in period, attack rates of ≥3 attacks/month were observed in 52% of patients overall. - All lanadelumab treatment arms produced clinically meaningful and statistically significant reductions in the mean HAE attack rate compared to placebo across all primary and secondary endpoints in the Intent-to-Treat population (ITT) as shown in Table 3. - The mean reduction in HAE attack rate was consistently higher across the lanadelumab treatment arms compared to placebo regardless of the baseline history of prior long-term prophylaxis, laryngeal attacks, or attack rate during the run-in period. - Additional pre-defined exploratory endpoints included the percentage of patients who were attack free for the entire 26-week treatment period and the percentage of patients achieving threshold (≥50%, ≥70%, ≥90%) reductions in HAE attack rates compared to run-in during the 26-week treatment period. A ≥50% reduction in HAE attack rate was observed in 100% of patients on 300 mg q2wks or q4wks and 89% on 150 mg q4wks compared to 32% of placebo patients. A ≥70% reduction in HAE attack rates was observed in 89%, 76%, and 79% of patients on 300 mg q2wks, 300 mg q4wks, and 150 mg q4wks, respectively, compared to 10% of placebo patients. A ≥90% reduction in HAE attack rates was observed 67%, 55%, and 64% of patients on 300 mg q2wks, 300 mg q4wks, and 150 mg q4wks, respectively, compared to 5% of placebo patients. - The percentage of attack-free patients for the entire 26-week treatment period was 44%, 31%, and 39% in the lanadelumab 300 mg q2wks, 300 mg q4wks, and 150 mg q4wks groups respectively, compared to 2% of placebo patients. Trial 2 (NCT02741596) - Patients who completed Trial 1 were eligible to rollover into an open-label extension study. Rollover patients, regardless of randomization group in Trial 1, received a single dose of lanadelumab 300 mg at study entry and were followed until the first HAE attack occurred. All efficacy endpoints were exploratory in this uncontrolled, unblinded study. At week 4 post-dose, approximately 80% of patients who had been in the 300 mg q2wks treatment group (N=25) in Trial 1 remained attack-free. After the first HAE attack, all patients received open-label treatment with lanadelumab 300 mg q2wks. # How Supplied - Lanadelumab (lanadelumab-flyo) injection is a ready-to-use, clear to slightly opalescent, colorless to slightly yellow solution supplied in a carton containing one single-dose glass vial with chlorobutyl rubber stopper, aluminum crimp seal and polypropylene flip-off cap. - 300 mg/2 mL (150 mg/mL) vial. ## Storage - Store vials refrigerated at 36°F to 46°F (2°C to 8°C). - Do not freeze. Do not shake. - Keep the vial in the original carton in order to protect the vial from light. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information Hypersensitivity - Advise patients to seek immediate medical attention if they experience any symptoms of serious hypersensitivity reactions. Self-administration: - Ensure that the patient/caregiver receives clear instructions and training on subcutaneous administration and has demonstrated the ability to perform a subcutaneous injection. - Instruct patients or caregivers in the technique of proper syringe and needle disposal, and advise them not to reuse these items. Instruct patients to dispose needles and syringes in a puncture-resistant container. - Be sure that you read, understand, and follow the Instructions for Use before injecting lanadelumab. A healthcare provider should show you how to prepare and inject lanadelumab properly before you use it for the first time. Contact your healthcare provider if you have any questions. Important information: - Lanadelumab is a ready-to-use solution for injection under the skin (subcutaneous). It is supplied in a single-dose, glass vial. - Your healthcare provider will prescribe the dose that you should take. - Only use the syringes, transfer needles, and injection needles that your healthcare provider prescribes. - Only use the syringes, transfer needles and injection needles 1 time. Throw away (dispose of) any used syringes and needles. Storing lanadelumab: - Store lanadelumab in the refrigerator at 36°F to 46°F (2°C to 8°C). Do not freeze. - Store lanadelumab in the original carton to protect the vial from light. - Do not shake lanadelumab. - Keep lanadelumab and all medicines out of the reach of children. Supplies needed for your lanadelumab Injection STEP 1: Prepare for your injection - Gather all supplies and place them on a well-lighted flat work surface. - Take the vial out of the refrigerator 15 minutes before use and allow it to reach room temperature before preparing an injection. - Check the expiration date on the box and vial label of lanadelumab. Do not use if the expiration date has passed. - Check the supplies for damage. Do not use if they appear damaged. - Clean your work area and wash your hands before preparing your dose. Do not touch any surface or body part, especially your face, after washing your hands before injection. - Remove the vial from the packaging. Do not use the vial if the plastic cap covering is missing. STEP 2: Attach transfer needle to syringe STEP 3: Transfer lanadelumab into syringe and switch to the injection needle STEP 4: Select and prepare injection site STEP 5: Inject lanadelumab STEP 6: THROW AWAY (DISPOSE OF) NEEDLE AND SYRINGE - For more information, visit www.takhzyro.com - This Instructions for Use has been approved by the U.S. Food and Drug Administration. # Precautions with Alcohol Alcohol-Lanadelumab interaction has not been established. Talk to your doctor regarding the effects of taking alcohol with this medication. # Brand Names Takhzyro # Look-Alike Drug Names There is limited information regarding Lanadelumab Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	Lanadelumab Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Zach Leibowitz [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 Lanadelumab is a plasma kallikrein inhibitor (monoclonal antibody) that is FDA approved for the prophylaxis to prevent attacks of hereditary angioedema (HAE) in patients 12 years and older. Common adverse reactions include injection site reactions, upper respiratory infections, headache, rash, myalgia, dizziness, and diarrhea. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) Indication - Lanadelumab is indicated for prophylaxis to prevent attacks of hereditary angioedema (HAE) in patients 12 years and older. Dosage - The recommended starting dose is 300 mg every 2 weeks. A dosing interval of 300 mg every 4 weeks is also effective and may be considered if the patient is well-controlled (e.g., attack free) for more than 6 months. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding lanadelumab Off-Label Guideline-Supported Use and Dosage (Adult) in the drug label. ### Non–Guideline-Supported Use There is limited information regarding lanadelumab Off-Label Non-Guideline-Supported Use and Dosage (Adult) in the drug label. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) Indication - Lanadelumab is indicated for prophylaxis to prevent attacks of hereditary angioedema (HAE) in patients 12 years and older. - The safety and efficacy of lanadelumab in pediatric patients < 12 years of age have not been established. Dosage - The recommended starting dose for pediatric patients 12 years or older is 300 mg every 2 weeks. A dosing interval of 300 mg every 4 weeks is also effective and may be considered if the patient is well-controlled (e.g., attack free) for more than 6 months. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding lanadelumab Off-Label Guideline-Supported Use and Dosage (Pediatric) in the drug label. ### Non–Guideline-Supported Use There is limited information regarding lanadelumab Off-Label Non-Guideline-Supported Use and Dosage (Pediatric) in the drug label. # Contraindications None. # Warnings - Hypersensitivity reactions have been observed. In case of a severe hypersensitivity reaction, discontinue lanadelumab administration and institute appropriate treatment. # 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 practice. - The safety of lanadelumab is primarily based on a 26-week, randomized, double-blind, parallel-group and placebo-controlled study (Trial 1) in 125 patients with Type I or II HAE. Eligible patients were also able to participate in an open-label extension study (Trial 2) up to 130 weeks. In Trial 1, a total of 84 patients with HAE aged 12 years and older received at least one dose of lanadelumab. Overall, 70% of patients were female and 90% of patients were Caucasian with a mean age of 41 years. The proportion of patients who discontinued study drug prematurely due to adverse events was 1.2% for lanadelumab-treated patients and 4.9% for placebo-treated patients. No deaths occurred in the trial. - The safety profile of lanadelumab was generally similar across all subgroups of patients, including analysis by age, sex, and geographic region. - Table 1 shows adverse reactions occurring in ≥10% of patients in any lanadelumab treatment group that also occurred at a higher rate than in the placebo treatment group in Trial 1. - Injection site reactions primarily consisted mainly of pain, erythema, and bruising at the injection site. There was no meaningful difference in injection site reactions with self-administration. Less Common Adverse Reactions - Other adverse reactions that occurred at a higher incidence in lanadelumab-treated patients compared to placebo include hypersensitivity (1% vs 0%), increased aspartate transaminase (2% vs 0%), and increased alanine transaminase (2% vs 0%). - Safety data from the ongoing open-label extension study, consisting of 109 rollover patients from Trial 1 and 103 non-rollover HAE patients, is consistent with controlled safety data from Trial 1. Laboratory Abnormalities Transaminase elevations - During the placebo-controlled treatment period in Trial 1, the number of lanadelumab-treated patients with maximum transaminase (ALT or AST) levels >8, >5, or >3 times the upper limit of normal (ULN) was 1 (1.2%), 0 (0%), or 3 (3.6%) respectively, compared to 0 in the placebo-treated patients. These transaminase elevations were asymptomatic and transient. No patients had elevated total bilirubin >2× ULN. One lanadelumab-treated patient permanently discontinued treatment due to elevated transaminases (4.1× ULN AST). None of the patients were reported to have serious adverse reactions of elevated transaminases. ## Immunogenicity - As with all therapeutic proteins, there is a potential for immunogenicity. The detection of antibody formation is highly dependent on the sensitivity and 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 lanadelumab-flyo in the study described below with the incidence of antibodies in other studies or to other products may be misleading. - In Trial 1, 10 (12%) lanadelumab-flyo-treated and 2 (5%) placebo-treated patients had at least 1 anti-drug antibody (ADA)-positive sample during the treatment period; antibody titers were low (range: 20 to 1280). The ADA response observed was transient in 2/10 lanadelumab-flyo and 1/2 placebo-treated patients. Pre-existing low titer antibodies were observed in 3 lanadelumab-flyo-treated patients and 1 placebo-treated patient with ADAs. Two patients receiving 150 mg q4wks had low titer antibodies classified as neutralizing. - The development of ADA including neutralizing antibodies against lanadelumab-flyo did not appear to adversely affect pharmacokinetics (PK), pharmacodynamics (PD), safety or clinical response. ## Postmarketing Experience There is limited information regarding Lanadelumab Postmarketing Experience in the drug label. # Drug Interactions - No dedicated drug interaction studies have been conducted. Coagulation tests - Lanadelumab can increase activated partial thromboplastin time (aPTT) due to an interaction of lanadelumab with the aPTT assay. The reagents used in the aPTT laboratory test initiate intrinsic coagulation through the activation of plasma kallikrein in the contact system. Inhibition of plasma kallikrein by lanadelumab can increase aPTT in this assay. In Trial 1, prolongation of aPTT (>1× ULN) was observed at one or more time points in 3, 9, and 11 patients treated with lanadelumab 150 mg q4 wks, 300 mg q4 wks, and 300 mg q2 wks, respectively, compared to 5 placebo-treated patients. Only one patient in the 300 mg q2 wks treatment group experienced transient aPTT prolongation ≥1.5× ULN which was confounded by ongoing heparin therapy. None of the increases in aPTT in patients treated with lanadelumab were associated with abnormal bleeding adverse events. There were no differences in INR values between treatment groups. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): Risk Summary - There are no available data on lanadelumab use in pregnant women to inform any drug associated risks. Monoclonal antibodies such as lanadelumab-flyo are transported across the placenta during the third trimester of pregnancy; therefore, potential effects on a fetus are likely to be greater during the third trimester of pregnancy. An enhanced pre-and postnatal development (ePPND) study conducted in pregnant monkeys at doses resulting in exposures of up to 33 times the exposure achieved (on an AUC basis) at the maximum recommended human dose (MRHD) revealed no evidence of harm to the developing fetus. - The background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. Animal Data - In the ePPND study, pregnant cynomolgus monkeys were administered lanadelumab-flyo once weekly at subcutaneous doses resulting in up to 33 times the exposure at the MRHD (on an AUC basis with maternal subcutaneous doses up to 50 mg/kg/week) from gestation day 20, at the beginning of organogenesis, through to parturition. There were no lanadelumab-flyo-related effects on maintenance of pregnancy or parturition. Maternal lanadelumab-flyo treatment had no effects on embryo-fetal development, survival, growth, or postnatal development of offspring through 3 months of age. Lanadelumab-flyo crossed the placenta in monkeys. Offspring were exposed to lanadelumab-flyo at approximately 50% of the maternal plasma concentration out to postnatal day 21 (PND 21). Lanadelumab-flyo concentrations were approximately equivalent in maternal and offspring plasma at PND 90. Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Lanadelumab in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Lanadelumab during labor and delivery. ### Nursing Mothers Risk Summary - There are no data on the presence of lanadelumab-flyo in human milk, its effects on the breastfed infant, or its effects on milk production. Lanadelumab-flyo was detected in the milk of lactating cynomolgus monkeys at approximately 0.2% of the maternal plasma concentration. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for lanadelumab and any potential adverse effects on the breastfed infant from lanadelumab or from the underlying maternal condition. Animal Data - Available pharmacokinetic data in cynomolgus monkeys have shown excretion of lanadelumab-flyo in milk at approximately 0.2% of the maternal plasma level. ### Pediatric Use - The safety and efficacy of lanadelumab were evaluated in a subgroup of patients (N=10) aged 12 to <18 years in Trial 1. Results of the subgroup analysis by age were consistent with overall study results. An additional 13 adolescent patients aged 12 to <18 years were enrolled in the open-label extension study. - The safety and efficacy of lanadelumab in pediatric patients < 12 years of age have not been established. ### Geriatic Use - The safety and efficacy of lanadelumab were evaluated in a subgroup of patients (N=5) aged ≥65 years in Trial 1. Results of the subgroup analysis by age were consistent with overall study results. ### Gender There is no FDA guidance on the use of Lanadelumab with respect to specific gender populations. ### Race There is no FDA guidance on the use of Lanadelumab with respect to specific racial populations. ### Renal Impairment There is no FDA guidance on the use of Lanadelumab in patients with renal impairment. ### Hepatic Impairment There is no FDA guidance on the use of Lanadelumab in patients with hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Lanadelumab in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Lanadelumab in patients who are immunocompromised. # Administration and Monitoring ### Administration - The recommended starting dose is 300 mg every 2 weeks. A dosing interval of 300 mg every 4 weeks is also effective and may be considered if the patient is well-controlled (e.g., attack free) for more than 6 months. - Lanadelumab is administered subcutaneously only. - Lanadelumab is provided as a ready-to-use solution in a single-dose vial that does not require additional reconstitution or dilution for administration. Lanadelumab is supplied as a clear to slightly opalescent, colorless to slightly yellow solution. Do not use the vial if it appears discolored or contains visible particles. Avoid vigorous agitation of the vial. - Lanadelumab is intended for self-administration or administration by a caregiver. The patient or caregiver should be trained by a healthcare professional. - Take the lanadelumab vial out of the refrigerator 15 minutes before injecting to allow it to equilibrate to room temperature. - Using aseptic technique, withdraw the prescribed dose of lanadelumab from the vial using an 18-gauge needle. Change the needle on the syringe to a 27-gauge, ½-inch needle or other needle suitable for subcutaneous injection. Inject lanadelumab subcutaneously into the abdomen, thigh, or upper arm. Patients should inject the complete dose as prescribed by their physician. In clinical studies, the majority of patients self-administered lanadelumab over 10 to 60 seconds. - Lanadelumab should be administered within 2 hours of preparing the dosing syringe. After the dosing syringe is prepared, it can be refrigerated at 36ºF to 46ºF (2°C to 8°C) and must be used within 8 hours. - Discard any unused portions of drug remaining in the vial and syringe. - For detailed instructions on the preparation and administration of lanadelumab see INSTRUCTIONS FOR USE. ### Monitoring There is limited information regarding Lanadelumab Monitoring in the drug label. # IV Compatibility There is limited information regarding the compatibility of Lanadelumab and IV administrations. # Overdosage - There is no clinical experience with overdosage of lanadelumab. # Pharmacology ## Mechanism of Action - Lanadelumab-flyo is a fully human monoclonal antibody (IgG1/κ-light chain) that binds plasma kallikrein and inhibits its proteolytic activity. Plasma kallikrein is a protease that cleaves high-molecular-weight-kininogen (HMWK) to generate cleaved HMWK (cHMWK) and bradykinin, a potent vasodilator that increases vascular permeability resulting in swelling and pain associated with HAE. In patients with HAE due to C1-inhibitor (C1-INH) deficiency or dysfunction, normal regulation of plasma kallikrein activity is not present, which leads to uncontrolled increases in plasma kallikrein activity and results in angioedema attacks. Lanadelumab-flyo decreases plasma kallikrein activity to control excess bradykinin generation in patients with HAE. ## Structure There is limited information regarding Lanadelumab Structure in the drug label. ## Pharmacodynamics - Concentration-dependent inhibition of plasma kallikrein, measured as reduction of cHMWK levels, was demonstrated after subcutaneous administration of lanadelumab 150 mg q4wks, 300 mg q4wks or 300 mg q2wks in patients with HAE. - Lanadelumab did not prolong the QT/QTc interval. ## Pharmacokinetics - Following subcutaneous administration, the pharmacokinetics of lanadelumab-flyo was approximately dose-proportional in the therapeutic dose range in patients with HAE (Table 2). The pharmacokinetic properties and exposure (steady state) of lanadelumab-flyo in HAE patients, following subcutaneous administration of 150 mg q4wks, 300 mg q4wks and 300 mg q2wks, are provided in Table 2. Following subcutaneous administration of lanadelumab, peak plasma concentrations are reached within 5 days, and terminal elimination half-life is ~2 weeks. The anticipated time to reach steady state concentration was approximately 70 days. At steady-state, the mean accumulation ratio is approximately 1.44, 1.42, and 2.43 for dosing regimen of 150 mg q4wks, 300 mg q4wks and 300 mg q2wks, respectively. Specific Populations - Population pharmacokinetic analyses showed that age, gender and race did not meaningfully influence the pharmacokinetics of lanadelumab-flyo after correcting for body weight. Body weight was identified as an important covariate describing the variability of clearance and volume of distribution, resulting in higher exposure (AUC and Cmax) in lighter patients. However, this difference is not considered to be clinically relevant and no dose adjustments are recommended for any of these demographics. Pediatric Population - Based on population pharmacokinetics (PK) analyses, the mean lanadelumab-flyo (±SD) AUCss was 629 (204) µgday/mL following SC administration of lanadelumab 300 mg every 2 weeks in pediatric patients 12 to less than 18 years of age. This is approximately 37% higher than the mean AUCss in adult patients (460 μgday/mL) under the same dosing regimen, due to lower body weight in pediatric patients. Renal Impairment - No dedicated studies have been conducted to evaluate the PK of lanadelumab-flyo in renal impairment patients. Based on population pharmacokinetic analysis, renal impairment (estimated GFR: 60 to 89 mL/min/1.73m2, [mild, N=98] and 30 to 59 mL/min/1.73m2, [moderate, N=9]) had no effect on the clearance or volume of distribution of lanadelumab-flyo. Concomitant medications - The use of analgesic, antibacterial, antihistamine, anti-inflammatory and antirheumatic medications had no effect on clearance and volume of distribution of lanadelumab-flyo. - For breakthrough HAE attacks, use of rescue medications such as plasma-derived and recombinant C1-INH, icatibant or ecallantide had no effects on clearance and volume of distribution of lanadelumab-flyo. ## Nonclinical Toxicology - Animal studies have not been conducted to evaluate the carcinogenic potential of lanadelumab-flyo. Published literature supports bradykinin, which is elevated in HAE, as a pro-tumorigenic molecule. However, the malignancy risk in humans from an antibody that inhibits plasma kallikrein activity, such as lanadelumab-flyo, which lowers bradykinin levels, is currently unknown. - Male and female fertility were unaffected based upon no observed adverse histopathological findings in the reproductive organs from sexually mature cynomolgus monkeys that received lanadelumab-flyo for 13 weeks at subcutaneous doses up to 50 mg/kg/week (resulting in approximately 22 times the exposure at the MRHD on an AUC basis). # Clinical Studies Trial 1 (NCT02586805) - The efficacy of lanadelumab for the prevention of angioedema attacks in patients 12 years of age and older with Type I or II HAE was demonstrated in a multicenter, randomized, double-blind, placebo-controlled parallel-group study (Trial 1). - The study included 125 adult and adolescent patients with Type I or II HAE who experienced at least one investigator-confirmed attack per 4 weeks during the run-in period. Patients were randomized into 1 of 4 parallel treatment arms, stratified by baseline attack rate, in a 3:2:2:2 ratio (placebo, lanadelumab-flyo 150 mg q4wks, lanadelumab-flyo 300 mg q4wks, or lanadelumab-flyo 300 mg q2wks by subcutaneous injection) for the 26-week treatment period. Patients ≥18 years of age were required to discontinue other prophylactic HAE medications prior to entering the study; however, all patients were allowed to use rescue medications for treatment of breakthrough HAE attacks. - Overall, 90% of patients had Type I HAE. A history of laryngeal angioedema attacks was reported in 65% of patients and 56% were on prior long-term prophylaxis. During the study run-in period, attack rates of ≥3 attacks/month were observed in 52% of patients overall. - All lanadelumab treatment arms produced clinically meaningful and statistically significant reductions in the mean HAE attack rate compared to placebo across all primary and secondary endpoints in the Intent-to-Treat population (ITT) as shown in Table 3. - The mean reduction in HAE attack rate was consistently higher across the lanadelumab treatment arms compared to placebo regardless of the baseline history of prior long-term prophylaxis, laryngeal attacks, or attack rate during the run-in period. - Additional pre-defined exploratory endpoints included the percentage of patients who were attack free for the entire 26-week treatment period and the percentage of patients achieving threshold (≥50%, ≥70%, ≥90%) reductions in HAE attack rates compared to run-in during the 26-week treatment period. A ≥50% reduction in HAE attack rate was observed in 100% of patients on 300 mg q2wks or q4wks and 89% on 150 mg q4wks compared to 32% of placebo patients. A ≥70% reduction in HAE attack rates was observed in 89%, 76%, and 79% of patients on 300 mg q2wks, 300 mg q4wks, and 150 mg q4wks, respectively, compared to 10% of placebo patients. A ≥90% reduction in HAE attack rates was observed 67%, 55%, and 64% of patients on 300 mg q2wks, 300 mg q4wks, and 150 mg q4wks, respectively, compared to 5% of placebo patients. - The percentage of attack-free patients for the entire 26-week treatment period was 44%, 31%, and 39% in the lanadelumab 300 mg q2wks, 300 mg q4wks, and 150 mg q4wks groups respectively, compared to 2% of placebo patients. Trial 2 (NCT02741596) - Patients who completed Trial 1 were eligible to rollover into an open-label extension study. Rollover patients, regardless of randomization group in Trial 1, received a single dose of lanadelumab 300 mg at study entry and were followed until the first HAE attack occurred. All efficacy endpoints were exploratory in this uncontrolled, unblinded study. At week 4 post-dose, approximately 80% of patients who had been in the 300 mg q2wks treatment group (N=25) in Trial 1 remained attack-free. After the first HAE attack, all patients received open-label treatment with lanadelumab 300 mg q2wks. # How Supplied - Lanadelumab (lanadelumab-flyo) injection is a ready-to-use, clear to slightly opalescent, colorless to slightly yellow solution supplied in a carton containing one single-dose glass vial with chlorobutyl rubber stopper, aluminum crimp seal and polypropylene flip-off cap. - 300 mg/2 mL (150 mg/mL) vial. ## Storage - Store vials refrigerated at 36°F to 46°F (2°C to 8°C). - Do not freeze. Do not shake. - Keep the vial in the original carton in order to protect the vial from light. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information Hypersensitivity - Advise patients to seek immediate medical attention if they experience any symptoms of serious hypersensitivity reactions. Self-administration: - Ensure that the patient/caregiver receives clear instructions and training on subcutaneous administration and has demonstrated the ability to perform a subcutaneous injection. - Instruct patients or caregivers in the technique of proper syringe and needle disposal, and advise them not to reuse these items. Instruct patients to dispose needles and syringes in a puncture-resistant container. - Be sure that you read, understand, and follow the Instructions for Use before injecting lanadelumab. A healthcare provider should show you how to prepare and inject lanadelumab properly before you use it for the first time. Contact your healthcare provider if you have any questions. Important information: - Lanadelumab is a ready-to-use solution for injection under the skin (subcutaneous). It is supplied in a single-dose, glass vial. - Your healthcare provider will prescribe the dose that you should take. - Only use the syringes, transfer needles, and injection needles that your healthcare provider prescribes. - Only use the syringes, transfer needles and injection needles 1 time. Throw away (dispose of) any used syringes and needles. Storing lanadelumab: - Store lanadelumab in the refrigerator at 36°F to 46°F (2°C to 8°C). Do not freeze. - Store lanadelumab in the original carton to protect the vial from light. - Do not shake lanadelumab. - Keep lanadelumab and all medicines out of the reach of children. Supplies needed for your lanadelumab Injection STEP 1: Prepare for your injection - Gather all supplies and place them on a well-lighted flat work surface. - Take the vial out of the refrigerator 15 minutes before use and allow it to reach room temperature before preparing an injection. - Check the expiration date on the box and vial label of lanadelumab. Do not use if the expiration date has passed. - Check the supplies for damage. Do not use if they appear damaged. - Clean your work area and wash your hands before preparing your dose. Do not touch any surface or body part, especially your face, after washing your hands before injection. - Remove the vial from the packaging. Do not use the vial if the plastic cap covering is missing. STEP 2: Attach transfer needle to syringe STEP 3: Transfer lanadelumab into syringe and switch to the injection needle STEP 4: Select and prepare injection site STEP 5: Inject lanadelumab STEP 6: THROW AWAY (DISPOSE OF) NEEDLE AND SYRINGE - For more information, visit www.takhzyro.com - This Instructions for Use has been approved by the U.S. Food and Drug Administration. # Precautions with Alcohol Alcohol-Lanadelumab interaction has not been established. Talk to your doctor regarding the effects of taking alcohol with this medication. # Brand Names Takhzyro # Look-Alike Drug Names There is limited information regarding Lanadelumab Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	https://www.wikidoc.org/index.php/Lanadelumab
9e647026ad91d9a150a50eb89b937bc9b6561a53	wikidoc	Large-print	Large-print Large-print (also large-type or large-font) describes a type of book or other (paper, online or otherwise) published material in which the typeface (or font), and sometimes the medium, are considerably larger than usual, to accommodate people who have poor vision. Often public special-needs libraries will stock large-print versions of books, along with versions written in Braille. Among librarians Large Print is defined as print that is at least 16 points in size. Large Print book publishing in English began in 1964 in Leicester, England when Frederick Thorpe, a retired book and magazine distributor, decided to meet the needs of elderly poor-sighted readers by reprinting older classic books in editions about twice the physical size of the original book.The type inside was enlarged to about twice the size of the original printing. The books were given plain dustjackets with type only, color-coded to indicate categories like mysteries (black), general fiction (red), romances (blue), westerns (orange) and so forth. These editions met the need but were difficult for frail elderly readers to handle because of they were oversize. In 1969 Thorpe's company, Ulverscroft, began to retypeset the books in 16 point type and print them in normal-sized bindings, again with color-coded plain jackets. This change greatly increased the acceptance of Large Print in public libraries. Thorpe himself became a Large Print ambassador, travelling around the English-speaking world promoting the acquisition of Large Print books for seniors. Today Large Print editions of some current books are published simultaneously with regular print editions by their publishers and usually feature the same full-color jackets and jacket designs. Many, if not most public libraries in the English-speaking world have Large Print sections and most bookstores do carry some Large Print editions.	Large-print Large-print (also large-type or large-font) describes a type of book or other (paper, online or otherwise) published material in which the typeface (or font), and sometimes the medium, are considerably larger than usual, to accommodate people who have poor vision. Often public special-needs libraries will stock large-print versions of books, along with versions written in Braille. Among librarians Large Print is defined as print that is at least 16 points in size. Large Print book publishing in English began in 1964 in Leicester, England when Frederick Thorpe, a retired book and magazine distributor, decided to meet the needs of elderly poor-sighted readers by reprinting older classic books in editions about twice the physical size of the original book.[1]The type inside was enlarged to about twice the size of the original printing. The books were given plain dustjackets with type only, color-coded to indicate categories like mysteries (black), general fiction (red), romances (blue), westerns (orange) and so forth. These editions met the need but were difficult for frail elderly readers to handle because of they were oversize. In 1969 Thorpe's company, Ulverscroft, began to retypeset the books in 16 point type and print them in normal-sized bindings, again with color-coded plain jackets. This change greatly increased the acceptance of Large Print in public libraries. Thorpe himself became a Large Print ambassador, travelling around the English-speaking world promoting the acquisition of Large Print books for seniors. Today Large Print editions of some current books are published simultaneously with regular print editions by their publishers and usually feature the same full-color jackets and jacket designs. Many, if not most public libraries in the English-speaking world have Large Print sections and most bookstores do carry some Large Print editions.	https://www.wikidoc.org/index.php/Large-print
9a3fe9d39c6d449a3401f27c62e40602631b5dea	wikidoc	Vocal folds	Vocal folds # Overview The vocal folds, also known popularly as vocal cords, are composed of twin infoldings of mucous membrane stretched horizontally across the larynx. They vibrate, modulating the flow of air being expelled from the lungs during phonation. Open during inhalation, closed when holding one's breath, and vibrating for speech or singing (opening and closing 440 times per second when singing A above middle C); the folds are controlled via the vagus nerve. They are white because of scant blood circulation. # Vocal fold oscillation The larynx is a major (but not the only) source of sound in speech, generating sound through the rhythmic opening and closing of the vocal folds. To oscillate, the vocal folds are brought near enough together such that air pressure builds up beneath the larynx. The folds are pushed apart by this increased subglottal pressure, with the inferior part of each fold leading the superior part. The natural resilience of the folds brings them back together. Under the correct conditions, this oscillation pattern will sustain itself. In essence, sound is generated in the larynx by chopping up a steady flow of air into little puffs. The pitch of a person's voice is a that is determined by a number of different factors, but largely by the fundamental frequency of the sound generated by the larynx. A person's natural fundamental frequency is influenced by many factors, including the length, size, and tension of the vocal folds. In an adult male, this frequency averages about 125 Hz, adult females around 210 Hz, in children the frequency is over 300 Hz. # Sex differences Men and women have different vocal fold sizes. Adult male voices are usually lower pitched and have larger folds. The male vocal folds (which would be measured vertically in the opposite diagram), are between 17 mm and 25 mm in length. Matching the female body, which on the whole has less muscle than the male, females have smaller folds. The female vocal folds are between 12.5 mm and 17.5 mm in length. The folds are located just above the trachea or the windpipe which travels from the lungs. Food and drink does not pass through the folds but is instead taken through the esophagus, an unlinked tube. Both tubes are separated by the tongue and an automatic gag reflex. When food goes down through the folds and trachea it causes choking. Folds in both sexes are ligaments within the larynx. They are attached at the back (side nearest the spinal cord) to the arytenoid cartilages, and at the front (side under the chin) to the thyroid cartilage. Their outer edges (as shown in the illustration) are attached to muscle in the larynx while their inner edges, or margins are free (the hole). They are constructed from epithelium, but they have a few muscle fibres on them, namely the vocalis muscle which tightens the front part of the ligament near to the thyroid cartilage. They are flat triangular bands and are pearly white in colour - whiter in females than they are in males. Above both sides of the vocal cord (the hole and the ligament itself) is the vestibular fold or false vocal fold, which has a small sac between its two folds (not illustrated). The difference in vocal fold size between men and women means that they have differently pitched voices. Additionally, genetics also causes variances amongst the same sex, with men's and women's voices being categorised into types. The term vocal cords is occasionally misspelled 'vocal chords', possibly due to the musical connotations or to confusion with the geometrical definition of the word "chord". # False vocal folds The vocal folds discussed above are sometimes called 'true vocal folds' to distinguish them from the false vocal folds. These are a pair of thick folds of mucous membrane that sit just above, and protect, the more delicate true folds. They have minimal role in normal phonation, but are often used in musical screaming and the death grunt singing style. The false folds are also called vestibular folds and ventricular folds. They can be seen on the diagram above as ventricular folds. False vocal folds, when surgically removed, can regenerate completely.	Vocal folds Template:Infobox Anatomy Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview The vocal folds, also known popularly as vocal cords, are composed of twin infoldings of mucous membrane stretched horizontally across the larynx. They vibrate, modulating the flow of air being expelled from the lungs during phonation. Open during inhalation, closed when holding one's breath, and vibrating for speech or singing (opening and closing 440 times per second when singing A above middle C); the folds are controlled via the vagus nerve. They are white because of scant blood circulation. # Vocal fold oscillation The larynx is a major (but not the only) source of sound in speech, generating sound through the rhythmic opening and closing of the vocal folds. To oscillate, the vocal folds are brought near enough together such that air pressure builds up beneath the larynx. The folds are pushed apart by this increased subglottal pressure, with the inferior part of each fold leading the superior part. The natural resilience of the folds brings them back together. Under the correct conditions, this oscillation pattern will sustain itself. In essence, sound is generated in the larynx by chopping up a steady flow of air into little puffs. The pitch of a person's voice is a [percept] that is determined by a number of different factors, but largely by the fundamental frequency of the sound generated by the larynx. A person's natural fundamental frequency is influenced by many factors, including the length, size, and tension of the vocal folds. In an adult male, this frequency averages about 125 Hz, adult females around 210 Hz, in children the frequency is over 300 Hz. # Sex differences Men and women have different vocal fold sizes. Adult male voices are usually lower pitched and have larger folds. The male vocal folds (which would be measured vertically in the opposite diagram), are between 17 mm and 25 mm in length.[1] Matching the female body, which on the whole has less muscle than the male, females have smaller folds. The female vocal folds are between 12.5 mm and 17.5 mm in length.[1] The folds are located just above the trachea or the windpipe which travels from the lungs. Food and drink does not pass through the folds but is instead taken through the esophagus, an unlinked tube. Both tubes are separated by the tongue and an automatic gag reflex. When food goes down through the folds and trachea it causes choking. Folds in both sexes are ligaments within the larynx. They are attached at the back (side nearest the spinal cord) to the arytenoid cartilages, and at the front (side under the chin) to the thyroid cartilage. Their outer edges (as shown in the illustration) are attached to muscle in the larynx while their inner edges, or margins are free (the hole). They are constructed from epithelium, but they have a few muscle fibres on them, namely the vocalis muscle which tightens the front part of the ligament near to the thyroid cartilage. They are flat triangular bands and are pearly white in colour - whiter in females than they are in males. Above both sides of the vocal cord (the hole and the ligament itself) is the vestibular fold or false vocal fold, which has a small sac between its two folds (not illustrated).[1] The difference in vocal fold size between men and women means that they have differently pitched voices. Additionally, genetics also causes variances amongst the same sex, with men's and women's voices being categorised into types. The term vocal cords is occasionally misspelled 'vocal chords', possibly due to the musical connotations or to confusion with the geometrical definition of the word "chord". # False vocal folds The vocal folds discussed above are sometimes called 'true vocal folds' to distinguish them from the false vocal folds. These are a pair of thick folds of mucous membrane that sit just above, and protect, the more delicate true folds. They have minimal role in normal phonation, but are often used in musical screaming and the death grunt singing style. The false folds are also called vestibular folds and ventricular folds. They can be seen on the diagram above as ventricular folds. False vocal folds, when surgically removed, can regenerate completely.	https://www.wikidoc.org/index.php/Laryngeal_cord
c05ea8c25e4b875cea1c8c58de4a18b04e137c5d	wikidoc	Lassa virus	Lassa virus # Overview Lassa fever is caused by the Lassa virus, a member of the zoonotic Arenaviridae family. It is an enveloped, single-stranded, bisegmented RNA virus. The natural reservoir of Lassa virus is the Mastomys natalensis rodent (multimammate rat/mouse) that sheds the virus in urine and fecal droppings. # Microbiological Characteristics ## Taxonomy - Viruses; ssRNA viruses; ssRNA negative-strand viruses; Arenaviridae; Mammarenavirus ## Biology - Lassa virus belongs to Arenaviridae. - The Arenaviridae are a family of viruses whose members are generally associated with rodent-transmitted diseases in humans (zoonotic). Each virus usually is associated with a particular rodent host species in which it is maintained. ## Structure - Lassa virus is an enveloped, single-stranded, bisegmented, ambisense RNA virus. ## Genome - Lassa virus genome is contained in two RNA segments, each of which encodes 2 viral proteins (total 4 viral proteins) The large segment encodes RNA polymerase (L) and a small zinc-binding protein (Z) that regulates transcription and replication The small segment encodes the nucleoprotein (NP) and the surface glycoprotein precursor (GP or viral spike). The GP protein is cleaved into the envelope glycoproteins, GP1 and GP2, that bind to the alpha-dystroglycan receptor and mediate host cell entry - The large segment encodes RNA polymerase (L) and a small zinc-binding protein (Z) that regulates transcription and replication - The small segment encodes the nucleoprotein (NP) and the surface glycoprotein precursor (GP or viral spike). The GP protein is cleaved into the envelope glycoproteins, GP1 and GP2, that bind to the alpha-dystroglycan receptor and mediate host cell entry - Nucleotide studies of the genome have shown that Lassa has four lineages: Three in Nigeria and a fourth in Guinea, Liberia, and Sierra Leone. The Nigerian strains are thought to be ancestral to the others.. # Natural Reservoir - The most common natural reservoir of Lassa virus is the rodent, Mastomys natalensis. Mastomys natalensis is commonly known as the “multimammate rat/mouse” due to the female’s multiple and prominent mammary glands. - The mastomys rodents are abundant in the Savannas and forests of West, Central, and East Africa. - Once infected, the rodent is able to excrete the virus in the urine and feces for an extended time period. Mastomys rodents breed frequently, produce large numbers of offspring, and commonly inhabit human homes with food storage. All of these factors contribute to the relatively efficient spread of Lassa virus from infected rodents to humans. # Gallery The images below display key features of the Lassa virus. - This transmission electron micrograph (TEM) demonstrates Lassa virus virions adjacent to host cell debris.Retrieved from the Public Health Image Library (PHIL), Centers for Disease Control and Prevention. - This highly magnified transmission electron micrograph (TEM) demonstrates ultrastructural details of 3 Lassa virus virions.Retrieved from the Public Health Image Library (PHIL), Centers for Disease Control and Prevention. - This transmission electron micrograph depicted eight virions (viral particles) of an Arenavirus.Retrieved from the Public Health Image Library (PHIL), Centers for Disease Control and Prevention.	Lassa virus Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Ammu Susheela, M.D. [2] # Overview Lassa fever is caused by the Lassa virus, a member of the zoonotic Arenaviridae family. It is an enveloped, single-stranded, bisegmented RNA virus. The natural reservoir of Lassa virus is the Mastomys natalensis rodent (multimammate rat/mouse) that sheds the virus in urine and fecal droppings. # Microbiological Characteristics ## Taxonomy - Viruses; ssRNA viruses; ssRNA negative-strand viruses; Arenaviridae; Mammarenavirus [1] ## Biology - Lassa virus belongs to Arenaviridae.[2] - The Arenaviridae are a family of viruses whose members are generally associated with rodent-transmitted diseases in humans (zoonotic). Each virus usually is associated with a particular rodent host species in which it is maintained. ## Structure - Lassa virus is an enveloped, single-stranded, bisegmented, ambisense RNA virus. ## Genome - Lassa virus genome is contained in two RNA segments, each of which encodes 2 viral proteins (total 4 viral proteins)[3][4] The large segment encodes RNA polymerase (L) and a small zinc-binding protein (Z) that regulates transcription and replication[5][6] The small segment encodes the nucleoprotein (NP) and the surface glycoprotein precursor (GP or viral spike). The GP protein is cleaved into the envelope glycoproteins, GP1 and GP2, that bind to the alpha-dystroglycan receptor and mediate host cell entry[7] - The large segment encodes RNA polymerase (L) and a small zinc-binding protein (Z) that regulates transcription and replication[5][6] - The small segment encodes the nucleoprotein (NP) and the surface glycoprotein precursor (GP or viral spike). The GP protein is cleaved into the envelope glycoproteins, GP1 and GP2, that bind to the alpha-dystroglycan receptor and mediate host cell entry[7] - Nucleotide studies of the genome have shown that Lassa has four lineages: Three in Nigeria and a fourth in Guinea, Liberia, and Sierra Leone. The Nigerian strains are thought to be ancestral to the others.[8]. # Natural Reservoir - The most common natural reservoir of Lassa virus is the rodent, Mastomys natalensis. Mastomys natalensis is commonly known as the “multimammate rat/mouse” due to the female’s multiple and prominent mammary glands. - The mastomys rodents are abundant in the Savannas and forests of West, Central, and East Africa. - Once infected, the rodent is able to excrete the virus in the urine and feces for an extended time period. Mastomys rodents breed frequently, produce large numbers of offspring, and commonly inhabit human homes with food storage. All of these factors contribute to the relatively efficient spread of Lassa virus from infected rodents to humans. # Gallery The images below display key features of the Lassa virus. - This transmission electron micrograph (TEM) demonstrates Lassa virus virions adjacent to host cell debris.Retrieved from the Public Health Image Library (PHIL), Centers for Disease Control and Prevention.[10] - This highly magnified transmission electron micrograph (TEM) demonstrates ultrastructural details of 3 Lassa virus virions.Retrieved from the Public Health Image Library (PHIL), Centers for Disease Control and Prevention.[10] - This transmission electron micrograph depicted eight virions (viral particles) of an Arenavirus.Retrieved from the Public Health Image Library (PHIL), Centers for Disease Control and Prevention.[10]	https://www.wikidoc.org/index.php/Lassa_fever_causes
103454311dc9e2991d779673f03c7fe9259a5848	wikidoc	Latanoprost	Latanoprost # 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 Latanoprost is a prostaglandin that is FDA approved for the {{{indicationType}}} of open angle glaucoma. Common adverse reactions include blurred vision, burning sensation in eye, conjunctival hyperemia, foreign body sensation, iris color change, itching of eye, punctate keratopathy. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) - Dosing Information - Latanoprost ophthalmic solution is indicated for the reduction of elevated intraocular pressure in patients with open-angle glaucoma or ocular hypertension - The recommended dosage is one drop (1.5 mcg) in the affected eye(s) once daily in the evening. - If one dose is missed, treatment should continue with the next dose as normal. - The dosage of Latanoprost Ophthalmic Solution should not exceed once daily; the combined use of two or more prostaglandins, or prostaglandin analogs including Latanoprost Ophthalmic Solution is not recommended. It has been shown that administration of these prostaglandin drug products more than once daily may decrease the intraocular pressure lowering effect or cause paradoxical elevations in IOP. - Reduction of the intraocular pressure starts approximately 3 to 4 hours after administration and the maximum effect is reached after 8 to 12 hours. - Latanoprost Ophthalmic Solution may be used concomitantly with other topical ophthalmic drug products to lower intraocular pressure. If more than one topical ophthalmic drug is being used, the drugs should be administered at least five (5) minutes apart. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Latanoprost in adult patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Latanoprost in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) There is limited information regarding FDA-Labeled Use of Latanoprost in pediatric patients. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Latanoprost in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Latanoprost in pediatric patients. # Contraindications - Known hypersensitivity to latanoprost, benzalkonium chloride or any other ingredients in this product. # Warnings - Latanoprost ophthalmic solution has been reported to cause changes to pigmented tissues. The most frequently reported changes have been increased pigmentation of the iris, periorbital tissue (eyelid) and eyelashes, and growth of eyelashes. Pigmentation is expected to increase as long as latanoprost ophthalmic solution is administered. After discontinuation of latanoprost ophthalmic solution, pigmentation of the iris is likely to be permanent while pigmentation of the periorbital tissue and eyelash changes have been reported to be reversible in some patients. Patients who receive treatment should be informed of the possibility of increased pigmentation. The effects of increased pigmentation beyond 5 years are not known. ### Precautions - Latanoprost ophthalmic solution may gradually increase the pigmentation of the iris. The eye color change is due to increased melanin content in the stromal melanocytes of the iris rather than to an increase in the number of melanocytes. This change may not be noticeable for several months to years. Typically, the brown pigmentation around the pupil spreads concentrically towards the periphery of the iris and the entire iris or parts of the iris become more brownish. Neither nevi nor freckles of the iris appear to be affected by treatment. While treatment with latanoprost ophthalmic solution can be continued in patients who develop noticeably increased iris pigmentation, these patients should be examined regularly. - During clinical trials, the increase in brown iris pigment has not been shown to progress further upon discontinuation of treatment, but the resultant color change may be permanent. - Eyelid skin darkening, which may be reversible, has been reported in association with the use of latanoprost ophthalmic solution. - Latanoprost ophthalmic solution may gradually change eyelashes and vellus hair in the treated eye; these changes include increased length, thickness, pigmentation, the number of lashes or hairs, and misdirected growth of eyelashes. Eyelash changes are usually reversible upon discontinuation of treatment. - Latanoprost ophthalmic solution should be used with caution in patients with a history of intraocular inflammation (iritis/uveitis) and should generally not be used in patients with active intraocular inflammation. - Macular edema, including cystoid macular edema, has been reported during treatment with latanoprost ophthalmic solution. These reports have mainly occurred in aphakic patients, in pseudophakic patients with a torn posterior lens capsule, or in patients with known risk factors for macular edema. Latanoprost ophthalmic solution should be used with caution in patients who do not have an intact posterior capsule or who have known risk factors for macular edema. - There is limited experience with latanoprost ophthalmic solution in the treatment of angle closure, inflammatory or neovascular glaucoma. - There have been reports of bacterial keratitis associated with the use of multiple-dose containers of topical ophthalmic products. These containers had been inadvertently contaminated by patients who, in most cases, had a concurrent corneal disease or a disruption of the ocular epithelial surface. - Contact lenses should be removed prior to the administration of latanoprost ophthalmic solution, and may be reinserted 15 minutes after administration. # Adverse Reactions ## Clinical Trials Experience - Adverse events referred to in other sections of this insert - Eyelash changes (increased length, thickness, pigmentation, and number of lashes); eyelid skin darkening; intraocular inflammation (iritis/uveitis); iris pigmentation changes; and macular edema, including cystoid macular edema. - Controlled Clinical Trials - The ocular adverse events and ocular signs and symptoms reported in 5 to 15% of the patients on latanoprost ophthalmic solution in the three 6-month, multi-center, double-masked, active-controlled trials were blurred vision, burning and stinging, conjunctival hyperemia, foreign body sensation, itching, increased pigmentation of the iris, and punctate epithelial keratopathy. - Local conjunctival hyperemia was observed; however, less than 1% of the patients treated with latanoprost ophthalmic solution required discontinuation of therapy because of intolerance to conjunctival hyperemia. - In addition to the above listed ocular events/signs and symptoms, the following were reported in 1 to 4% of the patients: dry eye, excessive tearing, eye pain, lid crusting, lid discomfort/pain, lid edema, lid erythema, and photophobia. - The following events were reported in less than 1% of the patients: conjunctivitis, diplopia and discharge from the eye. - During clinical studies, there were extremely rare reports of the following: retinal artery embolus, retinal detachment, and vitreous hemorrhage from diabetic retinopathy. - The most common systemic adverse events seen with latanoprost ophthalmic solution were upper respiratory tract infection/cold/flu, which occurred at a rate of approximately 4%. Chest pain/angina pectoris, muscle/joint/back pain, and rash/allergic skin reaction each occurred at a rate of 1 to 2%. ## Postmarketing Experience - The following events have been identified during postmarketing use of latanoprost ophthalmic solution in clinical practice. Because they are reported voluntarily from a population of unknown size, estimates of frequency cannot be made. The events, which have been chosen for inclusion due to either their seriousness, frequency of reporting, possible causal connection to latanoprost ophthalmic solution, or a combination of these factors, include: asthma and exacerbation of asthma; corneal edema and erosions; dyspnea; eyelash and vellus hair changes (increased length, thickness, pigmentation, and number); eyelid skin darkening; herpes keratitis; intraocular inflammation (iritis/ uveitis); keratitis; macular edema, including cystoid macular edema; misdirected eyelashes sometimes resulting in eye irritation; dizziness, headache, and toxic epidermal necrolysis. # Drug Interactions - In vitro studies have shown that precipitation occurs when eye drops containing thimerosal are mixed with latanoprost ophthalmic solution. If such drugs are used they should be administered at least five (5) minutes apart. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): - Pregnancy Category C' - Reproduction studies have been performed in rats and rabbits. In rabbits an incidence of 4 of 16 dams had no viable fetuses at a dose that was approximately 80 times the maximum human dose, and the highest nonembryocidal dose in rabbits was approximately 15 times the maximum human dose. There are no adequate and well-controlled studies in pregnant women. Latanoprost ophthalmic solution 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 Latanoprost in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Latanoprost during labor and delivery. ### Nursing Mothers - It is not known whether this drug or its metabolites are excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when latanoprost ophthalmic solution is administered to a nursing woman. ### Pediatric Use - Safety and effectiveness in pediatric patients have not been established. ### Geriatic Use - No overall differences in safety or effectiveness have been observed between elderly and younger patients. ### Gender There is no FDA guidance on the use of Latanoprost with respect to specific gender populations. ### Race There is no FDA guidance on the use of Latanoprost with respect to specific racial populations. ### Renal Impairment There is no FDA guidance on the use of Latanoprost in patients with renal impairment. ### Hepatic Impairment There is no FDA guidance on the use of Latanoprost in patients with hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Latanoprost in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Latanoprost in patients who are immunocompromised. # Administration and Monitoring ### Administration - Topical ### Monitoring There is limited information regarding Monitoring of Latanoprost in the drug label. # IV Compatibility There is limited information regarding IV Compatibility of Latanoprost in the drug label. # Overdosage ## Acute Overdose ### Signs and Symptoms - Apart from ocular irritation and conjunctival or episcleral hyperemia, the ocular effects of latanoprost administered at high doses are not known. Intravenous administration of large doses of latanoprost in monkeys has been associated with transient bronchoconstriction; however, in 11 patients with bronchial asthma treated with latanoprost, bronchoconstriction was not induced. Intravenous infusion of up to 3 mcg/kg in healthy volunteers produced mean plasma concentrations 200 times higher than during clinical treatment and no adverse reactions were observed. Intravenous dosages of 5.5 to 10 mcg/kg caused abdominal pain, dizziness, fatigue, hot flushes, nausea and sweating. ### Management - If overdosage with latanoprost ophthalmic solution occurs, treatment should be symptomatic. ## Chronic Overdose There is limited information regarding Chronic Overdose of Latanoprost in the drug label. # Pharmacology ## Mechanism of Action - Latanoprost is a prostanoid selective FP receptor agonist that is believed to reduce the intraocular pressure (IOP) by increasing the outflow of aqueous humor. Studies in animals and man suggest that the main mechanism of action is increased uveoscleral outflow. Elevated IOP represents a major risk factor for glaucomatous field loss. The higher the level of IOP, the greater the likelihood of optic nerve damage and visual field loss. ## Structure - Latanoprost is a prostaglandin F2α analogue. Its chemical name is isopropyl-(Z)-7 cyclopentyl]-5-heptenoate. Its molecular formula is C26H40O5 and its chemical structure is: - Latanoprost is a colorless to slightly yellow oil that is very soluble in acetonitrile and freely soluble in acetone, ethanol, ethyl acetate, isopropanol, methanol and octanol. It is practically insoluble in water. - Latanoprost Ophthalmic Solution is supplied as a sterile, isotonic, buffered aqueous solution of latanoprost with a pH of approximately 6.7 and an osmolality of approximately 267 mOsmol/kg. Each mL of Latanoprost Ophthalmic Solution contains 50 micrograms of latanoprost. Benzalkonium chloride, 0.02% is added as a preservative. The inactive ingredients are: sodium chloride, sodium dihydrogen phosphate monohydrate, disodium hydrogen phosphate anhydrous and water for injection. One drop contains approximately 1.5 mcg of latanoprost. ## Pharmacodynamics There is limited information regarding Pharmacodynamics of Latanoprost in the drug label. ## Pharmacokinetics - Absorption: Latanoprost is absorbed through the cornea where the isopropyl ester prodrug is hydrolyzed to the acid form to become biologically active. Studies in man indicate that the peak concentration in the aqueous humor is reached about two hours after topical administration. - Distribution: The distribution volume in humans is 0.16 ± 0.02 L/kg. The acid of latanoprost can be measured in aqueous humor during the first 4 hours, and in plasma only during the first hour after local administration. - Metabolism: Latanoprost, an isopropyl ester prodrug, is hydrolyzed by esterases in the cornea to the biologically active acid. The active acid of latanoprost reaching the systemic circulation is primarily metabolized by the liver to the 1,2-dinor and 1,2,3,4-tetranor metabolites via fatty acid β-oxidation. - Excretion: The elimination of the acid of latanoprost from human plasma is rapid (t1/2=17 min) after both intravenous and topical administration. Systemic clearance is approximately 7 mL/min/kg. Following hepatic β-oxidation, the metabolites are mainly eliminated via the kidneys. Approximately 88% and 98% of the administered dose is recovered in the urine after topical and intravenous dosing, respectively. ## Nonclinical Toxicology - In monkeys, latanoprost has been shown to induce increased pigmentation of the iris. The mechanism of increased pigmentation seems to be stimulation of melanin production in melanocytes of the iris, with no proliferative changes observed. The change in iris color may be permanent. - Ocular administration of latanoprost at a dose of 6 mcg/eye/day (4 times the daily human dose) to cynomolgus monkeys has also been shown to induce increased palpebral fissure. This effect was reversible upon discontinuation of the drug. - Latanoprost was not mutagenic in bacteria, in mouse lymphoma or in mouse micronucleus tests. - Chromosome aberrations were observed in vitro with human lymphocytes. - Latanoprost was not carcinogenic in either mice or rats when administered by oral gavage at doses of up to 170 mcg/kg/day (approximately 2,800 times the recommended maximum human dose) for up to 20 and 24 months, respectively. - Additional in vitro and in vivo studies on unscheduled DNA synthesis in rats were negative. Latanoprost has not been found to have any effect on male or female fertility in animal studies. # Clinical Studies - Patients with mean baseline intraocular pressure of 24 to 25 mmHg who were treated for 6 months in multi-center, randomized, controlled trials demonstrated 6 to 8 mmHg reductions in intraocular pressure. This IOP reduction with latanoprost ophthalmic solution 0.005% dosed once daily was equivalent to the effect of timolol 0.5% dosed twice daily. - A 3-year open-label, prospective safety study with a 2-year extension phase was conducted to evaluate the progression of increased iris pigmentation with continuous use of latanoprost ophthalmic solution once-daily as adjunctive therapy in 519 patients with open-angle glaucoma. The analysis was based on observed-cases population of the 380 patients who continued in the extension phase. - Results showed that the onset of noticeable increased iris pigmentation occurred within the first year of treatment for the majority of the patients who developed noticeable increased iris pigmentation. Patients continued to show signs of increasing iris pigmentation throughout the five years of the study. Observation of increased iris pigmentation did not affect the incidence, nature or severity of adverse events (other than increased iris pigmentation) recorded in the study. IOP reduction was similar regardless of the development of increased iris pigmentation during the study. # How Supplied - Latanoprost Ophthalmic Solution is a sterile, clear, isotonic, buffered, preserved, colorless solution of latanoprost 0.005% (50 mcg/mL). It is supplied as a 2.5 mL solution in a 5 mL natural low density polyethylene bottle with a natural low density polyethylene dropper tip and a turquoise polypropylene screw cap. - 2.5 mL fill, 0.005% (50 mcg/mL) - NDC 0517-0830-01 Package of 1 bottle - NDC 0517-0830-03 Multi-pack of 3 bottles - Storage - Protect from light. Store unopened bottle(s) under refrigeration at 2° to 8°C (36° to 46°F). During shipment to the patient, the bottle may be maintained at temperatures up to 40°C (104°F) for a period not exceeding 8 days. Once a bottle is opened for use, it may be stored at room temperature up to 25°C (77°F) for 6 weeks. ## Storage There is limited information regarding Latanoprost Storage in the drug label. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information - Patients should be advised about the potential for increased brown pigmentation of the iris, which may be permanent. Patients should also be informed about the possibility of eyelid skin darkening, which may be reversible after discontinuation of latanoprost ophthalmic solution. - Patients should also be informed of the possibility of eyelash and vellus hair changes in the treated eye during treatment with latanoprost ophthalmic solution. These changes may result in a disparity between eyes in length, thickness, pigmentation, number of eyelashes or vellus hairs, and/or direction of eyelash growth. Eyelash changes are usually reversible upon discontinuation of treatment. - Patients should be instructed to avoid allowing the tip of the dispensing container to contact the eye or surrounding structures because this could cause the tip to become contaminated by common bacteria known to cause ocular infections. Serious damage to the eye and subsequent loss of vision may result from using contaminated solutions. - Patients also should be advised that if they develop an intercurrent ocular condition (e.g., trauma, or infection) or have ocular surgery, they should immediately seek their physician's advice concerning the continued use of the multiple-dose container. - Patients should be advised that if they develop any ocular reactions, particularly conjunctivitis and lid reactions, they should immediately seek their physician's advice. - Patients should also be advised that latanoprost ophthalmic solution contains benzalkonium chloride, which may be absorbed by contact lenses. Contact lenses should be removed prior to administration of the solution. Lenses may be reinserted 15 minutes following administration of latanoprost ophthalmic solution. - If more than one topical ophthalmic drug is being used, the drugs should be administered at least five (5) minutes apart. # Precautions with Alcohol - Alcohol-Latanoprost interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - LATANOPROST ® # Look-Alike Drug Names There is limited information regarding Latanoprost Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	Latanoprost 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 Latanoprost is a prostaglandin that is FDA approved for the {{{indicationType}}} of open angle glaucoma. Common adverse reactions include blurred vision, burning sensation in eye, conjunctival hyperemia, foreign body sensation, iris color change, itching of eye, punctate keratopathy. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) - Dosing Information - Latanoprost ophthalmic solution is indicated for the reduction of elevated intraocular pressure in patients with open-angle glaucoma or ocular hypertension - The recommended dosage is one drop (1.5 mcg) in the affected eye(s) once daily in the evening. - If one dose is missed, treatment should continue with the next dose as normal. - The dosage of Latanoprost Ophthalmic Solution should not exceed once daily; the combined use of two or more prostaglandins, or prostaglandin analogs including Latanoprost Ophthalmic Solution is not recommended. It has been shown that administration of these prostaglandin drug products more than once daily may decrease the intraocular pressure lowering effect or cause paradoxical elevations in IOP. - Reduction of the intraocular pressure starts approximately 3 to 4 hours after administration and the maximum effect is reached after 8 to 12 hours. - Latanoprost Ophthalmic Solution may be used concomitantly with other topical ophthalmic drug products to lower intraocular pressure. If more than one topical ophthalmic drug is being used, the drugs should be administered at least five (5) minutes apart. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Latanoprost in adult patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Latanoprost in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) There is limited information regarding FDA-Labeled Use of Latanoprost in pediatric patients. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Latanoprost in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Latanoprost in pediatric patients. # Contraindications - Known hypersensitivity to latanoprost, benzalkonium chloride or any other ingredients in this product. # Warnings - Latanoprost ophthalmic solution has been reported to cause changes to pigmented tissues. The most frequently reported changes have been increased pigmentation of the iris, periorbital tissue (eyelid) and eyelashes, and growth of eyelashes. Pigmentation is expected to increase as long as latanoprost ophthalmic solution is administered. After discontinuation of latanoprost ophthalmic solution, pigmentation of the iris is likely to be permanent while pigmentation of the periorbital tissue and eyelash changes have been reported to be reversible in some patients. Patients who receive treatment should be informed of the possibility of increased pigmentation. The effects of increased pigmentation beyond 5 years are not known. ### Precautions - Latanoprost ophthalmic solution may gradually increase the pigmentation of the iris. The eye color change is due to increased melanin content in the stromal melanocytes of the iris rather than to an increase in the number of melanocytes. This change may not be noticeable for several months to years. Typically, the brown pigmentation around the pupil spreads concentrically towards the periphery of the iris and the entire iris or parts of the iris become more brownish. Neither nevi nor freckles of the iris appear to be affected by treatment. While treatment with latanoprost ophthalmic solution can be continued in patients who develop noticeably increased iris pigmentation, these patients should be examined regularly. - During clinical trials, the increase in brown iris pigment has not been shown to progress further upon discontinuation of treatment, but the resultant color change may be permanent. - Eyelid skin darkening, which may be reversible, has been reported in association with the use of latanoprost ophthalmic solution. - Latanoprost ophthalmic solution may gradually change eyelashes and vellus hair in the treated eye; these changes include increased length, thickness, pigmentation, the number of lashes or hairs, and misdirected growth of eyelashes. Eyelash changes are usually reversible upon discontinuation of treatment. - Latanoprost ophthalmic solution should be used with caution in patients with a history of intraocular inflammation (iritis/uveitis) and should generally not be used in patients with active intraocular inflammation. - Macular edema, including cystoid macular edema, has been reported during treatment with latanoprost ophthalmic solution. These reports have mainly occurred in aphakic patients, in pseudophakic patients with a torn posterior lens capsule, or in patients with known risk factors for macular edema. Latanoprost ophthalmic solution should be used with caution in patients who do not have an intact posterior capsule or who have known risk factors for macular edema. - There is limited experience with latanoprost ophthalmic solution in the treatment of angle closure, inflammatory or neovascular glaucoma. - There have been reports of bacterial keratitis associated with the use of multiple-dose containers of topical ophthalmic products. These containers had been inadvertently contaminated by patients who, in most cases, had a concurrent corneal disease or a disruption of the ocular epithelial surface. - Contact lenses should be removed prior to the administration of latanoprost ophthalmic solution, and may be reinserted 15 minutes after administration. # Adverse Reactions ## Clinical Trials Experience - Adverse events referred to in other sections of this insert - Eyelash changes (increased length, thickness, pigmentation, and number of lashes); eyelid skin darkening; intraocular inflammation (iritis/uveitis); iris pigmentation changes; and macular edema, including cystoid macular edema. - Controlled Clinical Trials - The ocular adverse events and ocular signs and symptoms reported in 5 to 15% of the patients on latanoprost ophthalmic solution in the three 6-month, multi-center, double-masked, active-controlled trials were blurred vision, burning and stinging, conjunctival hyperemia, foreign body sensation, itching, increased pigmentation of the iris, and punctate epithelial keratopathy. - Local conjunctival hyperemia was observed; however, less than 1% of the patients treated with latanoprost ophthalmic solution required discontinuation of therapy because of intolerance to conjunctival hyperemia. - In addition to the above listed ocular events/signs and symptoms, the following were reported in 1 to 4% of the patients: dry eye, excessive tearing, eye pain, lid crusting, lid discomfort/pain, lid edema, lid erythema, and photophobia. - The following events were reported in less than 1% of the patients: conjunctivitis, diplopia and discharge from the eye. - During clinical studies, there were extremely rare reports of the following: retinal artery embolus, retinal detachment, and vitreous hemorrhage from diabetic retinopathy. - The most common systemic adverse events seen with latanoprost ophthalmic solution were upper respiratory tract infection/cold/flu, which occurred at a rate of approximately 4%. Chest pain/angina pectoris, muscle/joint/back pain, and rash/allergic skin reaction each occurred at a rate of 1 to 2%. ## Postmarketing Experience - The following events have been identified during postmarketing use of latanoprost ophthalmic solution in clinical practice. Because they are reported voluntarily from a population of unknown size, estimates of frequency cannot be made. The events, which have been chosen for inclusion due to either their seriousness, frequency of reporting, possible causal connection to latanoprost ophthalmic solution, or a combination of these factors, include: asthma and exacerbation of asthma; corneal edema and erosions; dyspnea; eyelash and vellus hair changes (increased length, thickness, pigmentation, and number); eyelid skin darkening; herpes keratitis; intraocular inflammation (iritis/ uveitis); keratitis; macular edema, including cystoid macular edema; misdirected eyelashes sometimes resulting in eye irritation; dizziness, headache, and toxic epidermal necrolysis. # Drug Interactions - In vitro studies have shown that precipitation occurs when eye drops containing thimerosal are mixed with latanoprost ophthalmic solution. If such drugs are used they should be administered at least five (5) minutes apart. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): - Pregnancy Category C' - Reproduction studies have been performed in rats and rabbits. In rabbits an incidence of 4 of 16 dams had no viable fetuses at a dose that was approximately 80 times the maximum human dose, and the highest nonembryocidal dose in rabbits was approximately 15 times the maximum human dose. There are no adequate and well-controlled studies in pregnant women. Latanoprost ophthalmic solution 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 Latanoprost in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Latanoprost during labor and delivery. ### Nursing Mothers - It is not known whether this drug or its metabolites are excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when latanoprost ophthalmic solution is administered to a nursing woman. ### Pediatric Use - Safety and effectiveness in pediatric patients have not been established. ### Geriatic Use - No overall differences in safety or effectiveness have been observed between elderly and younger patients. ### Gender There is no FDA guidance on the use of Latanoprost with respect to specific gender populations. ### Race There is no FDA guidance on the use of Latanoprost with respect to specific racial populations. ### Renal Impairment There is no FDA guidance on the use of Latanoprost in patients with renal impairment. ### Hepatic Impairment There is no FDA guidance on the use of Latanoprost in patients with hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Latanoprost in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Latanoprost in patients who are immunocompromised. # Administration and Monitoring ### Administration - Topical ### Monitoring There is limited information regarding Monitoring of Latanoprost in the drug label. # IV Compatibility There is limited information regarding IV Compatibility of Latanoprost in the drug label. # Overdosage ## Acute Overdose ### Signs and Symptoms - Apart from ocular irritation and conjunctival or episcleral hyperemia, the ocular effects of latanoprost administered at high doses are not known. Intravenous administration of large doses of latanoprost in monkeys has been associated with transient bronchoconstriction; however, in 11 patients with bronchial asthma treated with latanoprost, bronchoconstriction was not induced. Intravenous infusion of up to 3 mcg/kg in healthy volunteers produced mean plasma concentrations 200 times higher than during clinical treatment and no adverse reactions were observed. Intravenous dosages of 5.5 to 10 mcg/kg caused abdominal pain, dizziness, fatigue, hot flushes, nausea and sweating. ### Management - If overdosage with latanoprost ophthalmic solution occurs, treatment should be symptomatic. ## Chronic Overdose There is limited information regarding Chronic Overdose of Latanoprost in the drug label. # Pharmacology ## Mechanism of Action - Latanoprost is a prostanoid selective FP receptor agonist that is believed to reduce the intraocular pressure (IOP) by increasing the outflow of aqueous humor. Studies in animals and man suggest that the main mechanism of action is increased uveoscleral outflow. Elevated IOP represents a major risk factor for glaucomatous field loss. The higher the level of IOP, the greater the likelihood of optic nerve damage and visual field loss. ## Structure - Latanoprost is a prostaglandin F2α analogue. Its chemical name is isopropyl-(Z)-7 [(1R,2R,3R,5S)3,5-dihydroxy-2-[(3R)-3-hydroxy-5-phenylpentyl]cyclopentyl]-5-heptenoate. Its molecular formula is C26H40O5 and its chemical structure is: - Latanoprost is a colorless to slightly yellow oil that is very soluble in acetonitrile and freely soluble in acetone, ethanol, ethyl acetate, isopropanol, methanol and octanol. It is practically insoluble in water. - Latanoprost Ophthalmic Solution is supplied as a sterile, isotonic, buffered aqueous solution of latanoprost with a pH of approximately 6.7 and an osmolality of approximately 267 mOsmol/kg. Each mL of Latanoprost Ophthalmic Solution contains 50 micrograms of latanoprost. Benzalkonium chloride, 0.02% is added as a preservative. The inactive ingredients are: sodium chloride, sodium dihydrogen phosphate monohydrate, disodium hydrogen phosphate anhydrous and water for injection. One drop contains approximately 1.5 mcg of latanoprost. ## Pharmacodynamics There is limited information regarding Pharmacodynamics of Latanoprost in the drug label. ## Pharmacokinetics - Absorption: Latanoprost is absorbed through the cornea where the isopropyl ester prodrug is hydrolyzed to the acid form to become biologically active. Studies in man indicate that the peak concentration in the aqueous humor is reached about two hours after topical administration. - Distribution: The distribution volume in humans is 0.16 ± 0.02 L/kg. The acid of latanoprost can be measured in aqueous humor during the first 4 hours, and in plasma only during the first hour after local administration. - Metabolism: Latanoprost, an isopropyl ester prodrug, is hydrolyzed by esterases in the cornea to the biologically active acid. The active acid of latanoprost reaching the systemic circulation is primarily metabolized by the liver to the 1,2-dinor and 1,2,3,4-tetranor metabolites via fatty acid β-oxidation. - Excretion: The elimination of the acid of latanoprost from human plasma is rapid (t1/2=17 min) after both intravenous and topical administration. Systemic clearance is approximately 7 mL/min/kg. Following hepatic β-oxidation, the metabolites are mainly eliminated via the kidneys. Approximately 88% and 98% of the administered dose is recovered in the urine after topical and intravenous dosing, respectively. ## Nonclinical Toxicology - In monkeys, latanoprost has been shown to induce increased pigmentation of the iris. The mechanism of increased pigmentation seems to be stimulation of melanin production in melanocytes of the iris, with no proliferative changes observed. The change in iris color may be permanent. - Ocular administration of latanoprost at a dose of 6 mcg/eye/day (4 times the daily human dose) to cynomolgus monkeys has also been shown to induce increased palpebral fissure. This effect was reversible upon discontinuation of the drug. - Latanoprost was not mutagenic in bacteria, in mouse lymphoma or in mouse micronucleus tests. - Chromosome aberrations were observed in vitro with human lymphocytes. - Latanoprost was not carcinogenic in either mice or rats when administered by oral gavage at doses of up to 170 mcg/kg/day (approximately 2,800 times the recommended maximum human dose) for up to 20 and 24 months, respectively. - Additional in vitro and in vivo studies on unscheduled DNA synthesis in rats were negative. Latanoprost has not been found to have any effect on male or female fertility in animal studies. # Clinical Studies - Patients with mean baseline intraocular pressure of 24 to 25 mmHg who were treated for 6 months in multi-center, randomized, controlled trials demonstrated 6 to 8 mmHg reductions in intraocular pressure. This IOP reduction with latanoprost ophthalmic solution 0.005% dosed once daily was equivalent to the effect of timolol 0.5% dosed twice daily. - A 3-year open-label, prospective safety study with a 2-year extension phase was conducted to evaluate the progression of increased iris pigmentation with continuous use of latanoprost ophthalmic solution once-daily as adjunctive therapy in 519 patients with open-angle glaucoma. The analysis was based on observed-cases population of the 380 patients who continued in the extension phase. - Results showed that the onset of noticeable increased iris pigmentation occurred within the first year of treatment for the majority of the patients who developed noticeable increased iris pigmentation. Patients continued to show signs of increasing iris pigmentation throughout the five years of the study. Observation of increased iris pigmentation did not affect the incidence, nature or severity of adverse events (other than increased iris pigmentation) recorded in the study. IOP reduction was similar regardless of the development of increased iris pigmentation during the study. # How Supplied - Latanoprost Ophthalmic Solution is a sterile, clear, isotonic, buffered, preserved, colorless solution of latanoprost 0.005% (50 mcg/mL). It is supplied as a 2.5 mL solution in a 5 mL natural low density polyethylene bottle with a natural low density polyethylene dropper tip and a turquoise polypropylene screw cap. - 2.5 mL fill, 0.005% (50 mcg/mL) - NDC 0517-0830-01 Package of 1 bottle - NDC 0517-0830-03 Multi-pack of 3 bottles - Storage - Protect from light. Store unopened bottle(s) under refrigeration at 2° to 8°C (36° to 46°F). During shipment to the patient, the bottle may be maintained at temperatures up to 40°C (104°F) for a period not exceeding 8 days. Once a bottle is opened for use, it may be stored at room temperature up to 25°C (77°F) for 6 weeks. ## Storage There is limited information regarding Latanoprost Storage in the drug label. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information - Patients should be advised about the potential for increased brown pigmentation of the iris, which may be permanent. Patients should also be informed about the possibility of eyelid skin darkening, which may be reversible after discontinuation of latanoprost ophthalmic solution. - Patients should also be informed of the possibility of eyelash and vellus hair changes in the treated eye during treatment with latanoprost ophthalmic solution. These changes may result in a disparity between eyes in length, thickness, pigmentation, number of eyelashes or vellus hairs, and/or direction of eyelash growth. Eyelash changes are usually reversible upon discontinuation of treatment. - Patients should be instructed to avoid allowing the tip of the dispensing container to contact the eye or surrounding structures because this could cause the tip to become contaminated by common bacteria known to cause ocular infections. Serious damage to the eye and subsequent loss of vision may result from using contaminated solutions. - Patients also should be advised that if they develop an intercurrent ocular condition (e.g., trauma, or infection) or have ocular surgery, they should immediately seek their physician's advice concerning the continued use of the multiple-dose container. - Patients should be advised that if they develop any ocular reactions, particularly conjunctivitis and lid reactions, they should immediately seek their physician's advice. - Patients should also be advised that latanoprost ophthalmic solution contains benzalkonium chloride, which may be absorbed by contact lenses. Contact lenses should be removed prior to administration of the solution. Lenses may be reinserted 15 minutes following administration of latanoprost ophthalmic solution. - If more than one topical ophthalmic drug is being used, the drugs should be administered at least five (5) minutes apart. # Precautions with Alcohol - Alcohol-Latanoprost interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - LATANOPROST ®[1] # Look-Alike Drug Names There is limited information regarding Latanoprost Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	https://www.wikidoc.org/index.php/Latanoprost
40448cf1c839d62366f2ff9a27b72ab746f591e8	wikidoc	Latent heat	Latent heat In thermochemistry, latent heat is the amount of energy in the form of heat released or absorbed by a substance during a change of phase (i.e. solid, liquid, or gas), – also called a phase transition. The term was introduced around 1750 by Joseph Black as derived from the Latin latere, to lie hidden. The term is now dated, replaced by "enthalpy of transformation". Two latent heats (or enthalpies) are typically described: latent heat of fusion (melting), and latent heat of vaporization (boiling). The names describe the direction of heat flow from one phase to the next: solid → liquid → gas. The change is endothermic, i.e. the system absorbs energy, when the change is from solid to liquid to gas. It is exothermic (the process releases energy) when it is in the opposite direction. For example, in the atmosphere, when a molecule of water evaporates from the surface of any body of water, energy is transported by the water molecule into a lower temperature air parcel that contains more water vapor than its surroundings. Because energy is needed to overcome the molecular forces of attraction between water particles, the process of transition from a parcel of water to a parcel of vapor requires the input of energy causing a drop in temperature in its surroundings. If the water vapor condenses back to a liquid or solid phase onto a surface, the latent energy absorbed during evaporation is released as sensible heat onto the surface. The large value of the enthalpy of condensation of water vapor is the reason that steam is a far more effective heating medium than boiling water, and is more hazardous. # Latent heat equation The equation for latent heat is: where: In other words, specific latent heat is found when energy is divided by mass. # Table of latent heats	Latent heat In thermochemistry, latent heat is the amount of energy in the form of heat released or absorbed by a substance during a change of phase (i.e. solid, liquid, or gas), – also called a phase transition.[1][2] The term was introduced around 1750 by Joseph Black as derived from the Latin latere, to lie hidden. The term is now dated, replaced by "enthalpy of transformation". Two latent heats (or enthalpies) are typically described: latent heat of fusion (melting), and latent heat of vaporization (boiling). The names describe the direction of heat flow from one phase to the next: solid → liquid → gas. The change is endothermic, i.e. the system absorbs energy, when the change is from solid to liquid to gas. It is exothermic (the process releases energy) when it is in the opposite direction. For example, in the atmosphere, when a molecule of water evaporates from the surface of any body of water, energy is transported by the water molecule into a lower temperature air parcel that contains more water vapor than its surroundings. Because energy is needed to overcome the molecular forces of attraction between water particles, the process of transition from a parcel of water to a parcel of vapor requires the input of energy causing a drop in temperature in its surroundings. If the water vapor condenses back to a liquid or solid phase onto a surface, the latent energy absorbed during evaporation is released as sensible heat onto the surface. The large value of the enthalpy of condensation of water vapor is the reason that steam is a far more effective heating medium than boiling water, and is more hazardous. # Latent heat equation The equation for latent heat is: where: In other words, specific latent heat is found when energy is divided by mass. # Table of latent heats	https://www.wikidoc.org/index.php/Latent_heat
f1dfbfecba5faf32f961580845e6b2bb27b58008	wikidoc	Leflunomide	Leflunomide # 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 Leflunomide is a pyrimidine synthesis inhibitor that is FDA approved for the {{{indicationType}}} of rheumatoid arthritis. There is a Black Box Warning for this drug as shown here. Common adverse reactions include alopecia, rash, diarrhea, ulcer of mouth, dizziness, headache, respiratory tract infection. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) - Leflunomide tablets, USP are indicated in adults for the treatment of active rheumatoid arthritis (RA): - to reduce signs and symptoms - to inhibit structural damage as evidenced by X-ray erosions and joint space narrowing - to improve physical function. - Aspirin, nonsteroidal anti-inflammatory agents and/or low dose corticosteroids may be continued during treatment with leflunomide. The combined use of leflunomide with antimalarials, intramuscular or oral gold, D penicillamine, azathioprine, or methotrexate has not been adequately studied. - Loading Dose - Due to the long half-life in patients with RA and recommended dosing interval (24 hours), a loading dose is needed to provide steady-state concentrations more rapidly. It is recommended that leflunomide therapy be initiated with a loading dose of one 100 mg tablet per day for three days. - Elimination of the loading dose regimen may decrease the risk of adverse events. This could be especially important for patients at increased risk of hematologic or hepatic toxicity, such as those receiving concomitant treatment with methotrexate or other immunosuppressive agents or on such medications in the recent past. - Maintenance Therapy - Daily dosing of 20 mg is recommended for treatment of patients with RA. A small cohort of patients (n=104), treated with 25 mg/day, experienced a greater incidence of side effects; alopecia, weight loss, liver enzyme elevations. Doses higher than 20 mg/day are not recommended. If dosing at 20 mg/day is not well tolerated clinically, the dose may be decreased to 10 mg daily. Due to the prolonged half-life of the active metabolite of leflunomide, patients should be carefully observed after dose reduction, since it may take several weeks for metabolite levels to decline. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Leflunomide in adult patients. ### Non–Guideline-Supported Use - Dosing Information - Leflunomide (20 mg daily). - Dosing Information - Leflunomide 20 mg/day. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) There is limited information regarding FDA-Labeled Use of Leflunomide in pediatric patients. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Leflunomide in pediatric patients. ### Non–Guideline-Supported Use - Dosing Information - Patients weighing less than 20 kg received 100 mg for 1 day, then 10 mg every other day; those weighing between 20 and 40 kg received 100 mg for 2 days, then 10 mg per day; those weighing greater than 40 kg received 100 mg for 3 days, then 20 mg every day. # Contraindications - Leflunomide is contraindicated in patients with known hypersensitivity to leflunomide or any of the other components of leflunomide. - Leflunomide can cause fetal harm when administered to a pregnant woman. Leflunomide, when administered orally to rats during organogenesis at a dose of 15 mg/kg, was teratogenic (most notably anophthalmia or microophthalmia and internal hydrocephalus). The systemic exposure of rats at this dose was approximately 1/10 the human exposure level based on AUC. Under these exposure conditions, leflunomide also caused a decrease in the maternal body weight and an increase in embryolethality with a decrease in fetal body weight for surviving fetuses. In rabbits, oral treatment with 10 mg/kg of leflunomide during organogenesis resulted in fused, dysplastic sternebrae. The exposure level at this dose was essentially equivalent to the maximum human exposure level based on AUC. At a 1 mg/kg dose, leflunomide was not teratogenic in rats and rabbits. - When female rats were treated with 1.25 mg/kg of leflunomide beginning 14 days before mating and continuing until the end of lactation, the offspring exhibited marked (greater than 90%) decreases in postnatal survival. The systemic exposure level at 1.25 mg/kg was approximately 1/100 the human exposure level based on AUC. - Leflunomide is contraindicated in women who are or may become pregnant. 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 fetus. # Warnings - Hepatotoxicity - Severe liver injury, including fatal liver failure, has been reported in some patients treated with leflunomide. Patients with pre- existing acute or chronic liver disease, or those with serum alanine aminotransferase (ALT) >2xULN before initiating treatment, should not be treated with leflunomide. Use caution when leflunomide is given with other potentially hepatotoxic drugs. Monitoring of ALT levels is recommended at least monthly for six months after starting leflunomide, and thereafter every 6 to 8 weeks. If ALT elevation > 3 fold ULN occurs, interrupt leflunomide therapy while investigating the probable cause of the ALT elevation by close observation and additional tests. If likely leflunomide-induced, start cholestyramine washout and monitor liver tests weekly until normalized. If leflunomide-induced liver injury is unlikely because some other probable cause has been found, resumption of leflunomide therapy may be considered. - In addition, if leflunomide and methotrexate are given concomitantly, ACR guidelines for monitoring methotrexate liver toxicity must be followed with ALT, AST, and serum albumin testing monthly. - In clinical trials, leflunomide treatment as monotherapy or in combination with methotrexate was associated with elevations of liver enzymes, primarily ALT and AST, in a significant number of patients; these effects were generally reversible. Most transaminase elevations were mild (≤ 2-fold ULN) and usually resolved while continuing treatment. Marked elevations (>3-fold ULN) occurred infrequently and reversed with dose reduction or discontinuation of treatment. Table 8 shows liver enzyme elevations seen with monthly monitoring in clinical trials US301 and MN301. It was notable that the absence of folate use in MN302 was associated with a considerably greater incidence of liver enzyme elevation on methotrexate. - In a 6 month study of 263 patients with persistent active rheumatoid arthritis despite methotrexate therapy, and with normal LFTs, leflunomide was added to a group of 130 patients starting at 10 mg per day and increased to 20 mg as needed. An increase in ALT greater than or equal to three times the ULN was observed in 3.8% of patients compared to 0.8% in 133 patients continued on methotrexate with placebo added. - Immunosuppression Potential/Bone Marrow Suppression - Leflunomide is not recommended for patients with severe immunodeficiency, bone marrow dysplasia, or severe, uncontrolled infections. In the event that a serious infection occurs, it may be necessary to interrupt therapy with leflunomide and administer cholestyramine or charcoal. Medications like leflunomide that have immunosuppression potential may cause patients to be more susceptible to infections, including opportunistic infections, especially Pneumocystis jiroveci pneumonia, tuberculosis (including extra-pulmonary tuberculosis), and aspergillosis. Severe infections including sepsis, which may be fatal, have been reported in patients receiving leflunomide, especially Pneumocystis jiroveci pneumonia and aspergillosis. Most of the reports were confounded by concomitant immunosuppressant therapy and/or comorbid illness which, in addition to rheumatoid disease, may predispose patients to infection. - There have been rare reports of pancytopenia, agranulocytosis and thrombocytopenia in patients receiving leflunomide alone. These events have been reported most frequently in patients who received concomitant treatment with methotrexate or other immunosuppressive agents, or who had recently discontinued these therapies; in some cases, patients had a prior history of a significant hematologic abnormality. - Patients taking leflunomide should have platelet, white blood cell count and hemoglobin or hematocrit monitored at baseline and monthly for six months following initiation of therapy and every 6- to 8 weeks thereafter. If used with concomitant methotrexate and/or other potential immunosuppressive agents, chronic monitoring should be monthly. - If evidence of bone marrow suppression occurs in a patient taking leflunomide, treatment with leflunomide should be stopped, and cholestyramine or charcoal should be used to reduce the plasma concentration of leflunomide active metabolite. - In any situation in which the decision is made to switch from leflunomide to another anti-rheumatic agent with a known potential for hematologic suppression, it would be prudent to monitor for hematologic toxicity, because there will be overlap of systemic exposure to both compounds. Leflunomide washout with cholestyramine or charcoal may decrease this risk, but also may induce disease worsening if the patient had been responding to leflunomide treatment. - Skin Reactions - Rare cases of Stevens-Johnson syndrome and toxic epidermal necrolysis have been reported in patients receiving leflunomide. If a patient taking leflunomide develops any of these conditions, leflunomide therapy should be stopped, and a drug elimination procedure is recommended. - Malignancy - The risk of malignancy, particularly lymphoproliferative disorders, is increased with the use of some immunosuppression medications. There is a potential for immunosuppression with leflunomide. No apparent increase in the incidence of malignancies and lymphoproliferative disorders was reported in the clinical trials of leflunomide, but larger and longer-term studies would be needed to determine whether there is an increased risk of malignancy or lymphoproliferative disorders with leflunomide. - Use in Women of Childbearing Potential - There are no adequate and well-controlled studies evaluating leflunomide in pregnant women. However, based on animal studies, leflunomide may increase the risk of fetal death or teratogenic effects when administered to a pregnant woman. Women of childbearing potential must not be started on leflunomide until pregnancy is excluded and it has been confirmed that they are using reliable contraception. Before starting treatment with leflunomide, patients must be fully counseled on the potential for serious risk to the fetus. - The patient must be advised that if there is any delay in onset of menses or any other reason to suspect pregnancy, they must notify the physician immediately for pregnancy testing and, if positive, the physician and patient must discuss the risk to the pregnancy. It is possible that rapidly lowering the blood level of the active metabolite by instituting the drug elimination procedure described below at the first delay of menses may decrease the risk to the fetus from leflunomide. - Upon discontinuing leflunomide, it is recommended that all women of childbearing potential undergo the drug elimination procedure described below. Women receiving leflunomide treatment who wish to become pregnant must discontinue leflunomide and undergo the drug elimination procedure described below which includes verification of M1 metabolite plasma levels less than 0.02 mg/L (0.02 mcg/mL). Human plasma levels of the active metabolite (M1) less than 0.02 mg/L (0.02 mcg/mL) are expected to have minimal risk based on available animal data. - Peripheral Neuropathy - Cases of peripheral neuropathy have been reported in patients receiving leflunomide. Most patients recovered after discontinuation of leflunomide, but some patients had persistent symptoms. Age older than 60 years, concomitant neurotoxic medications, and diabetes may increase the risk for peripheral neuropathy. If a patient taking leflunomide develops a peripheral neuropathy, consider discontinuing leflunomide therapy and performing the drug elimination procedure. - Drug Elimination Procedure - The following drug elimination procedure is recommended to achieve non-detectable plasma levels (less than 0.02 mg/L or 0.02 mcg/mL) after stopping treatment with leflunomide: Administer cholestyramine 8 grams 3 times daily for 11 days. (The 11 days do not need to be consecutive unless there is a need to lower the plasma level rapidly.) Verify plasma levels less than 0.02 mg/L (0.02 mcg/mL) by two separate tests at least 14 days apart. If plasma levels are higher than 0.02 mg/L, additional cholestyramine treatment should be considered. - Administer cholestyramine 8 grams 3 times daily for 11 days. (The 11 days do not need to be consecutive unless there is a need to lower the plasma level rapidly.) - Verify plasma levels less than 0.02 mg/L (0.02 mcg/mL) by two separate tests at least 14 days apart. If plasma levels are higher than 0.02 mg/L, additional cholestyramine treatment should be considered. - Without the drug elimination procedure, it may take up to 2 years to reach plasma M1 metabolite levels less than 0.02 mg/L due to individual variation in drug clearance. ### Precautions - Need for Drug Elimination - The active metabolite of leflunomide is eliminated slowly from the plasma. In instances of any serious toxicity from leflunomide, including hypersensitivity, use of a drug elimination procedure as described in this section is highly recommended to reduce the drug concentration more rapidly after stopping leflunomide therapy. If hypersensitivity is the suspected clinical mechanism, more prolonged cholestyramine or charcoal administration may be necessary to achieve rapid and sufficient clearance. The duration may be modified based on the clinical status of the patient. - Cholestyramine given orally at a dose of 8 g three times a day for 24 hours to three healthy volunteers decreased plasma levels of M1 by approximately 40% in 24 hours and by 49 to 65% in 48 hours. - Administration of activated charcoal (powder made into a suspension) orally or via nasogastric tube (50 g every 6 hours for 24 hours) has been shown to reduce plasma concentrations of the active metabolite, M1, by 37% in 24 hours and by 48% in 48 hours. - These drug elimination procedures may be repeated if clinically necessary. - Respiratory - Interstitial lung disease has been reported during treatment with leflunomide and has been associated with fatal outcomes. The risk of its occurrence is increased in patients with a history of interstitial lung disease. Interstitial lung disease is a potentially fatal disorder, which may occur acutely at any time during therapy and has a variable clinical presentation. New onset or worsening pulmonary symptoms, such as cough and dyspnea, with or without associated fever, may be a reason for discontinuation of the therapy and for further investigation as appropriate. If discontinuation of the drug is necessary, initiation of wash-out procedures should be considered. - Tuberculosis Reactivation - Prior to initiating immunomodulatory therapies, including leflunomide, patients should be screened for latent tuberculosis infection with a tuberculin skin test. Leflunomide has not been studied in patients with a positive tuberculosis screen, and the safety of leflunomide in individuals with latent tuberculosis infection is unknown. Patients testing positive in tuberculosis screening should be treated by standard medical practice prior to therapy with leflunomide. - Renal Insufficiency - Single dose studies in dialysis patients show a doubling of the free fraction of M1 in plasma. There is no clinical experience in the use of leflunomide in patients with renal impairment. Caution should be used when administering this drug in this population. - Vaccinations - No clinical data are available on the efficacy and safety of vaccinations during leflunomide treatment. Vaccination with live vaccines is, however, not recommended. The long half-life of leflunomide should be considered when contemplating administration of a live vaccine after stopping leflunomide. - Blood Pressure Monitoring - Blood pressure should be checked before start of leflunomide treatment and periodically thereafter. # Adverse Reactions ## Clinical Trials Experience - Adverse reactions associated with the use of leflunomide in RA include diarrhea, elevated liver enzymes (ALT and AST), alopecia and rash. In the controlled studies at one year, the following adverse events were reported, regardless of causality. (See Table 9.) - Adverse events during a second year of treatment with leflunomide in clinical trials were consistent with those observed during the first year of treatment and occurred at a similar or lower incidence. - In addition, the following adverse events have been reported in 1% to <3% of the RA patients in the leflunomide treatment group in controlled clinical trials. Abscess, cyst, fever, hernia, malaise, pain, neck pain, pelvic pain; Angina pectoris, migraine, palpitation, tachycardia, varicose vein, vasculitis, vasodilatation; Cholelithiasis, colitis, constipation, esophagitis, flatulence, gastritis, gingivitis, melena, oral moniliasis, pharyngitis, salivary gland enlarged, stomatitis (or aphthous stomatitis), tooth disorder; Diabetes mellitus, hyperthyroidism; Anemia (including iron deficiency anemia), ecchymosis; Creatine phosphokinase increased, hyperglycemia, hyperlipidemia, peripheral edema; Arthrosis, bone necrosis, bone pain, bursitis, muscle cramps, myalgia, tendon rupture; Anxiety, depression, dry mouth, insomnia, neuralgia, neuritis, sleep disorder, sweating increased, vertigo; Asthma, dyspnea, epistaxis, lung disorder; Acne, contact dermatitis, fungal dermatitis, hair discoloration, hematoma, herpes simplex, herpes zoster, maculopapular rash, nail disorder, skin discoloration, skin disorder, skin nodule, subcutaneous nodule, ulcer skin; Blurred vision, cataract, conjunctivitis, eye disorder, taste perversion; Albuminuria, cystitis, dysuria, hematuria, menstrual disorder, prostate disorder, urinary frequency, vaginal moniliasis. - Other less common adverse events seen in clinical trials include: 1 case of anaphylactic reaction occurred in Phase 2 following rechallenge of drug after withdrawal due to rash (rare); urticaria; eosinophilia; transient thrombocytopenia (rare); and leukopenia <2000 WBC/mm3 (rare). - Adverse events during a second year of treatment with leflunomide in clinical trials were consistent with those observed during the first year of treatment and occurred at a similar or lower incidence. - Adverse Reactions (Pediatric Patients) - The safety of leflunomide was studied in 74 patients with polyarticular course juvenile rheumatoid arthritis ranging in age from 3 to 17 years (47 patients from the active-controlled study and 27 from an open-label safety and pharmacokinetic study). The most common adverse events included abdominal pain, diarrhea, nausea, vomiting, oral ulcers, upper respiratory tract infections, alopecia, rash, headache, and dizziness. Less common adverse events included anemia, hypertension, and weight loss. Fourteen pediatric patients experienced ALT and/or AST elevations, nine between 1.2 and 3-fold the upper limit of normal, five between 3 and 8-fold the upper limit of normal. ## Postmarketing Experience - In post-marketing experience, the following have been reported: Opportunistic infections, severe infections including sepsis that may be fatal; Pancreatitis Agranulocytosis, leukopenia, neutropenia, pancytopenia, thrombocytopenia Angioedema Hepatitis, jaundice/cholestasis, severe liver injury such as hepatic failure and acute hepatic necrosis that may be fatal; Interstitial lung disease, including interstitial pneumonitis and pulmonary fibrosis, which may be fatal; Peripheral neuropathy Erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis, vasculitis including cutaneous necrotizing vasculitis, cutaneous lupus erythematosus, pustular psoriasis or worsening psoriasis. # Drug Interactions - Cholestyramine and Charcoal - Administration of cholestyramine or activated charcoal in patients (n=13) and volunteers (n=96) resulted in a rapid and significant decrease in plasma M1 (the active metabolite of leflunomide) concentration. - Hepatotoxic Drugs - Increased side effects may occur when leflunomide is given concomitantly with hepatotoxic substances. This is also to be considered when leflunomide treatment is followed by such drugs without a drug elimination procedure. In a small (n=30) combination study of leflunomide with methotrexate, a 2- to 3-fold elevation in liver enzymes was seen in 5 of 30 patients. All elevations resolved, 2 with continuation of both drugs and 3 after discontinuation of leflunomide. A >3-fold increase was seen in another 5 patients. All of these also resolved, 2 with continuation of both drugs and 3 after discontinuation of leflunomide. Three patients met "ACR criteria" for liver biopsy (1: Roegnik Grade I, 2: Roegnik Grade IIIa). No pharmacokinetic interaction was identified. - NSAIDs - In in vitro studies, M1 was shown to cause increases ranging from 13 to 50% in the free fraction of diclofenac and ibuprofen at concentrations in the clinical range. The clinical significance of this finding is unknown; however, there was extensive concomitant use of NSAIDs in clinical studies and no differential effect was observed. - Tolbutamide - In in vitro studies, M1 was shown to cause increases ranging from 13 to 50% in the free fraction of tolbutamide at concentrations in the clinical range. The clinical significance of this finding is unknown. - Rifampin - Following concomitant administration of a single dose of leflunomide to subjects receiving multiple doses of rifampin, M1 peak levels were increased (~40%) over those seen when leflunomide was given alone. Because of the potential for leflunomide levels to continue to increase with multiple dosing, caution should be used if patients are to be receiving both leflunomide and rifampin. - Warfarin - Increased INR (International Normalized Ratio) when leflunomide and warfarin were co-administered has been rarely reported. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): - Pregnancy Category X - (See CONTRAINDICATIONS section.) Pregnancy Registry: To monitor fetal outcomes of pregnant women exposed to leflunomide, health care providers are encouraged to register such patients by calling 1-877-311-8972. Pregnancy Category (AUS): - Australian Drug Evaluation Committee (ADEC) Pregnancy Category There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Leflunomide in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Leflunomide during labor and delivery. ### Nursing Mothers - Leflunomide should not be used by nursing mothers. It is not known whether leflunomide is excreted in human milk. Many drugs are excreted in human milk, and there is a potential for serious adverse reactions in nursing infants from leflunomide. Therefore, a decision should be made whether to proceed with nursing or to initiate treatment with leflunomide, taking into account the importance of the drug to the mother. ### Pediatric Use - The safety and effectiveness of leflunomide in pediatric patients with polyarticular course juvenile rheumatoid arthritis (JRA) have not been fully evaluated. ### Geriatic Use - Of the total number of subjects in controlled clinical (Phase III) studies of leflunomide, 234 subjects were 65 years and over. 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, but greater sensitivity of some older individuals cannot be ruled out. No dosage adjustment is needed in patients over 65. ### Gender - Available information does not suggest that leflunomide would be associated with an increased risk of male-mediated fetal toxicity. However, animal studies to evaluate this specific risk have not been conducted. To minimize any possible risk, men wishing to father a child should consider discontinuing use of leflunomide and taking cholestyramine 8 grams 3 times daily for 11 days. ### Race There is no FDA guidance on the use of Leflunomide with respect to specific racial populations. ### Renal Impairment There is no FDA guidance on the use of Leflunomide in patients with renal impairment. ### Hepatic Impairment There is no FDA guidance on the use of Leflunomide in patients with hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Leflunomide in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Leflunomide in patients who are immunocompromised. # Administration and Monitoring ### Administration - Oral ### Monitoring There is limited information regarding Monitoring of Leflunomide in the drug label. # IV Compatibility There is limited information regarding IV Compatibility of Leflunomide in the drug label. # Overdosage ## Acute Overdose ### Signs and Symptoms - In mouse and rat acute toxicology studies, the minimally toxic dose for oral leflunomide was 200 to 500 mg/kg and 100 mg/kg, respectively (approximately >350 times the maximum recommended human dose, respectively). - There were no adverse events reported in the majority of case reports of overdose. Adverse events were consistent with the safety profile for leflunomide. The most frequent adverse events observed were diarrhea, abdominal pain, leukopenia, anemia and elevated liver function tests. ### Management - In the event of a significant overdose or toxicity, cholestyramine or charcoal administration is recommended to accelerate elimination. - In the event of a significant overdose or toxicity, cholestyramine or charcoal administration is recommended to accelerate elimination. - Studies with both hemodialysis and CAPD (chronic ambulatory peritoneal dialysis) indicate that M1, the primary metabolite of leflunomide, is not dialyzable. ## Chronic Overdose - There have been reports of chronic overdose in patients taking leflunomide at daily dose up to five times the recommended daily dose and reports of acute overdose in adults or children. # Pharmacology ## Mechanism of Action - Leflunomide is an isoxazole immunomodulatory agent which inhibits dihydroorotate dehydrogenase (an enzyme involved in de novo pyrimidine synthesis) and has antiproliferative activity. Several in vivo and in vitro experimental models have demonstrated an anti-inflammatory effect. ## Structure - Leflunomide is a pyrimidine synthesis inhibitor. The chemical name for leflunomide is N-(4'-trifluoromethylphenyl)-5-methylisoxazole-4-carboxamide. It has an empirical formula C12H9F3N2O2, a molecular weight of 270.2 and the following structural formula: - Leflunomide tablets, USP is available for oral administration as tablets containing 10 or 20 mg of active drug. Each leflunomide tablet, USP contains anhydrous lactose, colloidal silicon dioxide, crospovidone, and magnesium stearate. ## Pharmacodynamics There is limited information regarding Pharmacodynamics of Leflunomide in the drug label. ## Pharmacokinetics - Following oral administration, leflunomide is metabolized to an active metabolite A77 1726 (hereafter referred to as M1) which is responsible for essentially all of its activity in vivo. Plasma levels of leflunomide are occasionally seen, at very low levels. Studies of the pharmacokinetics of leflunomide have primarily examined the plasma concentrations of this active metabolite. - Absorption - Following oral administration, peak levels of the active metabolite, M1, occurred between 6 to 12 hours after dosing. Due to the very long half-life of M1 (~2 weeks), a loading dose of 100 mg for 3 days was used in clinical studies to facilitate the rapid attainment of steady-state levels of M1. Without a loading dose, it is estimated that attainment of steady-state plasma concentrations would require nearly two months of dosing. The resulting plasma concentrations following both loading doses and continued clinical dosing indicate that M1 plasma levels are dose proportional. - Relative to an oral solution, leflunomide tablets are 80% bioavailable. Co-administration of leflunomide tablets with a high fat meal did not have a significant impact on M1 plasma levels. - Distribution - M1 has a low volume of distribution (Vss = 0.13 L/kg) and is extensively bound (>99.3%) to albumin in healthy subjects. Protein binding has been shown to be linear at therapeutic concentrations. The free fraction of M1 is slightly higher in patients with rheumatoid arthritis and approximately doubled in patients with chronic renal failure; the mechanism and significance of these increases are unknown. - Metabolism - Leflunomide is metabolized to one primary (M1) and many minor metabolites. Of these minor metabolites, only 4-trifluoromethylaniline (TFMA) is quantifiable, occurring at low levels in the plasma of some patients. The parent compound is rarely detectable in plasma. At the present time the specific site of leflunomide metabolism is unknown. In vivo and in vitro studies suggest a role for both the GI wall and the liver in drug metabolism. No specific enzyme has been identified as the primary route of metabolism for leflunomide; however, hepatic cytosolic and microsomal cellular fractions have been identified as sites of drug metabolism. - Elimination - The active metabolite M1 is eliminated by further metabolism and subsequent renal excretion as well as by direct biliary excretion. In a 28 day study of drug elimination (n=3) using a single dose of radiolabeled compound, approximately 43% of the total radioactivity was eliminated in the urine and 48% was eliminated in the feces. Subsequent analysis of the samples revealed the primary urinary metabolites to be leflunomide glucuronides and an oxanilic acid derivative of M1. The primary fecal metabolite was M1. Of these two routes of elimination, renal elimination is more significant over the first 96 hours after which fecal elimination begins to predominate. In a study involving the intravenous administration of M1, the clearance was estimated to be 31 mL/hr. - In small studies using activated charcoal (n=1) or cholestyramine (n=3) to facilitate drug elimination, the in vivo plasma half-life of M1 was reduced from >1 week to approximately 1 day, Similar reductions in plasma half-life were observed for a series of volunteers (n=96) enrolled in pharmacokinetic trials who were given cholestyramine. This suggests that biliary recycling is a major contributor to the long elimination half-life of M1. Studies with both hemodialysis and CAPD (chronic ambulatory peritoneal dialysis) indicate that M1 is not dialyzable. - Special Populations - Gender - Gender has not been shown to cause a consistent change in the in vivo pharmacokinetics of M1. - Age - Age has been shown to cause a change in the in vivo pharmacokinetics of M1. - Smoking - A population based pharmacokinetic analysis of the phase III data indicates that smokers have a 38% increase in clearance over non-smokers; however, no difference in clinical efficacy was seen between smokers and nonsmokers. - Chronic Renal Insufficiency - In single dose studies in patients (n=6) with chronic renal insufficiency requiring either chronic ambulatory peritoneal dialysis (CAPD) or hemodialysis, neither had a significant impact on circulating levels of M1. The free fraction of M1 was almost doubled, but the mechanism of this increase is not known. In light of the fact that the kidney plays a role in drug elimination and without adequate studies of leflunomide use in subjects with renal insufficiency, caution should be used when leflunomide is administered to these patients. - Hepatic Insufficiency - Studies of the effect of hepatic insufficiency on M1 pharmacokinetics have not been done. Given the need to metabolize leflunomide into the active species, the role of the liver in drug elimination/recycling, and the possible risk of increased hepatic toxicity, the use of leflunomide in patients with hepatic insufficiency is not recommended. - Pediatrics - The pharmacokinetics of M1 following oral administration of leflunomide have been investigated in 73 pediatric patients with polyarticular course Juvenile Rheumatoid Arthritis (JRA) who ranged in age from 3 to 17 years. The results of a population pharmacokinetic analysis of these trials have demonstrated that pediatric patients with body weights ≤40 kg have a reduced clearance of M1 (see Table 2) relative to adult rheumatoid arthritis patients. - Drug Interactions - In vivo drug interaction studies have demonstrated a lack of a significant drug interaction between leflunomide and tri-phasic oral contraceptives, and cimetidine. - In vitro studies of protein binding indicated that warfarin did not affect M1 protein binding. At the same time M1 was shown to cause increases ranging from 13 to 50% in the free fraction of diclofenac, ibuprofen and tolbutamide at concentrations in the clinical range. In vitro studies of drug metabolism indicate that M1 inhibits CYP 450 2C9, which is responsible for the metabolism of phenytoin, tolbutamide, warfarin and many NSAIDs. M1 has been shown to inhibit the formation of 4′-hydroxydiclofenac from diclofenac in vitro. The clinical significance of these findings with regard to phenytoin and tolbutamide is unknown; however, there was extensive concomitant use of NSAIDs in the clinical studies and no differential effect was observed. - Methotrexate - Coadministration, in 30 patients, of leflunomide (100 mg/day x 2 days followed by 10 to 20 mg/day) with methotrexate (10 to 25 mg/week, with folate) demonstrated no pharmacokinetic interaction between the two drugs. However, co-administration increased risk of hepatotoxicity. - Rifampin - Following concomitant administration of a single dose of leflunomide to subjects receiving multiple doses of rifampin, M1 peak levels were increased (~40%) over those seen when leflunomide was given alone. Because of the potential for leflunomide levels to continue to increase with multiple dosing, caution should be used if patients are to receive both leflunomide and rifampin. ## Nonclinical Toxicology - No evidence of carcinogenicity was observed in a 2-year bioassay in rats at oral doses of leflunomide up to the maximally tolerated dose of 6 mg/kg (approximately 1/40 the maximum human M1 systemic exposure based on AUC). However, male mice in a 2-year bioassay exhibited an increased incidence in lymphoma at an oral dose of 15 mg/kg, the highest dose studied (1.7 times the human M1 exposure based on AUC). Female mice, in the same study, exhibited a dose-related increased incidence of bronchoalveolar adenomas and carcinomas combined beginning at 1.5 mg/kg (approximately 1/10 the human M1 exposure based on AUC). The significance of the findings in mice relative to the clinical use of leflunomide is not known. - Leflunomide was not mutagenic in the Ames Assay, the Unscheduled DNA Synthesis Assay, or in the HGPRT Gene Mutation Assay. In addition, leflunomide was not clastogenic in the in vivo Mouse Micronucleus Assay nor in the in vivo Cytogenetic Test in Chinese Hamster Bone Marrow Cells. However, 4-trifluoromethylaniline (TFMA), a minor metabolite of leflunomide, was mutagenic in the Ames Assay and in the HGPRT Gene Mutation Assay, and was clastogenic in the in vitro Assay for Chromosome Aberrations in the Chinese Hamster Cells. TFMA was not clastogenic in the in vivo Mouse Micronucleus Assay nor in the in vivo Cytogenetic Test in Chinese Hamster Bone Marrow Cells. Leflunomide had no effect on fertility in either male or female rats at oral doses up to 4.0 mg/kg (approximately 1/30 the human M1 exposure based on AUC). # Clinical Studies - The efficacy of leflunomide in the treatment of rheumatoid arthritis (RA) was demonstrated in three controlled trials showing reduction in signs and symptoms, and inhibition of structural damage. In two placebo controlled trials, efficacy was demonstrated for improvement in physical function. - Reduction of signs and symptoms - Relief of signs and symptoms was assessed using the American College of Rheumatology (ACR) 20 Responder Index, a composite of clinical, laboratory, and functional measures in rheumatoid arthritis. An "ACR20 Responder" is a patient who had ≥ 20% improvement in both tender and swollen joint counts and in 3 of the following 5 criteria: physician global assessment, patient global assessment, functional ability measure , visual analog pain scale, and erythrocyte sedimentation rate or C-reactive protein. An "ACR20 Responder at Endpoint" is a patient who completed the study and was an ACR20 Responder at the completion of the study. - Inhibition of structural damage - Inhibition of structural damage compared to control was assessed using the Sharp Score (Sharp, JT. Scoring Radiographic Abnormalities in Rheumatoid Arthritis, Radiologic Clinics of North America, 1996; vol. 34, pp. 233 to 241), a composite score of X-ray erosions and joint space narrowing in hands/wrists and forefeet. - Improvement in physical function - Improvement in physical function was assessed using the Health Assessment Questionnaire (HAQ) and the Medical Outcomes Survey Short Form (SF-36). - In all leflunomide monotherapy studies, an initial loading dose of 100 mg per day for three days only was used followed by 20 mg per day thereafter. - US301 Clinical Trial in Adults - Study US301, a 2 year study, randomized 482 patients with active RA of at least 6 months duration to leflunomide 20 mg/day (n=182), methotrexate 7.5 mg/week increasing to 15 mg/week (n=182), or placebo (n=118). All patients received folate 1 mg BID. Primary analysis was at 52 weeks with blinded treatment to 104 weeks. - Overall, 235 of the 508 randomized treated patients (482 in primary data analysis and an additional 26 patients), continued into a second 12 months of double-blind treatment (98 leflunomide, 101 methotrexate, 36 placebo). Leflunomide dose continued at 20 mg/day and the methotrexate dose could be increased to a maximum of 20 mg/week. In total, 190 patients (83 leflunomide, 80 methotrexate, 27 placebo) completed 2 years of double-blind treatment. - The rate and reason for withdrawal is summarized in Table 3. - 1 Includes: lost to follow up, protocol violation, noncompliance, voluntary withdrawal, investigator discretion. - MN301/303/305 Clinical Trial in Adults - Study MN301 randomized 358 patients with active RA to leflunomide 20 mg/day (n=133), sulfasalazine 2.0 g/day (n=133), or placebo (n=92). Treatment duration was 24 weeks. An extension of the study was an optional 6-month blinded continuation of MN301 without the placebo arm, resulting in a 12-month comparison of leflunomide and sulfasalazine (study MN303). - Of the 168 patients who completed 12 months of treatment in MN301 and MN303, 146 patients (87%) entered a 1-year extension study of double blind active treatment (MN305; 60 leflunomide, 60 sulfasalazine, 26 placebo/sulfasalazine). Patients continued on the same daily dosage of leflunomide or sulfasalazine that they had been taking at the completion of MN301/303. A total of 121 patients (53 leflunomide, 47 sulfasalazine, 21 placebo/sulfasalazine) completed the 2 years of double-blind treatment. - Patient withdrawal data in MN301/303/305 is summarized in Table 4. - MN302/304 Clinical Trial in Adults - Study MN302 randomized 999 patients with active RA to leflunomide 20 mg/day (n=501) or methotrexate at 7.5 mg/week increasing to 15 mg/week (n=498). Folate supplementation was used in 10% of patients. Treatment duration was 52 weeks. - Of the 736 patients who completed 52 weeks of treatment in study MN302, 612 (83%) entered the double-blind, 1-year extension study MN304 (292 leflunomide, 320 methotrexate). Patients continued on the same daily dosage of leflunomide or methotrexate that they had been taking at the completion of MN302. There were 533 patients (256 leflunomide, 277 methotrexate) who completed 2 years of double-blind treatment. - Patient withdrawal data in MN302/304 is summarized in Table 5. - Signs and symptoms Rheumatoid Arthritis - The ACR20 Responder at Endpoint rates are shown in Figure 1. Leflunomide was statistically significantly superior to placebo in reducing the signs and symptoms of RA by the primary efficacy analysis, ACR20 Responder at Endpoint, in study US301 (at the primary 12 months endpoint) and MN301 (at 6 month endpoint). ACR20 Responder at Endpoint rates with leflunomide treatment were consistent across the 6 and 12 month studies (41 to 49%). No consistent differences were demonstrated between leflunomide and methotrexate or between leflunomide and sulfasalazine. Leflunomide treatment effect was evident by 1 month, stabilized by 3 to 6 months, and continued throughout the course of treatment as shown in Figure 2. - ACR50 and ACR70 Responders are defined in an analogous manner to the ACR20 Responder, but use improvements of 50% or 70%, respectively (Table 6). Mean change for the individual components of the ACR Responder Index are shown in Table 7. - Table 7 shows the results of the components of the ACR response criteria for US301, MN301, and MN302. Leflunomide was significantly superior to placebo in all components of the ACR Response criteria in study US301 and MN301. In addition, leflunomide was significantly superior to placebo in improving morning stiffness, a measure of RA disease activity, not included in the ACR Response criteria. No consistent differences were demonstrated between leflunomide and the active comparators. - Maintenance of effect - After completing 12 months of treatment, patients continuing on study treatment were evaluated for an additional 12 months of double-blind treatment (total treatment period of 2 years) in studies US301, MN305, and MN304. ACR Responder rates at 12 months were maintained over 2 years in most patients continuing a second year of treatment. - Improvement from baseline in the individual components of the ACR responder criteria was also sustained in most patients during the second year of leflunomide treatment in all three trials. - Inhibition of structural damage - The change from baseline to endpoint in progression of structural disease, as measured by the Sharp X-ray score, is displayed in Figure 3. Leflunomide was statistically significantly superior to placebo in inhibiting the progression of disease by the Sharp Score. No consistent differences were demonstrated between leflunomide and methotrexate or between leflunomide and sulfasalazine. - Improvement in physical function - The Health Assessment Questionnaire (HAQ) assesses a patient's physical function and degree of disability. The mean change from baseline in functional ability as measured by the HAQ Disability Index (HAQ DI) in the 6 and 12 month placebo and active controlled trials is shown in Figure 4. Leflunomide was statistically significantly superior to placebo in improving physical function. Superiority to placebo was demonstrated consistently across all eight HAQ DI subscales (dressing, arising, eating, walking, hygiene, reach, grip and activities) in both placebo controlled studies. - The Medical Outcomes Survey Short Form 36 (SF-36), a generic health-related quality of life questionnaire, further addresses physical function. In US301, at 12 months, leflunomide provided statistically significant improvements compared to placebo in the Physical Component Summary (PCS) Score. - Maintenance of effect - The improvement in physical function demonstrated at 6 and 12 months was maintained over two years. In those patients continuing therapy for a second year, this improvement in physical function as measured by HAQ and SF-36 (PCS) was maintained. - Clinical Trials in Pediatrics - Leflunomide was studied in a single multicenter, double-blind, active-controlled trial in 94 patients (1:1 randomization) with polyarticular course juvenile rheumatoid arthritis (JRA) as defined by the American College of Rheumatology (ACR). Approximately 68% of pediatric patients receiving leflunomide, versus 89% of pediatric patients receiving the active comparator, improved by Week 16 (end-of-study) employing the JRA Definition of Improvement (DOI) ≥ 30 % responder endpoint. In this trial, the loading dose and maintenance dose of leflunomide was based on three weight categories: 40 kg. The response rate to leflunomide in pediatric patients ≤40 kg was less robust than in pediatric patients >40 kg suggesting suboptimal dosing in smaller weight pediatric patients, as studied, resulting in less than efficacious plasma concentrations, despite reduced clearance of M1. # How Supplied - eflunomide tablets, USP 10 mg are white, round tablets engraved “LE” over “10” on one side and engraved “APO” on the other side. They are supplied as follows: - Bottles of 30 NDC 60505-2502-1 - Bottles of 100 NDC 60505-2502-2 - Bottles of 1000 NDC 60505-2502-3 - Leflunomide tablets, USP 20 mg are white, triangular-shaped tablets engraved “LE” over “20” on one side and engraved “APO” on the other side. They are supplied as follows: - Bottles of 30 NDC 60505-2503-1 - Bottles of 100 NDC 60505-2503-2 - Bottles of 1000 NDC 60505-2503-3 - Store at 25 °C (77 °F); excursions permitted to 15 to 30 °C (59 to 86 °F). Protect from light. ## Storage There is limited information regarding Leflunomide Storage in the drug label. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information - The potential for increased risk of birth defects should be discussed with female patients of childbearing potential. It is recommended that physicians advise women that they may be at increased risk of having a child with birth defects if they are pregnant when taking leflunomide, become pregnant while taking leflunomide, or do not wait to become pregnant until they have stopped taking leflunomide and followed the drug elimination procedure. - Patients should be advised of the possibility of rare, serious skin reactions. Patients should be instructed to inform their physicians promptly if they develop a skin rash or mucous membrane lesions. - Patients should be advised of the potential hepatotoxic effects of leflunomide and of the need for monitoring liver enzymes. Patients should be instructed to notify their physicians if they develop symptoms such as unusual tiredness, abdominal pain or jaundice. - Patients should be advised that they may develop a lowering of their blood counts and should have frequent hematologic monitoring. This is particularly important for patients who are receiving other immunosuppressive therapy concurrently with leflunomide, who have recently discontinued such therapy before starting treatment with leflunomide, or who have had a history of a significant hematologic abnormality. Patients should be instructed to notify their physicians promptly if they notice symptoms of pancytopenia (such as easy bruising or bleeding, recurrent infections, fever, paleness or unusual tiredness). - Patients should be informed about the early warning signs of interstitial lung disease and asked to contact their physician as soon as possible if these symptoms appear or worsen during therapy. # Precautions with Alcohol - Alcohol-Leflunomide interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - LEFLUNOMIDE® # Look-Alike Drug Names There is limited information regarding Leflunomide Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	Leflunomide 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. # Black Box Warning # Overview Leflunomide is a pyrimidine synthesis inhibitor that is FDA approved for the {{{indicationType}}} of rheumatoid arthritis. There is a Black Box Warning for this drug as shown here. Common adverse reactions include alopecia, rash, diarrhea, ulcer of mouth, dizziness, headache, respiratory tract infection. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) - Leflunomide tablets, USP are indicated in adults for the treatment of active rheumatoid arthritis (RA): - to reduce signs and symptoms - to inhibit structural damage as evidenced by X-ray erosions and joint space narrowing - to improve physical function. - Aspirin, nonsteroidal anti-inflammatory agents and/or low dose corticosteroids may be continued during treatment with leflunomide. The combined use of leflunomide with antimalarials, intramuscular or oral gold, D penicillamine, azathioprine, or methotrexate has not been adequately studied. - Loading Dose - Due to the long half-life in patients with RA and recommended dosing interval (24 hours), a loading dose is needed to provide steady-state concentrations more rapidly. It is recommended that leflunomide therapy be initiated with a loading dose of one 100 mg tablet per day for three days. - Elimination of the loading dose regimen may decrease the risk of adverse events. This could be especially important for patients at increased risk of hematologic or hepatic toxicity, such as those receiving concomitant treatment with methotrexate or other immunosuppressive agents or on such medications in the recent past. - Maintenance Therapy - Daily dosing of 20 mg is recommended for treatment of patients with RA. A small cohort of patients (n=104), treated with 25 mg/day, experienced a greater incidence of side effects; alopecia, weight loss, liver enzyme elevations. Doses higher than 20 mg/day are not recommended. If dosing at 20 mg/day is not well tolerated clinically, the dose may be decreased to 10 mg daily. Due to the prolonged half-life of the active metabolite of leflunomide, patients should be carefully observed after dose reduction, since it may take several weeks for metabolite levels to decline. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Leflunomide in adult patients. ### Non–Guideline-Supported Use - Dosing Information - Leflunomide (20 mg daily). - Dosing Information - Leflunomide 20 mg/day. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) There is limited information regarding FDA-Labeled Use of Leflunomide in pediatric patients. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Leflunomide in pediatric patients. ### Non–Guideline-Supported Use - Dosing Information - Patients weighing less than 20 kg received 100 mg for 1 day, then 10 mg every other day; those weighing between 20 and 40 kg received 100 mg for 2 days, then 10 mg per day; those weighing greater than 40 kg received 100 mg for 3 days, then 20 mg every day. # Contraindications - Leflunomide is contraindicated in patients with known hypersensitivity to leflunomide or any of the other components of leflunomide. - Leflunomide can cause fetal harm when administered to a pregnant woman. Leflunomide, when administered orally to rats during organogenesis at a dose of 15 mg/kg, was teratogenic (most notably anophthalmia or microophthalmia and internal hydrocephalus). The systemic exposure of rats at this dose was approximately 1/10 the human exposure level based on AUC. Under these exposure conditions, leflunomide also caused a decrease in the maternal body weight and an increase in embryolethality with a decrease in fetal body weight for surviving fetuses. In rabbits, oral treatment with 10 mg/kg of leflunomide during organogenesis resulted in fused, dysplastic sternebrae. The exposure level at this dose was essentially equivalent to the maximum human exposure level based on AUC. At a 1 mg/kg dose, leflunomide was not teratogenic in rats and rabbits. - When female rats were treated with 1.25 mg/kg of leflunomide beginning 14 days before mating and continuing until the end of lactation, the offspring exhibited marked (greater than 90%) decreases in postnatal survival. The systemic exposure level at 1.25 mg/kg was approximately 1/100 the human exposure level based on AUC. - Leflunomide is contraindicated in women who are or may become pregnant. 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 fetus. # Warnings - Hepatotoxicity - Severe liver injury, including fatal liver failure, has been reported in some patients treated with leflunomide. Patients with pre- existing acute or chronic liver disease, or those with serum alanine aminotransferase (ALT) >2xULN before initiating treatment, should not be treated with leflunomide. Use caution when leflunomide is given with other potentially hepatotoxic drugs. Monitoring of ALT levels is recommended at least monthly for six months after starting leflunomide, and thereafter every 6 to 8 weeks. If ALT elevation > 3 fold ULN occurs, interrupt leflunomide therapy while investigating the probable cause of the ALT elevation by close observation and additional tests. If likely leflunomide-induced, start cholestyramine washout and monitor liver tests weekly until normalized. If leflunomide-induced liver injury is unlikely because some other probable cause has been found, resumption of leflunomide therapy may be considered. - In addition, if leflunomide and methotrexate are given concomitantly, ACR guidelines for monitoring methotrexate liver toxicity must be followed with ALT, AST, and serum albumin testing monthly. - In clinical trials, leflunomide treatment as monotherapy or in combination with methotrexate was associated with elevations of liver enzymes, primarily ALT and AST, in a significant number of patients; these effects were generally reversible. Most transaminase elevations were mild (≤ 2-fold ULN) and usually resolved while continuing treatment. Marked elevations (>3-fold ULN) occurred infrequently and reversed with dose reduction or discontinuation of treatment. Table 8 shows liver enzyme elevations seen with monthly monitoring in clinical trials US301 and MN301. It was notable that the absence of folate use in MN302 was associated with a considerably greater incidence of liver enzyme elevation on methotrexate. - In a 6 month study of 263 patients with persistent active rheumatoid arthritis despite methotrexate therapy, and with normal LFTs, leflunomide was added to a group of 130 patients starting at 10 mg per day and increased to 20 mg as needed. An increase in ALT greater than or equal to three times the ULN was observed in 3.8% of patients compared to 0.8% in 133 patients continued on methotrexate with placebo added. - Immunosuppression Potential/Bone Marrow Suppression - Leflunomide is not recommended for patients with severe immunodeficiency, bone marrow dysplasia, or severe, uncontrolled infections. In the event that a serious infection occurs, it may be necessary to interrupt therapy with leflunomide and administer cholestyramine or charcoal. Medications like leflunomide that have immunosuppression potential may cause patients to be more susceptible to infections, including opportunistic infections, especially Pneumocystis jiroveci pneumonia, tuberculosis (including extra-pulmonary tuberculosis), and aspergillosis. Severe infections including sepsis, which may be fatal, have been reported in patients receiving leflunomide, especially Pneumocystis jiroveci pneumonia and aspergillosis. Most of the reports were confounded by concomitant immunosuppressant therapy and/or comorbid illness which, in addition to rheumatoid disease, may predispose patients to infection. - There have been rare reports of pancytopenia, agranulocytosis and thrombocytopenia in patients receiving leflunomide alone. These events have been reported most frequently in patients who received concomitant treatment with methotrexate or other immunosuppressive agents, or who had recently discontinued these therapies; in some cases, patients had a prior history of a significant hematologic abnormality. - Patients taking leflunomide should have platelet, white blood cell count and hemoglobin or hematocrit monitored at baseline and monthly for six months following initiation of therapy and every 6- to 8 weeks thereafter. If used with concomitant methotrexate and/or other potential immunosuppressive agents, chronic monitoring should be monthly. - If evidence of bone marrow suppression occurs in a patient taking leflunomide, treatment with leflunomide should be stopped, and cholestyramine or charcoal should be used to reduce the plasma concentration of leflunomide active metabolite. - In any situation in which the decision is made to switch from leflunomide to another anti-rheumatic agent with a known potential for hematologic suppression, it would be prudent to monitor for hematologic toxicity, because there will be overlap of systemic exposure to both compounds. Leflunomide washout with cholestyramine or charcoal may decrease this risk, but also may induce disease worsening if the patient had been responding to leflunomide treatment. - Skin Reactions - Rare cases of Stevens-Johnson syndrome and toxic epidermal necrolysis have been reported in patients receiving leflunomide. If a patient taking leflunomide develops any of these conditions, leflunomide therapy should be stopped, and a drug elimination procedure is recommended. - Malignancy - The risk of malignancy, particularly lymphoproliferative disorders, is increased with the use of some immunosuppression medications. There is a potential for immunosuppression with leflunomide. No apparent increase in the incidence of malignancies and lymphoproliferative disorders was reported in the clinical trials of leflunomide, but larger and longer-term studies would be needed to determine whether there is an increased risk of malignancy or lymphoproliferative disorders with leflunomide. - Use in Women of Childbearing Potential - There are no adequate and well-controlled studies evaluating leflunomide in pregnant women. However, based on animal studies, leflunomide may increase the risk of fetal death or teratogenic effects when administered to a pregnant woman. Women of childbearing potential must not be started on leflunomide until pregnancy is excluded and it has been confirmed that they are using reliable contraception. Before starting treatment with leflunomide, patients must be fully counseled on the potential for serious risk to the fetus. - The patient must be advised that if there is any delay in onset of menses or any other reason to suspect pregnancy, they must notify the physician immediately for pregnancy testing and, if positive, the physician and patient must discuss the risk to the pregnancy. It is possible that rapidly lowering the blood level of the active metabolite by instituting the drug elimination procedure described below at the first delay of menses may decrease the risk to the fetus from leflunomide. - Upon discontinuing leflunomide, it is recommended that all women of childbearing potential undergo the drug elimination procedure described below. Women receiving leflunomide treatment who wish to become pregnant must discontinue leflunomide and undergo the drug elimination procedure described below which includes verification of M1 metabolite plasma levels less than 0.02 mg/L (0.02 mcg/mL). Human plasma levels of the active metabolite (M1) less than 0.02 mg/L (0.02 mcg/mL) are expected to have minimal risk based on available animal data. - Peripheral Neuropathy - Cases of peripheral neuropathy have been reported in patients receiving leflunomide. Most patients recovered after discontinuation of leflunomide, but some patients had persistent symptoms. Age older than 60 years, concomitant neurotoxic medications, and diabetes may increase the risk for peripheral neuropathy. If a patient taking leflunomide develops a peripheral neuropathy, consider discontinuing leflunomide therapy and performing the drug elimination procedure. - Drug Elimination Procedure - The following drug elimination procedure is recommended to achieve non-detectable plasma levels (less than 0.02 mg/L or 0.02 mcg/mL) after stopping treatment with leflunomide: Administer cholestyramine 8 grams 3 times daily for 11 days. (The 11 days do not need to be consecutive unless there is a need to lower the plasma level rapidly.) Verify plasma levels less than 0.02 mg/L (0.02 mcg/mL) by two separate tests at least 14 days apart. If plasma levels are higher than 0.02 mg/L, additional cholestyramine treatment should be considered. - Administer cholestyramine 8 grams 3 times daily for 11 days. (The 11 days do not need to be consecutive unless there is a need to lower the plasma level rapidly.) - Verify plasma levels less than 0.02 mg/L (0.02 mcg/mL) by two separate tests at least 14 days apart. If plasma levels are higher than 0.02 mg/L, additional cholestyramine treatment should be considered. - Without the drug elimination procedure, it may take up to 2 years to reach plasma M1 metabolite levels less than 0.02 mg/L due to individual variation in drug clearance. ### Precautions - Need for Drug Elimination - The active metabolite of leflunomide is eliminated slowly from the plasma. In instances of any serious toxicity from leflunomide, including hypersensitivity, use of a drug elimination procedure as described in this section is highly recommended to reduce the drug concentration more rapidly after stopping leflunomide therapy. If hypersensitivity is the suspected clinical mechanism, more prolonged cholestyramine or charcoal administration may be necessary to achieve rapid and sufficient clearance. The duration may be modified based on the clinical status of the patient. - Cholestyramine given orally at a dose of 8 g three times a day for 24 hours to three healthy volunteers decreased plasma levels of M1 by approximately 40% in 24 hours and by 49 to 65% in 48 hours. - Administration of activated charcoal (powder made into a suspension) orally or via nasogastric tube (50 g every 6 hours for 24 hours) has been shown to reduce plasma concentrations of the active metabolite, M1, by 37% in 24 hours and by 48% in 48 hours. - These drug elimination procedures may be repeated if clinically necessary. - Respiratory - Interstitial lung disease has been reported during treatment with leflunomide and has been associated with fatal outcomes. The risk of its occurrence is increased in patients with a history of interstitial lung disease. Interstitial lung disease is a potentially fatal disorder, which may occur acutely at any time during therapy and has a variable clinical presentation. New onset or worsening pulmonary symptoms, such as cough and dyspnea, with or without associated fever, may be a reason for discontinuation of the therapy and for further investigation as appropriate. If discontinuation of the drug is necessary, initiation of wash-out procedures should be considered. - Tuberculosis Reactivation - Prior to initiating immunomodulatory therapies, including leflunomide, patients should be screened for latent tuberculosis infection with a tuberculin skin test. Leflunomide has not been studied in patients with a positive tuberculosis screen, and the safety of leflunomide in individuals with latent tuberculosis infection is unknown. Patients testing positive in tuberculosis screening should be treated by standard medical practice prior to therapy with leflunomide. - Renal Insufficiency - Single dose studies in dialysis patients show a doubling of the free fraction of M1 in plasma. There is no clinical experience in the use of leflunomide in patients with renal impairment. Caution should be used when administering this drug in this population. - Vaccinations - No clinical data are available on the efficacy and safety of vaccinations during leflunomide treatment. Vaccination with live vaccines is, however, not recommended. The long half-life of leflunomide should be considered when contemplating administration of a live vaccine after stopping leflunomide. - Blood Pressure Monitoring - Blood pressure should be checked before start of leflunomide treatment and periodically thereafter. # Adverse Reactions ## Clinical Trials Experience - Adverse reactions associated with the use of leflunomide in RA include diarrhea, elevated liver enzymes (ALT and AST), alopecia and rash. In the controlled studies at one year, the following adverse events were reported, regardless of causality. (See Table 9.) - Adverse events during a second year of treatment with leflunomide in clinical trials were consistent with those observed during the first year of treatment and occurred at a similar or lower incidence. - In addition, the following adverse events have been reported in 1% to <3% of the RA patients in the leflunomide treatment group in controlled clinical trials. Abscess, cyst, fever, hernia, malaise, pain, neck pain, pelvic pain; Angina pectoris, migraine, palpitation, tachycardia, varicose vein, vasculitis, vasodilatation; Cholelithiasis, colitis, constipation, esophagitis, flatulence, gastritis, gingivitis, melena, oral moniliasis, pharyngitis, salivary gland enlarged, stomatitis (or aphthous stomatitis), tooth disorder; Diabetes mellitus, hyperthyroidism; Anemia (including iron deficiency anemia), ecchymosis; Creatine phosphokinase increased, hyperglycemia, hyperlipidemia, peripheral edema; Arthrosis, bone necrosis, bone pain, bursitis, muscle cramps, myalgia, tendon rupture; Anxiety, depression, dry mouth, insomnia, neuralgia, neuritis, sleep disorder, sweating increased, vertigo; Asthma, dyspnea, epistaxis, lung disorder; Acne, contact dermatitis, fungal dermatitis, hair discoloration, hematoma, herpes simplex, herpes zoster, maculopapular rash, nail disorder, skin discoloration, skin disorder, skin nodule, subcutaneous nodule, ulcer skin; Blurred vision, cataract, conjunctivitis, eye disorder, taste perversion; Albuminuria, cystitis, dysuria, hematuria, menstrual disorder, prostate disorder, urinary frequency, vaginal moniliasis. - Other less common adverse events seen in clinical trials include: 1 case of anaphylactic reaction occurred in Phase 2 following rechallenge of drug after withdrawal due to rash (rare); urticaria; eosinophilia; transient thrombocytopenia (rare); and leukopenia <2000 WBC/mm3 (rare). - Adverse events during a second year of treatment with leflunomide in clinical trials were consistent with those observed during the first year of treatment and occurred at a similar or lower incidence. - Adverse Reactions (Pediatric Patients) - The safety of leflunomide was studied in 74 patients with polyarticular course juvenile rheumatoid arthritis ranging in age from 3 to 17 years (47 patients from the active-controlled study and 27 from an open-label safety and pharmacokinetic study). The most common adverse events included abdominal pain, diarrhea, nausea, vomiting, oral ulcers, upper respiratory tract infections, alopecia, rash, headache, and dizziness. Less common adverse events included anemia, hypertension, and weight loss. Fourteen pediatric patients experienced ALT and/or AST elevations, nine between 1.2 and 3-fold the upper limit of normal, five between 3 and 8-fold the upper limit of normal. ## Postmarketing Experience - In post-marketing experience, the following have been reported: Opportunistic infections, severe infections including sepsis that may be fatal; Pancreatitis Agranulocytosis, leukopenia, neutropenia, pancytopenia, thrombocytopenia Angioedema Hepatitis, jaundice/cholestasis, severe liver injury such as hepatic failure and acute hepatic necrosis that may be fatal; Interstitial lung disease, including interstitial pneumonitis and pulmonary fibrosis, which may be fatal; Peripheral neuropathy Erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis, vasculitis including cutaneous necrotizing vasculitis, cutaneous lupus erythematosus, pustular psoriasis or worsening psoriasis. # Drug Interactions - Cholestyramine and Charcoal - Administration of cholestyramine or activated charcoal in patients (n=13) and volunteers (n=96) resulted in a rapid and significant decrease in plasma M1 (the active metabolite of leflunomide) concentration. - Hepatotoxic Drugs - Increased side effects may occur when leflunomide is given concomitantly with hepatotoxic substances. This is also to be considered when leflunomide treatment is followed by such drugs without a drug elimination procedure. In a small (n=30) combination study of leflunomide with methotrexate, a 2- to 3-fold elevation in liver enzymes was seen in 5 of 30 patients. All elevations resolved, 2 with continuation of both drugs and 3 after discontinuation of leflunomide. A >3-fold increase was seen in another 5 patients. All of these also resolved, 2 with continuation of both drugs and 3 after discontinuation of leflunomide. Three patients met "ACR criteria" for liver biopsy (1: Roegnik Grade I, 2: Roegnik Grade IIIa). No pharmacokinetic interaction was identified. - NSAIDs - In in vitro studies, M1 was shown to cause increases ranging from 13 to 50% in the free fraction of diclofenac and ibuprofen at concentrations in the clinical range. The clinical significance of this finding is unknown; however, there was extensive concomitant use of NSAIDs in clinical studies and no differential effect was observed. - Tolbutamide - In in vitro studies, M1 was shown to cause increases ranging from 13 to 50% in the free fraction of tolbutamide at concentrations in the clinical range. The clinical significance of this finding is unknown. - Rifampin - Following concomitant administration of a single dose of leflunomide to subjects receiving multiple doses of rifampin, M1 peak levels were increased (~40%) over those seen when leflunomide was given alone. Because of the potential for leflunomide levels to continue to increase with multiple dosing, caution should be used if patients are to be receiving both leflunomide and rifampin. - Warfarin - Increased INR (International Normalized Ratio) when leflunomide and warfarin were co-administered has been rarely reported. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): - Pregnancy Category X - (See CONTRAINDICATIONS section.) Pregnancy Registry: To monitor fetal outcomes of pregnant women exposed to leflunomide, health care providers are encouraged to register such patients by calling 1-877-311-8972. Pregnancy Category (AUS): - Australian Drug Evaluation Committee (ADEC) Pregnancy Category There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Leflunomide in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Leflunomide during labor and delivery. ### Nursing Mothers - Leflunomide should not be used by nursing mothers. It is not known whether leflunomide is excreted in human milk. Many drugs are excreted in human milk, and there is a potential for serious adverse reactions in nursing infants from leflunomide. Therefore, a decision should be made whether to proceed with nursing or to initiate treatment with leflunomide, taking into account the importance of the drug to the mother. ### Pediatric Use - The safety and effectiveness of leflunomide in pediatric patients with polyarticular course juvenile rheumatoid arthritis (JRA) have not been fully evaluated. ### Geriatic Use - Of the total number of subjects in controlled clinical (Phase III) studies of leflunomide, 234 subjects were 65 years and over. 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, but greater sensitivity of some older individuals cannot be ruled out. No dosage adjustment is needed in patients over 65. ### Gender - Available information does not suggest that leflunomide would be associated with an increased risk of male-mediated fetal toxicity. However, animal studies to evaluate this specific risk have not been conducted. To minimize any possible risk, men wishing to father a child should consider discontinuing use of leflunomide and taking cholestyramine 8 grams 3 times daily for 11 days. ### Race There is no FDA guidance on the use of Leflunomide with respect to specific racial populations. ### Renal Impairment There is no FDA guidance on the use of Leflunomide in patients with renal impairment. ### Hepatic Impairment There is no FDA guidance on the use of Leflunomide in patients with hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Leflunomide in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Leflunomide in patients who are immunocompromised. # Administration and Monitoring ### Administration - Oral ### Monitoring There is limited information regarding Monitoring of Leflunomide in the drug label. # IV Compatibility There is limited information regarding IV Compatibility of Leflunomide in the drug label. # Overdosage ## Acute Overdose ### Signs and Symptoms - In mouse and rat acute toxicology studies, the minimally toxic dose for oral leflunomide was 200 to 500 mg/kg and 100 mg/kg, respectively (approximately >350 times the maximum recommended human dose, respectively). - There were no adverse events reported in the majority of case reports of overdose. Adverse events were consistent with the safety profile for leflunomide. The most frequent adverse events observed were diarrhea, abdominal pain, leukopenia, anemia and elevated liver function tests. ### Management - In the event of a significant overdose or toxicity, cholestyramine or charcoal administration is recommended to accelerate elimination. - In the event of a significant overdose or toxicity, cholestyramine or charcoal administration is recommended to accelerate elimination. - Studies with both hemodialysis and CAPD (chronic ambulatory peritoneal dialysis) indicate that M1, the primary metabolite of leflunomide, is not dialyzable. ## Chronic Overdose - There have been reports of chronic overdose in patients taking leflunomide at daily dose up to five times the recommended daily dose and reports of acute overdose in adults or children. # Pharmacology ## Mechanism of Action - Leflunomide is an isoxazole immunomodulatory agent which inhibits dihydroorotate dehydrogenase (an enzyme involved in de novo pyrimidine synthesis) and has antiproliferative activity. Several in vivo and in vitro experimental models have demonstrated an anti-inflammatory effect. ## Structure - Leflunomide is a pyrimidine synthesis inhibitor. The chemical name for leflunomide is N-(4'-trifluoromethylphenyl)-5-methylisoxazole-4-carboxamide. It has an empirical formula C12H9F3N2O2, a molecular weight of 270.2 and the following structural formula: - Leflunomide tablets, USP is available for oral administration as tablets containing 10 or 20 mg of active drug. Each leflunomide tablet, USP contains anhydrous lactose, colloidal silicon dioxide, crospovidone, and magnesium stearate. ## Pharmacodynamics There is limited information regarding Pharmacodynamics of Leflunomide in the drug label. ## Pharmacokinetics - Following oral administration, leflunomide is metabolized to an active metabolite A77 1726 (hereafter referred to as M1) which is responsible for essentially all of its activity in vivo. Plasma levels of leflunomide are occasionally seen, at very low levels. Studies of the pharmacokinetics of leflunomide have primarily examined the plasma concentrations of this active metabolite. - Absorption - Following oral administration, peak levels of the active metabolite, M1, occurred between 6 to 12 hours after dosing. Due to the very long half-life of M1 (~2 weeks), a loading dose of 100 mg for 3 days was used in clinical studies to facilitate the rapid attainment of steady-state levels of M1. Without a loading dose, it is estimated that attainment of steady-state plasma concentrations would require nearly two months of dosing. The resulting plasma concentrations following both loading doses and continued clinical dosing indicate that M1 plasma levels are dose proportional. - Relative to an oral solution, leflunomide tablets are 80% bioavailable. Co-administration of leflunomide tablets with a high fat meal did not have a significant impact on M1 plasma levels. - Distribution - M1 has a low volume of distribution (Vss = 0.13 L/kg) and is extensively bound (>99.3%) to albumin in healthy subjects. Protein binding has been shown to be linear at therapeutic concentrations. The free fraction of M1 is slightly higher in patients with rheumatoid arthritis and approximately doubled in patients with chronic renal failure; the mechanism and significance of these increases are unknown. - Metabolism - Leflunomide is metabolized to one primary (M1) and many minor metabolites. Of these minor metabolites, only 4-trifluoromethylaniline (TFMA) is quantifiable, occurring at low levels in the plasma of some patients. The parent compound is rarely detectable in plasma. At the present time the specific site of leflunomide metabolism is unknown. In vivo and in vitro studies suggest a role for both the GI wall and the liver in drug metabolism. No specific enzyme has been identified as the primary route of metabolism for leflunomide; however, hepatic cytosolic and microsomal cellular fractions have been identified as sites of drug metabolism. - Elimination - The active metabolite M1 is eliminated by further metabolism and subsequent renal excretion as well as by direct biliary excretion. In a 28 day study of drug elimination (n=3) using a single dose of radiolabeled compound, approximately 43% of the total radioactivity was eliminated in the urine and 48% was eliminated in the feces. Subsequent analysis of the samples revealed the primary urinary metabolites to be leflunomide glucuronides and an oxanilic acid derivative of M1. The primary fecal metabolite was M1. Of these two routes of elimination, renal elimination is more significant over the first 96 hours after which fecal elimination begins to predominate. In a study involving the intravenous administration of M1, the clearance was estimated to be 31 mL/hr. - In small studies using activated charcoal (n=1) or cholestyramine (n=3) to facilitate drug elimination, the in vivo plasma half-life of M1 was reduced from >1 week to approximately 1 day, Similar reductions in plasma half-life were observed for a series of volunteers (n=96) enrolled in pharmacokinetic trials who were given cholestyramine. This suggests that biliary recycling is a major contributor to the long elimination half-life of M1. Studies with both hemodialysis and CAPD (chronic ambulatory peritoneal dialysis) indicate that M1 is not dialyzable. - Special Populations - Gender - Gender has not been shown to cause a consistent change in the in vivo pharmacokinetics of M1. - Age - Age has been shown to cause a change in the in vivo pharmacokinetics of M1. - Smoking - A population based pharmacokinetic analysis of the phase III data indicates that smokers have a 38% increase in clearance over non-smokers; however, no difference in clinical efficacy was seen between smokers and nonsmokers. - Chronic Renal Insufficiency - In single dose studies in patients (n=6) with chronic renal insufficiency requiring either chronic ambulatory peritoneal dialysis (CAPD) or hemodialysis, neither had a significant impact on circulating levels of M1. The free fraction of M1 was almost doubled, but the mechanism of this increase is not known. In light of the fact that the kidney plays a role in drug elimination and without adequate studies of leflunomide use in subjects with renal insufficiency, caution should be used when leflunomide is administered to these patients. - Hepatic Insufficiency - Studies of the effect of hepatic insufficiency on M1 pharmacokinetics have not been done. Given the need to metabolize leflunomide into the active species, the role of the liver in drug elimination/recycling, and the possible risk of increased hepatic toxicity, the use of leflunomide in patients with hepatic insufficiency is not recommended. - Pediatrics - The pharmacokinetics of M1 following oral administration of leflunomide have been investigated in 73 pediatric patients with polyarticular course Juvenile Rheumatoid Arthritis (JRA) who ranged in age from 3 to 17 years. The results of a population pharmacokinetic analysis of these trials have demonstrated that pediatric patients with body weights ≤40 kg have a reduced clearance of M1 (see Table 2) relative to adult rheumatoid arthritis patients. - Drug Interactions - In vivo drug interaction studies have demonstrated a lack of a significant drug interaction between leflunomide and tri-phasic oral contraceptives, and cimetidine. - In vitro studies of protein binding indicated that warfarin did not affect M1 protein binding. At the same time M1 was shown to cause increases ranging from 13 to 50% in the free fraction of diclofenac, ibuprofen and tolbutamide at concentrations in the clinical range. In vitro studies of drug metabolism indicate that M1 inhibits CYP 450 2C9, which is responsible for the metabolism of phenytoin, tolbutamide, warfarin and many NSAIDs. M1 has been shown to inhibit the formation of 4′-hydroxydiclofenac from diclofenac in vitro. The clinical significance of these findings with regard to phenytoin and tolbutamide is unknown; however, there was extensive concomitant use of NSAIDs in the clinical studies and no differential effect was observed. - Methotrexate - Coadministration, in 30 patients, of leflunomide (100 mg/day x 2 days followed by 10 to 20 mg/day) with methotrexate (10 to 25 mg/week, with folate) demonstrated no pharmacokinetic interaction between the two drugs. However, co-administration increased risk of hepatotoxicity. - Rifampin - Following concomitant administration of a single dose of leflunomide to subjects receiving multiple doses of rifampin, M1 peak levels were increased (~40%) over those seen when leflunomide was given alone. Because of the potential for leflunomide levels to continue to increase with multiple dosing, caution should be used if patients are to receive both leflunomide and rifampin. ## Nonclinical Toxicology - No evidence of carcinogenicity was observed in a 2-year bioassay in rats at oral doses of leflunomide up to the maximally tolerated dose of 6 mg/kg (approximately 1/40 the maximum human M1 systemic exposure based on AUC). However, male mice in a 2-year bioassay exhibited an increased incidence in lymphoma at an oral dose of 15 mg/kg, the highest dose studied (1.7 times the human M1 exposure based on AUC). Female mice, in the same study, exhibited a dose-related increased incidence of bronchoalveolar adenomas and carcinomas combined beginning at 1.5 mg/kg (approximately 1/10 the human M1 exposure based on AUC). The significance of the findings in mice relative to the clinical use of leflunomide is not known. - Leflunomide was not mutagenic in the Ames Assay, the Unscheduled DNA Synthesis Assay, or in the HGPRT Gene Mutation Assay. In addition, leflunomide was not clastogenic in the in vivo Mouse Micronucleus Assay nor in the in vivo Cytogenetic Test in Chinese Hamster Bone Marrow Cells. However, 4-trifluoromethylaniline (TFMA), a minor metabolite of leflunomide, was mutagenic in the Ames Assay and in the HGPRT Gene Mutation Assay, and was clastogenic in the in vitro Assay for Chromosome Aberrations in the Chinese Hamster Cells. TFMA was not clastogenic in the in vivo Mouse Micronucleus Assay nor in the in vivo Cytogenetic Test in Chinese Hamster Bone Marrow Cells. Leflunomide had no effect on fertility in either male or female rats at oral doses up to 4.0 mg/kg (approximately 1/30 the human M1 exposure based on AUC). # Clinical Studies - The efficacy of leflunomide in the treatment of rheumatoid arthritis (RA) was demonstrated in three controlled trials showing reduction in signs and symptoms, and inhibition of structural damage. In two placebo controlled trials, efficacy was demonstrated for improvement in physical function. - Reduction of signs and symptoms - Relief of signs and symptoms was assessed using the American College of Rheumatology (ACR) 20 Responder Index, a composite of clinical, laboratory, and functional measures in rheumatoid arthritis. An "ACR20 Responder" is a patient who had ≥ 20% improvement in both tender and swollen joint counts and in 3 of the following 5 criteria: physician global assessment, patient global assessment, functional ability measure [Modified Health Assessment Questionnaire (MHAQ)], visual analog pain scale, and erythrocyte sedimentation rate or C-reactive protein. An "ACR20 Responder at Endpoint" is a patient who completed the study and was an ACR20 Responder at the completion of the study. - Inhibition of structural damage - Inhibition of structural damage compared to control was assessed using the Sharp Score (Sharp, JT. Scoring Radiographic Abnormalities in Rheumatoid Arthritis, Radiologic Clinics of North America, 1996; vol. 34, pp. 233 to 241), a composite score of X-ray erosions and joint space narrowing in hands/wrists and forefeet. - Improvement in physical function - Improvement in physical function was assessed using the Health Assessment Questionnaire (HAQ) and the Medical Outcomes Survey Short Form (SF-36). - In all leflunomide monotherapy studies, an initial loading dose of 100 mg per day for three days only was used followed by 20 mg per day thereafter. - US301 Clinical Trial in Adults - Study US301, a 2 year study, randomized 482 patients with active RA of at least 6 months duration to leflunomide 20 mg/day (n=182), methotrexate 7.5 mg/week increasing to 15 mg/week (n=182), or placebo (n=118). All patients received folate 1 mg BID. Primary analysis was at 52 weeks with blinded treatment to 104 weeks. - Overall, 235 of the 508 randomized treated patients (482 in primary data analysis and an additional 26 patients), continued into a second 12 months of double-blind treatment (98 leflunomide, 101 methotrexate, 36 placebo). Leflunomide dose continued at 20 mg/day and the methotrexate dose could be increased to a maximum of 20 mg/week. In total, 190 patients (83 leflunomide, 80 methotrexate, 27 placebo) completed 2 years of double-blind treatment. - The rate and reason for withdrawal is summarized in Table 3. - 1 Includes: lost to follow up, protocol violation, noncompliance, voluntary withdrawal, investigator discretion. - MN301/303/305 Clinical Trial in Adults - Study MN301 randomized 358 patients with active RA to leflunomide 20 mg/day (n=133), sulfasalazine 2.0 g/day (n=133), or placebo (n=92). Treatment duration was 24 weeks. An extension of the study was an optional 6-month blinded continuation of MN301 without the placebo arm, resulting in a 12-month comparison of leflunomide and sulfasalazine (study MN303). - Of the 168 patients who completed 12 months of treatment in MN301 and MN303, 146 patients (87%) entered a 1-year extension study of double blind active treatment (MN305; 60 leflunomide, 60 sulfasalazine, 26 placebo/sulfasalazine). Patients continued on the same daily dosage of leflunomide or sulfasalazine that they had been taking at the completion of MN301/303. A total of 121 patients (53 leflunomide, 47 sulfasalazine, 21 placebo/sulfasalazine) completed the 2 years of double-blind treatment. - Patient withdrawal data in MN301/303/305 is summarized in Table 4. - MN302/304 Clinical Trial in Adults - Study MN302 randomized 999 patients with active RA to leflunomide 20 mg/day (n=501) or methotrexate at 7.5 mg/week increasing to 15 mg/week (n=498). Folate supplementation was used in 10% of patients. Treatment duration was 52 weeks. - Of the 736 patients who completed 52 weeks of treatment in study MN302, 612 (83%) entered the double-blind, 1-year extension study MN304 (292 leflunomide, 320 methotrexate). Patients continued on the same daily dosage of leflunomide or methotrexate that they had been taking at the completion of MN302. There were 533 patients (256 leflunomide, 277 methotrexate) who completed 2 years of double-blind treatment. - Patient withdrawal data in MN302/304 is summarized in Table 5. - Signs and symptoms Rheumatoid Arthritis - The ACR20 Responder at Endpoint rates are shown in Figure 1. Leflunomide was statistically significantly superior to placebo in reducing the signs and symptoms of RA by the primary efficacy analysis, ACR20 Responder at Endpoint, in study US301 (at the primary 12 months endpoint) and MN301 (at 6 month endpoint). ACR20 Responder at Endpoint rates with leflunomide treatment were consistent across the 6 and 12 month studies (41 to 49%). No consistent differences were demonstrated between leflunomide and methotrexate or between leflunomide and sulfasalazine. Leflunomide treatment effect was evident by 1 month, stabilized by 3 to 6 months, and continued throughout the course of treatment as shown in Figure 2. - ACR50 and ACR70 Responders are defined in an analogous manner to the ACR20 Responder, but use improvements of 50% or 70%, respectively (Table 6). Mean change for the individual components of the ACR Responder Index are shown in Table 7. - Table 7 shows the results of the components of the ACR response criteria for US301, MN301, and MN302. Leflunomide was significantly superior to placebo in all components of the ACR Response criteria in study US301 and MN301. In addition, leflunomide was significantly superior to placebo in improving morning stiffness, a measure of RA disease activity, not included in the ACR Response criteria. No consistent differences were demonstrated between leflunomide and the active comparators. - Maintenance of effect - After completing 12 months of treatment, patients continuing on study treatment were evaluated for an additional 12 months of double-blind treatment (total treatment period of 2 years) in studies US301, MN305, and MN304. ACR Responder rates at 12 months were maintained over 2 years in most patients continuing a second year of treatment. - Improvement from baseline in the individual components of the ACR responder criteria was also sustained in most patients during the second year of leflunomide treatment in all three trials. - Inhibition of structural damage - The change from baseline to endpoint in progression of structural disease, as measured by the Sharp X-ray score, is displayed in Figure 3. Leflunomide was statistically significantly superior to placebo in inhibiting the progression of disease by the Sharp Score. No consistent differences were demonstrated between leflunomide and methotrexate or between leflunomide and sulfasalazine. - Improvement in physical function - The Health Assessment Questionnaire (HAQ) assesses a patient's physical function and degree of disability. The mean change from baseline in functional ability as measured by the HAQ Disability Index (HAQ DI) in the 6 and 12 month placebo and active controlled trials is shown in Figure 4. Leflunomide was statistically significantly superior to placebo in improving physical function. Superiority to placebo was demonstrated consistently across all eight HAQ DI subscales (dressing, arising, eating, walking, hygiene, reach, grip and activities) in both placebo controlled studies. - The Medical Outcomes Survey Short Form 36 (SF-36), a generic health-related quality of life questionnaire, further addresses physical function. In US301, at 12 months, leflunomide provided statistically significant improvements compared to placebo in the Physical Component Summary (PCS) Score. - Maintenance of effect - The improvement in physical function demonstrated at 6 and 12 months was maintained over two years. In those patients continuing therapy for a second year, this improvement in physical function as measured by HAQ and SF-36 (PCS) was maintained. - Clinical Trials in Pediatrics - Leflunomide was studied in a single multicenter, double-blind, active-controlled trial in 94 patients (1:1 randomization) with polyarticular course juvenile rheumatoid arthritis (JRA) as defined by the American College of Rheumatology (ACR). Approximately 68% of pediatric patients receiving leflunomide, versus 89% of pediatric patients receiving the active comparator, improved by Week 16 (end-of-study) employing the JRA Definition of Improvement (DOI) ≥ 30 % responder endpoint. In this trial, the loading dose and maintenance dose of leflunomide was based on three weight categories: <20 kg, 20 to 40kg, and >40 kg. The response rate to leflunomide in pediatric patients ≤40 kg was less robust than in pediatric patients >40 kg suggesting suboptimal dosing in smaller weight pediatric patients, as studied, resulting in less than efficacious plasma concentrations, despite reduced clearance of M1. # How Supplied - eflunomide tablets, USP 10 mg are white, round tablets engraved “LE” over “10” on one side and engraved “APO” on the other side. They are supplied as follows: - Bottles of 30 NDC 60505-2502-1 - Bottles of 100 NDC 60505-2502-2 - Bottles of 1000 NDC 60505-2502-3 - Leflunomide tablets, USP 20 mg are white, triangular-shaped tablets engraved “LE” over “20” on one side and engraved “APO” on the other side. They are supplied as follows: - Bottles of 30 NDC 60505-2503-1 - Bottles of 100 NDC 60505-2503-2 - Bottles of 1000 NDC 60505-2503-3 - Store at 25 °C (77 °F); excursions permitted to 15 to 30 °C (59 to 86 °F). Protect from light. ## Storage There is limited information regarding Leflunomide Storage in the drug label. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information - The potential for increased risk of birth defects should be discussed with female patients of childbearing potential. It is recommended that physicians advise women that they may be at increased risk of having a child with birth defects if they are pregnant when taking leflunomide, become pregnant while taking leflunomide, or do not wait to become pregnant until they have stopped taking leflunomide and followed the drug elimination procedure. - Patients should be advised of the possibility of rare, serious skin reactions. Patients should be instructed to inform their physicians promptly if they develop a skin rash or mucous membrane lesions. - Patients should be advised of the potential hepatotoxic effects of leflunomide and of the need for monitoring liver enzymes. Patients should be instructed to notify their physicians if they develop symptoms such as unusual tiredness, abdominal pain or jaundice. - Patients should be advised that they may develop a lowering of their blood counts and should have frequent hematologic monitoring. This is particularly important for patients who are receiving other immunosuppressive therapy concurrently with leflunomide, who have recently discontinued such therapy before starting treatment with leflunomide, or who have had a history of a significant hematologic abnormality. Patients should be instructed to notify their physicians promptly if they notice symptoms of pancytopenia (such as easy bruising or bleeding, recurrent infections, fever, paleness or unusual tiredness). - Patients should be informed about the early warning signs of interstitial lung disease and asked to contact their physician as soon as possible if these symptoms appear or worsen during therapy. # Precautions with Alcohol - Alcohol-Leflunomide interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - LEFLUNOMIDE®[2] # Look-Alike Drug Names There is limited information regarding Leflunomide Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	https://www.wikidoc.org/index.php/Leflunomide
344cd5c858049c926cccdd9343436fe24278c2f9	wikidoc	Lethal dose	Lethal dose # Overview A lethal dose (LD) is an indication of the lethality of a given substance or type of radiation. Because resistance varies from one individual to another, the 'lethal dose' represents a dose (usually recorded as dose per kilogram of subject body weight) at which a given percentage of subjects will die. The most commonly-used lethality indicator is the LD50 (or LD50), a dose at which 50% of subjects will die. LD measurements are often used to describe the power of venoms in animals such as snakes. Animal-based LD measurements are a commonly-used technique in drug research, although many researchers are now shifting away from such methods. LD figures depend not only on the species of animal, but also on the mode of administration. For instance, a toxic substance inhaled or injected into the bloodstream may require a much smaller dosage than if the same substance is swallowed. LD values for humans are generally estimated by extrapolating results from testing on animals or on human cell cultures. One common form of extrapolation involves measuring LD on animals like mice or dogs, converting to dosage per kilogram of biomass, and extrapolating to human norms. While animal-extrapolated LD values are correlated to lethality in humans, the degree of error is sometimes very large. The biology of test animals, while similar to that of humans in many respects, sometimes differs in important aspects. For instance, mouse tissue is approximately fifty times less responsive than human tissue to the venom of the Sydney funnel-web. The square-cube law can also complicate the scaling relationships involved. Currently, the only known LD50 values obtained directly on humans are from Nazi human experimentation. # Relates chapters - Lowest published lethal dose cs:Smrtelná dávka sr:Смртоносна доза sv:Letal dos ur:خوراک مرگ	Lethal dose Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview A lethal dose (LD) is an indication of the lethality of a given substance or type of radiation. Because resistance varies from one individual to another, the 'lethal dose' represents a dose (usually recorded as dose per kilogram of subject body weight) at which a given percentage of subjects will die. The most commonly-used lethality indicator is the LD50 (or LD50), a dose at which 50% of subjects will die. LD measurements are often used to describe the power of venoms in animals such as snakes. Animal-based LD measurements are a commonly-used technique in drug research, although many researchers are now shifting away from such methods. LD figures depend not only on the species of animal, but also on the mode of administration. For instance, a toxic substance inhaled or injected into the bloodstream may require a much smaller dosage than if the same substance is swallowed. LD values for humans are generally estimated by extrapolating results from testing on animals or on human cell cultures. One common form of extrapolation involves measuring LD on animals like mice or dogs, converting to dosage per kilogram of biomass, and extrapolating to human norms. While animal-extrapolated LD values are correlated to lethality in humans, the degree of error is sometimes very large. The biology of test animals, while similar to that of humans in many respects, sometimes differs in important aspects. For instance, mouse tissue is approximately fifty times less responsive than human tissue to the venom of the Sydney funnel-web. The square-cube law can also complicate the scaling relationships involved. Currently, the only known LD50 values obtained directly on humans are from Nazi human experimentation. # Relates chapters - Lowest published lethal dose cs:Smrtelná dávka sr:Смртоносна доза sv:Letal dos ur:خوراک مرگ Template:WikiDoc Sources	https://www.wikidoc.org/index.php/Lethal_dose
aec041abb5e99b3a50f4d92740d784b662cc3885	wikidoc	Leukonychia	Leukonychia Synonyms and keywords: Leuconychia # Overview Leukonychia is a medical term for white discoloration appearing on nails. It is derived from the Greek words Leuko white and Onyx nail. The most common cause is injury to the base of the nail (the matrix) where the nail is formed. # Classification Leukonychia Totalis: This condition is a whitening of the entire nail. This may be due to hypoalbuminaemia, a genetic condition, or a side effect of sulphonamides, a family of antibiotics. Leukonychia Partialis: This condition is whitening of parts of the nail. There are several types of this condition. Leukonychia Striata or Transverse Leukonychia: This is a whitening or discoloration of the nail in bands or "stria". It may be caused by cirrhosis, chemotherapy, or physical injury to the nail matrix. (i.e. excessive nail "tapping" or slamming in a car door). This condition looks similar to Mee's lines, a condition caused by Arsenic, Lead, or other heavy metal poisoning. True Leukonychia: This is the most common form of Leukonychia, small white spots on the nails. Picking and biting of the nails are a prominent cause in young children and nail biters. In most cases, when white spots appear on a single or a couple of fingers or toes, the most common cause is injury to the base (matrix) of the nail. When this is the case, white spots disappear after around eight months, which is the amount of time necessary for nails to regrow completely. White spots showing up on all or nearly all nails for longer periods of time (months and years) can be due to one of several reasons. One common explanation is zinc deficiency. # Pathophysiology ## Associated Conditions - Kidney disease - Liver disease # Causes ## Causes In Alphabetical Order - Anemia - Arsenic poisoning - Calcium deficiency - Cardiac Diseases - Cirrhosis - Congenital isolated nail dysplasia - Darier's disease - Fever - Hypoalbuminemia - Iron deficiency - Leprosy - Malabsorption - Mycosis - Nitrate solution - Silver solution - Sulphonamides - Noxa - Steatocystoma multiplex - Trauma - Vitiligo - Witkop syndrome - Zinc deficiency # Diagnosis ## Past Medical History A doctor will take a thorough medical history, and may test liver and kidney function. ### Physical Examination - Leukonychia. Adapted from Dermatology Atlas. - Leukonychia. Adapted from Dermatology Atlas. # Treatment ## Pharmacotherapy ### Chronic Pharmacotherapies If a zinc deficiency is identified, a diet rich in zinc or zinc supplements may be administered.	Leukonychia Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1];Associate Editor(s)-in-Chief: Kiran Singh, M.D. [2] Synonyms and keywords: Leuconychia # Overview Leukonychia is a medical term for white discoloration appearing on nails. It is derived from the Greek words Leuko white and Onyx nail. The most common cause is injury to the base of the nail (the matrix) where the nail is formed. # Classification Leukonychia Totalis: This condition is a whitening of the entire nail. This may be due to hypoalbuminaemia, a genetic condition, or a side effect of sulphonamides, a family of antibiotics.[1] Leukonychia Partialis: This condition is whitening of parts of the nail. There are several types of this condition. Leukonychia Striata or Transverse Leukonychia: This is a whitening or discoloration of the nail in bands or "stria". It may be caused by cirrhosis, chemotherapy, or physical injury to the nail matrix. (i.e. excessive nail "tapping" or slamming in a car door).[2] This condition looks similar to Mee's lines, a condition caused by Arsenic, Lead, or other heavy metal poisoning. True Leukonychia: This is the most common form of Leukonychia, small white spots on the nails. Picking and biting of the nails are a prominent cause in young children and nail biters. In most cases, when white spots appear on a single or a couple of fingers or toes, the most common cause is injury to the base (matrix) of the nail. When this is the case, white spots disappear after around eight months, which is the amount of time necessary for nails to regrow completely.[3] White spots showing up on all or nearly all nails for longer periods of time (months and years) can be due to one of several reasons. One common explanation is zinc deficiency.[4] # Pathophysiology ## Associated Conditions - Kidney disease - Liver disease # Causes ## Causes In Alphabetical Order - Anemia - Arsenic poisoning - Calcium deficiency - Cardiac Diseases - Cirrhosis - Congenital isolated nail dysplasia - Darier's disease - Fever - Hypoalbuminemia - Iron deficiency - Leprosy - Malabsorption - Mycosis - Nitrate solution - Silver solution - Sulphonamides - Noxa - Steatocystoma multiplex - Trauma - Vitiligo - Witkop syndrome - Zinc deficiency # Diagnosis ## Past Medical History A doctor will take a thorough medical history, and may test liver and kidney function. ### Physical Examination - Leukonychia. Adapted from Dermatology Atlas.[5] - Leukonychia. Adapted from Dermatology Atlas.[5] # Treatment ## Pharmacotherapy ### Chronic Pharmacotherapies If a zinc deficiency is identified, a diet rich in zinc or zinc supplements may be administered.	https://www.wikidoc.org/index.php/Leuconychia
0eec6463cbfe4ff46a088455ad29ccf8e3333279	wikidoc	Leukotriene	Leukotriene # Overview Leukotrienes are naturally produced eicosanoid lipid mediators, which may be responsible for a number of the effects of asthma and allergies. Leukotrienes use both autocrine signalling and paracrine signalling to regulate the body's response. Leukotrienes are produced in the body from arachidonic acid by the enzyme 5-lipoxygenase. Their production by the body is part of a complex response that usually includes the production of histamine. # Types Examples of leukotrienes are LTA4, LTB4, LTC4, LTD4, LTE4, and LTF4. LTC4, LTD4 and LTE4 are often called cysteinyl leukotrienes due to the presence of the amino acid in their structure. Collectively, the cysteinyl leukotrienes make up the slow reacting substance of anaphylaxis (SRS-A). There has also been postulated the existence of LTG4, a metabolite of LTE4 in which the cysteinyl moiety has been oxidized to an alpha-keto-acid (i.e., the cysteine has been replaced by a pyruvate). Very little is known about this putative leukotriene. # History and name The name leukotriene, introduced by Swedish biochemist Bengt Samuelsson in 1979, comes from the words leukocyte and triene (indicating the compound's three conjugated double bonds). What would be later named leukotriene C, "slow reaction smooth muscle-stimulating substance" (SRS) was originally described between 1938 and 1940 by Feldberg and Kellaway. The researchers isolated SRS from lung tissue after a prolonged period following exposure to snake venom and histamine. Leukotrienes are commercially available to the research community. # Biochemistry ## Synthesis Leukotrienes are synthesized in the cell from arachidonic acid by 5-lipoxygenase. The catalytic mechanism involves the insertion of an oxygen moiety at a specific position in the arachidonic acid backbone. The lipoxygenase pathway is active in leukocytes, including mast cells, eosinophils, neutrophils, monocytes and basophils. When such cells are activated, arachidonic acid is liberated from cell membrane phospholipids by phospholipase A2, and donated by the 5-lipoxygenase activating protein (FLAP) to 5-lipoxygenase, which converts it in two steps to leukotriene A4, an unstable epoxide. In cells equipped with LTA4 hydrolase, such as neutrophils and monocytes, LTA4 is converted to the dihydroxy acid leukotriene LTB4, which is a powerful chemoattractant for neutrophils acting at BLT1 and BLT2 receptors on the plasma membrane of these cells. In cells that express LTC4 synthase, such as mast cells and eosinophils, LTA4 is conjugated with the tripeptide glutathione to form the first of the cysteinyl-leukotrienes, LTC4. Outside the cell, LTC4 can be converted by ubiquitous enzymes to form successively LTD4 and LTE4, which retain biological activity. The cysteinyl-leukotrienes act at their cell-surface receptors CysLT1 and CysLT2 on target cells to contract bronchial and vascular smooth muscle, to increase permeability of small blood vessels, to enhance secretion of mucus in the airway and gut, and to recruit leukocytes to sites of inflammation. Both LTB4 and the cysteinyl-leukotrienes (LTC4, LTD4, LTE4) are partly degraded in local tissues, and ultimately become inactive metabolites in the liver. ## Function Leukotrienes act principally on a subfamily of G protein coupled receptors. They may also act upon peroxisome proliferator-activated receptors. Leukotrienes are involved in asthmatic and allergic reactions and act to sustain inflammatory reactions; several leukotriene receptor antagonists (e.g. montelukast and zafirlukast) are used to treat asthma. Recent research points to a role of 5-lipoxygenase in cardiovascular and neuropsychiatric illnesses. Leukotrienes are very important agents in the inflammatory response. Some such as LTB4 have a chemotactic effect on migrating neutrophils, and as such help to bring the necessary cells to the tissue. Leukotrienes also have a powerful effect in vasoconstriction particularly of venules and of bronchoconstriction, they also increase vascular permeability. # Leukotrienes in asthma Leukotrienes assist in the pathophysiology of asthma, causing or potentiating the following symptoms: - airflow obstruction - increased secretion of mucus - mucosal accumulation - bronchoconstriction - infiltration of inflammatory cells in the airway wall ## Role of cysteinyl leukotrienes Cysteinyl leukotriene receptors CysLT1 and CysLT2 are present on mast cells, eosinophil and endothelial cells. During cysteinyl leukotriene interaction, they can stimulate proinflammatory activities such as endothelial cell adherence and chemokine production by mast cells. As well as mediating inflammation, they induce asthma and other inflammatory disorders, thereby reducing the airflow to the alveoli. In excess, the cysteinyl leukotrienes can induce anaphylactic shock. ## Leukotriene modifiers # Related Chpaters - A chemical synthesis of Leukotriene A methyl ester	Leukotriene Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview Leukotrienes are naturally produced eicosanoid lipid mediators, which may be responsible for a number of the effects of asthma and allergies. Leukotrienes use both autocrine signalling and paracrine signalling to regulate the body's response. Leukotrienes are produced in the body from arachidonic acid by the enzyme 5-lipoxygenase. Their production by the body is part of a complex response that usually includes the production of histamine. # Types Examples of leukotrienes are LTA4, LTB4, LTC4, LTD4, LTE4, and LTF4. LTC4, LTD4 and LTE4 are often called cysteinyl leukotrienes due to the presence of the amino acid in their structure. Collectively, the cysteinyl leukotrienes make up the slow reacting substance of anaphylaxis (SRS-A). There has also been postulated the existence of LTG4, a metabolite of LTE4 in which the cysteinyl moiety has been oxidized to an alpha-keto-acid (i.e., the cysteine has been replaced by a pyruvate). Very little is known about this putative leukotriene. # History and name The name leukotriene, introduced by Swedish biochemist Bengt Samuelsson in 1979, comes from the words leukocyte and triene (indicating the compound's three conjugated double bonds). What would be later named leukotriene C, "slow reaction smooth muscle-stimulating substance" (SRS) was originally described between 1938 and 1940 by Feldberg and Kellaway.[1][2][3] The researchers isolated SRS from lung tissue after a prolonged period following exposure to snake venom and histamine. Leukotrienes are commercially available to the research community. # Biochemistry ## Synthesis Leukotrienes are synthesized in the cell from arachidonic acid by 5-lipoxygenase. The catalytic mechanism involves the insertion of an oxygen moiety at a specific position in the arachidonic acid backbone. The lipoxygenase pathway is active in leukocytes, including mast cells, eosinophils, neutrophils, monocytes and basophils. When such cells are activated, arachidonic acid is liberated from cell membrane phospholipids by phospholipase A2, and donated by the 5-lipoxygenase activating protein (FLAP) to 5-lipoxygenase, which converts it in two steps to leukotriene A4, an unstable epoxide. In cells equipped with LTA4 hydrolase, such as neutrophils and monocytes, LTA4 is converted to the dihydroxy acid leukotriene LTB4, which is a powerful chemoattractant for neutrophils acting at BLT1 and BLT2 receptors on the plasma membrane of these cells. In cells that express LTC4 synthase, such as mast cells and eosinophils, LTA4 is conjugated with the tripeptide glutathione to form the first of the cysteinyl-leukotrienes, LTC4. Outside the cell, LTC4 can be converted by ubiquitous enzymes to form successively LTD4 and LTE4, which retain biological activity. The cysteinyl-leukotrienes act at their cell-surface receptors CysLT1 and CysLT2 on target cells to contract bronchial and vascular smooth muscle, to increase permeability of small blood vessels, to enhance secretion of mucus in the airway and gut, and to recruit leukocytes to sites of inflammation. Both LTB4 and the cysteinyl-leukotrienes (LTC4, LTD4, LTE4) are partly degraded in local tissues, and ultimately become inactive metabolites in the liver. ## Function Leukotrienes act principally on a subfamily of G protein coupled receptors. They may also act upon peroxisome proliferator-activated receptors. Leukotrienes are involved in asthmatic and allergic reactions and act to sustain inflammatory reactions; several leukotriene receptor antagonists (e.g. montelukast and zafirlukast) are used to treat asthma. Recent research points to a role of 5-lipoxygenase in cardiovascular and neuropsychiatric illnesses.[4] Leukotrienes are very important agents in the inflammatory response. Some such as LTB4 have a chemotactic effect on migrating neutrophils, and as such help to bring the necessary cells to the tissue. Leukotrienes also have a powerful effect in vasoconstriction particularly of venules and of bronchoconstriction, they also increase vascular permeability. # Leukotrienes in asthma Leukotrienes assist in the pathophysiology of asthma, causing or potentiating the following symptoms: - airflow obstruction - increased secretion of mucus - mucosal accumulation - bronchoconstriction - infiltration of inflammatory cells in the airway wall ## Role of cysteinyl leukotrienes Cysteinyl leukotriene receptors CysLT1 and CysLT2 are present on mast cells, eosinophil and endothelial cells. During cysteinyl leukotriene interaction, they can stimulate proinflammatory activities such as endothelial cell adherence and chemokine production by mast cells. As well as mediating inflammation, they induce asthma and other inflammatory disorders, thereby reducing the airflow to the alveoli. In excess, the cysteinyl leukotrienes can induce anaphylactic shock.[5] ## Leukotriene modifiers # Related Chpaters - A chemical synthesis of Leukotriene A methyl ester	https://www.wikidoc.org/index.php/Leukotriene
c31f099ece6fd57197b2010cc2c7961709b9ba4f	wikidoc	Levorphanol	Levorphanol # 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 Levorphanol is an analgesic opioid that is FDA approved for the {{{indicationType}}} of chronic pain, pain (moderate to severe) and premedication for anesthetic procedure - Surgical procedure. Common adverse reactions include cardiovascular: hypotension, dermatologic: pruritus, gastrointestinal: constipation, nausea, vomitingpsychiatric: altered mental status, disturbance in mood. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) - Dosage should be individualized based on degree of pain, clinical setting, physical condition of the patient, and kind and dose of concurrent medication - Pain, chronic: initial, total daily dose 1/15 to 1/12 of total daily dose of oral morphine; wait 72 h between dose adjustments - Pain (Moderate to Severe): up to 1 mg IV injection in divided doses, may repeat in 3 to 6 h as needed; max 4 to 8 mg daily - Pain (Moderate to Severe): 1 to 2 mg IM/SC, may repeat in 6 to 8 h as needed; max 3 to 8 mg IM daily - Pain (Moderate to Severe): 2 mg orally, may repeat in 6 to 8 h as needed; may increase dose up to 3 mg every 6 to 8 h if needed; max 6 to 12 mg daily - Premedication for anesthetic procedure - surgical procedure: 1 to 2 mg IM/SC 60 to 90 min before surgery ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information about Off-Label Guideline-Supported Use of Levorphanol in adult patients. ### Non–Guideline-Supported Use There is limited information about Off-Label Non–Guideline-Supported Use of Levorphanol in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) - Safety and effectiveness in pediatric patients have not been established ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information about Off-Label Guideline-Supported Use of Levorphanol in pediatric patients. ### Non–Guideline-Supported Use There is limited information about Off-Label Non–Guideline-Supported Use of Levorphanol in pediatric patients. # Contraindications - Levorphanol is contraindicated in patients hypersensitive to levorphanol tartrate. # Warnings - Levorphanol, like morphine, may be expected to produce serious or potentially fatal respiratory depression if given in an excessive dose, too frequently, or if given in full dosage to compromised or vulnerable patients. This is because the doses required to produce analgesia in the general clinical population may cause serious respiratory depression in vulnerable patients. Safe usage of this potent opioid requires that the dose and dosage interval be individualized to each patient based on the severity of the pain, weight, age, diagnosis and physical status of the patient, and the kind and dose of concurrently administered medication. - The initial dose of Levorphanol should be reduced by 50% or more when the drug is given to patients with any condition affecting respiratory reserve or in conjunction with other drugs affecting the respiratory center. Subsequent doses should then be individually titrated according to the patient’s response. Respiratory depression produced by levorphanol tartrate can be reversed by naloxone, a specific antagonist (see Overdosage). - Because Levorphanol causes respiratory depression, it should be administered with caution to patients with impaired respiratory reserve or respiratory depression from some other cause (eg, from other medication, uremia, severe infection, obstructive respiratory conditions, restrictive respiratory diseases, intrapulmonary shunting or chronic bronchial asthma). As with other strong opioids, use of Levorphanol in acute or severe bronchial asthma is not recommended (see Respiratory Depression). - The respiratory depressant effects of Levorphanol with carbon dioxide retention and secondary elevation of cerebral spinal fluid pressure may be markedly exaggerated in the presence of head injury, other intracranial lesions or pre-existing increase in intracranial pressure. Opioids, including Levorphanol, produce effects that may obscure neurological signs of further increase in pressure in patients with head injuries. In addition, Levorphanol may affect level of consciousness that may complicate neurological evaluation. - The use of Levorphanol in acute myocardial infarction or in cardiac patients with myocardial dysfunction or coronary insufficiency should be limited because the effects of levorphanol on the work of the heart are unknown. - The administration of Levorphanol may result in severe hypotension in the postoperative patient or in any individual whose ability to maintain blood pressure has been compromised by a depleted blood volume or by administration of drugs, such as phenothiazines or general anesthetics. Opioids may produce orthostatic hypotension in ambulatory patients. - Levorphanol should be administered with caution to patients with extensive liver disease who may be vulnerable to excessive sedation due to increased pharmacodynamic sensitivity or impaired metabolism of the drug. - Levorphanol has been shown to cause moderate to marked rises in pressure in the common bile duct when given in analgesic doses. It is not recommended for use in biliary surgery. - Levorphanol has an abuse potential as great as morphine, and the prescription of this drug must always balance the prospective benefits against the risk of abuse and dependence. The use of levorphanol in patients with a history of alcohol or other drug dependence, either active or in remission, has not been specifically studied (see drug abuse and dependence). # Adverse Reactions ## Clinical Trials Experience - In approximately 1400 patients treated with Levorphanol in controlled clinical trials, the type and incidence of side effects were those expected of an opioid analgesic, and no unforeseen or unusual toxicity was reported. - Drugs of this type are expected to produce a cluster of typical opioid effects in addition to analgesia, consisting of nausea, vomiting, altered mood and mentation, pruritus, flushing, difficulties in urination, constipation and biliary spasm. The frequency and intensity of these effects appears to be dose related. Although listed as adverse events these are expected pharmacologic actions of these drugs and should be interpreted as such by the clinician. - The following adverse events have been reported with the use of Levorphanol: - Body as a Whole: abdominal pain, dry mouth, sweating - Cardiovascular System: cardiac arrest, shock, hypotension, arrhythmias including bradycardia and tachycardia, palpitations, extra-systoles - Digestive System: nausea, vomiting, dyspepsia, biliary tract spasm - Nervous System: coma, suicide attempt, convulsions, depression, dizziness, confusion, lethargy, abnormal dreams, abnormal thinking, nervousness, drug withdrawal, hypokinesia, dyskinesia, hyperkinesia, CNS stimulation, personality disorder, amnesia, insomnia - Respiratory System: apnea, cyanosis, hypoventilation - Skin & Appendages: pruritus, urticaria, rash, injection site reaction - Special Senses: abnormal vision, pupillary disorder, diplopia - Urogenital System: kidney failure, urinary retention, difficulty urinating ## Postmarketing Experience There is limited information regarding Levorphanol Postmarketing Experience in the drug label. # Drug Interactions - Interactions with Other CNS Agents: Concurrent use of Levorphanol with all central nervous system depressants (eg, alcohol, sedatives, hypnotics, other opioids, general anesthetics, barbitu-rates, tricyclic antidepressants, phenothiazines, tranquilizers, skeletal muscle relaxants and antihistamines) may result in additive central nervous system depressant effects. Respiratory depression, hypotension, and profound sedation or coma may occur. When such combined therapy is contemplated, the dose of one or both agents should be reduced. Although no interaction between MAO inhibitors and Levorphanol has been observed, it is not recommended for use with MAO inhibitors. - Most cases of serious or fatal adverse events involving Levorphanol reported to the manufacturer or the FDA have involved either the administration of large initial doses or too frequent doses of the drug to nonopioid tolerant patients, or the simultaneous administration of levorphanol with other drugs affecting respiration (see INDIVIDUALIZATION OF DOSAGE and WARNINGS). The initial dose of levorphanol should be reduced by approximately 50% or more when it is given to patients along with another drug affecting respiration. - Interactions with Mixed Agonist/Antagonist Opioid Analgesics: Agonist/antagonist analgesics (eg, pentazocine, nalbuphine, butorphanol, dezocine and buprenorphine) should NOT be administered to a patient who has received or is receiving a course of therapy with a pure agonist opioid analgesic such as Levorphanol. In opioid-dependent patients, mixed agonist/antagonist analgesics may precipitate withdrawal symptoms. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): C - Pregnancy Category C. Levorphanol has been shown to be teratogenic in mice when given at a single oral dose of 25 mg/kg. The tested dose caused a near 50% mortality of the mouse embryos. There are no adequate and well-controlled studies in pregnant women. Levorphanol should be used in pregnancy only if the potential benefit justifies the potential risk to the fetus. - Babies born to mothers who have been taking opioids regularly prior to delivery may be physically dependent. - A study in rabbits has demonstrated that at doses of 1.5 to 20 mg/kg, Levorphanol administered intravenously crosses the placental barrier and depresses fetal respiration. Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Levorphanol in women who are pregnant. ### Labor and Delivery - The use of Levorphanol in labor and delivery in humans has not been studied. However, as with other opioids, administration of Levorphanol to the mother during labor and delivery may result in respiratory depression in the newborn. Therefore, its use during labor and delivery is not recommended. ### Nursing Mothers - Studies of levorphanol concentrations in breast milk have not been performed. However, morphine, which is structurally similar to levorphanol, is excreted in human milk. Because of the potential for serious adverse reactions from Levorphanol in nursing infants, 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 - Levorphanol is not recommended in children under the age of 18 years as the safety and efficacy of the drug in this population has not been established. ### Geriatic Use - The initial dose of Levorphanol should be reduced by 50% or more in the infirm elderly patient, even though there have been no reports of unexpected adverse events in older populations. All drugs of this class may be associated with a profound or prolonged effect in elderly patients for both pharmacokinetic and pharmacodynamic reasons and caution is indicated. ### Gender There is no FDA guidance on the use of Levorphanol with respect to specific gender populations. ### Race There is no FDA guidance on the use of Levorphanol with respect to specific racial populations. ### Renal Impairment There is no FDA guidance on the use of Levorphanol in patients with renal impairment. ### Hepatic Impairment There is no FDA guidance on the use of Levorphanol in patients with hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Levorphanol in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Levorphanol in patients who are immunocompromised. # Administration and Monitoring ### Administration There is limited information regarding Levorphanol Administration in the drug label. ### Monitoring There is limited information regarding Levorphanol Monitoring in the drug label. # IV Compatibility There is limited information regarding the compatibility of Levorphanol and IV administrations. # Overdosage - Most reports of overdosage known to the manufacturer and to the FDA involve three clinical situations. These are: 1. the use of larger than recommended doses or too frequent doses, 2. administration of the drug to children or small adults without any reduction in dosage, and 3. the use of the drug in ordinary dosage in patients compromised by concurrent illness. - As with all opioids, overdose can occur due to accidental or intentional misuse of this product, especially in infants and children who may gain access to the drug in the home. Based on its pharmacology, levorphanol overdosage would be expected to produce signs of respiratory depression, cardiovascular failure (especially in predisposed patients) and/or central nervous system depression. Serious overdosage with Levorphanol is characterized by respiratory depression (a decrease in respiratory rate and/or tidal volume, periodic breathing, cyanosis), extreme somnolence progressing to stupor or coma, skeletal muscle flaccidity, cold and clammy skin, constricted pupils, and sometimes bradycardia and hypotension. In severe overdosage, apnea, circulatory collapse, cardiac arrest and death may occur. - Treatment: The specific treatment of suspected levorphanol tartrate overdosage is immediate establishment of an adequate airway and ventilation, followed (if necessary) by intravenous naloxone. The respiratory and cardiac status of the patient should be continuously monitored and appropriate supportive measures instituted, such as oxygen, intravenous fluids and/or vasopressors, if required. Physicians are reminded that the duration of levorphanol action far exceeds the duration of action of naloxone, and repeated dosing with naloxone may be required. Naloxone should be administered cautiously to persons known or suspected to be physically dependent on Levorphanol. In such cases an abrupt and complete reversal of opioid effects may precipitate an acute abstinence syndrome. If necessary to administer naloxone to the physically dependent patient, the antagonist should be administered with extreme care and by titration with smaller than usual doses of the antagonist. # Pharmacology ## Mechanism of Action - There is limited information about the mechanism of action of Levorphanol. ## Structure - Levorphanol (levorphanol tartrate) is a potent opioid analgesic with empirical formula C17H23NOC4H6O62H2O and molecular weight 443.5. Each mg of levorphanol tartrate is equivalent to 0.58 mg levorphanol base. Chemically levorphanol is levo-3-hydroxy-N-methylmorphinan. The USP nomenclature is 17-methylmorphinan 3-ol tartrate (1:1)(Salt) dihydrate. The material has 3 asymmetric carbon atoms. The chemical structure is: - Levorphanol tartrate is a white crystalline powder, soluble in water and ether but insoluble in chloroform. - Each 1-mL ampul contains 2 mg levorphanol tartrate, 1.8 mg methyl paraben preservative, 0.2 mg propyl paraben preservative, sodium hydroxide to adjust pH to approximately 4.3 and Water for Injection. - Each milliliter in the 10 mL vials contains 2 mg levorphanol tartrate, 4.5 mg phenol preservative, sodium hydroxide to adjust pH to approximately 4.3 and Water for Injection. - Each tablet contains 2 mg levorphanol tartrate, lactose, corn starch, stearic acid and talc. ## Pharmacodynamics - Levorphanol is a potent synthetic opioid similar to morphine in its actions. Like other mu-agonist opioids it is believed to act at receptors in the periventricular and periaqueductal gray matter in both the brain and spinal cord to alter the transmission and perception of pain. Onset of analgesia and peak analgesic effect following administration of levorphanol are similar to morphine when administered at equianalgesic doses. - Levorphanol produces a degree of respiratory depression similar to that produced by morphine at equianalgesic doses, and like many mu-opioid drugs, levorphanol produces euphoria or has a positive effect on mood in many individuals. Two mg of intramuscular levorphanol tartrate depresses respiration to a degree approximately equivalent to that produced by 10 to 15 mg of intramuscular morphine in man. The hemodynamic changes after intravenous administration of levorphanol have not been studied in man but are expected to clinically resemble those seen after morphine. - As with other opioids, the blood levels required for analgesia are determined by the opioid tolerance of the patient and are likely to rise with chronic use. The rate of development of tolerance is highly variable and is determined by the dose, dosing interval, age, use of concomitant drugs and physical status of the patient. While blood levels of opioid drugs may be helpful in assessing individual cases, dosage is usually adjusted by careful clinical observation of the patient. ## Pharmacokinetics - The pharmacokinetics of levorphanol have been studied in a limited number of cancer patients following intravenous (IV), intramuscular (IM) and oral (PO) administration. Following IV administration, plasma concentrations of levorphanol decline in a triexponential manner with a terminal half-life of approximately 11 to 16 hours and a clearance of 0.78 to 1.1 L/kg/hr. Based on terminal half-life, steady-state plasma concentrations should be achieved by the third day of dosing. Levorphanol is rapidly distributed (<1 hr) and redistributed (1 to 2 hours) following IV administration and has a steady-state volume of distribution of 10 to 13 L/kg. In vitro studies of protein binding indicate that levorphanol is only 40% bound to plasma proteins. - No pharmacokinetic studies of the absorption of IM levorphanol are available, but clinical data suggests that absorption is rapid with onset of effects within 15 to 30 minutes of administration. - Levorphanol is well absorbed after PO administration with peak plasma concentrations occurring approximately 1 hour after dosing. The bioavailability of levorphanol tablets compared to IM or IV administration is not known. - Plasma concentrations of levorphanol following chronic administration in patients with cancer increased with the dose, but the analgesic effect was dependent on the degree of opioid tolerance of the patient. Expected steady-state plasma concentrations for a 6-hour dosing interval can reach 2 to 5 times those following a single dose, depending on the patient’s individual clearance of the drug. Very high plasma concentrations of levorphanol can be reached in patients on chronic therapy due to the long half-life of the drug. One study in 11 patients using the drug for control of cancer pain reported plasma concentrations from 5 to 10 ng/mL after a single 2-mg dose up to 50 to 100 ng/mL after repeated oral doses of 20 to 50 mg/day. - Animal studies suggest that levorphanol is extensively metabolized in the liver and is eliminated as the glucuronide metabolite. This renally excreted inactive glucuronide metabolite accumulates with chronic dosing in plasma at concentrations that reach fivefold that of the parent compound. - The effects of age, gender, hepatic and renal disease on the pharmacokinetics of levorphanol are not known. As with all drugs of this class, patients at the extremes of age are expected to be more susceptible to adverse effects because of a greater pharmacodynamic sensitivity and probable increased variability in pharmacokinetics due to age or disease. ## Nonclinical Toxicology There is limited information regarding Levorphanol Nonclinical Toxicology in the drug label. # Clinical Studies There is limited information regarding Levorphanol Clinical Studies in the drug label. # How Supplied - Ampuls: 1 mL, 2 mg/mL levorphanol tartrate – boxes of 10 (NDC 0187-3072-10). - Multiple-Dose Vials: 10 mL, 2 mg/mL levorphanol tartrate – boxes of 1 (NDC 0187-3074-20). - Scored Oral Tablets: 2 mg round, white, flat beveled edge tablets in bottles of 100 (NDC 0187-3251-10); with LEVO engraved on one side and 3251 and full bisect scored on the other side. ## Storage - Storage: Tablets should be stored at 25°C (77°F); excursions permitted to 15°C- 30°C (59°F - 86°F). - Dispense in tight containers as defined in USP/NF. - Parenteral dosage forms should be stored at 25°C (77°F); excursions permitted to 15°C - 30°C (59°F - 86°F). - DEA Order Form Required. - Manufactured for: # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information There is limited information regarding Levorphanol Patient Counseling Information in the drug label. # Precautions with Alcohol Alcohol-Levorphanol 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 Levorphanol Brand Names in the drug label. # Look-Alike Drug Names There is limited information regarding Levorphanol Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	Levorphanol 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 Levorphanol is an analgesic opioid that is FDA approved for the {{{indicationType}}} of chronic pain, pain (moderate to severe) and premedication for anesthetic procedure - Surgical procedure. Common adverse reactions include cardiovascular: hypotension, dermatologic: pruritus, gastrointestinal: constipation, nausea, vomitingpsychiatric: altered mental status, disturbance in mood. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) - Dosage should be individualized based on degree of pain, clinical setting, physical condition of the patient, and kind and dose of concurrent medication - Pain, chronic: initial, total daily dose 1/15 to 1/12 of total daily dose of oral morphine; wait 72 h between dose adjustments - Pain (Moderate to Severe): up to 1 mg IV injection in divided doses, may repeat in 3 to 6 h as needed; max 4 to 8 mg daily - Pain (Moderate to Severe): 1 to 2 mg IM/SC, may repeat in 6 to 8 h as needed; max 3 to 8 mg IM daily - Pain (Moderate to Severe): 2 mg orally, may repeat in 6 to 8 h as needed; may increase dose up to 3 mg every 6 to 8 h if needed; max 6 to 12 mg daily - Premedication for anesthetic procedure - surgical procedure: 1 to 2 mg IM/SC 60 to 90 min before surgery ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information about Off-Label Guideline-Supported Use of Levorphanol in adult patients. ### Non–Guideline-Supported Use There is limited information about Off-Label Non–Guideline-Supported Use of Levorphanol in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) - Safety and effectiveness in pediatric patients have not been established ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information about Off-Label Guideline-Supported Use of Levorphanol in pediatric patients. ### Non–Guideline-Supported Use There is limited information about Off-Label Non–Guideline-Supported Use of Levorphanol in pediatric patients. # Contraindications - Levorphanol is contraindicated in patients hypersensitive to levorphanol tartrate. # Warnings - Levorphanol, like morphine, may be expected to produce serious or potentially fatal respiratory depression if given in an excessive dose, too frequently, or if given in full dosage to compromised or vulnerable patients. This is because the doses required to produce analgesia in the general clinical population may cause serious respiratory depression in vulnerable patients. Safe usage of this potent opioid requires that the dose and dosage interval be individualized to each patient based on the severity of the pain, weight, age, diagnosis and physical status of the patient, and the kind and dose of concurrently administered medication. - The initial dose of Levorphanol should be reduced by 50% or more when the drug is given to patients with any condition affecting respiratory reserve or in conjunction with other drugs affecting the respiratory center. Subsequent doses should then be individually titrated according to the patient’s response. Respiratory depression produced by levorphanol tartrate can be reversed by naloxone, a specific antagonist (see Overdosage). - Because Levorphanol causes respiratory depression, it should be administered with caution to patients with impaired respiratory reserve or respiratory depression from some other cause (eg, from other medication, uremia, severe infection, obstructive respiratory conditions, restrictive respiratory diseases, intrapulmonary shunting or chronic bronchial asthma). As with other strong opioids, use of Levorphanol in acute or severe bronchial asthma is not recommended (see Respiratory Depression). - The respiratory depressant effects of Levorphanol with carbon dioxide retention and secondary elevation of cerebral spinal fluid pressure may be markedly exaggerated in the presence of head injury, other intracranial lesions or pre-existing increase in intracranial pressure. Opioids, including Levorphanol, produce effects that may obscure neurological signs of further increase in pressure in patients with head injuries. In addition, Levorphanol may affect level of consciousness that may complicate neurological evaluation. - The use of Levorphanol in acute myocardial infarction or in cardiac patients with myocardial dysfunction or coronary insufficiency should be limited because the effects of levorphanol on the work of the heart are unknown. - The administration of Levorphanol may result in severe hypotension in the postoperative patient or in any individual whose ability to maintain blood pressure has been compromised by a depleted blood volume or by administration of drugs, such as phenothiazines or general anesthetics. Opioids may produce orthostatic hypotension in ambulatory patients. - Levorphanol should be administered with caution to patients with extensive liver disease who may be vulnerable to excessive sedation due to increased pharmacodynamic sensitivity or impaired metabolism of the drug. - Levorphanol has been shown to cause moderate to marked rises in pressure in the common bile duct when given in analgesic doses. It is not recommended for use in biliary surgery. - Levorphanol has an abuse potential as great as morphine, and the prescription of this drug must always balance the prospective benefits against the risk of abuse and dependence. The use of levorphanol in patients with a history of alcohol or other drug dependence, either active or in remission, has not been specifically studied (see drug abuse and dependence). # Adverse Reactions ## Clinical Trials Experience - In approximately 1400 patients treated with Levorphanol in controlled clinical trials, the type and incidence of side effects were those expected of an opioid analgesic, and no unforeseen or unusual toxicity was reported. - Drugs of this type are expected to produce a cluster of typical opioid effects in addition to analgesia, consisting of nausea, vomiting, altered mood and mentation, pruritus, flushing, difficulties in urination, constipation and biliary spasm. The frequency and intensity of these effects appears to be dose related. Although listed as adverse events these are expected pharmacologic actions of these drugs and should be interpreted as such by the clinician. - The following adverse events have been reported with the use of Levorphanol: - Body as a Whole: abdominal pain, dry mouth, sweating - Cardiovascular System: cardiac arrest, shock, hypotension, arrhythmias including bradycardia and tachycardia, palpitations, extra-systoles - Digestive System: nausea, vomiting, dyspepsia, biliary tract spasm - Nervous System: coma, suicide attempt, convulsions, depression, dizziness, confusion, lethargy, abnormal dreams, abnormal thinking, nervousness, drug withdrawal, hypokinesia, dyskinesia, hyperkinesia, CNS stimulation, personality disorder, amnesia, insomnia - Respiratory System: apnea, cyanosis, hypoventilation - Skin & Appendages: pruritus, urticaria, rash, injection site reaction - Special Senses: abnormal vision, pupillary disorder, diplopia - Urogenital System: kidney failure, urinary retention, difficulty urinating ## Postmarketing Experience There is limited information regarding Levorphanol Postmarketing Experience in the drug label. # Drug Interactions - Interactions with Other CNS Agents: Concurrent use of Levorphanol with all central nervous system depressants (eg, alcohol, sedatives, hypnotics, other opioids, general anesthetics, barbitu-rates, tricyclic antidepressants, phenothiazines, tranquilizers, skeletal muscle relaxants and antihistamines) may result in additive central nervous system depressant effects. Respiratory depression, hypotension, and profound sedation or coma may occur. When such combined therapy is contemplated, the dose of one or both agents should be reduced. Although no interaction between MAO inhibitors and Levorphanol has been observed, it is not recommended for use with MAO inhibitors. - Most cases of serious or fatal adverse events involving Levorphanol reported to the manufacturer or the FDA have involved either the administration of large initial doses or too frequent doses of the drug to nonopioid tolerant patients, or the simultaneous administration of levorphanol with other drugs affecting respiration (see INDIVIDUALIZATION OF DOSAGE and WARNINGS). The initial dose of levorphanol should be reduced by approximately 50% or more when it is given to patients along with another drug affecting respiration. - Interactions with Mixed Agonist/Antagonist Opioid Analgesics: Agonist/antagonist analgesics (eg, pentazocine, nalbuphine, butorphanol, dezocine and buprenorphine) should NOT be administered to a patient who has received or is receiving a course of therapy with a pure agonist opioid analgesic such as Levorphanol. In opioid-dependent patients, mixed agonist/antagonist analgesics may precipitate withdrawal symptoms. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): C - Pregnancy Category C. Levorphanol has been shown to be teratogenic in mice when given at a single oral dose of 25 mg/kg. The tested dose caused a near 50% mortality of the mouse embryos. There are no adequate and well-controlled studies in pregnant women. Levorphanol should be used in pregnancy only if the potential benefit justifies the potential risk to the fetus. - Babies born to mothers who have been taking opioids regularly prior to delivery may be physically dependent. - A study in rabbits has demonstrated that at doses of 1.5 to 20 mg/kg, Levorphanol administered intravenously crosses the placental barrier and depresses fetal respiration. Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Levorphanol in women who are pregnant. ### Labor and Delivery - The use of Levorphanol in labor and delivery in humans has not been studied. However, as with other opioids, administration of Levorphanol to the mother during labor and delivery may result in respiratory depression in the newborn. Therefore, its use during labor and delivery is not recommended. ### Nursing Mothers - Studies of levorphanol concentrations in breast milk have not been performed. However, morphine, which is structurally similar to levorphanol, is excreted in human milk. Because of the potential for serious adverse reactions from Levorphanol in nursing infants, 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 - Levorphanol is not recommended in children under the age of 18 years as the safety and efficacy of the drug in this population has not been established. ### Geriatic Use - The initial dose of Levorphanol should be reduced by 50% or more in the infirm elderly patient, even though there have been no reports of unexpected adverse events in older populations. All drugs of this class may be associated with a profound or prolonged effect in elderly patients for both pharmacokinetic and pharmacodynamic reasons and caution is indicated. ### Gender There is no FDA guidance on the use of Levorphanol with respect to specific gender populations. ### Race There is no FDA guidance on the use of Levorphanol with respect to specific racial populations. ### Renal Impairment There is no FDA guidance on the use of Levorphanol in patients with renal impairment. ### Hepatic Impairment There is no FDA guidance on the use of Levorphanol in patients with hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Levorphanol in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Levorphanol in patients who are immunocompromised. # Administration and Monitoring ### Administration There is limited information regarding Levorphanol Administration in the drug label. ### Monitoring There is limited information regarding Levorphanol Monitoring in the drug label. # IV Compatibility There is limited information regarding the compatibility of Levorphanol and IV administrations. # Overdosage - Most reports of overdosage known to the manufacturer and to the FDA involve three clinical situations. These are: 1. the use of larger than recommended doses or too frequent doses, 2. administration of the drug to children or small adults without any reduction in dosage, and 3. the use of the drug in ordinary dosage in patients compromised by concurrent illness. - As with all opioids, overdose can occur due to accidental or intentional misuse of this product, especially in infants and children who may gain access to the drug in the home. Based on its pharmacology, levorphanol overdosage would be expected to produce signs of respiratory depression, cardiovascular failure (especially in predisposed patients) and/or central nervous system depression. Serious overdosage with Levorphanol is characterized by respiratory depression (a decrease in respiratory rate and/or tidal volume, periodic breathing, cyanosis), extreme somnolence progressing to stupor or coma, skeletal muscle flaccidity, cold and clammy skin, constricted pupils, and sometimes bradycardia and hypotension. In severe overdosage, apnea, circulatory collapse, cardiac arrest and death may occur. - Treatment: The specific treatment of suspected levorphanol tartrate overdosage is immediate establishment of an adequate airway and ventilation, followed (if necessary) by intravenous naloxone. The respiratory and cardiac status of the patient should be continuously monitored and appropriate supportive measures instituted, such as oxygen, intravenous fluids and/or vasopressors, if required. Physicians are reminded that the duration of levorphanol action far exceeds the duration of action of naloxone, and repeated dosing with naloxone may be required. Naloxone should be administered cautiously to persons known or suspected to be physically dependent on Levorphanol. In such cases an abrupt and complete reversal of opioid effects may precipitate an acute abstinence syndrome. If necessary to administer naloxone to the physically dependent patient, the antagonist should be administered with extreme care and by titration with smaller than usual doses of the antagonist. # Pharmacology ## Mechanism of Action - There is limited information about the mechanism of action of Levorphanol. ## Structure - Levorphanol (levorphanol tartrate) is a potent opioid analgesic with empirical formula C17H23NO•C4H6O6•2H2O and molecular weight 443.5. Each mg of levorphanol tartrate is equivalent to 0.58 mg levorphanol base. Chemically levorphanol is levo-3-hydroxy-N-methylmorphinan. The USP nomenclature is 17-methylmorphinan 3-ol tartrate (1:1)(Salt) dihydrate. The material has 3 asymmetric carbon atoms. The chemical structure is: - Levorphanol tartrate is a white crystalline powder, soluble in water and ether but insoluble in chloroform. - Each 1-mL ampul contains 2 mg levorphanol tartrate, 1.8 mg methyl paraben preservative, 0.2 mg propyl paraben preservative, sodium hydroxide to adjust pH to approximately 4.3 and Water for Injection. - Each milliliter in the 10 mL vials contains 2 mg levorphanol tartrate, 4.5 mg phenol preservative, sodium hydroxide to adjust pH to approximately 4.3 and Water for Injection. - Each tablet contains 2 mg levorphanol tartrate, lactose, corn starch, stearic acid and talc. ## Pharmacodynamics - Levorphanol is a potent synthetic opioid similar to morphine in its actions. Like other mu-agonist opioids it is believed to act at receptors in the periventricular and periaqueductal gray matter in both the brain and spinal cord to alter the transmission and perception of pain. Onset of analgesia and peak analgesic effect following administration of levorphanol are similar to morphine when administered at equianalgesic doses. - Levorphanol produces a degree of respiratory depression similar to that produced by morphine at equianalgesic doses, and like many mu-opioid drugs, levorphanol produces euphoria or has a positive effect on mood in many individuals. Two mg of intramuscular levorphanol tartrate depresses respiration to a degree approximately equivalent to that produced by 10 to 15 mg of intramuscular morphine in man. The hemodynamic changes after intravenous administration of levorphanol have not been studied in man but are expected to clinically resemble those seen after morphine. - As with other opioids, the blood levels required for analgesia are determined by the opioid tolerance of the patient and are likely to rise with chronic use. The rate of development of tolerance is highly variable and is determined by the dose, dosing interval, age, use of concomitant drugs and physical status of the patient. While blood levels of opioid drugs may be helpful in assessing individual cases, dosage is usually adjusted by careful clinical observation of the patient. ## Pharmacokinetics - The pharmacokinetics of levorphanol have been studied in a limited number of cancer patients following intravenous (IV), intramuscular (IM) and oral (PO) administration. Following IV administration, plasma concentrations of levorphanol decline in a triexponential manner with a terminal half-life of approximately 11 to 16 hours and a clearance of 0.78 to 1.1 L/kg/hr. Based on terminal half-life, steady-state plasma concentrations should be achieved by the third day of dosing. Levorphanol is rapidly distributed (<1 hr) and redistributed (1 to 2 hours) following IV administration and has a steady-state volume of distribution of 10 to 13 L/kg. In vitro studies of protein binding indicate that levorphanol is only 40% bound to plasma proteins. - No pharmacokinetic studies of the absorption of IM levorphanol are available, but clinical data suggests that absorption is rapid with onset of effects within 15 to 30 minutes of administration. - Levorphanol is well absorbed after PO administration with peak plasma concentrations occurring approximately 1 hour after dosing. The bioavailability of levorphanol tablets compared to IM or IV administration is not known. - Plasma concentrations of levorphanol following chronic administration in patients with cancer increased with the dose, but the analgesic effect was dependent on the degree of opioid tolerance of the patient. Expected steady-state plasma concentrations for a 6-hour dosing interval can reach 2 to 5 times those following a single dose, depending on the patient’s individual clearance of the drug. Very high plasma concentrations of levorphanol can be reached in patients on chronic therapy due to the long half-life of the drug. One study in 11 patients using the drug for control of cancer pain reported plasma concentrations from 5 to 10 ng/mL after a single 2-mg dose up to 50 to 100 ng/mL after repeated oral doses of 20 to 50 mg/day. - Animal studies suggest that levorphanol is extensively metabolized in the liver and is eliminated as the glucuronide metabolite. This renally excreted inactive glucuronide metabolite accumulates with chronic dosing in plasma at concentrations that reach fivefold that of the parent compound. - The effects of age, gender, hepatic and renal disease on the pharmacokinetics of levorphanol are not known. As with all drugs of this class, patients at the extremes of age are expected to be more susceptible to adverse effects because of a greater pharmacodynamic sensitivity and probable increased variability in pharmacokinetics due to age or disease. ## Nonclinical Toxicology There is limited information regarding Levorphanol Nonclinical Toxicology in the drug label. # Clinical Studies There is limited information regarding Levorphanol Clinical Studies in the drug label. # How Supplied - Ampuls: 1 mL, 2 mg/mL levorphanol tartrate – boxes of 10 (NDC 0187-3072-10). - Multiple-Dose Vials: 10 mL, 2 mg/mL levorphanol tartrate – boxes of 1 (NDC 0187-3074-20). - Scored Oral Tablets: 2 mg round, white, flat beveled edge tablets in bottles of 100 (NDC 0187-3251-10); with LEVO engraved on one side and 3251 and full bisect scored on the other side. ## Storage - Storage: Tablets should be stored at 25°C (77°F); excursions permitted to 15°C- 30°C (59°F - 86°F). - Dispense in tight containers as defined in USP/NF. - Parenteral dosage forms should be stored at 25°C (77°F); excursions permitted to 15°C - 30°C (59°F - 86°F). - DEA Order Form Required. - Manufactured for: # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information There is limited information regarding Levorphanol Patient Counseling Information in the drug label. # Precautions with Alcohol Alcohol-Levorphanol 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 Levorphanol Brand Names in the drug label. # Look-Alike Drug Names There is limited information regarding Levorphanol Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	https://www.wikidoc.org/index.php/Levo-Dromoran
6cb52870a8ff26f19e092338b38e6aefd06ca4e8	wikidoc	Leydig cell	Leydig cell Leydig cells, also known as interstitial cells of Leydig, are found adjacent to the seminiferous tubules in the testicle. They can secrete testosterone and are often closely related to nerves. Leydig cells have round vesicular nuclei and a granular eosinophilic cytoplasm. # Nomenclature Leydig cells are named after the German anatomist Franz Leydig, who discovered them in 1850. # Functions Leydig cells release a class of hormones called androgens (19-carbon steroids). They secrete testosterone, androstenedione and dehydroepiandrosterone (DHEA), when stimulated by the pituitary hormone luteinizing hormone (LH). LH increases cholesterol desmolase activity (an enzyme associated with the conversion of cholesterol to pregnenolone), leading to testosterone synthesis secretion by Leydig cells. Follicle-stimulating hormone (FSH) increases the response of Leydig cells to LH by increasing the number of LH receptors expressed on Leydig cells. # Ultrastructure Leydig cells are polygonal, eosinophilic cells with a round vesicular nucleus and contain lipid droplets. They contain abundant smooth endoplasmic reticulum, which accounts for their eosinophilia. Frequently, lipofuscin pigment and rod-shaped crystal-like structures (Reinke's crystals) are found. # Development Leydig cells form during the 16th and 20th week of gestation and are quiescent until puberty. # Additional images - Section of a genital cord of the testis of a human embryo 3.5 cm. long.	Leydig cell Template:Infobox Anatomy Leydig cells, also known as interstitial cells of Leydig, are found adjacent to the seminiferous tubules in the testicle. They can secrete testosterone and are often closely related to nerves. Leydig cells have round vesicular nuclei and a granular eosinophilic cytoplasm. # Nomenclature Leydig cells are named after the German anatomist Franz Leydig, who discovered them in 1850.[1] # Functions Leydig cells release a class of hormones called androgens (19-carbon steroids). They secrete testosterone, androstenedione and dehydroepiandrosterone (DHEA), when stimulated by the pituitary hormone luteinizing hormone (LH). LH increases cholesterol desmolase activity (an enzyme associated with the conversion of cholesterol to pregnenolone), leading to testosterone synthesis secretion by Leydig cells. Follicle-stimulating hormone (FSH) increases the response of Leydig cells to LH by increasing the number of LH receptors expressed on Leydig cells. # Ultrastructure Leydig cells are polygonal, eosinophilic cells with a round vesicular nucleus and contain lipid droplets. They contain abundant smooth endoplasmic reticulum, which accounts for their eosinophilia. Frequently, lipofuscin pigment and rod-shaped crystal-like structures (Reinke's crystals) are found.[2][3] # Development Leydig cells form during the 16th and 20th week of gestation and are quiescent until puberty. # Additional images - Section of a genital cord of the testis of a human embryo 3.5 cm. long.	https://www.wikidoc.org/index.php/Leydig
456d5347d07b8da6d90fd5bbc708a71c822df6bc	wikidoc	Linaclotide	Linaclotide # 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 Linaclotide is a guanylate cyclase-C agonist that is FDA approved for the {{{indicationType}}} of irritable bowel syndrome with constipation (IBS-C), chronic idiopathic constipation (CIC). There is a Black Box Warning for this drug as shown here. Common adverse reactions include diarrhea, abdominal pain, flatulence and abdominal distension. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) - The recommended dose of LINZESS is 290 mcg taken orally once daily on an empty stomach, at least 30 minutes prior to the first meal of the day. - The recommended dose of LINZESS is 145 mcg taken orally once daily on an empty stomach, at least 30 minutes prior to the first meal of the day. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Linaclotide in adult patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Linaclotide in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) There is limited information regarding FDA-Labeled Use of Linaclotide in pediatric patients. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Linaclotide in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Linaclotide in pediatric patients. # Contraindications - Pediatric patients under 6 years of age. - Patients with known or suspected mechanical gastrointestinal obstruction. # Warnings ### Precautions - Pediatric Risk - LINZESS is contraindicated in children under 6 years of age. The safety and effectiveness of LINZESS in pediatric patients under 18 years of age have not been established. In neonatal mice, increased fluid secretion as a consequence of GC-C agonism resulted in mortality within the first 24 hours due to dehydration. Due to increased intestinal expression of GC-C, children under 6 years of age may be more likely than older children and adults to develop significant diarrhea and its potentially serious consequences. - Avoid use of LINZESS in pediatric patients 6 through 17 years of age. Although there were no deaths in older juvenile mice, given the deaths in young juvenile mice and the lack of clinical safety and efficacy data in pediatric patients, avoid the use of LINZESS in pediatric patients 6 through 17 years of age. - Diarrhea - Diarrhea was the most common adverse reaction of LINZESS-treated patients in the pooled IBS-C and CIC double-blind placebo-controlled trials. Severe diarrhea was reported in 2% of the LINZESS-treated patients. The incidence of diarrhea was similar between the IBS-C and CIC populations. - Instruct patients to stop LINZESS if severe diarrhea occurs and to contact their healthcare provider. The healthcare provider should consider dose suspension and rehydration. # 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 with rates in the clinical trials of another drug and may not reflect the rates observed in practice. - During clinical development, approximately 2570, 2040, and 1220 patients with either IBS-C or CIC were treated with LINZESS for 6 months or longer, 1 year or longer, and 18 months or longer, respectively (not mutually exclusive). - Most Common Adverse Reactions - The data described below reflect exposure to LINZESS in the two placebo-controlled clinical trials involving 1605 adult patients with IBS-C (Trials 1 and 2). Patients were randomized to receive placebo or 290 mcg LINZESS once daily on an empty stomach for up to 26 weeks. Demographic characteristics were comparable between treatment groups. Table 1 provides the incidence of adverse reactions reported in at least 2% of IBS-C patients in the LINZESS treatment group and at an incidence that was greater than in the placebo group. - Diarrhea - Diarrhea was the most commonly reported adverse reaction of the LINZESS-treated patients in the pooled IBS-C pivotal placebo-controlled trials. In these trials, 20% of LINZESS-treated patients reported diarrhea compared to 3% of placebo-treated patients. Severe diarrhea was reported in 2% of the LINZESS-treated patients versus less than 1% of the placebo-treated patients, and 5% of LINZESS-treated patients discontinued due to diarrhea vs less than 1% of placebo-treated patients. The majority of reported cases of diarrhea started within the first 2 weeks of LINZESS treatment. Fecal incontinence and dehydration were each reported in less than or equal to 1% of patients in the LINZESS treatment group. - Adverse Reactions Leading to Discontinuation - In placebo-controlled trials in patients with IBS-C, 9% of patients treated with LINZESS and 3% of patients treated with placebo discontinued prematurely due to adverse reactions. In the LINZESS treatment group, the most common reasons for discontinuation due to adverse reactions were diarrhea (5%) and abdominal pain (1%). In comparison, less than 1% of patients in the placebo group withdrew due to diarrhea or abdominal pain. - Adverse Reactions Leading to Dose Reductions - In the open-label, long-term trials, 2147 patients with IBS-C received 290 mcg of LINZESS daily for up to 18 months. In these trials, 29% of patients had their dose reduced or suspended secondary to adverse reactions, the majority of which were diarrhea or other GI adverse reactions. - Other Adverse Reactions - Adverse reactions that were reported in at least 1% and less than 2% of IBS-C patients in the LINZESS treatment group and at an incidence greater than in the placebo treatment group are listed below by body system: Gastroesophageal reflux disease, vomiting Fatigue - Other Adverse Events - In placebo-controlled trials in patients with IBS-C, less than 1% LINZESS-treated patients and no placebo-treated patients reported hematochezia; no patient in either treatment group reported melena. Less than 1% of LINZESS-treated and placebo-treated patients reported allergic reactions, urticaria, or hives as adverse events. - Most Common Adverse Reactions - The data described below reflect exposure to LINZESS in the two double-blind placebo-controlled clinical trials of 1275 adult patients with CIC (Trials 3 and 4). Patients were randomized to receive placebo or 145 mcg LINZESS or 290 mcg LINZESS once daily on an empty stomach, for at least 12 weeks. Demographic characteristics were comparable between both LINZESS treatment groups and placebo . Only data for the recommended LINZESS 145 mcg dose and placebo are presented. Table 2 provides the incidence of adverse reactions reported in at least 2% of CIC patients in the 145 mcg LINZESS treatment group and at an incidence that was greater than in the placebo treatment group. - Diarrhea - Diarrhea was the most commonly reported adverse reaction of the LINZESS-treated patients in the pooled CIC placebo-controlled trials. In these trials, 16% of LINZESS-treated patients reported diarrhea compared to 5% of placebo-treated patients. Severe diarrhea was reported in 2% of the 145 mcg LINZESS-treated patients versus less than 1% of the placebo-treated patients, and 5% of LINZESS-treated patients discontinued due to diarrhea vs less than 1% of placebo-treated patients. The majority of reported cases of diarrhea started within the first 2 weeks of LINZESS treatment. Fecal incontinence was reported in 1% of patients in the LINZESS treatment group, compared with less than 1% in the placebo group. Dehydration was reported in less than 1% of patients in the LINZESS treatment group. - Adverse Reactions Leading to Discontinuation - In placebo-controlled trials in patients with CIC, 8% of patients treated with LINZESS and 4% of patients treated with placebo discontinued prematurely due to adverse reactions. In the 145 mcg LINZESS treatment group, the most common reasons for discontinuation due to adverse reactions were diarrhea (5%) and abdominal pain (1%). In comparison, less than 1% of patients in the placebo group withdrew due to diarrhea or abdominal pain. - Adverse Reactions Leading to Dose Reductions - In the open-label, long-term trials, 1129 patients with CIC received 290 mcg of LINZESS daily for up to 18 months. In these trials, 27% of patients had their dose reduced or suspended secondary to adverse reactions, the majority of which were diarrhea or other GI adverse reactions. - Other Adverse Reactions - Adverse reactions that were reported in at least 1% of and less than 2% of CIC patients in the 145 mcg LINZESS treatment group and at an incidence greater than in the placebo treatment group are listed below by body system: Dyspepsia, fecal incontinence Viral gastroenteritis - Other Adverse Events - In placebo-controlled trials in patients with CIC, less than 1% of both LINZESS-treated and placebo-treated patients reported rectal hemorrhage, hematochezia or melena. Less than 1% of LINZESS-treated and placebo-treated patients reported allergic reactions, urticaria, or hives as adverse events. ## Postmarketing Experience There is limited information regarding Postmarketing Experience of Linaclotide in the drug label. # Drug Interactions - No drug-drug interaction studies have been conducted with LINZESS. Linaclotide and its active metabolite are not measurable in plasma following administration of the recommended clinical doses; hence, no systemic drug-drug interactions or drug interactions mediated by plasma protein binding of linaclotide or its metabolite are anticipated. - Linaclotide does not interact with the cytochrome P450 enzyme system based on the results of in vitro studies. In addition, linaclotide is neither a substrate nor an inhibitor of the efflux transporter P-glycoprotein (P-gp). # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): - Pregnancy Category C - Risk Summary - There are no adequate and well-controlled studies with LINZESS in pregnant women. In animal developmental studies, adverse fetal effects were observed only with maternal toxicity and at doses of linaclotide much higher than the maximum recommended human dose. LINZESS should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. - Animal Data - The potential for linaclotide to cause teratogenic effects was studied in rats, rabbits and mice. Oral administration of up to 100,000 mcg/kg/day in rats and 40,000 mcg/kg/day in rabbits produced no maternal toxicity and no effects on embryo-fetal development. In mice, oral dose levels of at least 40,000 mcg/kg/day produced severe maternal toxicity including death, reduction of gravid uterine and fetal weights, and effects on fetal morphology. Oral doses of 5000 mcg/kg/day did not produce maternal toxicity or any adverse effects on embryo-fetal development in mice. - The maximum recommended human dose is approximately 5 mcg/kg/day, based on a 60-kg body weight. Limited systemic exposure to linaclotide was achieved at the tested dose levels in animals (AUC = 40, 640, and 25 nghr/mL in rats, rabbits, and mice, respectively, at the highest dose levels), whereas no detectable exposure occurred in humans. Therefore, animal and human doses should not be compared directly for evaluating relative exposure. Pregnancy Category (AUS): - Australian Drug Evaluation Committee (ADEC) Pregnancy Category There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Linaclotide in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Linaclotide during labor and delivery. ### Nursing Mothers - It is not known whether linaclotide is excreted in human milk; however, linaclotide and its active metabolite are not measurable in plasma following administration of the recommended clinical doses. Caution should be exercised when LINZESS is administered to nursing women . ### Pediatric Use - LINZESS is contraindicated in children under 6 years of age. The safety and effectiveness of LINZESS in pediatric patients under 18 years of age have not been established. In neonatal mice, increased fluid secretion as a consequence of GC-C agonism resulted in mortality due to dehydration. Due to increased intestinal expression of GC-C, children under 6 years of age may be more likely than older children and adults to develop diarrhea and its potentially serious consequences. - Avoid use of LINZESS in pediatric patients 6 through 17 years of age. Although there were no deaths in older juvenile mice, given the deaths in young juvenile mice and the lack of clinical safety and efficacy data in pediatric patients, avoid the use of LINZESS in pediatric patients 6 through 17 years of age. ### Geriatic Use - Irritable Bowel Syndrome with Constipation (IBS-C) - Of 1605 IBS-C patients in the placebo-controlled clinical studies of LINZESS, 85 (5%) were at least 65 years of age, while 20 (1%) were at least 75 years old. Clinical studies of LINZESS did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. - Chronic Idiopathic Constipation (CIC) - Of 1275 CIC patients in the placebo-controlled clinical studies of LINZESS, 155 (12%) were at least 65 years of age, while 30 (2%) were at least 75 years old. Clinical trials of LINZESS did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. ### Gender There is no FDA guidance on the use of Linaclotide with respect to specific gender populations. ### Race There is no FDA guidance on the use of Linaclotide with respect to specific racial populations. ### Renal Impairment There is no FDA guidance on the use of Linaclotide in patients with renal impairment. ### Hepatic Impairment There is no FDA guidance on the use of Linaclotide in patients with hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Linaclotide in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Linaclotide in patients who are immunocompromised. # Administration and Monitoring ### Administration - Oral ### Monitoring There is limited information regarding Monitoring of Linaclotide in the drug label. # IV Compatibility There is limited information regarding IV Compatibility of Linaclotide in the drug label. # Overdosage ## Acute Overdose - There is limited experience with overdose of LINZESS. During the clinical development program of LINZESS, single doses of 2897 mcg were administered to 22 healthy volunteers; the safety profile in these subjects was consistent with that in the overall LINZESS-treated population, with diarrhea being the most commonly reported adverse reaction. ## Chronic Overdose There is limited information regarding Chronic Overdose of Linaclotide in the drug label. # Pharmacology ## Mechanism of Action - Linaclotide is a guanylate cyclase-C (GC-C) agonist. Both linaclotide and its active metabolite bind to GC-C and act locally on the luminal surface of the intestinal epithelium. Activation of GC-C results in an increase in both intracellular and extracellular concentrations of cyclic guanosine monophosphate (cGMP). Elevation in intracellular cGMP stimulates secretion of chloride and bicarbonate into the intestinal lumen, mainly through activation of the cystic fibrosis transmembrane conductance regulator (CFTR) ion channel, resulting in increased intestinal fluid and accelerated transit. In animal models, linaclotide has been shown to both accelerate GI transit and reduce intestinal pain. The linaclotide-induced reduction in visceral pain in animals is thought to be mediated by increased extracellular cGMP, which was shown to decrease the activity of pain-sensing nerves. ## Structure - LINZESS (linaclotide) is a guanylate cyclase-C agonist. Linaclotide is a 14-amino acid peptide with the following chemical name: L-cysteinyl-L-cysteinyl-L-glutamyl-L-tyrosyl-L-cysteinyl-L-cysteinyl-L-asparaginyl-L-prolyl-L-alanyl-L-cysteinyl-L-threonyl-glycyl-L-cysteinyl-L-tyrosine, cyclic (1-6), (2-10), (5-13)-tris (disulfide). - The molecular formula of linaclotide is C59H79N15O21S6 and its molecular weight is 1526.8. The amino acid sequence for linaclotide is shown below: - Linaclotide is an amorphous, white to off-white powder. It is slightly soluble in water and aqueous sodium chloride (0.9%). LINZESS contains linaclotide-coated beads in hard gelatin capsules. LINZESS is available as 145 mcg and 290 mcg capsules for oral administration. - The inactive ingredients of LINZESS capsules include: calcium chloride dihydrate, L-leucine, hypromellose, microcrystalline cellulose, gelatin, and titanium dioxide. ## Pharmacodynamics - Although the pharmacologic effects of LINZESS in humans have not been fully evaluated, in clinical studies, LINZESS has been shown to change stool consistency as measured by the Bristol Stool Form Scale (BSFS) and increase stool frequency. ## Pharmacokinetics - Absorption - LINZESS is minimally absorbed with low systemic availability following oral administration. Concentrations of linaclotide and its active metabolite in plasma are below the limit of quantitation after oral doses of 145 mcg or 290 mcg were administered. Therefore, standard pharmacokinetic parameters such as area under the curve (AUC), maximum concentration (Cmax), and half-life (t½) cannot be calculated. - Distribution - Given that linaclotide plasma concentrations following therapeutic oral doses are not measurable, linaclotide is expected to be minimally distributed to tissues. - Metabolism - Linaclotide is metabolized within the gastrointestinal tract to its principal, active metabolite by loss of the terminal tyrosine moiety. Both linaclotide and the metabolite are proteolytically degraded within the intestinal lumen to smaller peptides and naturally occurring amino acids. - Elimination - Active peptide recovery in the stool samples of fed and fasted subjects following the daily administration of 290 mcg of LINZESS for seven days averaged about 5% (fasted) and about 3% (fed) and virtually all as the active metabolite. - Food Effect - In a cross-over study, 18 healthy subjects were given LINZESS 290 mcg for 7 days both in the non-fed and fed state. Neither linaclotide nor its active metabolite was detected in the plasma. Taking LINZESS immediately after the high fat breakfast resulted in looser stools and a higher stool frequency compared with taking it in the fasted state. In clinical trials, LINZESS was administered on an empty stomach, at least 30 minutes before breakfast. - Specific Populations - Age and Gender - Clinical studies to determine the impact of age and gender on the pharmacokinetics of LINZESS have not been conducted. - Hepatic Impairment - LINZESS has not been specifically studied in patients who have hepatic impairment. Hepatic impairment is not expected to affect the metabolism or clearance of the parent drug or its metabolite because linaclotide is metabolized within the gastrointestinal tract. - Renal Impairment - LINZESS has not been specifically studied in patients who have renal impairment. Renal impairment is not expected to affect clearance of the parent drug or its metabolite because linaclotide has low systemic availability following oral administration and is metabolized within the gastrointestinal tract. ## Nonclinical Toxicology - Carcinogenesis - In 2-year carcinogenicity studies, linaclotide was not tumorigenic in rats at doses up to 3500 mcg/kg/day or in mice at doses up to 6000 mcg/kg/day. The maximum recommended human dose is approximately 5 mcg/kg/day based on a 60-kg bodyweight. Limited systemic exposure to linaclotide was achieved at the tested dose levels in animals, whereas no detectable exposure occurred in humans. Therefore, animal and human doses should not be compared directly for evaluating relative exposure. - Mutagenesis - Linaclotide was not genotoxic in an in vitro bacterial reverse mutation (Ames) assay or in the in vitro chromosomal aberration assay in cultured human peripheral blood lymphocytes. - Impairment of Fertility - Linaclotide had no effect on fertility or reproductive function in male and female rats at oral doses of up to 100,000 mcg/kg/day. - Animal Toxicology and/or Pharmacology - In toxicology studies in neonatal mice, linaclotide caused deaths at 10 mcg/kg/day after oral administration of 1 or 2 daily doses on post-natal day 7. These deaths were due to rapid and severe dehydration produced by significant fluid shifts into the intestinal lumen resulting from GC-C agonism in neonatal mice. Supplemental subcutaneous fluid administration prevented death after linaclotide administration in neonatal mice. - In studies conducted without supplemental fluid administration, tolerability to linaclotide increases with age in juvenile mice. In 2-week-old mice, linaclotide was well tolerated at a dose of 50 mcg/kg/day, but deaths occurred after a single oral dose of 100 mcg/kg. In 3-week-old mice, linaclotide was well tolerated at 100 mcg/kg/day, but deaths occurred after a single oral dose of 600 mcg/kg. Linaclotide was well tolerated and did not cause death in 4-week-old juvenile mice at a dose of 1,000 mcg/kg/day for 7 days and in 6-week-old juvenile mice at a dose of 20,000 mcg/kg/day for 28 days - Linaclotide did not cause death in adult mice, rats, rabbits and monkeys at dose levels up to 5,000 mcg/kg/day. The maximum recommended dose in adults is approximately 5 mcg/kg/day, based on a 60-kg body weight. Animal and human doses of linaclotide should not be compared directly for evaluating relative exposure. # Clinical Studies - The efficacy of LINZESS for the management of symptoms of IBS-C was established in two double-blind, placebo-controlled, randomized, multicenter trials in adult patients (Trials 1 and 2). A total of 800 patients in Trial 1 and 804 patients in Trial 2 received treatment with LINZESS 290 mcg or placebo once daily and were evaluated for efficacy. All patients met Rome II criteria for IBS and were required, during the 2-week baseline period, to meet the following criteria: - a mean abdominal pain score of at least 3 on a 0-to-10-point numeric rating scale - less than 3 complete spontaneous bowel movements (CSBMs) per week , and - less than or equal to 5 SBMs per week. - The trial designs were identical through the first 12 weeks, and thereafter differed only in that Trial 1 included a 4-week randomized withdrawal (RW) period, and Trial 2 continued for 14 additional weeks (total of 26 weeks) of double-blind treatment. During the trials, patients were allowed to continue stable doses of bulk laxatives or stool softeners but were not allowed to take laxatives, bismuth, prokinetic agents, or other drugs to treat IBS-C or chronic constipation. - Efficacy of LINZESS was assessed using overall responder analyses and change-from-baseline endpoints. Results for endpoints were based on information provided daily by patients in diaries. - The 4 primary efficacy responder endpoints were based on a patient being a weekly responder for either at least 9 out of the first 12 weeks of treatment or at least 6 out of the first 12 weeks of treatment. For the 9 out of 12 weeks combined primary responder endpoint, a patient had to have at least a 30% reduction from baseline in mean abdominal pain, at least 3 CSBMs and an increase of at least 1 CSBM from baseline, all in the same week, for at least 9 out of the first 12 weeks of treatment. Each of the 2 components of the 9 out of 12 weeks combined responder endpoint, abdominal pain and CSBMs, was also a primary endpoint. - For the 6 out of 12 weeks combined primary responder endpoint, a patient had to have at least a 30% reduction from baseline in mean abdominal pain and an increase of at least 1 CSBM from baseline, all in the same week, for at least 6 out of the first 12 weeks of treatment. To be considered a responder for this analysis, patients did not have to have at least 3 CSBMs per week. - The efficacy results for the 9 out of 12 weeks and the 6 out of 12 weeks responder endpoints are shown in Tables 3 and 4, respectively. In both trials, the proportion of patients who were responders to LINZESS 290 mcg was statistically significantly higher than with placebo. - In each trial, improvement from baseline in abdominal pain and CSBM frequency was seen over the first 12-weeks of the treatment periods. For change from baseline in the 11-point abdominal pain scale, LINZESS 290 mcg began to separate from placebo in the first week. Maximum effects were seen at weeks 6 - 9 and were maintained until the end of the study. The mean treatment difference from placebo at week 12 was a decrease in pain score of approximately 1.0 point in both trials (using an 11-point scale). Maximum effect on CSBM frequency occurred within the first week, and for change from baseline in CSBM frequency at week 12, the difference between placebo and LINZESS was approximately 1.5 CSBMs per week in both trials. - During the 4-week randomized withdrawal period in Trial 1, patients who received LINZESS during the 12-week treatment period were re-randomized to receive placebo or continue treatment on LINZESS 290 mcg. In LINZESS-treated patients re-randomized to placebo, CSBM frequency and abdominal-pain severity returned toward baseline within 1 week and did not result in worsening compared to baseline. Patients who continued on LINZESS maintained their response to therapy over the additional 4 weeks. Patients on placebo who were allocated to LINZESS had an increase in CSBM frequency and a decrease in abdominal pain levels that were similar to the levels observed in patients taking LINZESS during the treatment period. - The efficacy of LINZESS for the management of symptoms of CIC was established in two double-blind, placebo-controlled, randomized, multicenter clinical trials in adult patients (Trials 3 and 4). A total of 642 patients in Trial 3 and 630 patients in Trial 4 received treatment with LINZESS 145 mcg, 290 mcg, or placebo once daily and were evaluated for efficacy. All patients met modified Rome II criteria for functional constipation. Modified Rome II criteria were less than 3 Spontaneous Bowel Movements (SBMs) per week and 1 of the following symptoms for at least 12 weeks, which need not be consecutive, in the preceding 12 months: - Straining during greater than 25% of bowel movements - Lumpy or hard stools during greater than 25% of bowel movements - Sensation of incomplete evacuation during greater than 25% of bowel movements - Patients were also required to have less than 3 CSBMs per week and less than or equal to 6 SBMs per week during a 2-week baseline period. Patients were excluded if they met criteria for IBS-C or had fecal impaction that required emergency room treatment. - The trial designs were identical through the first 12 weeks. Trial 3 also included an additional 4-week randomized withdrawal (RW) period. During the trials, patients were allowed to continue stable doses of bulk laxatives or stool softeners but were not allowed to take laxatives, bismuth, prokinetic agents, or other drugs to treat chronic constipation. - Efficacy of LINZESS was assessed using overall responder analysis and change-from-baseline endpoints. Results for endpoints were based on information provided daily by patients in diaries. - A CSBM overall responder in the CIC trials was defined as a patient who had at least 3 CSBMs and an increase of at least 1 CSBM from baseline in a given week for at least 9 weeks out of the 12-week treatment period. The CSBM responder rates are shown in Table 5. During the individual double-blind placebo-controlled trials, LINZESS 290 mcg did not consistently offer additional clinically meaningful treatment benefit over placebo than that observed with the LINZESS 145 mcg dose. Therefore, the 145 mcg dose is the recommended dose. Only the data for the approved 145 mcg dose of LINZESS are presented in Table 5. - In Trials 3 and 4, the proportion of patients who were CSBM responders was statistically significantly greater with the LINZESS 145 mcg dose than with placebo. - CSBM frequency reached maximum level during week 1 and was also demonstrated over the remainder of the 12-week treatment period in Trial 3 and Trial 4. For the mean change from baseline in CSBM frequency at week 12, the difference between placebo and LINZESS was approximately 1.5 CSBMs. - On average, patients who received LINZESS across the 2 trials had significantly greater improvements compared with patients receiving placebo in stool frequency (CSBMs/week and SBMs/week), and stool consistency (as measured by the BSFS). - During the 4-week randomized withdrawal period in Trial 3, patients who received LINZESS during the 12-week treatment period were re-randomized to receive placebo or continue treatment on the same dose of LINZESS taken during the treatment period. In LINZESS-treated patients re-randomized to placebo, CSBM and SBM frequency returned toward baseline within 1 week and did not result in worsening compared to baseline. Patients who continued on LINZESS maintained their response to therapy over the additional 4 weeks. Patients on placebo who were allocated to LINZESS had an increase in CSBM and SBM frequency similar to the levels observed in patients taking LINZESS during the treatment period. # How Supplied - 145 mcg Capsules: White to off-white opaque hard gelatin capsules with grey imprint "FL 145" - Bottle of 30: NDC 0456-1201-30 - 290 mcg Capsules: White to off-white opaque hard gelatin capsules with grey imprint "FL 290" - Bottle of 30: NDC 0456-1202-30 - Storage - Store at 25°C (77°F); excursions permitted between 15°C and 30°C (59°F and 86°F) . - Keep LINZESS in the original container. Do not subdivide or repackage. Protect from moisture. Do not remove desiccant from the container. Keep bottles tightly closed in a dry place. ## Storage There is limited information regarding Linaclotide Storage in the drug label. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information - Patients should be instructed as follows: - Do not give LINZESS to children who are under 6 years of age. It may harm them. You should not give LINZESS to children 6 to 17 years of age. It may harm them. - Keep LINZESS in the original container. Do not subdivide or repackage. Protect from moisture. Do not remove desiccant from the container. Keep bottles closed tightly in a dry place. - Take LINZESS once daily on an empty stomach as prescribed. Swallow the capsule whole and do not break apart or chew. - If you miss a dose, skip the missed dose. Just take the next dose at your regular time. Do not take 2 doses at the same time. - Stop LINZESS and contact your physician if you experience severe diarrhea. - Seek immediate medical attention if you develop unusual or severe abdominal pain, and /or severe diarrhea, especially if in combination with hematochezia or melena. # Precautions with Alcohol - Alcohol-Linaclotide interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - LINZESS® # Look-Alike Drug Names There is limited information regarding Linaclotide Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	Linaclotide 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. # Black Box Warning # Overview Linaclotide is a guanylate cyclase-C agonist that is FDA approved for the {{{indicationType}}} of irritable bowel syndrome with constipation (IBS-C), chronic idiopathic constipation (CIC). There is a Black Box Warning for this drug as shown here. Common adverse reactions include diarrhea, abdominal pain, flatulence and abdominal distension. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) - The recommended dose of LINZESS is 290 mcg taken orally once daily on an empty stomach, at least 30 minutes prior to the first meal of the day. - The recommended dose of LINZESS is 145 mcg taken orally once daily on an empty stomach, at least 30 minutes prior to the first meal of the day. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Linaclotide in adult patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Linaclotide in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) There is limited information regarding FDA-Labeled Use of Linaclotide in pediatric patients. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Linaclotide in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Linaclotide in pediatric patients. # Contraindications - Pediatric patients under 6 years of age. - Patients with known or suspected mechanical gastrointestinal obstruction. # Warnings ### Precautions - Pediatric Risk - LINZESS is contraindicated in children under 6 years of age. The safety and effectiveness of LINZESS in pediatric patients under 18 years of age have not been established. In neonatal mice, increased fluid secretion as a consequence of GC-C agonism resulted in mortality within the first 24 hours due to dehydration. Due to increased intestinal expression of GC-C, children under 6 years of age may be more likely than older children and adults to develop significant diarrhea and its potentially serious consequences. - Avoid use of LINZESS in pediatric patients 6 through 17 years of age. Although there were no deaths in older juvenile mice, given the deaths in young juvenile mice and the lack of clinical safety and efficacy data in pediatric patients, avoid the use of LINZESS in pediatric patients 6 through 17 years of age. - Diarrhea - Diarrhea was the most common adverse reaction of LINZESS-treated patients in the pooled IBS-C and CIC double-blind placebo-controlled trials. Severe diarrhea was reported in 2% of the LINZESS-treated patients. The incidence of diarrhea was similar between the IBS-C and CIC populations. - Instruct patients to stop LINZESS if severe diarrhea occurs and to contact their healthcare provider. The healthcare provider should consider dose suspension and rehydration. # 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 with rates in the clinical trials of another drug and may not reflect the rates observed in practice. - During clinical development, approximately 2570, 2040, and 1220 patients with either IBS-C or CIC were treated with LINZESS for 6 months or longer, 1 year or longer, and 18 months or longer, respectively (not mutually exclusive). - Most Common Adverse Reactions - The data described below reflect exposure to LINZESS in the two placebo-controlled clinical trials involving 1605 adult patients with IBS-C (Trials 1 and 2). Patients were randomized to receive placebo or 290 mcg LINZESS once daily on an empty stomach for up to 26 weeks. Demographic characteristics were comparable between treatment groups. Table 1 provides the incidence of adverse reactions reported in at least 2% of IBS-C patients in the LINZESS treatment group and at an incidence that was greater than in the placebo group. - Diarrhea - Diarrhea was the most commonly reported adverse reaction of the LINZESS-treated patients in the pooled IBS-C pivotal placebo-controlled trials. In these trials, 20% of LINZESS-treated patients reported diarrhea compared to 3% of placebo-treated patients. Severe diarrhea was reported in 2% of the LINZESS-treated patients versus less than 1% of the placebo-treated patients, and 5% of LINZESS-treated patients discontinued due to diarrhea vs less than 1% of placebo-treated patients. The majority of reported cases of diarrhea started within the first 2 weeks of LINZESS treatment. Fecal incontinence and dehydration were each reported in less than or equal to 1% of patients in the LINZESS treatment group. - Adverse Reactions Leading to Discontinuation - In placebo-controlled trials in patients with IBS-C, 9% of patients treated with LINZESS and 3% of patients treated with placebo discontinued prematurely due to adverse reactions. In the LINZESS treatment group, the most common reasons for discontinuation due to adverse reactions were diarrhea (5%) and abdominal pain (1%). In comparison, less than 1% of patients in the placebo group withdrew due to diarrhea or abdominal pain. - Adverse Reactions Leading to Dose Reductions - In the open-label, long-term trials, 2147 patients with IBS-C received 290 mcg of LINZESS daily for up to 18 months. In these trials, 29% of patients had their dose reduced or suspended secondary to adverse reactions, the majority of which were diarrhea or other GI adverse reactions. - Other Adverse Reactions - Adverse reactions that were reported in at least 1% and less than 2% of IBS-C patients in the LINZESS treatment group and at an incidence greater than in the placebo treatment group are listed below by body system: Gastroesophageal reflux disease, vomiting Fatigue - Other Adverse Events - In placebo-controlled trials in patients with IBS-C, less than 1% LINZESS-treated patients and no placebo-treated patients reported hematochezia; no patient in either treatment group reported melena. Less than 1% of LINZESS-treated and placebo-treated patients reported allergic reactions, urticaria, or hives as adverse events. - Most Common Adverse Reactions - The data described below reflect exposure to LINZESS in the two double-blind placebo-controlled clinical trials of 1275 adult patients with CIC (Trials 3 and 4). Patients were randomized to receive placebo or 145 mcg LINZESS or 290 mcg LINZESS once daily on an empty stomach, for at least 12 weeks. Demographic characteristics were comparable between both LINZESS treatment groups and placebo [see Clinical Studies (14.2)]. Only data for the recommended LINZESS 145 mcg dose and placebo are presented. Table 2 provides the incidence of adverse reactions reported in at least 2% of CIC patients in the 145 mcg LINZESS treatment group and at an incidence that was greater than in the placebo treatment group. - Diarrhea - Diarrhea was the most commonly reported adverse reaction of the LINZESS-treated patients in the pooled CIC placebo-controlled trials. In these trials, 16% of LINZESS-treated patients reported diarrhea compared to 5% of placebo-treated patients. Severe diarrhea was reported in 2% of the 145 mcg LINZESS-treated patients versus less than 1% of the placebo-treated patients, and 5% of LINZESS-treated patients discontinued due to diarrhea vs less than 1% of placebo-treated patients. The majority of reported cases of diarrhea started within the first 2 weeks of LINZESS treatment. Fecal incontinence was reported in 1% of patients in the LINZESS treatment group, compared with less than 1% in the placebo group. Dehydration was reported in less than 1% of patients in the LINZESS treatment group. - Adverse Reactions Leading to Discontinuation - In placebo-controlled trials in patients with CIC, 8% of patients treated with LINZESS and 4% of patients treated with placebo discontinued prematurely due to adverse reactions. In the 145 mcg LINZESS treatment group, the most common reasons for discontinuation due to adverse reactions were diarrhea (5%) and abdominal pain (1%). In comparison, less than 1% of patients in the placebo group withdrew due to diarrhea or abdominal pain. - Adverse Reactions Leading to Dose Reductions - In the open-label, long-term trials, 1129 patients with CIC received 290 mcg of LINZESS daily for up to 18 months. In these trials, 27% of patients had their dose reduced or suspended secondary to adverse reactions, the majority of which were diarrhea or other GI adverse reactions. - Other Adverse Reactions - Adverse reactions that were reported in at least 1% of and less than 2% of CIC patients in the 145 mcg LINZESS treatment group and at an incidence greater than in the placebo treatment group are listed below by body system: Dyspepsia, fecal incontinence Viral gastroenteritis - Other Adverse Events - In placebo-controlled trials in patients with CIC, less than 1% of both LINZESS-treated and placebo-treated patients reported rectal hemorrhage, hematochezia or melena. Less than 1% of LINZESS-treated and placebo-treated patients reported allergic reactions, urticaria, or hives as adverse events. ## Postmarketing Experience There is limited information regarding Postmarketing Experience of Linaclotide in the drug label. # Drug Interactions - No drug-drug interaction studies have been conducted with LINZESS. Linaclotide and its active metabolite are not measurable in plasma following administration of the recommended clinical doses; hence, no systemic drug-drug interactions or drug interactions mediated by plasma protein binding of linaclotide or its metabolite are anticipated. - Linaclotide does not interact with the cytochrome P450 enzyme system based on the results of in vitro studies. In addition, linaclotide is neither a substrate nor an inhibitor of the efflux transporter P-glycoprotein (P-gp). # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): - Pregnancy Category C - Risk Summary - There are no adequate and well-controlled studies with LINZESS in pregnant women. In animal developmental studies, adverse fetal effects were observed only with maternal toxicity and at doses of linaclotide much higher than the maximum recommended human dose. LINZESS should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. - Animal Data - The potential for linaclotide to cause teratogenic effects was studied in rats, rabbits and mice. Oral administration of up to 100,000 mcg/kg/day in rats and 40,000 mcg/kg/day in rabbits produced no maternal toxicity and no effects on embryo-fetal development. In mice, oral dose levels of at least 40,000 mcg/kg/day produced severe maternal toxicity including death, reduction of gravid uterine and fetal weights, and effects on fetal morphology. Oral doses of 5000 mcg/kg/day did not produce maternal toxicity or any adverse effects on embryo-fetal development in mice. - The maximum recommended human dose is approximately 5 mcg/kg/day, based on a 60-kg body weight. Limited systemic exposure to linaclotide was achieved at the tested dose levels in animals (AUC = 40, 640, and 25 ng•hr/mL in rats, rabbits, and mice, respectively, at the highest dose levels), whereas no detectable exposure occurred in humans. Therefore, animal and human doses should not be compared directly for evaluating relative exposure. Pregnancy Category (AUS): - Australian Drug Evaluation Committee (ADEC) Pregnancy Category There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Linaclotide in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Linaclotide during labor and delivery. ### Nursing Mothers - It is not known whether linaclotide is excreted in human milk; however, linaclotide and its active metabolite are not measurable in plasma following administration of the recommended clinical doses. Caution should be exercised when LINZESS is administered to nursing women [see Contraindications (4), Warnings and Precautions (5.1) and Use in Specific Populations (8.4)]. ### Pediatric Use - LINZESS is contraindicated in children under 6 years of age. The safety and effectiveness of LINZESS in pediatric patients under 18 years of age have not been established. In neonatal mice, increased fluid secretion as a consequence of GC-C agonism resulted in mortality due to dehydration. Due to increased intestinal expression of GC-C, children under 6 years of age may be more likely than older children and adults to develop diarrhea and its potentially serious consequences. - Avoid use of LINZESS in pediatric patients 6 through 17 years of age. Although there were no deaths in older juvenile mice, given the deaths in young juvenile mice and the lack of clinical safety and efficacy data in pediatric patients, avoid the use of LINZESS in pediatric patients 6 through 17 years of age. ### Geriatic Use - Irritable Bowel Syndrome with Constipation (IBS-C) - Of 1605 IBS-C patients in the placebo-controlled clinical studies of LINZESS, 85 (5%) were at least 65 years of age, while 20 (1%) were at least 75 years old. Clinical studies of LINZESS did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. - Chronic Idiopathic Constipation (CIC) - Of 1275 CIC patients in the placebo-controlled clinical studies of LINZESS, 155 (12%) were at least 65 years of age, while 30 (2%) were at least 75 years old. Clinical trials of LINZESS did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. ### Gender There is no FDA guidance on the use of Linaclotide with respect to specific gender populations. ### Race There is no FDA guidance on the use of Linaclotide with respect to specific racial populations. ### Renal Impairment There is no FDA guidance on the use of Linaclotide in patients with renal impairment. ### Hepatic Impairment There is no FDA guidance on the use of Linaclotide in patients with hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Linaclotide in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Linaclotide in patients who are immunocompromised. # Administration and Monitoring ### Administration - Oral ### Monitoring There is limited information regarding Monitoring of Linaclotide in the drug label. # IV Compatibility There is limited information regarding IV Compatibility of Linaclotide in the drug label. # Overdosage ## Acute Overdose - There is limited experience with overdose of LINZESS. During the clinical development program of LINZESS, single doses of 2897 mcg were administered to 22 healthy volunteers; the safety profile in these subjects was consistent with that in the overall LINZESS-treated population, with diarrhea being the most commonly reported adverse reaction. ## Chronic Overdose There is limited information regarding Chronic Overdose of Linaclotide in the drug label. # Pharmacology ## Mechanism of Action - Linaclotide is a guanylate cyclase-C (GC-C) agonist. Both linaclotide and its active metabolite bind to GC-C and act locally on the luminal surface of the intestinal epithelium. Activation of GC-C results in an increase in both intracellular and extracellular concentrations of cyclic guanosine monophosphate (cGMP). Elevation in intracellular cGMP stimulates secretion of chloride and bicarbonate into the intestinal lumen, mainly through activation of the cystic fibrosis transmembrane conductance regulator (CFTR) ion channel, resulting in increased intestinal fluid and accelerated transit. In animal models, linaclotide has been shown to both accelerate GI transit and reduce intestinal pain. The linaclotide-induced reduction in visceral pain in animals is thought to be mediated by increased extracellular cGMP, which was shown to decrease the activity of pain-sensing nerves. ## Structure - LINZESS (linaclotide) is a guanylate cyclase-C agonist. Linaclotide is a 14-amino acid peptide with the following chemical name: L-cysteinyl-L-cysteinyl-L-glutamyl-L-tyrosyl-L-cysteinyl-L-cysteinyl-L-asparaginyl-L-prolyl-L-alanyl-L-cysteinyl-L-threonyl-glycyl-L-cysteinyl-L-tyrosine, cyclic (1-6), (2-10), (5-13)-tris (disulfide). - The molecular formula of linaclotide is C59H79N15O21S6 and its molecular weight is 1526.8. The amino acid sequence for linaclotide is shown below: - Linaclotide is an amorphous, white to off-white powder. It is slightly soluble in water and aqueous sodium chloride (0.9%). LINZESS contains linaclotide-coated beads in hard gelatin capsules. LINZESS is available as 145 mcg and 290 mcg capsules for oral administration. - The inactive ingredients of LINZESS capsules include: calcium chloride dihydrate, L-leucine, hypromellose, microcrystalline cellulose, gelatin, and titanium dioxide. ## Pharmacodynamics - Although the pharmacologic effects of LINZESS in humans have not been fully evaluated, in clinical studies, LINZESS has been shown to change stool consistency as measured by the Bristol Stool Form Scale (BSFS) and increase stool frequency. ## Pharmacokinetics - Absorption - LINZESS is minimally absorbed with low systemic availability following oral administration. Concentrations of linaclotide and its active metabolite in plasma are below the limit of quantitation after oral doses of 145 mcg or 290 mcg were administered. Therefore, standard pharmacokinetic parameters such as area under the curve (AUC), maximum concentration (Cmax), and half-life (t½) cannot be calculated. - Distribution - Given that linaclotide plasma concentrations following therapeutic oral doses are not measurable, linaclotide is expected to be minimally distributed to tissues. - Metabolism - Linaclotide is metabolized within the gastrointestinal tract to its principal, active metabolite by loss of the terminal tyrosine moiety. Both linaclotide and the metabolite are proteolytically degraded within the intestinal lumen to smaller peptides and naturally occurring amino acids. - Elimination - Active peptide recovery in the stool samples of fed and fasted subjects following the daily administration of 290 mcg of LINZESS for seven days averaged about 5% (fasted) and about 3% (fed) and virtually all as the active metabolite. - Food Effect - In a cross-over study, 18 healthy subjects were given LINZESS 290 mcg for 7 days both in the non-fed and fed state. Neither linaclotide nor its active metabolite was detected in the plasma. Taking LINZESS immediately after the high fat breakfast resulted in looser stools and a higher stool frequency compared with taking it in the fasted state. In clinical trials, LINZESS was administered on an empty stomach, at least 30 minutes before breakfast. - Specific Populations - Age and Gender - Clinical studies to determine the impact of age and gender on the pharmacokinetics of LINZESS have not been conducted. - Hepatic Impairment - LINZESS has not been specifically studied in patients who have hepatic impairment. Hepatic impairment is not expected to affect the metabolism or clearance of the parent drug or its metabolite because linaclotide is metabolized within the gastrointestinal tract. - Renal Impairment - LINZESS has not been specifically studied in patients who have renal impairment. Renal impairment is not expected to affect clearance of the parent drug or its metabolite because linaclotide has low systemic availability following oral administration and is metabolized within the gastrointestinal tract. ## Nonclinical Toxicology - Carcinogenesis - In 2-year carcinogenicity studies, linaclotide was not tumorigenic in rats at doses up to 3500 mcg/kg/day or in mice at doses up to 6000 mcg/kg/day. The maximum recommended human dose is approximately 5 mcg/kg/day based on a 60-kg bodyweight. Limited systemic exposure to linaclotide was achieved at the tested dose levels in animals, whereas no detectable exposure occurred in humans. Therefore, animal and human doses should not be compared directly for evaluating relative exposure. - Mutagenesis - Linaclotide was not genotoxic in an in vitro bacterial reverse mutation (Ames) assay or in the in vitro chromosomal aberration assay in cultured human peripheral blood lymphocytes. - Impairment of Fertility - Linaclotide had no effect on fertility or reproductive function in male and female rats at oral doses of up to 100,000 mcg/kg/day. - Animal Toxicology and/or Pharmacology - In toxicology studies in neonatal mice, linaclotide caused deaths at 10 mcg/kg/day after oral administration of 1 or 2 daily doses on post-natal day 7. These deaths were due to rapid and severe dehydration produced by significant fluid shifts into the intestinal lumen resulting from GC-C agonism in neonatal mice. Supplemental subcutaneous fluid administration prevented death after linaclotide administration in neonatal mice. - In studies conducted without supplemental fluid administration, tolerability to linaclotide increases with age in juvenile mice. In 2-week-old mice, linaclotide was well tolerated at a dose of 50 mcg/kg/day, but deaths occurred after a single oral dose of 100 mcg/kg. In 3-week-old mice, linaclotide was well tolerated at 100 mcg/kg/day, but deaths occurred after a single oral dose of 600 mcg/kg. Linaclotide was well tolerated and did not cause death in 4-week-old juvenile mice at a dose of 1,000 mcg/kg/day for 7 days and in 6-week-old juvenile mice at a dose of 20,000 mcg/kg/day for 28 days - Linaclotide did not cause death in adult mice, rats, rabbits and monkeys at dose levels up to 5,000 mcg/kg/day. The maximum recommended dose in adults is approximately 5 mcg/kg/day, based on a 60-kg body weight. Animal and human doses of linaclotide should not be compared directly for evaluating relative exposure. # Clinical Studies - The efficacy of LINZESS for the management of symptoms of IBS-C was established in two double-blind, placebo-controlled, randomized, multicenter trials in adult patients (Trials 1 and 2). A total of 800 patients in Trial 1 and 804 patients in Trial 2 [overall mean age of 44 years (range 18 - 87 years with 5% at least 65 years of age), 90% female, 77% white, 19% black, and 12% Hispanic] received treatment with LINZESS 290 mcg or placebo once daily and were evaluated for efficacy. All patients met Rome II criteria for IBS and were required, during the 2-week baseline period, to meet the following criteria: - a mean abdominal pain score of at least 3 on a 0-to-10-point numeric rating scale - less than 3 complete spontaneous bowel movements (CSBMs) per week [a CSBM is a spontaneous bowel movement (SBM) that is associated with a sense of complete evacuation; a SBM is a bowel movement occurring in the absence of laxative use], and - less than or equal to 5 SBMs per week. - The trial designs were identical through the first 12 weeks, and thereafter differed only in that Trial 1 included a 4-week randomized withdrawal (RW) period, and Trial 2 continued for 14 additional weeks (total of 26 weeks) of double-blind treatment. During the trials, patients were allowed to continue stable doses of bulk laxatives or stool softeners but were not allowed to take laxatives, bismuth, prokinetic agents, or other drugs to treat IBS-C or chronic constipation. - Efficacy of LINZESS was assessed using overall responder analyses and change-from-baseline endpoints. Results for endpoints were based on information provided daily by patients in diaries. - The 4 primary efficacy responder endpoints were based on a patient being a weekly responder for either at least 9 out of the first 12 weeks of treatment or at least 6 out of the first 12 weeks of treatment. For the 9 out of 12 weeks combined primary responder endpoint, a patient had to have at least a 30% reduction from baseline in mean abdominal pain, at least 3 CSBMs and an increase of at least 1 CSBM from baseline, all in the same week, for at least 9 out of the first 12 weeks of treatment. Each of the 2 components of the 9 out of 12 weeks combined responder endpoint, abdominal pain and CSBMs, was also a primary endpoint. - For the 6 out of 12 weeks combined primary responder endpoint, a patient had to have at least a 30% reduction from baseline in mean abdominal pain and an increase of at least 1 CSBM from baseline, all in the same week, for at least 6 out of the first 12 weeks of treatment. To be considered a responder for this analysis, patients did not have to have at least 3 CSBMs per week. - The efficacy results for the 9 out of 12 weeks and the 6 out of 12 weeks responder endpoints are shown in Tables 3 and 4, respectively. In both trials, the proportion of patients who were responders to LINZESS 290 mcg was statistically significantly higher than with placebo. - In each trial, improvement from baseline in abdominal pain and CSBM frequency was seen over the first 12-weeks of the treatment periods. For change from baseline in the 11-point abdominal pain scale, LINZESS 290 mcg began to separate from placebo in the first week. Maximum effects were seen at weeks 6 - 9 and were maintained until the end of the study. The mean treatment difference from placebo at week 12 was a decrease in pain score of approximately 1.0 point in both trials (using an 11-point scale). Maximum effect on CSBM frequency occurred within the first week, and for change from baseline in CSBM frequency at week 12, the difference between placebo and LINZESS was approximately 1.5 CSBMs per week in both trials. - During the 4-week randomized withdrawal period in Trial 1, patients who received LINZESS during the 12-week treatment period were re-randomized to receive placebo or continue treatment on LINZESS 290 mcg. In LINZESS-treated patients re-randomized to placebo, CSBM frequency and abdominal-pain severity returned toward baseline within 1 week and did not result in worsening compared to baseline. Patients who continued on LINZESS maintained their response to therapy over the additional 4 weeks. Patients on placebo who were allocated to LINZESS had an increase in CSBM frequency and a decrease in abdominal pain levels that were similar to the levels observed in patients taking LINZESS during the treatment period. - The efficacy of LINZESS for the management of symptoms of CIC was established in two double-blind, placebo-controlled, randomized, multicenter clinical trials in adult patients (Trials 3 and 4). A total of 642 patients in Trial 3 and 630 patients in Trial 4 [overall mean age of 48 years (range 18 - 85 years with 12% at least 65 years of age), 89% female, 76% white, 22% black, 10% Hispanic] received treatment with LINZESS 145 mcg, 290 mcg, or placebo once daily and were evaluated for efficacy. All patients met modified Rome II criteria for functional constipation. Modified Rome II criteria were less than 3 Spontaneous Bowel Movements (SBMs) per week and 1 of the following symptoms for at least 12 weeks, which need not be consecutive, in the preceding 12 months: - Straining during greater than 25% of bowel movements - Lumpy or hard stools during greater than 25% of bowel movements - Sensation of incomplete evacuation during greater than 25% of bowel movements - Patients were also required to have less than 3 CSBMs per week and less than or equal to 6 SBMs per week during a 2-week baseline period. Patients were excluded if they met criteria for IBS-C or had fecal impaction that required emergency room treatment. - The trial designs were identical through the first 12 weeks. Trial 3 also included an additional 4-week randomized withdrawal (RW) period. During the trials, patients were allowed to continue stable doses of bulk laxatives or stool softeners but were not allowed to take laxatives, bismuth, prokinetic agents, or other drugs to treat chronic constipation. - Efficacy of LINZESS was assessed using overall responder analysis and change-from-baseline endpoints. Results for endpoints were based on information provided daily by patients in diaries. - A CSBM overall responder in the CIC trials was defined as a patient who had at least 3 CSBMs and an increase of at least 1 CSBM from baseline in a given week for at least 9 weeks out of the 12-week treatment period. The CSBM responder rates are shown in Table 5. During the individual double-blind placebo-controlled trials, LINZESS 290 mcg did not consistently offer additional clinically meaningful treatment benefit over placebo than that observed with the LINZESS 145 mcg dose. Therefore, the 145 mcg dose is the recommended dose. Only the data for the approved 145 mcg dose of LINZESS are presented in Table 5. - In Trials 3 and 4, the proportion of patients who were CSBM responders was statistically significantly greater with the LINZESS 145 mcg dose than with placebo. - CSBM frequency reached maximum level during week 1 and was also demonstrated over the remainder of the 12-week treatment period in Trial 3 and Trial 4. For the mean change from baseline in CSBM frequency at week 12, the difference between placebo and LINZESS was approximately 1.5 CSBMs. - On average, patients who received LINZESS across the 2 trials had significantly greater improvements compared with patients receiving placebo in stool frequency (CSBMs/week and SBMs/week), and stool consistency (as measured by the BSFS). - During the 4-week randomized withdrawal period in Trial 3, patients who received LINZESS during the 12-week treatment period were re-randomized to receive placebo or continue treatment on the same dose of LINZESS taken during the treatment period. In LINZESS-treated patients re-randomized to placebo, CSBM and SBM frequency returned toward baseline within 1 week and did not result in worsening compared to baseline. Patients who continued on LINZESS maintained their response to therapy over the additional 4 weeks. Patients on placebo who were allocated to LINZESS had an increase in CSBM and SBM frequency similar to the levels observed in patients taking LINZESS during the treatment period. # How Supplied - 145 mcg Capsules: White to off-white opaque hard gelatin capsules with grey imprint "FL 145" - Bottle of 30: NDC 0456-1201-30 - 290 mcg Capsules: White to off-white opaque hard gelatin capsules with grey imprint "FL 290" - Bottle of 30: NDC 0456-1202-30 - Storage - Store at 25°C (77°F); excursions permitted between 15°C and 30°C (59°F and 86°F) [see USP Controlled Room Temperature]. - Keep LINZESS in the original container. Do not subdivide or repackage. Protect from moisture. Do not remove desiccant from the container. Keep bottles tightly closed in a dry place. ## Storage There is limited information regarding Linaclotide Storage in the drug label. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information - Patients should be instructed as follows: - Do not give LINZESS to children who are under 6 years of age. It may harm them. You should not give LINZESS to children 6 to 17 years of age. It may harm them. - Keep LINZESS in the original container. Do not subdivide or repackage. Protect from moisture. Do not remove desiccant from the container. Keep bottles closed tightly in a dry place. - Take LINZESS once daily on an empty stomach as prescribed. Swallow the capsule whole and do not break apart or chew. - If you miss a dose, skip the missed dose. Just take the next dose at your regular time. Do not take 2 doses at the same time. - Stop LINZESS and contact your physician if you experience severe diarrhea. - Seek immediate medical attention if you develop unusual or severe abdominal pain, and /or severe diarrhea, especially if in combination with hematochezia or melena. # Precautions with Alcohol - Alcohol-Linaclotide interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - LINZESS®[1] # Look-Alike Drug Names There is limited information regarding Linaclotide Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	https://www.wikidoc.org/index.php/Linaclotide
a36fb063ba89e35554cae2c9b38e5cb5c3ccb267	wikidoc	Linagliptin	Linagliptin # 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 Linagliptin is a dipeptidyl peptidase-4 (DPP-4) inhibitor that is FDA approved for the {{{indicationType}}} of type 2 diabetes mellitus. Common adverse reactions include hypoglycemia and nasopharyngitis. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) - Dosing Information - TRADJENTA tablets are indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. - The recommended dose of TRADJENTA is 5 mg once daily. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Linagliptin in adult patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Linagliptin in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) There is limited information regarding FDA-Labeled Use of Linagliptin in pediatric patients. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Linagliptin in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Linagliptin in pediatric patients. # Contraindications - TRADJENTA is contraindicated in patients with a history of a hypersensitivity reaction to linagliptin, such as anaphylaxis, angioedema, exfoliative skin conditions, urticaria, or bronchial hyperreactivity. # Warnings ### Precautions - Pancreatitis - There have been postmarketing reports of acute pancreatitis, including fatal pancreatitis, in patients taking TRADJENTA. Take careful notice of potential signs and symptoms of pancreatitis. If pancreatitis is suspected, promptly discontinue TRADJENTA and initiate appropriate management. It is unknown whether patients with a history of pancreatitis are at increased risk for the development of pancreatitis while using TRADJENTA. - Use with Medications Known to Cause Hypoglycemia - Insulin secretagogues and insulin are known to cause hypoglycemia. The use of TRADJENTA in combination with an insulin secretagogue (e.g., sulfonylurea) was associated with a higher rate of hypoglycemia compared with placebo in a clinical trial. The use of TRADJENTA in combination with insulin in subjects with severe renal impairment was associated with a higher rate of hypoglycemia. Therefore, a lower dose of the insulin secretagogue or insulin may be required to reduce the risk of hypoglycemia when used in combination with TRADJENTA. - Hypersensitivity Reactions - There have been postmarketing reports of serious hypersensitivity reactions in patients treated with TRADJENTA. These reactions include anaphylaxis, angioedema, and exfoliative skin conditions. Onset of these reactions occurred within the first 3 months after initiation of treatment with TRADJENTA, with some reports occurring after the first dose. If a serious hypersensitivity reaction is suspected, discontinue TRADJENTA, assess for other potential causes for the event, and institute alternative treatment for diabetes. - Angioedema has also been reported with other dipeptidyl peptidase-4 (DPP-4) inhibitors. Use caution in a patient with a history of angioedema to another DPP-4 inhibitor because it is unknown whether such patients will be predisposed to angioedema with TRADJENTA. - Macrovascular Outcomes - There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with TRADJENTA tablets or any other antidiabetic drug # 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 practice. - The safety evaluation of TRADJENTA 5 mg once daily in patients with type 2 diabetes is based on 14 placebo-controlled trials, 1 active-controlled study, and one study in patients with severe renal impairment. In the 14 placebo-controlled studies, a total of 3625 patients were randomized and treated with TRADJENTA 5 mg daily and 2176 with placebo. The mean exposure in patients treated with TRADJENTA across studies was 29.6 weeks. The maximum follow-up was 78 weeks. - TRADJENTA 5 mg once daily was studied as monotherapy in three placebo-controlled trials of 18 and 24 weeks’ duration and in five additional placebo-controlled studies lasting ≤18 weeks. The use of TRADJENTA in combination with other antihyperglycemic agents was studied in six placebo-controlled trials: two with metformin (12 and 24 weeks’ treatment duration); one with a sulfonylurea (18 weeks’ treatment duration); one with metformin and sulfonylurea (24 weeks’ treatment duration); one with pioglitazone (24 weeks’ treatment duration); and one with insulin (primary endpoint at 24 weeks). - In a pooled dataset of 14 placebo-controlled clinical trials, adverse reactions that occurred in ≥2% of patients receiving TRADJENTA (n = 3625) and more commonly than in patients given placebo (n = 2176), are shown in Table 1. The overall incidence of adverse events with TRADJENTA were similar to placebo. - Rates for other adverse reactions for TRADJENTA 5 mg vs placebo when TRADJENTA was used in combination with specific anti-diabetic agents were: urinary tract infection (3.1% vs 0%) and hypertriglyceridemia (2.4% vs 0%) when TRADJENTA was used as add-on to sulfonylurea; hyperlipidemia (2.7% vs 0.8%) and weight increased (2.3% vs 0.8%) when TRADJENTA was used as add-on to pioglitazone; and constipation (2.1% vs 1%) when TRADJENTA was used as add-on to basal insulin therapy. - Following 104 weeks’ treatment in a controlled study comparing TRADJENTA with glimepiride in which all patients were also receiving metformin, adverse reactions reported in ≥5% of patients treated with TRADJENTA (n = 776) and more frequently than in patients treated with a sulfonylurea (n = 775) were back pain (9.1% vs 8.4%), arthralgia (8.1% vs 6.1%), upper respiratory tract infection (8.0% vs 7.6%), headache (6.4% vs 5.2%), cough (6.1% vs 4.9%), and pain in extremity (5.3% vs 3.9%). - Other adverse reactions reported in clinical studies with treatment of TRADJENTA were hypersensitivity (e.g., urticaria, angioedema, localized skin exfoliation, or bronchial hyperreactivity), and myalgia. In the clinical trial program, pancreatitis was reported in 15.2 cases per 10,000 patient year exposure while being treated with TRADJENTA compared with 3.7 cases per 10,000 patient year exposure while being treated with comparator (placebo and active comparator, sulfonylurea). Three additional cases of pancreatitis were reported following the last administered dose of linagliptin. - Hypoglycemia - In the placebo-controlled studies, 199 (6.6%) of the total 2994 patients treated with TRADJENTA 5 mg reported hypoglycemia compared to 56 patients (3.6%) of 1546 placebo-treated patients. The incidence of hypoglycemia was similar to placebo when TRADJENTA was administered as monotherapy or in combination with metformin, or with pioglitazone. When TRADJENTA was administered in combination with metformin and a sulfonylurea, 181 of 792 (22.9%) patients reported hypoglycemia compared with 39 of 263 (14.8%) patients administered placebo in combination with metformin and a sulfonylurea. Adverse reactions of hypoglycemia were based on all reports of hypoglycemia. A concurrent glucose measurement was not required or was normal in some patients. Therefore, it is not possible to conclusively determine that all these reports reflect true hypoglycemia. - In the study of patients receiving TRADJENTA as add-on therapy to a stable dose of insulin for up to 52 weeks (n=1261), no significant difference in the incidence of investigator reported hypoglycemia, defined as all symptomatic or asymptomatic episodes with a self measured blood glucose ≤70 mg/dL, was noted between the TRADJENTA- (31.4%) and placebo- (32.9%) treated groups. During the same time period, severe hypoglycemic events, defined as requiring the assistance of another person to actively administer carbohydrate, glucagon or other resuscitative actions, were reported in 11 (1.7%) of TRADJENTA treated patients and 7 (1.1%) of placebo treated patients. Events that were considered life-threatening or required hospitalization were reported in 3 (0.5%) patients on TRADJENTA and 1 (0.2%) on placebo. - Use in Renal Impairment - ADJENTA was compared to placebo as add-on to pre-existing antidiabetic therapy over 52 weeks in 133 patients with severe renal impairment (estimated GFR <;&lt30 mL/min). For the initial 12 weeks of the study, background antidiabetic therapy was kept stable and included insulin, sulfonylurea, glinides, and pioglitazone. For the remainder of the trial, dose adjustments in antidiabetic background therapy were allowed. - In general, the incidence of adverse events including severe hypoglycemia was similar to those reported in other TRADJENTA trials. The observed incidence of hypoglycemia was higher (TRADJENTA, 63% compared to placebo, 49%) due to an increase in asymptomatic hypoglycemic events especially during the first 12 weeks when background glycemic therapies were kept stable. Ten TRADJENTA-treated patients (15%) and 11 placebo-treated patients (17%) reported at least one episode of confirmed symptomatic hypoglycemia (accompanying finger stick glucose ≤54 mg/dL). During the same time period, severe hypoglycemic events, defined as an event requiring the assistance of another person to actively administer carbohydrate, glucagon or other resuscitative actions, were reported in 3 (4.4%) TRADJENTA-treated patients and 3 (4.6%) placebo-treated patients. Events that were considered life-threatening or required hospitalization were reported in 2 (2.9%) patients on TRADJENTA and 1 (1.5%) patient on placebo. - Renal function as measured by mean eGFR and creatinine clearance did not change over 52 weeks’ treatment compared to placebo. ## Postmarketing Experience - Additional adverse reactions have been identified during postapproval use of TRADJENTA. Because these reactions 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. - Acute pancreatitis, including fatal pancreatitis. - Hypersensitivity reactions including anaphylaxis, angioedema, and exfoliative skin conditions. - Rash. # Drug Interactions - Inducers of P-glycoprotein or CYP3A4 Enzymes - Rifampin decreased linagliptin exposure, suggesting that the efficacy of TRADJENTA may be reduced when administered in combination with a strong P-gp or CYP3A4 inducer. Therefore, use of alternative treatments is strongly recommended when linagliptin is to be administered with a strong P-gp or CYP3A4 inducer. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): - Pregnancy Category B - Reproduction studies have been performed in rats and rabbits. There are, however, 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. - Linagliptin administered during the period of organogenesis was not teratogenic at doses up to 30 mg/kg in the rat and 150 mg/kg in the rabbit, or approximately 49 and 1943 times the clinical dose based on AUC exposure. Doses of linagliptin causing maternal toxicity in the rat and the rabbit also caused developmental delays in skeletal ossification and slightly increased embryofetal loss in the rat (1000 times the clinical dose) and increased fetal resorptions and visceral and skeletal variations in the rabbit (1943 times the clinical dose). - Linagliptin administered to female rats from gestation day 6 to lactation day 21 resulted in decreased body weight and delays in physical and behavioral development in male and female offspring at maternally toxic doses (exposures >1000 times the clinical dose). No functional, behavioral, or reproductive toxicity was observed in offspring of rats exposed to 49 times the clinical dose. - Linagliptin crossed the placenta into the fetus following oral dosing in pregnant rats and rabbits. Pregnancy Category (AUS): - Australian Drug Evaluation Committee (ADEC) Pregnancy Category There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Linagliptin in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Linagliptin during labor and delivery. ### Nursing Mothers - Available animal data have shown excretion of linagliptin in milk at a milk-to-plasma ratio of 4:1. 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 TRADJENTA is administered to a nursing woman. ### Pediatric Use - Safety and effectiveness of TRADJENTA in pediatric patients under 18 years of age have not been established. ### Geriatic Use - There were 4040 type 2 diabetes patients treated with linagliptin 5 mg from 15 clinical trials of TRADJENTA; 1085 (27%) were 65 years and over, while 131 (3%) were 75 years and over. Of these patients, 2566 were enrolled in 12 double-blind placebo-controlled studies; 591 (23%) were 65 years and over, while 82 (3%) were 75 years and over. No overall differences in safety or effectiveness were observed between patients 65 years and over and younger patients. Therefore, no dose adjustment is recommended in the elderly population. While clinical studies of linagliptin have not identified differences in response between the elderly and younger patients, greater sensitivity of some older individuals cannot be ruled out. ### Gender There is no FDA guidance on the use of Linagliptin with respect to specific gender populations. ### Race There is no FDA guidance on the use of Linagliptin with respect to specific racial populations. ### Renal Impairment - No dose adjustment is recommended for patients with renal impairment. ### Hepatic Impairment - No dose adjustment is recommended for patients with hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Linagliptin in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Linagliptin in patients who are immunocompromised. # Administration and Monitoring ### Administration - Oral ### Monitoring There is limited information regarding Monitoring of Linagliptin in the drug label. # IV Compatibility There is limited information regarding IV Compatibility of Linagliptin in the drug label. # Overdosage ## Acute Overdose ### Signs and Symptoms - During controlled clinical trials in healthy subjects, with single doses of up to 600 mg of TRADJENTA (equivalent to 120 times the recommended daily dose) there were no dose-related clinical adverse drug reactions. There is no experience with doses above 600 mg in humans. ### Management - In the event of an overdose with TRADJENTA, contact the Poison Control Center. Employ the usual supportive measures (e.g., remove unabsorbed material from the gastrointestinal tract, employ clinical monitoring, and institute supportive treatment) as dictated by the patient’s clinical status. Removal of linagliptin by hemodialysis or peritoneal dialysis is unlikely. ## Chronic Overdose There is limited information regarding Chronic Overdose of Linagliptin in the drug label. # Pharmacology ## Mechanism of Action - Linagliptin is an inhibitor of DPP-4, an enzyme that degrades the incretin hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). Thus, linagliptin increases the concentrations of active incretin hormones, stimulating the release of insulin in a glucose-dependent manner and decreasing the levels of glucagon in the circulation. Both incretin hormones are involved in the physiological regulation of glucose homeostasis. Incretin hormones are secreted at a low basal level throughout the day and levels rise immediately after meal intake. GLP-1 and GIP increase insulin biosynthesis and secretion from pancreatic beta-cells in the presence of normal and elevated blood glucose levels. Furthermore, GLP-1 also reduces glucagon secretion from pancreatic alpha-cells, resulting in a reduction in hepatic glucose output. ## Structure - TRADJENTA (linagliptin) tablets contain, as the active ingredient, an orally-active inhibitor of the dipeptidyl peptidase-4 (DPP-4) enzyme. - Linagliptin is described chemically as 1H-Purine-2,6-dione, 8--7-(2-butyn-1-yl)-3,7-dihydro-3-methyl-1-- - The empirical formula is C25H28N8O2 and the molecular weight is 472.54 g/mol. The structural formula is: - Linagliptin is a white to yellowish, not or only slightly hygroscopic solid substance. It is very slightly soluble in water (0.9 mg/mL). Linagliptin is soluble in methanol (ca. 60 mg/mL), sparingly soluble in ethanol (ca. 10 mg/mL), very slightly soluble in isopropanol (<;&lt1 mg/mL), and very slightly soluble in acetone (ca. 1 mg/mL). - Each film-coated tablet of TRADJENTA contains 5 mg of linagliptin free base and the following inactive ingredients: mannitol, pregelatinized starch, corn starch, copovidone, and magnesium stearate. In addition, the film coating contains the following inactive ingredients: hypromellose, titanium dioxide, talc, polyethylene glycol, and red ferric oxide. ## Pharmacodynamics - Linagliptin binds to DPP-4 in a reversible manner and thus increases the concentrations of incretin hormones. Linagliptin glucose dependently increases insulin secretion and lowers glucagon secretion, thus resulting in better regulation of glucose homeostasis. Linagliptin binds selectively to DPP-4, and selectively inhibits DPP-4 but not DPP-8 or DPP-9 activity in vitro at concentrations approximating therapeutic exposures. - Cardiac Electrophysiology - In a randomized, placebo-controlled, active-comparator, 4-way crossover study, 36 healthy subjects were administered a single oral dose of linagliptin 5 mg, linagliptin 100 mg (20 times the recommended dose), moxifloxacin, and placebo. No increase in QTc was observed with either the recommended dose of 5 mg or the 100-mg dose. At the 100-mg dose, peak linagliptin plasma concentrations were approximately 38-fold higher than the peak concentrations following a 5-mg dose. ## Pharmacokinetics - The pharmacokinetics of linagliptin has been characterized in healthy subjects and patients with type 2 diabetes. After oral administration of a single 5-mg dose to healthy subjects, peak plasma concentrations of linagliptin occurred at approximately 1.5 hours post dose (Tmax); the mean plasma area under the curve (AUC) was 139 nmol*h/L and maximum concentration (Cmax) was 8.9 nmol/L. - Plasma concentrations of linagliptin decline in at least a biphasic manner with a long terminal half-life (>100 hours), related to the saturable binding of linagliptin to DPP-4. The prolonged elimination phase does not contribute to the accumulation of the drug. The effective half-life for accumulation of linagliptin, as determined from oral administration of multiple doses of linagliptin 5 mg, is approximately 12 hours. After once-daily dosing, steady-state plasma concentrations of linagliptin 5 mg are reached by the third dose, and Cmax and AUC increased by a factor of 1.3 at steady state compared with the first dose. The intra-subject and inter-subject coefficients of variation for linagliptin AUC were small (12.6% and 28.5%, respectively). Plasma AUC of linagliptin increased in a less than dose-proportional manner in the dose range of 1 to 10 mg. The pharmacokinetics of linagliptin is similar in healthy subjects and in patients with type 2 diabetes. - Absorption - The absolute bioavailability of linagliptin is approximately 30%. High-fat meal reduced Cmax by 15% and increased AUC by 4%; this effect is not clinically relevant. TRADJENTA may be administered with or without food. - Distribution - The mean apparent volume of distribution at steady state following a single intravenous dose of linagliptin 5 mg to healthy subjects is approximately 1110 L, indicating that linagliptin extensively distributes to the tissues. Plasma protein binding of linagliptin is concentration-dependent, decreasing from about 99% at 1 nmol/L to 75%-89% at ≥30 nmol/L, reflecting saturation of binding to DPP-4 with increasing concentration of linagliptin. At high concentrations, where DPP-4 is fully saturated, 70% to 80% of linagliptin remains bound to plasma proteins and 20% to 30% is unbound in plasma. Plasma binding is not altered in patients with renal or hepatic impairment. - Metabolism - Following oral administration, the majority (about 90%) of linagliptin is excreted unchanged, indicating that metabolism represents a minor elimination pathway. A small fraction of absorbed linagliptin is metabolized to a pharmacologically inactive metabolite, which shows a steady-state exposure of 13.3% relative to linagliptin. - Excretion - Following administration of an oral -linagliptin dose to healthy subjects, approximately 85% of the administered radioactivity was eliminated via the enterohepatic system (80%) or urine (5%) within 4 days of dosing. Renal clearance at steady state was approximately 70 mL/min. - Specific Populations - Renal Impairment - An open-label pharmacokinetic study evaluated the pharmacokinetics of linagliptin 5 mg in male and female patients with varying degrees of chronic renal impairment. The study included 6 healthy subjects with normal renal function (creatinine clearance ≥80 mL/min), 6 patients with mild renal impairment (CrCl 50 to <80 mL/min), 6 patients with moderate renal impairment (CrCl 30 to <50 mL/min), 10 patients with type 2 diabetes mellitus and severe renal impairment (CrCl <30 mL/min), and 11 patients with type 2 diabetes mellitus and normal renal function. Creatinine clearance was measured by 24-hour urinary creatinine clearance measurements or estimated from serum creatinine based on the Cockcroft-Gault formula. - Under steady-state conditions, linagliptin exposure in patients with mild renal impairment was comparable to healthy subjects. - In patients with moderate renal impairment under steady-state conditions, mean exposure of linagliptin increased (AUCτ,ss by 71% and Cmax by 46%) compared with healthy subjects. This increase was not associated with a prolonged accumulation half-life, terminal half-life, or an increased accumulation factor. Renal excretion of linagliptin was below 5% of the administered dose and was not affected by decreased renal function. - Patients with type 2 diabetes mellitus and severe renal impairment showed steady-state exposure approximately 40% higher than that of patients with type 2 diabetes mellitus and normal renal function (increase in AUCτ,ss by 42% and Cmax by 35%). For both type 2 diabetes mellitus groups, renal excretion was below 7% of the administered dose. - These findings were further supported by the results of population pharmacokinetic analyses. - Hepatic Impairment - In patients with mild hepatic impairment (Child-Pugh class A), steady-state exposure (AUCτ,ss) of linagliptin was approximately 25% lower and Cmax,ss was approximately 36% lower than in healthy subjects. In patients with moderate hepatic impairment (Child-Pugh class B), AUCss of linagliptin was about 14% lower and Cmax,ss was approximately 8% lower than in healthy subjects. Patients with severe hepatic impairment (Child-Pugh class C) had comparable exposure of linagliptin in terms of AUC0-24 and approximately 23% lower Cmax compared with healthy subjects. Reductions in the pharmacokinetic parameters seen in patients with hepatic impairment did not result in reductions in DPP-4 inhibition. - Body Mass Index (BMI)/Weight - No dose adjustment is necessary based on BMI/weight. BMI/weight had no clinically meaningful effect on the pharmacokinetics of linagliptin based on a population pharmacokinetic analysis. - Gender - No dose adjustment is necessary based on gender. Gender had no clinically meaningful effect on the pharmacokinetics of linagliptin based on a population pharmacokinetic analysis. - Geriatric - Age did not have a clinically meaningful impact on the pharmacokinetics of linagliptin based on a population pharmacokinetic analysis. - Pediatric - Studies characterizing the pharmacokinetics of linagliptin in pediatric patients have not yet been performed. - Race - No dose adjustment is necessary based on race. Race had no clinically meaningful effect on the pharmacokinetics of linagliptin based on available pharmacokinetic data, including subjects of White, Hispanic, Black, and Asian racial groups. - Drug Interactions - In vitro Assessment of Drug Interactions - Linagliptin is a weak to moderate inhibitor of CYP isozyme CYP3A4, but does not inhibit other CYP isozymes and is not an inducer of CYP isozymes, including CYP1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, and 4A11. - Linagliptin is a P-glycoprotein (P-gp) substrate, and inhibits P-gp mediated transport of digoxin at high concentrations. Based on these results and in vivo drug interaction studies, linagliptin is considered unlikely to cause interactions with other P-gp substrates at therapeutic concentrations. - In vivo Assessment of Drug Interactions - Strong inducers of CYP3A4 or P-gp (e.g., rifampin) decrease exposure to linagliptin to subtherapeutic and likely ineffective concentrations. For patients requiring use of such drugs, an alternative to linagliptin is strongly recommended. In vivo studies indicated evidence of a low propensity for causing drug interactions with substrates of CYP3A4, CYP2C9, CYP2C8, P-gp and organic cationic transporter (OCT). No dose adjustment of TRADJENTA is recommended based on results of the described pharmacokinetic studies. ## Nonclinical Toxicology - Linagliptin did not increase the incidence of tumors in male and female rats in a 2-year study at doses of 6, 18, and 60 mg/kg. The highest dose of 60 mg/kg is approximately 418 times the clinical dose of 5 mg/day based on AUC exposure. Linagliptin did not increase the incidence of tumors in mice in a 2-year study at doses up to 80 mg/kg (males) and 25 mg/kg (females), or approximately 35- and 270-times the clinical dose based on AUC exposure. Higher doses of linagliptin in female mice (80 mg/kg) increased the incidence of lymphoma at approximately 215-times the clinical dose based on AUC exposure. - Linagliptin was not mutagenic or clastogenic with or without metabolic activation in the Ames bacterial mutagenicity assay, a chromosomal aberration test in human lymphocytes, and an in vivo micronucleus assay. - In fertility studies in rats, linagliptin had no adverse effects on early embryonic development, mating, fertility, or bearing live young up to the highest dose of 240 mg/kg (approximately 943-times the clinical dose based on AUC exposure). # Clinical Studies - TRADJENTA has been studied as monotherapy and in combination with metformin, glimepiride, pioglitazone, and insulin. - A total of 3648 patients with type 2 diabetes were randomized and exposed to linagliptin for at least 12 weeks in 10 double-blind, placebo-controlled clinical efficacy studies evaluating the effects of TRADJENTA on glycemic control. The overall ethnic/racial distribution in these studies was 69% White, 29% Asian, and 2.5% Black, and included 16% Hispanic/Latino patients. Fifty two percent of patients were male. Patients had an overall mean age of 57 years (range 20 to 91 years). In addition, an active (glimepiride)-controlled study of 104 weeks’ duration was conducted in 1551 patients with type 2 diabetes who had inadequate glycemic control on metformin, and a placebo-controlled study of 52 weeks’ duration was conducted in 133 patients with type 2 diabetes and severe chronic renal impairment (eGFR <30 mL/min). - In patients with type 2 diabetes, treatment with TRADJENTA produced clinically significant improvements in hemoglobin A1c (A1C), fasting plasma glucose (FPG), and 2-hour post-prandial glucose (PPG) compared with placebo. - A total of 730 patients with type 2 diabetes participated in 2 double-blind, placebo-controlled studies, one of 18 weeks’ and another of 24 weeks’ duration, to evaluate the efficacy and safety of TRADJENTA monotherapy. In both monotherapy studies, patients currently on an antihyperglycemic agent discontinued the agent and underwent a diet, exercise, and drug washout period of about 6 weeks that included an open-label placebo run-in during the last 2 weeks. Patients with inadequate glycemic control (A1C 7% to 10%) after the washout period were randomized; patients not currently on antihyperglycemic agents (off therapy for at least 8 weeks) with inadequate glycemic control (A1C 7% to 10%) were randomized after completing the 2-week, open-label, placebo run-in period. In the 18-week study, only patients ineligible for metformin were recruited. In the 18-week study, 76 patients were randomized to placebo and 151 to TRADJENTA 5 mg; in the 24-week study, 167 patients were randomized to placebo and 336 to TRADJENTA 5 mg. Patients who failed to meet specific glycemic goals during the 18-week study received rescue therapy with pioglitazone and/or insulin; metformin rescue therapy was used in the 24-week trial. - Treatment with TRADJENTA 5 mg daily provided statistically significant improvements in A1C, FPG, and 2-hour PPG compared with placebo (Table 4). In the 18-week study, 12% of patients receiving TRADJENTA 5 mg and 18% who received placebo required rescue therapy. In the 24-week study, 10.2% of patients receiving TRADJENTA 5 mg and 20.9% of patients receiving placebo required rescue therapy. The improvement in A1C compared with placebo was not affected by gender, age, race, prior antihyperglycemic therapy, baseline BMI, or a standard index of insulin resistance (HOMA-IR). As is typical for trials of agents to treat type 2 diabetes, the mean reduction in A1C with TRADJENTA appears to be related to the degree of A1C elevation at baseline. In these 18- and 24-week studies, the changes from baseline in A1C were -0.4% and -0.4%, respectively, for those given TRADJENTA, and 0.1% and 0.3%, respectively, for those given placebo. Change from baseline in body weight did not differ significantly between the groups. - Add-on Combination Therapy with Metformin - A total of 701 patients with type 2 diabetes participated in a 24-week, randomized, double-blind, placebo-controlled study designed to assess the efficacy of TRADJENTA in combination with metformin. Patients already on metformin (n = 491) at a dose of at least 1500 mg per day were randomized after completing a 2-week, open-label, placebo run-in period. Patients on metformin and another antihyperglycemic agent (n = 207) were randomized after a run-in period of approximately 6 weeks on metformin (at a dose of at least 1500 mg per day) in monotherapy. Patients were randomized to the addition of either TRADJENTA 5 mg or placebo, administered once daily. Patients who failed to meet specific glycemic goals during the studies were treated with glimepiride rescue. - In combination with metformin, TRADJENTA provided statistically significant improvements in A1C, FPG, and 2-hour PPG compared with placebo (Table 5). Rescue glycemic therapy was used in 7.8% of patients treated with TRADJENTA 5 mg and in 18.9% of patients treated with placebo. A similar decrease in body weight was observed for both treatment groups. - A total of 791 patients with type 2 diabetes mellitus and inadequate glycemic control on diet and exercise participated in the 24-week, randomized, double-blind, portion of this placebo-controlled factorial study designed to assess the efficacy of TRADJENTA as initial therapy with metformin. Patients on an antihyperglycemic agent (52%) underwent a drug washout period of 4 weeks’ duration. After the washout period and after completing a 2-week single-blind placebo run-in period, patients with inadequate glycemic control (A1C ≥7.0% to ≤10.5%) were randomized. Patients with inadequate glycemic control (A1C ≥7.5% to <11.0%) not on antihyperglycemic agents at study entry (48%) immediately entered the 2-week, single-blind, placebo run-in period and then were randomized. Randomization was stratified by baseline A1C (<8.5% vs ≥8.5%) and use of a prior oral antidiabetic drug (none vs monotherapy). Patients were randomized in a 1:2:2:2:2:2 ratio to either placebo or one of 5 active-treatment arms. Approximately equal numbers of patients were randomized to receive initial therapy with 5 mg of TRADJENTA once daily, 500 mg or 1000 mg of metformin twice daily, or 2.5 mg of linagliptin twice daily in combination with 500 mg or 1000 mg of metformin twice daily. Patients who failed to meet specific glycemic goals during the study were treated with sulfonylurea, thiazolidinedione, or insulin rescue therapy. - Initial therapy with the combination of linagliptin and metformin provided significant improvements in A1C and fasting plasma glucose (FPG) compared to placebo, to metformin alone, and to linagliptin alone (Table 6). - The adjusted mean treatment difference in A1C from baseline to week 24 (LOCF) was -0.5% (95% CI -0.7, -0.3; p<0.0001) for linagliptin 2.5 mg/metformin 1000 mg twice daily compared to metformin 1000 twice daily; -1.1% (95% CI -1.4, -0.9; p<0.0001) for linagliptin 2.5 mg/metformin 1000 mg twice daily compared to TRADJENTA 5 mg once daily; -0.6% (95% CI -0.8, -0.4; p<0.0001) for linagliptin 2.5 mg/metformin 500 mg twice daily compared to metformin 500 mg twice daily; and -0.8% (95% CI -1.0, -0.6; p<0.0001) for linagliptin 2.5 mg/metformin 500 mg twice daily compared to TRADJENTA 5 mg once daily. - Lipid effects were generally neutral. No meaningful change in body weight was noted in any of the 6 treatment groups. - The efficacy of TRADJENTA was evaluated in a 104-week, double-blind, glimepiride-controlled, non-inferiority study in patients with type 2 diabetes with insufficient glycemic control despite metformin therapy. Patients being treated with metformin only entered a run-in period of 2 weeks’ duration, whereas patients pretreated with metformin and one additional antihyperglycemic agent entered a run-in treatment period of 6 weeks’ duration with metformin monotherapy (dose of ≥1500 mg/day) and washout of the other agent. After an additional 2-week placebo run-in period, those with inadequate glycemic control (A1C 6.5% to 10%) were randomized 1:1 to the addition of TRADJENTA 5 mg once daily or glimepiride. Randomization was stratified by baseline HbA1c (<8.5% vs ≥8.5%), and the previous use of antidiabetic drugs (metformin alone vs metformin plus one other OAD). Patients receiving glimepiride were given an initial dose of 1 mg/day and then electively titrated over the next 12 weeks to a maximum dose of 4 mg/day as needed to optimize glycemic control. Thereafter, the glimepiride dose was to be kept constant, except for down-titration to prevent hypoglycemia. - After 52 and 104 weeks, TRADJENTA and glimepiride both had reductions from baseline in A1C (52 weeks: -0.4% for TRADJENTA, -0.6% for glimepiride; 104 weeks: -0.2% for TRADJENTA, -0.4% for glimepiride) from a baseline mean of 7.7% (Table 7). The mean difference between groups in A1C change from baseline was 0.2% with 2-sided 97.5% confidence interval (0.1%, 0.3%) for the intent-to-treat population using last observation carried forward. These results were consistent with the completers analysis. - Patients treated with linagliptin had a mean baseline body weight of 86 kg and were observed to have an adjusted mean decrease in body weight of 1.1 kg at 52 weeks and 1.4 kg at 104 weeks. Patients on glimepiride had a mean baseline body weight of 87 kg and were observed to have an adjusted mean increase from baseline in body weight of 1.4 kg at 52 weeks and 1.3 kg at 104 weeks (treatment difference p<0.0001 for both timepoints). - A total of 389 patients with type 2 diabetes participated in a 24-week, randomized, double-blind, placebo-controlled study designed to assess the efficacy of TRADJENTA in combination with pioglitazone. Therapy was stopped in patients on oral antihyperglycemic therapy for a period of 6 weeks (4 weeks followed by a 2-week, open-label, placebo run-in period). Drug-naïve patients entered directly into the 2-week placebo run-in period. After the run-in period, patients were randomized to receive either TRADJENTA 5 mg or placebo, both in addition to pioglitazone 30 mg daily. Patients who failed to meet specific glycemic goals during the studies were treated with metformin rescue. Glycemic endpoints measured were A1C and FPG. - In initial combination with pioglitazone 30 mg, TRADJENTA 5 mg provided statistically significant improvements in A1C and FPG compared to placebo with pioglitazone (Table 8). Rescue therapy was used in 7.9% of patients treated with TRADJENTA 5 mg/pioglitazone 30 mg and 14.1% of patients treated with placebo/pioglitazone 30 mg. Patient weight increased in both groups during the study with an adjusted mean change from baseline of 2.3 kg and 1.2 kg in the TRADJENTA 5 mg/pioglitazone 30 mg and placebo/pioglitazone 30 mg groups, respectively (p = 0.0141). - A total of 245 patients with type 2 diabetes participated in an 18-week, randomized, double-blind, placebo-controlled study designed to assess the efficacy of TRADJENTA in combination with sulfonylurea (SU). Patients on sulfonylurea monotherapy (n = 142) were randomized after completing a 2-week, single-blind, placebo run-in period. Patients on a sulfonylurea plus one additional oral antihyperglycemic agent (n = 103) were randomized after a wash-out period of 4 weeks and a 2-week, single-blind, placebo run-in period. Patients were randomized to the addition of TRADJENTA 5 mg or to placebo, each administered once daily. Patients who failed to meet specific glycemic goals during the studies were treated with metformin rescue. Glycemic endpoints measured included A1C and FPG. - In combination with a sulfonylurea, TRADJENTA provided statistically significant improvements in A1C compared with placebo following 18 weeks’ treatment; the improvements in FPG observed with TRADJENTA were not statistically significant compared with placebo (Table 9). Rescue therapy was used in 7.6% of patients treated with TRADJENTA 5 mg and 15.9% of patients treated with placebo. There was no significant difference between TRADJENTA and placebo in body weight. - A total of 1058 patients with type 2 diabetes participated in a 24-week, randomized, double-blind, placebo-controlled study designed to assess the efficacy of TRADJENTA in combination with a sulfonylurea and metformin. The most common sulfonylureas used by patients in the study were: glimepiride (31%), glibenclamide (26%), and gliclazide (26%, not available in the United States). Patients on a sulfonylurea and metformin were randomized to receive TRADJENTA 5 mg or placebo, each administered once daily. Patients who failed to meet specific glycemic goals during the study were treated with pioglitazone rescue. Glycemic endpoints measured included A1C and FPG. - In combination with a sulfonylurea and metformin, TRADJENTA provided statistically significant improvements in A1C and FPG compared with placebo (Table 10). In the entire study population (patients on TRADJENTA in combination with sulfonylurea and metformin), a mean reduction from baseline relative to placebo in A1C of -0.6% and in FPG of -13 mg/dL was seen. Rescue therapy was used in 5.4% of patients treated with TRADJENTA 5 mg and in 13% of patients treated with placebo. Change from baseline in body weight did not differ significantly between the groups. - A total of 1261 patients with type 2 diabetes inadequately controlled on basal insulin alone or basal insulin in combination with oral drugs participated in a randomized, double-blind placebo-controlled trial designed to evaluate the efficacy of TRADJENTA as add-on therapy to basal insulin over 24 weeks. Randomization was stratified by baseline HbA1c (7% and <10% were included in the study including 709 patients with renal impairment (eGFR <90 mL/min), most of whom (n=575) were categorized as mild renal impairment (eGFR 60 to <90 mL/min). Patients entered a 2 week placebo run-in period on basal insulin (e.g., insulin glargine, insulin detemir, or NPH insulin) with or without metformin and/or pioglitazone background therapy. Following the run-in period, patients with inadequate glycemic control were randomized to the addition of either 5 mg of TRADJENTA or placebo, administered once daily. Patients were maintained on a stable dose of insulin prior to enrollment, during the run-in period, and during the first 24 weeks of treatment. Patients who failed to meet specific glycemic goals during the double-blind treatment period were rescued by increasing background insulin dose. - TRADJENTA used in combination with insulin (with or without metformin and/or pioglitazone), provided statistically significant improvements in A1C and FPG compared to placebo (Table 11) after 24 weeks of treatment. The mean total daily insulin dose at baseline was 42 units for patients treated with TRADJENTA and 40 units for patients treated with placebo. Background baseline diabetes therapy included use of: insulin alone (16.1%), insulin combined with metformin only (75.5%), insulin combined with metformin and pioglitazone (7.4%), and insulin combined with pioglitazone only (1%). The mean change from baseline to Week 24 in the daily dose of insulin was +1.3 IU in the placebo group and +0.6 IU in the TRADJENTA group. The mean change in body weight from baseline to Week 24 was similar in the two treatment groups. The rate of hypoglycemia, defined as all symptomatic or asymptomatic episodes with a self measured blood glucose was also similar in both groups (21.4% TRADJENTA; 22.9% placebo) in the first 24 weeks of the study. - The difference between treatment with linagliptin and placebo in terms of adjusted mean change from baseline in HbA1c after 24 weeks was comparable for patients with no renal impairment (eGFR ≥90 mL/min, n=539), with mild renal impairment (eGFR 60 to <90 mL/min, n= 565), or with moderate renal impairment (eGFR 30 to <60 mL/min, n=124). - A total of 133 patients with type 2 diabetes participated in a 52 week, double-blind, randomized, placebo-controlled trial designed to evaluate the efficacy and safety of TRADJENTA in patients with both type 2 diabetes and severe chronic renal impairment. Participants with an estimated (based on the four variables modified diet in renal disease equation) GFR value of 8%) and background antidiabetic therapy (insulin or any combination with insulin, SU or glinides as monotherapy and pioglitazone or any other antidiabetics excluding any other DPP-4 inhibitors). For the initial 12 weeks of the study, background antidiabetic therapy was kept stable and included insulin, sulfonylurea, glinides, and pioglitazone. For the remainder of the trial, dose adjustments in antidiabetic background therapy were allowed. At baseline in this trial, 62.5% of patients were receiving insulin alone as background diabetes therapy, and 12.5% were receiving sulfonylurea alone. - After 12 weeks of treatment, TRADJENTA 5 mg provided statistically significant improvement in A1C compared to placebo, with an adjusted mean change of -0.6% compared to placebo (95% confidence interval -0.9, -0.3) based on the analysis using last observation carried forward (LOCF). With adjustments in antidiabetic background therapy after the initial 12 weeks, efficacy was maintained for 52 weeks, with an adjusted mean change from baseline in A1C of -0.7% compared to placebo (95% confidence interval -1.0, -0.4) based on analysis using LOCF. # How Supplied - TRADJENTA tablets are available as light red, round, biconvex, bevel-edged, film-coated tablets containing 5 mg of linagliptin. TRADJENTA tablets are debossed with “D5” on one side and the Boehringer Ingelheim logo on the other side. - They are supplied as follows: - Bottles of 30 (NDC 0597-0140-30) - Bottles of 90 (NDC 0597-0140-90) - Cartons containing 10 blister cards of 10 tablets each (10 x 10) (NDC 0597-0140-61), institutional pack. - If repackaging is required, dispense in a tight container as defined in USP. - Storage - Store at 25°C (77°F); excursions permitted to 15°-30°C (59°-86°F). Store in a safe place out of reach of children. ## Storage There is limited information regarding Linagliptin Storage in the drug label. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information - Inform patients of the potential risks and benefits of TRADJENTA and of alternative modes of therapy. Also inform patients about the importance of adherence to dietary instructions, regular physical activity, periodic blood glucose monitoring and A1C testing, recognition and management of hypoglycemia and hyperglycemia, and assessment for diabetes complications. Advise patients to seek medical advice promptly during periods of stress such as fever, trauma, infection, or surgery, as medication requirements may change. - Inform patients that acute pancreatitis has been reported during postmarketing use of TRADJENTA. Inform patients that persistent severe abdominal pain, sometimes radiating to the back, which may or may not be accompanied by vomiting, is the hallmark symptom of acute pancreatitis. Instruct patients to discontinue TRADJENTA promptly and contact their physician if persistent severe abdominal pain occurs. - Inform patients that the incidence of hypoglycemia is increased when TRADJENTA is added to a sulfonylurea or insulin and that a lower dose of the sulfonylurea or insulin may be required to reduce the risk of hypoglycemia. - Inform patients that serious allergic reactions, such as anaphylaxis, angioedema, and exfoliative skin conditions, have been reported during postmarketing use of TRADJENTA. If symptoms of allergic reactions (such as rash, skin flaking or peeling, urticaria, swelling of the skin, or swelling of the face, lips, tongue, and throat that may cause difficulty in breathing or swallowing) occur, patients must stop taking TRADJENTA and seek medical advice promptly. - Instruct patients to take TRADJENTA only as prescribed. If a dose is missed, advise patients not to double their next dose. - Instruct patients to read the Medication Guide before starting TRADJENTA therapy and to reread it each time the prescription is renewed. Instruct patients to inform their doctor or pharmacist if they develop any unusual symptom, or if any known symptom persists or worsens. - Inform patients that response to all diabetic therapies should be monitored by periodic measurements of blood glucose and A1C levels, with a goal of decreasing these levels toward the normal range. A1C monitoring is especially useful for evaluating long-term glycemic control. # Precautions with Alcohol - Alcohol-Linagliptin interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - TRADJENTA® # Look-Alike Drug Names There is limited information regarding Linagliptin Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	Linagliptin 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 Linagliptin is a dipeptidyl peptidase-4 (DPP-4) inhibitor that is FDA approved for the {{{indicationType}}} of type 2 diabetes mellitus. Common adverse reactions include hypoglycemia and nasopharyngitis. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) - Dosing Information - TRADJENTA tablets are indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. - The recommended dose of TRADJENTA is 5 mg once daily. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Linagliptin in adult patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Linagliptin in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) There is limited information regarding FDA-Labeled Use of Linagliptin in pediatric patients. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Linagliptin in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Linagliptin in pediatric patients. # Contraindications - TRADJENTA is contraindicated in patients with a history of a hypersensitivity reaction to linagliptin, such as anaphylaxis, angioedema, exfoliative skin conditions, urticaria, or bronchial hyperreactivity. # Warnings ### Precautions - Pancreatitis - There have been postmarketing reports of acute pancreatitis, including fatal pancreatitis, in patients taking TRADJENTA. Take careful notice of potential signs and symptoms of pancreatitis. If pancreatitis is suspected, promptly discontinue TRADJENTA and initiate appropriate management. It is unknown whether patients with a history of pancreatitis are at increased risk for the development of pancreatitis while using TRADJENTA. - Use with Medications Known to Cause Hypoglycemia - Insulin secretagogues and insulin are known to cause hypoglycemia. The use of TRADJENTA in combination with an insulin secretagogue (e.g., sulfonylurea) was associated with a higher rate of hypoglycemia compared with placebo in a clinical trial. The use of TRADJENTA in combination with insulin in subjects with severe renal impairment was associated with a higher rate of hypoglycemia. Therefore, a lower dose of the insulin secretagogue or insulin may be required to reduce the risk of hypoglycemia when used in combination with TRADJENTA. - Hypersensitivity Reactions - There have been postmarketing reports of serious hypersensitivity reactions in patients treated with TRADJENTA. These reactions include anaphylaxis, angioedema, and exfoliative skin conditions. Onset of these reactions occurred within the first 3 months after initiation of treatment with TRADJENTA, with some reports occurring after the first dose. If a serious hypersensitivity reaction is suspected, discontinue TRADJENTA, assess for other potential causes for the event, and institute alternative treatment for diabetes. - Angioedema has also been reported with other dipeptidyl peptidase-4 (DPP-4) inhibitors. Use caution in a patient with a history of angioedema to another DPP-4 inhibitor because it is unknown whether such patients will be predisposed to angioedema with TRADJENTA. - Macrovascular Outcomes - There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with TRADJENTA tablets or any other antidiabetic drug # 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 practice. - The safety evaluation of TRADJENTA 5 mg once daily in patients with type 2 diabetes is based on 14 placebo-controlled trials, 1 active-controlled study, and one study in patients with severe renal impairment. In the 14 placebo-controlled studies, a total of 3625 patients were randomized and treated with TRADJENTA 5 mg daily and 2176 with placebo. The mean exposure in patients treated with TRADJENTA across studies was 29.6 weeks. The maximum follow-up was 78 weeks. - TRADJENTA 5 mg once daily was studied as monotherapy in three placebo-controlled trials of 18 and 24 weeks’ duration and in five additional placebo-controlled studies lasting ≤18 weeks. The use of TRADJENTA in combination with other antihyperglycemic agents was studied in six placebo-controlled trials: two with metformin (12 and 24 weeks’ treatment duration); one with a sulfonylurea (18 weeks’ treatment duration); one with metformin and sulfonylurea (24 weeks’ treatment duration); one with pioglitazone (24 weeks’ treatment duration); and one with insulin (primary endpoint at 24 weeks). - In a pooled dataset of 14 placebo-controlled clinical trials, adverse reactions that occurred in ≥2% of patients receiving TRADJENTA (n = 3625) and more commonly than in patients given placebo (n = 2176), are shown in Table 1. The overall incidence of adverse events with TRADJENTA were similar to placebo. - Rates for other adverse reactions for TRADJENTA 5 mg vs placebo when TRADJENTA was used in combination with specific anti-diabetic agents were: urinary tract infection (3.1% vs 0%) and hypertriglyceridemia (2.4% vs 0%) when TRADJENTA was used as add-on to sulfonylurea; hyperlipidemia (2.7% vs 0.8%) and weight increased (2.3% vs 0.8%) when TRADJENTA was used as add-on to pioglitazone; and constipation (2.1% vs 1%) when TRADJENTA was used as add-on to basal insulin therapy. - Following 104 weeks’ treatment in a controlled study comparing TRADJENTA with glimepiride in which all patients were also receiving metformin, adverse reactions reported in ≥5% of patients treated with TRADJENTA (n = 776) and more frequently than in patients treated with a sulfonylurea (n = 775) were back pain (9.1% vs 8.4%), arthralgia (8.1% vs 6.1%), upper respiratory tract infection (8.0% vs 7.6%), headache (6.4% vs 5.2%), cough (6.1% vs 4.9%), and pain in extremity (5.3% vs 3.9%). - Other adverse reactions reported in clinical studies with treatment of TRADJENTA were hypersensitivity (e.g., urticaria, angioedema, localized skin exfoliation, or bronchial hyperreactivity), and myalgia. In the clinical trial program, pancreatitis was reported in 15.2 cases per 10,000 patient year exposure while being treated with TRADJENTA compared with 3.7 cases per 10,000 patient year exposure while being treated with comparator (placebo and active comparator, sulfonylurea). Three additional cases of pancreatitis were reported following the last administered dose of linagliptin. - Hypoglycemia - In the placebo-controlled studies, 199 (6.6%) of the total 2994 patients treated with TRADJENTA 5 mg reported hypoglycemia compared to 56 patients (3.6%) of 1546 placebo-treated patients. The incidence of hypoglycemia was similar to placebo when TRADJENTA was administered as monotherapy or in combination with metformin, or with pioglitazone. When TRADJENTA was administered in combination with metformin and a sulfonylurea, 181 of 792 (22.9%) patients reported hypoglycemia compared with 39 of 263 (14.8%) patients administered placebo in combination with metformin and a sulfonylurea. Adverse reactions of hypoglycemia were based on all reports of hypoglycemia. A concurrent glucose measurement was not required or was normal in some patients. Therefore, it is not possible to conclusively determine that all these reports reflect true hypoglycemia. - In the study of patients receiving TRADJENTA as add-on therapy to a stable dose of insulin for up to 52 weeks (n=1261), no significant difference in the incidence of investigator reported hypoglycemia, defined as all symptomatic or asymptomatic episodes with a self measured blood glucose ≤70 mg/dL, was noted between the TRADJENTA- (31.4%) and placebo- (32.9%) treated groups. During the same time period, severe hypoglycemic events, defined as requiring the assistance of another person to actively administer carbohydrate, glucagon or other resuscitative actions, were reported in 11 (1.7%) of TRADJENTA treated patients and 7 (1.1%) of placebo treated patients. Events that were considered life-threatening or required hospitalization were reported in 3 (0.5%) patients on TRADJENTA and 1 (0.2%) on placebo. - Use in Renal Impairment - ADJENTA was compared to placebo as add-on to pre-existing antidiabetic therapy over 52 weeks in 133 patients with severe renal impairment (estimated GFR <;&lt30 mL/min). For the initial 12 weeks of the study, background antidiabetic therapy was kept stable and included insulin, sulfonylurea, glinides, and pioglitazone. For the remainder of the trial, dose adjustments in antidiabetic background therapy were allowed. - In general, the incidence of adverse events including severe hypoglycemia was similar to those reported in other TRADJENTA trials. The observed incidence of hypoglycemia was higher (TRADJENTA, 63% compared to placebo, 49%) due to an increase in asymptomatic hypoglycemic events especially during the first 12 weeks when background glycemic therapies were kept stable. Ten TRADJENTA-treated patients (15%) and 11 placebo-treated patients (17%) reported at least one episode of confirmed symptomatic hypoglycemia (accompanying finger stick glucose ≤54 mg/dL). During the same time period, severe hypoglycemic events, defined as an event requiring the assistance of another person to actively administer carbohydrate, glucagon or other resuscitative actions, were reported in 3 (4.4%) TRADJENTA-treated patients and 3 (4.6%) placebo-treated patients. Events that were considered life-threatening or required hospitalization were reported in 2 (2.9%) patients on TRADJENTA and 1 (1.5%) patient on placebo. - Renal function as measured by mean eGFR and creatinine clearance did not change over 52 weeks’ treatment compared to placebo. ## Postmarketing Experience - Additional adverse reactions have been identified during postapproval use of TRADJENTA. Because these reactions 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. - Acute pancreatitis, including fatal pancreatitis. - Hypersensitivity reactions including anaphylaxis, angioedema, and exfoliative skin conditions. - Rash. # Drug Interactions - Inducers of P-glycoprotein or CYP3A4 Enzymes - Rifampin decreased linagliptin exposure, suggesting that the efficacy of TRADJENTA may be reduced when administered in combination with a strong P-gp or CYP3A4 inducer. Therefore, use of alternative treatments is strongly recommended when linagliptin is to be administered with a strong P-gp or CYP3A4 inducer. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): - Pregnancy Category B - Reproduction studies have been performed in rats and rabbits. There are, however, 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. - Linagliptin administered during the period of organogenesis was not teratogenic at doses up to 30 mg/kg in the rat and 150 mg/kg in the rabbit, or approximately 49 and 1943 times the clinical dose based on AUC exposure. Doses of linagliptin causing maternal toxicity in the rat and the rabbit also caused developmental delays in skeletal ossification and slightly increased embryofetal loss in the rat (1000 times the clinical dose) and increased fetal resorptions and visceral and skeletal variations in the rabbit (1943 times the clinical dose). - Linagliptin administered to female rats from gestation day 6 to lactation day 21 resulted in decreased body weight and delays in physical and behavioral development in male and female offspring at maternally toxic doses (exposures >1000 times the clinical dose). No functional, behavioral, or reproductive toxicity was observed in offspring of rats exposed to 49 times the clinical dose. - Linagliptin crossed the placenta into the fetus following oral dosing in pregnant rats and rabbits. Pregnancy Category (AUS): - Australian Drug Evaluation Committee (ADEC) Pregnancy Category There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Linagliptin in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Linagliptin during labor and delivery. ### Nursing Mothers - Available animal data have shown excretion of linagliptin in milk at a milk-to-plasma ratio of 4:1. 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 TRADJENTA is administered to a nursing woman. ### Pediatric Use - Safety and effectiveness of TRADJENTA in pediatric patients under 18 years of age have not been established. ### Geriatic Use - There were 4040 type 2 diabetes patients treated with linagliptin 5 mg from 15 clinical trials of TRADJENTA; 1085 (27%) were 65 years and over, while 131 (3%) were 75 years and over. Of these patients, 2566 were enrolled in 12 double-blind placebo-controlled studies; 591 (23%) were 65 years and over, while 82 (3%) were 75 years and over. No overall differences in safety or effectiveness were observed between patients 65 years and over and younger patients. Therefore, no dose adjustment is recommended in the elderly population. While clinical studies of linagliptin have not identified differences in response between the elderly and younger patients, greater sensitivity of some older individuals cannot be ruled out. ### Gender There is no FDA guidance on the use of Linagliptin with respect to specific gender populations. ### Race There is no FDA guidance on the use of Linagliptin with respect to specific racial populations. ### Renal Impairment - No dose adjustment is recommended for patients with renal impairment. ### Hepatic Impairment - No dose adjustment is recommended for patients with hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Linagliptin in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Linagliptin in patients who are immunocompromised. # Administration and Monitoring ### Administration - Oral ### Monitoring There is limited information regarding Monitoring of Linagliptin in the drug label. # IV Compatibility There is limited information regarding IV Compatibility of Linagliptin in the drug label. # Overdosage ## Acute Overdose ### Signs and Symptoms - During controlled clinical trials in healthy subjects, with single doses of up to 600 mg of TRADJENTA (equivalent to 120 times the recommended daily dose) there were no dose-related clinical adverse drug reactions. There is no experience with doses above 600 mg in humans. ### Management - In the event of an overdose with TRADJENTA, contact the Poison Control Center. Employ the usual supportive measures (e.g., remove unabsorbed material from the gastrointestinal tract, employ clinical monitoring, and institute supportive treatment) as dictated by the patient’s clinical status. Removal of linagliptin by hemodialysis or peritoneal dialysis is unlikely. ## Chronic Overdose There is limited information regarding Chronic Overdose of Linagliptin in the drug label. # Pharmacology ## Mechanism of Action - Linagliptin is an inhibitor of DPP-4, an enzyme that degrades the incretin hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). Thus, linagliptin increases the concentrations of active incretin hormones, stimulating the release of insulin in a glucose-dependent manner and decreasing the levels of glucagon in the circulation. Both incretin hormones are involved in the physiological regulation of glucose homeostasis. Incretin hormones are secreted at a low basal level throughout the day and levels rise immediately after meal intake. GLP-1 and GIP increase insulin biosynthesis and secretion from pancreatic beta-cells in the presence of normal and elevated blood glucose levels. Furthermore, GLP-1 also reduces glucagon secretion from pancreatic alpha-cells, resulting in a reduction in hepatic glucose output. ## Structure - TRADJENTA (linagliptin) tablets contain, as the active ingredient, an orally-active inhibitor of the dipeptidyl peptidase-4 (DPP-4) enzyme. - Linagliptin is described chemically as 1H-Purine-2,6-dione, 8-[(3R)-3-amino-1-piperidinyl]-7-(2-butyn-1-yl)-3,7-dihydro-3-methyl-1-[(4-methyl-2-quinazolinyl)methyl]- - The empirical formula is C25H28N8O2 and the molecular weight is 472.54 g/mol. The structural formula is: - Linagliptin is a white to yellowish, not or only slightly hygroscopic solid substance. It is very slightly soluble in water (0.9 mg/mL). Linagliptin is soluble in methanol (ca. 60 mg/mL), sparingly soluble in ethanol (ca. 10 mg/mL), very slightly soluble in isopropanol (<;&lt1 mg/mL), and very slightly soluble in acetone (ca. 1 mg/mL). - Each film-coated tablet of TRADJENTA contains 5 mg of linagliptin free base and the following inactive ingredients: mannitol, pregelatinized starch, corn starch, copovidone, and magnesium stearate. In addition, the film coating contains the following inactive ingredients: hypromellose, titanium dioxide, talc, polyethylene glycol, and red ferric oxide. ## Pharmacodynamics - Linagliptin binds to DPP-4 in a reversible manner and thus increases the concentrations of incretin hormones. Linagliptin glucose dependently increases insulin secretion and lowers glucagon secretion, thus resulting in better regulation of glucose homeostasis. Linagliptin binds selectively to DPP-4, and selectively inhibits DPP-4 but not DPP-8 or DPP-9 activity in vitro at concentrations approximating therapeutic exposures. - Cardiac Electrophysiology - In a randomized, placebo-controlled, active-comparator, 4-way crossover study, 36 healthy subjects were administered a single oral dose of linagliptin 5 mg, linagliptin 100 mg (20 times the recommended dose), moxifloxacin, and placebo. No increase in QTc was observed with either the recommended dose of 5 mg or the 100-mg dose. At the 100-mg dose, peak linagliptin plasma concentrations were approximately 38-fold higher than the peak concentrations following a 5-mg dose. ## Pharmacokinetics - The pharmacokinetics of linagliptin has been characterized in healthy subjects and patients with type 2 diabetes. After oral administration of a single 5-mg dose to healthy subjects, peak plasma concentrations of linagliptin occurred at approximately 1.5 hours post dose (Tmax); the mean plasma area under the curve (AUC) was 139 nmol*h/L and maximum concentration (Cmax) was 8.9 nmol/L. - Plasma concentrations of linagliptin decline in at least a biphasic manner with a long terminal half-life (>100 hours), related to the saturable binding of linagliptin to DPP-4. The prolonged elimination phase does not contribute to the accumulation of the drug. The effective half-life for accumulation of linagliptin, as determined from oral administration of multiple doses of linagliptin 5 mg, is approximately 12 hours. After once-daily dosing, steady-state plasma concentrations of linagliptin 5 mg are reached by the third dose, and Cmax and AUC increased by a factor of 1.3 at steady state compared with the first dose. The intra-subject and inter-subject coefficients of variation for linagliptin AUC were small (12.6% and 28.5%, respectively). Plasma AUC of linagliptin increased in a less than dose-proportional manner in the dose range of 1 to 10 mg. The pharmacokinetics of linagliptin is similar in healthy subjects and in patients with type 2 diabetes. - Absorption - The absolute bioavailability of linagliptin is approximately 30%. High-fat meal reduced Cmax by 15% and increased AUC by 4%; this effect is not clinically relevant. TRADJENTA may be administered with or without food. - Distribution - The mean apparent volume of distribution at steady state following a single intravenous dose of linagliptin 5 mg to healthy subjects is approximately 1110 L, indicating that linagliptin extensively distributes to the tissues. Plasma protein binding of linagliptin is concentration-dependent, decreasing from about 99% at 1 nmol/L to 75%-89% at ≥30 nmol/L, reflecting saturation of binding to DPP-4 with increasing concentration of linagliptin. At high concentrations, where DPP-4 is fully saturated, 70% to 80% of linagliptin remains bound to plasma proteins and 20% to 30% is unbound in plasma. Plasma binding is not altered in patients with renal or hepatic impairment. - Metabolism - Following oral administration, the majority (about 90%) of linagliptin is excreted unchanged, indicating that metabolism represents a minor elimination pathway. A small fraction of absorbed linagliptin is metabolized to a pharmacologically inactive metabolite, which shows a steady-state exposure of 13.3% relative to linagliptin. - Excretion - Following administration of an oral [14C]-linagliptin dose to healthy subjects, approximately 85% of the administered radioactivity was eliminated via the enterohepatic system (80%) or urine (5%) within 4 days of dosing. Renal clearance at steady state was approximately 70 mL/min. - Specific Populations - Renal Impairment - An open-label pharmacokinetic study evaluated the pharmacokinetics of linagliptin 5 mg in male and female patients with varying degrees of chronic renal impairment. The study included 6 healthy subjects with normal renal function (creatinine clearance [CrCl] ≥80 mL/min), 6 patients with mild renal impairment (CrCl 50 to <80 mL/min), 6 patients with moderate renal impairment (CrCl 30 to <50 mL/min), 10 patients with type 2 diabetes mellitus and severe renal impairment (CrCl <30 mL/min), and 11 patients with type 2 diabetes mellitus and normal renal function. Creatinine clearance was measured by 24-hour urinary creatinine clearance measurements or estimated from serum creatinine based on the Cockcroft-Gault formula. - Under steady-state conditions, linagliptin exposure in patients with mild renal impairment was comparable to healthy subjects. - In patients with moderate renal impairment under steady-state conditions, mean exposure of linagliptin increased (AUCτ,ss by 71% and Cmax by 46%) compared with healthy subjects. This increase was not associated with a prolonged accumulation half-life, terminal half-life, or an increased accumulation factor. Renal excretion of linagliptin was below 5% of the administered dose and was not affected by decreased renal function. - Patients with type 2 diabetes mellitus and severe renal impairment showed steady-state exposure approximately 40% higher than that of patients with type 2 diabetes mellitus and normal renal function (increase in AUCτ,ss by 42% and Cmax by 35%). For both type 2 diabetes mellitus groups, renal excretion was below 7% of the administered dose. - These findings were further supported by the results of population pharmacokinetic analyses. - Hepatic Impairment - In patients with mild hepatic impairment (Child-Pugh class A), steady-state exposure (AUCτ,ss) of linagliptin was approximately 25% lower and Cmax,ss was approximately 36% lower than in healthy subjects. In patients with moderate hepatic impairment (Child-Pugh class B), AUCss of linagliptin was about 14% lower and Cmax,ss was approximately 8% lower than in healthy subjects. Patients with severe hepatic impairment (Child-Pugh class C) had comparable exposure of linagliptin in terms of AUC0-24 and approximately 23% lower Cmax compared with healthy subjects. Reductions in the pharmacokinetic parameters seen in patients with hepatic impairment did not result in reductions in DPP-4 inhibition. - Body Mass Index (BMI)/Weight - No dose adjustment is necessary based on BMI/weight. BMI/weight had no clinically meaningful effect on the pharmacokinetics of linagliptin based on a population pharmacokinetic analysis. - Gender - No dose adjustment is necessary based on gender. Gender had no clinically meaningful effect on the pharmacokinetics of linagliptin based on a population pharmacokinetic analysis. - Geriatric - Age did not have a clinically meaningful impact on the pharmacokinetics of linagliptin based on a population pharmacokinetic analysis. - Pediatric - Studies characterizing the pharmacokinetics of linagliptin in pediatric patients have not yet been performed. - Race - No dose adjustment is necessary based on race. Race had no clinically meaningful effect on the pharmacokinetics of linagliptin based on available pharmacokinetic data, including subjects of White, Hispanic, Black, and Asian racial groups. - Drug Interactions - In vitro Assessment of Drug Interactions - Linagliptin is a weak to moderate inhibitor of CYP isozyme CYP3A4, but does not inhibit other CYP isozymes and is not an inducer of CYP isozymes, including CYP1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, and 4A11. - Linagliptin is a P-glycoprotein (P-gp) substrate, and inhibits P-gp mediated transport of digoxin at high concentrations. Based on these results and in vivo drug interaction studies, linagliptin is considered unlikely to cause interactions with other P-gp substrates at therapeutic concentrations. - In vivo Assessment of Drug Interactions - Strong inducers of CYP3A4 or P-gp (e.g., rifampin) decrease exposure to linagliptin to subtherapeutic and likely ineffective concentrations. For patients requiring use of such drugs, an alternative to linagliptin is strongly recommended. In vivo studies indicated evidence of a low propensity for causing drug interactions with substrates of CYP3A4, CYP2C9, CYP2C8, P-gp and organic cationic transporter (OCT). No dose adjustment of TRADJENTA is recommended based on results of the described pharmacokinetic studies. ## Nonclinical Toxicology - Linagliptin did not increase the incidence of tumors in male and female rats in a 2-year study at doses of 6, 18, and 60 mg/kg. The highest dose of 60 mg/kg is approximately 418 times the clinical dose of 5 mg/day based on AUC exposure. Linagliptin did not increase the incidence of tumors in mice in a 2-year study at doses up to 80 mg/kg (males) and 25 mg/kg (females), or approximately 35- and 270-times the clinical dose based on AUC exposure. Higher doses of linagliptin in female mice (80 mg/kg) increased the incidence of lymphoma at approximately 215-times the clinical dose based on AUC exposure. - Linagliptin was not mutagenic or clastogenic with or without metabolic activation in the Ames bacterial mutagenicity assay, a chromosomal aberration test in human lymphocytes, and an in vivo micronucleus assay. - In fertility studies in rats, linagliptin had no adverse effects on early embryonic development, mating, fertility, or bearing live young up to the highest dose of 240 mg/kg (approximately 943-times the clinical dose based on AUC exposure). # Clinical Studies - TRADJENTA has been studied as monotherapy and in combination with metformin, glimepiride, pioglitazone, and insulin. - A total of 3648 patients with type 2 diabetes were randomized and exposed to linagliptin for at least 12 weeks in 10 double-blind, placebo-controlled clinical efficacy studies evaluating the effects of TRADJENTA on glycemic control. The overall ethnic/racial distribution in these studies was 69% White, 29% Asian, and 2.5% Black, and included 16% Hispanic/Latino patients. Fifty two percent of patients were male. Patients had an overall mean age of 57 years (range 20 to 91 years). In addition, an active (glimepiride)-controlled study of 104 weeks’ duration was conducted in 1551 patients with type 2 diabetes who had inadequate glycemic control on metformin, and a placebo-controlled study of 52 weeks’ duration was conducted in 133 patients with type 2 diabetes and severe chronic renal impairment (eGFR <30 mL/min). - In patients with type 2 diabetes, treatment with TRADJENTA produced clinically significant improvements in hemoglobin A1c (A1C), fasting plasma glucose (FPG), and 2-hour post-prandial glucose (PPG) compared with placebo. - A total of 730 patients with type 2 diabetes participated in 2 double-blind, placebo-controlled studies, one of 18 weeks’ and another of 24 weeks’ duration, to evaluate the efficacy and safety of TRADJENTA monotherapy. In both monotherapy studies, patients currently on an antihyperglycemic agent discontinued the agent and underwent a diet, exercise, and drug washout period of about 6 weeks that included an open-label placebo run-in during the last 2 weeks. Patients with inadequate glycemic control (A1C 7% to 10%) after the washout period were randomized; patients not currently on antihyperglycemic agents (off therapy for at least 8 weeks) with inadequate glycemic control (A1C 7% to 10%) were randomized after completing the 2-week, open-label, placebo run-in period. In the 18-week study, only patients ineligible for metformin were recruited. In the 18-week study, 76 patients were randomized to placebo and 151 to TRADJENTA 5 mg; in the 24-week study, 167 patients were randomized to placebo and 336 to TRADJENTA 5 mg. Patients who failed to meet specific glycemic goals during the 18-week study received rescue therapy with pioglitazone and/or insulin; metformin rescue therapy was used in the 24-week trial. - Treatment with TRADJENTA 5 mg daily provided statistically significant improvements in A1C, FPG, and 2-hour PPG compared with placebo (Table 4). In the 18-week study, 12% of patients receiving TRADJENTA 5 mg and 18% who received placebo required rescue therapy. In the 24-week study, 10.2% of patients receiving TRADJENTA 5 mg and 20.9% of patients receiving placebo required rescue therapy. The improvement in A1C compared with placebo was not affected by gender, age, race, prior antihyperglycemic therapy, baseline BMI, or a standard index of insulin resistance (HOMA-IR). As is typical for trials of agents to treat type 2 diabetes, the mean reduction in A1C with TRADJENTA appears to be related to the degree of A1C elevation at baseline. In these 18- and 24-week studies, the changes from baseline in A1C were -0.4% and -0.4%, respectively, for those given TRADJENTA, and 0.1% and 0.3%, respectively, for those given placebo. Change from baseline in body weight did not differ significantly between the groups. - Add-on Combination Therapy with Metformin - A total of 701 patients with type 2 diabetes participated in a 24-week, randomized, double-blind, placebo-controlled study designed to assess the efficacy of TRADJENTA in combination with metformin. Patients already on metformin (n = 491) at a dose of at least 1500 mg per day were randomized after completing a 2-week, open-label, placebo run-in period. Patients on metformin and another antihyperglycemic agent (n = 207) were randomized after a run-in period of approximately 6 weeks on metformin (at a dose of at least 1500 mg per day) in monotherapy. Patients were randomized to the addition of either TRADJENTA 5 mg or placebo, administered once daily. Patients who failed to meet specific glycemic goals during the studies were treated with glimepiride rescue. - In combination with metformin, TRADJENTA provided statistically significant improvements in A1C, FPG, and 2-hour PPG compared with placebo (Table 5). Rescue glycemic therapy was used in 7.8% of patients treated with TRADJENTA 5 mg and in 18.9% of patients treated with placebo. A similar decrease in body weight was observed for both treatment groups. - A total of 791 patients with type 2 diabetes mellitus and inadequate glycemic control on diet and exercise participated in the 24-week, randomized, double-blind, portion of this placebo-controlled factorial study designed to assess the efficacy of TRADJENTA as initial therapy with metformin. Patients on an antihyperglycemic agent (52%) underwent a drug washout period of 4 weeks’ duration. After the washout period and after completing a 2-week single-blind placebo run-in period, patients with inadequate glycemic control (A1C ≥7.0% to ≤10.5%) were randomized. Patients with inadequate glycemic control (A1C ≥7.5% to <11.0%) not on antihyperglycemic agents at study entry (48%) immediately entered the 2-week, single-blind, placebo run-in period and then were randomized. Randomization was stratified by baseline A1C (<8.5% vs ≥8.5%) and use of a prior oral antidiabetic drug (none vs monotherapy). Patients were randomized in a 1:2:2:2:2:2 ratio to either placebo or one of 5 active-treatment arms. Approximately equal numbers of patients were randomized to receive initial therapy with 5 mg of TRADJENTA once daily, 500 mg or 1000 mg of metformin twice daily, or 2.5 mg of linagliptin twice daily in combination with 500 mg or 1000 mg of metformin twice daily. Patients who failed to meet specific glycemic goals during the study were treated with sulfonylurea, thiazolidinedione, or insulin rescue therapy. - Initial therapy with the combination of linagliptin and metformin provided significant improvements in A1C and fasting plasma glucose (FPG) compared to placebo, to metformin alone, and to linagliptin alone (Table 6). - The adjusted mean treatment difference in A1C from baseline to week 24 (LOCF) was -0.5% (95% CI -0.7, -0.3; p<0.0001) for linagliptin 2.5 mg/metformin 1000 mg twice daily compared to metformin 1000 twice daily; -1.1% (95% CI -1.4, -0.9; p<0.0001) for linagliptin 2.5 mg/metformin 1000 mg twice daily compared to TRADJENTA 5 mg once daily; -0.6% (95% CI -0.8, -0.4; p<0.0001) for linagliptin 2.5 mg/metformin 500 mg twice daily compared to metformin 500 mg twice daily; and -0.8% (95% CI -1.0, -0.6; p<0.0001) for linagliptin 2.5 mg/metformin 500 mg twice daily compared to TRADJENTA 5 mg once daily. - Lipid effects were generally neutral. No meaningful change in body weight was noted in any of the 6 treatment groups. - The efficacy of TRADJENTA was evaluated in a 104-week, double-blind, glimepiride-controlled, non-inferiority study in patients with type 2 diabetes with insufficient glycemic control despite metformin therapy. Patients being treated with metformin only entered a run-in period of 2 weeks’ duration, whereas patients pretreated with metformin and one additional antihyperglycemic agent entered a run-in treatment period of 6 weeks’ duration with metformin monotherapy (dose of ≥1500 mg/day) and washout of the other agent. After an additional 2-week placebo run-in period, those with inadequate glycemic control (A1C 6.5% to 10%) were randomized 1:1 to the addition of TRADJENTA 5 mg once daily or glimepiride. Randomization was stratified by baseline HbA1c (<8.5% vs ≥8.5%), and the previous use of antidiabetic drugs (metformin alone vs metformin plus one other OAD). Patients receiving glimepiride were given an initial dose of 1 mg/day and then electively titrated over the next 12 weeks to a maximum dose of 4 mg/day as needed to optimize glycemic control. Thereafter, the glimepiride dose was to be kept constant, except for down-titration to prevent hypoglycemia. - After 52 and 104 weeks, TRADJENTA and glimepiride both had reductions from baseline in A1C (52 weeks: -0.4% for TRADJENTA, -0.6% for glimepiride; 104 weeks: -0.2% for TRADJENTA, -0.4% for glimepiride) from a baseline mean of 7.7% (Table 7). The mean difference between groups in A1C change from baseline was 0.2% with 2-sided 97.5% confidence interval (0.1%, 0.3%) for the intent-to-treat population using last observation carried forward. These results were consistent with the completers analysis. - Patients treated with linagliptin had a mean baseline body weight of 86 kg and were observed to have an adjusted mean decrease in body weight of 1.1 kg at 52 weeks and 1.4 kg at 104 weeks. Patients on glimepiride had a mean baseline body weight of 87 kg and were observed to have an adjusted mean increase from baseline in body weight of 1.4 kg at 52 weeks and 1.3 kg at 104 weeks (treatment difference p<0.0001 for both timepoints). - A total of 389 patients with type 2 diabetes participated in a 24-week, randomized, double-blind, placebo-controlled study designed to assess the efficacy of TRADJENTA in combination with pioglitazone. Therapy was stopped in patients on oral antihyperglycemic therapy for a period of 6 weeks (4 weeks followed by a 2-week, open-label, placebo run-in period). Drug-naïve patients entered directly into the 2-week placebo run-in period. After the run-in period, patients were randomized to receive either TRADJENTA 5 mg or placebo, both in addition to pioglitazone 30 mg daily. Patients who failed to meet specific glycemic goals during the studies were treated with metformin rescue. Glycemic endpoints measured were A1C and FPG. - In initial combination with pioglitazone 30 mg, TRADJENTA 5 mg provided statistically significant improvements in A1C and FPG compared to placebo with pioglitazone (Table 8). Rescue therapy was used in 7.9% of patients treated with TRADJENTA 5 mg/pioglitazone 30 mg and 14.1% of patients treated with placebo/pioglitazone 30 mg. Patient weight increased in both groups during the study with an adjusted mean change from baseline of 2.3 kg and 1.2 kg in the TRADJENTA 5 mg/pioglitazone 30 mg and placebo/pioglitazone 30 mg groups, respectively (p = 0.0141). - A total of 245 patients with type 2 diabetes participated in an 18-week, randomized, double-blind, placebo-controlled study designed to assess the efficacy of TRADJENTA in combination with sulfonylurea (SU). Patients on sulfonylurea monotherapy (n = 142) were randomized after completing a 2-week, single-blind, placebo run-in period. Patients on a sulfonylurea plus one additional oral antihyperglycemic agent (n = 103) were randomized after a wash-out period of 4 weeks and a 2-week, single-blind, placebo run-in period. Patients were randomized to the addition of TRADJENTA 5 mg or to placebo, each administered once daily. Patients who failed to meet specific glycemic goals during the studies were treated with metformin rescue. Glycemic endpoints measured included A1C and FPG. - In combination with a sulfonylurea, TRADJENTA provided statistically significant improvements in A1C compared with placebo following 18 weeks’ treatment; the improvements in FPG observed with TRADJENTA were not statistically significant compared with placebo (Table 9). Rescue therapy was used in 7.6% of patients treated with TRADJENTA 5 mg and 15.9% of patients treated with placebo. There was no significant difference between TRADJENTA and placebo in body weight. - A total of 1058 patients with type 2 diabetes participated in a 24-week, randomized, double-blind, placebo-controlled study designed to assess the efficacy of TRADJENTA in combination with a sulfonylurea and metformin. The most common sulfonylureas used by patients in the study were: glimepiride (31%), glibenclamide (26%), and gliclazide (26%, not available in the United States). Patients on a sulfonylurea and metformin were randomized to receive TRADJENTA 5 mg or placebo, each administered once daily. Patients who failed to meet specific glycemic goals during the study were treated with pioglitazone rescue. Glycemic endpoints measured included A1C and FPG. - In combination with a sulfonylurea and metformin, TRADJENTA provided statistically significant improvements in A1C and FPG compared with placebo (Table 10). In the entire study population (patients on TRADJENTA in combination with sulfonylurea and metformin), a mean reduction from baseline relative to placebo in A1C of -0.6% and in FPG of -13 mg/dL was seen. Rescue therapy was used in 5.4% of patients treated with TRADJENTA 5 mg and in 13% of patients treated with placebo. Change from baseline in body weight did not differ significantly between the groups. - A total of 1261 patients with type 2 diabetes inadequately controlled on basal insulin alone or basal insulin in combination with oral drugs participated in a randomized, double-blind placebo-controlled trial designed to evaluate the efficacy of TRADJENTA as add-on therapy to basal insulin over 24 weeks. Randomization was stratified by baseline HbA1c (<;&lt8.5% vs ≥8.5%), renal function impairment status (based on baseline eGFR), and concomitant use of oral antidiabetic drugs (none, metformin only, pioglitazone only, metformin + pioglitazone). Patients with a baseline A1C of >7% and <10% were included in the study including 709 patients with renal impairment (eGFR <90 mL/min), most of whom (n=575) were categorized as mild renal impairment (eGFR 60 to <90 mL/min). Patients entered a 2 week placebo run-in period on basal insulin (e.g., insulin glargine, insulin detemir, or NPH insulin) with or without metformin and/or pioglitazone background therapy. Following the run-in period, patients with inadequate glycemic control were randomized to the addition of either 5 mg of TRADJENTA or placebo, administered once daily. Patients were maintained on a stable dose of insulin prior to enrollment, during the run-in period, and during the first 24 weeks of treatment. Patients who failed to meet specific glycemic goals during the double-blind treatment period were rescued by increasing background insulin dose. - TRADJENTA used in combination with insulin (with or without metformin and/or pioglitazone), provided statistically significant improvements in A1C and FPG compared to placebo (Table 11) after 24 weeks of treatment. The mean total daily insulin dose at baseline was 42 units for patients treated with TRADJENTA and 40 units for patients treated with placebo. Background baseline diabetes therapy included use of: insulin alone (16.1%), insulin combined with metformin only (75.5%), insulin combined with metformin and pioglitazone (7.4%), and insulin combined with pioglitazone only (1%). The mean change from baseline to Week 24 in the daily dose of insulin was +1.3 IU in the placebo group and +0.6 IU in the TRADJENTA group. The mean change in body weight from baseline to Week 24 was similar in the two treatment groups. The rate of hypoglycemia, defined as all symptomatic or asymptomatic episodes with a self measured blood glucose was also similar in both groups (21.4% TRADJENTA; 22.9% placebo) in the first 24 weeks of the study. - The difference between treatment with linagliptin and placebo in terms of adjusted mean change from baseline in HbA1c after 24 weeks was comparable for patients with no renal impairment (eGFR ≥90 mL/min, n=539), with mild renal impairment (eGFR 60 to <90 mL/min, n= 565), or with moderate renal impairment (eGFR 30 to <60 mL/min, n=124). - A total of 133 patients with type 2 diabetes participated in a 52 week, double-blind, randomized, placebo-controlled trial designed to evaluate the efficacy and safety of TRADJENTA in patients with both type 2 diabetes and severe chronic renal impairment. Participants with an estimated (based on the four variables modified diet in renal disease [MDRD] equation) GFR value of <;&lt30 mL/min were eligible to participate in the study. Randomization was stratified by baseline HbA1c (≤8% and >8%) and background antidiabetic therapy (insulin or any combination with insulin, SU or glinides as monotherapy and pioglitazone or any other antidiabetics excluding any other DPP-4 inhibitors). For the initial 12 weeks of the study, background antidiabetic therapy was kept stable and included insulin, sulfonylurea, glinides, and pioglitazone. For the remainder of the trial, dose adjustments in antidiabetic background therapy were allowed. At baseline in this trial, 62.5% of patients were receiving insulin alone as background diabetes therapy, and 12.5% were receiving sulfonylurea alone. - After 12 weeks of treatment, TRADJENTA 5 mg provided statistically significant improvement in A1C compared to placebo, with an adjusted mean change of -0.6% compared to placebo (95% confidence interval -0.9, -0.3) based on the analysis using last observation carried forward (LOCF). With adjustments in antidiabetic background therapy after the initial 12 weeks, efficacy was maintained for 52 weeks, with an adjusted mean change from baseline in A1C of -0.7% compared to placebo (95% confidence interval -1.0, -0.4) based on analysis using LOCF. # How Supplied - TRADJENTA tablets are available as light red, round, biconvex, bevel-edged, film-coated tablets containing 5 mg of linagliptin. TRADJENTA tablets are debossed with “D5” on one side and the Boehringer Ingelheim logo on the other side. - They are supplied as follows: - Bottles of 30 (NDC 0597-0140-30) - Bottles of 90 (NDC 0597-0140-90) - Cartons containing 10 blister cards of 10 tablets each (10 x 10) (NDC 0597-0140-61), institutional pack. - If repackaging is required, dispense in a tight container as defined in USP. - Storage - Store at 25°C (77°F); excursions permitted to 15°-30°C (59°-86°F). Store in a safe place out of reach of children. ## Storage There is limited information regarding Linagliptin Storage in the drug label. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information - Inform patients of the potential risks and benefits of TRADJENTA and of alternative modes of therapy. Also inform patients about the importance of adherence to dietary instructions, regular physical activity, periodic blood glucose monitoring and A1C testing, recognition and management of hypoglycemia and hyperglycemia, and assessment for diabetes complications. Advise patients to seek medical advice promptly during periods of stress such as fever, trauma, infection, or surgery, as medication requirements may change. - Inform patients that acute pancreatitis has been reported during postmarketing use of TRADJENTA. Inform patients that persistent severe abdominal pain, sometimes radiating to the back, which may or may not be accompanied by vomiting, is the hallmark symptom of acute pancreatitis. Instruct patients to discontinue TRADJENTA promptly and contact their physician if persistent severe abdominal pain occurs. - Inform patients that the incidence of hypoglycemia is increased when TRADJENTA is added to a sulfonylurea or insulin and that a lower dose of the sulfonylurea or insulin may be required to reduce the risk of hypoglycemia. - Inform patients that serious allergic reactions, such as anaphylaxis, angioedema, and exfoliative skin conditions, have been reported during postmarketing use of TRADJENTA. If symptoms of allergic reactions (such as rash, skin flaking or peeling, urticaria, swelling of the skin, or swelling of the face, lips, tongue, and throat that may cause difficulty in breathing or swallowing) occur, patients must stop taking TRADJENTA and seek medical advice promptly. - Instruct patients to take TRADJENTA only as prescribed. If a dose is missed, advise patients not to double their next dose. - Instruct patients to read the Medication Guide before starting TRADJENTA therapy and to reread it each time the prescription is renewed. Instruct patients to inform their doctor or pharmacist if they develop any unusual symptom, or if any known symptom persists or worsens. - Inform patients that response to all diabetic therapies should be monitored by periodic measurements of blood glucose and A1C levels, with a goal of decreasing these levels toward the normal range. A1C monitoring is especially useful for evaluating long-term glycemic control. # Precautions with Alcohol - Alcohol-Linagliptin interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - TRADJENTA®[1] # Look-Alike Drug Names There is limited information regarding Linagliptin Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	https://www.wikidoc.org/index.php/Linagliptin
946d6964eba907bcfa8904ebe765a3d40f3ff880	wikidoc	Linda Peeno	Linda Peeno Linda Peeno is a physician, ethicist and lecturer from Louisville, Kentucky known for being a whistleblower for the United States managed healthcare industry. Following employment as a medical reviewer for Humana and medical director at Blue Cross/Blue Shield Health Plans, she became a critic of how U.S. HMOs drive profits through denial of care. On May 30, 1996, Peeno testified before Congress as to the downside of managed care. In the 2002 Showtime docudrama Damaged Care, Laura Dern portrayed Peeno as she transitioned from health care industry employee to whistleblower. In 2007, Peeno was prominently featured in the Michael Moore movie Sicko, which included portions of her May 1996 appearance before Congress. On June 28, 2007, in a statement about Sicko, Humana declared that Peeno was never a Humana associate, but rather a "part-time contractor". Humana also disputed the portions of Congressional testimony that were shown by saying that because the patient's specific healthcare plan didn't cover heart transplants, the denial of coverage was valid.	Linda Peeno Linda Peeno is a physician, ethicist and lecturer from Louisville, Kentucky known for being a whistleblower for the United States managed healthcare industry. Following employment as a medical reviewer for Humana and medical director at Blue Cross/Blue Shield Health Plans, she became a critic of how U.S. HMOs drive profits through denial of care. On May 30, 1996, Peeno testified before Congress as to the downside of managed care.[1] In the 2002 Showtime docudrama Damaged Care, Laura Dern portrayed Peeno as she transitioned from health care industry employee to whistleblower. In 2007, Peeno was prominently featured in the Michael Moore movie Sicko, which included portions of her May 1996 appearance before Congress. On June 28, 2007, in a statement about Sicko, Humana declared that Peeno was never a Humana associate, but rather a "part-time contractor". Humana also disputed the portions of Congressional testimony that were shown by saying that because the patient's specific healthcare plan didn't cover heart transplants, the denial of coverage was valid.[2]	https://www.wikidoc.org/index.php/Linda_Peeno
58a166379292f4359656554ebd2ea0e0a19000df	wikidoc	Linda Sloan	Linda Sloan Linda Sloan is a Canadian politician and current municipal councillor in Edmonton, Alberta. Sloan graduated from the Foothills Hospital School of Nursing in 1982 and began work as a registered nurse. She soon became involved in the Staff Nurses Associations of Alberta (which she led from 1992 until 1997), the National Federation of Nurses Unions, and the Alberta Association of Registered Nurses. In 1997, she ran for the Legislative Assembly of Alberta in the riding of Edmonton Riverview as a candidate for the Liberal Party of Alberta. She defeated her closest rival, Progressive Conservative Gwen Harris by more than 900 votes. While in the legislature, Sloan served as Liberal opposition critic for social services, child welfare, and disability programs. In this capacity, she supported extending adoption rights to homosexual couples and sponsored a private member's bill calling for the creation of a children's advocate who would report directly to the legislature. When Liberal leader Grant Mitchell resigned in 1998, Sloan became one of four candidates to replace him. Nancy MacBeth won on the first ballot. Sloan declined to seek re-election in 2001, and ran for city council in 2004. She finished second of nine candidates in Ward 1 (behind incumbent councillor and Sloan's former Liberal caucus colleague Karen Leibovici) and was elected. While on city council, she has served as councillor responsible for the Senior Citizens portfolio. Linda Sloan is married with two children.	Linda Sloan Linda Sloan is a Canadian politician and current municipal councillor in Edmonton, Alberta. Sloan graduated from the Foothills Hospital School of Nursing in 1982 and began work as a registered nurse.[1] She soon became involved in the Staff Nurses Associations of Alberta (which she led from 1992 until 1997), the National Federation of Nurses Unions, and the Alberta Association of Registered Nurses.[2] In 1997, she ran for the Legislative Assembly of Alberta in the riding of Edmonton Riverview as a candidate for the Liberal Party of Alberta.[3] She defeated her closest rival, Progressive Conservative Gwen Harris by more than 900 votes. While in the legislature, Sloan served as Liberal opposition critic for social services, child welfare, and disability programs.[4] In this capacity, she supported extending adoption rights to homosexual couples and sponsored a private member's bill calling for the creation of a children's advocate who would report directly to the legislature.[5][6] When Liberal leader Grant Mitchell resigned in 1998, Sloan became one of four candidates to replace him.[7] Nancy MacBeth won on the first ballot. Sloan declined to seek re-election in 2001, and ran for city council in 2004.[8] She finished second of nine candidates in Ward 1 (behind incumbent councillor and Sloan's former Liberal caucus colleague Karen Leibovici) and was elected.[9] While on city council, she has served as councillor responsible for the Senior Citizens portfolio.[10] Linda Sloan is married with two children.[11] Template:Start box Template:Succession box Template:End box # External links - Linda Sloan profile Edmonton City Council # Sources - ↑ http://www.edmonton.ca/portal/server.pt/gateway/PTARGS_0_0_265_210_0_43/http%3B/CMSServer/COEWeb/linda+sloan/Linda+Sloan+Career+Highlights.htm - ↑ http://www.edmonton.ca/portal/server.pt/gateway/PTARGS_0_0_265_210_0_43/http%3B/CMSServer/COEWeb/linda+sloan/Linda+Sloan+Career+Highlights.htm - ↑ http://www.electionsalberta.ab.ca/1997election.html - ↑ http://www.assembly.ab.ca/ISYS/LADDAR_files%5Cdocs%5Chouserecords%5Ctb%5Clegislature_24%5Csession_3%5C19990216_1200_01_tb.pdf - ↑ http://www.planetout.com/news/article-print.html?1999/03/25/3 - ↑ http://www.teachers.ab.ca/Albertas+Education+System/Eye+on+Education+in+Alberta/Bills+and+Motions/1999.htm - ↑ http://www.teachers.ab.ca/Quick+Links/Publications/ATA+News/Volume+32/Number+9/In+the+News/Leave+private+school+funding+as+is+say+Liberal+leadership+candidates.htm - ↑ http://www.mapleleafweb.com/articles/districtwatch.shtml - ↑ http://www.edmonton.ca/portal/server.pt/gateway/PTARGS_0_0_383_214_0_43/http%3B/CMSServer/NR/rdonlyres/0D03078A-FCEF-4349-8FF7-EC13C830EE9A/23138/Councillorward1.doc - ↑ http://www.lindasloan.com/ - ↑ http://www.edmonton.ca/portal/server.pt/gateway/PTARGS_0_2_265_210_0_43/http;/CMSServer/COEWeb/linda%20sloan/	https://www.wikidoc.org/index.php/Linda_Sloan
29e1a184eeb80c90c40b384395f14d0480297302	wikidoc	Linea negra	Linea negra # Overview Linea negra (Latin for "black line") also known as Linea nigra is a dark vertical line that appears on the abdomen during pregnancy. # Pathophysiology It is a type of hyperpigmentation resulting from increased production of the pigment melanin thought to be caused by increased estrogen, the same process that causes the areolas to darken. Why this process of hyperpigmentation occurs on the midline of the abdomen is uncertain. Fair-skinned women show this symptom less often than women with darker pigmentation. Before it appears it may be more faintly visible as a linea alba ("white line"). # Epidemiology and demographics Linea nigra tends to appear around the second trimester. Some research suggests there may be a link between linea nigra and insulin. # Diagnosis ## Signs and symptoms The brownish streak is usually about a centimeter in width. The line runs vertically along the midline of the abdomen from the pubis to the xiphoid process — the bottom-most part of the rib cage in the center or tip of the sternum. # Treatment No treatment is required. Supplementing the diet with folic acid is said to reduce the discoloration. After birth, the line fades slowly, but may never disappear entirely, and sun exposure may cause it to recur.	Linea negra Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview Linea negra (Latin for "black line") also known as Linea nigra is a dark vertical line that appears on the abdomen during pregnancy. # Pathophysiology It is a type of hyperpigmentation resulting from increased production of the pigment melanin thought to be caused by increased estrogen, the same process that causes the areolas to darken.[1] Why this process of hyperpigmentation occurs on the midline of the abdomen is uncertain. Fair-skinned women show this symptom less often than women with darker pigmentation. Before it appears it may be more faintly visible as a linea alba ("white line"). # Epidemiology and demographics Linea nigra tends to appear around the second trimester. Some research suggests there may be a link between linea nigra and insulin. # Diagnosis ## Signs and symptoms The brownish streak is usually about a centimeter in width. The line runs vertically along the midline of the abdomen from the pubis to the xiphoid process — the bottom-most part of the rib cage in the center or tip of the sternum. # Treatment No treatment is required. Supplementing the diet with folic acid is said to reduce the discoloration. After birth, the line fades slowly, but may never disappear entirely, and sun exposure may cause it to recur.[1]	https://www.wikidoc.org/index.php/Linea_negra
724aae81aa8be540a799f1e9fb4520d8d32c116e	wikidoc	Linseed oil	Linseed oil Linseed oil, also known as flax seed oil, is a yellowish drying oil derived from the dried ripe seeds of the flax plant (Linum usitatissimum, Linaceae). It is obtained by pressing, followed by an optional stage of solvent extraction. Cold-pressed oil obtained without solvent extraction is marketed as flaxseed oil. # Uses ## Nutritional supplement If it is very fresh, refrigerated and unprocessed, linseed oil is suitable for human consumption, and is used as a nutritional supplement. It is rich in omega-3 fatty acids, especially alpha-linolenic acid, which appears to be beneficial for preventing heart disease, inflammatory bowel disease, arthritis and a variety of other health conditions. Regular flaxseed oil contains between 52 and 63 % alpha linolenic acid (C18:3 n-3). Plant breeders have developed flaxseed with high alpha linolenic acid content (70 %) and very low alpha linoleic acid content (< 3%). Flaxseed also contains a group of chemicals called lignans that may play a role in the prevention of cancer. ## Paint binder Linseed oil is the most commonly used carrier in oil paint. It can also be used as a painting medium, making oil paints more fluid, transparent and glossy. It is available in varieties such as Cold Pressed, alkali refined, sun Bleached, sun thickened, and polymerised (stand oil). ## Wood finish When used as a wood finish, linseed oil does not cover the surface as varnish does, but soaks into the (visible and microscopic) pores, leaving a shiny but not glossy surface that shows off the grain. Wood treated with linseed oil not only is resistant to denting, and scratches are easily repaired, but the wood and oil surface is not as hard as a modern varnish, and it slowly absorbs moisture if allowed to stay wet. Soft wood benefits from the protection from denting but requires more applications and even more drying time than harder wood does, if the grain is to be completely filled. The oil penetrates deeply and fills the grain, because it dries slowly and shrinks little or not at all on hardening. Like other oil finishes Garden furniture treated with linseed oil may develop Mildew. Linseed oil is not completely denatured, so it can encourage rather than discourage mildew growth. Oiled wood is yellowish and darkens with age. It is a traditional finish for gun stocks, however a very fine finish may require months to obtain. ## Additional uses - Animal feeds - Putty - Sealants - Caulking compounds - Brake linings - Linoleum - Earthen floors - Adobe - Textiles - Bicycle maintenance as a thread fixative, rust inhibitor and lubricant - Foundry products - Leather treatment - Polishes, varnishes and oil paints - Composition ornament for moulded decoration - Animal care products - Wood preservation - Synthetic resins - Industrial Lubricant - Treatment for the raw willow wood used to make cricket bats. Linseed oil has a special cultural place in cricket-playing countries. # Boiled linseed oil Boiled linseed oil is used as a paint binder or as a wood finish on its own. Heating the oil makes it polymerize and oxidize, effectively making it thicker and shortening the drying time. Today most products labeled as "boiled linseed oil" are a combination of raw linseed oil, petroleum-based solvent and metallic dryers. The use of metallic dryers makes boiled linseed oil inedible. There are some products available that contain only heat-treated linseed oil, without exposure to oxygen. Heat treated linseed oil is thicker and dries very slowly. These are usually labeled as "polymerized" or "stand" oils, though some may still be labeled as boiled. # Spontaneous combustion Rags dampened with boiled linseed oil are a fire hazard, because they provide a large surface area for oxidation of the oil. The oxidation is an exothermic reaction which accelerates as the rags get hotter. Such rags should be washed, soaked with water or incinerated to avoid unexpected spontaneous combustion. # Nutrient content Nutrition information from a typical commercially available flaxseed oil:. It should be noted that linseed oil has a very high concentration of phytoestrogens. Per 1 Tbsp (14 g) - Calories: 130 - Calories from fat:130 - Total fat: 14g - Omega-3: 8g - Omega-6: 2g - Omega-9: 3g	Linseed oil Linseed oil, also known as flax seed oil, is a yellowish drying oil derived from the dried ripe seeds of the flax plant (Linum usitatissimum, Linaceae). It is obtained by pressing, followed by an optional stage of solvent extraction. Cold-pressed oil obtained without solvent extraction is marketed as flaxseed oil. # Uses ## Nutritional supplement If it is very fresh, refrigerated and unprocessed, linseed oil is suitable for human consumption, and is used as a nutritional supplement. It is rich in omega-3 fatty acids, especially alpha-linolenic acid, which appears to be beneficial for preventing heart disease, inflammatory bowel disease, arthritis and a variety of other health conditions.[citation needed] Regular flaxseed oil contains between 52 and 63 % alpha linolenic acid (C18:3 n-3). Plant breeders have developed flaxseed with high alpha linolenic acid content (70 %)[1] and very low alpha linoleic acid content (< 3%).[2] Flaxseed also contains a group of chemicals called lignans that may play a role in the prevention of cancer.[3] ## Paint binder Linseed oil is the most commonly used carrier in oil paint. It can also be used as a painting medium, making oil paints more fluid, transparent and glossy. It is available in varieties such as Cold Pressed, alkali refined, sun Bleached, sun thickened, and polymerised (stand oil). ## Wood finish When used as a wood finish, linseed oil does not cover the surface as varnish does, but soaks into the (visible and microscopic) pores, leaving a shiny but not glossy surface that shows off the grain. Wood treated with linseed oil not only is resistant to denting, and scratches are easily repaired, but the wood and oil surface is not as hard as a modern varnish, and it slowly absorbs moisture if allowed to stay wet. Soft wood benefits from the protection from denting but requires more applications and even more drying time than harder wood does, if the grain is to be completely filled. The oil penetrates deeply and fills the grain, because it dries slowly and shrinks little or not at all on hardening. Like other oil finishes Garden furniture treated with linseed oil may develop Mildew. Linseed oil is not completely denatured, so it can encourage rather than discourage mildew growth. Oiled wood is yellowish and darkens with age. It is a traditional finish for gun stocks, however a very fine finish may require months to obtain. ## Additional uses - Animal feeds - Putty - Sealants - Caulking compounds - Brake linings - Linoleum - Earthen floors - Adobe - Textiles - Bicycle maintenance as a thread fixative, rust inhibitor and lubricant - Foundry products - Leather treatment - Polishes, varnishes and oil paints - Composition ornament for moulded decoration - Animal care products - Wood preservation - Synthetic resins - Industrial Lubricant - Treatment for the raw willow wood used to make cricket bats. Linseed oil has a special cultural place in cricket-playing countries. # Boiled linseed oil Boiled linseed oil is used as a paint binder or as a wood finish on its own. Heating the oil makes it polymerize and oxidize, effectively making it thicker and shortening the drying time. Today most products labeled as "boiled linseed oil" are a combination of raw linseed oil, petroleum-based solvent and metallic dryers. The use of metallic dryers makes boiled linseed oil inedible. There are some products available that contain only heat-treated linseed oil, without exposure to oxygen. Heat treated linseed oil is thicker and dries very slowly. These are usually labeled as "polymerized" or "stand" oils, though some may still be labeled as boiled. # Spontaneous combustion Rags dampened with boiled linseed oil are a fire hazard, because they provide a large surface area for oxidation of the oil. The oxidation is an exothermic reaction which accelerates as the rags get hotter. Such rags should be washed, soaked with water or incinerated to avoid unexpected spontaneous combustion. # Nutrient content Nutrition information from a typical commercially available flaxseed oil:[citation needed]. It should be noted that linseed oil has a very high concentration of phytoestrogens. Per 1 Tbsp (14 g) - Calories: 130 - Calories from fat:130 - Total fat: 14g - Omega-3: 8g - Omega-6: 2g - Omega-9: 3g	https://www.wikidoc.org/index.php/Linseed_oil
ec7e31072c4f903315a159768bdd4419dc556dc7	wikidoc	Lipocalin-2	Lipocalin-2 Lipocalin-2 (LCN2), also known as oncogene 24p3 or neutrophil gelatinase-associated lipocalin (NGAL), is a protein that in humans is encoded by the LCN2 gene. NGAL is involved in innate immunity by sequestrating iron that in turn limits bacterial growth. It is expressed in neutrophils and in low levels in the kidney, prostate, and epithelia of the respiratory and alimentary tracts. NGAL is used as a biomarker of kidney injury. # Function The binding of NGAL to bacterial siderophores is important in the innate immune response to bacterial infection. Upon encountering invading bacteria the toll-like receptors on immune cells stimulate the synthesis and secretion of NGAL. Secreted NGAL then limits bacterial growth by sequestering iron-containing siderophores. Lipocalin-2 binds, next to bacterial siderophores, also to the mammalian siderophore 2,5-dihydroxybenzoic acid (2,5-DHBA). This complex ensures that excess free iron does not accumulate in the cytoplasm. Mammalian cells lacking 2,5-DHBA accumulate abnormal intracellular levels of iron leading to high levels of reactive oxygen species. Lipocalin-2 also functions as a growth factor. # Clinical significance In the case of acute kidney injury (AKI), NGAL is secreted in high levels into the blood and urine within 2 hours of injury. Because NGAL is protease resistant and small, the protein is easily excreted and detected in the urine. NGAL levels in patients with AKI have been associated with the severity of their prognosis and can be used as a biomarker for AKI NGAL can also be used as an early diagnosis for procedures such as chronic kidney disease, contrast induced nephropathy, and kidney transplant. Kidney health is most frequently measured by serum creatinine. Serum creatinine is a marker of kidney function, whereas NGAL is a marker of kidney injury. NGAL levels are a more precise and sensitive marker for diagnosing AKI than serum creatinine levels. In fact, the increase in urinary excretion of NGAL has been proven to be due to tubular alterations that take place before any damage can be detected by other methods Therefore, monitoring NGAL levels reduces delayed AKI diagnosis and treatment. Using a more sensitive and specific marker allows for earlier diagnosis, correct responses to AKI, and reduced risk of morbidity and mortality. The NGAL level measured in an individual is proportional to the severity of the AKI. Individuals positive for NGAL tend to have higher incidence of renal replacement therapy and have higher rates of in-hospital mortality, both in the presence and the absence of serum creatinine. Therefore, an individual may have AKI without the presence of serum creatinine. The ability to diagnose AKI before acute kidney failure is financially beneficial and favorable for preventative health measures. More than 10% of people in the United States will develop some kind of chronic kidney disease (CKD), with higher incidences for individuals that suffer from obesity, elevated cholesterol, and a family history of CKD. There is no point of return once there is a significant injury to the kidney; therefore, early diagnosis of kidney injury is important for preventing AKI. Using NGAL as a biomarker can lower hospital costs because fewer patients will reach a critical stage in kidney injury. Ultimately, diagnosis of AKI with NGAL can reduce the time a patient stays in a hospital. For example, the early diagnosis of AKI with NGAL as a biomarker can help a patient avoid kidney dialysis. NGAL may be used to detect and monitor the potential additive effects of different comorbid factors (e.g. hypertension and hyperglycemia), which makes it a very useful marker, since there is an increasing number of patients with comorbidities. # Laboratory measurement Renal expression of NGAL increases in the kidneys after injury for a variety of reasons. The level of NGAL in the urine and plasma increases within 2 hours of kidney injury. It is possible to measure NGAL in serum or urine in the range of 25 to 5,000 ng/mL by current laboratory tests. Low levels for NGAL have been considered to be 20 ng/mL, medium levels 200 ng/mL, and high levels 1200 ng/mL. A study on children with pediatric cardiopulmonary bypass operations showed that urinary NGAL concentrations above 50 ng/mL 2 hours after surgery is indicative of serum creatinine levels 50% over basal values. Normally, children tend to have almost undetectable levels of NGAL. Therefore, studies that include children are considered to be “pure.” Adult patients presenting for cardiopulmonary bypass surgery are not considered to be “pure” in NGAL studies because adults often have other disorders such as inflammatory conditions, which can cause slight increases in NGAL. AKI studies investigating the use of NGAL as a biomarker often compare serum creatinine and NGAL production. Unfortunately, serum creatinine production is variable and can reflect hemodynamic variation in the glomerular filtration rate formerly known as prerenal azotemia; therefore, the comparison is not always reliable because creatinine and NGAL measure different components of renal (dys)function. The demonstration that NGAL does not rise in the setting of transient changes in creatinine can help clinicians determine whether changes in creatinine reflect kidney damage or rather only non specific or mild functional changes in kidney function. Lipocalin-2 (NGAL) is typically assessed for clinical or research purposes using ELISA or Immunoturbidimetric assays. In summary, hundreds of clinical studies demonstrate that NGAL measures kidney injury.	Lipocalin-2 Lipocalin-2 (LCN2), also known as oncogene 24p3 or neutrophil gelatinase-associated lipocalin (NGAL), is a protein that in humans is encoded by the LCN2 gene.[1][2][3] NGAL is involved in innate immunity by sequestrating iron that in turn limits bacterial growth.[4] It is expressed in neutrophils and in low levels in the kidney, prostate, and epithelia of the respiratory and alimentary tracts.[3][5] NGAL is used as a biomarker of kidney injury.[6] # Function The binding of NGAL to bacterial siderophores is important in the innate immune response to bacterial infection. Upon encountering invading bacteria the toll-like receptors on immune cells stimulate the synthesis and secretion of NGAL. Secreted NGAL then limits bacterial growth by sequestering iron-containing siderophores.[7][8][9] Lipocalin-2 binds, next to bacterial siderophores, also to the mammalian siderophore 2,5-dihydroxybenzoic acid (2,5-DHBA). This complex ensures that excess free iron does not accumulate in the cytoplasm. Mammalian cells lacking 2,5-DHBA accumulate abnormal intracellular levels of iron leading to high levels of reactive oxygen species.[10] Lipocalin-2 also functions as a growth factor.[8] # Clinical significance In the case of acute kidney injury (AKI), NGAL is secreted in high levels into the blood and urine within 2 hours of injury.[11] Because NGAL is protease resistant and small, the protein is easily excreted and detected in the urine.[12] NGAL levels in patients with AKI have been associated with the severity of their prognosis and can be used as a biomarker for AKI[11] NGAL can also be used as an early diagnosis for procedures such as chronic kidney disease, contrast induced nephropathy, and kidney transplant.[13] Kidney health is most frequently measured by serum creatinine. Serum creatinine is a marker of kidney function, whereas NGAL is a marker of kidney injury.[14] NGAL levels are a more precise and sensitive marker for diagnosing AKI than serum creatinine levels. In fact, the increase in urinary excretion of NGAL has been proven to be due to tubular alterations that take place before any damage can be detected by other methods [15] Therefore, monitoring NGAL levels reduces delayed AKI diagnosis and treatment.[16] Using a more sensitive and specific marker allows for earlier diagnosis, correct responses to AKI, and reduced risk of morbidity and mortality.[17] The NGAL level measured in an individual is proportional to the severity of the AKI.[17] Individuals positive for NGAL tend to have higher incidence of renal replacement therapy and have higher rates of in-hospital mortality, both in the presence and the absence of serum creatinine.[17] Therefore, an individual may have AKI without the presence of serum creatinine. The ability to diagnose AKI before acute kidney failure is financially beneficial and favorable for preventative health measures[citation needed]. More than 10% of people in the United States will develop some kind of chronic kidney disease (CKD), with higher incidences for individuals that suffer from obesity, elevated cholesterol, and a family history of CKD. There is no point of return once there is a significant injury to the kidney; therefore, early diagnosis of kidney injury is important for preventing AKI. Using NGAL as a biomarker can lower hospital costs because fewer patients will reach a critical stage in kidney injury. Ultimately, diagnosis of AKI with NGAL can reduce the time a patient stays in a hospital. For example, the early diagnosis of AKI with NGAL as a biomarker can help a patient avoid kidney dialysis. NGAL may be used to detect and monitor the potential additive effects of different comorbid factors (e.g. hypertension and hyperglycemia), which makes it a very useful marker, since there is an increasing number of patients with comorbidities.[15] # Laboratory measurement Renal expression of NGAL increases in the kidneys after injury for a variety of reasons. The level of NGAL in the urine and plasma increases within 2 hours of kidney injury. It is possible to measure NGAL in serum or urine in the range of 25 to 5,000 ng/mL by current laboratory tests.[18] Low levels for NGAL have been considered to be 20 ng/mL, medium levels 200 ng/mL, and high levels 1200 ng/mL.[18] A study on children with pediatric cardiopulmonary bypass operations showed that urinary NGAL concentrations above 50 ng/mL 2 hours after surgery is indicative of serum creatinine levels 50% over basal values. Normally, children tend to have almost undetectable levels of NGAL.[19] Therefore, studies that include children are considered to be “pure.” Adult patients presenting for cardiopulmonary bypass surgery are not considered to be “pure” in NGAL studies because adults often have other disorders such as inflammatory conditions, which can cause slight increases in NGAL.[citation needed] AKI studies investigating the use of NGAL as a biomarker often compare serum creatinine and NGAL production. Unfortunately, serum creatinine production is variable and can reflect hemodynamic variation in the glomerular filtration rate formerly known as prerenal azotemia; therefore, the comparison is not always reliable because creatinine and NGAL measure different components of renal (dys)function.[12] The demonstration that NGAL does not rise in the setting of transient changes in creatinine can help clinicians determine whether changes in creatinine reflect kidney damage or rather only non specific or mild functional changes in kidney function. Lipocalin-2 (NGAL) is typically assessed for clinical or research purposes using ELISA or Immunoturbidimetric assays. In summary, hundreds of clinical studies demonstrate that NGAL measures kidney injury.	https://www.wikidoc.org/index.php/Lipocalin-2
e4c18697f636eb418888d9f77951a724320c5e96	wikidoc	Lipogenesis	Lipogenesis # Overview Lipogenesis is the process by which glucose is converted to fatty acids, which are subsequently esterified to glycerol to form the triacylglycerols that are packaged in VLDL and secreted from the liver. Lipogenesis encompasses the processes of fatty acid synthesis and subsequent triglyceride synthesis. Lipogenesis starts with acetyl-CoA and builds up by the addition of two carbons units. The synthesis occurs in the cytoplasm in contrast to the degradation (oxidation) which occurs in the mitochondria. Many of the enzymes for the fatty acid synthesis are organized into a multienzyme complex called fatty acid synthetase . # Control and Regulation Insulin is an indicator of the blood sugar level of the body, as its concentration increases proportionally with blood sugar levels. Thus a large insulin level is associated with the fed state. As one might expect therefore, it increases the rate of storage pathways, such as lipogenesis. Insulin stimulates lipogenesis in three main ways. ## Malonyl-coenzyme A In fat synthesis, the enzyme pyruvate dehydrogenase, which forms acetyl-coA, and also acetyl-coA carboxylase which forms malonyl-coA are obvious control points. These are activated by insulin. This leads to an overall increase in the levels of malonyl-coenzyme A, which is the substrate required for fat synthesis. Thus, the flux down storage pathway is increased when there is sufficient glucose in the 'fed' state. ## Pyruvate dehydrogenase dephosphorylation Pyruvate dehyrdrogenase dephosphorylation is increased with the release of insulin. The dephosphorylated form is more active. This mechanism is not clear, as insulin binds to extra-cellular parts of protein receptors and pyruvate dehydrogenase is found in the mitochondrial matrix. There must be some sort of secondary messenger process. This mechanism leads to the increased rate of catalysis of this enzyme, so increases the levels of acetyl-coA. Increased levels of acetyl-coA will not only increase the flux through the fat synthesis pathway, but also the citric acid cycle. ## Acetyl-coA carboxylase Insulin affects ACC in a similar way to PDH. It leads to its dephosphorylation. Glucagon has an antagonistic effect and increases phosphorylation, therefore inhibiting ACC, and slowing fat synthesis. This inhibition mechanism is thought to be something to do with ACC-dependent protein kinase. Affecting ACC affects the rate of acetyl-coA conversion to malonyl-coA. Malonyl-coA increae pushes the equilibrium over to increase production of fatty acids through biosynthesis. AMP activated protein kinase acts as a measure of the ATP needs of a cell and acts to phosphorylse ACC. When ATP is depleted there is a rise in 5'AMP. This rise activates AMP-activated protein kinase, which phosphorylates ACC and thereby inhibits fat synthesis. This is a useful way to ensure that glucose is not diverted down a storage pathway in times when energy levels are low. ACC is also activated by citrate. This means that when there is abundant acetyl-coA in the cell cytoplasm for fat synthesis it proceeds at an appropriate rate. Note: Research now shows that glucose metabolism (exact metabolite to be determined), aside from insulin's influence on lipogenic enzyme genes, can induce the gene products for Liver pyruvate kinase, acetyl-CoA carboxylase and fatty acid synthase. These genes are induced by the transcription factors ChREBP/Mlx via high blood glucose levels and presently unknown signaling events. Insulin induction is due to SREBP-1c, which is also involved in cholesterol metabolism. Work from Howard Towle, Cathrine Postic, and K. Uyeda can be referenced for ChREBP/Mlx effects described above.	Lipogenesis # Overview Lipogenesis is the process by which glucose is converted to fatty acids, which are subsequently esterified to glycerol to form the triacylglycerols that are packaged in VLDL and secreted from the liver. Lipogenesis encompasses the processes of fatty acid synthesis and subsequent triglyceride synthesis. Lipogenesis starts with acetyl-CoA and builds up by the addition of two carbons units. The synthesis occurs in the cytoplasm in contrast to the degradation (oxidation) which occurs in the mitochondria. Many of the enzymes for the fatty acid synthesis are organized into a multienzyme complex called fatty acid synthetase [1]. # Control and Regulation Insulin is an indicator of the blood sugar level of the body, as its concentration increases proportionally with blood sugar levels. Thus a large insulin level is associated with the fed state. As one might expect therefore, it increases the rate of storage pathways, such as lipogenesis. Insulin stimulates lipogenesis in three main ways. ## Malonyl-coenzyme A In fat synthesis, the enzyme pyruvate dehydrogenase, which forms acetyl-coA, and also acetyl-coA carboxylase which forms malonyl-coA are obvious control points. These are activated by insulin. This leads to an overall increase in the levels of malonyl-coenzyme A, which is the substrate required for fat synthesis. Thus, the flux down storage pathway is increased when there is sufficient glucose in the 'fed' state. ## Pyruvate dehydrogenase dephosphorylation Pyruvate dehyrdrogenase dephosphorylation is increased with the release of insulin. The dephosphorylated form is more active. This mechanism is not clear, as insulin binds to extra-cellular parts of protein receptors and pyruvate dehydrogenase is found in the mitochondrial matrix. There must be some sort of secondary messenger process. This mechanism leads to the increased rate of catalysis of this enzyme, so increases the levels of acetyl-coA. Increased levels of acetyl-coA will not only increase the flux through the fat synthesis pathway, but also the citric acid cycle. ## Acetyl-coA carboxylase Insulin affects ACC in a similar way to PDH. It leads to its dephosphorylation. Glucagon has an antagonistic effect and increases phosphorylation, therefore inhibiting ACC, and slowing fat synthesis. This inhibition mechanism is thought to be something to do with ACC-dependent protein kinase. Affecting ACC affects the rate of acetyl-coA conversion to malonyl-coA. Malonyl-coA increae pushes the equilibrium over to increase production of fatty acids through biosynthesis. AMP activated protein kinase acts as a measure of the ATP needs of a cell and acts to phosphorylse ACC. When ATP is depleted there is a rise in 5'AMP. This rise activates AMP-activated protein kinase, which phosphorylates ACC and thereby inhibits fat synthesis. This is a useful way to ensure that glucose is not diverted down a storage pathway in times when energy levels are low. ACC is also activated by citrate. This means that when there is abundant acetyl-coA in the cell cytoplasm for fat synthesis it proceeds at an appropriate rate. Note: Research now shows that glucose metabolism (exact metabolite to be determined), aside from insulin's influence on lipogenic enzyme genes, can induce the gene products for Liver pyruvate kinase, acetyl-CoA carboxylase and fatty acid synthase. These genes are induced by the transcription factors ChREBP/Mlx via high blood glucose levels and presently unknown signaling events. Insulin induction is due to SREBP-1c, which is also involved in cholesterol metabolism. Work from Howard Towle, Cathrine Postic, and K. Uyeda can be referenced for ChREBP/Mlx effects described above.	https://www.wikidoc.org/index.php/Lipogenesis
5269ceb850f89342fd2b92b1d3e4888409226479	wikidoc	Lipoprotein	Lipoprotein # Overview Lipoproteins are complex particles composed of a water-repelling core of mainly lipids as non-polar cholesterol esters (CEs) and triglycerides (TGs) surrounded by an amphipathic phospholipid monolayer that includes unesterified free cholesterol (FC) and proteins known as apolipoproteins or aproteins. Apolipoproteins provide a framework for lipoprotein assembly; determine the metabolic fate of the lipoprotein by activating or inhibiting key enzymes; and finally act as ligands for receptor molecules. Lipoproteins are classified into five classes, defined by their respective density on electrophoresis as Chylomicrons, Very Low Density Lipoproteins (VLDL), Intermediate Density Lipoproteins (IDL), Low Density Lipoprotein (LDL) and High Density Lipoproteins (HDL). # Definition # Classification Lipoproteins can be classified according to their density, size and constituents. It is also possible to classify lipoproteins as "alpha" and "beta", akin to the classification of proteins in serum protein electrophoresis. The lipoproteins that have a low density are the triglyceride rich proteins which include chylomicrons, chylomicron remnants and VLDL. LDL, HDL and lipoprotein(a) have a less triglyceride content and a higher density. Shown below is a table summarizing the structure of each lipoprotein. # Function The lipids are often an essential part of the complex, even if they seem to have no catalytic activity themselves. To isolate transmembrane lipoproteins from their associated membranes, detergents are often needed. All cells use and rely on fats and, for all animal cells, cholesterol as building blocks to create the multiple membranes which cells use to both control internal water content, internal water soluble elements and to organize their internal structure and protein enzymatic systems. Lipoproteins in the blood, a water medium, carry fats around the body. The protein particles have charged groups aimed outward so as to attract water molecules; this makes them soluble in the salt water based blood pool. Triglyceride-fats and cholesterol are carried internally, shielded by the protein particle from the water. The interaction of the proteins forming the surface of the particles with (a) enzymes in the blood, (b) with each other and (c) with specific proteins on the surfaces of cells determine whether triglycerides and cholesterol will be added to or removed from the lipoprotein transport particles. Regarding atheroma development and progression vs. regression, the key issue has always been cholesterol transport patterns, not cholesterol concentration itself. Shown below is a table summarizing the function of each lipoprotein.	Lipoprotein Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview Lipoproteins are complex particles composed of a water-repelling core of mainly lipids as non-polar cholesterol esters (CEs) and triglycerides (TGs) surrounded by an amphipathic phospholipid monolayer that includes unesterified free cholesterol (FC) and proteins known as apolipoproteins or aproteins. Apolipoproteins provide a framework for lipoprotein assembly; determine the metabolic fate of the lipoprotein by activating or inhibiting key enzymes; and finally act as ligands for receptor molecules. Lipoproteins are classified into five classes, defined by their respective density on electrophoresis as Chylomicrons, Very Low Density Lipoproteins (VLDL), Intermediate Density Lipoproteins (IDL), Low Density Lipoprotein (LDL) and High Density Lipoproteins (HDL). # Definition # Classification Lipoproteins can be classified according to their density, size and constituents. It is also possible to classify lipoproteins as "alpha" and "beta", akin to the classification of proteins in serum protein electrophoresis. The lipoproteins that have a low density are the triglyceride rich proteins which include chylomicrons, chylomicron remnants and VLDL. LDL, HDL and lipoprotein(a) have a less triglyceride content and a higher density. Shown below is a table summarizing the structure of each lipoprotein.[1] # Function The lipids are often an essential part of the complex, even if they seem to have no catalytic activity themselves. To isolate transmembrane lipoproteins from their associated membranes, detergents are often needed. All cells use and rely on fats and, for all animal cells, cholesterol as building blocks to create the multiple membranes which cells use to both control internal water content, internal water soluble elements and to organize their internal structure and protein enzymatic systems. Lipoproteins in the blood, a water medium, carry fats around the body. The protein particles have charged groups aimed outward so as to attract water molecules; this makes them soluble in the salt water based blood pool. Triglyceride-fats and cholesterol are carried internally, shielded by the protein particle from the water. The interaction of the proteins forming the surface of the particles with (a) enzymes in the blood, (b) with each other and (c) with specific proteins on the surfaces of cells determine whether triglycerides and cholesterol will be added to or removed from the lipoprotein transport particles. Regarding atheroma development and progression vs. regression, the key issue has always been cholesterol transport patterns, not cholesterol concentration itself. Shown below is a table summarizing the function of each lipoprotein.	https://www.wikidoc.org/index.php/Lipoprotein
d8f08e395dd4dadc16e0f4926bd45ba8cbdb40cf	wikidoc	Liposuction	Liposuction # Overview Liposuction, also known as lipoplasty ("fat modeling"), liposculpture or suction lipectomy ("suction-assisted fat removal") is a cosmetic surgery operation that removes fat from many different sites on the human body. Areas affected can range from the abdomen, thighs, buttocks, to the neck, backs of the arms and elsewhere. The fat is usually removed via a cannula (a hollow tube) and aspirator (a suction device). Liposuction is not a low-effort alternative to exercise and diet. It is a form of body contouring with significant attendant risks and is not a weight loss method. The amount of fat removed varies by doctor, method, and patient, but the average amount is typically less than 10 pounds (5 kg). There are several factors that limit the amount of fat that can be safely removed in one session. Ultimately, the operating physician and the patient make the decision. There are negative aspects to removing too much fat. Unusual "lumpiness" and/or "dents" in the skin can be seen in those patients "over-suctioned". The more fat removed the higher the surgical risk. As shown previously, reports of people removing 50 pounds (22.7 kg) of fat are exaggerated. However, the contouring possible with liposuction may cause the appearance of weight loss to be greater than the actual amount of fat removed. The procedure may be performed under general or local ("tumescent") anesthesia. The safety of the technique relates not only to the amount of tissue removed, but to the choice of anesthetic and the patient's overall health. It is ideal for the patient to be as fit as possible before the procedure and to have given up smoking for several months. # History Relatively modern techniques for body contouring and removal of fat date back to French surgeon, Charles Dujarier. A tragic case that resulted in gangrene in the leg of a French model in a procedure performed by Dr. Dujarier in 1926 set back interest in body contouring for decades to follow. Liposuction evolved from work in the late 1960s from surgeons in Europe using primitive curetage techniques which were largely ignored, as they achieved irregular results with significant morbidity and bleeding. Modern liposuction first burst on the scene in a presentation by the French surgeon, Dr. Yves-Gerard Illouz, in 1982. The "Illouz Method" featured a technique of suction-assisted lipolysis using blunt cannulas and high-vacuum suction and demonstrated both reproducible good results and low morbidity. During the 1980s, many U.S. surgeons experimented with liposuction, developing some variations, and achieving mixed results. In 1985, two U.S. dermatologists described the tumescent technique, which added high volumes of fluid containing a local anesthetic allowing the procedure to be done in an office setting under intravenous sedation rather than general anesthesia. Concerns over the high volume of fluid and potential toxicity of lidocaine with tumescent techniques eventually led to the concept of lower volume "super wet" tumescence. In the late 1990s, ultrasound was introduced to facilitate the fat removal by first liquefying it using ultrasonic energy. After a flurry of initial interest, an increase in reported complications tempered the enthusiasm of many practitioners. In 2005-6, two new, FDA-approved technologies introduced laser-assisted liposuction. One technology employs a laser at high frequency, the other, a cold laser at low frequency. What the two laser technologies have in common is a refinement in the preparation of fat cells for removal that allows for a less invasive procedure. For patients, this can mean a smaller incision, and easier, more precise use of the cannula. The patient benefit, according to clinical trials and studies conducted by the medical technology firms and by surgeons employing the new technologies, is less tissue trauma and abbreviated wearing of the compression garment or girdle worn compared to other methods of liposuction. Overall, the advantages of 30 years of improvements have been that more fat cells can more easily be removed, with less blood loss, less discomfort, and less risk. Recent developments suggest that the recovery period can be shortened as well. # Popularity Removal of very large volumes of fat is a complex and potentially life-threatening procedure. The American Society of Plastic Surgeons defines "large" in this context as being more than 5 liters. Most often, liposuction is performed on: - The abdomen and thighs in women - The abdomen and flanks in men # Candidacy Not everybody is a good candidate for liposuction. As stated earlier, it is not a good alternative to dieting or exercising. To be a good candidate, one must be: - Over 18 - In good general health - Have tried a diet and exercise regime, and find that the last 10 or 15 pounds persist in certain pockets on the body. Diabetes, any infection, or heart or circulation problems usually nullify one's eligibility for the procedure. In older people, the skin is usually less elastic, so it does not tighten so readily around the new shape. In this case, other procedures can be added to the liposuction, such as an abdominoplasty (tummy tuck). # Approaches The basic surgical challenge of any liposuction procedure is: - To remove the right amount of fat - To cause the least disturbance of neighboring tissue, such as blood vessels and connective tissue - To leave the person’s fluid balance undisturbed - To cause the least discomfort to both patient and surgeon As techniques have been refined, many ideas have emerged that have brought liposuction closer to being safe, easy, painless, and effective. # Techniques Liposuction techniques can be further categorized by the amount of fluid injection and by the mechanism in which the cannula works. ## Amount of fluid injection ### Dry liposuction The dry method does not use any fluid injection at all. This method is seldom used today. ### Wet liposuction A small amount of fluid, less in volume than the amount of fat to be removed, is injected into the area. It contains: - Lidocaine: as a local anesthetic - Epinephrine: to contract the blood vessels and thus minimize bleeding - A salt solution: to make it saline, like our body fluids This fluid helps to loosen the fat cells and reduce bruising. The fat cells are then suctioned out as in the basic procedure. ### Super-wet liposuction In this method, the infusate volume is in about the same amount as the volume of fat expected to be removed. This is the preferred technique for high-volume liposuction by many plastic surgeons as it better balances hemostasis and potential fluid overload (as with the tumescent technique). It takes one to three hours, depending on the size of the treated area(s). It may require either: - IV sedation as well as the local lidocaine, or - Complete anesthesia ### Tumescent liposuction In the classic tumescent technique, a large amount of fluid is injected into the area, perhaps as much as 3 or 4 times the volume of fat to be removed. It is the same saline fluid as the super wet technique, but its increased quantity creates space between the muscle and the fatty tissue, which creates more room for the suction tube (cannula) that the surgeon uses to remove the fat cells. Depending on the size of the area(s) being worked, this procedure takes longer than other techniques must as the large amount of infiltrate must be introduced slowly. The high volumes of fluid and local anesthetic required for this technique have limited its use with larger people. ### Laser assisted liposuction Laser assisted liposuction may involve either of two technologies, both of which received FDA approval in 2006. These technologies have been adopted by physicians seeking an advance in liposculpture procedures. The Erchonia Neira 4L laser produces a low-level, or cold, output that has no thermal effect on the body's tissue. According to Erchonia, this technology is currently in use at a handful of cosmetic plastic surgery practices in the US. Specifically calibrated to destabilize or liquefy the fat, without affecting surrounding tissue, the patient feels neither heat nor sensation from the laser's application. The cosmetic surgeon then uses a small cannula to remove the destabilized fat cells. According to Erchonia, the liquefaction of the fat cells allows for a substantially less invasive procedure, with less trauma to surrounding tissue. Laser assisted liposuction may also refer to a laser technology, known in the US as SmartLipo, that employs a cannula tipped with a diode laser emitter. According to Cynosure, the cold laser's US maker and marketer, a small cannula threaded and tipped with a 1064-nm Nd:YAG laser fiber is inserted through a small incision. It delivers energy directly to subcutaneous fat cells-causing them to rupture. The emitted fat melting energy also coagulates surrounding tissue, thus inducing collagen retraction and tissue tightening. The surgeon monitors cannula placement by following a visible red light that shines through the skin and tissue. This is from a “guide” optical fibre in the cannula. Typically, when SmartLipo is used, fat is not removed by a suction device, but rather, dissipates through the body’s natural processes, Laser assisted liposuction of either type is considered to be minimally invasive when compared to traditional liposuction techniques. ## Mechanism of liposuction ### Suction-assisted liposuction (SAL) Suction-assisted liposuction is the standard method of liposuction. In this approach, a small cannula (like a straw) is inserted through a small incision. It is attached to a vacuum device. The surgeon pushes and pulls it carefully through the fat layer, breaking up the fat cells and drawing them out of the body by suction. ### Microcannula liposuction Microcannula or very small liposuction cannula that makes possible fine, close to surface contouring, sometimes through much smaller incisions. ### Ultrasound-assisted liposuction (UAL) Also referred to as ultrasonic liposuction. A specialized cannula is used which transmits ultrasound vibrations within the body. This vibration bursts the walls of the fat cells, emulsifying the fat, i.e., liquefying it, and making it easier to suction out. - UAL is a good choice for working on more fibrous areas, like the upper back, or male breast area - It takes longer to do than traditional liposuction, but not longer than tumescent liposuction - There is slightly less blood loss - So far, there appears to be slightly more risk of seromas forming (pockets of fluid) which may have to be drained with a needle After ultrasonic liposuction, it is necessary to perform suction-assisted liposuction to remove the liquified fat. ### Power-assisted liposuction (PAL) PAL uses a specialized cannula with mechanized movement, so that the surgeon does not need to make as many manual movements. Otherwise it is similar to traditional UAL. ### External ultrasound-assisted liposuction (XUAL or EUAL) XUAL is a type of UAL where the ultrasonic energy is applied from outside the body, through the skin, making the specialized cannula of the UAL procedure unnecessary. It was developed because surgeons found that in some cases, the UAL method caused skin necrosis (death) and seromas, which are pockets of a pale yellowish fluid from the body, analogous to hematomas (pockets of red blood cells). XUAL is a possible way to avoid such complications by having the ultrasound applied externally. It can also potentially: - Cause less discomfort for the patient, both during the procedure and afterwards - Decrease blood loss - Allow better access through scar tissue - Treat larger areas At this time however, it is not widely used and studies are not conclusive as to its effectiveness. ### Water-assisted liposuction (WAL) WAL uses a thin fan-shaped water beam, which loosens the structure of the fat tissue, so that it can be removed by a special cannula. During the liposuction the water is continually added and almost immediately aspirated via the same cannula. WAL requires less infiltration solution and much less intraoperative swelling. This allows the surgeon to better realize the target result. The cannula movements are very subtle, helped by the water beam. This is a new technique that there is not much published yet in the medical literature. - Not approved by the FDA in the US. ## Stitches To stitch or not to stitch; that is the surgeon's decision. Since the incisions are small, and since the amount of fluid that must drain out is large: - Some surgeons opt to leave the incisions open, the better to clear the patient's body of excess fluid. They find that the unimpeded departure of that fluid allows the incisions to heal more quickly by themselves. - Others stitch them only partially, leaving space for the fluid to drain out - Others delay stitching until most of the fluid has drained out, about 1 or 2 days. In either case, while the fluid is draining, dressings need to be changed often. After one to three days, small self-adhesive bandages are sufficient. # Preparation Before receiving any of the procedures described above: - No anticoagulants should be taken for two weeks before the surgery. - If receiving general anesthesia or sedation, and the surgery will be in the morning, fasting from midnight the night before is required. If only local anesthesia will be used, fasting is not required. - Smoking must be avoided for about two months prior to surgery. Nicotine interferes with circulation and can result in loss of tissue. # The procedure In all liposuction methods, there are certain things that should be done when having the procedure: - The candidate and the surgeon will agree ahead of time on exactly which area(s) will be treated and both will discuss what outcome to expect - A consent form is signed on the day of surgery - An antibiotic will be given either about an hour beforehand, or afterwards - The targeted areas are marked on the body while the candidate is in a standing position - Sometimes photos will be taken of the area to be treated, so the patient will have before and after photos - In the operating room, a sterilizing solution such as Betadine, is applied to the relevant areas - Local anesthetic is injected and the patient may be given a sedative, either orally, or through an IV injection - Incisions are small, about a quarter to a third of an inch - The patient will probably have an IV fluid line, since they will be losing fluid with the fat, and the fluid balance must be kept intact - There will be some monitoring devices attached to the body to keep track of the blood pressure, heart rate, and blood oxygen level - The patient will feel only a scraping or rasping sensation from the cannula movement - Usually the patient can get up, walk around, and go home the same day if they did not receive general anesthesia, although they’ll need someone else to drive # Recovery Depending on the extent of the liposuction, patients are generally able to return to work or school between two days and two weeks. A compression garment or bandage is worn for two to four weeks. If non-absorbable sutures are placed, they will be removed after five to ten days. - Any pain is controlled by a prescription or over-the-counter medication, and may last as long as two weeks, depending on the particular procedure - Swelling will subside in anywhere from two weeks to two months - Bruising will fade after a few days or maybe as long as two weeks later - Numbness may last for several weeks - Normal activity can be resumed anywhere from several days to several weeks afterwards, depending on the procedure - The final result will be evident anywhere from one to six months after surgery, although the patient will see noticeable difference within days or weeks, as swelling subsides ## Expediting recovery The patient should: - Drink enough water to prevent dehydration - Avoid using ice packs or heating pads on the treated areas - Postpone soaking the wounds until they are sealed (usually 48 hours for sutured wounds and a little longer for unsutured ones). - If any dizziness is experienced, the patient should take it easy: stand up slowly, get some help for the shower, remove the compression garment slowly, etc. The suctioned fat cells are permanently gone. However, if the patient does not diet and exercise properly, the remaining fat cell neighbors could still enlarge, creating irregularities. # Side effects A side effect, as opposed to a complication, is medically minor, although it can be uncomfortable, annoying, and even painful. - Bruising: can be painful in the short term, and should fade after a few weeks. - Swelling: should subside gradually over a month or two. - Scars: will vary in size depending on the particular procedure, and should fade over the weeks. Scarring is an individual thing, partly dependent on heredity. For some, scar healing may take as long as a year. - Pain: should be temporary and controlled by either over-the-counter medication, or by a prescription. - Numbness: sometimes persists for a few weeks. - Limited mobility: will depend on the exact procedure. There could be various factors limiting movement for a short while, such as: - Wearing a compression garment - Keeping the head elevated - Temporary swelling or pain The surgeon should advise on how soon the patient can resume normal activity. # Possible complications As with any surgery, there are certain risks, beyond the temporary and minor side effects. The surgeon may mention them during a consultation. Careful patient selection minimizes their occurrence. Their likelihood is somewhat increased when treated areas are very large or numerous and a large amount of fat is removed. During the 1990s there were some deaths as a result of liposuction, as well as alarmingly high rates of complication. By studying more and educating themselves further, surgeons have reduced complication rates. A study published in Dermatologic Surgery (July 2004, pp. 967-978), found that: - “The overall clinical complication rate ... was 0.7% (5 of 702) ” - The minor complication rate was 0.57% - The major complication rate was 0.14% with one patient requiring hospitalization The more serious possible complications include: - Allergic reaction to medications or material used during surgery. - Infection: any time the body is incised or punctured, bacteria can get in and cause an infection. During liposuction, multiple small puncture wounds are made for inserting the cannula, that can vary in size depending on the technique. - Damage to the skin: most surgeons work on the deeper levels of fat, so as to avoid wounding the skin any more than they must for the insertion of the cannula. - Sometimes the cannula can damage tissue beneath the skin, which may show up as a spotted appearance on the skin surface. - Skin necrosis (dead skin) is a rare complication, in which the skin falls off in the necrotic area. The problem can vary in degree. The resulting wound then needs to heal typically requiring extended wound care. - Puncture of an internal organ: since the surgeon can't see the cannula, sometimes it damages an internal organ, such as the intestines during abdominal liposuction. Such damage can be corrected surgically, although in rare cases it can be fatal. An experienced cosmetic surgeon is unlikely to puncture any internal organ. - Contour irregularities: sometimes the skin may look bumpy and/or withered, because of uneven fat removal, or poor skin elasticity. Not all patients heal in the same way, and with older patients the healing may be slower and a bit imperfect. Sometimes a small touch-up procedure can help. - Thromboembolism and fat embolisation: although liposuction is a low-risk procedure for thromboembolism including pulmonary embolism, the risk can't be ignored. - Burns: sometimes the cannula movement can cause friction burns to skin or nerves. Also, in UAL, the heat from the ultrasound device can cause injury to the skin or deeper tissue. - Lidocaine toxicity: when the super-wet or tumescent methods are used, too much saline fluid may be injected, or the fluid may contain too high a concentration of lidocaine. Then the lidocaine may become too much for that particular person’s system. Lidocaine poisoning at first causes tingling and numbness and eventually seizures, followed by unconsciousness and respiratory or cardiac arrest. - Fluid imbalance: since fat contains a lot of fluid and is removed in liposuction, and since the surgeon injects fluid for the procedure, even a very large amount of it for tumescent liposuction, there is a danger of the body’s fluid balance being disturbed. This could happen afterwards, after the patient is at home. If too much fluid remains in the body, the heart, lungs and kidneys could be badly affected. The cosmetic surgeon should give the participant a written list of symptoms to watch for, along with instructions for post-op self-care. # Combined with other procedures ## Liposuction and tightening / lifting skin Liposuction is not a good tool for tightening the skin. The removal of quantities of fat from under the skin can leave the skin even more loose. When drooping skin and fat are the issue, then lift such as a Rhytidectomy Facelift, Mastopexy Breast Lift, Abdominoplasty Tummy Tuck, or Lower body lift, Thigh Lift, or Buttock Lift are better tools and may include liposuction during surgery to refine the sculpture. SAL in combination with other surgery is common, but may have higher complication rates. When done simultaneously, SAL is done minimally in the areas of the undermined tissues to minimize further insult to the blood supply.	Liposuction Editors-In-Chief: Martin I. Newman, M.D., FACS, Cleveland Clinic Florida, [8]; Michel C. Samson, M.D., FRCSC, FACS [9] # Overview Liposuction, also known as lipoplasty ("fat modeling"), liposculpture or suction lipectomy ("suction-assisted fat removal") is a cosmetic surgery operation that removes fat from many different sites on the human body. Areas affected can range from the abdomen, thighs, buttocks, to the neck, backs of the arms and elsewhere. The fat is usually removed via a cannula (a hollow tube) and aspirator (a suction device). Liposuction is not a low-effort alternative to exercise and diet. It is a form of body contouring with significant attendant risks[1] and is not a weight loss method. The amount of fat removed varies by doctor, method, and patient, but the average amount is typically less than 10 pounds (5 kg). There are several factors that limit the amount of fat that can be safely removed in one session. Ultimately, the operating physician and the patient make the decision. There are negative aspects to removing too much fat. Unusual "lumpiness" and/or "dents" in the skin can be seen in those patients "over-suctioned". The more fat removed the higher the surgical risk. As shown previously, reports of people removing 50 pounds (22.7 kg) of fat are exaggerated. However, the contouring possible with liposuction may cause the appearance of weight loss to be greater than the actual amount of fat removed. The procedure may be performed under general or local ("tumescent") anesthesia. The safety of the technique relates not only to the amount of tissue removed, but to the choice of anesthetic and the patient's overall health. It is ideal for the patient to be as fit as possible before the procedure and to have given up smoking for several months. # History Relatively modern techniques for body contouring and removal of fat date back to French surgeon, Charles Dujarier. A tragic case that resulted in gangrene in the leg of a French model in a procedure performed by Dr. Dujarier in 1926 set back interest in body contouring for decades to follow.[2] Liposuction evolved from work in the late 1960s from surgeons in Europe using primitive curetage techniques which were largely ignored, as they achieved irregular results with significant morbidity and bleeding. Modern liposuction first burst on the scene in a presentation by the French surgeon, Dr. Yves-Gerard Illouz, in 1982. The "Illouz Method" featured a technique of suction-assisted lipolysis using blunt cannulas and high-vacuum suction and demonstrated both reproducible good results and low morbidity. During the 1980s, many U.S. surgeons experimented with liposuction, developing some variations, and achieving mixed results. In 1985, two U.S. dermatologists described the tumescent technique, which added high volumes of fluid containing a local anesthetic allowing the procedure to be done in an office setting under intravenous sedation rather than general anesthesia. Concerns over the high volume of fluid and potential toxicity of lidocaine with tumescent techniques eventually led to the concept of lower volume "super wet" tumescence. In the late 1990s, ultrasound was introduced to facilitate the fat removal by first liquefying it using ultrasonic energy. After a flurry of initial interest, an increase in reported complications tempered the enthusiasm of many practitioners. In 2005-6, two new, FDA-approved technologies introduced laser-assisted liposuction. One technology employs a laser at high frequency, the other, a cold laser at low frequency. What the two laser technologies have in common is a refinement in the preparation of fat cells for removal that allows for a less invasive procedure. For patients, this can mean a smaller incision, and easier, more precise use of the cannula. The patient benefit, according to clinical trials and studies conducted by the medical technology firms and by surgeons employing the new technologies, is less tissue trauma and abbreviated wearing of the compression garment or girdle worn compared to other methods of liposuction. Overall, the advantages of 30 years of improvements have been that more fat cells can more easily be removed, with less blood loss, less discomfort, and less risk. Recent developments suggest that the recovery period can be shortened as well. # Popularity Removal of very large volumes of fat is a complex and potentially life-threatening procedure. The American Society of Plastic Surgeons defines "large" in this context as being more than 5 liters. Most often, liposuction is performed on: - The abdomen and thighs in women - The abdomen and flanks in men # Candidacy Not everybody is a good candidate for liposuction. As stated earlier, it is not a good alternative to dieting or exercising. To be a good candidate, one must be: - Over 18 - In good general health - Have tried a diet and exercise regime, and find that the last 10 or 15 pounds persist in certain pockets on the body. Diabetes, any infection, or heart or circulation problems usually nullify one's eligibility for the procedure. In older people, the skin is usually less elastic, so it does not tighten so readily around the new shape. In this case, other procedures can be added to the liposuction, such as an abdominoplasty (tummy tuck). # Approaches The basic surgical challenge of any liposuction procedure is: - To remove the right amount of fat - To cause the least disturbance of neighboring tissue, such as blood vessels and connective tissue - To leave the person’s fluid balance undisturbed - To cause the least discomfort to both patient and surgeon As techniques have been refined, many ideas have emerged that have brought liposuction closer to being safe, easy, painless, and effective. # Techniques Liposuction techniques can be further categorized by the amount of fluid injection and by the mechanism in which the cannula works. ## Amount of fluid injection ### Dry liposuction The dry method does not use any fluid injection at all. This method is seldom used today. ### Wet liposuction A small amount of fluid, less in volume than the amount of fat to be removed, is injected into the area. It contains: - Lidocaine: as a local anesthetic - Epinephrine: to contract the blood vessels and thus minimize bleeding - A salt solution: to make it saline, like our body fluids This fluid helps to loosen the fat cells and reduce bruising. The fat cells are then suctioned out as in the basic procedure. ### Super-wet liposuction In this method, the infusate volume is in about the same amount as the volume of fat expected to be removed. This is the preferred technique for high-volume liposuction by many plastic surgeons as it better balances hemostasis and potential fluid overload (as with the tumescent technique). It takes one to three hours, depending on the size of the treated area(s). It may require either: - IV sedation as well as the local lidocaine, or - Complete anesthesia ### Tumescent liposuction In the classic tumescent technique, a large amount of fluid is injected into the area, perhaps as much as 3 or 4 times the volume of fat to be removed. It is the same saline fluid as the super wet technique, but its increased quantity creates space between the muscle and the fatty tissue, which creates more room for the suction tube (cannula) that the surgeon uses to remove the fat cells. Depending on the size of the area(s) being worked, this procedure takes longer than other techniques must as the large amount of infiltrate must be introduced slowly. The high volumes of fluid and local anesthetic required for this technique have limited its use with larger people. ### Laser assisted liposuction Laser assisted liposuction may involve either of two technologies, both of which received FDA approval in 2006. These technologies have been adopted by physicians seeking an advance in liposculpture procedures. The Erchonia Neira 4L laser produces a low-level, or cold, output that has no thermal effect on the body's tissue. According to Erchonia, this technology is currently in use at a handful of cosmetic plastic surgery practices in the US. Specifically calibrated to destabilize or liquefy the fat, without affecting surrounding tissue, the patient feels neither heat nor sensation from the laser's application. The cosmetic surgeon then uses a small cannula to remove the destabilized fat cells. According to Erchonia, the liquefaction of the fat cells allows for a substantially less invasive procedure, with less trauma to surrounding tissue. Laser assisted liposuction may also refer to a laser technology, known in the US as SmartLipo, that employs a cannula tipped with a diode laser emitter. According to Cynosure, the cold laser's US maker and marketer, a small cannula threaded and tipped with a 1064-nm Nd:YAG laser fiber is inserted through a small incision.[3] It delivers energy directly to subcutaneous fat cells-causing them to rupture. The emitted fat melting energy also coagulates surrounding tissue, thus inducing collagen retraction and tissue tightening. The surgeon monitors cannula placement by following a visible red light that shines through the skin and tissue. This is from a “guide” optical fibre in the cannula. Typically, when SmartLipo is used, fat is not removed by a suction device, but rather, dissipates through the body’s natural processes, Laser assisted liposuction of either type is considered to be minimally invasive when compared to traditional liposuction techniques. ## Mechanism of liposuction ### Suction-assisted liposuction (SAL) Suction-assisted liposuction is the standard method of liposuction. In this approach, a small cannula (like a straw) is inserted through a small incision. It is attached to a vacuum device. The surgeon pushes and pulls it carefully through the fat layer, breaking up the fat cells and drawing them out of the body by suction. ### Microcannula liposuction Microcannula or very small liposuction cannula that makes possible fine, close to surface contouring, sometimes through much smaller incisions. ### Ultrasound-assisted liposuction (UAL) Also referred to as ultrasonic liposuction. A specialized cannula is used which transmits ultrasound vibrations within the body. This vibration bursts the walls of the fat cells, emulsifying the fat, i.e., liquefying it, and making it easier to suction out. - UAL is a good choice for working on more fibrous areas, like the upper back, or male breast area - It takes longer to do than traditional liposuction, but not longer than tumescent liposuction - There is slightly less blood loss - So far, there appears to be slightly more risk of seromas forming (pockets of fluid) which may have to be drained with a needle After ultrasonic liposuction, it is necessary to perform suction-assisted liposuction to remove the liquified fat. ### Power-assisted liposuction (PAL) PAL uses a specialized cannula with mechanized movement, so that the surgeon does not need to make as many manual movements. Otherwise it is similar to traditional UAL. ### External ultrasound-assisted liposuction (XUAL or EUAL) XUAL is a type of UAL where the ultrasonic energy is applied from outside the body, through the skin, making the specialized cannula of the UAL procedure unnecessary. It was developed because surgeons found that in some cases, the UAL method caused skin necrosis (death) and seromas, which are pockets of a pale yellowish fluid from the body, analogous to hematomas (pockets of red blood cells). XUAL is a possible way to avoid such complications by having the ultrasound applied externally. It can also potentially: - Cause less discomfort for the patient, both during the procedure and afterwards - Decrease blood loss - Allow better access through scar tissue - Treat larger areas At this time however, it is not widely used and studies are not conclusive as to its effectiveness. ### Water-assisted liposuction (WAL) WAL uses a thin fan-shaped water beam, which loosens the structure of the fat tissue, so that it can be removed by a special cannula. During the liposuction the water is continually added and almost immediately aspirated via the same cannula. WAL requires less infiltration solution and much less intraoperative swelling. This allows the surgeon to better realize the target result. The cannula movements are very subtle, helped by the water beam. This is a new technique that there is not much published yet in the medical literature. - Not approved by the FDA in the US. ## Stitches To stitch or not to stitch; that is the surgeon's decision. Since the incisions are small, and since the amount of fluid that must drain out is large: - Some surgeons opt to leave the incisions open, the better to clear the patient's body of excess fluid. They find that the unimpeded departure of that fluid allows the incisions to heal more quickly by themselves. - Others stitch them only partially, leaving space for the fluid to drain out [4][5] [6] - Others delay stitching until most of the fluid has drained out, about 1 or 2 days. In either case, while the fluid is draining, dressings need to be changed often. After one to three days, small self-adhesive bandages are sufficient. # Preparation Before receiving any of the procedures described above: - No anticoagulants should be taken for two weeks before the surgery. - If receiving general anesthesia or sedation, and the surgery will be in the morning, fasting from midnight the night before is required. If only local anesthesia will be used, fasting is not required. - Smoking must be avoided for about two months prior to surgery. Nicotine interferes with circulation and can result in loss of tissue. # The procedure In all liposuction methods, there are certain things that should be done when having the procedure: - The candidate and the surgeon will agree ahead of time on exactly which area(s) will be treated and both will discuss what outcome to expect - A consent form is signed on the day of surgery - An antibiotic will be given either about an hour beforehand, or afterwards - The targeted areas are marked on the body while the candidate is in a standing position - Sometimes photos will be taken of the area to be treated, so the patient will have before and after photos - In the operating room, a sterilizing solution such as Betadine, is applied to the relevant areas - Local anesthetic is injected and the patient may be given a sedative, either orally, or through an IV injection - Incisions are small, about a quarter to a third of an inch - The patient will probably have an IV fluid line, since they will be losing fluid with the fat, and the fluid balance must be kept intact - There will be some monitoring devices attached to the body to keep track of the blood pressure, heart rate, and blood oxygen level - The patient will feel only a scraping or rasping sensation from the cannula movement - Usually the patient can get up, walk around, and go home the same day if they did not receive general anesthesia, although they’ll need someone else to drive # Recovery Depending on the extent of the liposuction, patients are generally able to return to work or school between two days and two weeks. A compression garment or bandage is worn for two to four weeks. If non-absorbable sutures are placed, they will be removed after five to ten days. - Any pain is controlled by a prescription or over-the-counter medication, and may last as long as two weeks, depending on the particular procedure - Swelling will subside in anywhere from two weeks to two months - Bruising will fade after a few days or maybe as long as two weeks later - Numbness may last for several weeks - Normal activity can be resumed anywhere from several days to several weeks afterwards, depending on the procedure - The final result will be evident anywhere from one to six months after surgery, although the patient will see noticeable difference within days or weeks, as swelling subsides ## Expediting recovery The patient should: - Drink enough water to prevent dehydration - Avoid using ice packs or heating pads on the treated areas - Postpone soaking the wounds until they are sealed (usually 48 hours for sutured wounds and a little longer for unsutured ones). - If any dizziness is experienced, the patient should take it easy: stand up slowly, get some help for the shower, remove the compression garment slowly, etc. The suctioned fat cells are permanently gone. However, if the patient does not diet and exercise properly, the remaining fat cell neighbors could still enlarge, creating irregularities. # Side effects A side effect, as opposed to a complication, is medically minor, although it can be uncomfortable, annoying, and even painful. - Bruising: can be painful in the short term, and should fade after a few weeks. - Swelling: should subside gradually over a month or two. - Scars: will vary in size depending on the particular procedure, and should fade over the weeks. Scarring is an individual thing, partly dependent on heredity. For some, scar healing may take as long as a year. - Pain: should be temporary and controlled by either over-the-counter medication, or by a prescription. - Numbness: sometimes persists for a few weeks. - Limited mobility: will depend on the exact procedure. There could be various factors limiting movement for a short while, such as: - Wearing a compression garment - Keeping the head elevated - Temporary swelling or pain The surgeon should advise on how soon the patient can resume normal activity. # Possible complications As with any surgery, there are certain risks, beyond the temporary and minor side effects. The surgeon may mention them during a consultation. Careful patient selection minimizes their occurrence. Their likelihood is somewhat increased when treated areas are very large or numerous and a large amount of fat is removed.[7] During the 1990s there were some deaths as a result of liposuction, as well as alarmingly high rates of complication. By studying more and educating themselves further, surgeons have reduced complication rates. A study published in Dermatologic Surgery (July 2004, pp. 967-978), found that: - “The overall clinical complication rate [for liposuction] ... was 0.7% (5 of 702) ” - The minor complication rate was 0.57% - The major complication rate was 0.14% with one patient requiring hospitalization The more serious possible complications include: - Allergic reaction to medications or material used during surgery. - Infection: any time the body is incised or punctured, bacteria can get in and cause an infection. During liposuction, multiple small puncture wounds are made for inserting the cannula, that can vary in size depending on the technique. - Damage to the skin: most surgeons work on the deeper levels of fat, so as to avoid wounding the skin any more than they must for the insertion of the cannula. - Sometimes the cannula can damage tissue beneath the skin, which may show up as a spotted appearance on the skin surface. - Skin necrosis (dead skin) is a rare complication, in which the skin falls off in the necrotic area. The problem can vary in degree. The resulting wound then needs to heal typically requiring extended wound care. - Puncture of an internal organ: since the surgeon can't see the cannula, sometimes it damages an internal organ, such as the intestines during abdominal liposuction. Such damage can be corrected surgically, although in rare cases it can be fatal. An experienced cosmetic surgeon is unlikely to puncture any internal organ. - Contour irregularities: sometimes the skin may look bumpy and/or withered, because of uneven fat removal, or poor skin elasticity. Not all patients heal in the same way, and with older patients the healing may be slower and a bit imperfect. Sometimes a small touch-up procedure can help. - Thromboembolism and fat embolisation: although liposuction is a low-risk procedure for thromboembolism including pulmonary embolism, the risk can't be ignored.[8][9] - Burns: sometimes the cannula movement can cause friction burns to skin or nerves. Also, in UAL, the heat from the ultrasound device can cause injury to the skin or deeper tissue. - Lidocaine toxicity: when the super-wet or tumescent methods are used, too much saline fluid may be injected, or the fluid may contain too high a concentration of lidocaine. Then the lidocaine may become too much for that particular person’s system. Lidocaine poisoning at first causes tingling and numbness and eventually seizures, followed by unconsciousness and respiratory or cardiac arrest. - Fluid imbalance: since fat contains a lot of fluid and is removed in liposuction, and since the surgeon injects fluid for the procedure, even a very large amount of it for tumescent liposuction, there is a danger of the body’s fluid balance being disturbed. This could happen afterwards, after the patient is at home. If too much fluid remains in the body, the heart, lungs and kidneys could be badly affected. The cosmetic surgeon should give the participant a written list of symptoms to watch for, along with instructions for post-op self-care. # Combined with other procedures ## Liposuction and tightening / lifting skin Liposuction is not a good tool for tightening the skin. The removal of quantities of fat from under the skin can leave the skin even more loose. When drooping skin and fat are the issue, then lift such as a Rhytidectomy Facelift, Mastopexy Breast Lift, Abdominoplasty Tummy Tuck, or Lower body lift, Thigh Lift, or Buttock Lift are better tools and may include liposuction during surgery to refine the sculpture. SAL in combination with other surgery is common, but may have higher complication rates. When done simultaneously, SAL is done minimally in the areas of the undermined tissues to minimize further insult to the blood supply.	https://www.wikidoc.org/index.php/Liposuction
e4276d7d2555ab47b6abdcd1e7aa6e8f2f8e9460	wikidoc	Liraglutide	Liraglutide # 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 Liraglutide is a peptide hormones that is FDA approved for the treatment of type 2 diabetes mellitus. There is a Black Box Warning for this drug as shown here. Common adverse reactions include hypoglycemia，constipation，diarrhea，nausea，vomiting，headache，upper respiratory infection. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) ### Type 2 Diabetes Mellitus - Dosing information - Victoza can be administered once daily at any time of day, independently of meals, and can be injected subcutaneously in the abdomen, thigh or upper arm. The injection site and timing can be changed without dose adjustment. - InitiaL dosage: 0.6 mg/day for one week. - The 0.6 mg dose is a starting dose intended to reduce gastrointestinal symptoms during initial titration, and is not effective for glycemic control. - After one week at 0.6 mg per day, the dose should be increased to 1.2 mg. If the 1.2 mg dose does not result in acceptable glycemic control, the dose can be increased to 1.8 mg. - When initiating Victoza, consider reducing the dose of concomitantly administered insulin secretagogues (such as sulfonylureas) to reduce the risk of hypoglycemia - When using Victoza with insulin, administer as separate injections. Never mix. It is acceptable to inject Victoza and insulin in the same body region but the injections should not be adjacent to each other. - Victoza solution should be inspected prior to each injection, and the solution should be used only if it is clear, colorless, and contains no particles. - If a dose is missed, the once-daily regimen should be resumed as prescribed with the next scheduled dose. An extra dose or increase in dose should not be taken to make-up for the missed dose. - Based on the elimination half-life, patients should be advised to reinitiate Victoza at ‘’‘0.6 mg’‘’ if more than 3 days have elapsed since the last Victoza dose. This approach will mitigate any gastrointestinal symptoms associated with reinitiation of treatment. Upon reinitiation, Victoza should be titrated at the discretion of the prescribing healthcare provider. ### Important Limitations of Use - Because of the uncertain relevance of the rodent thyroid C-cell tumor findings to humans, prescribe Victoza only to patients for whom the potential benefits are considered to outweigh the potential risk. Victoza is not recommended as first-line therapy for patients who have inadequate glycemic control on diet and exercise. - Based on spontaneous postmarketing reports, acute pancreatitis, including fatal and non-fatal hemorrhagic or necrotizing pancreatitis has been observed in patients treated with Victoza. Victoza has not been studied in patients with a history of pancreatitis. It is unknown whether patients with a history of pancreatitis are at increased risk for pancreatitis while using Victoza. Other antidiabetic therapies should be considered in patients with a history of pancreatitis. - Victoza is not a substitute for insulin. Victoza should not be used in patients with type 1 diabetes mellitus or for the treatment of diabetic ketoacidosis, as it would not be effective in these settings. - The concurrent use of Victoza and prandial insulin has not been studied. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Liraglutide in adult patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Liraglutide in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) Safety and effectiveness of Victoza have not been established in pediatric patients. Victoza is not recommended for use in pediatric patients. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Liraglutide in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Liraglutide in pediatric patients. # Contraindications - Do not use in patients with a personal or family history of medullary thyroid carcinoma (MTC) or in patients with Multiple Endocrine Neoplasia syndrome type 2 (MEN 2). - Do not use in patients with a prior serious hypersensitivity reaction to Victoza or to any of the product components. # Warnings - Liraglutide causes dose-dependent and treatment-duration-dependent thyroid C-cell tumors (adenomas and/or carcinomas) at clinically relevant exposures in both genders of rats and mice. Malignant thyroid C-cell carcinomas were detected in rats and mice. A statistically significant increase in cancer was observed in rats receiving liraglutide at 8-times clinical exposure compared to controls. It is unknown whether Victoza will cause thyroid C-cell tumors, including medullary thyroid carcinoma (MTC), in humans, as the human relevance of liraglutide-induced rodent thyroid C-cell tumors could not be determined by clinical or nonclinical studies - In the clinical trials, there have been 6 reported cases of thyroid C-cell hyperplasia among Victoza-treated patients and 2 cases in comparator-treated patients (1.3 vs. 1.0 cases per 1000 patient-years). One comparator-treated patient with MTC had pre-treatment serum calcitonin concentrations >1000 ng/L suggesting pre-existing disease. All of these cases were diagnosed after thyroidectomy, which was prompted by abnormal results on routine, protocol-specified measurements of serum calcitonin. Five of the six Victoza-treated patients had elevated calcitonin concentrations at baseline and throughout the trial. One Victoza and one non-Victoza-treated patient developed elevated calcitonin concentrations while on treatment. - Calcitonin, a biological marker of MTC, was measured throughout the clinical development program. The serum calcitonin assay used in the Victoza clinical trials had a lower limit of quantification (LLOQ) of 0.7 ng/L and the upper limit of the reference range was 5.0 ng/L for women and 8.4 ng/L for men. At Weeks 26 and 52 in the clinical trials, adjusted mean serum calcitonin concentrations were higher in Victoza-treated patients compared to placebo-treated patients but not compared to patients receiving active comparator. At these timepoints, the adjusted mean serum calcitonin values (~ 1.0 ng/L) were just above the LLOQ with between-group differences in adjusted mean serum calcitonin values of approximately 0.1 ng/L or less. Among patients with pre-treatment serum calcitonin below the upper limit of the reference range, shifts to above the upper limit of the reference range which persisted in subsequent measurements occurred most frequently among patients treated with Victoza 1.8 mg/day. In trials with on-treatment serum calcitonin measurements out to 5-6 months, 1.9% of patients treated with Victoza 1.8 mg/day developed new and persistent calcitonin elevations above the upper limit of the reference range compared to 0.8-1.1% of patients treated with control medication or the 0.6 and 1.2 mg doses of Victoza. In trials with on-treatment serum calcitonin measurements out to 12 months, 1.3% of patients treated with Victoza 1.8 mg/day had new and persistent elevations of calcitonin from below or within the reference range to above the upper limit of the reference range, compared to 0.6%, 0% and 1.0% of patients treated with Victoza 1.2 mg, placebo and active control, respectively. Otherwise, Victoza did not produce consistent dose-dependent or time-dependent increases in serum calcitonin. - Patients with MTC usually have calcitonin values >50 ng/L. In Victoza clinical trials, among patients with pre-treatment serum calcitonin 50 ng/L. The Victoza-treated patient who developed serum calcitonin >50 ng/L had an elevated pre-treatment serum calcitonin of 10.7 ng/L that increased to 30.7 ng/L at Week 12 and 53.5 ng/L at the end of the 6-month trial. Follow-up serum calcitonin was 22.3 ng/L more than 2.5 years after the last dose of Victoza. The largest increase in serum calcitonin in a comparator-treated patient was seen with glimepiride in a patient whose serum calcitonin increased from 19.3 ng/L at baseline to 44.8 ng/L at Week 65 and 38.1 ng/L at Week 104. Among patients who began with serum calcitonin 20 ng/L occurred in 0.7% of Victoza-treated patients, 0.3% of placebo-treated patients, and 0.5% of active-comparator-treated patients, with an incidence of 1.1% among patients treated with 1.8 mg/day of Victoza. The clinical significance of these findings is unknown. - Counsel patients regarding the risk for MTC and the symptoms of thyroid tumors (e.g. a mass in the neck, dysphagia, dyspnea or persistent hoarseness). It is unknown whether monitoring with serum calcitonin or thyroid ultrasound will mitigate the potential risk of MTC, and such monitoring may increase the risk of unnecessary procedures, due to low test specificity for serum calcitonin and a high background incidence of thyroid disease. Patients with thyroid nodules noted on physical examination or neck imaging obtained for other reasons should be referred to an endocrinologist for further evaluation. Although routine monitoring of serum calcitonin is of uncertain value in patients treated with Victoza, if serum calcitonin is measured and found to be elevated, the patient should be referred to an endocrinologist for further evaluation. ### Pancreatitis - Based on spontaneous postmarketing reports, acute pancreatitis, including fatal and non-fatal hemorrhagic or necrotizing pancreatitis, has been observed in patients treated with Victoza. After initiation of Victoza, observe patients carefully for signs and symptoms of pancreatitis (including persistent severe abdominal pain, sometimes radiating to the back and which may or may not be accompanied by vomiting). If pancreatitis is suspected, Victoza should promptly be discontinued and appropriate management should be initiated. If pancreatitis is confirmed, Victoza should not be restarted. Consider antidiabetic therapies other than Victoza in patients with a history of pancreatitis. - In clinical trials of Victoza, there have been 13 cases of pancreatitis among Victoza-treated patients and 1 case in a comparator (glimepiride) treated patient (2.7 vs. 0.5 cases per 1000 patient-years). Nine of the 13 cases with Victoza were reported as acute pancreatitis and four were reported as chronic pancreatitis. In one case in a Victoza-treated patient, pancreatitis, with necrosis, was observed and led to death; however clinical causality could not be established. Some patients had other risk factors for pancreatitis, such as a history of cholelithiasis or alcohol abuse. - Patients receiving Victoza in combination with an insulin secretagogue (e.g., sulfonylurea) or insulin may have an increased risk of hypoglycemia. The risk of hypoglycemia may be lowered by a reduction in the dose of sulfonylurea (or other concomitantly administered insulin secretagogues) or insulin. - Victoza has not been found to be directly nephrotoxic in animal studies or clinical trials. There have been postmarketing reports of acute renal failure and worsening of chronic renal failure, which may sometimes require hemodialysis in Victoza-treated patients. Some of these events were reported in patients without known underlying renal disease. A majority of the reported events occurred in patients who had experienced nausea, vomiting, diarrhea, or dehydration . Some of the reported events occurred in patients receiving one or more medications known to affect renal function or hydration status. Altered renal function has been reversed in many of the reported cases with supportive treatment and discontinuation of potentially causative agents, including Victoza. Use caution when initiating or escalating doses of Victoza in patients with renal impairment. - There have been postmarketing reports of serious hypersensitivity reactions (e.g., anaphylactic reactions and angioedema) in patients treated with Victoza. If a hypersensitivity reaction occurs, the patient should discontinue Victoza and other suspect medications and promptly seek medical advice. - Angioedema has also been reported with other GLP-1 receptor agonists. Use caution in a patient with a history of angioedema with another GLP-1 receptor agonist because it is unknown whether such patients will be predisposed to angioedema with Victoza. - There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with Victoza or any other antidiabetic drug. # 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 practice. - The safety of Victoza has been evaluated in 8 clinical trials : - A double-blind 52-week monotherapy trial compared Victoza 1.2 mg daily, Victoza 1.8 mg daily, and glimepiride 8 mg daily. A double-blind 26 week add-on to metformin trial compared Victoza 0.6 mg once-daily, Victoza 1.2 mg once-daily, Victoza 1.8 mg once-daily, placebo, and glimepiride 4 mg once-daily. - A double-blind 26 week add-on to metformin trial compared Victoza 0.6 mg once-daily, Victoza 1.2 mg once-daily, Victoza 1.8 mg once-daily, placebo, and glimepiride 4 mg once-daily. - A double-blind 26 week add-on to glimepiride trial compared Victoza 0.6 mg daily, Victoza 1.2 mg once-daily, Victoza 1.8 mg once-daily, placebo, and rosiglitazone 4 mg once-daily. - A 26 week add-on to metformin + glimepiride trial, compared double-blind Victoza 1.8 mg once-daily, double-blind placebo, and open-label insulin glargine once-daily. - A double-blind 26-week add-on to metformin + rosiglitazone trial compared Victoza 1.2 mg once-daily, Victoza 1.8 mg once-daily and placebo. - An open-label 26-week add-on to metformin and/or sulfonylurea trial compared Victoza 1.8 mg once-daily and exenatide 10 mcg twice-daily. - An open-label 26-week add-on to metformin trial compared Victoza 1.2 mg once-daily, Victoza 1.8 mg once-daily, and sitagliptin 100 mg once-daily. - An open-label 26-week trial compared insulin detemir as add-on to Victoza 1.8 mg + metformin to continued treatment with Victoza + metformin alone. - Withdrawals - The incidence of withdrawal due to adverse events was 7.8% for Victoza-treated patients and 3.4% for comparator-treated patients in the five double-blind controlled trials of 26 weeks duration or longer. This difference was driven by withdrawals due to gastrointestinal adverse reactions, which occurred in 5.0% of Victoza-treated patients and 0.5% of comparator-treated patients. In these five trials, the most common adverse reactions leading to withdrawal for Victoza-treated patients were nausea (2.8% versus 0% for comparator) and vomiting (1.5% versus 0.1% for comparator). Withdrawal due to gastrointestinal adverse events mainly occurred during the first 2-3 months of the trials. - Common adverse reactions - Tables 1, 2, 3 and 4 summarize common adverse reactions (hypoglycemia is discussed separately) reported in seven of the eight controlled trials of 26 weeks duration or longer. Most of these adverse reactions were gastrointestinal in nature. - In the five double-blind clinical trials of 26 weeks duration or longer, gastrointestinal adverse reactions were reported in 41% of Victoza-treated patients and were dose-related. :Gastrointestinal adverse reactions occurred in 17% of comparator-treated patients. Common adverse reactions that occurred at a higher incidence among Victoza-treated patients included nausea, vomiting, diarrhea, dyspepsia and constipation. - In the five double-blind and three open-label clinical trials of 26 weeks duration or longer, the percentage of patients who reported nausea declined over time. In the five double-blind trials approximately 13% of Victoza-treated patients and 2% of comparator-treated patients reported nausea during the first 2 weeks of treatment. - In the 26-week open-label trial comparing Victoza to exenatide, both in combination with metformin and/or sulfonylurea, gastrointestinal adverse reactions were reported at a similar incidence in the Victoza and exenatide treatment groups (Table 3). - In the 26-week open-label trial comparing Victoza 1.2 mg, Victoza 1.8 mg and sitagliptin 100 mg, all in combination with metformin, gastrointestinal adverse reactions were reported at a higher incidence with Victoza than sitagliptin (Table 4). - In the remaining 26-week trial, all patients received Victoza 1.8 mg + metformin during a 12-week run-in period. During the run-in period, 167 patients (17% of enrolled total) withdrew from the trial: 76 (46% of withdrawals) of these patients doing so because of gastrointestinal adverse reactions and 15 (9% of withdrawals) doing so due to other adverse events. :Only those patients who completed the run-in period with inadequate glycemic control were randomized to 26 weeks of add-on therapy with insulin detemir or continued, unchanged treatment with Victoza 1.8 mg + metformin. During this randomized 26-week period, diarrhea was the only adverse reaction reported in ≥5% of patients treated with Victoza 1.8 mg + metformin + insulin detemir (11.7%) and greater than in patients treated with Victoza 1.8 mg and metformin alone (6.9%). - Immunogenicity - Consistent with the potentially immunogenic properties of protein and peptide pharmaceuticals, patients treated with Victoza may develop anti-liraglutide antibodies. Approximately 50-70% of Victoza-treated patients in the five double-blind clinical trials of 26 weeks duration or longer were tested for the presence of anti-liraglutide antibodies at the end of treatment. Low titers (concentrations not requiring dilution of serum) of anti-liraglutide antibodies were detected in 8.6% of these Victoza-treated patients. Sampling was not performed uniformly across all patients in the clinical trials, and this may have resulted in an underestimate of the actual percentage of patients who developed antibodies. Cross-reacting anti-liraglutide antibodies to native glucagon-like peptide-1 (GLP-1) occurred in 6.9% of the Victoza-treated patients in the double-blind 52-week monotherapy trial and in 4.8% of the Victoza-treated patients in the double-blind 26-week add-on combination therapy trials. These cross-reacting antibodies were not tested for neutralizing effect against native GLP-1, and thus the potential for clinically significant neutralization of native GLP-1 was not assessed. Antibodies that had a neutralizing effect on liraglutide in an in vitro assay occurred in 2.3% of the Victoza-treated patients in the double-blind 52-week monotherapy trial and in 1.0% of the Victoza-treated patients in the double-blind 26-week add-on combination therapy trials. - Among Victoza-treated patients who developed anti-liraglutide antibodies, the most common category of adverse events was that of infections, which occurred among 40% of these patients compared to 36%, 34% and 35% of antibody-negative Victoza-treated, placebo-treated and active-control-treated patients, respectively. The specific infections which occurred with greater frequency among Victoza-treated antibody-positive patients were primarily nonserious upper respiratory tract infections, which occurred among 11% of Victoza-treated antibody-positive patients; and among 7%, 7% and 5% of antibody-negative Victoza-treated, placebo-treated and active-control-treated patients, respectively. Among Victoza-treated antibody-negative patients, the most common category of adverse events was that of gastrointestinal events, which occurred in 43%, 18% and 19% of antibody-negative Victoza-treated, placebo-treated and active-control-treated patients, respectively. Antibody formation was not associated with reduced efficacy of Victoza when comparing mean HbA1c of all antibody-positive and all antibody-negative patients. However, the 3 patients with the highest titers of anti-liraglutide antibodies had no reduction in HbA1c with Victoza treatment. - In the five double-blind clinical trials of Victoza, events from a composite of adverse events potentially related to immunogenicity (e.g. urticaria, angioedema) occurred among 0.8% of Victoza-treated patients and among 0.4% of comparator-treated patients. Urticaria accounted for approximately one-half of the events in this composite for Victoza-treated patients. :Patients who developed anti-liraglutide antibodies were not more likely to develop events from the immunogenicity events composite than were patients who did not develop anti-liraglutide antibodies. - Injection site reactions - Injection site reactions (e.g., injection site rash, erythema) were reported in approximately 2% of Victoza-treated patients in the five double-blind clinical trials of at least 26 weeks duration. Less than 0.2% of Victoza-treated patients discontinued due to injection site reactions. - Papillary thyroid carcinoma - In clinical trials of Victoza, there were 7 reported cases of papillary thyroid carcinoma in patients treated with Victoza and 1 case in a comparator-treated patient (1.5 vs. 0.5 cases per 1000 patient-years). Most of these papillary thyroid carcinomas were <1 cm in greatest diameter and were diagnosed in surgical pathology specimens after thyroidectomy prompted by findings on protocol-specified screening with serum calcitonin or thyroid ultrasound. - Hypoglycemia - In the eight clinical trials of at least 26 weeks duration, hypoglycemia requiring the assistance of another person for treatment occurred in 11 Victoza-treated patients (2.3 cases per 1000 patient-years) and in two exenatide-treated patients. Of these 11 Victoza-treated patients, six patients were concomitantly using metformin and a sulfonylurea, one was concomitantly using a sulfonylurea, two were concomitantly using metformin (blood glucose values were 65 and 94 mg/dL) and two were using Victoza as monotherapy (one of these patients was undergoing an intravenous glucose tolerance test and the other was receiving insulin as treatment during a hospital stay). For these two patients on Victoza monotherapy, the insulin treatment was the likely explanation for the hypoglycemia. - In the 26-week open-label trial comparing Victoza to sitagliptin, the incidence of hypoglycemic events defined as symptoms accompanied by a fingerstick glucose <56 mg/dL was comparable among the treatment groups (approximately 5%). - In a pooled analysis of clinical trials, the incidence rate (per 1,000 patient-years) for malignant neoplasms (based on investigator-reported events, medical history, pathology reports, and surgical reports from both blinded and open-label study periods) was 10.9 for Victoza, 6.3 for placebo, and 7.2 for active comparator. After excluding papillary thyroid carcinoma events , no particular cancer cell type predominated. Seven malignant neoplasm events were reported beyond 1 year of exposure to study medication, six events among Victoza-treated patients (4 colon, 1 prostate and 1 nasopharyngeal), no events with placebo and one event with active comparator (colon). Causality has not been established. - In the five clinical trials of at least 26 weeks duration, mildly elevated serum bilirubin concentrations (elevations to no more than twice the upper limit of the reference range) occurred in 4.0% of Victoza-treated patients, 2.1% of placebo-treated patients and 3.5% of active-comparator-treated patients. This finding was not accompanied by abnormalities in other liver tests. The significance of this isolated finding is unknown. - Victoza did not have adverse effects on blood pressure. Mean increases from baseline in heart rate of 2 to 3 beats per minute have been observed with Victoza compared to placebo. The long-term clinical effects of the increase in pulse rate have not been established. ## Postmarketing Experience - The following additional adverse reactions have been reported during post-approval use of Victoza. Because these events 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. - Dehydration resulting from nausea, vomiting and diarrhea. - Increased serum creatinine, acute renal failure or worsening of chronic renal failure, sometimes requiring hemodialysis. - Angioedema and anaphylactic reactions. - Allergic reactions: rash and pruritus - Acute pancreatitis, hemorrhagic and necrotizing pancreatitis sometimes resulting in death # Drug Interactions ## Oral Medications - Victoza causes a delay of gastric emptying, and thereby has the potential to impact the absorption of concomitantly administered oral medications. In clinical pharmacology trials, Victoza did not affect the absorption of the tested orally administered medications to any clinically relevant degree. Nonetheless, caution should be exercised when oral medications are concomitantly administered with Victoza. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): C - There are no adequate and well-controlled studies of Victoza in pregnant women. Victoza should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Liraglutide has been shown to be teratogenic in rats at or above 0.8 times the human systemic exposures resulting from the maximum recommended human dose (MRHD) of 1.8 mg/day based on plasma area under the time-concentration curve (AUC). Liraglutide has been shown to cause reduced growth and increased total major abnormalities in rabbits at systemic exposures below human exposure at the MRHD based on plasma AUC. - Female rats given subcutaneous doses of 0.1, 0.25 and 1.0 mg/kg/day liraglutide beginning 2 weeks before mating through gestation day 17 had estimated systemic exposures 0.8-, 3-, and 11-times the human exposure at the MRHD based on plasma AUC comparison. The number of early embryonic deaths in the 1 mg/kg/day group increased slightly. Fetal abnormalities and variations in kidneys and blood vessels, irregular ossification of the skull, and a more complete state of ossification occurred at all doses. Mottled liver and minimally kinked ribs occurred at the highest dose. The incidence of fetal malformations in liraglutide-treated groups exceeding concurrent and historical controls were misshapen oropharynx and/or narrowed opening into larynx at 0.1 mg/kg/day and umbilical hernia at 0.1 and 0.25 mg/kg/day. - Pregnant rabbits given subcutaneous doses of 0.01, 0.025 and 0.05 mg/kg/day liraglutide from gestation day 6 through day 18 inclusive, had estimated systemic exposures less than the human exposure at the MRHD of 1.8 mg/day at all doses, based on plasma AUC. Liraglutide decreased fetal weight and dose-dependently increased the incidence of total major fetal abnormalities at all doses. The incidence of malformations exceeded concurrent and historical controls at 0.01 mg/kg/day (kidneys, scapula), ≥ 0.01 mg/kg/day (eyes, forelimb), 0.025 mg/kg/day (brain, tail and sacral vertebrae, major blood vessels and heart, umbilicus), ≥ 0.025 mg/kg/day (sternum) and at 0.05 mg/kg/day (parietal bones, major blood vessels). Irregular ossification and/or skeletal abnormalities occurred in the skull and jaw, vertebrae and ribs, sternum, pelvis, tail, and scapula; and dose-dependent minor skeletal variations were observed. Visceral abnormalities occurred in blood vessels, lung, liver, and esophagus. Bilobed or bifurcated gallbladder was seen in all treatment groups, but not in the control group. - In pregnant female rats given subcutaneous doses of 0.1, 0.25 and 1.0 mg/kg/day liraglutide from gestation day 6 through weaning or termination of nursing on lactation day 24, estimated systemic exposures were 0.8-, 3-, and 11-times human exposure at the MRHD of 1.8 mg/day, based on plasma AUC. A slight delay in parturition was observed in the majority of treated rats. Group mean body weight of neonatal rats from liraglutide-treated dams was lower than neonatal rats from control group dams. Bloody scabs and agitated behavior occurred in male rats descended from dams treated with 1 mg/kg/day liraglutide. Group mean body weight from birth to postpartum day 14 trended lower in F2 generation rats descended from liraglutide-treated rats compared to F2 generation rats descended from controls, but differences did not reach statistical significance for any group. Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Liraglutide in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Liraglutide during labor and delivery. ### Nursing Mothers - It is not known whether Victoza is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for tumorigenicity shown for liraglutide in animal studies, a decision should be made whether to discontinue nursing or to discontinue Victoza, taking into account the importance of the drug to the mother. In lactating rats, liraglutide was excreted unchanged in milk at concentrations approximately 50% of maternal plasma concentrations. ### Pediatric Use - Safety and effectiveness of Victoza have not been established in pediatric patients. Victoza is not recommended for use in pediatric patients. ### Geriatic Use - In the Victoza clinical trials, a total of 797 (20%) of the patients were 65 years of age and over and 113 (2.8%) were 75 years of age and over. No overall differences in safety or effectiveness were observed between these patients and younger patients, but greater sensitivity of some older individuals cannot be ruled out. ### Gender There is no FDA guidance on the use of Liraglutide with respect to specific gender populations. ### Race There is no FDA guidance on the use of Liraglutide with respect to specific racial populations. ### Renal Impairment - There is limited experience with Victoza in patients with mild, moderate, and severe renal impairment, including end-stage renal disease. However, there have been postmarketing reports of acute renal failure and worsening of chronic renal failure, which may sometimes require hemodialysis . Victoza should be used with caution in this patient population. No dose adjustment of Victoza is recommended for patients with renal impairment. ### Hepatic Impairment - There is limited experience in patients with mild, moderate or severe hepatic impairment. Therefore, Victoza should be used with caution in this patient population. No dose adjustment of Victoza is recommended for patients with hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Liraglutide in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Liraglutide in patients who are immunocompromised. ### Gastroparesis - Victoza slows gastric emptying. Victoza has not been studied in patients with pre-existing gastroparesis. # Administration and Monitoring ### Administration Intramuscular ### Monitoring FDA Package Insert for Abcixmab contains no information regarding drug monitoring. # IV Compatibility There is limited information about the IV Compatibility. # Overdosage - Overdoses have been reported in clinical trials and post-marketing use of Victoza. Effects have included severe nausea and severe vomiting. In the event of overdosage, appropriate supportive treatment should be initiated according to the patient’s clinical signs and symptoms. # Pharmacology ## Mechanism of Action - Liraglutide is an acylated human Glucagon-Like Peptide-1 (GLP-1) receptor agonist with 97% amino acid sequence homology to endogenous human GLP-1(7-37). GLP-1(7-37) represents <20% of total circulating endogenous GLP-1. Like GLP-1(7-37), liraglutide activates the GLP-1 receptor, a membrane-bound cell-surface receptor coupled to adenylyl cyclase by the stimulatory G-protein, Gs, in pancreatic beta cells. Liraglutide increases intracellular cyclic AMP (cAMP) leading to insulin release in the presence of elevated glucose concentrations. This insulin secretion subsides as blood glucose concentrations decrease and approach euglycemia. Liraglutide also decreases glucagon secretion in a glucose-dependent manner. The mechanism of blood glucose lowering also involves a delay in gastric emptying. - GLP-1(7-37) has a half-life of 1.5-2 minutes due to degradation by the ubiquitous endogenous enzymes, dipeptidyl peptidase IV (DPP-IV) and neutral endopeptidases (NEP). Unlike native GLP-1, liraglutide is stable against metabolic degradation by both peptidases and has a plasma half-life of 13 hours after subcutaneous administration. The pharmacokinetic profile of liraglutide, which makes it suitable for once daily administration, is a result of self-association that delays absorption, plasma protein binding and stability against metabolic degradation by DPP-IV and NEP. ## Structure - Victoza contains liraglutide, an analog of human GLP-1 and acts as a GLP-1 receptor agonist. The peptide precursor of liraglutide, produced by a process that includes expression of recombinant DNA in Saccharomyces cerevisiae, has been engineered to be 97% homologous to native human GLP-1 by substituting arginine for lysine at position 34. Liraglutide is made by attaching a C-16 fatty acid (palmitic acid) with a glutamic acid spacer on the remaining lysine residue at position 26 of the peptide precursor. The molecular formula of liraglutide is C172H265N43O51 and the molecular weight is 3751.2 Daltons. The structural formula (Figure 1) is: - Victoza is a clear, colorless solution. Each 1 mL of Victoza solution contains 6 mg of liraglutide. Each pre-filled pen contains a 3 mL solution of Victoza equivalent to 18 mg liraglutide (free-base, anhydrous) and the following inactive ingredients: disodium phosphate dihydrate, 1.42 mg; propylene glycol, 14 mg; phenol, 5.5 mg; and water for injection. ## Pharmacodynamics - Victoza’s pharmacodynamic profile is consistent with its pharmacokinetic profile observed after single subcutaneous administration as Victoza lowered fasting, premeal and postprandial glucose throughout the day. - Fasting and postprandial glucose was measured before and up to 5 hours after a standardized meal after treatment to steady state with 0.6, 1.2 and 1.8 mg Victoza or placebo. Compared to placebo, the postprandial plasma glucose AUC0-300min was 35% lower after Victoza 1.2 mg and 38% lower after Victoza 1.8 mg. Glucose-dependent insulin secretion - The effect of a single dose of 7.5 mcg/kg (~ 0.7 mg) Victoza on insulin secretion rates (ISR) was investigated in 10 patients with type 2 diabetes during graded glucose infusion. In these patients, on average, the ISR response was increased in a glucose-dependent manner (Figure 2). Glucagon secretion - Victoza lowered blood glucose by stimulating insulin secretion and lowering glucagon secretion. A single dose of Victoza 7.5 mcg/kg (~ 0.7 mg) did not impair glucagon response to low glucose concentrations. Gastric emptying - Victoza causes a delay of gastric emptying, thereby reducing the rate at which postprandial glucose appears in the circulation. Cardiac Electrophysiology (QTc) - The effect of Victoza on cardiac repolarization was tested in a QTc study. Victoza at steady state concentrations with daily doses up to 1.8 mg did not produce QTc prolongation. ## Pharmacokinetics Absorption - Following subcutaneous administration, maximum concentrations of liraglutide are achieved at 8-12 hours post dosing. The mean peak (Cmax) and total (AUC) exposures of liraglutide were 35 ng/mL and 960 ng·h/mL, respectively, for a subcutaneous single dose of 0.6 mg. After subcutaneous single dose administrations, Cmax and AUC of liraglutide increased proportionally over the therapeutic dose range of 0.6 mg to 1.8 mg. At 1.8 mg Victoza, the average steady state concentration of liraglutide over 24 hours was approximately 128 ng/mL. AUC0-∞ was equivalent between upper arm and abdomen, and between upper arm and thigh. AUC0-∞ from thigh was 22% lower than that from abdomen. However, liraglutide exposures were considered comparable among these three subcutaneous injection sites. Absolute bioavailability of liraglutide following subcutaneous administration is approximately 55%. Distribution - The mean apparent volume of distribution after subcutaneous administration of Victoza 0.6 mg is approximately 13 L. The mean volume of distribution after intravenous administration of Victoza is 0.07 L/kg. Liraglutide is extensively bound to plasma protein (>98%). Metabolism - During the initial 24 hours following administration of a single -liraglutide dose to healthy subjects, the major component in plasma was intact liraglutide. Liraglutide is endogenously metabolized in a similar manner to large proteins without a specific organ as a major route of elimination. Elimination - Following a -liraglutide dose, intact liraglutide was not detected in urine or feces. Only a minor part of the administered radioactivity was excreted as liraglutide-related metabolites in urine or feces (6% and 5%, respectively). The majority of urine and feces radioactivity was excreted during the first 6-8 days. The mean apparent clearance following subcutaneous administration of a single dose of liraglutide is approximately 1.2 L/h with an elimination half-life of approximately 13 hours, making Victoza suitable for once daily administration. ## Specific Populations Elderly - Age had no effect on the pharmacokinetics of Victoza based on a pharmacokinetic study in healthy elderly subjects (65 to 83 years) and population pharmacokinetic analyses of patients 18 to 80 years of age . Gender - Based on the results of population pharmacokinetic analyses, females have 34% lower weight-adjusted clearance of Victoza compared to males. Based on the exposure response data, no dose adjustment is necessary based on gender. Race and Ethnicity - Race and ethnicity had no effect on the pharmacokinetics of Victoza based on the results of population pharmacokinetic analyses that included Caucasian, Black, Asian and Hispanic/Non-Hispanic subjects. Body Weight - Body weight significantly affects the pharmacokinetics of Victoza based on results of population pharmacokinetic analyses. The exposure of liraglutide decreases with an increase in baseline body weight. However, the 1.2 mg and 1.8 mg daily doses of Victoza provided adequate systemic exposures over the body weight range of 40 – 160 kg evaluated in the clinical trials. Liraglutide was not studied in patients with body weight >160 kg. Pediatric - Victoza has not been studied in pediatric patients . Renal Impairment - The single-dose pharmacokinetics of Victoza were evaluated in subjects with varying degrees of renal impairment. Subjects with mild (estimated creatinine clearance 50-80 mL/min) to severe (estimated creatinine clearance <30 mL/min) renal impairment and subjects with end-stage renal disease requiring dialysis were included in the trial. Compared to healthy subjects, liraglutide AUC in mild, moderate, and severe renal impairment and in end-stage renal disease was on average 35%, 19%, 29% and 30% lower, respectively . Hepatic Impairment - The single-dose pharmacokinetics of Victoza were evaluated in subjects with varying degrees of hepatic impairment. Subjects with mild (Child Pugh score 5-6) to severe (Child Pugh score > 9) hepatic impairment were included in the trial. Compared to healthy subjects, liraglutide AUC in subjects with mild, moderate and severe hepatic impairment was on average 11%, 14% and 42% lower, respectively ### Drug Interactions ### In vitro assessment of drug-drug interactions - Victoza has low potential for pharmacokinetic drug-drug interactions related to cytochrome P450 (CYP) and plasma protein binding. ### In vivo assessment of drug-drug interactions - The drug-drug interaction studies were performed at steady state with Victoza 1.8 mg/day. Before administration of concomitant treatment, subjects underwent a 0.6 mg weekly dose increase to reach the maximum dose of 1.8 mg/day. Administration of the interacting drugs was timed so that Cmax of Victoza (8-12 h) would coincide with the absorption peak of the co-administered drugs. ### Digoxin - A single dose of Digoxin 1 mg was administered 7 hours after the dose of Victoza at steady state. The concomitant administration with Victoza resulted in a reduction of Digoxin AUC by 16%; Cmax decreased by 31%. Digoxin median time to maximal concentration (Tmax) was delayed from 1 h to 1.5 h. ### Lisinopril - A single dose of Lisinopril 20 mg was administered 5 minutes after the dose of Victoza at steady state. The co-administration with Victoza resulted in a reduction of Lisinopril AUC by 15%; Cmax decreased by 27%. Lisinopril median Tmax was delayed from 6 h to 8 h with Victoza. ### Atorvastatin - Victoza did not change the overall exposure (AUC) of Atorvastatin following a single dose of Atorvastatin 40 mg, administered 5 hours after the dose of Victoza at steady state. Atorvastatin Cmax was decreased by 38% and median Tmax was delayed from 1 h to 3 h with Victoza. ### Acetaminophen - Victoza did not change the overall exposure (AUC) of Acetaminophen following a single dose of Acetaminophen 1000 mg, administered 8 hours after the dose of Victoza at steady state. Acetaminophen Cmax was decreased by 31% and median Tmax was delayed up to 15 minutes. ### Griseofulvin - Victoza did not change the overall exposure (AUC) of Griseofulvin following co-administration of a single dose of Griseofulvin 500 mg with Victoza at steady state. Griseofulvin Cmax increased by 37% while median Tmax did not change. ### Oral Contraceptives - A single dose of an oral contraceptive combination product containing 0.03 mg ethinylestradiol and 0.15 mg levonorgestrel was administered under fed conditions and 7 hours after the dose of Victoza at steady state. Victoza lowered ethinylestradiol and levonorgestrel Cmax by 12% and 13%, respectively. There was no effect of Victoza on the overall exposure (AUC) of ethinylestradiol. Victoza increased the levonorgestrel AUC0-∞ by 18%. Victoza delayed Tmax for both ethinylestradiol and levonorgestrel by 1.5 h. ### Insulin Detemir - No pharmacokinetic interaction was observed between Victoza and insulin detemir when separate subcutaneous injections of insulin detemir 0.5 Unit/kg (single-dose) and Victoza 1.8 mg (steady state) were administered in patients with type 2 diabetes. ## Nonclinical Toxicology ### Carcinogenesis, Mutagenesis, Impairment of Fertility - A 104-week carcinogenicity study was conducted in male and female CD-1 mice at doses of 0.03, 0.2, 1.0, and 3.0 mg/kg/day liraglutide administered by bolus subcutaneous injection yielding systemic exposures 0.2-, 2-, 10- and 45-times the human exposure, respectively, at the MRHD of 1.8 mg/day based on plasma AUC comparison. A dose-related increase in benign thyroid C-cell adenomas was seen in the 1.0 and the 3.0 mg/kg/day groups with incidences of 13% and 19% in males and 6% and 20% in females, respectively. C-cell adenomas did not occur in control groups or 0.03 and 0.2 mg/kg/day groups. Treatment-related malignant C-cell carcinomas occurred in 3% of females in the 3.0 mg/kg/day group. Thyroid C-cell tumors are rare findings during carcinogenicity testing in mice. A treatment-related increase in fibrosarcomas was seen on the dorsal skin and subcutis, the body surface used for drug injection, in males in the 3 mg/kg/day group. These fibrosarcomas were attributed to the high local concentration of drug near the injection site. The liraglutide concentration in the clinical formulation (6 mg/mL) is 10-times higher than the concentration in the formulation used to administer 3 mg/kg/day liraglutide to mice in the carcinogenicity study (0.6 mg/mL). - A 104-week carcinogenicity study was conducted in male and female Sprague Dawley rats at doses of 0.075, 0.25 and 0.75 mg/kg/day liraglutide administered by bolus subcutaneous injection with exposures 0.5-, 2- and 8-times the human exposure, respectively, resulting from the MRHD based on plasma AUC comparison. A treatment-related increase in benign thyroid C-cell adenomas was seen in males in 0.25 and 0.75 mg/kg/day liraglutide groups with incidences of 12%, 16%, 42%, and 46% and in all female liraglutide-treated groups with incidences of 10%, 27%, 33%, and 56% in 0 (control), 0.075, 0.25, and 0.75 mg/kg/day groups, respectively. A treatment-related increase in malignant thyroid C-cell carcinomas was observed in all male liraglutide-treated groups with incidences of 2%, 8%, 6%, and 14% and in females at 0.25 and 0.75 mg/kg/day with incidences of 0%, 0%, 4%, and 6% in 0 (control), 0.075, 0.25, and 0.75 mg/kg/day groups, respectively. Thyroid C-cell carcinomas are rare findings during carcinogenicity testing in rats. - Human relevance of thyroid C-cell tumors in mice and rats is unknown and could not be determined by clinical studies or nonclinical studies. - Liraglutide was negative with and without metabolic activation in the Ames test for mutagenicity and in a human peripheral blood lymphocyte chromosome aberration test for clastogenicity. Liraglutide was negative in repeat-dose in vivo micronucleus tests in rats. - In rat fertility studies using subcutaneous doses of 0.1, 0.25 and 1.0 mg/kg/day liraglutide, males were treated for 4 weeks prior to and throughout mating and females were treated 2 weeks prior to and throughout mating until gestation day 17. No direct adverse effects on male fertility was observed at doses up to 1.0 mg/kg/day, a high dose yielding an estimated systemic exposure 11- times the human exposure at the MRHD, based on plasma AUC. In female rats, an increase in early embryonic deaths occurred at 1.0 mg/kg/day. Reduced body weight gain and food consumption were observed in females at the 1.0 mg/kg/day dose. # Clinical Studies - A total of 6090 patients with type 2 diabetes participated in 8 phase 3 trials. There were 5 double-blind (one of these trials had an open-label active control insulin glargine arm), randomized, controlled clinical trials, one of 52 weeks duration and four of 26 weeks duration. There were also three 26 week open-label trials; one comparing Victoza to twice-daily exenatide, one comparing Victoza to sitagliptin and one comparing Victoza+metformin+insulin detemir to Victoza+metformin alone. These multinational trials were conducted to evaluate the glycemic efficacy and safety of Victoza in type 2 diabetes as monotherapy and in combination with one or two oral anti-diabetic medications or insulin detemir. The 7 add-on combination therapy trials enrolled patients who were previously treated with anti-diabetic therapy, and approximately two-thirds of patients in the monotherapy trial also were previously treated with anti-diabetic therapy. In total, 272 (4%) of the 6090 patients in these 8 trials were new to anti-diabetic therapy. In these 8 clinical trials, patients ranged in age from 18-80 years old and 54% were men. Approximately 82% of patients were Caucasian, and 6% were Black. In the 5 trials where ethnicity was captured, 10% of patients were Hispanic/Latino (n=630). - In each of the placebo controlled trials, treatment with Victoza produced clinically and statistically significant improvements in hemoglobin A1c and fasting plasma glucose (FPG) compared to placebo. - All Victoza-treated patients started at 0.6 mg/day. The dose was increased in weekly intervals by 0.6 mg to reach 1.2 mg or 1.8 mg for patients randomized to these higher doses. Victoza 0.6 mg is not effective for glycemic control and is intended only as a starting dose to reduce gastrointestinal intolerance . ## Monotherapy - In this 52-week trial, 746 patients were randomized to Victoza 1.2 mg, Victoza 1.8 mg, or glimepiride 8 mg. Patients who were randomized to glimepiride were initially treated with 2 mg daily for two weeks, increasing to 4 mg daily for another two weeks, and finally increasing to 8 mg daily. Treatment with Victoza 1.8 mg and 1.2 mg resulted in a statistically significant reduction in HbA1c compared to glimepiride (Table 6). The percentage of patients who discontinued due to ineffective therapy was 3.6% in the Victoza 1.8 mg treatment group, 6.0% in the Victoza 1.2 mg treatment group, and 10.1% in the glimepiride-treatment group. ## Combination Therapy Add-on to metformin - In this 26-week trial, 1091 patients were randomized to Victoza 0.6 mg, Victoza 1.2 mg, Victoza 1.8 mg, placebo, or glimepiride 4 mg (one-half of the maximal approved dose in the United States), all as add-on to metformin. Randomization occurred after a 6-week run-in period consisting of a 3-week initial forced metformin titration period followed by a maintenance period of another 3 weeks. During the titration period, doses of metformin were increased up to 2000 mg/day. - Treatment with Victoza 1.2 mg and 1.8 mg as add-on to metformin resulted in a significant mean HbA1c reduction relative to placebo add-on to metformin and resulted in a similar mean HbA1c reduction relative to glimepiride 4 mg add-on to metformin (Table 7). The percentage of patients who discontinued due to ineffective therapy was 5.4% in the Victoza 1.8 mg + metformin treatment group, 3.3% in the Victoza 1.2 mg + metformin treatment group, 23.8% in the placebo + metformin treatment group, and 3.7% in the glimepiride + metformin treated group. Victoza Compared to Sitagliptin, Both as Add-on to metformin - In this 26–week, open-label trial, 665 patients on a background of metformin ≥1500 mg per day were randomized to Victoza 1.2 mg once-daily, Victoza 1.8 mg once-daily or sitagliptin 100 mg once-daily, all dosed according to approved labeling. Patients were to continue their current treatment on metformin at a stable, pre-trial dose level and dosing frequency. The primary endpoint was the change in HbA1c from baseline to Week 26. Treatment with Victoza 1.2 mg and Victoza 1.8 mg resulted in statistically significant reductions in HbA1c relative to sitagliptin 100 mg (Table 8). The percentage of patients who discontinued due to ineffective therapy was 3.1% in the Victoza 1.2 mg group, 0.5% in the Victoza 1.8 mg treatment group, and 4.1% in the sitagliptin 100 mg treatment group. From a mean baseline body weight of 94 kg, there was a mean reduction of 2.7 kg for Victoza 1.2 mg, 3.3 kg for Victoza 1.8 mg, and 0.8 kg for sitagliptin 100 mg. Figure 4 Mean HbA1c for patients who completed the 26-week trial and for the Last Observation Carried Forward (LOCF, intent-to-treat) data at Week 26 Combination Therapy with metformin and Insulin - This 26-week open-label trial enrolled 988 patients with inadequate glycemic control (HbA1c 7-10%) on metformin (≥1500 mg/day) alone or inadequate glycemic control (HbA1c 7-8.5%) on metformin (≥1500 mg/day) and a sulfonylurea. Patients who were on metformin and a sulfonylurea discontinued the sulfonylurea then all patients entered a 12-week run-in period during which they received add-on therapy with Victoza titrated to 1.8 mg once-daily. At the end of the run-in period, 498 patients (50%) achieved HbA1c <7% with Victoza 1.8 mg and metformin and continued treatment in a non-randomized, observational arm. Another 167 patients (17%) withdrew from the trial during the run-in period with approximately one-half of these patients doing so because of gastrointestinal adverse reactions . The remaining 323 patients with HbA1c ≥7% (33% of those who entered the run-in period) were randomized to 26 weeks of once-daily insulin detemir administered in the evening as add-on therapy (N=162) or to continued, unchanged treatment with Victoza 1.8 mg and metformin (N=161). The starting dose of insulin detemir was 10 units/day and the mean dose at the end of the 26-week randomized period was 39 units/day. During the 26 week randomized treatment period, the percentage of patients who discontinued due to ineffective therapy was 11.2% in the group randomized to continued treatment with Victoza 1.8 mg and metformin and 1.2% in the group randomized to add-on therapy with insulin detemir. Treatment with insulin detemir as add-on to Victoza 1.8 mg + metformin resulted in statistically significant reductions in HbA1c and FPG compared to continued, unchanged treatment with Victoza 1.8 mg + metformin alone (Table 9). From a mean baseline body weight of 96 kg after randomization, there was a mean reduction of 0.3 kg in the patients who received insulin detemir add-on therapy compared to a mean reduction of 1.1 kg in the patients who continued on unchanged treatment with Victoza 1.8 mg + metformin alone. Add-on to Sulfonylurea - In this 26-week trial, 1041 patients were randomized to Victoza 0.6 mg, Victoza 1.2 mg, Victoza 1.8 mg, placebo, or rosiglitazone 4 mg (one-half of the maximal approved dose in the United States), all as add-on to glimepiride. Randomization occurred after a 4-week run-in period consisting of an initial, 2-week, forced-glimepiride titration period followed by a maintenance period of another 2 weeks. During the titration period, doses of glimepiride were increased to 4 mg/day. The doses of glimepiride could be reduced (at the discretion of the investigator) from 4 mg/day to 3 mg/day or 2 mg/day (minimum) after randomization, in the event of unacceptable hypoglycemia or other adverse events. Treatment with Victoza 1.2 mg and 1.8 mg as add-on to glimepiride resulted in a statistically significant reduction in mean HbA1c compared to placebo add-on to glimepiride (Table 10). The percentage of patients who discontinued due to ineffective therapy was 3.0% in the Victoza 1.8 mg + glimepiride treatment group, 3.5% in the Victoza 1.2 mg + glimepiride treatment group, 17.5% in the placebo + glimepiride treatment group, and 6.9% in the rosiglitazone + glimepiride treatment group. Add-on to metformin and Sulfonylurea - In this 26-week trial, 581 patients were randomized to Victoza 1.8 mg, placebo, or insulin glargine, all as add-on to metformin and glimepiride. Randomization took place after a 6-week run-in period consisting of a 3-week forced metformin and glimepiride titration period followed by a maintenance period of another 3 weeks. During the titration period, doses of metformin and glimepiride were to be increased up to 2000 mg/day and 4 mg/day, respectively. After randomization, patients randomized to Victoza 1.8 mg underwent a 2 week period of titration with Victoza. During the trial, the Victoza and metformin doses were fixed, although glimepiride and insulin glargine doses could be adjusted. Patients titrated glargine twice-weekly during the first 8 weeks of treatment based on self-measured fasting plasma glucose on the day of titration. After Week 8, the frequency of insulin glargine titration was left to the discretion of the investigator, but, at a minimum, the glargine dose was to be revised, if necessary, at Weeks 12 and 18. Only 20% of glargine-treated patients achieved the pre-specified target fasting plasma glucose of ≤100 mg/dL. Therefore, optimal titration of the insulin glargine dose was not achieved in most patients. Treatment with Victoza as add-on to glimepiride and metformin resulted in a statistically significant mean reduction in HbA1c compared to placebo add-on to glimepiride and metformin (Table 11). The percentage of patients who discontinued due to ineffective therapy was 0.9% in the Victoza 1.8 mg + metformin + glimepiride treatment group, 0.4% in the insulin glargine + metformin + glimepiride treatment group, and 11.3% in the placebo + metformin + glimepiride treatment group. Victoza Compared to Exenatide, Both as Add-on to metformin and/or Sulfonylurea Therapy - In this 26–week, open-label trial, 464 patients on a background of metformin monotherapy, sulfonylurea monotherapy or a combination of metformin and sulfonylurea were randomized to once daily Victoza 1.8 mg or exenatide 10 mcg twice daily. Maximally tolerated doses of background therapy were to remain unchanged for the duration of the trial. Patients randomized to exenatide started on a dose of 5 mcg twice-daily for 4 weeks and then were escalated to 10 mcg twice daily. Treatment with Victoza 1.8 mg resulted in statistically significant reductions in HbA1c and FPG relative to exenatide (Table 12). The percentage of patients who discontinued for ineffective therapy was 0.4% in the Victoza treatment group and 0% in the exenatide treatment group. Both treatment groups had a mean decrease from baseline in body weight of approximately 3 kg. Add-on to metformin and Thiazolidinedione - In this 26-week trial, 533 patients were randomized to Victoza 1.2 mg, Victoza 1.8 mg or placebo, all as add-on to rosiglitazone (8 mg) plus metformin (2000 mg). Patients underwent a 9 week run-in period (3-week forced dose escalation followed by a 6-week dose maintenance phase) with rosiglitazone (starting at 4 mg and increasing to 8 mg/day within 2 weeks) and metformin (starting at 500 mg with increasing weekly increments of 500 mg to a final dose of 2000 mg/day). Only patients who tolerated the final dose of rosiglitazone (8 mg/day) and metformin (2000 mg/day) and completed the 6-week dose maintenance phase were eligible for randomization into the trial. Treatment with Victoza as add-on to metformin and rosiglitazone produced a statistically significant reduction in mean HbA1c compared to placebo add-on to metformin and rosiglitazone (Table 13). The percentage of patients who discontinued due to ineffective therapy was 1.7% in the Victoza 1.8 mg + metformin + rosiglitazone treatment group, 1.7% in the Victoza 1.2 mg + metformin + rosiglitazone treatment group, and 16.4% in the placebo + metformin + rosiglitazone treatment group. # How Supplied - Victoza is available in the following package sizes containing disposable, pre-filled, multi-dose pens. Each individual pen delivers doses of 0.6 mg, 1.2 mg, or 1.8 mg (6 mg/mL, 3 mL). - 2 x Victoza pen NDC 0169-4060-12 - 3 x Victoza pen NDC 0169-4060-13 - Each Victoza pen is for use by a single patient. A Victoza pen should never be shared between patients, even if the needle is changed. ## Storage - Prior to first use, Victoza should be stored in a refrigerator between 36ºF to 46ºF (2ºC to 8ºC) (Table 14). Do not store in the freezer or directly adjacent to the refrigerator cooling element. Do not freeze Victoza and do not use Victoza if it has been frozen. - After initial use of the Victoza pen, the pen can be stored for 30 days at controlled room temperature (59°F to 86°F; 15°C to 30°C) or in a refrigerator (36°F to 46°F; 2°C to 8°C). Keep the pen cap on when not in use. Victoza should be protected from excessive heat and sunlight. Always remove and safely discard the needle after each injection and store the Victoza pen without an injection needle attached. This will reduce the potential for contamination, infection, and leakage while also ensuring dosing accuracy. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information ## FDA-Approved Medication Guide See separate leaflet. ## Risk of Thyroid C-cell Tumors - Patients should be informed that liraglutide causes benign and malignant thyroid C-cell tumors in mice and rats and that the human relevance of this finding is unknown. Patients should be counseled to report symptoms of thyroid tumors (e.g., a lump in the neck, hoarseness, dysphagia or dyspnea) to their physician. ## dehydration and Renal Failure - Patients treated with Victoza should be advised of the potential risk of dehydration due to gastrointestinal adverse reactions and take precautions to avoid fluid depletion. Patients should be informed of the potential risk for worsening renal function, which in some cases may require dialysis. ## pancreatitis - Patients should be informed of the potential risk for pancreatitis. Explain that persistent severe abdominal pain that may radiate to the back and which may or may not be accompanied by vomiting, is the hallmark symptom of acute pancreatitis. Instruct patients to discontinue Victoza promptly and contact their physician if persistent severe abdominal pain occurs . ## Hypersensitivity Reactions - Patients should be informed that serious hypersensitivity reactions have been reported during postmarketing use of Victoza. If symptoms of hypersensitivity reactions occur, patients must stop taking Victoza and seek medical advice promptly. ## Never Share a Victoza Pen Between Patients - Counsel patients that they should never share a Victoza pen with another person, even if the needle is changed. Sharing of the pen between patients may pose a risk of transmission of infection. ## Instructions - Patients should be informed of the potential risks and benefits of Victoza and of alternative modes of therapy. Patients should also be informed about the importance of adherence to dietary instructions, regular physical activity, periodic blood glucose monitoring and A1c testing, recognition and management of hypoglycemia and hyperglycemia, and assessment for diabetes complications. During periods of stress such as fever, trauma, infection, or surgery, medication requirements may change and patients should be advised to seek medical advice promptly. - Patients should be advised that the most common side effects of Victoza are headache, nausea and diarrhea. nausea is most common when first starting Victoza, but decreases over time in the majority of patients and does not typically require discontinuation of Victoza. - Physicians should instruct their patients to read the Patient Medication Guide before starting Victoza therapy and to reread each time the prescription is renewed. Patients should be instructed to inform their doctor or pharmacist if they develop any unusual symptom, or if any known symptom persists or worsens. - Inform patients not to take an extra dose of Victoza to make up for a missed dose. If a dose is missed, the once-daily regimen should be resumed as prescribed with the next scheduled dose. - If more than 3 days have elapsed since the last dose, the patient should be advised to reinitiate Victoza at 0.6 mg to mitigate any gastrointestinal symptoms associated with reinitiation of treatment. Victoza should be titrated at the discretion of the prescribing physician. ## Laboratory Tests - Patients should be informed that response to all diabetic therapies should be monitored by periodic measurements of blood glucose and A1c levels, with a goal of decreasing these levels towards the normal range. A1c is especially useful for evaluating long-term glycemic control. # Precautions with Alcohol Alcohol-Liraglutide interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names VICTOZA # Look-Alike Drug Names There is limited information about the look-alike drug names. # Drug Shortage Status # Price	Liraglutide Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Sheng Shi, 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 Liraglutide is a peptide hormones that is FDA approved for the treatment of type 2 diabetes mellitus. There is a Black Box Warning for this drug as shown here. Common adverse reactions include hypoglycemia，constipation，diarrhea，nausea，vomiting，headache，upper respiratory infection. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) ### Type 2 Diabetes Mellitus - Dosing information - Victoza can be administered once daily at any time of day, independently of meals, and can be injected subcutaneously in the abdomen, thigh or upper arm. The injection site and timing can be changed without dose adjustment. - InitiaL dosage: 0.6 mg/day for one week. - The 0.6 mg dose is a starting dose intended to reduce gastrointestinal symptoms during initial titration, and is not effective for glycemic control. - After one week at 0.6 mg per day, the dose should be increased to 1.2 mg. If the 1.2 mg dose does not result in acceptable glycemic control, the dose can be increased to 1.8 mg. - When initiating Victoza, consider reducing the dose of concomitantly administered insulin secretagogues (such as sulfonylureas) to reduce the risk of hypoglycemia - When using Victoza with insulin, administer as separate injections. Never mix. It is acceptable to inject Victoza and insulin in the same body region but the injections should not be adjacent to each other. - Victoza solution should be inspected prior to each injection, and the solution should be used only if it is clear, colorless, and contains no particles. - If a dose is missed, the once-daily regimen should be resumed as prescribed with the next scheduled dose. An extra dose or increase in dose should not be taken to make-up for the missed dose. - Based on the elimination half-life, patients should be advised to reinitiate Victoza at ‘’‘0.6 mg’‘’ if more than 3 days have elapsed since the last Victoza dose. This approach will mitigate any gastrointestinal symptoms associated with reinitiation of treatment. Upon reinitiation, Victoza should be titrated at the discretion of the prescribing healthcare provider. ### Important Limitations of Use - Because of the uncertain relevance of the rodent thyroid C-cell tumor findings to humans, prescribe Victoza only to patients for whom the potential benefits are considered to outweigh the potential risk. Victoza is not recommended as first-line therapy for patients who have inadequate glycemic control on diet and exercise. - Based on spontaneous postmarketing reports, acute pancreatitis, including fatal and non-fatal hemorrhagic or necrotizing pancreatitis has been observed in patients treated with Victoza. Victoza has not been studied in patients with a history of pancreatitis. It is unknown whether patients with a history of pancreatitis are at increased risk for pancreatitis while using Victoza. Other antidiabetic therapies should be considered in patients with a history of pancreatitis. - Victoza is not a substitute for insulin. Victoza should not be used in patients with type 1 diabetes mellitus or for the treatment of diabetic ketoacidosis, as it would not be effective in these settings. - The concurrent use of Victoza and prandial insulin has not been studied. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Liraglutide in adult patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Liraglutide in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) Safety and effectiveness of Victoza have not been established in pediatric patients. Victoza is not recommended for use in pediatric patients. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Liraglutide in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Liraglutide in pediatric patients. # Contraindications - Do not use in patients with a personal or family history of medullary thyroid carcinoma (MTC) or in patients with Multiple Endocrine Neoplasia syndrome type 2 (MEN 2). - Do not use in patients with a prior serious hypersensitivity reaction to Victoza or to any of the product components. # Warnings - Liraglutide causes dose-dependent and treatment-duration-dependent thyroid C-cell tumors (adenomas and/or carcinomas) at clinically relevant exposures in both genders of rats and mice. Malignant thyroid C-cell carcinomas were detected in rats and mice. A statistically significant increase in cancer was observed in rats receiving liraglutide at 8-times clinical exposure compared to controls. It is unknown whether Victoza will cause thyroid C-cell tumors, including medullary thyroid carcinoma (MTC), in humans, as the human relevance of liraglutide-induced rodent thyroid C-cell tumors could not be determined by clinical or nonclinical studies - In the clinical trials, there have been 6 reported cases of thyroid C-cell hyperplasia among Victoza-treated patients and 2 cases in comparator-treated patients (1.3 vs. 1.0 cases per 1000 patient-years). One comparator-treated patient with MTC had pre-treatment serum calcitonin concentrations >1000 ng/L suggesting pre-existing disease. All of these cases were diagnosed after thyroidectomy, which was prompted by abnormal results on routine, protocol-specified measurements of serum calcitonin. Five of the six Victoza-treated patients had elevated calcitonin concentrations at baseline and throughout the trial. One Victoza and one non-Victoza-treated patient developed elevated calcitonin concentrations while on treatment. - Calcitonin, a biological marker of MTC, was measured throughout the clinical development program. The serum calcitonin assay used in the Victoza clinical trials had a lower limit of quantification (LLOQ) of 0.7 ng/L and the upper limit of the reference range was 5.0 ng/L for women and 8.4 ng/L for men. At Weeks 26 and 52 in the clinical trials, adjusted mean serum calcitonin concentrations were higher in Victoza-treated patients compared to placebo-treated patients but not compared to patients receiving active comparator. At these timepoints, the adjusted mean serum calcitonin values (~ 1.0 ng/L) were just above the LLOQ with between-group differences in adjusted mean serum calcitonin values of approximately 0.1 ng/L or less. Among patients with pre-treatment serum calcitonin below the upper limit of the reference range, shifts to above the upper limit of the reference range which persisted in subsequent measurements occurred most frequently among patients treated with Victoza 1.8 mg/day. In trials with on-treatment serum calcitonin measurements out to 5-6 months, 1.9% of patients treated with Victoza 1.8 mg/day developed new and persistent calcitonin elevations above the upper limit of the reference range compared to 0.8-1.1% of patients treated with control medication or the 0.6 and 1.2 mg doses of Victoza. In trials with on-treatment serum calcitonin measurements out to 12 months, 1.3% of patients treated with Victoza 1.8 mg/day had new and persistent elevations of calcitonin from below or within the reference range to above the upper limit of the reference range, compared to 0.6%, 0% and 1.0% of patients treated with Victoza 1.2 mg, placebo and active control, respectively. Otherwise, Victoza did not produce consistent dose-dependent or time-dependent increases in serum calcitonin. - Patients with MTC usually have calcitonin values >50 ng/L. In Victoza clinical trials, among patients with pre-treatment serum calcitonin <50 ng/L, one Victoza-treated patient and no comparator-treated patients developed serum calcitonin >50 ng/L. The Victoza-treated patient who developed serum calcitonin >50 ng/L had an elevated pre-treatment serum calcitonin of 10.7 ng/L that increased to 30.7 ng/L at Week 12 and 53.5 ng/L at the end of the 6-month trial. Follow-up serum calcitonin was 22.3 ng/L more than 2.5 years after the last dose of Victoza. The largest increase in serum calcitonin in a comparator-treated patient was seen with glimepiride in a patient whose serum calcitonin increased from 19.3 ng/L at baseline to 44.8 ng/L at Week 65 and 38.1 ng/L at Week 104. Among patients who began with serum calcitonin <20 ng/L, calcitonin elevations to >20 ng/L occurred in 0.7% of Victoza-treated patients, 0.3% of placebo-treated patients, and 0.5% of active-comparator-treated patients, with an incidence of 1.1% among patients treated with 1.8 mg/day of Victoza. The clinical significance of these findings is unknown. - Counsel patients regarding the risk for MTC and the symptoms of thyroid tumors (e.g. a mass in the neck, dysphagia, dyspnea or persistent hoarseness). It is unknown whether monitoring with serum calcitonin or thyroid ultrasound will mitigate the potential risk of MTC, and such monitoring may increase the risk of unnecessary procedures, due to low test specificity for serum calcitonin and a high background incidence of thyroid disease. Patients with thyroid nodules noted on physical examination or neck imaging obtained for other reasons should be referred to an endocrinologist for further evaluation. Although routine monitoring of serum calcitonin is of uncertain value in patients treated with Victoza, if serum calcitonin is measured and found to be elevated, the patient should be referred to an endocrinologist for further evaluation. ### Pancreatitis - Based on spontaneous postmarketing reports, acute pancreatitis, including fatal and non-fatal hemorrhagic or necrotizing pancreatitis, has been observed in patients treated with Victoza. After initiation of Victoza, observe patients carefully for signs and symptoms of pancreatitis (including persistent severe abdominal pain, sometimes radiating to the back and which may or may not be accompanied by vomiting). If pancreatitis is suspected, Victoza should promptly be discontinued and appropriate management should be initiated. If pancreatitis is confirmed, Victoza should not be restarted. Consider antidiabetic therapies other than Victoza in patients with a history of pancreatitis. - In clinical trials of Victoza, there have been 13 cases of pancreatitis among Victoza-treated patients and 1 case in a comparator (glimepiride) treated patient (2.7 vs. 0.5 cases per 1000 patient-years). Nine of the 13 cases with Victoza were reported as acute pancreatitis and four were reported as chronic pancreatitis. In one case in a Victoza-treated patient, pancreatitis, with necrosis, was observed and led to death; however clinical causality could not be established. Some patients had other risk factors for pancreatitis, such as a history of cholelithiasis or alcohol abuse. - Patients receiving Victoza in combination with an insulin secretagogue (e.g., sulfonylurea) or insulin may have an increased risk of hypoglycemia. The risk of hypoglycemia may be lowered by a reduction in the dose of sulfonylurea (or other concomitantly administered insulin secretagogues) or insulin. - Victoza has not been found to be directly nephrotoxic in animal studies or clinical trials. There have been postmarketing reports of acute renal failure and worsening of chronic renal failure, which may sometimes require hemodialysis in Victoza-treated patients. Some of these events were reported in patients without known underlying renal disease. A majority of the reported events occurred in patients who had experienced nausea, vomiting, diarrhea, or dehydration . Some of the reported events occurred in patients receiving one or more medications known to affect renal function or hydration status. Altered renal function has been reversed in many of the reported cases with supportive treatment and discontinuation of potentially causative agents, including Victoza. Use caution when initiating or escalating doses of Victoza in patients with renal impairment. - There have been postmarketing reports of serious hypersensitivity reactions (e.g., anaphylactic reactions and angioedema) in patients treated with Victoza. If a hypersensitivity reaction occurs, the patient should discontinue Victoza and other suspect medications and promptly seek medical advice. - Angioedema has also been reported with other GLP-1 receptor agonists. Use caution in a patient with a history of angioedema with another GLP-1 receptor agonist because it is unknown whether such patients will be predisposed to angioedema with Victoza. - There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with Victoza or any other antidiabetic drug. # 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 practice. - The safety of Victoza has been evaluated in 8 clinical trials : - A double-blind 52-week monotherapy trial compared Victoza 1.2 mg daily, Victoza 1.8 mg daily, and glimepiride 8 mg daily. A double-blind 26 week add-on to metformin trial compared Victoza 0.6 mg once-daily, Victoza 1.2 mg once-daily, Victoza 1.8 mg once-daily, placebo, and glimepiride 4 mg once-daily. - A double-blind 26 week add-on to metformin trial compared Victoza 0.6 mg once-daily, Victoza 1.2 mg once-daily, Victoza 1.8 mg once-daily, placebo, and glimepiride 4 mg once-daily. - A double-blind 26 week add-on to glimepiride trial compared Victoza 0.6 mg daily, Victoza 1.2 mg once-daily, Victoza 1.8 mg once-daily, placebo, and rosiglitazone 4 mg once-daily. - A 26 week add-on to metformin + glimepiride trial, compared double-blind Victoza 1.8 mg once-daily, double-blind placebo, and open-label insulin glargine once-daily. - A double-blind 26-week add-on to metformin + rosiglitazone trial compared Victoza 1.2 mg once-daily, Victoza 1.8 mg once-daily and placebo. - An open-label 26-week add-on to metformin and/or sulfonylurea trial compared Victoza 1.8 mg once-daily and exenatide 10 mcg twice-daily. - An open-label 26-week add-on to metformin trial compared Victoza 1.2 mg once-daily, Victoza 1.8 mg once-daily, and sitagliptin 100 mg once-daily. - An open-label 26-week trial compared insulin detemir as add-on to Victoza 1.8 mg + metformin to continued treatment with Victoza + metformin alone. - Withdrawals - The incidence of withdrawal due to adverse events was 7.8% for Victoza-treated patients and 3.4% for comparator-treated patients in the five double-blind controlled trials of 26 weeks duration or longer. This difference was driven by withdrawals due to gastrointestinal adverse reactions, which occurred in 5.0% of Victoza-treated patients and 0.5% of comparator-treated patients. In these five trials, the most common adverse reactions leading to withdrawal for Victoza-treated patients were nausea (2.8% versus 0% for comparator) and vomiting (1.5% versus 0.1% for comparator). Withdrawal due to gastrointestinal adverse events mainly occurred during the first 2-3 months of the trials. - Common adverse reactions - Tables 1, 2, 3 and 4 summarize common adverse reactions (hypoglycemia is discussed separately) reported in seven of the eight controlled trials of 26 weeks duration or longer. Most of these adverse reactions were gastrointestinal in nature. - In the five double-blind clinical trials of 26 weeks duration or longer, gastrointestinal adverse reactions were reported in 41% of Victoza-treated patients and were dose-related. :Gastrointestinal adverse reactions occurred in 17% of comparator-treated patients. Common adverse reactions that occurred at a higher incidence among Victoza-treated patients included nausea, vomiting, diarrhea, dyspepsia and constipation. - In the five double-blind and three open-label clinical trials of 26 weeks duration or longer, the percentage of patients who reported nausea declined over time. In the five double-blind trials approximately 13% of Victoza-treated patients and 2% of comparator-treated patients reported nausea during the first 2 weeks of treatment. - In the 26-week open-label trial comparing Victoza to exenatide, both in combination with metformin and/or sulfonylurea, gastrointestinal adverse reactions were reported at a similar incidence in the Victoza and exenatide treatment groups (Table 3). - In the 26-week open-label trial comparing Victoza 1.2 mg, Victoza 1.8 mg and sitagliptin 100 mg, all in combination with metformin, gastrointestinal adverse reactions were reported at a higher incidence with Victoza than sitagliptin (Table 4). - In the remaining 26-week trial, all patients received Victoza 1.8 mg + metformin during a 12-week run-in period. During the run-in period, 167 patients (17% of enrolled total) withdrew from the trial: 76 (46% of withdrawals) of these patients doing so because of gastrointestinal adverse reactions and 15 (9% of withdrawals) doing so due to other adverse events. :Only those patients who completed the run-in period with inadequate glycemic control were randomized to 26 weeks of add-on therapy with insulin detemir or continued, unchanged treatment with Victoza 1.8 mg + metformin. During this randomized 26-week period, diarrhea was the only adverse reaction reported in ≥5% of patients treated with Victoza 1.8 mg + metformin + insulin detemir (11.7%) and greater than in patients treated with Victoza 1.8 mg and metformin alone (6.9%). - Immunogenicity - Consistent with the potentially immunogenic properties of protein and peptide pharmaceuticals, patients treated with Victoza may develop anti-liraglutide antibodies. Approximately 50-70% of Victoza-treated patients in the five double-blind clinical trials of 26 weeks duration or longer were tested for the presence of anti-liraglutide antibodies at the end of treatment. Low titers (concentrations not requiring dilution of serum) of anti-liraglutide antibodies were detected in 8.6% of these Victoza-treated patients. Sampling was not performed uniformly across all patients in the clinical trials, and this may have resulted in an underestimate of the actual percentage of patients who developed antibodies. Cross-reacting anti-liraglutide antibodies to native glucagon-like peptide-1 (GLP-1) occurred in 6.9% of the Victoza-treated patients in the double-blind 52-week monotherapy trial and in 4.8% of the Victoza-treated patients in the double-blind 26-week add-on combination therapy trials. These cross-reacting antibodies were not tested for neutralizing effect against native GLP-1, and thus the potential for clinically significant neutralization of native GLP-1 was not assessed. Antibodies that had a neutralizing effect on liraglutide in an in vitro assay occurred in 2.3% of the Victoza-treated patients in the double-blind 52-week monotherapy trial and in 1.0% of the Victoza-treated patients in the double-blind 26-week add-on combination therapy trials. - Among Victoza-treated patients who developed anti-liraglutide antibodies, the most common category of adverse events was that of infections, which occurred among 40% of these patients compared to 36%, 34% and 35% of antibody-negative Victoza-treated, placebo-treated and active-control-treated patients, respectively. The specific infections which occurred with greater frequency among Victoza-treated antibody-positive patients were primarily nonserious upper respiratory tract infections, which occurred among 11% of Victoza-treated antibody-positive patients; and among 7%, 7% and 5% of antibody-negative Victoza-treated, placebo-treated and active-control-treated patients, respectively. Among Victoza-treated antibody-negative patients, the most common category of adverse events was that of gastrointestinal events, which occurred in 43%, 18% and 19% of antibody-negative Victoza-treated, placebo-treated and active-control-treated patients, respectively. Antibody formation was not associated with reduced efficacy of Victoza when comparing mean HbA1c of all antibody-positive and all antibody-negative patients. However, the 3 patients with the highest titers of anti-liraglutide antibodies had no reduction in HbA1c with Victoza treatment. - In the five double-blind clinical trials of Victoza, events from a composite of adverse events potentially related to immunogenicity (e.g. urticaria, angioedema) occurred among 0.8% of Victoza-treated patients and among 0.4% of comparator-treated patients. Urticaria accounted for approximately one-half of the events in this composite for Victoza-treated patients. :Patients who developed anti-liraglutide antibodies were not more likely to develop events from the immunogenicity events composite than were patients who did not develop anti-liraglutide antibodies. - Injection site reactions - Injection site reactions (e.g., injection site rash, erythema) were reported in approximately 2% of Victoza-treated patients in the five double-blind clinical trials of at least 26 weeks duration. Less than 0.2% of Victoza-treated patients discontinued due to injection site reactions. - Papillary thyroid carcinoma - In clinical trials of Victoza, there were 7 reported cases of papillary thyroid carcinoma in patients treated with Victoza and 1 case in a comparator-treated patient (1.5 vs. 0.5 cases per 1000 patient-years). Most of these papillary thyroid carcinomas were <1 cm in greatest diameter and were diagnosed in surgical pathology specimens after thyroidectomy prompted by findings on protocol-specified screening with serum calcitonin or thyroid ultrasound. - Hypoglycemia - In the eight clinical trials of at least 26 weeks duration, hypoglycemia requiring the assistance of another person for treatment occurred in 11 Victoza-treated patients (2.3 cases per 1000 patient-years) and in two exenatide-treated patients. Of these 11 Victoza-treated patients, six patients were concomitantly using metformin and a sulfonylurea, one was concomitantly using a sulfonylurea, two were concomitantly using metformin (blood glucose values were 65 and 94 mg/dL) and two were using Victoza as monotherapy (one of these patients was undergoing an intravenous glucose tolerance test and the other was receiving insulin as treatment during a hospital stay). For these two patients on Victoza monotherapy, the insulin treatment was the likely explanation for the hypoglycemia. - In the 26-week open-label trial comparing Victoza to sitagliptin, the incidence of hypoglycemic events defined as symptoms accompanied by a fingerstick glucose <56 mg/dL was comparable among the treatment groups (approximately 5%). - In a pooled analysis of clinical trials, the incidence rate (per 1,000 patient-years) for malignant neoplasms (based on investigator-reported events, medical history, pathology reports, and surgical reports from both blinded and open-label study periods) was 10.9 for Victoza, 6.3 for placebo, and 7.2 for active comparator. After excluding papillary thyroid carcinoma events , no particular cancer cell type predominated. Seven malignant neoplasm events were reported beyond 1 year of exposure to study medication, six events among Victoza-treated patients (4 colon, 1 prostate and 1 nasopharyngeal), no events with placebo and one event with active comparator (colon). Causality has not been established. - In the five clinical trials of at least 26 weeks duration, mildly elevated serum bilirubin concentrations (elevations to no more than twice the upper limit of the reference range) occurred in 4.0% of Victoza-treated patients, 2.1% of placebo-treated patients and 3.5% of active-comparator-treated patients. This finding was not accompanied by abnormalities in other liver tests. The significance of this isolated finding is unknown. - Victoza did not have adverse effects on blood pressure. Mean increases from baseline in heart rate of 2 to 3 beats per minute have been observed with Victoza compared to placebo. The long-term clinical effects of the increase in pulse rate have not been established. ## Postmarketing Experience - The following additional adverse reactions have been reported during post-approval use of Victoza. Because these events 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. - Dehydration resulting from nausea, vomiting and diarrhea. - Increased serum creatinine, acute renal failure or worsening of chronic renal failure, sometimes requiring hemodialysis. - Angioedema and anaphylactic reactions. - Allergic reactions: rash and pruritus - Acute pancreatitis, hemorrhagic and necrotizing pancreatitis sometimes resulting in death # Drug Interactions ## Oral Medications - Victoza causes a delay of gastric emptying, and thereby has the potential to impact the absorption of concomitantly administered oral medications. In clinical pharmacology trials, Victoza did not affect the absorption of the tested orally administered medications to any clinically relevant degree. Nonetheless, caution should be exercised when oral medications are concomitantly administered with Victoza. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): C - There are no adequate and well-controlled studies of Victoza in pregnant women. Victoza should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Liraglutide has been shown to be teratogenic in rats at or above 0.8 times the human systemic exposures resulting from the maximum recommended human dose (MRHD) of 1.8 mg/day based on plasma area under the time-concentration curve (AUC). Liraglutide has been shown to cause reduced growth and increased total major abnormalities in rabbits at systemic exposures below human exposure at the MRHD based on plasma AUC. - Female rats given subcutaneous doses of 0.1, 0.25 and 1.0 mg/kg/day liraglutide beginning 2 weeks before mating through gestation day 17 had estimated systemic exposures 0.8-, 3-, and 11-times the human exposure at the MRHD based on plasma AUC comparison. The number of early embryonic deaths in the 1 mg/kg/day group increased slightly. Fetal abnormalities and variations in kidneys and blood vessels, irregular ossification of the skull, and a more complete state of ossification occurred at all doses. Mottled liver and minimally kinked ribs occurred at the highest dose. The incidence of fetal malformations in liraglutide-treated groups exceeding concurrent and historical controls were misshapen oropharynx and/or narrowed opening into larynx at 0.1 mg/kg/day and umbilical hernia at 0.1 and 0.25 mg/kg/day. - Pregnant rabbits given subcutaneous doses of 0.01, 0.025 and 0.05 mg/kg/day liraglutide from gestation day 6 through day 18 inclusive, had estimated systemic exposures less than the human exposure at the MRHD of 1.8 mg/day at all doses, based on plasma AUC. Liraglutide decreased fetal weight and dose-dependently increased the incidence of total major fetal abnormalities at all doses. The incidence of malformations exceeded concurrent and historical controls at 0.01 mg/kg/day (kidneys, scapula), ≥ 0.01 mg/kg/day (eyes, forelimb), 0.025 mg/kg/day (brain, tail and sacral vertebrae, major blood vessels and heart, umbilicus), ≥ 0.025 mg/kg/day (sternum) and at 0.05 mg/kg/day (parietal bones, major blood vessels). Irregular ossification and/or skeletal abnormalities occurred in the skull and jaw, vertebrae and ribs, sternum, pelvis, tail, and scapula; and dose-dependent minor skeletal variations were observed. Visceral abnormalities occurred in blood vessels, lung, liver, and esophagus. Bilobed or bifurcated gallbladder was seen in all treatment groups, but not in the control group. - In pregnant female rats given subcutaneous doses of 0.1, 0.25 and 1.0 mg/kg/day liraglutide from gestation day 6 through weaning or termination of nursing on lactation day 24, estimated systemic exposures were 0.8-, 3-, and 11-times human exposure at the MRHD of 1.8 mg/day, based on plasma AUC. A slight delay in parturition was observed in the majority of treated rats. Group mean body weight of neonatal rats from liraglutide-treated dams was lower than neonatal rats from control group dams. Bloody scabs and agitated behavior occurred in male rats descended from dams treated with 1 mg/kg/day liraglutide. Group mean body weight from birth to postpartum day 14 trended lower in F2 generation rats descended from liraglutide-treated rats compared to F2 generation rats descended from controls, but differences did not reach statistical significance for any group. Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Liraglutide in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Liraglutide during labor and delivery. ### Nursing Mothers - It is not known whether Victoza is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for tumorigenicity shown for liraglutide in animal studies, a decision should be made whether to discontinue nursing or to discontinue Victoza, taking into account the importance of the drug to the mother. In lactating rats, liraglutide was excreted unchanged in milk at concentrations approximately 50% of maternal plasma concentrations. ### Pediatric Use - Safety and effectiveness of Victoza have not been established in pediatric patients. Victoza is not recommended for use in pediatric patients. ### Geriatic Use - In the Victoza clinical trials, a total of 797 (20%) of the patients were 65 years of age and over and 113 (2.8%) were 75 years of age and over. No overall differences in safety or effectiveness were observed between these patients and younger patients, but greater sensitivity of some older individuals cannot be ruled out. ### Gender There is no FDA guidance on the use of Liraglutide with respect to specific gender populations. ### Race There is no FDA guidance on the use of Liraglutide with respect to specific racial populations. ### Renal Impairment - There is limited experience with Victoza in patients with mild, moderate, and severe renal impairment, including end-stage renal disease. However, there have been postmarketing reports of acute renal failure and worsening of chronic renal failure, which may sometimes require hemodialysis . Victoza should be used with caution in this patient population. No dose adjustment of Victoza is recommended for patients with renal impairment. ### Hepatic Impairment - There is limited experience in patients with mild, moderate or severe hepatic impairment. Therefore, Victoza should be used with caution in this patient population. No dose adjustment of Victoza is recommended for patients with hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Liraglutide in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Liraglutide in patients who are immunocompromised. ### Gastroparesis - Victoza slows gastric emptying. Victoza has not been studied in patients with pre-existing gastroparesis. # Administration and Monitoring ### Administration Intramuscular ### Monitoring FDA Package Insert for Abcixmab contains no information regarding drug monitoring. # IV Compatibility There is limited information about the IV Compatibility. # Overdosage - Overdoses have been reported in clinical trials and post-marketing use of Victoza. Effects have included severe nausea and severe vomiting. In the event of overdosage, appropriate supportive treatment should be initiated according to the patient’s clinical signs and symptoms. # Pharmacology Template:Infobox drug2 ## Mechanism of Action - Liraglutide is an acylated human Glucagon-Like Peptide-1 (GLP-1) receptor agonist with 97% amino acid sequence homology to endogenous human GLP-1(7-37). GLP-1(7-37) represents <20% of total circulating endogenous GLP-1. Like GLP-1(7-37), liraglutide activates the GLP-1 receptor, a membrane-bound cell-surface receptor coupled to adenylyl cyclase by the stimulatory G-protein, Gs, in pancreatic beta cells. Liraglutide increases intracellular cyclic AMP (cAMP) leading to insulin release in the presence of elevated glucose concentrations. This insulin secretion subsides as blood glucose concentrations decrease and approach euglycemia. Liraglutide also decreases glucagon secretion in a glucose-dependent manner. The mechanism of blood glucose lowering also involves a delay in gastric emptying. - GLP-1(7-37) has a half-life of 1.5-2 minutes due to degradation by the ubiquitous endogenous enzymes, dipeptidyl peptidase IV (DPP-IV) and neutral endopeptidases (NEP). Unlike native GLP-1, liraglutide is stable against metabolic degradation by both peptidases and has a plasma half-life of 13 hours after subcutaneous administration. The pharmacokinetic profile of liraglutide, which makes it suitable for once daily administration, is a result of self-association that delays absorption, plasma protein binding and stability against metabolic degradation by DPP-IV and NEP. ## Structure - Victoza contains liraglutide, an analog of human GLP-1 and acts as a GLP-1 receptor agonist. The peptide precursor of liraglutide, produced by a process that includes expression of recombinant DNA in Saccharomyces cerevisiae, has been engineered to be 97% homologous to native human GLP-1 by substituting arginine for lysine at position 34. Liraglutide is made by attaching a C-16 fatty acid (palmitic acid) with a glutamic acid spacer on the remaining lysine residue at position 26 of the peptide precursor. The molecular formula of liraglutide is C172H265N43O51 and the molecular weight is 3751.2 Daltons. The structural formula (Figure 1) is: - Victoza is a clear, colorless solution. Each 1 mL of Victoza solution contains 6 mg of liraglutide. Each pre-filled pen contains a 3 mL solution of Victoza equivalent to 18 mg liraglutide (free-base, anhydrous) and the following inactive ingredients: disodium phosphate dihydrate, 1.42 mg; propylene glycol, 14 mg; phenol, 5.5 mg; and water for injection. ## Pharmacodynamics - Victoza’s pharmacodynamic profile is consistent with its pharmacokinetic profile observed after single subcutaneous administration as Victoza lowered fasting, premeal and postprandial glucose throughout the day. - Fasting and postprandial glucose was measured before and up to 5 hours after a standardized meal after treatment to steady state with 0.6, 1.2 and 1.8 mg Victoza or placebo. Compared to placebo, the postprandial plasma glucose AUC0-300min was 35% lower after Victoza 1.2 mg and 38% lower after Victoza 1.8 mg. Glucose-dependent insulin secretion - The effect of a single dose of 7.5 mcg/kg (~ 0.7 mg) Victoza on insulin secretion rates (ISR) was investigated in 10 patients with type 2 diabetes during graded glucose infusion. In these patients, on average, the ISR response was increased in a glucose-dependent manner (Figure 2). Glucagon secretion - Victoza lowered blood glucose by stimulating insulin secretion and lowering glucagon secretion. A single dose of Victoza 7.5 mcg/kg (~ 0.7 mg) did not impair glucagon response to low glucose concentrations. Gastric emptying - Victoza causes a delay of gastric emptying, thereby reducing the rate at which postprandial glucose appears in the circulation. Cardiac Electrophysiology (QTc) - The effect of Victoza on cardiac repolarization was tested in a QTc study. Victoza at steady state concentrations with daily doses up to 1.8 mg did not produce QTc prolongation. ## Pharmacokinetics Absorption - Following subcutaneous administration, maximum concentrations of liraglutide are achieved at 8-12 hours post dosing. The mean peak (Cmax) and total (AUC) exposures of liraglutide were 35 ng/mL and 960 ng·h/mL, respectively, for a subcutaneous single dose of 0.6 mg. After subcutaneous single dose administrations, Cmax and AUC of liraglutide increased proportionally over the therapeutic dose range of 0.6 mg to 1.8 mg. At 1.8 mg Victoza, the average steady state concentration of liraglutide over 24 hours was approximately 128 ng/mL. AUC0-∞ was equivalent between upper arm and abdomen, and between upper arm and thigh. AUC0-∞ from thigh was 22% lower than that from abdomen. However, liraglutide exposures were considered comparable among these three subcutaneous injection sites. Absolute bioavailability of liraglutide following subcutaneous administration is approximately 55%. Distribution - The mean apparent volume of distribution after subcutaneous administration of Victoza 0.6 mg is approximately 13 L. The mean volume of distribution after intravenous administration of Victoza is 0.07 L/kg. Liraglutide is extensively bound to plasma protein (>98%). Metabolism - During the initial 24 hours following administration of a single [3H]-liraglutide dose to healthy subjects, the major component in plasma was intact liraglutide. Liraglutide is endogenously metabolized in a similar manner to large proteins without a specific organ as a major route of elimination. Elimination - Following a [3H]-liraglutide dose, intact liraglutide was not detected in urine or feces. Only a minor part of the administered radioactivity was excreted as liraglutide-related metabolites in urine or feces (6% and 5%, respectively). The majority of urine and feces radioactivity was excreted during the first 6-8 days. The mean apparent clearance following subcutaneous administration of a single dose of liraglutide is approximately 1.2 L/h with an elimination half-life of approximately 13 hours, making Victoza suitable for once daily administration. ## Specific Populations Elderly - Age had no effect on the pharmacokinetics of Victoza based on a pharmacokinetic study in healthy elderly subjects (65 to 83 years) and population pharmacokinetic analyses of patients 18 to 80 years of age . Gender - Based on the results of population pharmacokinetic analyses, females have 34% lower weight-adjusted clearance of Victoza compared to males. Based on the exposure response data, no dose adjustment is necessary based on gender. Race and Ethnicity - Race and ethnicity had no effect on the pharmacokinetics of Victoza based on the results of population pharmacokinetic analyses that included Caucasian, Black, Asian and Hispanic/Non-Hispanic subjects. Body Weight - Body weight significantly affects the pharmacokinetics of Victoza based on results of population pharmacokinetic analyses. The exposure of liraglutide decreases with an increase in baseline body weight. However, the 1.2 mg and 1.8 mg daily doses of Victoza provided adequate systemic exposures over the body weight range of 40 – 160 kg evaluated in the clinical trials. Liraglutide was not studied in patients with body weight >160 kg. Pediatric - Victoza has not been studied in pediatric patients . Renal Impairment - The single-dose pharmacokinetics of Victoza were evaluated in subjects with varying degrees of renal impairment. Subjects with mild (estimated creatinine clearance 50-80 mL/min) to severe (estimated creatinine clearance <30 mL/min) renal impairment and subjects with end-stage renal disease requiring dialysis were included in the trial. Compared to healthy subjects, liraglutide AUC in mild, moderate, and severe renal impairment and in end-stage renal disease was on average 35%, 19%, 29% and 30% lower, respectively [see Use in Specific Populations (8.6)]. Hepatic Impairment - The single-dose pharmacokinetics of Victoza were evaluated in subjects with varying degrees of hepatic impairment. Subjects with mild (Child Pugh score 5-6) to severe (Child Pugh score > 9) hepatic impairment were included in the trial. Compared to healthy subjects, liraglutide AUC in subjects with mild, moderate and severe hepatic impairment was on average 11%, 14% and 42% lower, respectively ### Drug Interactions ### In vitro assessment of drug-drug interactions - Victoza has low potential for pharmacokinetic drug-drug interactions related to cytochrome P450 (CYP) and plasma protein binding. ### In vivo assessment of drug-drug interactions - The drug-drug interaction studies were performed at steady state with Victoza 1.8 mg/day. Before administration of concomitant treatment, subjects underwent a 0.6 mg weekly dose increase to reach the maximum dose of 1.8 mg/day. Administration of the interacting drugs was timed so that Cmax of Victoza (8-12 h) would coincide with the absorption peak of the co-administered drugs. ### Digoxin - A single dose of Digoxin 1 mg was administered 7 hours after the dose of Victoza at steady state. The concomitant administration with Victoza resulted in a reduction of Digoxin AUC by 16%; Cmax decreased by 31%. Digoxin median time to maximal concentration (Tmax) was delayed from 1 h to 1.5 h. ### Lisinopril - A single dose of Lisinopril 20 mg was administered 5 minutes after the dose of Victoza at steady state. The co-administration with Victoza resulted in a reduction of Lisinopril AUC by 15%; Cmax decreased by 27%. Lisinopril median Tmax was delayed from 6 h to 8 h with Victoza. ### Atorvastatin - Victoza did not change the overall exposure (AUC) of Atorvastatin following a single dose of Atorvastatin 40 mg, administered 5 hours after the dose of Victoza at steady state. Atorvastatin Cmax was decreased by 38% and median Tmax was delayed from 1 h to 3 h with Victoza. ### Acetaminophen - Victoza did not change the overall exposure (AUC) of Acetaminophen following a single dose of Acetaminophen 1000 mg, administered 8 hours after the dose of Victoza at steady state. Acetaminophen Cmax was decreased by 31% and median Tmax was delayed up to 15 minutes. ### Griseofulvin - Victoza did not change the overall exposure (AUC) of Griseofulvin following co-administration of a single dose of Griseofulvin 500 mg with Victoza at steady state. Griseofulvin Cmax increased by 37% while median Tmax did not change. ### Oral Contraceptives - A single dose of an oral contraceptive combination product containing 0.03 mg ethinylestradiol and 0.15 mg levonorgestrel was administered under fed conditions and 7 hours after the dose of Victoza at steady state. Victoza lowered ethinylestradiol and levonorgestrel Cmax by 12% and 13%, respectively. There was no effect of Victoza on the overall exposure (AUC) of ethinylestradiol. Victoza increased the levonorgestrel AUC0-∞ by 18%. Victoza delayed Tmax for both ethinylestradiol and levonorgestrel by 1.5 h. ### Insulin Detemir - No pharmacokinetic interaction was observed between Victoza and insulin detemir when separate subcutaneous injections of insulin detemir 0.5 Unit/kg (single-dose) and Victoza 1.8 mg (steady state) were administered in patients with type 2 diabetes. ## Nonclinical Toxicology ### Carcinogenesis, Mutagenesis, Impairment of Fertility - A 104-week carcinogenicity study was conducted in male and female CD-1 mice at doses of 0.03, 0.2, 1.0, and 3.0 mg/kg/day liraglutide administered by bolus subcutaneous injection yielding systemic exposures 0.2-, 2-, 10- and 45-times the human exposure, respectively, at the MRHD of 1.8 mg/day based on plasma AUC comparison. A dose-related increase in benign thyroid C-cell adenomas was seen in the 1.0 and the 3.0 mg/kg/day groups with incidences of 13% and 19% in males and 6% and 20% in females, respectively. C-cell adenomas did not occur in control groups or 0.03 and 0.2 mg/kg/day groups. Treatment-related malignant C-cell carcinomas occurred in 3% of females in the 3.0 mg/kg/day group. Thyroid C-cell tumors are rare findings during carcinogenicity testing in mice. A treatment-related increase in fibrosarcomas was seen on the dorsal skin and subcutis, the body surface used for drug injection, in males in the 3 mg/kg/day group. These fibrosarcomas were attributed to the high local concentration of drug near the injection site. The liraglutide concentration in the clinical formulation (6 mg/mL) is 10-times higher than the concentration in the formulation used to administer 3 mg/kg/day liraglutide to mice in the carcinogenicity study (0.6 mg/mL). - A 104-week carcinogenicity study was conducted in male and female Sprague Dawley rats at doses of 0.075, 0.25 and 0.75 mg/kg/day liraglutide administered by bolus subcutaneous injection with exposures 0.5-, 2- and 8-times the human exposure, respectively, resulting from the MRHD based on plasma AUC comparison. A treatment-related increase in benign thyroid C-cell adenomas was seen in males in 0.25 and 0.75 mg/kg/day liraglutide groups with incidences of 12%, 16%, 42%, and 46% and in all female liraglutide-treated groups with incidences of 10%, 27%, 33%, and 56% in 0 (control), 0.075, 0.25, and 0.75 mg/kg/day groups, respectively. A treatment-related increase in malignant thyroid C-cell carcinomas was observed in all male liraglutide-treated groups with incidences of 2%, 8%, 6%, and 14% and in females at 0.25 and 0.75 mg/kg/day with incidences of 0%, 0%, 4%, and 6% in 0 (control), 0.075, 0.25, and 0.75 mg/kg/day groups, respectively. Thyroid C-cell carcinomas are rare findings during carcinogenicity testing in rats. - Human relevance of thyroid C-cell tumors in mice and rats is unknown and could not be determined by clinical studies or nonclinical studies. - Liraglutide was negative with and without metabolic activation in the Ames test for mutagenicity and in a human peripheral blood lymphocyte chromosome aberration test for clastogenicity. Liraglutide was negative in repeat-dose in vivo micronucleus tests in rats. - In rat fertility studies using subcutaneous doses of 0.1, 0.25 and 1.0 mg/kg/day liraglutide, males were treated for 4 weeks prior to and throughout mating and females were treated 2 weeks prior to and throughout mating until gestation day 17. No direct adverse effects on male fertility was observed at doses up to 1.0 mg/kg/day, a high dose yielding an estimated systemic exposure 11- times the human exposure at the MRHD, based on plasma AUC. In female rats, an increase in early embryonic deaths occurred at 1.0 mg/kg/day. Reduced body weight gain and food consumption were observed in females at the 1.0 mg/kg/day dose. # Clinical Studies - A total of 6090 patients with type 2 diabetes participated in 8 phase 3 trials. There were 5 double-blind (one of these trials had an open-label active control insulin glargine arm), randomized, controlled clinical trials, one of 52 weeks duration and four of 26 weeks duration. There were also three 26 week open-label trials; one comparing Victoza to twice-daily exenatide, one comparing Victoza to sitagliptin and one comparing Victoza+metformin+insulin detemir to Victoza+metformin alone. These multinational trials were conducted to evaluate the glycemic efficacy and safety of Victoza in type 2 diabetes as monotherapy and in combination with one or two oral anti-diabetic medications or insulin detemir. The 7 add-on combination therapy trials enrolled patients who were previously treated with anti-diabetic therapy, and approximately two-thirds of patients in the monotherapy trial also were previously treated with anti-diabetic therapy. In total, 272 (4%) of the 6090 patients in these 8 trials were new to anti-diabetic therapy. In these 8 clinical trials, patients ranged in age from 18-80 years old and 54% were men. Approximately 82% of patients were Caucasian, and 6% were Black. In the 5 trials where ethnicity was captured, 10% of patients were Hispanic/Latino (n=630). - In each of the placebo controlled trials, treatment with Victoza produced clinically and statistically significant improvements in hemoglobin A1c and fasting plasma glucose (FPG) compared to placebo. - All Victoza-treated patients started at 0.6 mg/day. The dose was increased in weekly intervals by 0.6 mg to reach 1.2 mg or 1.8 mg for patients randomized to these higher doses. Victoza 0.6 mg is not effective for glycemic control and is intended only as a starting dose to reduce gastrointestinal intolerance . ## Monotherapy - In this 52-week trial, 746 patients were randomized to Victoza 1.2 mg, Victoza 1.8 mg, or glimepiride 8 mg. Patients who were randomized to glimepiride were initially treated with 2 mg daily for two weeks, increasing to 4 mg daily for another two weeks, and finally increasing to 8 mg daily. Treatment with Victoza 1.8 mg and 1.2 mg resulted in a statistically significant reduction in HbA1c compared to glimepiride (Table 6). The percentage of patients who discontinued due to ineffective therapy was 3.6% in the Victoza 1.8 mg treatment group, 6.0% in the Victoza 1.2 mg treatment group, and 10.1% in the glimepiride-treatment group. ## Combination Therapy Add-on to metformin - In this 26-week trial, 1091 patients were randomized to Victoza 0.6 mg, Victoza 1.2 mg, Victoza 1.8 mg, placebo, or glimepiride 4 mg (one-half of the maximal approved dose in the United States), all as add-on to metformin. Randomization occurred after a 6-week run-in period consisting of a 3-week initial forced metformin titration period followed by a maintenance period of another 3 weeks. During the titration period, doses of metformin were increased up to 2000 mg/day. - Treatment with Victoza 1.2 mg and 1.8 mg as add-on to metformin resulted in a significant mean HbA1c reduction relative to placebo add-on to metformin and resulted in a similar mean HbA1c reduction relative to glimepiride 4 mg add-on to metformin (Table 7). The percentage of patients who discontinued due to ineffective therapy was 5.4% in the Victoza 1.8 mg + metformin treatment group, 3.3% in the Victoza 1.2 mg + metformin treatment group, 23.8% in the placebo + metformin treatment group, and 3.7% in the glimepiride + metformin treated group. Victoza Compared to Sitagliptin, Both as Add-on to metformin - In this 26–week, open-label trial, 665 patients on a background of metformin ≥1500 mg per day were randomized to Victoza 1.2 mg once-daily, Victoza 1.8 mg once-daily or sitagliptin 100 mg once-daily, all dosed according to approved labeling. Patients were to continue their current treatment on metformin at a stable, pre-trial dose level and dosing frequency. The primary endpoint was the change in HbA1c from baseline to Week 26. Treatment with Victoza 1.2 mg and Victoza 1.8 mg resulted in statistically significant reductions in HbA1c relative to sitagliptin 100 mg (Table 8). The percentage of patients who discontinued due to ineffective therapy was 3.1% in the Victoza 1.2 mg group, 0.5% in the Victoza 1.8 mg treatment group, and 4.1% in the sitagliptin 100 mg treatment group. From a mean baseline body weight of 94 kg, there was a mean reduction of 2.7 kg for Victoza 1.2 mg, 3.3 kg for Victoza 1.8 mg, and 0.8 kg for sitagliptin 100 mg. Figure 4 Mean HbA1c for patients who completed the 26-week trial and for the Last Observation Carried Forward (LOCF, intent-to-treat) data at Week 26 Combination Therapy with metformin and Insulin - This 26-week open-label trial enrolled 988 patients with inadequate glycemic control (HbA1c 7-10%) on metformin (≥1500 mg/day) alone or inadequate glycemic control (HbA1c 7-8.5%) on metformin (≥1500 mg/day) and a sulfonylurea. Patients who were on metformin and a sulfonylurea discontinued the sulfonylurea then all patients entered a 12-week run-in period during which they received add-on therapy with Victoza titrated to 1.8 mg once-daily. At the end of the run-in period, 498 patients (50%) achieved HbA1c <7% with Victoza 1.8 mg and metformin and continued treatment in a non-randomized, observational arm. Another 167 patients (17%) withdrew from the trial during the run-in period with approximately one-half of these patients doing so because of gastrointestinal adverse reactions [see Adverse Reactions (6.1)]. The remaining 323 patients with HbA1c ≥7% (33% of those who entered the run-in period) were randomized to 26 weeks of once-daily insulin detemir administered in the evening as add-on therapy (N=162) or to continued, unchanged treatment with Victoza 1.8 mg and metformin (N=161). The starting dose of insulin detemir was 10 units/day and the mean dose at the end of the 26-week randomized period was 39 units/day. During the 26 week randomized treatment period, the percentage of patients who discontinued due to ineffective therapy was 11.2% in the group randomized to continued treatment with Victoza 1.8 mg and metformin and 1.2% in the group randomized to add-on therapy with insulin detemir. Treatment with insulin detemir as add-on to Victoza 1.8 mg + metformin resulted in statistically significant reductions in HbA1c and FPG compared to continued, unchanged treatment with Victoza 1.8 mg + metformin alone (Table 9). From a mean baseline body weight of 96 kg after randomization, there was a mean reduction of 0.3 kg in the patients who received insulin detemir add-on therapy compared to a mean reduction of 1.1 kg in the patients who continued on unchanged treatment with Victoza 1.8 mg + metformin alone. Add-on to Sulfonylurea - In this 26-week trial, 1041 patients were randomized to Victoza 0.6 mg, Victoza 1.2 mg, Victoza 1.8 mg, placebo, or rosiglitazone 4 mg (one-half of the maximal approved dose in the United States), all as add-on to glimepiride. Randomization occurred after a 4-week run-in period consisting of an initial, 2-week, forced-glimepiride titration period followed by a maintenance period of another 2 weeks. During the titration period, doses of glimepiride were increased to 4 mg/day. The doses of glimepiride could be reduced (at the discretion of the investigator) from 4 mg/day to 3 mg/day or 2 mg/day (minimum) after randomization, in the event of unacceptable hypoglycemia or other adverse events. Treatment with Victoza 1.2 mg and 1.8 mg as add-on to glimepiride resulted in a statistically significant reduction in mean HbA1c compared to placebo add-on to glimepiride (Table 10). The percentage of patients who discontinued due to ineffective therapy was 3.0% in the Victoza 1.8 mg + glimepiride treatment group, 3.5% in the Victoza 1.2 mg + glimepiride treatment group, 17.5% in the placebo + glimepiride treatment group, and 6.9% in the rosiglitazone + glimepiride treatment group. Add-on to metformin and Sulfonylurea - In this 26-week trial, 581 patients were randomized to Victoza 1.8 mg, placebo, or insulin glargine, all as add-on to metformin and glimepiride. Randomization took place after a 6-week run-in period consisting of a 3-week forced metformin and glimepiride titration period followed by a maintenance period of another 3 weeks. During the titration period, doses of metformin and glimepiride were to be increased up to 2000 mg/day and 4 mg/day, respectively. After randomization, patients randomized to Victoza 1.8 mg underwent a 2 week period of titration with Victoza. During the trial, the Victoza and metformin doses were fixed, although glimepiride and insulin glargine doses could be adjusted. Patients titrated glargine twice-weekly during the first 8 weeks of treatment based on self-measured fasting plasma glucose on the day of titration. After Week 8, the frequency of insulin glargine titration was left to the discretion of the investigator, but, at a minimum, the glargine dose was to be revised, if necessary, at Weeks 12 and 18. Only 20% of glargine-treated patients achieved the pre-specified target fasting plasma glucose of ≤100 mg/dL. Therefore, optimal titration of the insulin glargine dose was not achieved in most patients. Treatment with Victoza as add-on to glimepiride and metformin resulted in a statistically significant mean reduction in HbA1c compared to placebo add-on to glimepiride and metformin (Table 11). The percentage of patients who discontinued due to ineffective therapy was 0.9% in the Victoza 1.8 mg + metformin + glimepiride treatment group, 0.4% in the insulin glargine + metformin + glimepiride treatment group, and 11.3% in the placebo + metformin + glimepiride treatment group. Victoza Compared to Exenatide, Both as Add-on to metformin and/or Sulfonylurea Therapy - In this 26–week, open-label trial, 464 patients on a background of metformin monotherapy, sulfonylurea monotherapy or a combination of metformin and sulfonylurea were randomized to once daily Victoza 1.8 mg or exenatide 10 mcg twice daily. Maximally tolerated doses of background therapy were to remain unchanged for the duration of the trial. Patients randomized to exenatide started on a dose of 5 mcg twice-daily for 4 weeks and then were escalated to 10 mcg twice daily. Treatment with Victoza 1.8 mg resulted in statistically significant reductions in HbA1c and FPG relative to exenatide (Table 12). The percentage of patients who discontinued for ineffective therapy was 0.4% in the Victoza treatment group and 0% in the exenatide treatment group. Both treatment groups had a mean decrease from baseline in body weight of approximately 3 kg. Add-on to metformin and Thiazolidinedione - In this 26-week trial, 533 patients were randomized to Victoza 1.2 mg, Victoza 1.8 mg or placebo, all as add-on to rosiglitazone (8 mg) plus metformin (2000 mg). Patients underwent a 9 week run-in period (3-week forced dose escalation followed by a 6-week dose maintenance phase) with rosiglitazone (starting at 4 mg and increasing to 8 mg/day within 2 weeks) and metformin (starting at 500 mg with increasing weekly increments of 500 mg to a final dose of 2000 mg/day). Only patients who tolerated the final dose of rosiglitazone (8 mg/day) and metformin (2000 mg/day) and completed the 6-week dose maintenance phase were eligible for randomization into the trial. Treatment with Victoza as add-on to metformin and rosiglitazone produced a statistically significant reduction in mean HbA1c compared to placebo add-on to metformin and rosiglitazone (Table 13). The percentage of patients who discontinued due to ineffective therapy was 1.7% in the Victoza 1.8 mg + metformin + rosiglitazone treatment group, 1.7% in the Victoza 1.2 mg + metformin + rosiglitazone treatment group, and 16.4% in the placebo + metformin + rosiglitazone treatment group. # How Supplied - Victoza is available in the following package sizes containing disposable, pre-filled, multi-dose pens. Each individual pen delivers doses of 0.6 mg, 1.2 mg, or 1.8 mg (6 mg/mL, 3 mL). - 2 x Victoza pen NDC 0169-4060-12 - 3 x Victoza pen NDC 0169-4060-13 - Each Victoza pen is for use by a single patient. A Victoza pen should never be shared between patients, even if the needle is changed. ## Storage - Prior to first use, Victoza should be stored in a refrigerator between 36ºF to 46ºF (2ºC to 8ºC) (Table 14). Do not store in the freezer or directly adjacent to the refrigerator cooling element. Do not freeze Victoza and do not use Victoza if it has been frozen. - After initial use of the Victoza pen, the pen can be stored for 30 days at controlled room temperature (59°F to 86°F; 15°C to 30°C) or in a refrigerator (36°F to 46°F; 2°C to 8°C). Keep the pen cap on when not in use. Victoza should be protected from excessive heat and sunlight. Always remove and safely discard the needle after each injection and store the Victoza pen without an injection needle attached. This will reduce the potential for contamination, infection, and leakage while also ensuring dosing accuracy. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information ## FDA-Approved Medication Guide See separate leaflet. ## Risk of Thyroid C-cell Tumors - Patients should be informed that liraglutide causes benign and malignant thyroid C-cell tumors in mice and rats and that the human relevance of this finding is unknown. Patients should be counseled to report symptoms of thyroid tumors (e.g., a lump in the neck, hoarseness, dysphagia or dyspnea) to their physician. ## dehydration and Renal Failure - Patients treated with Victoza should be advised of the potential risk of dehydration due to gastrointestinal adverse reactions and take precautions to avoid fluid depletion. Patients should be informed of the potential risk for worsening renal function, which in some cases may require dialysis. ## pancreatitis - Patients should be informed of the potential risk for pancreatitis. Explain that persistent severe abdominal pain that may radiate to the back and which may or may not be accompanied by vomiting, is the hallmark symptom of acute pancreatitis. Instruct patients to discontinue Victoza promptly and contact their physician if persistent severe abdominal pain occurs [see Warnings and Precautions (5.2)]. ## Hypersensitivity Reactions - Patients should be informed that serious hypersensitivity reactions have been reported during postmarketing use of Victoza. If symptoms of hypersensitivity reactions occur, patients must stop taking Victoza and seek medical advice promptly. ## Never Share a Victoza Pen Between Patients - Counsel patients that they should never share a Victoza pen with another person, even if the needle is changed. Sharing of the pen between patients may pose a risk of transmission of infection. ## Instructions - Patients should be informed of the potential risks and benefits of Victoza and of alternative modes of therapy. Patients should also be informed about the importance of adherence to dietary instructions, regular physical activity, periodic blood glucose monitoring and A1c testing, recognition and management of hypoglycemia and hyperglycemia, and assessment for diabetes complications. During periods of stress such as fever, trauma, infection, or surgery, medication requirements may change and patients should be advised to seek medical advice promptly. - Patients should be advised that the most common side effects of Victoza are headache, nausea and diarrhea. nausea is most common when first starting Victoza, but decreases over time in the majority of patients and does not typically require discontinuation of Victoza. - Physicians should instruct their patients to read the Patient Medication Guide before starting Victoza therapy and to reread each time the prescription is renewed. Patients should be instructed to inform their doctor or pharmacist if they develop any unusual symptom, or if any known symptom persists or worsens. - Inform patients not to take an extra dose of Victoza to make up for a missed dose. If a dose is missed, the once-daily regimen should be resumed as prescribed with the next scheduled dose. - If more than 3 days have elapsed since the last dose, the patient should be advised to reinitiate Victoza at 0.6 mg to mitigate any gastrointestinal symptoms associated with reinitiation of treatment. Victoza should be titrated at the discretion of the prescribing physician. ## Laboratory Tests - Patients should be informed that response to all diabetic therapies should be monitored by periodic measurements of blood glucose and A1c levels, with a goal of decreasing these levels towards the normal range. A1c is especially useful for evaluating long-term glycemic control. # Precautions with Alcohol Alcohol-Liraglutide interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names VICTOZA # Look-Alike Drug Names There is limited information about the look-alike drug names. # Drug Shortage Status # Price	https://www.wikidoc.org/index.php/Liraglutide
6e6aa31318bc02afebfebf53feb3d0daac885ec9	wikidoc	Lofepramine	Lofepramine # Overview Lofepramine (brand name: Lomont (UK) Emdalen (ZA), Gamanil (IE, UK (discontinued)) & Tymelyt (discontinued)) is a third generation tricyclic antidepressant which was introduced in 1983 for the treatment of depressive disorders. Lofepramine is less sedating than, for instance, amitriptyline, and is safer in overdose than older tricyclics. # Indications In the United Kingdom, Lofepramine is licensed for the treatment of depression which is its primary use in medicine. # Side effects - Common Constipation Dry Mouth Blurred Vision Sleepiness - Constipation - Dry Mouth - Blurred Vision - Sleepiness - Uncommon Central nervous system side-effects, particularly in the elderly, anxiety, dizziness, agitation, confusion, sleep disturbances, irritability, and paraesthesia Headache Nausea Palpitations Urinary Retention Sexual Dysfunction - Central nervous system side-effects, particularly in the elderly, anxiety, dizziness, agitation, confusion, sleep disturbances, irritability, and paraesthesia - Headache - Nausea - Palpitations - Urinary Retention - Sexual Dysfunction - Rare Constipation (leading to paralytic ileus, particularly in the elderly) Skin Rashes - Constipation (leading to paralytic ileus, particularly in the elderly) - Skin Rashes - Very Rare Blurred Vision (precipitation of angle-closure glaucoma) - Blurred Vision (precipitation of angle-closure glaucoma) ## Other side effects Delusions, nightmares, facial oedema, general feeling of being unwell, bleeding from skin, inflammation of mucous membranes, loss of taste, psychiatric problems such as self-harm, pins and needles, sweating, dizziness. Can cause behavioural disturbance in the young. May produce weight gain or cause changes in the levels of blood sugar. Some patients report muscular discomfort, particularly in the shoulders. # Interactions Lofepramine is known to interact with - Alcohol. Increased sedative effect - Antiepileptics. Possibly antagonise the anticonvulsant effect of antiepileptics by lowering the convulsive threshold - Antihistamines. Possible increase of antimuscarinic and sedative effects - Antimuscarinics. Possible increase of antimuscarinic side-effects - Anxiolytics and Hypnotics. Increased sedative effect - Apraclonidine. Avoidance advised by manufacturer of apraclonidine - Brimonidine. Avoidance advised by manufacturer of brimonidine - Diazoxide. Enhanced hypotensive effect - Hydralazine. Enhanced hypotensive effect - Monoamine oxidase inhibitors (MAOIs). Do not start until 2 weeks after stopping MAOIs, also MAOIs should not be started until at least 1–2 weeks after stopping tricyclic-related antidepressants - Moclobemide. do not start moclobemide for at least 1 week after stopping tricyclic-related antidepressants - Nitrates. Possibly reduce effects of sublingual tablets of nitrates (failure to dissolve under tongue owing to dry mouth) - Sodium Nitroprusside. Enhanced hypotensive effect # Contraindications - In the immediate recovery period after myocardial infarction - In arrhythmias (particularly heart block) - In the manic phase of bipolar disorder - In acute porphyria - With Amiodarone - With Terfenadine - In severe liver and/or severe renal impairment # Mechanism of action Lofepramine is a strong inhibitor of norepinephrine reuptake (Ki=5.4 nM) and a moderate inhibitor of serotonin reuptake (Ki=70 nM). It is a weak-intermediate level antagonist of the muscarinic acetylcholine receptors (Ki values of 67 nM, 330 nM, 130 nM, 340 nM, 460 nM for M1, M2, M3, M4 & M5 respectively). The measured affinity of Lofepramine at different receptor or transporter binding sites are listed below: # Pharmacokinetics It is partially converted to its active metabolite desipramine in vivo. However, it is unlikely this property plays a substantial role in its overall effects as lofepramine exhibits lower toxicity and anticholinergic side effects relative to desipramine while retaining equivalent antidepressant efficacy. # Warnings To be used with caution for epileptic patients or those with glaucoma or psychosis. Lofepramine should not be given to people who have suffered liver failure or heart disease. Not advisable for use in pregnant women. # Availability In the United Kingdom, lofepramine is marketed (as the hydrochloride salt) in the form of 70 mg tablets and 5ml oral suspension as the generic Lomont.	Lofepramine Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview Lofepramine (brand name: Lomont (UK) Emdalen (ZA), Gamanil (IE, UK (discontinued)) & Tymelyt (discontinued)) is a third generation[3] tricyclic antidepressant which was introduced in 1983 for the treatment of depressive disorders.[4] Lofepramine is less sedating than, for instance, amitriptyline, and is safer in overdose than older tricyclics.[2] # Indications In the United Kingdom, Lofepramine is licensed for the treatment of depression which is its primary use in medicine.[2][5] # Side effects[6] - Common Constipation Dry Mouth Blurred Vision Sleepiness - Constipation - Dry Mouth - Blurred Vision - Sleepiness - Uncommon Central nervous system side-effects, particularly in the elderly, anxiety, dizziness, agitation, confusion, sleep disturbances, irritability, and paraesthesia Headache Nausea Palpitations Urinary Retention Sexual Dysfunction - Central nervous system side-effects, particularly in the elderly, anxiety, dizziness, agitation, confusion, sleep disturbances, irritability, and paraesthesia - Headache - Nausea - Palpitations - Urinary Retention - Sexual Dysfunction - Rare Constipation (leading to paralytic ileus, particularly in the elderly) Skin Rashes - Constipation (leading to paralytic ileus, particularly in the elderly) - Skin Rashes - Very Rare Blurred Vision (precipitation of angle-closure glaucoma) - Blurred Vision (precipitation of angle-closure glaucoma) ## Other side effects Delusions, nightmares, facial oedema, general feeling of being unwell, bleeding from skin, inflammation of mucous membranes, loss of taste, psychiatric problems such as self-harm, pins and needles, sweating, dizziness. Can cause behavioural disturbance in the young. May produce weight gain or cause changes in the levels of blood sugar. Some patients report muscular discomfort, particularly in the shoulders. # Interactions[7] Lofepramine is known to interact with - Alcohol. Increased sedative effect - Antiepileptics. Possibly antagonise the anticonvulsant effect of antiepileptics by lowering the convulsive threshold - Antihistamines. Possible increase of antimuscarinic and sedative effects - Antimuscarinics. Possible increase of antimuscarinic side-effects - Anxiolytics and Hypnotics. Increased sedative effect - Apraclonidine. Avoidance advised by manufacturer of apraclonidine - Brimonidine. Avoidance advised by manufacturer of brimonidine - Diazoxide. Enhanced hypotensive effect - Hydralazine. Enhanced hypotensive effect - Monoamine oxidase inhibitors (MAOIs). Do not start until 2 weeks after stopping MAOIs, also MAOIs should not be started until at least 1–2 weeks after stopping tricyclic-related antidepressants - Moclobemide. do not start moclobemide for at least 1 week after stopping tricyclic-related antidepressants - Nitrates. Possibly reduce effects of sublingual tablets of nitrates (failure to dissolve under tongue owing to dry mouth) - Sodium Nitroprusside. Enhanced hypotensive effect # Contraindications - In the immediate recovery period after myocardial infarction - In arrhythmias (particularly heart block) - In the manic phase of bipolar disorder - In acute porphyria[8] - With Amiodarone - With Terfenadine - In severe liver and/or severe renal impairment[9] # Mechanism of action Lofepramine is a strong inhibitor of norepinephrine reuptake (Ki=5.4 nM) and a moderate inhibitor of serotonin reuptake (Ki=70 nM).[10] It is a weak-intermediate level antagonist of the muscarinic acetylcholine receptors (Ki values of 67 nM, 330 nM, 130 nM, 340 nM, 460 nM for M1, M2, M3, M4 & M5 respectively).[10] The measured affinity [Kd (nM)] of Lofepramine at different receptor or transporter binding sites are listed below: # Pharmacokinetics It is partially converted to its active metabolite desipramine in vivo.[4] However, it is unlikely this property plays a substantial role in its overall effects as lofepramine exhibits lower toxicity and anticholinergic side effects relative to desipramine while retaining equivalent antidepressant efficacy.[4] # Warnings To be used with caution for epileptic patients or those with glaucoma or psychosis. Lofepramine should not be given to people who have suffered liver failure or heart disease. Not advisable for use in pregnant women. # Availability In the United Kingdom, lofepramine is marketed (as the hydrochloride salt) in the form of 70 mg tablets and 5ml oral suspension as the generic Lomont.[11]	https://www.wikidoc.org/index.php/Lofepramine
06923b4dfc77cf43ec2b0b8084e2af774e69900e	wikidoc	Longissimus	Longissimus # Overview The longissimus is the muscle lateral to the semispinalis. It is the longest subdivision of the sacrospinalis that extends forward into the transverse processes of the posterior cervical vertebrae. # Longissimus dorsi The Longissimus dorsi is the intermediate and largest of the continuations of the Sacrospinalis. In the lumbar region, where it is as yet blended with the Iliocostalis lumborum, some of its fibers are attached to the whole length of the posterior surfaces of the transverse processes and the accessory processes of the lumbar vertebræ, and to the anterior layer of the lumbodorsal fascia. In the thoracic region it is inserted, by rounded tendons, into the tips of the transverse processes of all the thoracic vertebræ, and by fleshy processes into the lower nine or ten ribs between their tubercles and angles. # Longissimus cervicis The Longissimus cervicis (Transversalis cervicis), situated medial to the Longissimus dorsi, arises by long thin tendons from the summits of the transverse processes of the upper four or five thoracic vertebræ, and is inserted by similar tendons into the posterior tubercles of the transverse processes of the cervical vertebrae from the second to the sixth inclusive. # Longissimus capitis The Longissimus capitis (Trachelomastoid muscle) lies medial to the Longissimus cervicis, between it and the Semispinalis capitis. It arises by tendons from the transverse processes of the upper four or five thoracic vertebræ, and the articular processes of the lower three or four cervical vertebrae, and is inserted into the posterior margin of the mastoid process, beneath the Splenius capitis and Sternocleidomastoideus. It is almost always crossed by a tendinous intersection near its insertion.	Longissimus Template:Muscle infobox # Overview The longissimus is the muscle lateral to the semispinalis. It is the longest subdivision of the sacrospinalis that extends forward into the transverse processes of the posterior cervical vertebrae. # Longissimus dorsi The Longissimus dorsi is the intermediate and largest of the continuations of the Sacrospinalis. In the lumbar region, where it is as yet blended with the Iliocostalis lumborum, some of its fibers are attached to the whole length of the posterior surfaces of the transverse processes and the accessory processes of the lumbar vertebræ, and to the anterior layer of the lumbodorsal fascia. In the thoracic region it is inserted, by rounded tendons, into the tips of the transverse processes of all the thoracic vertebræ, and by fleshy processes into the lower nine or ten ribs between their tubercles and angles. # Longissimus cervicis The Longissimus cervicis (Transversalis cervicis), situated medial to the Longissimus dorsi, arises by long thin tendons from the summits of the transverse processes of the upper four or five thoracic vertebræ, and is inserted by similar tendons into the posterior tubercles of the transverse processes of the cervical vertebrae from the second to the sixth inclusive. # Longissimus capitis The Longissimus capitis (Trachelomastoid muscle) lies medial to the Longissimus cervicis, between it and the Semispinalis capitis. It arises by tendons from the transverse processes of the upper four or five thoracic vertebræ, and the articular processes of the lower three or four cervical vertebrae, and is inserted into the posterior margin of the mastoid process, beneath the Splenius capitis and Sternocleidomastoideus. It is almost always crossed by a tendinous intersection near its insertion.	https://www.wikidoc.org/index.php/Longissimus
62dd73ab84b400de67c4fdd4550c077fa54f9a75	wikidoc	Loteprednol	Loteprednol # 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 Loteprednol is a corticosteroid that is FDA approved for the {{{indicationType}}} of post-operative inflammation and pain following ocular surgery. Common adverse reactions include anterior chamber inflammation, eye pain, and foreign body sensation. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) - Dosing Information - Invert closed bottle and shake once to fill tip before instilling drops. - Apply one to two drops of LOTEMAX into the conjunctival sac of the affected eye four times daily beginning the day after surgery and continuing throughout the first 2 weeks of the post-operative period. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Loteprednol in adult patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Loteprednol in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) There is limited information regarding FDA-Labeled Use of Loteprednol in pediatric patients. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Loteprednol in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Loteprednol in pediatric patients. # Contraindications - LOTEMAX, as with other ophthalmic corticosteroids, is contraindicated in most viral diseases of the cornea and conjunctiva including epithelial herpes simplex keratitis (dendritic keratitis), vaccinia, and varicella, and also in mycobacterial infection of the eye and fungal diseases of ocular structures # Warnings ### Precautions - Intraocular Pressure (IOP) Increase - Prolonged use of corticosteroids may result in glaucoma with damage to the optic nerve, defects in visual acuity and fields of vision. Steroids should be used with caution in the presence of glaucoma. If this product is used for 10 days or longer, intraocular pressure should be monitored. - Cataracts - Use of corticosteroids may result in posterior subcapsular cataract formation. - Delayed Healing - The use of steroids after cataract surgery may delay healing and increase the incidence of bleb formation. In those diseases causing thinning of the cornea or sclera, perforations have been known to occur with the use of topical steroids. The initial prescription and renewal of the medication order should be made by a physician only after examination of the patient with the aid of magnification such as slit lamp biomicroscopy and, where appropriate, fluorescein staining. - Bacterial Infections - Prolonged use of corticosteroids may suppress the host response and thus increase the hazard of secondary ocular infections. In acute purulent conditions of the eye, steroids may mask infection or enhance existing infection. - Viral Infections - Employment of a corticosteroid medication in the treatment of patients with a history of herpes simplex requires great caution. Use of ocular steroids may prolong the course and may exacerbate the severity of many viral infections of the eye (including herpes simplex). - Fungal Infections - Fungal infections of the cornea are particularly prone to develop coincidentally with long-term local steroid application. Fungus invasion must be considered in any persistent corneal ulceration where a steroid has been used or is in use. Fungal cultures should be taken when appropriate. - Contact Lens Wear - Patients should not wear contact lenses during their course of therapy with LOTEMAX # Adverse Reactions ## Clinical Trials Experience Adverse reactions associated with ophthalmic steroids include elevated intraocular pressure, which may be associated with infrequent optic nerve damage, visual acuity and field defects, posterior subcapsular cataract formation, delayed wound healing and secondary ocular infection from pathogens including herpes simplex, and perforation of the globe where there is thinning of the cornea or sclera. The most common adverse drug reactions reported were anterior chamber inflammation (5%), eye pain (2%), and foreign body sensation (2%). ## Postmarketing Experience There is limited information regarding Postmarketing Experience of Loteprednol in the drug label. # Drug Interactions There is limited information regarding Loteprednol Drug Interactions in the drug label. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): - Pregnancy Category C - Loteprednol etabonate has been shown to be embryotoxic (delayed ossification) and teratogenic (increased incidence of meningocele, abnormal left common carotid artery, and limb flexures) when administered orally to rabbits during organogenesis at a dose of 3 mg/kg/day (35 times the maximum daily clinical dose), a dose which caused no maternal toxicity. The no-observed-effect-level (NOEL) for these effects was 0.5 mg/kg/day (6 times the maximum daily clinical dose). Oral treatment of rats during organogenesis resulted in teratogenicity (absent innominate artery at ≥5 mg/kg/day doses, and cleft palate and umbilical hernia at ≥50 mg/kg/day) and embryotoxicity (increased post-implantation losses at 100 mg/kg/day and decreased fetal body weight and skeletal ossification with ≥50 mg/kg/day). Treatment of rats with 0.5 mg/kg/day (6 times the maximum clinical dose) during organogenesis did not result in any reproductive toxicity. Loteprednol etabonate was maternally toxic (significantly reduced body weight gain during treatment) when administered to pregnant rats during organogenesis at doses of ≥5 mg/kg/day. - Oral exposure of female rats to 50 mg/kg/day of loteprednol etabonate from the start of the fetal period through the end of lactation, a maternally toxic treatment regimen (significantly decreased body weight gain), gave rise to decreased growth and survival, and retarded development in the offspring during lactation; the NOEL for these effects was 5 mg/kg/day. Loteprednol etabonate had no effect on the duration of gestation or parturition when administered orally to pregnant rats at doses up to 50 mg/kg/day during the fetal period. - There are no adequate and well controlled studies in pregnant women. LOTEMAX® 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 Loteprednol in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Loteprednol during labor and delivery. ### Nursing Mothers - It is not known whether topical ophthalmic administration of corticosteroids could result in sufficient systemic absorption to produce detectable quantities in human milk. Systemic steroids appear in human milk and could suppress growth, interfere with endogenous corticosteroid production, or cause other untoward effects. Caution should be exercised when LOTEMAX is administered to a nursing woman. ### Pediatric Use - Safety and effectiveness in pediatric patients have not been established. ### Geriatic Use There is no FDA guidance on the use of Loteprednol with respect to geriatric patients. ### Gender There is no FDA guidance on the use of Loteprednol with respect to specific gender populations. ### Race There is no FDA guidance on the use of Loteprednol with respect to specific racial populations. ### Renal Impairment There is no FDA guidance on the use of Loteprednol in patients with renal impairment. ### Hepatic Impairment There is no FDA guidance on the use of Loteprednol in patients with hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Loteprednol in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Loteprednol in patients who are immunocompromised. # Administration and Monitoring ### Administration - Topical ### Monitoring There is limited information regarding Monitoring of Loteprednol in the drug label. # IV Compatibility There is limited information regarding IV Compatibility of Loteprednol in the drug label. # Overdosage ## Acute Overdose ## Chronic Overdose There is limited information regarding Chronic Overdose of Loteprednol in the drug label. # Pharmacology There is limited information regarding Loteprednol Pharmacology in the drug label. ## Mechanism of Action - Corticosteroids inhibit the inflammatory response to a variety of inciting agents and probably delay or slow healing. They inhibit the edema, fibrin deposition, capillary dilation, leukocyte migration, capillary proliferation, fibroblast proliferation, deposition of collagen, and scar formation associated with inflammation. While glucocorticoids are known to bind to and activate the glucocorticoid receptor, the molecular mechanisms involved in glucocorticoid/glucocorticoid receptor-dependent modulation of inflammation are not clearly established. However, corticosteroids are thought to inhibit prostaglandin production through several independent mechanisms. ## Structure - LOTEMAX (loteprednol etabonate ophthalmic gel) 0.5% contains a sterile, topical corticosteroid for ophthalmic use. Loteprednol etabonate is a white to off-white powder. - Loteprednol etabonate is represented by the following structural formula: - Chemical Name: - chloromethyl 17α--11β-hydroxy-3-oxoandrosta-1,4-diene-17β-carboxylate ## Pharmacodynamics There is limited information regarding Pharmacodynamics of Loteprednol in the drug label. ## Pharmacokinetics - Loteprednol is lipid soluble and can penetrate into cells. Loteprednol etabonate is synthesized through structural modifications of prednisolone-related compounds so that it will undergo a predictable transformation to an inactive metabolite. Based upon in vivo and in vitro preclinical metabolism studies, loteprednol etabonate undergoes extensive metabolism to the inactive carboxylic acid metabolites, PJ-91 and PJ-90. The systemic exposure to loteprednol etabonate following ocular administration of LOTEMAX has not been studied in humans. ## Nonclinical Toxicology - Long-term animal studies have not been conducted to evaluate the carcinogenic potential of loteprednol etabonate. Loteprednol etabonate was not genotoxic in vitro in the Ames test, the mouse lymphoma tk assay, or in a chromosome aberration test in human lymphocytes, or in vivo in the single dose mouse micronucleus assay. Treatment of male and female rats with up to 50 mg/kg/day and 25 mg/kg/day of loteprednol etabonate, respectively, (600 and 300 times the maximum clinical dose, respectively) prior to and during mating did not impair fertility in either gender. # Clinical Studies - In two randomized, multicenter, double-masked, parallel-group, vehicle-controlled studies in 813 subjects with, post-operative inflammation, LOTEMAX was more effective compared to its vehicle in resolving anterior chamber inflammation and pain following cataract surgery. Primary endpoints were complete resolution of anterior chamber cells (cell count of 0) and no pain at post-operative day 8. - In these studies, LOTEMAX had a statistically significant higher incidence of subjects with complete clearing of anterior chamber cells (31% vs. 14-16%) and were pain free at post-operative day 8 (73-76% vs. 42-46%). # How Supplied - LOTEMAX® (loteprednol etabonate ophthalmic gel) 0.5% is a sterile ophthalmic gel supplied in a white low density polyethylene plastic bottle with a white controlled drop tip and a pink polypropylene cap in the following size: - 5 g in a 10 mL bottle (NDC 24208-503-07) - Use only if imprinted neckband is intact. - Storage: Store upright at 15º-25º C (59º-77º F). ## Storage There is limited information regarding Loteprednol Storage in the drug label. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information - Administration - Invert closed bottle and shake once to fill tip before instilling drops. - Risk of Contamination - Patients should be advised not to allow the dropper tip to touch any surface, as this may contaminate the gel. - Contact Lens Wear - Patients should be advised not to wear contact lenses when using LOTEMAX. - Risk of Secondary Infection - If pain develops, redness, itching or inflammation becomes aggravated, the patient should be advised to consult a physician. # Precautions with Alcohol - Alcohol-Loteprednol interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - LOTEMAX® # Look-Alike Drug Names There is limited information regarding Loteprednol Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	Loteprednol 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 Loteprednol is a corticosteroid that is FDA approved for the {{{indicationType}}} of post-operative inflammation and pain following ocular surgery. Common adverse reactions include anterior chamber inflammation, eye pain, and foreign body sensation. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) - Dosing Information - Invert closed bottle and shake once to fill tip before instilling drops. - Apply one to two drops of LOTEMAX into the conjunctival sac of the affected eye four times daily beginning the day after surgery and continuing throughout the first 2 weeks of the post-operative period. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Loteprednol in adult patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Loteprednol in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) There is limited information regarding FDA-Labeled Use of Loteprednol in pediatric patients. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Loteprednol in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Loteprednol in pediatric patients. # Contraindications - LOTEMAX, as with other ophthalmic corticosteroids, is contraindicated in most viral diseases of the cornea and conjunctiva including epithelial herpes simplex keratitis (dendritic keratitis), vaccinia, and varicella, and also in mycobacterial infection of the eye and fungal diseases of ocular structures # Warnings ### Precautions - Intraocular Pressure (IOP) Increase - Prolonged use of corticosteroids may result in glaucoma with damage to the optic nerve, defects in visual acuity and fields of vision. Steroids should be used with caution in the presence of glaucoma. If this product is used for 10 days or longer, intraocular pressure should be monitored. - Cataracts - Use of corticosteroids may result in posterior subcapsular cataract formation. - Delayed Healing - The use of steroids after cataract surgery may delay healing and increase the incidence of bleb formation. In those diseases causing thinning of the cornea or sclera, perforations have been known to occur with the use of topical steroids. The initial prescription and renewal of the medication order should be made by a physician only after examination of the patient with the aid of magnification such as slit lamp biomicroscopy and, where appropriate, fluorescein staining. - Bacterial Infections - Prolonged use of corticosteroids may suppress the host response and thus increase the hazard of secondary ocular infections. In acute purulent conditions of the eye, steroids may mask infection or enhance existing infection. - Viral Infections - Employment of a corticosteroid medication in the treatment of patients with a history of herpes simplex requires great caution. Use of ocular steroids may prolong the course and may exacerbate the severity of many viral infections of the eye (including herpes simplex). - Fungal Infections - Fungal infections of the cornea are particularly prone to develop coincidentally with long-term local steroid application. Fungus invasion must be considered in any persistent corneal ulceration where a steroid has been used or is in use. Fungal cultures should be taken when appropriate. - Contact Lens Wear - Patients should not wear contact lenses during their course of therapy with LOTEMAX # Adverse Reactions ## Clinical Trials Experience Adverse reactions associated with ophthalmic steroids include elevated intraocular pressure, which may be associated with infrequent optic nerve damage, visual acuity and field defects, posterior subcapsular cataract formation, delayed wound healing and secondary ocular infection from pathogens including herpes simplex, and perforation of the globe where there is thinning of the cornea or sclera. The most common adverse drug reactions reported were anterior chamber inflammation (5%), eye pain (2%), and foreign body sensation (2%). ## Postmarketing Experience There is limited information regarding Postmarketing Experience of Loteprednol in the drug label. # Drug Interactions There is limited information regarding Loteprednol Drug Interactions in the drug label. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): - Pregnancy Category C - Loteprednol etabonate has been shown to be embryotoxic (delayed ossification) and teratogenic (increased incidence of meningocele, abnormal left common carotid artery, and limb flexures) when administered orally to rabbits during organogenesis at a dose of 3 mg/kg/day (35 times the maximum daily clinical dose), a dose which caused no maternal toxicity. The no-observed-effect-level (NOEL) for these effects was 0.5 mg/kg/day (6 times the maximum daily clinical dose). Oral treatment of rats during organogenesis resulted in teratogenicity (absent innominate artery at ≥5 mg/kg/day doses, and cleft palate and umbilical hernia at ≥50 mg/kg/day) and embryotoxicity (increased post-implantation losses at 100 mg/kg/day and decreased fetal body weight and skeletal ossification with ≥50 mg/kg/day). Treatment of rats with 0.5 mg/kg/day (6 times the maximum clinical dose) during organogenesis did not result in any reproductive toxicity. Loteprednol etabonate was maternally toxic (significantly reduced body weight gain during treatment) when administered to pregnant rats during organogenesis at doses of ≥5 mg/kg/day. - Oral exposure of female rats to 50 mg/kg/day of loteprednol etabonate from the start of the fetal period through the end of lactation, a maternally toxic treatment regimen (significantly decreased body weight gain), gave rise to decreased growth and survival, and retarded development in the offspring during lactation; the NOEL for these effects was 5 mg/kg/day. Loteprednol etabonate had no effect on the duration of gestation or parturition when administered orally to pregnant rats at doses up to 50 mg/kg/day during the fetal period. - There are no adequate and well controlled studies in pregnant women. LOTEMAX® 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 Loteprednol in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Loteprednol during labor and delivery. ### Nursing Mothers - It is not known whether topical ophthalmic administration of corticosteroids could result in sufficient systemic absorption to produce detectable quantities in human milk. Systemic steroids appear in human milk and could suppress growth, interfere with endogenous corticosteroid production, or cause other untoward effects. Caution should be exercised when LOTEMAX is administered to a nursing woman. ### Pediatric Use - Safety and effectiveness in pediatric patients have not been established. ### Geriatic Use There is no FDA guidance on the use of Loteprednol with respect to geriatric patients. ### Gender There is no FDA guidance on the use of Loteprednol with respect to specific gender populations. ### Race There is no FDA guidance on the use of Loteprednol with respect to specific racial populations. ### Renal Impairment There is no FDA guidance on the use of Loteprednol in patients with renal impairment. ### Hepatic Impairment There is no FDA guidance on the use of Loteprednol in patients with hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Loteprednol in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Loteprednol in patients who are immunocompromised. # Administration and Monitoring ### Administration - Topical ### Monitoring There is limited information regarding Monitoring of Loteprednol in the drug label. # IV Compatibility There is limited information regarding IV Compatibility of Loteprednol in the drug label. # Overdosage ## Acute Overdose ## Chronic Overdose There is limited information regarding Chronic Overdose of Loteprednol in the drug label. # Pharmacology There is limited information regarding Loteprednol Pharmacology in the drug label. ## Mechanism of Action - Corticosteroids inhibit the inflammatory response to a variety of inciting agents and probably delay or slow healing. They inhibit the edema, fibrin deposition, capillary dilation, leukocyte migration, capillary proliferation, fibroblast proliferation, deposition of collagen, and scar formation associated with inflammation. While glucocorticoids are known to bind to and activate the glucocorticoid receptor, the molecular mechanisms involved in glucocorticoid/glucocorticoid receptor-dependent modulation of inflammation are not clearly established. However, corticosteroids are thought to inhibit prostaglandin production through several independent mechanisms. ## Structure - LOTEMAX (loteprednol etabonate ophthalmic gel) 0.5% contains a sterile, topical corticosteroid for ophthalmic use. Loteprednol etabonate is a white to off-white powder. - Loteprednol etabonate is represented by the following structural formula: - Chemical Name: - chloromethyl 17α-[(ethoxycarbonyl)oxy]-11β-hydroxy-3-oxoandrosta-1,4-diene-17β-carboxylate ## Pharmacodynamics There is limited information regarding Pharmacodynamics of Loteprednol in the drug label. ## Pharmacokinetics - Loteprednol is lipid soluble and can penetrate into cells. Loteprednol etabonate is synthesized through structural modifications of prednisolone-related compounds so that it will undergo a predictable transformation to an inactive metabolite. Based upon in vivo and in vitro preclinical metabolism studies, loteprednol etabonate undergoes extensive metabolism to the inactive carboxylic acid metabolites, PJ-91 and PJ-90. The systemic exposure to loteprednol etabonate following ocular administration of LOTEMAX has not been studied in humans. ## Nonclinical Toxicology - Long-term animal studies have not been conducted to evaluate the carcinogenic potential of loteprednol etabonate. Loteprednol etabonate was not genotoxic in vitro in the Ames test, the mouse lymphoma tk assay, or in a chromosome aberration test in human lymphocytes, or in vivo in the single dose mouse micronucleus assay. Treatment of male and female rats with up to 50 mg/kg/day and 25 mg/kg/day of loteprednol etabonate, respectively, (600 and 300 times the maximum clinical dose, respectively) prior to and during mating did not impair fertility in either gender. # Clinical Studies - In two randomized, multicenter, double-masked, parallel-group, vehicle-controlled studies in 813 subjects with, post-operative inflammation, LOTEMAX was more effective compared to its vehicle in resolving anterior chamber inflammation and pain following cataract surgery. Primary endpoints were complete resolution of anterior chamber cells (cell count of 0) and no pain at post-operative day 8. - In these studies, LOTEMAX had a statistically significant higher incidence of subjects with complete clearing of anterior chamber cells (31% vs. 14-16%) and were pain free at post-operative day 8 (73-76% vs. 42-46%). # How Supplied - LOTEMAX® (loteprednol etabonate ophthalmic gel) 0.5% is a sterile ophthalmic gel supplied in a white low density polyethylene plastic bottle with a white controlled drop tip and a pink polypropylene cap in the following size: - 5 g in a 10 mL bottle (NDC 24208-503-07) - Use only if imprinted neckband is intact. - Storage: Store upright at 15º-25º C (59º-77º F). ## Storage There is limited information regarding Loteprednol Storage in the drug label. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information - Administration - Invert closed bottle and shake once to fill tip before instilling drops. - Risk of Contamination - Patients should be advised not to allow the dropper tip to touch any surface, as this may contaminate the gel. - Contact Lens Wear - Patients should be advised not to wear contact lenses when using LOTEMAX. - Risk of Secondary Infection - If pain develops, redness, itching or inflammation becomes aggravated, the patient should be advised to consult a physician. # Precautions with Alcohol - Alcohol-Loteprednol interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - LOTEMAX®[1] # Look-Alike Drug Names There is limited information regarding Loteprednol Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	https://www.wikidoc.org/index.php/Loteprednol
bed782b70ab8e578331bfd093e37feafc2dedd4b	wikidoc	Lotka's law	Lotka's law Lotka's law, named after Alfred J. Lotka, is one of a variety of special applications of Zipf's law. It describes the frequency of publication by authors in any given field. It states that the number of authors making n contributions is about 1/n^{a} of those making one contribution, where a nearly always equals two. More plainly, the number of authors publishing a certain number of articles is a fixed ratio to the number of authors publishing a single article. As the number of articles published increases, authors producing that many publications become less frequent. There are 1/4 as many authors publishing two articles within a specified time period as there are single-publication authors, 1/9 as many publishing three articles, 1/16 as many publishing four articles, etc. Though the law itself covers many disciplines, the actual ratios involved (as a function of 'a') are very discipline-specific. The general formula says: X^n Y = C -r Y = C / X^n where X is the number of publications, Y the relative frequency of authors with X publications, and n and C are constants depending on the specific field (n \approx 2) This law is believed to have applications in other fields for example in the military for fighter pilot kills. # Example For 100 authors, who on average each write one article each over a specific period, we have also: -f those making one contribution, i.e. a power law, where a is often nearly 2. It is an empirical observation rather than a necessary result. This form of the law is as originally published and is sometimes referred to as the "discrete Lotka power function".	Lotka's law Lotka's law[1], named after Alfred J. Lotka, is one of a variety of special applications of Zipf's law. It describes the frequency of publication by authors in any given field. It states that the number of authors making n contributions is about <math>1/n^{a}</math> of those making one contribution, where a nearly always equals two. More plainly, the number of authors publishing a certain number of articles is a fixed ratio to the number of authors publishing a single article. As the number of articles published increases, authors producing that many publications become less frequent. There are 1/4 as many authors publishing two articles within a specified time period as there are single-publication authors, 1/9 as many publishing three articles, 1/16 as many publishing four articles, etc. Though the law itself covers many disciplines, the actual ratios involved (as a function of 'a') are very discipline-specific. The general formula says: X^n Y = C </math> or Y = C / X^n </math>, where <math>X</math> is the number of publications, <math>Y</math> the relative frequency of authors with <math>X</math> publications, and <math>n</math> and <math>C</math> are constants depending on the specific field (<math>n \approx 2</math>) This law is believed to have applications in other fields for example in the military for fighter pilot kills. # Example For 100 authors, who on average each write one article each over a specific period, we have also: of those making one contribution, i.e. a power law, where a is often nearly 2. It is an empirical observation rather than a necessary result. This form of the law is as originally published and is sometimes referred to as the "discrete Lotka power function".[2]	https://www.wikidoc.org/index.php/Lotka%27s_law
05c5fbcf75f18511cddfcfb9cf8b29032374455e	wikidoc	Loxoscelism	Loxoscelism # Overview Loxoscelism is a condition produced by the bite of the recluse spiders (genus Loxosceles). It is the only proven cause of arachnogenic necrosis in humans. While there is no known therapy effective for loxoscelism, there has been research on potential antivenoms and vaccines. Due to the number of diseases that may mimic loxoscelism, it is frequently misdiagnosed by physicians. Although there are up to thirteen different Loxosceles species in North America (eleven native and two nonnative), Loxosceles reclusa is the species most often involved in serious envenomation. In South America, L. laeta, L. intermedia (found in Brazil and Argentina), and L. gaucho (Brazil) are the three species most often reported to cause necrotic bites. # Historical Perspective The first documented case of loxoscelism in the United States occurred in 1879 in Tennessee. # Pathophysiology ## Loxosceles toxins Loxosceles venom has several toxins, the most important of which is the tissue-destroying agent sphingomyelinase D, in all recluse species to varying degrees. Only one other known spider genus (Sicarius) and several pathogenic bacteria are known to contain this enzyme. # Natural history, Complications and prognosis ## Complications In patients with viscerocutaneous loxoscelism, Disseminated intravascular coagulation may appear in as many as 16% of patients, most often children. Occasionally, acute renal failure may develop from myonecrosis and rhabdomyolysis, leading to coma and eventual death. # Diagnosis ## History and Symptoms Loxoscelism may present with local and whole-body symptoms: - Necrotic cutaneous loxoscelism is the medical term for the reaction most common in loxoscelism. It is characterized by a localized gangrenous slough at the site of bite. Although the majority of Loxosceles bites result in minor skin irritation, severe envenomation, while rare, may produce painful ulcerative lesions up to 15.75 inches (40 cm) across. Such lesions often heal within 6 to 8 weeks, but can leave lasting scars. - Viscerocutaneous loxoscelism refers to the systemic manifestations that occur (infrequently) after Loxosceles bites. Symptoms include nausea and vomiting, malaise, fever, hemolytic anemia, and thrombocytopenia. Many necrotic lesions are erroneously attributed to the bite of the Brown Recluse, especially in areas outside of its natural habitat. Diagnosis can be difficult because it is usually necessary to retrieve the envenomating spider. There is no known concise chemical test to determine if the venom in a patient is from a Brown Recluse. The bite itself is not usually painful, and is in many cases not felt. Bite victims may delay seeking medical treatment for up to a week. The diagnosis is further complicated by the fact that the brown recluse does not have a remarkable physical appearance. Because of this, other, non-necrotic species are frequently mistakenly identified as a brown recluse. Only a certified arachnologist is able to positively identify a brown recluse specimen as such. One possible explanation for the disproportionate amount of misdiagnosed bites is the Tegenaria agrestis, also known as the Hobo spider. The T. agrestis may also have a necrotic bite, though these claims are disputed. The matter is being more diligently researched because of some strong circumstantial evidence that the T. agrestis is not necrotic. The area with the highest frequency of questionable brown recluse diagnoses, which is the North West United States, is not within the brown recluse’s range. It is, however, the main area where T. agrestis may be found. # Treatment Despite being the most dangerous type of spider bite in many areas, there is no established treatment for the bite of a Loxosceles spider. In many cases the body can heal itself, and the only treatment is to wait. There are, however, some remedies currently being researched. ## Anti-venoms Anti-venoms can be effective in controlling the symptoms of a necrotic bite. There are several anti-venoms commercially available in Brazil, which have been shown to be effective in controlling the spread of necrosis in rabbits. The effectiveness of such anti-venoms is very time-dependent. If administered immediately, they can almost entirely neutralize any ill effects. If too much time is allowed to pass, the treatment becomes ineffective. Most victims do not seek medical attention within the first twelve hours of being bitten, and most anti-venoms are largely ineffective at this point. Because of this, anti-venoms are perhaps more effective in theory than in practice. They have, however, been proven to be very effective if administered in a timely manner and should not be discarded as a legitimate technique when circumstances permit. ## Surgical treatment In cases where a large dermonecrotic lesion has developed, sometimes it is most effective to surgically remove the dead tissue. This is not ideal, since it will usually leave a large open sore behind, but in certain cases, the spread of necrosis is a great enough threat that it needs to be removed. If the necrosis is allowed to spread far enough, sometimes it is necessary to amputate a limb, or part of a limb, to prevent potentially deadly spread of necrosis. # Other species It is suspected that most if not all species of the Loxosceles genus have necrotic venom. Over fifty species have been identified in the genus, but significant research has only been conducted on species living in close proximity to humans. ## Loxosceles reclusa (Brown Recluse Spider) Among the spiders bearing necrotic venom, the Brown Recluse is the most commonly encountered by humans. The range of the brown recluse spider extends from southeastern Nebraska to southernmost Ohio and south into Georgia and most of Texas. It can be distinguished by violin shaped markings on its back, and this is the commonly known identifying feature. A more conclusive way to identify a brown recluse is by the number of eyes. The brown recluse has six eyes, an uncommon number among arachnids. However, many lesser known species of the Loxosceles genus are believed to have similar venoms. L. reclusa is a very non-aggressive species. There have been documented cases where a house has a very large population for many years without any of the human inhabitants being bitten. For this reason, L. reclusa bites are relatively rare, but, because of its fairly extensive range, its bite is the most common cause of loxoscelism in North America. ## Loxosceles laeta (Chilean Recluse Spider) Loxosceles laeta, commonly known as the Chilean Recluse Spider, is generally considered to be one of the most toxic species in the Loxosceles genus. It has a very wide range, having populations in Guatemala, Panama, Curaçao, Trinidad, Venezuela, Colombia, Ecuador, Peru, Bolivia, Chile and Argentina in South and Central America. In North America, there are populations in Vancouver, Canada, Massachusetts, California, Kansas and Florida. L. laeta can also be found in Finland and Australia. L. laeta has been documented at elevations between 200m and 2340m. This range can probably be attributed to the species ability to last long periods of time without food or water. The laeta is cryptozoic, meaning it lives in dark concealed places. This can often mean piles of wood or brick for the laeta, facilitating more transportation of the species into new areas. Another reason for the laeta’s strong populations is the high fertility rate among its females. Each female can produce up to fifteen egg sacs in its life, with between fifty and one hundred and fifty eggs in each. Loxosceles laeta eggs have a high egg fertility index. ## Loxosceles deserta L. deserta is found in the southwest corner of the United States. Human interactions with it are rare, because it usually is only found in native vegetation. It is not usually found within heavily populated areas, but its range does come near these areas. It is considered medically significant due to the high likelihood of human-to-spider encounters. ## Tegenaria agrestis (Hobo or Aggressive House Spider) Many necrotic lesions in the northwestern United States have been attributed to the bite of the brown recluse spider. Most of these diagnoses are probably erroneous, however, because this area is outside of the natural range of the brown recluse. In a significant amount of the homes of bite victims in the northwest, there have been large populations of T. agrestis. This has led many to believe that the Hobo Spider is also necrotic.	Loxoscelism Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview Loxoscelism is a condition produced by the bite of the recluse spiders (genus Loxosceles). It is the only proven cause of arachnogenic necrosis in humans.[1][n 1] While there is no known therapy effective for loxoscelism, there has been research on potential antivenoms and vaccines.[1] Due to the number of diseases that may mimic loxoscelism, it is frequently misdiagnosed by physicians.[n 2] Although there are up to thirteen different Loxosceles species in North America (eleven native and two nonnative), Loxosceles reclusa is the species most often involved in serious envenomation. In South America, L. laeta, L. intermedia (found in Brazil and Argentina), and L. gaucho (Brazil) are the three species most often reported to cause necrotic bites.[1] # Historical Perspective The first documented case of loxoscelism in the United States occurred in 1879 in Tennessee.[2] # Pathophysiology ## Loxosceles toxins Loxosceles venom has several toxins, the most important of which is the tissue-destroying agent sphingomyelinase D, in all recluse species to varying degrees. Only one other known spider genus (Sicarius) and several pathogenic bacteria are known to contain this enzyme.[1] # Natural history, Complications and prognosis ## Complications In patients with viscerocutaneous loxoscelism, Disseminated intravascular coagulation may appear in as many as 16% of patients, most often children. Occasionally, acute renal failure may develop from myonecrosis and rhabdomyolysis, leading to coma and eventual death.[1] # Diagnosis ## History and Symptoms Loxoscelism may present with local and whole-body symptoms: - Necrotic cutaneous loxoscelism is the medical term for the reaction most common in loxoscelism. It is characterized by a localized gangrenous slough at the site of bite. Although the majority of Loxosceles bites result in minor skin irritation, severe envenomation, while rare, may produce painful ulcerative lesions up to 15.75 inches (40 cm) across.[1] Such lesions often heal within 6 to 8 weeks, but can leave lasting scars. - Viscerocutaneous loxoscelism refers to the systemic manifestations that occur (infrequently) after Loxosceles bites. Symptoms include nausea and vomiting, malaise, fever, hemolytic anemia, and thrombocytopenia.[3] Many necrotic lesions are erroneously attributed to the bite of the Brown Recluse, especially in areas outside of its natural habitat. Diagnosis can be difficult because it is usually necessary to retrieve the envenomating spider. There is no known concise chemical test to determine if the venom in a patient is from a Brown Recluse. The bite itself is not usually painful, and is in many cases not felt. Bite victims may delay seeking medical treatment for up to a week. The diagnosis is further complicated by the fact that the brown recluse does not have a remarkable physical appearance. Because of this, other, non-necrotic species are frequently mistakenly identified as a brown recluse. Only a certified arachnologist is able to positively identify a brown recluse specimen as such. One possible explanation for the disproportionate amount of misdiagnosed bites is the Tegenaria agrestis, also known as the Hobo spider. The T. agrestis may also have a necrotic bite, though these claims are disputed. The matter is being more diligently researched because of some strong circumstantial evidence that the T. agrestis is not necrotic.[4] The area with the highest frequency of questionable brown recluse diagnoses, which is the North West United States, is not within the brown recluse’s range. It is, however, the main area where T. agrestis may be found. # Treatment Despite being the most dangerous type of spider bite in many areas, there is no established treatment for the bite of a Loxosceles spider. In many cases the body can heal itself, and the only treatment is to wait. There are, however, some remedies currently being researched. ## Anti-venoms Anti-venoms can be effective in controlling the symptoms of a necrotic bite. There are several anti-venoms commercially available in Brazil, which have been shown to be effective in controlling the spread of necrosis in rabbits.[5] The effectiveness of such anti-venoms is very time-dependent. If administered immediately, they can almost entirely neutralize any ill effects. If too much time is allowed to pass, the treatment becomes ineffective. Most victims do not seek medical attention within the first twelve hours of being bitten, and most anti-venoms are largely ineffective at this point. Because of this, anti-venoms are perhaps more effective in theory than in practice. They have, however, been proven to be very effective if administered in a timely manner and should not be discarded as a legitimate technique when circumstances permit. ## Surgical treatment In cases where a large dermonecrotic lesion has developed, sometimes it is most effective to surgically remove the dead tissue. This is not ideal, since it will usually leave a large open sore behind, but in certain cases, the spread of necrosis is a great enough threat that it needs to be removed. If the necrosis is allowed to spread far enough, sometimes it is necessary to amputate a limb, or part of a limb, to prevent potentially deadly spread of necrosis. # Other species It is suspected that most if not all species of the Loxosceles genus have necrotic venom. Over fifty species have been identified in the genus, but significant research has only been conducted on species living in close proximity to humans. ## Loxosceles reclusa (Brown Recluse Spider) Among the spiders bearing necrotic venom, the Brown Recluse is the most commonly encountered by humans. The range of the brown recluse spider extends from southeastern Nebraska to southernmost Ohio and south into Georgia and most of Texas. It can be distinguished by violin shaped markings on its back, and this is the commonly known identifying feature. A more conclusive way to identify a brown recluse is by the number of eyes. The brown recluse has six eyes, an uncommon number among arachnids. However, many lesser known species of the Loxosceles genus are believed to have similar venoms. L. reclusa is a very non-aggressive species.[6] There have been documented cases where a house has a very large population for many years without any of the human inhabitants being bitten. For this reason, L. reclusa bites are relatively rare, but, because of its fairly extensive range, its bite is the most common cause of loxoscelism in North America. ## Loxosceles laeta (Chilean Recluse Spider) Loxosceles laeta, commonly known as the Chilean Recluse Spider, is generally considered to be one of the most toxic species in the Loxosceles genus. It has a very wide range, having populations in Guatemala, Panama, Curaçao, Trinidad, Venezuela, Colombia, Ecuador, Peru, Bolivia, Chile and Argentina in South and Central America. In North America, there are populations in Vancouver, Canada, Massachusetts, California, Kansas and Florida. L. laeta can also be found in Finland and Australia. L. laeta has been documented at elevations between 200m and 2340m.[7] This range can probably be attributed to the species ability to last long periods of time without food or water. The laeta is cryptozoic, meaning it lives in dark concealed places. This can often mean piles of wood or brick for the laeta, facilitating more transportation of the species into new areas. Another reason for the laeta’s strong populations is the high fertility rate among its females. Each female can produce up to fifteen egg sacs in its life, with between fifty and one hundred and fifty eggs in each. Loxosceles laeta eggs have a high egg fertility index. ## Loxosceles deserta L. deserta is found in the southwest corner of the United States. Human interactions with it are rare, because it usually is only found in native vegetation. It is not usually found within heavily populated areas, but its range does come near these areas. It is considered medically significant due to the high likelihood of human-to-spider encounters. ## Tegenaria agrestis (Hobo or Aggressive House Spider) Many necrotic lesions in the northwestern United States have been attributed to the bite of the brown recluse spider. Most of these diagnoses are probably erroneous, however, because this area is outside of the natural range of the brown recluse. In a significant amount of the homes of bite victims in the northwest, there have been large populations of T. agrestis.[8] This has led many to believe that the Hobo Spider is also necrotic.	https://www.wikidoc.org/index.php/Loxoscelism
0e6078baf0112c34d16b73bbc3b39ceff430f1ca	wikidoc	Mineral oil	Mineral oil Mineral oil or liquid petrolatum is a by-product in the distillation of petroleum to produce gasoline. It is a transparent, colorless oil composed mainly of alkanes (typically 15 to 40 carbons) and cyclic paraffins, related to white petrolatum. Mineral oil is a substance of relatively low value, and it is produced in very large quantities. Mineral oil is available in light and heavy grades, and can often be found in drug stores. # Applications - Refined mineral oil is used as transformer oil. - Alkali metals are often submerged in mineral oil for storage or transportation. The oil prevents the metals from reacting with atmospheric moisture. - Mineral oil is sometimes taken orally as a laxative. It lubricates feces and intestinal mucous membranes, and limits the amount of water removed from feces. Typically, mineral oil is effective within six hours. While it has been reported that mineral oil may be absorbed when emulsified, most information shows that it passes harmlessly through the gastrointestinal system. If used at all, mineral oil should never be given internally to small children, pets, or anyone with a cough, hiatus hernia, or nocturnal reflux, and should be swallowed with care. Due to its low density, it is easily aspirated into the lungs, where it cannot be removed by the body and can cause serious complications such as lipoid pneumonia. While popular as a folk remedy, there are many safer alternatives available. - Mineral oil with added fragrance is marketed as baby oil in the US, UK and Canada. - Used as an ingredient in baby lotions, cold creams, ointments and other pharmaceuticals and low-grade cosmetics. - Certain mineral oils are used in livestock vaccines, as an adjuvant to stimulate a cell-medicated immune response to the vaccinating agent. - Used on eyelashes to prevent brittleness and/or breaking. - Used in small quantities (2–3 drops daily) to clean ears. Over a couple of weeks, the mineral oil softens dried or hardened earwax so that a gentle flush of water can remove it. In the case of a damaged or perforated eardrum, however, mineral oil should not be used, as oil in the middle ear can lead to ear infections. - Lubrication - Fuel, for items such as oil lamps. - Electric mineral-oil–filled space heaters - Coolant - Fog machines - Used in some guitar string cleaners - Automotive and aviation brake fluid that does not absorb water molecules by osmosis - Low viscosity mineral oil is sold as a preservative for wooden cutting boards and utensils. - A coating of mineral oil protects metal surfaces from moisture and oxidation. - Food-preparation butcher block surfaces are often conditioned periodically with mineral oil. - Light mineral oil is used in textile industries and used as a jute batching oil. - Mineral oil is used to darken soapstone countertops for aesthetic purposes. - It works (albeit poorly) as a release agent for molds, especially in fiberglass casting. - It is used as a release agent for baking pans and trays. - It is occasionally used in the food industry (particularly for candy). Some studies suggest that prolonged use might be unhealthy because of low accumulation levels in organs. It has been discouraged for use in children's foods, though it is still occasionally found in candies in China and Canada. - Used as a cleaner and solvent for inks in fine art printmaking as well as in oil painting, though turpentine is more often used. - In the poultry industry, plain mineral oil can be swabbed onto the feet of chickens infected with scaly mites on the shank, toes, and webs. Mineral oil suffocates these tiny parasites. - Some people have found success using mineral oil to remove henna used as a hair dye. - Using mineral oil or baby oil to reduce a grease, oil, or asphalt stain on clothing may be counter-intuitive, but is often effective, as the mineral oil dilutes and liquefies some of the stain thereby making it easier to clean out of the clothing. - Some people have used mineral oil as a cooling system for a computer, by completely submerging the computer's motherboard and system components into an aquarium tank filled with mineral oil. The oil does not have any long term effect on the components. A video and instructions on building a mineral oil cooled computer can be found here. - It is commonly used to create a "wear" effect on new clay poker chips, which, without the use of mineral oil, can only be accomplished through prolonged use of the poker chips. The chips are either placed in mineral oil (and left there for a short amount of time), or the oil is applied to each chip individually, and is then rubbed off, removing any chalky residue from the new chips, also improving the look and "feel" of the chips. - Used to cover gummy worms for the glossy effect it produces. # Other names for mineral oil - adepsine oil - alboline - baby oil - bayol 55 - cable oil - bayol f - blandlube - blandol white mineral oil - carnea 21 - clearteck - crystol 325 - crystosol - Diala-X, AX - drakeol - electrical insulating oil - ervol - filtrawhite - fonoline - frigol - glymol - Heat-treating oil - hevyteck - hydraulic oil - hydrocarbon oils - jute batching oil - kaydol - kondremul - kremol - LHM - lignite oil - liquid paraffin - lubricating oil - master Shimmer - mineral oil (saturated parrafin oil) - mineral oil hydrocarbon solvent (petroleum) - mineral oil mist - mineral oil, aromatic - mineral oil, paraffinic - mineral Seal Oil - molol - neo-cultol - nujol - oil mist - oil mist, mineral, severely refined - Oil mist, refined mineral - oil, petroleum - paraffin oil (class) - paraffin oil - parol - paroleine - peneteck - penreco - perfecta - petrogalar - petrolatum - petroleum hydrocarbons - petroleum, liquid - primol - primol 355 - primol d - protopet - saxol - tech pet - f triona b - uvasol - univolt N60, 80 - voltesso 35 - white mineral oil - white oil	Mineral oil Template:Cleanup-laundry Mineral oil or liquid petrolatum is a by-product in the distillation of petroleum to produce gasoline. It is a transparent, colorless oil composed mainly of alkanes (typically 15 to 40 carbons) [1] and cyclic paraffins, related to white petrolatum. Mineral oil is a substance of relatively low value, and it is produced in very large quantities. Mineral oil is available in light and heavy grades, and can often be found in drug stores. # Applications - Refined mineral oil is used as transformer oil. - Alkali metals are often submerged in mineral oil for storage or transportation. The oil prevents the metals from reacting with atmospheric moisture. - Mineral oil is sometimes taken orally as a laxative. It lubricates feces and intestinal mucous membranes, and limits the amount of water removed from feces. Typically, mineral oil is effective within six hours. While it has been reported that mineral oil may be absorbed when emulsified, most information shows that it passes harmlessly through the gastrointestinal system. If used at all, mineral oil should never be given internally to small children, pets, or anyone with a cough, hiatus hernia, or nocturnal reflux, and should be swallowed with care. Due to its low density, it is easily aspirated into the lungs, where it cannot be removed by the body and can cause serious complications such as lipoid pneumonia.[2] While popular as a folk remedy, there are many safer alternatives available. - Mineral oil with added fragrance is marketed as baby oil in the US, UK and Canada. - Used as an ingredient in baby lotions, cold creams, ointments and other pharmaceuticals and low-grade cosmetics. - Certain mineral oils are used in livestock vaccines, as an adjuvant to stimulate a cell-medicated immune response to the vaccinating agent. - Used on eyelashes to prevent brittleness and/or breaking. - Used in small quantities (2–3 drops daily) to clean ears. Over a couple of weeks, the mineral oil softens dried or hardened earwax so that a gentle flush of water can remove it. In the case of a damaged or perforated eardrum, however, mineral oil should not be used, as oil in the middle ear can lead to ear infections. - Lubrication - Fuel, for items such as oil lamps. - Electric mineral-oil–filled space heaters - Coolant - Fog machines - Used in some guitar string cleaners - Automotive and aviation brake fluid that does not absorb water molecules by osmosis - Low viscosity mineral oil is sold as a preservative for wooden cutting boards and utensils. - A coating of mineral oil protects metal surfaces from moisture and oxidation. - Food-preparation butcher block surfaces are often conditioned periodically with mineral oil. - Light mineral oil is used in textile industries and used as a jute batching oil. - Mineral oil is used to darken soapstone countertops for aesthetic purposes. - It works (albeit poorly) as a release agent for molds, especially in fiberglass casting. - It is used as a release agent for baking pans and trays. - It is occasionally used in the food industry (particularly for candy). Some studies suggest that prolonged use might be unhealthy because of low accumulation levels in organs. It has been discouraged for use in children's foods, though it is still occasionally found in candies in China and Canada. - Used as a cleaner and solvent for inks in fine art printmaking as well as in oil painting, though turpentine is more often used. - In the poultry industry, plain mineral oil can be swabbed onto the feet of chickens infected with scaly mites on the shank, toes, and webs. Mineral oil suffocates these tiny parasites. - Some people have found success using mineral oil to remove henna used as a hair dye. - Using mineral oil or baby oil to reduce a grease, oil, or asphalt stain on clothing may be counter-intuitive, but is often effective, as the mineral oil dilutes and liquefies some of the stain thereby making it easier to clean out of the clothing. - Some people have used mineral oil as a cooling system for a computer, by completely submerging the computer's motherboard and system components into an aquarium tank filled with mineral oil. The oil does not have any long term effect on the components. A video and instructions on building a mineral oil cooled computer can be found here. - It is commonly used to create a "wear" effect on new clay poker chips, which, without the use of mineral oil, can only be accomplished through prolonged use of the poker chips. The chips are either placed in mineral oil (and left there for a short amount of time), or the oil is applied to each chip individually, and is then rubbed off, removing any chalky residue from the new chips, also improving the look and "feel" of the chips. - Used to cover gummy worms for the glossy effect it produces. # Other names for mineral oil - adepsine oil - alboline - baby oil - bayol 55 - cable oil - bayol f - blandlube - blandol white mineral oil - carnea 21 - clearteck - crystol 325 - crystosol - Diala-X, AX - drakeol - electrical insulating oil - ervol - filtrawhite - fonoline - frigol - glymol - Heat-treating oil - hevyteck - hydraulic oil - hydrocarbon oils - jute batching oil - kaydol - kondremul - kremol - LHM - lignite oil - liquid paraffin - lubricating oil - master Shimmer - mineral oil (saturated parrafin oil) - mineral oil hydrocarbon solvent (petroleum) - mineral oil mist - mineral oil, aromatic - mineral oil, paraffinic - mineral Seal Oil - molol - neo-cultol - nujol - oil mist - oil mist, mineral, severely refined - Oil mist, refined mineral - oil, petroleum - paraffin oil (class) - paraffin oil - parol - paroleine - peneteck - penreco - perfecta - petrogalar - petrolatum - petroleum hydrocarbons - petroleum, liquid - primol - primol 355 - primol d - protopet - saxol - tech pet - f triona b - uvasol - univolt N60, 80 - voltesso 35 - white mineral oil - white oil	https://www.wikidoc.org/index.php/Lubricating_oil
07e89647c147079a9af20700a5e49919ab6f5463	wikidoc	Lubrication	Lubrication Lubrication is the process, or technique employed to reduce wear of one or both surfaces in close proximity, and moving relative to each another, by interposing a substance called lubricant between the surfaces to carry or to help carry the load (pressure generated) between the opposing surfaces. The interposed lubricant film can be a solid, (eg graphite, MoS2) a solid/liquid dispersion, a liquid, a liquid-liquid dispersion (greases) or exceptionally a gas. In the most common case the applied load is carried by pressure generated within the fluid due to the frictional viscous resistance to motion of the lubricating fluid between the surfaces. Lubrication can also describe the phenomenon when such reduction of wear occurs without human intervention (aquaplaning on a road). The science of friction, lubrication and wear is called tribology. When we talk about (adequate) lubrication smooth continuous equipment operation is assumed, with only mild wear, and without excessive stresses within the lubricated conjunctions to cause seizure at the conjunction, or break of any part of the equipment, and when such a catastrophic event does occur it means that the lubrication has broken down. # The regimes of lubrication When progressively increasing the load between the contacting surfaces three distinct situations can be observed with respect to the mode of lubrication, which are called regimes of lubrication: - Fluid film lubrication is the lubrication regime in which through viscous forces the load is fully supported by the lubricant within the space or gap between the parts in motion relative to one another (the lubricated conjunction) and solid-solid contact is avoided. Hydrostatic lubrication is a special case of fluid film lubrication in which an external pressure is applied to keep the lubricant in the conjunction, enabling it to support the external load. Hydrodynamic lubrication is also a special case of fluid film lubrication which occurs when the lubricant is able to support the load without external pressure, through hydrodynamic forces alone, which deform the shape of the interposing lubricant film into a wedge shape and drags the lubricant into the film, so that the externally applied load can be supported. - Hydrostatic lubrication is a special case of fluid film lubrication in which an external pressure is applied to keep the lubricant in the conjunction, enabling it to support the external load. - Hydrodynamic lubrication is also a special case of fluid film lubrication which occurs when the lubricant is able to support the load without external pressure, through hydrodynamic forces alone, which deform the shape of the interposing lubricant film into a wedge shape and drags the lubricant into the film, so that the externally applied load can be supported. - Elastohydrodynamic lubrication: The opposing surfaces are separated but there occurs some interaction between the raised solid features called asperities, and there is an elastic deformation on the contacting surface enlarging the load bearing area whereby the viscous resistance of the lubricant becomes capable of supporting the load. - Boundary lubrication (also called boundary film lubrication): The bodies come into closer contact at their asperities; the heat developed by the local pressures causes a condition which is called stick-slip and some asperities break off. At the elevated temperature and prssure conditions chemically reactive constituents of the lubricant react with the contact surface forming a highly resistant tenatious layer, or film on the moving solid surfaces (boundary film) which is capable of supporting the load and major wear or breakdown is avoided. Beside supporting the load the lubricant may have to perform other functions as well, for instance it may have to cool the contact areas, or to removes wear products, and for carrying out these functions the lubricant is constantly replaced from the contact areas either by the relative movement (hydrodynamics) or by externally induced forces. Lubrication is required for correct operation of mechanical systems engines, pumps, cams bearings, cutting tools etc where without lubrication the pressure between the surfacers in close proximity would generate enough heat for rapid surface damage which in a coarsened condition literally weld the surfaces together, causing seizure.	Lubrication Lubrication is the process, or technique employed to reduce wear of one or both surfaces in close proximity, and moving relative to each another, by interposing a substance called lubricant between the surfaces to carry or to help carry the load (pressure generated) between the opposing surfaces. The interposed lubricant film can be a solid, (eg graphite, MoS2)[1] a solid/liquid dispersion, a liquid, a liquid-liquid dispersion (greases) or exceptionally a gas. In the most common case the applied load is carried by pressure generated within the fluid due to the frictional viscous resistance to motion of the lubricating fluid between the surfaces. Lubrication can also describe the phenomenon when such reduction of wear occurs without human intervention (aquaplaning on a road). The science of friction, lubrication and wear is called tribology. When we talk about (adequate) lubrication smooth continuous equipment operation is assumed, with only mild wear, and without excessive stresses within the lubricated conjunctions to cause seizure at the conjunction, or break of any part of the equipment, and when such a catastrophic event does occur it means that the lubrication has broken down. # The regimes of lubrication When progressively increasing the load between the contacting surfaces three distinct situations can be observed with respect to the mode of lubrication, which are called regimes of lubrication: - Fluid film lubrication is the lubrication regime in which through viscous forces the load is fully supported by the lubricant within the space or gap between the parts in motion relative to one another (the lubricated conjunction) and solid-solid contact is avoided.[2] Hydrostatic lubrication is a special case of fluid film lubrication in which an external pressure is applied to keep the lubricant in the conjunction, enabling it to support the external load. Hydrodynamic lubrication is also a special case of fluid film lubrication which occurs when the lubricant is able to support the load without external pressure, through hydrodynamic forces alone, which deform the shape of the interposing lubricant film into a wedge shape and drags the lubricant into the film, so that the externally applied load can be supported. - Hydrostatic lubrication is a special case of fluid film lubrication in which an external pressure is applied to keep the lubricant in the conjunction, enabling it to support the external load. - Hydrodynamic lubrication is also a special case of fluid film lubrication which occurs when the lubricant is able to support the load without external pressure, through hydrodynamic forces alone, which deform the shape of the interposing lubricant film into a wedge shape and drags the lubricant into the film, so that the externally applied load can be supported. - Elastohydrodynamic lubrication: The opposing surfaces are separated but there occurs some interaction between the raised solid features called asperities, and there is an elastic deformation on the contacting surface enlarging the load bearing area whereby the viscous resistance of the lubricant becomes capable of supporting the load. - Boundary lubrication (also called boundary film lubrication): The bodies come into closer contact at their asperities; the heat developed by the local pressures causes a condition which is called stick-slip and some asperities break off. At the elevated temperature and prssure conditions chemically reactive constituents of the lubricant react with the contact surface forming a highly resistant tenatious layer, or film on the moving solid surfaces (boundary film) which is capable of supporting the load and major wear or breakdown is avoided. Beside supporting the load the lubricant may have to perform other functions as well, for instance it may have to cool the contact areas, or to removes wear products, and for carrying out these functions the lubricant is constantly replaced from the contact areas either by the relative movement (hydrodynamics) or by externally induced forces. Lubrication is required for correct operation of mechanical systems engines, pumps, cams bearings, cutting tools etc where without lubrication the pressure between the surfacers in close proximity would generate enough heat for rapid surface damage which in a coarsened condition literally weld the surfaces together, causing seizure.	https://www.wikidoc.org/index.php/Lubrication
b10d529e0ea102146e2c1bc2ba7e16a3f39b2ce8	wikidoc	Ranibizumab	Ranibizumab # 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 Ranibizumab is a Monoclonal antibodies that is FDA approved for the treatment of neovascular (wet) age-related macular degeneration (AMD), macular edema following retinal vein occlusion (RVO), diabetic macular edema (DME). Common adverse reactions include cataract, conjunctival hemorrhage, eye irritation, foreign body sensation, in the eyes, inflammatory disorder of the eye, pain in eye, raised intraocular pressure, visual disturbance, vitreous detachment, vitreous floaters. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) ### Neovascular (Wet) Age-Related Macular Degeneration (AMD) - Dosing information - Recommended dosage: 0.5 mg (0.05 mL of 10 mg/mL Ranibizumab solution) IV once a month (approximately 28 days). - Although not as effective, patients may be treated with 3 monthly doses followed by less frequent dosing with regular assessment. In the nine months after 3 initial monthly doses, less frequent dosing with 4-5 doses on average is expected to maintain visual acuity while monthly dosing may be expected to result in an additional average 1-2 letter gain. Patients should be assessed regularly - Although not as effective, patients may also be treated with one dose every 3 months after 4 monthly doses. Compared with continued monthly dosing, dosing every 3 months over the next 9 months will lead to an approximate 5-letter (1-line) loss of visual acuity benefit, on average. Patients should be assessed regularly ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Ranibizumab in adult patients. ### Non–Guideline-Supported Use ### Choroidal retinal neovascularization - Dosnig information - ’‘’1.25 mg/0.05 mL or 0.5 mg/0.05 mL ‘’‘ # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) The safety and effectiveness of Ranibizumab in pediatric patients have not been established. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Ranibizumab in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Ranibizumab in pediatric patients. # Contraindications ## Ocular or Periocular Infections Ranibizumab is contraindicated in patients with ocular or periocular infections. ## Hypersensitivity Ranibizumab is contraindicated in patients with known hypersensitivity to ranibizumab or any of the excipients in Ranibizumab. Hypersensitivity reactions may manifest as severe intraocular inflammation. # Warnings ## Endophthalmitis and Retinal Detachments Intravitreal injections, including those with Ranibizumab, have been associated with endophthalmitis and retinal detachments. Proper aseptic injection technique should always be used when administering Ranibizumab. In addition, patients should be monitored following the injection to permit early treatment should an infection occur. ## Increases in Intraocular Pressure Increases in intraocular pressure have been noted both pre-injection and post-injection (at 60 minutes) while being treated with Ranibizumab. Monitor intraocular pressure prior to and following intravitreal injection with Ranibizumab and manage appropriately. ## Thromboembolic Events Although there was a low rate of arterial thromboembolic events (ATEs) observed in the Ranibizumab clinical trials, there is a potential risk of ATEs following intravitreal use of VEGF inhibitors. ATEs are defined as nonfatal stroke, nonfatal myocardial infarction, or vascular death (including deaths of unknown cause). ### Neovascular (Wet) Age-Related Macular Degeneration The ATE rate in the three controlled neovascular AMD studies (AMD-1, AMD-2, AMD-3) during the first year was 1.9% (17 of 874) in the combined group of patients treated with 0.3 mg or 0.5 mg Ranibizumab compared with 1.1% (5 of 441) in patients from the control arms . In the second year of Studies AMD-1 and AMD-2, the ATE rate was 2.6% (19 of 721) in the combined group of Ranibizumab-treated patients compared with 2.9% (10 of 344) in patients from the control arms. In Study AMD-4, the ATE rates observed in the 0.5 mg arms during the first and second year were similar to rates observed in Studies AMD-1, AMD-2, and AMD-3. In a pooled analysis of 2-year controlled studies (AMD-1, AMD-2, and a study of Ranibizumab used adjunctively with verteporfin photodynamic therapy), the stroke rate (including both ischemic and hemorrhagic stroke) was 2.7% (13 of 484) in patients treated with 0.5 mg Ranibizumab compared to 1.1% (5 of 435) in patients in the control arms (odds ratio 2.2 (95% confidence interval (0.8-7.1))). ### Macular Edema Following Retinal Vein Occlusion The ATE rate in the two controlled RVO studies during the first 6 months was 0.8% in both the Ranibizumab and control arms of the studies (4 of 525 in the combined group of patients treated with 0.3 mg or 0.5 mg Ranibizumab and 2 of 260 in the control arms). The stroke rate was 0.2% (1 of 525) in the combined group of Ranibizumab-treated patients compared to 0.4% (1 of 260) in the control arms. ### Diabetic Macular Edema In a pooled analysis of Studies DME-1 and DME-2 , the ATE rate at 2 years was 7.2% (18 of 250) with 0.5 mg Ranibizumab, 5.6% (14 of 250) with 0.3 mg Ranibizumab, and 5.2% (13 of 250) with control. The stroke rate at 2 years was 3.2% (8 of 250) with 0.5 mg Ranibizumab, 1.2% (3 of 250) with 0.3 mg Ranibizumab, and 1.6% (4 of 250) with control. At 3 years, the ATE rate was 10.4% (26 of 249) with 0.5 mg Ranibizumab and 10.8% (27 of 250) with 0.3 mg Ranibizumab; the stroke rate was 4.8% (12 of 249) with 0.5 mg Ranibizumab and 2.0% (5 of 250) with 0.3 mg Ranibizumab. ## Fatal Events in DME Patients A pooled analysis of Studies DME-1 and DME-2 showed that fatalities in the first 2 years occurred in 4.4% (11 of 250) of patients treated with 0.5 mg Ranibizumab, in 2.8% (7 of 250) of patients treated with 0.3 mg Ranibizumab, and in 1.2% (3 of 250) of control patients. Over 3 years, fatalities occurred in 6.4% (16 of 249) of patients treated with 0.5 mg Ranibizumab and in 4.4% (11 of 250) of patients treated with 0.3 mg Ranibizumab. Although the rate of fatal events was low and included causes of death typical of patients with advanced diabetic complications, a potential relationship between these events and intravitreal use of VEGF inhibitors cannot be excluded. # Adverse Reactions ## Clinical Trials Experience Serious adverse reactions related to the injection procedure have occurred in < 0.1% of intravitreal injections, including endophthalmitis, rhegmatogenous retinal detachment, and iatrogenic traumatic cataract. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in one clinical trial of a drug cannot be directly compared with rates in the clinical trials of the same or another drug and may not reflect the rates observed in practice. The data below reflect exposure to 0.5 mg Ranibizumab in 440 patients with neovascular AMD in Studies AMD-1, AMD-2, and AMD-3, and 259 patients with macular edema following RVO. The data also reflect exposure to 0.3 mg Ranibizumab in 250 patients with DME. Safety data observed in Study AMD-4 were consistent with these results. On average, the rates and types of adverse reactions in patients were not significantly affected by dosing regimen. Ocular Reactions Table 1 shows frequently reported ocular adverse reactions in Ranibizumab-treated patients compared with the control group. Non-Ocular Reactions Non-ocular adverse reactions with an incidence of ≥ 5% in patients receiving Ranibizumab for DME, AMD, and/or RVO and which occurred at a ≥ 1% higher frequency in patients treated with Ranibizumab compared to control are shown in Table 2. Though less common, wound healing complications were also observed in some studies. ### Immunogenicity As with all therapeutic proteins, there is the potential for an immune response in patients treated with Ranibizumab. The immunogenicity data reflect the percentage of patients whose test results were considered positive for antibodies to Ranibizumab in immunoassays and are highly dependent on the sensitivity and specificity of the assays. The pre-treatment incidence of immunoreactivity to Ranibizumab was 0%-5% across treatment groups. After monthly dosing with Ranibizumab for 6 to 24 months, antibodies to Ranibizumab were detected in approximately 1%-9% of patients. The clinical significance of immunoreactivity to Ranibizumab is unclear at this time. Among neovascular AMD patients with the highest levels of immunoreactivity, some were noted to have iritis or vitritis. Intraocular inflammation was not observed in DME or RVO patients with the highest levels of immunoreactivity. ## Postmarketing Experience The following adverse reactions have been identified during post-approval use of Ranibizumab. 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. ‘’‘Ocular’‘’: Tear of retinal pigment epithelium among patients with neovascular AMD # Drug Interactions Drug interaction studies have not been conducted with Ranibizumab. Ranibizumab intravitreal injection has been used adjunctively with verteporfin photodynamic therapy (PDT). Twelve (12) of 105 (11%) patients with neovascular AMD developed serious intraocular inflammation; in 10 of the 12 patients, this occurred when Ranibizumab was administered 7 days (± 2 days) after verteporfin PDT. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): C There are no studies of Ranibizumab in pregnant women. An embryo-fetal developmental toxicity study was performed on pregnant cynomolgus monkeys. Pregnant animals received intravitreal injections of ranibizumab every 14 days starting on Day 20 of gestation, until Day 62 at doses of 0, 0.125, and 1 mg/eye. Skeletal abnormalities including incomplete and/or irregular ossification of bones in the skull, vertebral column, and hindlimbs and shortened supernumerary ribs were seen at a low incidence in fetuses from animals treated with 1 mg/eye of ranibizumab. The 1 mg/eye dose resulted in trough serum ranibizumab levels up to 13 times higher than predicted Cmax levels with single eye treatment in humans. No skeletal abnormalities were seen at the lower dose of 0.125 mg/eye, a dose which resulted in trough exposures equivalent to single eye treatment in humans. No effect on the weight or structure of the placenta, maternal toxicity, or embryotoxicity was observed. Animal reproduction studies are not always predictive of human response. It is also not known whether ranibizumab can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Based on the anti-VEGF mechanism of action for ranibizumab, treatment with Ranibizumab may pose a risk to embryo-fetal development (including teratogenicity) and reproductive capacity. Ranibizumab should be given to a pregnant woman only if clearly needed. Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Ranibizumab in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Ranibizumab during labor and delivery. ### Nursing Mothers It is not known whether ranibizumab is excreted in human milk. Because many drugs are excreted in human milk, and because the potential for absorption and harm to infant growth and development exists, caution should be exercised when Ranibizumab is administered to a nursing woman. ### Pediatric Use The safety and effectiveness of Ranibizumab in pediatric patients have not been established. ### Geriatic Use In the clinical studies, approximately 79% (2387 of 3005) of patients randomized to treatment with Ranibizumab were ≥ 65 years of age and approximately 54% (1636 of 3005) were ≥ 75 years of age. No notable differences in efficacy or safety were seen with increasing age in these studies. Age did not have a significant effect on systemic exposure. ### Gender There is no FDA guidance on the use of Ranibizumab with respect to specific gender populations. ### Race There is no FDA guidance on the use of Ranibizumab with respect to specific racial populations. ### Renal Impairment There is no FDA guidance on the use of Ranibizumab in patients with renal impairment. ### Hepatic Impairment There is no FDA guidance on the use of Ranibizumab in patients with hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Ranibizumab in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Ranibizumab in patients who are immunocompromised. # Administration and Monitoring ### Administration FOR OPHTHALMIC INTRAVITREAL INJECTION ONLY ### Monitoring FDA Package Insert for Ranibizumab contains no information regarding drug monitoring. # IV Compatibility There is limited information about the IV Compatibility. # Overdosage More concentrated doses as high as 2 mg ranibizumab in 0.05 mL have been administered to patients. No additional unexpected adverse reactions were seen. # Pharmacology ## Mechanism of Action Ranibizumab binds to the receptor binding site of active forms of VEGF-A, including the biologically active, cleaved form of this molecule, VEGF110. VEGF-A has been shown to cause neovascularization and leakage in models of ocular angiogenesis and vascular occlusion and is thought to contribute to pathophysiology of neovascular AMD, macular edema following RVO, and DME. The binding of ranibizumab to VEGF-A prevents the interaction of VEGF-A with its receptors (VEGF1 and VEGFR2) on the surface of endothelial cells, reducing endothelial cell proliferation, vascular leakage, and new blood vessel formation. ## Structure Ranibizumab® (ranibizumab injection) is a recombinant humanized IgG1 kappa isotype monoclonal antibody fragment designed for intraocular use. Ranibizumab binds to and inhibits the biologic activity of human vascular endothelial growth factor A (VEGF-A). Ranibizumab, which lacks an Fc region, has a molecular weight of approximately 48 kilodaltons and is produced by an E. coli expression system in a nutrient medium containing the antibiotic tetracycline. Tetracycline is not detectable in the final product. Ranibizumab is a sterile, colorless to pale yellow solution in a single-use glass vial. Ranibizumab is supplied as a preservative-free, sterile solution in a single-use glass vial designed to deliver 0.05 mL of 10 mg/mL Ranibizumab (0.5 mg dose vial) or 6 mg/mL Ranibizumab (0.3 mg dose vial) aqueous solution with 10 mM histidine HCl, 10% α,α-trehalose dihydrate, 0.01% polysorbate 20, pH 5.5. ## Pharmacodynamics Increased retinal thickness (i.e., center point thickness (CPT) or central foveal thickness (CFT)), as assessed by optical coherence tomography (OCT) is associated with neovascular AMD, macular edema following RVO, and DME. Leakage from choroidal neovascularization (CNV) as assessed by fluorescein angiography (FA) is associated with neovascular AMD. Neovascular (Wet) Age-Related Macular Degeneration In Study AMD-3, CPT was assessed by time domain (TD)-OCT in 118 of 184 patients. TD-OCT measurements were collected at baseline, Months 1, 2, 3, 5, 8, and 12. In patients treated with Ranibizumab, CPT decreased, on average, more than in the sham group from baseline through Month 12. CPT decreased by Month 1 and decreased further at Month 3, on average. In this study, CPT data did not provide information useful in influencing treatment decisions. In Study AMD-4, CFT was assessed by spectral domain (SD)-OCT in all patients; on average, CFT reductions were observed beginning at Day 7 following the first Ranibizumab injection through Month 24. CFT data did not provide information capable of predicting final visual acuity results . In patients treated with Ranibizumab, the area of CNV leakage, on average, decreased by Month 3 as assessed by FA. The area of CNV leakage for an individual patient was not correlated with visual acuity. Macular Edema Following Retinal Vein Occlusion On average, CPT reductions were observed in Studies RVO-1 and RVO-2 beginning at Day 7 following the first Ranibizumab injection through Month 6. CPT was not evaluated as a means to guide treatment decisions. Diabetic Macular Edema On average, CPT reductions were observed in Studies DME-1 and DME-2 beginning at Day 7 following the first Ranibizumab injection through Month 36. CPT data did not provide information useful in influencing treatment decisions. ## Pharmacokinetics In animal studies, following intravitreal injection, ranibizumab was cleared from the vitreous with a half-life of approximately 3 days. After reaching a maximum at approximately 1 day, the serum concentration of ranibizumab declined in parallel with the vitreous concentration. In these animal studies, systemic exposure of ranibizumab was more than 2000-fold lower than in the vitreous. In patients with neovascular AMD, following monthly intravitreal administration, maximum ranibizumab serum concentrations were low (0.3 ng/mL to 2.36 ng/mL). These levels were below the concentration of ranibizumab (11 ng/mL to 27 ng/mL) thought to be necessary to inhibit the biological activity of VEGF-A by 50%, as measured in an in vitro cellular proliferation assay. The maximum observed serum concentration was dose proportional over the dose range of 0.05 to 1 mg/eye. Serum ranibizumab concentrations in RVO and DME patients were similar to those observed in neovascular AMD patients. Based on a population pharmacokinetic analysis of patients with neovascular AMD, maximum serum concentrations of 1.5 ng/mL are predicted to be reached at approximately 1 day after monthly intravitreal administration of Ranibizumab 0.5 mg/eye. Based on the disappearance of ranibizumab from serum, the estimated average vitreous elimination half-life was approximately 9 days. Steady-state minimum concentration is predicted to be 0.22 ng/mL with a monthly dosing regimen. In humans, serum ranibizumab concentrations are predicted to be approximately 90,000-fold lower than vitreal concentrations. In pharmacokinetic covariate analyses, 48% (520/1091) of patients had renal impairment (35% mild, 11% moderate, and 2% severe). Because the increases in plasma ranibizumab exposures in these patients are not considered clinically significant, no dosage adjustment is needed based on renal impairment status. ## Nonclinical Toxicology ## Carcinogenesis, Mutagenesis, Impairment of Fertility No carcinogenicity or mutagenicity data are available for ranibizumab injection in animals or humans. No studies on the effects of ranibizumab on fertility have been conducted. Although systemic exposure following ocular administration is expected to be low, effects on female fertility are possible due to the anti-VEGF mechanism of action for ranibizumab # Clinical Studies Unless otherwise noted, visual acuity was measured at a distance of 4 meters. ## Neovascular (Wet) Age-Related Macular Degeneration (AMD) The safety and efficacy of Ranibizumab were assessed in three randomized, double-masked, sham- or active-controlled studies in patients with neovascular AMD. A total of 1323 patients (Ranibizumab 879, control 444) were enrolled in the three studies. Studies AMD-1 and AMD-2 In Study AMD-1, patients with minimally classic or occult (without classic) CNV lesions received monthly Ranibizumab 0.3 mg or 0.5 mg intravitreal injections or monthly sham injections. Data are available through Month 24. Patients treated with Ranibizumab in Study AMD-1 received a mean of 22 total treatments out of a possible 24 from Day 0 to Month 24. In Study AMD-2, patients with predominantly classic CNV lesions received one of the following: 1) monthly Ranibizumab 0.3 mg intravitreal injections and sham PDT; 2) monthly Ranibizumab 0.5 mg intravitreal injections and sham PDT; or 3) sham intravitreal injections and active verteporfin PDT. Sham PDT (or active verteporfin PDT) was given with the initial Ranibizumab (or sham) intravitreal injection and every 3 months thereafter if fluorescein angiography showed persistence or recurrence of leakage. Data are available through Month 24. Patients treated with Ranibizumab in Study AMD-2 received a mean of 21 total treatments out of a possible 24 from Day 0 through Month 24. In both studies, the primary efficacy endpoint was the proportion of patients who maintained vision, defined as losing fewer than 15 letters of visual acuity at 12 months compared with baseline. Almost all Ranibizumab-treated patients (approximately 95%) maintained their visual acuity. Among Ranibizumab-treated patients, 31% to 37% experienced a clinically significant improvement in vision, defined as gaining 15 or more letters at 12 months. The size of the lesion did not significantly affect the results. Detailed results are shown in Table 3, Table 4, and Figure 1 below. Visual acuity was measured at a distance of 2 meters Patients in the group treated with Ranibizumab had minimal observable CNV lesion growth, on average. At Month 12, the mean change in the total area of the CNV lesion was 0.1-0.3 disc areas (DA) for Ranibizumab versus 2.3-2.6 DA for the control arms. At Month 24, the mean change in the total area of the CNV lesion was 0.3-0.4 DA for Ranibizumab versus 2.9-3.1 DA for the control arms. Study AMD-3 Study AMD-3 was a randomized, double-masked, sham-controlled, two-year study designed to assess the safety and efficacy of Ranibizumab in patients with neovascular AMD (with or without a classic CNV component). Data are available through Month 12. Patients received Ranibizumab 0.3 mg or 0.5 mg intravitreal injections or sham injections once a month for 3 consecutive doses, followed by a dose administered once every 3 months for 9 months. A total of 184 patients were enrolled in this study (Ranibizumab 0.3 mg, 60; Ranibizumab 0.5 mg, 61; sham, 63); 171 (93%) completed 12 months of this study. Patients treated with Ranibizumab in Study AMD-3 received a mean of 6 total treatments out of a possible 6 from Day 0 through Month 12. In Study AMD-3, the primary efficacy endpoint was mean change in visual acuity at 12 months compared with baseline (see Figure 2). After an initial increase in visual acuity (following monthly dosing), on average, patients dosed once every 3 months with Ranibizumab lost visual acuity, returning to baseline at Month 12. In Study AMD-3, almost all Ranibizumab-treated patients (90%) lost fewer than 15 letters of visual acuity at Month 12. Study AMD-4 Study AMD-4 was a randomized, double-masked, active treatment-controlled, two-year study designed to assess the safety and efficacy of Ranibizumab 0.5 mg administered monthly or less frequently than monthly in patients with neovascular AMD. Patients randomized to the Ranibizumab 0.5 mg less frequent dosing arm received 3 monthly doses followed by monthly assessments where patients were eligible to receive Ranibizumab injections guided by pre-specified re-treatment criteria. A total of 550 patients were enrolled in the two 0.5 mg treatment groups with 467 (85%) completing through Month 24. Data are available through Month 24. Clinical results at Month 24 remain similar to that observed at Month 12. From Month 3 through Month 24, visual acuity decreased by 0.3 letters in the 0.5 mg less frequent dosing arm and increased by 0.7 letters in the 0.5 mg monthly arm. Over this 21 month period, patients in the 0.5 mg less frequent dosing and the 0.5 mg monthly arms averaged 10.3 and 18.5 injections, respectively. The distribution of injections received in the less frequent dosing arm is shown in Figure 4. ## Macular Edema Following Retinal Vein Occlusion (RVO) The safety and efficacy of Ranibizumab were assessed in two randomized, double-masked, 1-year studies in patients with macular edema following RVO. Sham controlled data are available through Month 6. Patient age ranged from 20 to 91 years, with a mean age of 67 years. A total of 789 patients (Ranibizumab 0.3 mg, 266 patients; Ranibizumab 0.5 mg, 261 patients; sham, 262 patients) were enrolled, with 739 (94%) patients completing through Month 6. All patients completing Month 6 were eligible to receive Ranibizumab injections guided by pre-specified re-treatment criteria until the end of the studies at Month 12. In Study RVO-1, patients with macular edema following branch or hemi-RVO, received monthly Ranibizumab 0.3 mg or 0.5 mg intravitreal injections or monthly sham injections for 6 months. All patients were eligible for macular focal/grid laser treatment beginning at Month 3 of the 6-month treatment period. Macular focal/grid laser treatment was given to 26 of 131 (20%) patients treated with 0.5 mg Ranibizumab and 71 of 132 (54%) patients treated with sham. In Study RVO-2, patients with macular edema following central RVO received monthly Ranibizumab 0.3 mg or 0.5 mg intravitreal injections or monthly sham injections for 6 months. At Month 6, after monthly treatment with 0.5 mg Ranibizumab, the following clinical results were observed: ## Diabetic Macular Edema (DME) The safety and efficacy of Ranibizumab were assessed in two randomized, double-masked, 3-year studies in patients with DME. The studies were sham-controlled through Month 24. Patient age ranged from 21 to 91 years, with a mean age of 62 years. A total of 759 patients (Ranibizumab 0.3 mg, 250 patients; Ranibizumab 0.5 mg, 252 patients; sham, 257 patients) were enrolled, with 582 (77%) completing through Month 36. In Studies DME-1 and DME-2, patients received monthly Ranibizumab 0.3 mg or 0.5 mg intravitreal injections or monthly sham injections during the 24-month controlled treatment period. From Months 25 through 36, patients who previously received sham were eligible to receive monthly Ranibizumab 0.5 mg and patients originally randomized to monthly Ranibizumab 0.3 mg or 0.5 mg continued to receive their assigned dose. All patients were eligible for macular focal/grid laser treatment beginning at Month 3 of the 24-month treatment period or panretinal photocoagulation (PRP) as needed. Through Month 24, macular focal/grid laser treatment was administered in 94 of 250 (38%) patients treated with Ranibizumab 0.3 mg and 185 of 257 (72%) patients treated with sham; PRP was administered in 2 of 250 (1%) patients treated with Ranibizumab 0.3 mg and 30 of 257 (12%) patients treated with sham. Compared to monthly Ranibizumab 0.3 mg, no additional benefit was observed with monthly treatment with Ranibizumab 0.5 mg. At Month 24, after monthly treatment with Ranibizumab 0.3 mg, the following clinical results were observed: VA outcomes observed at Month 24 in patients treated with Ranibizumab 0.3 mg were maintained with continued treatment through Month 36 in both DME studies. Patients in the sham arms who received Ranibizumab 0.5 mg beginning at Month 25 achieved lesser VA gains compared to patients who began treatment with Ranibizumab at the beginning of the studies. # How Supplied - Each Ranibizumab 0.5 mg carton (NDC 50242-080-01) contains a single-use, 2-cc glass vial with a BLUE CAP designed to deliver 0.05 mL of 10 mg/mL ranibizumab. - Each Ranibizumab 0.3 mg carton (NDC 50242-082-01) contains a single-use, 2-cc glass vial with a WHITE CAP designed to deliver 0.05 mL of 6 mg/mL ranibizumab. In addition, each carton contains one 5-micron, 19-gauge × 1-1/2-inch filter needle for withdrawal of the vial contents; one 30-gauge × 1/2-inch injection needle for the intravitreal injection; and one package insert . VIALS ARE FOR SINGLE-EYE USE ONLY. ## Storage Ranibizumab should be refrigerated at 2°-8°C (36°-46°F). DO NOT FREEZE. Do not use beyond the date stamped on the label. Ranibizumab vials should be protected from light. Store in the original carton until time of use. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information In the days following Ranibizumab administration, patients are at risk of developing endophthalmitis. If the eye becomes red, sensitive to light, painful, or develops a change in vision, the patient should seek immediate care from an ophthalmologist. Ranibizumab® Manufactured by: Genentech, Inc. A Member of the Roche Group 1 DNA Way South San Francisco, CA 94080-4990 Ranibizumab® is a registered trademark of Genentech, Inc. ©2014 Genentech, Inc. Representative sample of labeling (see the HOW SUPPLIED section for complete listing): PRINCIPAL DISPLAY PANEL - 0.5 mg Vial Carton NDC 50242-080-01 Ranibizumab® RANIBIZUMAB INJECTION 0.5 mg DOSE SINGLE-USE VIAL INDICATED FOR Neovascular (wet) age-related macular degeneration (wAMD) Macular edema following retinal vein occlusion (RVO) 0.5 mg wAMD # Precautions with Alcohol Alcohol-Ranibizumab interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names LUCENTIS # Look-Alike Drug Names There is limited information regarding Ranibizumab Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	Ranibizumab 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. # Overview Ranibizumab is a Monoclonal antibodies that is FDA approved for the treatment of neovascular (wet) age-related macular degeneration (AMD), macular edema following retinal vein occlusion (RVO), diabetic macular edema (DME). Common adverse reactions include cataract, conjunctival hemorrhage, eye irritation, foreign body sensation, in the eyes, inflammatory disorder of the eye, pain in eye, raised intraocular pressure, visual disturbance, vitreous detachment, vitreous floaters. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) ### Neovascular (Wet) Age-Related Macular Degeneration (AMD) - Dosing information - Recommended dosage: 0.5 mg (0.05 mL of 10 mg/mL Ranibizumab solution) IV once a month (approximately 28 days). - Although not as effective, patients may be treated with 3 monthly doses followed by less frequent dosing with regular assessment. In the nine months after 3 initial monthly doses, less frequent dosing with 4-5 doses on average is expected to maintain visual acuity while monthly dosing may be expected to result in an additional average 1-2 letter gain. Patients should be assessed regularly - Although not as effective, patients may also be treated with one dose every 3 months after 4 monthly doses. Compared with continued monthly dosing, dosing every 3 months over the next 9 months will lead to an approximate 5-letter (1-line) loss of visual acuity benefit, on average. Patients should be assessed regularly ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Ranibizumab in adult patients. ### Non–Guideline-Supported Use ### Choroidal retinal neovascularization - Dosnig information - ’‘’1.25 mg/0.05 mL or 0.5 mg/0.05 mL ‘’‘ [1] # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) The safety and effectiveness of Ranibizumab in pediatric patients have not been established. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Ranibizumab in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Ranibizumab in pediatric patients. # Contraindications ## Ocular or Periocular Infections Ranibizumab is contraindicated in patients with ocular or periocular infections. ## Hypersensitivity Ranibizumab is contraindicated in patients with known hypersensitivity to ranibizumab or any of the excipients in Ranibizumab. Hypersensitivity reactions may manifest as severe intraocular inflammation. # Warnings ## Endophthalmitis and Retinal Detachments Intravitreal injections, including those with Ranibizumab, have been associated with endophthalmitis and retinal detachments. Proper aseptic injection technique should always be used when administering Ranibizumab. In addition, patients should be monitored following the injection to permit early treatment should an infection occur. ## Increases in Intraocular Pressure Increases in intraocular pressure have been noted both pre-injection and post-injection (at 60 minutes) while being treated with Ranibizumab. Monitor intraocular pressure prior to and following intravitreal injection with Ranibizumab and manage appropriately. ## Thromboembolic Events Although there was a low rate of arterial thromboembolic events (ATEs) observed in the Ranibizumab clinical trials, there is a potential risk of ATEs following intravitreal use of VEGF inhibitors. ATEs are defined as nonfatal stroke, nonfatal myocardial infarction, or vascular death (including deaths of unknown cause). ### Neovascular (Wet) Age-Related Macular Degeneration The ATE rate in the three controlled neovascular AMD studies (AMD-1, AMD-2, AMD-3) during the first year was 1.9% (17 of 874) in the combined group of patients treated with 0.3 mg or 0.5 mg Ranibizumab compared with 1.1% (5 of 441) in patients from the control arms . In the second year of Studies AMD-1 and AMD-2, the ATE rate was 2.6% (19 of 721) in the combined group of Ranibizumab-treated patients compared with 2.9% (10 of 344) in patients from the control arms. In Study AMD-4, the ATE rates observed in the 0.5 mg arms during the first and second year were similar to rates observed in Studies AMD-1, AMD-2, and AMD-3. In a pooled analysis of 2-year controlled studies (AMD-1, AMD-2, and a study of Ranibizumab used adjunctively with verteporfin photodynamic therapy), the stroke rate (including both ischemic and hemorrhagic stroke) was 2.7% (13 of 484) in patients treated with 0.5 mg Ranibizumab compared to 1.1% (5 of 435) in patients in the control arms (odds ratio 2.2 (95% confidence interval (0.8-7.1))). ### Macular Edema Following Retinal Vein Occlusion The ATE rate in the two controlled RVO studies during the first 6 months was 0.8% in both the Ranibizumab and control arms of the studies (4 of 525 in the combined group of patients treated with 0.3 mg or 0.5 mg Ranibizumab and 2 of 260 in the control arms). The stroke rate was 0.2% (1 of 525) in the combined group of Ranibizumab-treated patients compared to 0.4% (1 of 260) in the control arms. ### Diabetic Macular Edema In a pooled analysis of Studies DME-1 and DME-2 , the ATE rate at 2 years was 7.2% (18 of 250) with 0.5 mg Ranibizumab, 5.6% (14 of 250) with 0.3 mg Ranibizumab, and 5.2% (13 of 250) with control. The stroke rate at 2 years was 3.2% (8 of 250) with 0.5 mg Ranibizumab, 1.2% (3 of 250) with 0.3 mg Ranibizumab, and 1.6% (4 of 250) with control. At 3 years, the ATE rate was 10.4% (26 of 249) with 0.5 mg Ranibizumab and 10.8% (27 of 250) with 0.3 mg Ranibizumab; the stroke rate was 4.8% (12 of 249) with 0.5 mg Ranibizumab and 2.0% (5 of 250) with 0.3 mg Ranibizumab. ## Fatal Events in DME Patients A pooled analysis of Studies DME-1 and DME-2 showed that fatalities in the first 2 years occurred in 4.4% (11 of 250) of patients treated with 0.5 mg Ranibizumab, in 2.8% (7 of 250) of patients treated with 0.3 mg Ranibizumab, and in 1.2% (3 of 250) of control patients. Over 3 years, fatalities occurred in 6.4% (16 of 249) of patients treated with 0.5 mg Ranibizumab and in 4.4% (11 of 250) of patients treated with 0.3 mg Ranibizumab. Although the rate of fatal events was low and included causes of death typical of patients with advanced diabetic complications, a potential relationship between these events and intravitreal use of VEGF inhibitors cannot be excluded. # Adverse Reactions ## Clinical Trials Experience Serious adverse reactions related to the injection procedure have occurred in < 0.1% of intravitreal injections, including endophthalmitis, rhegmatogenous retinal detachment, and iatrogenic traumatic cataract. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in one clinical trial of a drug cannot be directly compared with rates in the clinical trials of the same or another drug and may not reflect the rates observed in practice. The data below reflect exposure to 0.5 mg Ranibizumab in 440 patients with neovascular AMD in Studies AMD-1, AMD-2, and AMD-3, and 259 patients with macular edema following RVO. The data also reflect exposure to 0.3 mg Ranibizumab in 250 patients with DME. Safety data observed in Study AMD-4 were consistent with these results. On average, the rates and types of adverse reactions in patients were not significantly affected by dosing regimen. Ocular Reactions Table 1 shows frequently reported ocular adverse reactions in Ranibizumab-treated patients compared with the control group. Non-Ocular Reactions Non-ocular adverse reactions with an incidence of ≥ 5% in patients receiving Ranibizumab for DME, AMD, and/or RVO and which occurred at a ≥ 1% higher frequency in patients treated with Ranibizumab compared to control are shown in Table 2. Though less common, wound healing complications were also observed in some studies. ### Immunogenicity As with all therapeutic proteins, there is the potential for an immune response in patients treated with Ranibizumab. The immunogenicity data reflect the percentage of patients whose test results were considered positive for antibodies to Ranibizumab in immunoassays and are highly dependent on the sensitivity and specificity of the assays. The pre-treatment incidence of immunoreactivity to Ranibizumab was 0%-5% across treatment groups. After monthly dosing with Ranibizumab for 6 to 24 months, antibodies to Ranibizumab were detected in approximately 1%-9% of patients. The clinical significance of immunoreactivity to Ranibizumab is unclear at this time. Among neovascular AMD patients with the highest levels of immunoreactivity, some were noted to have iritis or vitritis. Intraocular inflammation was not observed in DME or RVO patients with the highest levels of immunoreactivity. ## Postmarketing Experience The following adverse reactions have been identified during post-approval use of Ranibizumab. 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. ‘’‘Ocular’‘’: Tear of retinal pigment epithelium among patients with neovascular AMD # Drug Interactions Drug interaction studies have not been conducted with Ranibizumab. Ranibizumab intravitreal injection has been used adjunctively with verteporfin photodynamic therapy (PDT). Twelve (12) of 105 (11%) patients with neovascular AMD developed serious intraocular inflammation; in 10 of the 12 patients, this occurred when Ranibizumab was administered 7 days (± 2 days) after verteporfin PDT. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): C There are no studies of Ranibizumab in pregnant women. An embryo-fetal developmental toxicity study was performed on pregnant cynomolgus monkeys. Pregnant animals received intravitreal injections of ranibizumab every 14 days starting on Day 20 of gestation, until Day 62 at doses of 0, 0.125, and 1 mg/eye. Skeletal abnormalities including incomplete and/or irregular ossification of bones in the skull, vertebral column, and hindlimbs and shortened supernumerary ribs were seen at a low incidence in fetuses from animals treated with 1 mg/eye of ranibizumab. The 1 mg/eye dose resulted in trough serum ranibizumab levels up to 13 times higher than predicted Cmax levels with single eye treatment in humans. No skeletal abnormalities were seen at the lower dose of 0.125 mg/eye, a dose which resulted in trough exposures equivalent to single eye treatment in humans. No effect on the weight or structure of the placenta, maternal toxicity, or embryotoxicity was observed. Animal reproduction studies are not always predictive of human response. It is also not known whether ranibizumab can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Based on the anti-VEGF mechanism of action for ranibizumab, treatment with Ranibizumab may pose a risk to embryo-fetal development (including teratogenicity) and reproductive capacity. Ranibizumab should be given to a pregnant woman only if clearly needed. Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Ranibizumab in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Ranibizumab during labor and delivery. ### Nursing Mothers It is not known whether ranibizumab is excreted in human milk. Because many drugs are excreted in human milk, and because the potential for absorption and harm to infant growth and development exists, caution should be exercised when Ranibizumab is administered to a nursing woman. ### Pediatric Use The safety and effectiveness of Ranibizumab in pediatric patients have not been established. ### Geriatic Use In the clinical studies, approximately 79% (2387 of 3005) of patients randomized to treatment with Ranibizumab were ≥ 65 years of age and approximately 54% (1636 of 3005) were ≥ 75 years of age. No notable differences in efficacy or safety were seen with increasing age in these studies. Age did not have a significant effect on systemic exposure. ### Gender There is no FDA guidance on the use of Ranibizumab with respect to specific gender populations. ### Race There is no FDA guidance on the use of Ranibizumab with respect to specific racial populations. ### Renal Impairment There is no FDA guidance on the use of Ranibizumab in patients with renal impairment. ### Hepatic Impairment There is no FDA guidance on the use of Ranibizumab in patients with hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Ranibizumab in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Ranibizumab in patients who are immunocompromised. # Administration and Monitoring ### Administration FOR OPHTHALMIC INTRAVITREAL INJECTION ONLY ### Monitoring FDA Package Insert for Ranibizumab contains no information regarding drug monitoring. # IV Compatibility There is limited information about the IV Compatibility. # Overdosage More concentrated doses as high as 2 mg ranibizumab in 0.05 mL have been administered to patients. No additional unexpected adverse reactions were seen. # Pharmacology ## Mechanism of Action Ranibizumab binds to the receptor binding site of active forms of VEGF-A, including the biologically active, cleaved form of this molecule, VEGF110. VEGF-A has been shown to cause neovascularization and leakage in models of ocular angiogenesis and vascular occlusion and is thought to contribute to pathophysiology of neovascular AMD, macular edema following RVO, and DME. The binding of ranibizumab to VEGF-A prevents the interaction of VEGF-A with its receptors (VEGF1 and VEGFR2) on the surface of endothelial cells, reducing endothelial cell proliferation, vascular leakage, and new blood vessel formation. ## Structure Ranibizumab® (ranibizumab injection) is a recombinant humanized IgG1 kappa isotype monoclonal antibody fragment designed for intraocular use. Ranibizumab binds to and inhibits the biologic activity of human vascular endothelial growth factor A (VEGF-A). Ranibizumab, which lacks an Fc region, has a molecular weight of approximately 48 kilodaltons and is produced by an E. coli expression system in a nutrient medium containing the antibiotic tetracycline. Tetracycline is not detectable in the final product. Ranibizumab is a sterile, colorless to pale yellow solution in a single-use glass vial. Ranibizumab is supplied as a preservative-free, sterile solution in a single-use glass vial designed to deliver 0.05 mL of 10 mg/mL Ranibizumab (0.5 mg dose vial) or 6 mg/mL Ranibizumab (0.3 mg dose vial) aqueous solution with 10 mM histidine HCl, 10% α,α-trehalose dihydrate, 0.01% polysorbate 20, pH 5.5. ## Pharmacodynamics Increased retinal thickness (i.e., center point thickness (CPT) or central foveal thickness (CFT)), as assessed by optical coherence tomography (OCT) is associated with neovascular AMD, macular edema following RVO, and DME. Leakage from choroidal neovascularization (CNV) as assessed by fluorescein angiography (FA) is associated with neovascular AMD. Neovascular (Wet) Age-Related Macular Degeneration In Study AMD-3, CPT was assessed by time domain (TD)-OCT in 118 of 184 patients. TD-OCT measurements were collected at baseline, Months 1, 2, 3, 5, 8, and 12. In patients treated with Ranibizumab, CPT decreased, on average, more than in the sham group from baseline through Month 12. CPT decreased by Month 1 and decreased further at Month 3, on average. In this study, CPT data did not provide information useful in influencing treatment decisions. In Study AMD-4, CFT was assessed by spectral domain (SD)-OCT in all patients; on average, CFT reductions were observed beginning at Day 7 following the first Ranibizumab injection through Month 24. CFT data did not provide information capable of predicting final visual acuity results . In patients treated with Ranibizumab, the area of CNV leakage, on average, decreased by Month 3 as assessed by FA. The area of CNV leakage for an individual patient was not correlated with visual acuity. Macular Edema Following Retinal Vein Occlusion On average, CPT reductions were observed in Studies RVO-1 and RVO-2 beginning at Day 7 following the first Ranibizumab injection through Month 6. CPT was not evaluated as a means to guide treatment decisions. Diabetic Macular Edema On average, CPT reductions were observed in Studies DME-1 and DME-2 beginning at Day 7 following the first Ranibizumab injection through Month 36. CPT data did not provide information useful in influencing treatment decisions. ## Pharmacokinetics In animal studies, following intravitreal injection, ranibizumab was cleared from the vitreous with a half-life of approximately 3 days. After reaching a maximum at approximately 1 day, the serum concentration of ranibizumab declined in parallel with the vitreous concentration. In these animal studies, systemic exposure of ranibizumab was more than 2000-fold lower than in the vitreous. In patients with neovascular AMD, following monthly intravitreal administration, maximum ranibizumab serum concentrations were low (0.3 ng/mL to 2.36 ng/mL). These levels were below the concentration of ranibizumab (11 ng/mL to 27 ng/mL) thought to be necessary to inhibit the biological activity of VEGF-A by 50%, as measured in an in vitro cellular proliferation assay. The maximum observed serum concentration was dose proportional over the dose range of 0.05 to 1 mg/eye. Serum ranibizumab concentrations in RVO and DME patients were similar to those observed in neovascular AMD patients. Based on a population pharmacokinetic analysis of patients with neovascular AMD, maximum serum concentrations of 1.5 ng/mL are predicted to be reached at approximately 1 day after monthly intravitreal administration of Ranibizumab 0.5 mg/eye. Based on the disappearance of ranibizumab from serum, the estimated average vitreous elimination half-life was approximately 9 days. Steady-state minimum concentration is predicted to be 0.22 ng/mL with a monthly dosing regimen. In humans, serum ranibizumab concentrations are predicted to be approximately 90,000-fold lower than vitreal concentrations. In pharmacokinetic covariate analyses, 48% (520/1091) of patients had renal impairment (35% mild, 11% moderate, and 2% severe). Because the increases in plasma ranibizumab exposures in these patients are not considered clinically significant, no dosage adjustment is needed based on renal impairment status. ## Nonclinical Toxicology ## Carcinogenesis, Mutagenesis, Impairment of Fertility No carcinogenicity or mutagenicity data are available for ranibizumab injection in animals or humans. No studies on the effects of ranibizumab on fertility have been conducted. Although systemic exposure following ocular administration is expected to be low, effects on female fertility are possible due to the anti-VEGF mechanism of action for ranibizumab # Clinical Studies Unless otherwise noted, visual acuity was measured at a distance of 4 meters. ## Neovascular (Wet) Age-Related Macular Degeneration (AMD) The safety and efficacy of Ranibizumab were assessed in three randomized, double-masked, sham- or active-controlled studies in patients with neovascular AMD. A total of 1323 patients (Ranibizumab 879, control 444) were enrolled in the three studies. Studies AMD-1 and AMD-2 In Study AMD-1, patients with minimally classic or occult (without classic) CNV lesions received monthly Ranibizumab 0.3 mg or 0.5 mg intravitreal injections or monthly sham injections. Data are available through Month 24. Patients treated with Ranibizumab in Study AMD-1 received a mean of 22 total treatments out of a possible 24 from Day 0 to Month 24. In Study AMD-2, patients with predominantly classic CNV lesions received one of the following: 1) monthly Ranibizumab 0.3 mg intravitreal injections and sham PDT; 2) monthly Ranibizumab 0.5 mg intravitreal injections and sham PDT; or 3) sham intravitreal injections and active verteporfin PDT. Sham PDT (or active verteporfin PDT) was given with the initial Ranibizumab (or sham) intravitreal injection and every 3 months thereafter if fluorescein angiography showed persistence or recurrence of leakage. Data are available through Month 24. Patients treated with Ranibizumab in Study AMD-2 received a mean of 21 total treatments out of a possible 24 from Day 0 through Month 24. In both studies, the primary efficacy endpoint was the proportion of patients who maintained vision, defined as losing fewer than 15 letters of visual acuity at 12 months compared with baseline. Almost all Ranibizumab-treated patients (approximately 95%) maintained their visual acuity. Among Ranibizumab-treated patients, 31% to 37% experienced a clinically significant improvement in vision, defined as gaining 15 or more letters at 12 months. The size of the lesion did not significantly affect the results. Detailed results are shown in Table 3, Table 4, and Figure 1 below. Visual acuity was measured at a distance of 2 meters Patients in the group treated with Ranibizumab had minimal observable CNV lesion growth, on average. At Month 12, the mean change in the total area of the CNV lesion was 0.1-0.3 disc areas (DA) for Ranibizumab versus 2.3-2.6 DA for the control arms. At Month 24, the mean change in the total area of the CNV lesion was 0.3-0.4 DA for Ranibizumab versus 2.9-3.1 DA for the control arms. Study AMD-3 Study AMD-3 was a randomized, double-masked, sham-controlled, two-year study designed to assess the safety and efficacy of Ranibizumab in patients with neovascular AMD (with or without a classic CNV component). Data are available through Month 12. Patients received Ranibizumab 0.3 mg or 0.5 mg intravitreal injections or sham injections once a month for 3 consecutive doses, followed by a dose administered once every 3 months for 9 months. A total of 184 patients were enrolled in this study (Ranibizumab 0.3 mg, 60; Ranibizumab 0.5 mg, 61; sham, 63); 171 (93%) completed 12 months of this study. Patients treated with Ranibizumab in Study AMD-3 received a mean of 6 total treatments out of a possible 6 from Day 0 through Month 12. In Study AMD-3, the primary efficacy endpoint was mean change in visual acuity at 12 months compared with baseline (see Figure 2). After an initial increase in visual acuity (following monthly dosing), on average, patients dosed once every 3 months with Ranibizumab lost visual acuity, returning to baseline at Month 12. In Study AMD-3, almost all Ranibizumab-treated patients (90%) lost fewer than 15 letters of visual acuity at Month 12. Study AMD-4 Study AMD-4 was a randomized, double-masked, active treatment-controlled, two-year study designed to assess the safety and efficacy of Ranibizumab 0.5 mg administered monthly or less frequently than monthly in patients with neovascular AMD. Patients randomized to the Ranibizumab 0.5 mg less frequent dosing arm received 3 monthly doses followed by monthly assessments where patients were eligible to receive Ranibizumab injections guided by pre-specified re-treatment criteria. A total of 550 patients were enrolled in the two 0.5 mg treatment groups with 467 (85%) completing through Month 24. Data are available through Month 24. Clinical results at Month 24 remain similar to that observed at Month 12. From Month 3 through Month 24, visual acuity decreased by 0.3 letters in the 0.5 mg less frequent dosing arm and increased by 0.7 letters in the 0.5 mg monthly arm. Over this 21 month period, patients in the 0.5 mg less frequent dosing and the 0.5 mg monthly arms averaged 10.3 and 18.5 injections, respectively. The distribution of injections received in the less frequent dosing arm is shown in Figure 4. ## Macular Edema Following Retinal Vein Occlusion (RVO) The safety and efficacy of Ranibizumab were assessed in two randomized, double-masked, 1-year studies in patients with macular edema following RVO. Sham controlled data are available through Month 6. Patient age ranged from 20 to 91 years, with a mean age of 67 years. A total of 789 patients (Ranibizumab 0.3 mg, 266 patients; Ranibizumab 0.5 mg, 261 patients; sham, 262 patients) were enrolled, with 739 (94%) patients completing through Month 6. All patients completing Month 6 were eligible to receive Ranibizumab injections guided by pre-specified re-treatment criteria until the end of the studies at Month 12. In Study RVO-1, patients with macular edema following branch or hemi-RVO, received monthly Ranibizumab 0.3 mg or 0.5 mg intravitreal injections or monthly sham injections for 6 months. All patients were eligible for macular focal/grid laser treatment beginning at Month 3 of the 6-month treatment period. Macular focal/grid laser treatment was given to 26 of 131 (20%) patients treated with 0.5 mg Ranibizumab and 71 of 132 (54%) patients treated with sham. In Study RVO-2, patients with macular edema following central RVO received monthly Ranibizumab 0.3 mg or 0.5 mg intravitreal injections or monthly sham injections for 6 months. At Month 6, after monthly treatment with 0.5 mg Ranibizumab, the following clinical results were observed: ## Diabetic Macular Edema (DME) The safety and efficacy of Ranibizumab were assessed in two randomized, double-masked, 3-year studies in patients with DME. The studies were sham-controlled through Month 24. Patient age ranged from 21 to 91 years, with a mean age of 62 years. A total of 759 patients (Ranibizumab 0.3 mg, 250 patients; Ranibizumab 0.5 mg, 252 patients; sham, 257 patients) were enrolled, with 582 (77%) completing through Month 36. In Studies DME-1 and DME-2, patients received monthly Ranibizumab 0.3 mg or 0.5 mg intravitreal injections or monthly sham injections during the 24-month controlled treatment period. From Months 25 through 36, patients who previously received sham were eligible to receive monthly Ranibizumab 0.5 mg and patients originally randomized to monthly Ranibizumab 0.3 mg or 0.5 mg continued to receive their assigned dose. All patients were eligible for macular focal/grid laser treatment beginning at Month 3 of the 24-month treatment period or panretinal photocoagulation (PRP) as needed. Through Month 24, macular focal/grid laser treatment was administered in 94 of 250 (38%) patients treated with Ranibizumab 0.3 mg and 185 of 257 (72%) patients treated with sham; PRP was administered in 2 of 250 (1%) patients treated with Ranibizumab 0.3 mg and 30 of 257 (12%) patients treated with sham. Compared to monthly Ranibizumab 0.3 mg, no additional benefit was observed with monthly treatment with Ranibizumab 0.5 mg. At Month 24, after monthly treatment with Ranibizumab 0.3 mg, the following clinical results were observed: VA outcomes observed at Month 24 in patients treated with Ranibizumab 0.3 mg were maintained with continued treatment through Month 36 in both DME studies. Patients in the sham arms who received Ranibizumab 0.5 mg beginning at Month 25 achieved lesser VA gains compared to patients who began treatment with Ranibizumab at the beginning of the studies. # How Supplied - Each Ranibizumab 0.5 mg carton (NDC 50242-080-01) contains a single-use, 2-cc glass vial with a BLUE CAP designed to deliver 0.05 mL of 10 mg/mL ranibizumab. - Each Ranibizumab 0.3 mg carton (NDC 50242-082-01) contains a single-use, 2-cc glass vial with a WHITE CAP designed to deliver 0.05 mL of 6 mg/mL ranibizumab. In addition, each carton contains one 5-micron, 19-gauge × 1-1/2-inch filter needle for withdrawal of the vial contents; one 30-gauge × 1/2-inch injection needle for the intravitreal injection; and one package insert . VIALS ARE FOR SINGLE-EYE USE ONLY. ## Storage Ranibizumab should be refrigerated at 2°-8°C (36°-46°F). DO NOT FREEZE. Do not use beyond the date stamped on the label. Ranibizumab vials should be protected from light. Store in the original carton until time of use. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information In the days following Ranibizumab administration, patients are at risk of developing endophthalmitis. If the eye becomes red, sensitive to light, painful, or develops a change in vision, the patient should seek immediate care from an ophthalmologist. Ranibizumab® [ranibizumab injection] Manufactured by: Genentech, Inc. A Member of the Roche Group 1 DNA Way South San Francisco, CA 94080-4990 Ranibizumab® is a registered trademark of Genentech, Inc. ©2014 Genentech, Inc. Representative sample of labeling (see the HOW SUPPLIED section for complete listing): PRINCIPAL DISPLAY PANEL - 0.5 mg Vial Carton NDC 50242-080-01 10140896 Ranibizumab® RANIBIZUMAB INJECTION 0.5 mg DOSE SINGLE-USE VIAL INDICATED FOR Neovascular (wet) age-related macular degeneration (wAMD) Macular edema following retinal vein occlusion (RVO) 0.5 mg wAMD # Precautions with Alcohol Alcohol-Ranibizumab interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names LUCENTIS # Look-Alike Drug Names There is limited information regarding Ranibizumab Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	https://www.wikidoc.org/index.php/Lucentis
36041c2d328231585df8bdf4f6557a8fe36a26c6	wikidoc	Lucid Dream	Lucid Dream A lucid dream, also known as a conscious dream, is a dream in which the person is aware that he or she is dreaming while the dream is in progress. When the dreamer is lucid, he or she can actively participate in the dream environment without any of the inhibitions or limitations that otherwise would feel natural to persons who incorrectly believe they are in the "real" waking world. Lucid dreams can be extremely real and vivid depending on a person's level of self-awareness during the lucid dream. A lucid dream can begin in one of two ways. A dream-initiated lucid dream (DILD) starts as a normal dream, and the dreamer eventually concludes that he or she is dreaming, while a wake-initiated lucid dream (WILD) occurs when the dreamer goes from a normal waking state directly into a dream state with no apparent lapse in consciousness. Lucid dreaming has been researched scientifically, and its existence is well established. Scientists such as Allan Hobson, with his neurophysiological approach to dream research, have helped to push the understanding of lucid dreaming into a less speculative realm. # Scientific history The first book on lucid dreams to recognize their scientific potential was Celia Green's 1968 study Lucid Dreams. Reviewing the past literature, as well as new data from subjects of her own, Green analyzed the main characteristics of such dreams and concluded that they were a category of experience quite distinct from ordinary dreams. She predicted that they would turn out to be associated with rapid eye movement sleep (REM sleep). Green was also the first to link lucid dreams to the phenomenon of false awakenings. Philosopher Norman Malcolm's 1959 text Dreaming argued against the possibility of checking the accuracy of dream reports. However, the realization that eye movements performed in dreams affected the dreamer's physical eyes provided a way to prove that actions agreed upon during waking life could be recalled and performed once lucid in a dream. The first evidence of this type was produced in the late 1970s by British parapsychologist Keith Hearne. A volunteer named Alan Worsley used eye movement to signal the onset of lucidity, which were recorded by a polysomnograph machine. Hearne's results were not widely distributed. The first peer-reviewed article was published some years later by Stephen LaBerge at Stanford University, who had independently developed a similar technique as part of his doctoral dissertation. During the 1980s, further scientific evidence to confirm the existence of lucid dreaming was produced as lucid dreamers were able to demonstrate to researchers that they were consciously aware of being in a dream state (again, primarily using eye movement signals). Additionally, techniques were developed which have been experimentally proven to enhance the likelihood of achieving this state. Research on techniques and effects of lucid dreaming continues at a number of universities and other centers, including LaBerge's Lucidity Institute. # Research and clinical applications ## Neurobiological model Neuroscientist J. Allan Hobson has hypothesized as to what might be occurring in the brain while lucid. The first step to lucid dreaming is recognizing that one is dreaming. This recognition might occur in the dorsolateral prefrontal cortex, which is one of the few areas deactivated during REM sleep and where working memory occurs. Once this area is activated and the recognition of dreaming occurs, the dreamer must be cautious to let the dream delusions continue but be conscious enough to recognize them. This process might be seen as the balance between reason and emotion. While maintaining this balance, the amygdala and parahippocampal cortex might be less intensely activated. To continue the intensity of the dream hallucinations, it is expected the pons and the parieto-occipital junction stay active. To verify this hypothesis, it would be necessary to observe the brain during lucid dreaming using a method such as a PET scan, which captures a snapshot of the blood flow to the brain. No such experiment has yet been performed. ## Treatment for nightmares People who suffer from nightmares would benefit from the ability to be aware they are dreaming. A pilot study was performed in 2006 that showed that lucid dreaming treatment was successful in reducing nightmare frequency. This treatment consisted of exposure to the idea, mastery of the technique, and lucidity exercises. It was not clear what aspects of the treatment were responsible for the success of overcoming nightmares, though the treatment as a whole was successful. Australian psychologist, Milan Colic, has explored the application of principles from narrative therapy with clients' lucid dreams to reduce the impact not only of nightmares during sleep, but also depression, self-mutilation, and other problems in waking life. Colic found that clients' preferred direction for their lives, as identified during therapeutic conversations, could lessen the distressing content of dreams, while understandings about life - and even characters - from lucid dreams could be invoked in 'real' life with marked therapeutic benefits. ## Perception of time while lucid dreaming The rate that time passes while lucid dreaming has been shown to be about the same as while waking. In 1985, LaBerge performed a pilot study where lucid dreamers counted out ten seconds while dreaming, signaling the end of counting with a pre-arranged eye signal measured with electrooculogram recording. LaBerge's results were confirmed by German researchers in 2004. The German study, by D. Erlacher and M. Schredl, also studied motor activity and found that deep knee bends took 44% longer to perform while lucid dreaming. ## Near-death and out-of-body experiences In a study of fourteen lucid dreamers performed in 1991, people who perform wake-initiated lucid dreams (WILD) reported experiences consistent with aspects of out-of-body experiences such as floating above their beds and the feeling of leaving their bodies. Due to the phenomenological overlap between lucid dreams, near death experiences, and out-of-body experiences, researchers say they believe a protocol could be developed to induce a lucid dream similar to a near-death experience in the laboratory. # Cultural history Even though it has only come to the attention of the general public in the last few decades, lucid dreaming is not a modern discovery. - A very early example of lucid dreaming is in a letter written by St. Augustine of Hippo in 415 AD. - As early as the eighth century, Tibetan Buddhists were practicing a form of yoga supposed to maintain full waking consciousness while in the dream state. This system is extensively discussed and explained in the book Dream Yoga and the Practice of Natural Light. One of the important messages of the book is the distinction between the Dzogchen meditation of Awareness and Dream Yoga. The Dzogchen Awareness meditation has also been referred to by the terms Rigpa Awareness, Contemplation, and Presence. Awareness during the sleep and dream states is associated with the Dzogchen practice of natural light. This practice only causes lucid dreams as a byproduct—in contrast to Dream yoga which is explicitly aimed at lucid dreaming. According to Buddhist teachers, the experience of lucidity helps us to understand the unreality of phenomena, which would otherwise be overwhelming during dream or the death experience. - An early recorded lucid dreamer was the philosopher and physician Sir Thomas Browne (1605–1682). Browne was fascinated by the world of dreams and stated of his own ability to lucid dream in his Religio Medici: "... yet in one dream I can compose a whole Comedy, behold the action, apprehend the jests and laugh my self awake at the conceits thereof;" - Marquis d'Hervey de Saint-Denys was probably the first person to argue that it is possible for anyone to learn to dream consciously. In 1867, he published his book Les Reves et les Moyens de Les Diriger; Observations Pratiques (Dreams and How to Guide them; Practical Observations), in which he documented more than twenty years of his own research into dreams. - The term lucid dreaming was coined by Dutch author and psychiatrist Frederik van Eeden in his 1913 article "A Study of Dreams". This book was highly anecdotal and not embraced by the scientific community. Some consider this a misnomer because it means much more than just "clear or vivid" dreaming. The alternative term conscious dreaming avoids this confusion. However, the term lucid was used by van Eeden in its sense of "having insight", as in the phrase a lucid interval applied to someone in temporary remission from a psychosis, rather than as a reference to the perceptual quality of the experience which may or may not be clear and vivid. - In the 1950s, the Senoi hunter-gatherers of Malaysia were reported to make extensive use of lucid dreaming to ensure mental health, although later studies refuted these claims. # Induction methods Many people report having experienced a lucid dream during their lives, often in childhood. Children seem to have lucid dreams more easily than adults. Although lucid dreaming is a conditioned skill, achieving lucid dreams on a regular basis can be difficult and is uncommon, even with training. Over time, several techniques have been developed to achieve a lucid dreaming state intentionally. The following are common factors that influence lucid dreaming and techniques that people use to help achieve a lucid dream: ### Dream recall Dream recall is simply the ability to remember dreams. Good dream recall is often described as the first step towards lucid dreaming. Better recall increases awareness of dreams in general; with limited dream recall, any lucid dreams one has can be forgotten entirely. The main technique used to improve dream recall is to keep a dream journal, writing down any dreams remembered the moment one awakes. An audio recorder can also be very helpful. It is important to record the dreams as quickly as possible as there is a strong tendency to forget what one has dreamt. It is suggested that for best recall, the waking dreamer should keep eyes closed while trying to remember the dream, and that one's dream journal be recorded in the present tense. Describing an experience as if presently in it can help the writer to recall more accurately the events of their dream. Dream recall can also be improved by staying still after waking up. This may have something to do with REM atonia (the condition of REM sleep in which the motor neurons are not stimulated and thus the body's muscles do not move). If one purposely prevents motor neurons from firing immediately after waking from a dream, recalling said dream becomes easier. Similarly, if the dreamer changes positions in the night, they may be able to recall certain events of their dream by testing different sleeping positions. ### Mnemonic induction of lucid dreams (MILD) The MILD technique is a common technique developed by Dr. Stephen LaBerge used to induce a lucid dream at will by setting an intention, while falling asleep, to remember to recognize that one is dreaming or to remember to look for dream signs when one is in a dream. ### Wake-back-to-bed (WBTB) The wake-back-to-bed technique is often the easiest way to encourage a lucid dream. The method involves going to sleep tired and waking up five to six hours later. Then, focusing all thoughts on lucid dreaming, staying awake for an hour and going back to sleep while practicing the MILD method. A 60% success rate has been shown in research using this technique. This is because the REM cycles get longer as the night goes on, and this technique takes advantage of the best REM cycle of the night. Because this REM cycle is longer and deeper, gaining lucidity during this time may result in a lengthier lucid dream. ### Cycle adjustment technique (CAT) The cycle adjustment technique, developed by Daniel Love, is an effective way to induce lucid dreaming. It involves adjusting one's sleep cycle to encourage awareness during the latter part of the sleep. First, the person wakes up 90 minutes before normal wake time until their sleep cycle begins to adjust. After this, the normal wake times and early wake times alternate. On the days with the normal wake times, the body is ready to wake up, and this increases alertness, making lucidity more likely. ### Wake-initiation of lucid dreams (WILD) The wake-initiated lucid dream "occurs when the sleeper enters REM sleep with unbroken self-awareness directly from the waking state". There are many techniques aimed at entering a WILD. The key to these techniques is recognizing the hypnagogic stage, which is within the border of being awake and being asleep. If a person is successful in staying aware while this stage occurs, he or she will eventually enter the dream state while being fully aware that it is a dream. There are key times at which this state is best entered; while success at normal bedtime after having been awake all day is very difficult, it is relatively easy after sleeping for 3–7 hours or in the afternoon during a nap. Techniques for inducing WILDs abound. Dreamers may count, envision themselves climbing or descending stairs, chant to themselves, control their breathing, count their breaths to keep their thoughts from drifting, concentrate on relaxing their body from their toes to their head, or allow images to flow through their "mind's eye" and envision themselves jumping into the image to maintain concentration and keep their mind awake, while still being calm enough to let their body sleep. During the actual transition into the dream state, one is likely to experience sleep paralysis, including rapid vibrations, a sequence of loud sounds and a feeling of twirling into another state of body awareness, "to drift off into another dimension". ### Induction devices Lucid dream induction is possible by the use of a physical device. The general principle works by taking advantage of the natural phenomenon of incorporating external stimuli into one's dreams. Usually a device is worn while sleeping that can detect when the sleeper enters a REM phase and triggers a noise and/or flashing lights with the goal of these stimuli being incorporated into the dreamer's dream. For example flashing lights might be translated to a car's headlights in a dream. A well-known dream-induction device is the NovaDreamer, designed in 1993 by experienced lucid dreamer Craig Webb, now an international speaker/trainer and executive director of The DREAMS Foundation. The NovaDreamer has been discontinued as of 2006. However, a newer version is being worked on, but as of now is not available. The REM Dreamer is a cheaper and more widely available version of the NovaDreamer. It has one motion sensor in the right eye that is best at recognizing horizontal movement of the eyes. When it picks up the eye’s movement it goes through a series of flashing LED lights that filter through into the person’s dream and triggers lucidity. Combining this with MILD can be incredibly effective. ### Additional techniques - Reality tests (as below) practiced in waking life can lead to a test taking place within a dream, leading to the realisation that one is dreaming. - Meditation and involvement in a conscious focusing on activities can strengthen the ability to experience lucid dreams by making the person more susceptible to noticing small discrepancies of their surroundings. - There is good reason to believe hypnotic suggestion may help one achieve lucidity. Michael Katz referenced using simple hypnotic induction for the purpose of initiating lucid dreams in his introduction to the first edition of the book Dream Yoga and the Practice of Natural Light. From the early 1980s, he went on to use this "guided nap" technique during dream yoga and lucid dream training. He conducts training internationally and maintains an archive of examples. # Reality testing Reality testing (or reality checking) is a common method used by people to determine whether or not they are dreaming. It involves performing an action with results that will be different if the tester is dreaming. By practicing these tests during waking life, one may eventually decide to perform such a test while dreaming, which may fail and let the dreamer realize that they are dreaming. Common reality tests include: - The nose reality check: Pinch your nose and if you are able to breathe, it's a dream - Try to stick your finger through the palm of your hand - Looking at one's digital watch (remembering the time), looking away, and looking back. As with text, the time will probably have changed randomly and radically at the second glance or contain strange letters and characters. (Analog watches do not usually change in dreams, while digital watches have great tendency to do so.) - Flipping a light switch. Light levels rarely change as a result of the switch flipping in dreams. - Looking into a mirror; in dreams, reflections from a mirror often appear to be blurred, distorted or incorrect. - Looking at the ground beneath one's feet or at one's hands. If one does this within a dream the difference in appearance of the ground or one's hands from the normal waking state is often enough to alert the conscious to the dream state. - Reading text. In a dream, the text in a book may change radically, even while reading. An inability to see the same passage twice is a good indication of a dream. - Try to turn on a fan, or go somewhere cold; in dreams, people rarely feel wind. - Try jumping into a lake, bathtub, or any other source of water. If you can breathe, it is a dream. ## Dream signs Another form of reality testing involves identifying one's dream signs, clues that one is dreaming. Dream signs are often categorized as follows: - Action — The dreamer, another dream character, or a thing does something unusual or impossible in waking life, such as being able to fly, or noticing photographs in a magazine or newspaper becoming three-dimensional with full movement. - Powerlessness — There may typically be a sensational loss of bodily strength. - Context — The place or situation in the dream is strange and includes fictional characters or places. - Form — The dreamer, another character, or an object changes shape, is oddly formed, or transforms. This may include the presence of unusual clothing or hair, or a third person view of the dreamer. - Awareness — A peculiar thought, a strong emotion, an unusual sensation, or an altered perception. In some cases when moving one's head from side to side, one may notice a strange stuttering or 'strobing' of the image. - Cohesion — Sometimes the dreamer may seem to teleport to another location in a dream, without a noticeable transition. # Supplements Several drugs have been shown to improve the probability of a lucid dream occurring and/or increase the length of such a dream: - Vitamin B6 can increase dream vividness when taken with tryptophan. This is due to the role this vitamin plays in the conversion of tryptophan to serotonin. # Prolonging lucid dreams One problem faced by people wishing to lucid dream is awakening prematurely. This premature awakening can be frustrating after investing considerable time into achieving lucidity in the first place. Stephen LaBerge proposed two ways to prolong a lucid dream. The first technique involves spinning one's dream body. He proposed that when spinning, the dreamer is engaging parts of the brain that may also be involved in REM activity, helping to prolong REM sleep. The second technique is rubbing one's hands. This technique is intended to engage the dreamer's brain in producing the sensation of rubbing hands, preventing the sensation of lying in bed from creeping into awareness. LaBerge tested his hypothesis by asking 34 volunteers to either spin, rub their hands, or do nothing. Results showed 90% of dreams were prolonged by hand rubbing and 96% prolonged by spinning. Only 33% of lucid dreams were prolonged with taking no action. Once the initial barrier of lucidity is broken, the dreamer’s next obstacle is the excitement of being conscious within a dream. It is key that the dreamer immediately relaxes upon becoming lucid. There are many methods that work, but in general saturating any of the senses with stimuli from the dream is important. Vision is usually the first sense to fade away, with touch commonly being the last. If the dream starts to fade, you can grab a hold of anything close by, making sure to feel the tactile sensation. Other techniques include shouting in a loud and clear voice, “INCREASE LUCIDITY!” inside the dream. People are often reluctant to do this, but it significantly stabilizes the dream and increases its vividness. The well-known author, Carlos Castaneda, suggests that the dreamer touch their tongue to the roof of their mouth, an action that greatly increases the realness of the dream. # Other associated phenomena ## Rapid eye movement (REM) When a person is dreaming, the eyes move rapidly. Scientific research has found that these eye movements correspond to the direction in which the dreamer is "looking" in his/her dreamscape; this has enabled trained lucid dreamers to communicate whilst dreaming to researchers by using eye movement signals. ## False awakening In a false awakening, one suddenly dreams of having been awakened. Commonly in a false awakening, the room is similar to the room in which the person fell asleep. If the person was lucid, they often believe that they are no longer dreaming and may start exiting the room and so forth. This can be a nemesis in the art of lucid dreaming, because it usually causes people to give up their awareness of being in a dream, but it can also cause someone to become lucid if the person does a reality check whenever he/she awakens. People who keep a dream journal and write down their dreams upon awakening sometimes report having to write down the same dream multiple times because of this phenomenon. It has also been known to cause bedwetting as one may dream that they have awoken to go to the restroom, but in reality are still dreaming. False awakenings can be a great vehicle toward lucidity. The makers of induction devices such as the NovaDreamer and the REM Dreamer recommend doing a reality check every time you awake so that when a false awakening occurs you will become lucid. People using these devices have most of their lucid dreams triggered through reality checks upon awakening. ## Sleep paralysis During REM sleep the body is paralyzed by a mechanism in the brain in order to prevent the movements, which occur in the dream, from causing the physical body to move. However, it is possible for this mechanism to be triggered before, during, or after normal sleep while the brain awakens. This can lead to a state where a person is lying in his or her bed and he or she feels paralyzed. Hypnagogic hallucination may occur in this state, especially auditory ones. Effects of sleep paralysis include heaviness or inability to move the muscles, rushing or pulsating noises, and brief hypnogogic imagery. Experiencing sleep paralysis is a necessary part of WILD, in which the dreamer essentially detaches his "dream" body from the paralyzed one. ## Out-of-body experience An out-of-body experience (OBE or sometimes OOBE) is an experience that typically involves a sensation of floating outside of one's body and, in some cases, perceiving one's physical body from a place outside one's body (autoscopy). About one in ten people has had an out-of-body experience at some time in their lives. Scientists know little about the phenomenon. # Why we are not always lucid in dreams Puzzling to many people, given the frequent bizarreness, illogic and dislocation of dreams, is why dreamers are not lucid all of the time. How can our dreaming selves accept as real so many settings, images and events that in waking life, we assume, would immediately jolt us into disbelief? The answer to this has been approached in three categories of investigation. - Depth psychology: the thrust of personality and psychotherapeutic approaches to this issue suggest that the unconscious “dream-work” is repressing or inhibiting critical evaluation of the dream in order to perform its salutary function. “Belief” in the dream symbols and experience is required for healing, personality integration or catharsis to take place. Lucidity can only arise if a person is relatively free of un-reconciled conflicts which form barriers. - Physiology: “seeing is believing” to the brain during any mental state. Even waking consciousness is liable to accept discontinuous or illogical experience as real if presented as such to the brain. Dream consciousness is similar to that of a hallucinating awake subject. Dream or hallucinatory images triggered by the brain stem are considered to be real, even if fantastic. The impulse to accept the evident is so strong the dreamer will often invent a memory or story to cover up an incongruous or unrealistic event in the dream. “That man has two heads!” is usually followed not with “I must be dreaming!” but with “Yes, I read in the paper about these famous Siamese twins.” - Developmental psychology: this approach suggests that the dream world is not really “unnatural” after all, since we were all dreaming as children long before we learned of all the physical and social laws that train the mind to a “reality.” Fluid imaginative constructions may have preceded the more rigid, logical waking rules and continue on as a normative lifeworld alongside the acquired, waking lifeworld. The dreaming “I” basically accepts its world as natural as does the waking “I” its world. Dreaming and waking consciousness differ only in their respective level of expectations, the waking “I” expecting a stricter set of “reality rules” as the child matures. The experience of “waking up” normally establishes the boundary between the two lifeworlds and cues the consciousness to adapt to waking “I” expectations. At times, however, this cue is false—a false awakening. Here the waking “I” (with its level of expectations) is activated even though the experience is still hallucinatory. Incongruous images or illogical events during this type of dream can result in lucidity as the dream is being judged by waking “standards.” # Lucid Dreaming in Popular Film - Waking Life (2002) - The Good Night (2007) - Vanilla Sky (2001) - The Science of Sleep (2006)	Lucid Dream Template:Wikibooks A lucid dream, also known as a conscious dream, is a dream in which the person is aware that he or she is dreaming while the dream is in progress. When the dreamer is lucid, he or she can actively participate in the dream environment without any of the inhibitions or limitations that otherwise would feel natural to persons who incorrectly believe they are in the "real" waking world. Lucid dreams can be extremely real and vivid depending on a person's level of self-awareness during the lucid dream.[1] A lucid dream can begin in one of two ways. A dream-initiated lucid dream (DILD) starts as a normal dream, and the dreamer eventually concludes that he or she is dreaming, while a wake-initiated lucid dream (WILD) occurs when the dreamer goes from a normal waking state directly into a dream state with no apparent lapse in consciousness. Lucid dreaming has been researched scientifically, and its existence is well established.[2][3] Scientists such as Allan Hobson, with his neurophysiological approach to dream research, have helped to push the understanding of lucid dreaming into a less speculative realm. # Scientific history The first book on lucid dreams to recognize their scientific potential was Celia Green's 1968 study Lucid Dreams[4]. Reviewing the past literature, as well as new data from subjects of her own, Green analyzed the main characteristics of such dreams and concluded that they were a category of experience quite distinct from ordinary dreams. She predicted that they would turn out to be associated with rapid eye movement sleep (REM sleep). Green was also the first to link lucid dreams to the phenomenon of false awakenings. Philosopher Norman Malcolm's 1959 text Dreaming argued against the possibility of checking the accuracy of dream reports. [5] However, the realization that eye movements performed in dreams affected the dreamer's physical eyes provided a way to prove that actions agreed upon during waking life could be recalled and performed once lucid in a dream. The first evidence of this type was produced in the late 1970s by British parapsychologist Keith Hearne. A volunteer named Alan Worsley used eye movement to signal the onset of lucidity, which were recorded by a polysomnograph machine. Hearne's results were not widely distributed. The first peer-reviewed article was published some years later by Stephen LaBerge at Stanford University, who had independently developed a similar technique as part of his doctoral dissertation. [6] During the 1980s, further scientific evidence to confirm the existence of lucid dreaming was produced as lucid dreamers were able to demonstrate to researchers that they were consciously aware of being in a dream state (again, primarily using eye movement signals).[3] Additionally, techniques were developed which have been experimentally proven to enhance the likelihood of achieving this state.[7] Research on techniques and effects of lucid dreaming continues at a number of universities and other centers, including LaBerge's Lucidity Institute. # Research and clinical applications ## Neurobiological model Neuroscientist J. Allan Hobson has hypothesized as to what might be occurring in the brain while lucid. The first step to lucid dreaming is recognizing that one is dreaming. This recognition might occur in the dorsolateral prefrontal cortex, which is one of the few areas deactivated during REM sleep and where working memory occurs. Once this area is activated and the recognition of dreaming occurs, the dreamer must be cautious to let the dream delusions continue but be conscious enough to recognize them. This process might be seen as the balance between reason and emotion. While maintaining this balance, the amygdala and parahippocampal cortex might be less intensely activated.[8] To continue the intensity of the dream hallucinations, it is expected the pons and the parieto-occipital junction stay active. To verify this hypothesis, it would be necessary to observe the brain during lucid dreaming using a method such as a PET scan, which captures a snapshot of the blood flow to the brain. No such experiment has yet been performed.[9] ## Treatment for nightmares People who suffer from nightmares would benefit from the ability to be aware they are dreaming. A pilot study was performed in 2006 that showed that lucid dreaming treatment was successful in reducing nightmare frequency. This treatment consisted of exposure to the idea, mastery of the technique, and lucidity exercises. It was not clear what aspects of the treatment were responsible for the success of overcoming nightmares, though the treatment as a whole was successful.[10] Australian psychologist, Milan Colic, has explored the application of principles from narrative therapy with clients' lucid dreams to reduce the impact not only of nightmares during sleep, but also depression, self-mutilation, and other problems in waking life. Colic found that clients' preferred direction for their lives, as identified during therapeutic conversations, could lessen the distressing content of dreams, while understandings about life - and even characters - from lucid dreams could be invoked in 'real' life with marked therapeutic benefits.[11] ## Perception of time while lucid dreaming The rate that time passes while lucid dreaming has been shown to be about the same as while waking. In 1985, LaBerge performed a pilot study where lucid dreamers counted out ten seconds while dreaming, signaling the end of counting with a pre-arranged eye signal measured with electrooculogram recording.[12] LaBerge's results were confirmed by German researchers in 2004. The German study, by D. Erlacher and M. Schredl, also studied motor activity and found that deep knee bends took 44% longer to perform while lucid dreaming.[13] ## Near-death and out-of-body experiences In a study of fourteen lucid dreamers performed in 1991, people who perform wake-initiated lucid dreams (WILD) reported experiences consistent with aspects of out-of-body experiences such as floating above their beds and the feeling of leaving their bodies.[14] Due to the phenomenological overlap between lucid dreams, near death experiences, and out-of-body experiences, researchers say they believe a protocol could be developed to induce a lucid dream similar to a near-death experience in the laboratory.[15] # Cultural history Even though it has only come to the attention of the general public in the last few decades, lucid dreaming is not a modern discovery. - A very early example of lucid dreaming is in a letter written by St. Augustine of Hippo in 415 AD.[16] - As early as the eighth century, Tibetan Buddhists were practicing a form of yoga supposed to maintain full waking consciousness while in the dream state.[17] This system is extensively discussed and explained in the book Dream Yoga and the Practice of Natural Light.[18] One of the important messages of the book is the distinction between the Dzogchen meditation of Awareness and Dream Yoga. The Dzogchen Awareness meditation has also been referred to by the terms Rigpa Awareness, Contemplation, and Presence. Awareness during the sleep and dream states is associated with the Dzogchen practice of natural light. This practice only causes lucid dreams as a byproduct—in contrast to Dream yoga which is explicitly aimed at lucid dreaming. According to Buddhist teachers, the experience of lucidity helps us to understand the unreality of phenomena, which would otherwise be overwhelming during dream or the death experience. - An early recorded lucid dreamer was the philosopher and physician Sir Thomas Browne (1605–1682). Browne was fascinated by the world of dreams and stated of his own ability to lucid dream in his Religio Medici: "... yet in one dream I can compose a whole Comedy, behold the action, apprehend the jests and laugh my self awake at the conceits thereof;"[19] - Marquis d'Hervey de Saint-Denys was probably the first person to argue that it is possible for anyone to learn to dream consciously. In 1867, he published his book Les Reves et les Moyens de Les Diriger; Observations Pratiques (Dreams and How to Guide them; Practical Observations), in which he documented more than twenty years of his own research into dreams. - The term lucid dreaming was coined by Dutch author and psychiatrist Frederik van Eeden in his 1913 article "A Study of Dreams".[20] This book was highly anecdotal and not embraced by the scientific community. Some consider this a misnomer because it means much more than just "clear or vivid" dreaming.[21] The alternative term conscious dreaming avoids this confusion. However, the term lucid was used by van Eeden in its sense of "having insight", as in the phrase a lucid interval applied to someone in temporary remission from a psychosis, rather than as a reference to the perceptual quality of the experience which may or may not be clear and vivid. - In the 1950s, the Senoi hunter-gatherers of Malaysia were reported to make extensive use of lucid dreaming to ensure mental health, although later studies refuted these claims.[22] # Induction methods Many people report having experienced a lucid dream during their lives, often in childhood. Children seem to have lucid dreams more easily than adults. Although lucid dreaming is a conditioned skill,[23] achieving lucid dreams on a regular basis can be difficult and is uncommon[citation needed], even with training. Over time, several techniques have been developed to achieve a lucid dreaming state intentionally. The following are common factors that influence lucid dreaming and techniques that people use to help achieve a lucid dream: ### Dream recall Dream recall is simply the ability to remember dreams. Good dream recall is often described as the first step towards lucid dreaming. Better recall increases awareness of dreams in general; with limited dream recall, any lucid dreams one has can be forgotten entirely. The main technique used to improve dream recall is to keep a dream journal, writing down any dreams remembered the moment one awakes. An audio recorder can also be very helpful[24]. It is important to record the dreams as quickly as possible as there is a strong tendency to forget what one has dreamt.[25] It is suggested that for best recall, the waking dreamer should keep eyes closed while trying to remember the dream, and that one's dream journal be recorded in the present tense[24]. Describing an experience as if presently in it can help the writer to recall more accurately the events of their dream.[citation needed] Dream recall can also be improved by staying still after waking up.[25] This may have something to do with REM atonia (the condition of REM sleep in which the motor neurons are not stimulated and thus the body's muscles do not move). If one purposely prevents motor neurons from firing immediately after waking from a dream, recalling said dream becomes easier. Similarly, if the dreamer changes positions in the night, they may be able to recall certain events of their dream by testing different sleeping positions.[citation needed] ### Mnemonic induction of lucid dreams (MILD) The MILD technique is a common technique developed by Dr. Stephen LaBerge used to induce a lucid dream at will by setting an intention, while falling asleep, to remember to recognize that one is dreaming or to remember to look for dream signs when one is in a dream. ### Wake-back-to-bed (WBTB) The wake-back-to-bed technique is often the easiest way to encourage a lucid dream. The method involves going to sleep tired and waking up five to six hours later. Then, focusing all thoughts on lucid dreaming, staying awake for an hour and going back to sleep while practicing the MILD method. A 60% success rate has been shown in research using this technique.[26] This is because the REM cycles get longer as the night goes on, and this technique takes advantage of the best REM cycle of the night. Because this REM cycle is longer and deeper, gaining lucidity during this time may result in a lengthier lucid dream.[26] ### Cycle adjustment technique (CAT) The cycle adjustment technique, developed by Daniel Love, is an effective way to induce lucid dreaming. It involves adjusting one's sleep cycle to encourage awareness during the latter part of the sleep. First, the person wakes up 90 minutes before normal wake time until their sleep cycle begins to adjust. After this, the normal wake times and early wake times alternate. On the days with the normal wake times, the body is ready to wake up, and this increases alertness, making lucidity more likely. ### Wake-initiation of lucid dreams (WILD) The wake-initiated lucid dream "occurs when the sleeper enters REM sleep with unbroken self-awareness directly from the waking state".[27] There are many techniques aimed at entering a WILD. The key to these techniques is recognizing the hypnagogic stage, which is within the border of being awake and being asleep. If a person is successful in staying aware while this stage occurs, he or she will eventually enter the dream state while being fully aware that it is a dream. There are key times at which this state is best entered; while success at normal bedtime after having been awake all day is very difficult, it is relatively easy after sleeping for 3–7 hours or in the afternoon during a nap. Techniques for inducing WILDs abound. Dreamers may count, envision themselves climbing or descending stairs, chant to themselves, control their breathing, count their breaths to keep their thoughts from drifting, concentrate on relaxing their body from their toes to their head, or allow images to flow through their "mind's eye" and envision themselves jumping into the image to maintain concentration and keep their mind awake, while still being calm enough to let their body sleep. During the actual transition into the dream state, one is likely to experience sleep paralysis, including rapid vibrations,[14] a sequence of loud sounds and a feeling of twirling into another state of body awareness, "to drift off into another dimension". ### Induction devices Lucid dream induction is possible by the use of a physical device. The general principle works by taking advantage of the natural phenomenon of incorporating external stimuli into one's dreams. Usually a device is worn while sleeping that can detect when the sleeper enters a REM phase and triggers a noise and/or flashing lights with the goal of these stimuli being incorporated into the dreamer's dream. For example flashing lights might be translated to a car's headlights in a dream. A well-known dream-induction device is the NovaDreamer, designed in 1993 by experienced lucid dreamer Craig Webb, now an international speaker/trainer and executive director of The DREAMS Foundation[28]. The NovaDreamer has been discontinued as of 2006. However, a newer version is being worked on, but as of now is not available.[29] The REM Dreamer is a cheaper and more widely available version of the NovaDreamer. It has one motion sensor in the right eye that is best at recognizing horizontal movement of the eyes. When it picks up the eye’s movement it goes through a series of flashing LED lights that filter through into the person’s dream and triggers lucidity. Combining this with MILD can be incredibly effective.[30] ### Additional techniques - Reality tests (as below) practiced in waking life can lead to a test taking place within a dream, leading to the realisation that one is dreaming. - Meditation and involvement in a conscious focusing on activities can strengthen the ability to experience lucid dreams by making the person more susceptible to noticing small discrepancies of their surroundings.[citation needed] - There is good reason to believe hypnotic suggestion may help one achieve lucidity.[31] Michael Katz referenced using simple hypnotic induction for the purpose of initiating lucid dreams in his introduction to the first edition of the book Dream Yoga and the Practice of Natural Light. From the early 1980s, he went on to use this "guided nap" technique during dream yoga and lucid dream training. He conducts training internationally and maintains an archive of examples.[32] # Reality testing Reality testing (or reality checking) is a common method used by people to determine whether or not they are dreaming. It involves performing an action with results that will be different if the tester is dreaming. By practicing these tests during waking life, one may eventually decide to perform such a test while dreaming, which may fail and let the dreamer realize that they are dreaming. Common reality tests include: - The nose reality check: Pinch your nose and if you are able to breathe, it's a dream[33] - Try to stick your finger through the palm of your hand[34] - Looking at one's digital watch (remembering the time), looking away, and looking back. As with text, the time will probably have changed randomly and radically at the second glance or contain strange letters and characters. (Analog watches do not usually change in dreams, while digital watches have great tendency to do so.)[35] - Flipping a light switch. Light levels rarely change as a result of the switch flipping in dreams.[36] - Looking into a mirror; in dreams, reflections from a mirror often appear to be blurred, distorted or incorrect.[36] - Looking at the ground beneath one's feet or at one's hands. If one does this within a dream the difference in appearance of the ground or one's hands from the normal waking state is often enough to alert the conscious to the dream state.[37] - Reading text. In a dream, the text in a book may change radically, even while reading. An inability to see the same passage twice is a good indication of a dream. - Try to turn on a fan, or go somewhere cold; in dreams, people rarely feel wind. - Try jumping into a lake, bathtub, or any other source of water. If you can breathe, it is a dream. ## Dream signs Another form of reality testing involves identifying one's dream signs, clues that one is dreaming. Dream signs are often categorized as follows: - Action — The dreamer, another dream character, or a thing does something unusual or impossible in waking life, such as being able to fly, or noticing photographs in a magazine or newspaper becoming three-dimensional with full movement. - Powerlessness — There may typically be a sensational loss of bodily strength. - Context — The place or situation in the dream is strange and includes fictional characters or places. - Form — The dreamer, another character, or an object changes shape, is oddly formed, or transforms. This may include the presence of unusual clothing or hair, or a third person view of the dreamer. - Awareness — A peculiar thought, a strong emotion, an unusual sensation, or an altered perception. In some cases when moving one's head from side to side, one may notice a strange stuttering or 'strobing' of the image. - Cohesion — Sometimes the dreamer may seem to teleport to another location in a dream, without a noticeable transition. # Supplements Several drugs have been shown to improve the probability of a lucid dream occurring and/or increase the length of such a dream: - Vitamin B6 can increase dream vividness when taken with tryptophan. This is due to the role this vitamin plays in the conversion of tryptophan to serotonin.[38] # Prolonging lucid dreams One problem faced by people wishing to lucid dream is awakening prematurely. This premature awakening can be frustrating after investing considerable time into achieving lucidity in the first place. Stephen LaBerge proposed two ways to prolong a lucid dream. The first technique involves spinning one's dream body. He proposed that when spinning, the dreamer is engaging parts of the brain that may also be involved in REM activity, helping to prolong REM sleep. The second technique is rubbing one's hands. This technique is intended to engage the dreamer's brain in producing the sensation of rubbing hands, preventing the sensation of lying in bed from creeping into awareness. LaBerge tested his hypothesis by asking 34 volunteers to either spin, rub their hands, or do nothing. Results showed 90% of dreams were prolonged by hand rubbing and 96% prolonged by spinning. Only 33% of lucid dreams were prolonged with taking no action.[39] Once the initial barrier of lucidity is broken, the dreamer’s next obstacle is the excitement of being conscious within a dream. It is key that the dreamer immediately relaxes upon becoming lucid. There are many methods that work, but in general saturating any of the senses with stimuli from the dream is important. Vision is usually the first sense to fade away, with touch commonly being the last. If the dream starts to fade, you can grab a hold of anything close by, making sure to feel the tactile sensation. Other techniques include shouting in a loud and clear voice, “INCREASE LUCIDITY!” inside the dream. People are often reluctant to do this, but it significantly stabilizes the dream and increases its vividness. The well-known author, Carlos Castaneda, suggests that the dreamer touch their tongue to the roof of their mouth, an action that greatly increases the realness of the dream.[40] # Other associated phenomena ## Rapid eye movement (REM) When a person is dreaming, the eyes move rapidly. Scientific research has found that these eye movements correspond to the direction in which the dreamer is "looking" in his/her dreamscape; this has enabled trained lucid dreamers to communicate whilst dreaming to researchers by using eye movement signals.[12] ## False awakening In a false awakening, one suddenly dreams of having been awakened. Commonly in a false awakening, the room is similar to the room in which the person fell asleep. If the person was lucid, they often believe that they are no longer dreaming and may start exiting the room and so forth. This can be a nemesis in the art of lucid dreaming, because it usually causes people to give up their awareness of being in a dream, but it can also cause someone to become lucid if the person does a reality check whenever he/she awakens. People who keep a dream journal and write down their dreams upon awakening sometimes report having to write down the same dream multiple times because of this phenomenon. It has also been known to cause bedwetting as one may dream that they have awoken to go to the restroom, but in reality are still dreaming. False awakenings can be a great vehicle toward lucidity. The makers of induction devices such as the NovaDreamer and the REM Dreamer recommend doing a reality check every time you awake so that when a false awakening occurs you will become lucid. People using these devices have most of their lucid dreams triggered through reality checks upon awakening.[41] ## Sleep paralysis During REM sleep the body is paralyzed by a mechanism in the brain in order to prevent the movements, which occur in the dream, from causing the physical body to move. However, it is possible for this mechanism to be triggered before, during, or after normal sleep while the brain awakens. This can lead to a state where a person is lying in his or her bed and he or she feels paralyzed. Hypnagogic hallucination may occur in this state, especially auditory ones. Effects of sleep paralysis include heaviness or inability to move the muscles, rushing or pulsating noises, and brief hypnogogic imagery. Experiencing sleep paralysis is a necessary part of WILD, in which the dreamer essentially detaches his "dream" body from the paralyzed one. ## Out-of-body experience An out-of-body experience (OBE or sometimes OOBE) is an experience that typically involves a sensation of floating outside of one's body and, in some cases, perceiving one's physical body from a place outside one's body (autoscopy). About one in ten people has had an out-of-body experience at some time in their lives.[42] Scientists know little about the phenomenon.[43] # Why we are not always lucid in dreams Puzzling to many people, given the frequent bizarreness, illogic and dislocation of dreams, is why dreamers are not lucid all of the time. How can our dreaming selves accept as real so many settings, images and events that in waking life, we assume, would immediately jolt us into disbelief? The answer to this has been approached in three categories of investigation. - Depth psychology: the thrust of personality and psychotherapeutic approaches to this issue suggest that the unconscious “dream-work” is repressing or inhibiting critical evaluation of the dream in order to perform its salutary function. “Belief” in the dream symbols and experience is required for healing, personality integration or catharsis to take place. Lucidity can only arise if a person is relatively free of un-reconciled conflicts which form barriers.[44] - Physiology: “seeing is believing” to the brain during any mental state. Even waking consciousness is liable to accept discontinuous or illogical experience as real if presented as such to the brain. [45] Dream consciousness is similar to that of a hallucinating awake subject. Dream or hallucinatory images triggered by the brain stem are considered to be real, even if fantastic. [46] The impulse to accept the evident is so strong the dreamer will often invent a memory or story to cover up an incongruous or unrealistic event in the dream. “That man has two heads!” is usually followed not with “I must be dreaming!” but with “Yes, I read in the paper about these famous Siamese twins.” [47] - Developmental psychology: this approach suggests that the dream world is not really “unnatural” after all, since we were all dreaming as children long before we learned of all the physical and social laws that train the mind to a “reality.” Fluid imaginative constructions may have preceded the more rigid, logical waking rules and continue on as a normative lifeworld alongside the acquired, waking lifeworld. The dreaming “I” basically accepts its world as natural as does the waking “I” its world. Dreaming and waking consciousness differ only in their respective level of expectations, the waking “I” expecting a stricter set of “reality rules” as the child matures. The experience of “waking up” normally establishes the boundary between the two lifeworlds and cues the consciousness to adapt to waking “I” expectations. At times, however, this cue is false—a false awakening. Here the waking “I” (with its level of expectations) is activated even though the experience is still hallucinatory. Incongruous images or illogical events during this type of dream can result in lucidity as the dream is being judged by waking “standards.” [48] # Lucid Dreaming in Popular Film - Waking Life (2002) - The Good Night (2007) - Vanilla Sky (2001) - The Science of Sleep (2006)	https://www.wikidoc.org/index.php/Lucid_Dream
39e3e024c05fa6754fd76418163ccc73ad7c2155	wikidoc	Lucid dream	Lucid dream A lucid dream is a dream in which the person is aware that he or she is dreaming while the dream is in progress. During lucid dreams, it is often possible to exert conscious control over the dream characters and environment, as well as to perform otherwise physically impossible feats. Lucid dreams are known to be extremely real and vivid. A lucid dream can begin in one of two ways. A dream-initiated lucid dream (DILD) starts as a normal dream, and the dreamer eventually concludes that he or she is dreaming, or a wake-initiated lucid dream (WILD) occurs when the dreamer goes from a normal waking state directly into a dream state with no apparent lapse in consciousness. Lucid dreaming has been researched scientifically, and its existence is well established. Scientists such as Allan Hobson, with his neurophysiological approach to dream research, have helped to push the understanding of lucid dreaming into a less speculative realm. # Scientific history The first book on lucid dreams to recognize their scientific potential was Celia Green's 1968 study Lucid Dreams. Reviewing the past literature, as well as new data from subjects of her own, Green analyzed the main characteristics of such dreams, and concluded that they were a category of experience quite distinct from ordinary dreams. She predicted that they would turn out to be associated with REM sleep. Green was also the first to link lucid dreams to the phenomenon of false awakenings. Philosopher Norman Malcolm's 1959 text Dreaming argued against the possibility of checking the accuracy of dream reports. However, the realisation that eye movements performed in dreams affected the dreamer's physical eyes provided a way to prove that actions agreed upon during waking life could be recalled and performed once lucid in a dream. The first evidence of this type was produced in the late 1970s by British parapsychologist Keith Hearne. A volunteer named Alan Worsley used eye movement to signal the onset of lucidity, which were recorded by a polysomnograph machine. Hearne's results were not widely distributed. The first peer reviewed article was published some years later by Stephen LaBerge at Stanford University who had independently developed a similar technique as part of his doctoral dissertation. During the 1980s, further scientific evidence to confirm the existence of lucid dreaming was produced as lucid dreamers were able to demonstrate to researchers that they were consciously aware of being in a dream state (again, primarily using eye movement signals). Additionally, techniques were developed which have been experimentally proven to enhance the likelihood of achieving this state. Research on techniques and effects of lucid dreaming continues at a number of universities and other centers such as LaBerge's The Lucidity Institute. # Research and clinical applications ## Neurobiological model Neuroscientist J. Allan Hobson has hypothesized as to what might be occurring in the brain while lucid. The first step to lucid dreaming is recognizing that one is dreaming. This recognition might occur in the dorsolateral prefrontal cortex which is one of the few areas deactivated during REM sleep, and where working memory occurs. Once this area is activated and the recognition of dreaming occurs the dreamer must be cautious to let the dream delusions continue, but be conscious enough to recognize them. This process might be seen as the balance between reason and emotion. While maintaining this balance the amygdala and parahippocampal cortex might be less intensely activated. To continue the intensity of the dream hallucinations it is expected the pons and the parieto-occipital junction cortex stay active. To verify this hypothesis it would be necessary to observe the brain during lucid dreaming using a method such as a PET scan, which captures a snapshot of the blood flow to the brain. No such experiment has yet been performed. ## Treatment for nightmares People who suffer from nightmares would benefit from the ability to be aware they are dreaming. A pilot study was performed in 2006 that showed lucid dreaming treatment was successful in reducing nightmare frequency. This treatment consisted of exposure to the idea, mastery of the technique, and lucidity exercises. It was not clear what aspects of the treatment were responsible for the success of overcoming nightmares, though the treatment as a whole was successful. ## Perception of time while lucid dreaming The rate that time passes while lucid dreaming has been shown to be about the same as while waking. In 1985 LaBerge performed a pilot study where lucid dreamers counted from one to ten (one-one thousand, two-one thousand, etc.) while dreaming, signaling the end of counting with a pre-arranged eye signal measured with Electrooculogram recording. LaBerge's results were confirmed by German researchers in 2004. The German study, by Erlacher, D. & Schredl, M also studied motor activity and found that deep knee bends took 44% longer to perform while lucid dreaming. ## Near-death and out-of-body experiences In a study of 14 lucid dreamers performed in 1991, people who perform wake initiated lucid dreams (WILD) reported experiences consistent with aspects of out-of-body experiences such as floating above their beds and the feeling of leaving their bodies. Due to the phenomenological overlap between lucid dreams, near death experiences, and out of body experiences researchers say they believe a protocol could be developed to induce a lucid dream similar to a near death experience in the laboratory. # Cultural history Even though it has only come to the attention of the general public in the last few decades, lucid dreaming is not a modern discovery. - In the fifth century, a very early example of lucid dreaming is in a letter written by St. Augustine of Hippo in 415 AD. - As early as the eighth century, Tibetan Buddhists were practicing a form of yoga supposed to maintain full waking consciousness while in the dream state. This system is extensively discussed and explained in the book Dream Yoga and the Practice of Natural Light, one of the important messages of which has been the distinction between the Dzogchen meditation of Awareness and Dream Yoga or lucid dreaming. The Dzogchen Awareness meditation has also been referred to by the terms Rigpa Awareness, Contemplation, and Presence. Awareness during the sleep and dream states is associated with the Dzogchen practice of natural light, and lucid dreams may be a byproduct. In contrast, the more relative but still important experience of lucid dreaming is referred to as Dream yoga, and lucid dreaming is the goal. The lucidity experience, according to Buddhist teachers, assists in understanding the unreality of phenomena, which otherwise, during dream or the death experience, might be overwhelming. - An early recorded lucid dreamer was the philosopher and physician Sir Thomas Browne (1605–1682). Browne was fascinated by the world of dreams and stated of his own ability to lucid dream in his Religio Medici: "... yet in one dream I can compose a whole Comedy, behold the action, apprehend the jests and laugh my self awake at the conceits thereof;" - Marquis d'Hervey de Saint-Denys was probably the first person to argue that it is possible for anyone to learn to dream consciously. In 1867, he published his book Les Reves et les Moyens de Les Diriger; Observations Pratiques (Dreams and How to Guide them; Practical Observations), in which he documented more than twenty years of his own research into dreams. - The term "lucid dreaming" was coined by Dutch author and psychiatrist Frederik van Eeden in his 1913 article A Study of Dreams. This book was highly anecdotal and not embraced by the scientific community. The term itself is considered by some to be a misnomer because it means much more than just "clear or vivid" dreaming. A better term might have been "conscious dreaming". On the other hand, the term 'lucid' was used by van Eeden in its sense of 'having insight', as in the phrase 'a lucid interval' applied to someone in temporary remission from a psychosis, rather than as referring to the perceptual quality of the experience, which may or may not be clear and vivid. To that extent van Eeden's phrase may still be considered appropriate. - In the 1950s the Senoi hunter-gatherers of Malaysia were reported to make extensive use of lucid dreaming to ensure mental health, although later studies refuted these claims. # Induction methods Many people report having experienced a lucid dream during their lives, often in childhood. Children seem to have lucid dreams more easily than adults. Although lucid dreaming is a conditioned skill, achieving lucid dreams on a regular basis can be difficult and is uncommon, even with training. Over time, several techniques have been developed to achieve a lucid dreaming state intentionally. The following are common factors that influence lucid dreaming, and techniques that people use to help achieve a lucid dream: ### Dream recall Dream recall is simply the ability to remember dreams. Good dream recall is often described as the first step towards lucid dreaming. Better recall increases awareness of dreams in general; with limited dream recall any lucid dreams one has can be forgotten entirely. The main technique used to improve dream recall is to keep a dream journal, writing down any dreams remembered the moment one awakes. It is important to record the dreams as quickly as possible as there is a strong tendency to forget what one has dreamt. It is suggested that one's dream journal be recorded in the present tense. Describing an experience as if presently in it can help the writer to recall more accurately the events of their dream. Dream recall can also be improved by staying still after waking up. This may be something to do with REM atonia (the condition of REM sleep in which the motor neurons are not stimulated and thus the body's muscles do not move). If one purposely prevents motor neurons from firing immediately after waking from a dream, recalling said dream becomes easier. Similarly, if the dreamer changes positions in the night they may be able to recall certain events of their dream by testing different sleeping positions. ### Mnemonic induction of lucid dreams (MILD) The MILD technique is a common technique developed by Dr Stephen LaBerge, used to induce a lucid dream at will by setting an intention, while falling asleep, to remember to recognize that one is dreaming, or to remember to look for dream signs when one is in a dream. ### Wake-back-to-bed (WBTB) The wake-back-to-bed technique is often the easiest way to encourage a lucid dream. The method involves going to sleep tired and waking up five hours later. Then, focusing all thoughts on lucid dreaming, staying awake for an hour and going back to sleep while practicing the MILD method. A 60% success rate has been shown in research using this technique. This is because the REM cycles get longer as the night goes on, and this technique takes advantage of the best REM cycle of the night. Because this REM cycle is longer and deeper, gaining lucidity during this time may result in a more lengthy lucid dream. ### Cycle adjustment technique (CAT) The cycle adjustment technique, developed by Daniel Love, is an effective way to induce lucid dreaming. It involves adjusting one's sleep cycle to encourage awareness during the latter part of the sleep. First, the person wakes up 90 minutes before normal wake time until their sleep cycle begins to adjust. After this, the normal wake times and early wake times alternate. On the days with the normal wake times, the body is ready to wake up, and this increases alertness, making lucidity more likely. ### Wake-initiation of lucid dreams (WILD) The wake-initiated lucid dream "occurs when the sleeper enters REM sleep with unbroken self-awareness directly from the waking state". There are many techniques aimed at entering a WILD. The key to these techniques is recognizing the hypnagogic stage, which is within the border of being awake and being asleep. If a person is successful in staying aware while this stage occurs, he or she will eventually enter the dream state while being fully aware that it is a dream. There are key times at which this state is best entered; while success at night after being awake for a long time is very difficult, it is relatively easy after being awake for 15 or so minutes and in the afternoon during a nap. Techniques for inducing WILDs abound. Dreamers may count, envision themselves climbing or descending stairs, chant to themselves, explore elaborate, passive sexual fantasies, control their breathing, counting their breaths to keep their thoughts from drifting, concentrate on relaxing their body from their toes to their head, allow images to flow through their "mind's eye" and envision themselves jumping into the image, to maintain concentration and keep their mind awake, while still being calm enough to let their body sleep. During the actual transition into the dream state, one is likely to experience sleep paralysis, including rapid vibrations, a sequence of loud sounds and a feeling of twirling into another state of body awareness, "to drift off into another dimension". Also there is frequently a sensation of falling rapidly or dropping through the bed as one enters the dream state. After the transition there may be the sensation of entering a dark black room from which one can induce any dream scenario of one's choosing, simply by concentrating on it. The key to success is not to panic, especially during the transition, which can be quite sudden. ### Induction devices Lucid dream induction is possible by the use of a physical device. The general principle works by taking advantage of the natural phenomenon of incorporating external stimuli into one's dreams. Usually a device is worn while sleeping that can detect when the sleeper enters a REM phase and triggers a noise and/or flashing lights with the goal of these stimuli being incorporated into the dreamer's dream. For example flashing lights might be translated to a car's headlights in a dream. A well known dream induction device is the Nova Dreamer which has been discontinued as of 2006. However, a newer version is being worked on, but as of now is not available . A European induction device known as the Rem dreamer is still in production. ### Additional techniques - Meditation, and involvement in a conscious focusing on activities can strengthen the ability to experience lucid dreams by making the person more susceptible to noticing small discrepancies of their surroundings. - Hypnotism may help one achieve lucidity. Michael Katz first referenced using simple hypnotic induction for the purpose of initiating lucid dreams in his introduction to the first edition of the book " Dream yoga and the Practice of Natural Light". He has subsequently since the early 1980's used this "guided nap" technique during dream yoga and lucid dream trainings he conducts internationally and maintains an archive of examples. # Reality testing Reality testing (or reality checking) is a common method used by people to determine whether or not they are dreaming. It involves performing an action with results that will be different if the tester is dreaming. By practicing these tests during waking life, one may eventually decide to perform such a test while dreaming, which may fail and let the dreamer realize that they are dreaming. Common reality tests include: - Reading some text, looking away from the text, and reading it again - in a dream, the text will probably have changed. - Looking at one's watch (remembering the time), looking away, and looking back. As with the text, the time will probably have changed randomly and radically at the second glance or contain strange letters and characters. - Flipping a light switch. Light levels rarely change in dreams. - Looking into a mirror; in dreams, reflections from a mirror often appear to be blurred, distorted or incorrect. - Plugging one's nose shut, and attempting to breathe through it, or attempting to breathe underwater. It is usually possible to breathe while doing this because the tester is not actually plugging their nose in real life. - Looking at one's hands one or more times. Hands may look distorted, or grow additional fingers in a dream. - Gripping and stretching a finger. In a dream, body image can become distorted, and pulling a finger can elongate it. Also, the number of fingers can shift when stared at. - Jumping into the air. Gravity is often distorted in a dream state and floating or flying may occur. - Looking around and seeing everything blurred, as if underwater. - Being able to move through solid objects like walls. - Putting one's finger through the palm of the other hand. - Closing one eye and looking at one's nose. The dreamer may not see their nose as everyday details that usually go unnoticed in waking life are often absent during a dream. ## Dream signs Another form of reality testing involves identifying one's dream signs, clues that one is dreaming. Dream signs are often categorized as follows: - Action — The dreamer, another dream character, or a thing does something unusual or impossible in waking life, such being able to fly, or noticing photographs in a magazine or newspaper becoming three-dimensional with full movement. - Context — The place or situation in the dream is strange, and includes fictional characters or places. - Form — The dreamer, another character, or an object changes shape, is oddly formed, or transforms. This may include the presence of unusual clothing or hair, or a third person view of the dreamer. - Awareness — A peculiar thought, a strong emotion, an unusual sensation, or an altered perception. In some cases when moving one's head from side to side, one may notice a strange stuttering or 'strobing' of the image. - Cohesion — Sometimes the dreamer may seem to teleport to another location in a dream, without a noticeable transition. # Prolonging lucid dreams One problem faced by people wishing to lucid dream is awakening prematurely. This premature awakening can be especially frustrating after investing considerable time into achieving lucidity in the first place. Stephen LaBerge proposed two ways to prolong a lucid dream. The first technique involves spinning one's dream body. He proposed that when spinning, the dreamer is engaging parts of the brain that may also be involved in REM activity, helping to prolong REM. The second technique is rubbing one's hands. This technique is intended to engage the dreamer's brain in producing the sensation of rubbing hands, preventing the sensation of lying in bed from creeping into awareness. LaBerge tested his hypothesis by asking 34 volunteers to either spin, rub their hands, or do nothing. Results showed 90% of dreams were prolonged by hand rubbing and 96% prolonged by spinning. Only 33% of lucid dreams were prolonged with taking no action. # Other associated phenomena This is often a nemesis in the art of lucid dreaming because it usually causes people to give up their awareness of being in a dream, but it can also cause someone to become lucid if the person does a reality check whenever he/she awakens. People who keep a dream journal and write down their dreams upon awakening sometimes report having to write down the same dream multiple times because of this phenomenon. It has also been known to cause bedwetting as one may dream that they have awoken to go to the restroom, but in reality are still dreaming.	Lucid dream Template:Wikibooks Editor-In-Chief: C. Michael Gibson, M.S., M.D. [2] A lucid dream is a dream in which the person is aware that he or she is dreaming while the dream is in progress. During lucid dreams, it is often possible to exert conscious control over the dream characters and environment, as well as to perform otherwise physically impossible feats. Lucid dreams are known to be extremely real and vivid. A lucid dream can begin in one of two ways. A dream-initiated lucid dream (DILD) starts as a normal dream, and the dreamer eventually concludes that he or she is dreaming, or a wake-initiated lucid dream (WILD) occurs when the dreamer goes from a normal waking state directly into a dream state with no apparent lapse in consciousness. Lucid dreaming has been researched scientifically, and its existence is well established.[1][2] Scientists such as Allan Hobson, with his neurophysiological approach to dream research, have helped to push the understanding of lucid dreaming into a less speculative realm. # Scientific history The first book on lucid dreams to recognize their scientific potential was Celia Green's 1968 study Lucid Dreams. Reviewing the past literature, as well as new data from subjects of her own, Green analyzed the main characteristics of such dreams, and concluded that they were a category of experience quite distinct from ordinary dreams. She predicted that they would turn out to be associated with REM sleep. Green was also the first to link lucid dreams to the phenomenon of false awakenings. Philosopher Norman Malcolm's 1959 text Dreaming argued against the possibility of checking the accuracy of dream reports. However, the realisation that eye movements performed in dreams affected the dreamer's physical eyes provided a way to prove that actions agreed upon during waking life could be recalled and performed once lucid in a dream. The first evidence of this type was produced in the late 1970s by British parapsychologist Keith Hearne. A volunteer named Alan Worsley used eye movement to signal the onset of lucidity, which were recorded by a polysomnograph machine. Hearne's results were not widely distributed. The first peer reviewed article was published some years later by Stephen LaBerge at Stanford University who had independently developed a similar technique as part of his doctoral dissertation. During the 1980s, further scientific evidence to confirm the existence of lucid dreaming was produced as lucid dreamers were able to demonstrate to researchers that they were consciously aware of being in a dream state (again, primarily using eye movement signals). Additionally, techniques were developed which have been experimentally proven to enhance the likelihood of achieving this state.[3] Research on techniques and effects of lucid dreaming continues at a number of universities and other centers such as LaBerge's The Lucidity Institute. # Research and clinical applications ## Neurobiological model Neuroscientist J. Allan Hobson has hypothesized as to what might be occurring in the brain while lucid. The first step to lucid dreaming is recognizing that one is dreaming. This recognition might occur in the dorsolateral prefrontal cortex which is one of the few areas deactivated during REM sleep, and where working memory occurs. Once this area is activated and the recognition of dreaming occurs the dreamer must be cautious to let the dream delusions continue, but be conscious enough to recognize them. This process might be seen as the balance between reason and emotion. While maintaining this balance the amygdala and parahippocampal cortex might be less intensely activated.[4] To continue the intensity of the dream hallucinations it is expected the pons and the parieto-occipital junction cortex stay active. To verify this hypothesis it would be necessary to observe the brain during lucid dreaming using a method such as a PET scan, which captures a snapshot of the blood flow to the brain. No such experiment has yet been performed.[5] ## Treatment for nightmares People who suffer from nightmares would benefit from the ability to be aware they are dreaming. A pilot study was performed in 2006 that showed lucid dreaming treatment was successful in reducing nightmare frequency. This treatment consisted of exposure to the idea, mastery of the technique, and lucidity exercises. It was not clear what aspects of the treatment were responsible for the success of overcoming nightmares, though the treatment as a whole was successful.[6] ## Perception of time while lucid dreaming The rate that time passes while lucid dreaming has been shown to be about the same as while waking. In 1985 LaBerge performed a pilot study where lucid dreamers counted from one to ten (one-one thousand, two-one thousand, etc.) while dreaming, signaling the end of counting with a pre-arranged eye signal measured with Electrooculogram recording.[7] LaBerge's results were confirmed by German researchers in 2004. The German study, by Erlacher, D. & Schredl, M also studied motor activity and found that deep knee bends took 44% longer to perform while lucid dreaming.[8] ## Near-death and out-of-body experiences In a study of 14 lucid dreamers performed in 1991, people who perform wake initiated lucid dreams (WILD) reported experiences consistent with aspects of out-of-body experiences such as floating above their beds and the feeling of leaving their bodies.[9] Due to the phenomenological overlap between lucid dreams, near death experiences, and out of body experiences researchers say they believe a protocol could be developed to induce a lucid dream similar to a near death experience in the laboratory.[10] # Cultural history Even though it has only come to the attention of the general public in the last few decades, lucid dreaming is not a modern discovery. - In the fifth century, a very early example of lucid dreaming is in a letter written by St. Augustine of Hippo in 415 AD.[11] - As early as the eighth century, Tibetan Buddhists were practicing a form of yoga supposed to maintain full waking consciousness while in the dream state.[12] This system is extensively discussed and explained in the book Dream Yoga and the Practice of Natural Light[13], one of the important messages of which has been the distinction between the Dzogchen meditation of Awareness and Dream Yoga or lucid dreaming. The Dzogchen Awareness meditation has also been referred to by the terms Rigpa Awareness, Contemplation, and Presence. Awareness during the sleep and dream states is associated with the Dzogchen practice of natural light, and lucid dreams may be a byproduct. In contrast, the more relative but still important experience of lucid dreaming is referred to as Dream yoga, and lucid dreaming is the goal. The lucidity experience, according to Buddhist teachers, assists in understanding the unreality of phenomena, which otherwise, during dream or the death experience, might be overwhelming. - An early recorded lucid dreamer was the philosopher and physician Sir Thomas Browne (1605–1682). Browne was fascinated by the world of dreams and stated of his own ability to lucid dream in his Religio Medici: "... yet in one dream I can compose a whole Comedy, behold the action, apprehend the jests and laugh my self awake at the conceits thereof;"[14] - Marquis d'Hervey de Saint-Denys was probably the first person to argue that it is possible for anyone to learn to dream consciously. In 1867, he published his book Les Reves et les Moyens de Les Diriger; Observations Pratiques (Dreams and How to Guide them; Practical Observations), in which he documented more than twenty years of his own research into dreams. - The term "lucid dreaming" was coined by Dutch author and psychiatrist Frederik van Eeden in his 1913 article A Study of Dreams.[15] This book was highly anecdotal and not embraced by the scientific community. The term itself is considered by some to be a misnomer because it means much more than just "clear or vivid" dreaming.[16] A better term might have been "conscious dreaming". On the other hand, the term 'lucid' was used by van Eeden in its sense of 'having insight', as in the phrase 'a lucid interval' applied to someone in temporary remission from a psychosis, rather than as referring to the perceptual quality of the experience, which may or may not be clear and vivid. To that extent van Eeden's phrase may still be considered appropriate. - In the 1950s the Senoi hunter-gatherers of Malaysia were reported to make extensive use of lucid dreaming to ensure mental health, although later studies refuted these claims.[17] # Induction methods Many people report having experienced a lucid dream during their lives, often in childhood. Children seem to have lucid dreams more easily than adults. Although lucid dreaming is a conditioned skill,[18] achieving lucid dreams on a regular basis can be difficult and is uncommon, even with training. Over time, several techniques have been developed to achieve a lucid dreaming state intentionally. The following are common factors that influence lucid dreaming, and techniques that people use to help achieve a lucid dream: ### Dream recall Dream recall is simply the ability to remember dreams. Good dream recall is often described as the first step towards lucid dreaming. Better recall increases awareness of dreams in general; with limited dream recall any lucid dreams one has can be forgotten entirely. The main technique used to improve dream recall is to keep a dream journal, writing down any dreams remembered the moment one awakes. It is important to record the dreams as quickly as possible as there is a strong tendency to forget what one has dreamt.[19] It is suggested that one's dream journal be recorded in the present tense. Describing an experience as if presently in it can help the writer to recall more accurately the events of their dream. Dream recall can also be improved by staying still after waking up.[19] This may be something to do with REM atonia (the condition of REM sleep in which the motor neurons are not stimulated and thus the body's muscles do not move). If one purposely prevents motor neurons from firing immediately after waking from a dream, recalling said dream becomes easier. Similarly, if the dreamer changes positions in the night they may be able to recall certain events of their dream by testing different sleeping positions. ### Mnemonic induction of lucid dreams (MILD) The MILD technique is a common technique developed by Dr Stephen LaBerge, used to induce a lucid dream at will by setting an intention, while falling asleep, to remember to recognize that one is dreaming, or to remember to look for dream signs when one is in a dream. ### Wake-back-to-bed (WBTB) The wake-back-to-bed technique is often the easiest way to encourage a lucid dream. The method involves going to sleep tired and waking up five hours later. Then, focusing all thoughts on lucid dreaming, staying awake for an hour and going back to sleep while practicing the MILD method. A 60% success rate has been shown in research using this technique.[20] This is because the REM cycles get longer as the night goes on, and this technique takes advantage of the best REM cycle of the night. Because this REM cycle is longer and deeper, gaining lucidity during this time may result in a more lengthy lucid dream.[20] ### Cycle adjustment technique (CAT) The cycle adjustment technique, developed by Daniel Love, is an effective way to induce lucid dreaming. It involves adjusting one's sleep cycle to encourage awareness during the latter part of the sleep. First, the person wakes up 90 minutes before normal wake time until their sleep cycle begins to adjust. After this, the normal wake times and early wake times alternate. On the days with the normal wake times, the body is ready to wake up, and this increases alertness, making lucidity more likely. ### Wake-initiation of lucid dreams (WILD) The wake-initiated lucid dream "occurs when the sleeper enters REM sleep with unbroken self-awareness directly from the waking state".[21] There are many techniques aimed at entering a WILD. The key to these techniques is recognizing the hypnagogic stage, which is within the border of being awake and being asleep. If a person is successful in staying aware while this stage occurs, he or she will eventually enter the dream state while being fully aware that it is a dream. There are key times at which this state is best entered; while success at night after being awake for a long time is very difficult, it is relatively easy after being awake for 15 or so minutes and in the afternoon during a nap. Techniques for inducing WILDs abound. Dreamers may count, envision themselves climbing or descending stairs, chant to themselves, explore elaborate, passive sexual fantasies, control their breathing, counting their breaths to keep their thoughts from drifting, concentrate on relaxing their body from their toes to their head, allow images to flow through their "mind's eye" and envision themselves jumping into the image, to maintain concentration and keep their mind awake, while still being calm enough to let their body sleep. During the actual transition into the dream state, one is likely to experience sleep paralysis, including rapid vibrations,[9] a sequence of loud sounds and a feeling of twirling into another state of body awareness, "to drift off into another dimension". Also there is frequently a sensation of falling rapidly or dropping through the bed as one enters the dream state. After the transition there may be the sensation of entering a dark black room from which one can induce any dream scenario of one's choosing, simply by concentrating on it. The key to success is not to panic, especially during the transition, which can be quite sudden. ### Induction devices Lucid dream induction is possible by the use of a physical device. The general principle works by taking advantage of the natural phenomenon of incorporating external stimuli into one's dreams. Usually a device is worn while sleeping that can detect when the sleeper enters a REM phase and triggers a noise and/or flashing lights with the goal of these stimuli being incorporated into the dreamer's dream. For example flashing lights might be translated to a car's headlights in a dream. A well known dream induction device is the Nova Dreamer which has been discontinued as of 2006. However, a newer version is being worked on, but as of now is not available [22]. A European induction device known as the Rem dreamer is still in production. ### Additional techniques - Meditation, and involvement in a conscious focusing on activities can strengthen the ability to experience lucid dreams by making the person more susceptible to noticing small discrepancies of their surroundings. [23] - Hypnotism may help one achieve lucidity.[24] Michael Katz first referenced using simple hypnotic induction for the purpose of initiating lucid dreams in his introduction to the first edition of the book " Dream yoga and the Practice of Natural Light". He has subsequently since the early 1980's used this "guided nap" technique during dream yoga and lucid dream trainings he conducts internationally and maintains an archive of examples.[25] # Reality testing Reality testing (or reality checking) is a common method used by people to determine whether or not they are dreaming. It involves performing an action with results that will be different if the tester is dreaming. By practicing these tests during waking life, one may eventually decide to perform such a test while dreaming, which may fail and let the dreamer realize that they are dreaming. Common reality tests include: - Reading some text, looking away from the text, and reading it again - in a dream, the text will probably have changed. - Looking at one's watch (remembering the time), looking away, and looking back. As with the text, the time will probably have changed randomly and radically at the second glance or contain strange letters and characters.[26] - Flipping a light switch. Light levels rarely change in dreams. - Looking into a mirror; in dreams, reflections from a mirror often appear to be blurred, distorted or incorrect.[27] - Plugging one's nose shut, and attempting to breathe through it, or attempting to breathe underwater. It is usually possible to breathe while doing this because the tester is not actually plugging their nose in real life. - Looking at one's hands one or more times. Hands may look distorted, or grow additional fingers in a dream. - Gripping and stretching a finger. In a dream, body image can become distorted, and pulling a finger can elongate it. Also, the number of fingers can shift when stared at. - Jumping into the air. Gravity is often distorted in a dream state and floating or flying may occur. - Looking around and seeing everything blurred, as if underwater. - Being able to move through solid objects like walls. - Putting one's finger through the palm of the other hand. - Closing one eye and looking at one's nose. The dreamer may not see their nose as everyday details that usually go unnoticed in waking life are often absent during a dream. ## Dream signs Another form of reality testing involves identifying one's dream signs, clues that one is dreaming. Dream signs are often categorized as follows: - Action — The dreamer, another dream character, or a thing does something unusual or impossible in waking life, such being able to fly, or noticing photographs in a magazine or newspaper becoming three-dimensional with full movement. - Context — The place or situation in the dream is strange, and includes fictional characters or places. - Form — The dreamer, another character, or an object changes shape, is oddly formed, or transforms. This may include the presence of unusual clothing or hair, or a third person view of the dreamer. - Awareness — A peculiar thought, a strong emotion, an unusual sensation, or an altered perception. In some cases when moving one's head from side to side, one may notice a strange stuttering or 'strobing' of the image. - Cohesion — Sometimes the dreamer may seem to teleport to another location in a dream, without a noticeable transition. # Prolonging lucid dreams One problem faced by people wishing to lucid dream is awakening prematurely. This premature awakening can be especially frustrating after investing considerable time into achieving lucidity in the first place. Stephen LaBerge proposed two ways to prolong a lucid dream. The first technique involves spinning one's dream body. He proposed that when spinning, the dreamer is engaging parts of the brain that may also be involved in REM activity, helping to prolong REM. The second technique is rubbing one's hands. This technique is intended to engage the dreamer's brain in producing the sensation of rubbing hands, preventing the sensation of lying in bed from creeping into awareness. LaBerge tested his hypothesis by asking 34 volunteers to either spin, rub their hands, or do nothing. Results showed 90% of dreams were prolonged by hand rubbing and 96% prolonged by spinning. Only 33% of lucid dreams were prolonged with taking no action.[28] # Other associated phenomena This is often a nemesis in the art of lucid dreaming because it usually causes people to give up their awareness of being in a dream, but it can also cause someone to become lucid if the person does a reality check whenever he/she awakens. People who keep a dream journal and write down their dreams upon awakening sometimes report having to write down the same dream multiple times because of this phenomenon. It has also been known to cause bedwetting as one may dream that they have awoken to go to the restroom, but in reality are still dreaming.	https://www.wikidoc.org/index.php/Lucid_dream
a490aa1300f14cd0dcdaf3f07e2ad71b70ca40fd	wikidoc	Lucinactant	Lucinactant # Overview Lucinactant (trade name Surfaxin) is a liquid medication used to treat infant respiratory distress syndrome. It was approved for use in the United States by the U.S. Food and Drug Administration (FDA) on March 6, 2012. # Medical uses Lucinactant is indicated to improve lung function and reduce duration and risk of mechanical ventilation in children. It can be used up to two years of age and is specified for children who are diagnosed with acute respiratory failure following exposure to a pathogen such as RSV or influenza, including H1N1. Lucinactant is also used to treat meconium aspiration syndrome. # Physical and chemical properties Lucinactant contains the peptide sinapultide (KL4 acetate), 1,2-dipalmitoyl-sn-glycero-3-phosphocholine, 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphoglycerol (as the sodium salt), and palmitic acid. # History The scientific groundwork for lucinactant was laid in the laboratory of Charles Cochrane at The Scripps Research Institute in the 1990s. The drug was then developed by Discovery Laboratories of Warrington, PA. The path through the approval process was unusually long, reflecting in part challenges in the manufacturing process that needed to be addressed before approval was granted. # Legal status Lucinactant is listed as an Orphan Drug Product by the US Food and Drug Administration for several conditions: - 07-30-1996 Treatment of meconium aspiration syndrome in newborn infants - 07-17-1995 Treatment of acute respiratory distress syndrome in adults. - 05-23-2006 Prevention of bronchopulmonary dysplasia in premature infants - 10-21-2005 Treatment of bronchopulmonary dysplasia in premature infants. - 10-18-1995 Treatment of respiratory distress syndrome in premature infants. Clinical trials in Latin America were criticized for protocol based in potentially unethical principles. A placebo was used and considered ethical by design since infants born in Latin America usually do not have access to life saving treatment. The intent of Discovery Labs was always to market Surfaxin in the United States, implying burdens on the Latin American children that outweighed the benefits.	Lucinactant Editor-In-Chief: C. Michael Gibson, M.S., M.D. [2] # Overview Lucinactant (trade name Surfaxin) is a liquid medication used to treat infant respiratory distress syndrome.[1] It was approved for use in the United States by the U.S. Food and Drug Administration (FDA) on March 6, 2012.[2] # Medical uses Lucinactant is indicated to improve lung function and reduce duration and risk of mechanical ventilation in children. It can be used up to two years of age and is specified for children who are diagnosed with acute respiratory failure following exposure to a pathogen such as RSV or influenza, including H1N1.[3][4][5] Lucinactant is also used to treat meconium aspiration syndrome.[5][6] # Physical and chemical properties Lucinactant contains the peptide sinapultide (KL4 acetate), 1,2-dipalmitoyl-sn-glycero-3-phosphocholine, 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphoglycerol (as the sodium salt), and palmitic acid. # History The scientific groundwork for lucinactant was laid in the laboratory of Charles Cochrane at The Scripps Research Institute in the 1990s.[7] The drug was then developed by Discovery Laboratories of Warrington, PA. The path through the approval process was unusually long, reflecting in part challenges in the manufacturing process that needed to be addressed before approval was granted.[8] # Legal status Lucinactant is listed as an Orphan Drug Product by the US Food and Drug Administration for several conditions:[9][10] - 07-30-1996 Treatment of meconium aspiration syndrome in newborn infants - 07-17-1995 Treatment of acute respiratory distress syndrome in adults. - 05-23-2006 Prevention of bronchopulmonary dysplasia in premature infants - 10-21-2005 Treatment of bronchopulmonary dysplasia in premature infants. - 10-18-1995 Treatment of respiratory distress syndrome in premature infants. Clinical trials in Latin America were criticized for protocol based in potentially unethical principles.[11] A placebo was used and considered ethical by design since infants born in Latin America usually do not have access to life saving treatment. The intent of Discovery Labs was always to market Surfaxin in the United States, implying burdens on the Latin American children that outweighed the benefits.	https://www.wikidoc.org/index.php/Lucinactant
0326a85d6e48eeee7074e56943b839d36fc000fd	wikidoc	Maprotiline	Maprotiline # 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 Maprotiline is a tetracyclic antidepressant that is FDA approved for the {{{indicationType}}} of bipolar disorder, depressed phase, depression, dysthymia, mixed anxiety and depressive disorder. There is a Black Box Warning for this drug as shown here. Common adverse reactions include constipation, xerostomia, dizziness , feeling nervous , myoclonus, somnolence, blurred vision, visual disturbance. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) - Bipolar disorder, depressed phase - Outpatients: 75 mg/day PO (2-3 divided doses) for 2 weeks; may increase in 25 mg increments up to a max of 225 mg/day in single or divided doses - Inpatients: 100-150 mg/day PO (2-3 divided doses) for 2 weeks; may increase in 25 mg increments up to a max of 225 mg/day in single or divided doses - Maintenance: 75-150 mg/day PO in single or divided doses - Depression - 75 mg/day PO (2-3 divided doses) for 2 weeks; increase in 25 mg increments up to a max of 225 mg/day in single or divided doses - Inpatients: 100-150 mg/day PO (2-3 divided doses) for 2 weeks, increase in 25 mg increments up to a max of 225 mg/day in single or divided doses - Maintenance: 75-150 mg/day ORALLY in single or divided doses - Dysthymia - 75 mg/day PO (2-3 divided doses) for 2 weeks, increase in 25 mg increments up to a max of 225 mg/day in single or divided doses - Inpatients: 100-150 mg/day PO (2-3 divided doses) for 2 weeks; may increase in 25 mg increments up to a MAX of 225 mg/day in single or divided doses - Maintenance: 75-150 mg/day ORALLY in single or divided doses - Mixed anxiety and depressive disorder - Outpatients 75 mg/day PO (2-3 divided doses) for 2 weeks, increase in 25 mg increments up to a max of 225 mg/day in single or divided doses - Inpatients: 100-150 mg/day PO (2-3 divided doses) for 2 weeks, increase in 25 mg increments up to a max of 225 mg/day in single or divided doses - Maintenance: 75-150 mg/day ORALLY in single or divided doses ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information about Off-Label Guideline-Supported Use of Maprotiline in adult patients. ### Non–Guideline-Supported Use - Pain - There is limited information about Off-Label Non–Guideline-Supported Use of Maprotiline in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) Safety has not been established below 18 years of age. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information about Off-Label Guideline-Supported Use of Maprotiline in pediatric patients. ### Non–Guideline-Supported Use - There is limited information about Off-Label Non–Guideline-Supported Use of Maprotiline in pediatric patients. # Contraindications - Contraindicated in patients hypersensitive to maprotiline and in patients with known or suspected seizure disorders. - It should not be given concomitantly with monoamine oxidase (MAO) inhibitors. - A minimum of 14 days should be allowed to elapse after discontinuation of MAO inhibitors before treatment with maprotiline is initiated. - Effects should be monitored with gradual increase in dosage until optimum response is achieved. - Not recommended for use during the acute phase of myocardial infarction. # Warnings 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 9 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. - 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 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. - 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 maprotiline 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 maprotiline is not approved for use in treating bipolar depression. Seizures have been associated with the use of maprotiline - Most of the seizures have occurred in patients without a known history of seizures. However, in some of these cases, other confounding factors were present, including concomitant medications known to lower the seizure threshold, rapid escalation of the dosage of maprotiline, and dosage that exceeded the recommended therapeutic range. The incidence of direct reports is less than 1/10 of 1%. The risk of seizures may be increased when maprotiline is taken concomitantly with phenothiazines, when the dosage of benzodiazepines is rapidly tapered in patients receiving maprotiline or when the recommended dosage of maprotiline hydrochloride is exceeded. While a cause and effect relationship has not been established, the risk of seizures in patients treated with maprotiline may be reduced by - Initiating therapy at a low dosage, - Maintaining the initial dosage for 2 weeks before raising it gradually in small increments as necessitated by the long half-life of maprotiline (average 51 hours), and - Keeping the dosage at the minimally effective level during maintenance therapy. (See dosage and administration.) - Extreme caution should be used when this drug is given to: - Patients with a history of myocardial infarction; - Patients with a history or presence of cardiovascular disease because of the possibility of conduction defects, arrhythmias, myocardial infarction, strokes and tachycardia. General precautions - The possibility of suicide in seriously depressed patients is inherent in their illness and may persist until significant remission occurs. Therefore, patients must be carefully supervised during all phases of treatment with maprotiline, and prescriptions should be written for the smallest number of tablets consistent with good patient management. - Hypomanic or manic episodes have been known to occur in some patients taking tricyclic antidepressant drugs, particularly in patients with cyclic disorders. Such occurrences have also been noted, rarely, with maprotiline. - Prior to elective surgery, maprotiline should be discontinued for as long as clinically feasible, since little is known about the interaction between maprotiline and general anesthetics. - Maprotiline should be administered with caution in patients with increased intraocular pressure, history of urinary retention, or history of narrow angle glaucoma because of the drug's anticholinergic properties. # Adverse Reactions ## Clinical Trials Experience Central Nervous System Cardiovascular psychiatric Gastrointestinal Hypersensitive Reactions Anticholinergic Miscellaneous ## Postmarketing Experience There is limited information regarding Maprotiline Postmarketing Experience in the drug label. # Drug Interactions - Anticholinergic or sympathomimetic drugs - Close supervision and careful adjustment of dosage are required when administering maprotiline concomitantly with anticholinergic or sympathomimetic drugs because of the possibility of additive atropine like effects. - Electroshock therapy - Concurrent administration of maprotiline with electroshock therapy should be avoided because of the lack of experience in this area. - Thyroid medication - Caution should be exercised when administering maprotiline to hyperthyroid patients or those on thyroid medication because of the possibility of enhanced potential for cardiovascular toxicity of maprotiline. - Guanethidine - Maprotiline should be used with caution in patients receiving guanethidine or similar agents since it may block the pharmacologic effects of these drugs. - Phenothiazines or benzodiazepines - The risk of seizures may be increased when maprotiline is taken concomitantly with phenothiazines or when the dosage of benzodiazepines is rapidly tapered in patients receiving maprotiline. - Hepatic enzyme inhibitors - Because of the pharmacologic similarity of maprotiline hydrochloride to the tricyclic antidepressants, the plasma concentration of maprotiline may be increased when the drug is given concomitantly with hepatic enzyme inhibitors (e.g., cimetidine, fluoxetine) and decreased by concomitant administration with hepatic enzyme inducers (e.g., barbiturates, phenytoin), as has occurred with tricyclic antidepressants. Adjustment of the dosage of maprotiline hydrochloride may therefore be necessary in such cases. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): B Reproduction studies have been performed in female laboratory rabbits, mice, and rats at doses up to 1.3, 7, and 9 times the maximum daily human dose respectively and have revealed no evidence of impaired fertility or harm to the fetus due to maprotiline. There are, however, 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. Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Maprotiline in women who are pregnant. ### Labor and Delivery Although the effect of maprotiline on labor and delivery is unknown, caution should be exercised as with any drug with CNS depressant action. ### Nursing Mothers Maprotiline is excreted in breast milk. At steady-state, the concentrations in milk correspond closely to the concentrations in whole blood. Caution should be exercised when maprotiline hydrochloride is administered to a nursing woman. ### Pediatric Use Safety and effectiveness in the pediatric population have not been established. Anyone considering the use of maprotiline in a child or adolescent must balance the potential risks with the clinical need. ### Geriatic Use There is no FDA guidance on the use of Maprotiline in geriatric settings. ### Gender There is no FDA guidance on the use of Maprotiline with respect to specific gender populations. ### Race There is no FDA guidance on the use of Maprotiline with respect to specific racial populations. ### Renal Impairment There is no FDA guidance on the use of Maprotiline in patients with renal impairment. ### Hepatic Impairment There is no FDA guidance on the use of Maprotiline in patients with hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Maprotiline in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Maprotiline in patients who are immunocompromised. # Administration and Monitoring ### Administration - A single daily dose is an alternative to divided daily doses. Therapeutic effects are sometimes seen within 3 to 7 days, although as long as 2 to 3 weeks are usually necessary. - Initial Adult Dosage - An initial dosage of 75 mg daily is suggested for outpatients with mild to moderate depression. However, in some patients, particularly the elderly, an initial dosage of 25 mg daily may be used. Because of the long half-life of maprotiline, the initial dosage should be maintained for 2 weeks. The dosage may then be increased gradually in 25 mg increments as required and tolerated. In most outpatients a maximum dose of 150 mg daily will result in therapeutic efficacy. It is recommended that this dose not be exceeded except in the most severely depressed patients. In such patients, dosage may be gradually increased to a maximum of 225 mg. - More severely depressed, hospitalized patients should be given an initial daily dose of 100 mg to 150 mg which may be gradually increased as required and tolerated. Most hospitalized patients with moderate to severe depression respond to a daily dose of 150 mg although dosages as high as 225 mg may be required in some cases. Daily dosage of 225 mg should not be exceeded. - Elderly Patients - In general, lower dosages are recommended for patients over 60 years of age. Dosages of 50 mg to 75 mg daily are usually satisfactory as maintenance therapy for elderly patients who do not tolerate higher amounts. ### Monitoring - Maintenance - Dosage during prolonged maintenance therapy should be kept at the lowest effective level. Dosage may be reduced to levels of 75 mg to 150 mg daily during such periods, with subsequent adjustment depending on therapeutic response. # IV Compatibility There is limited information regarding the compatibility of Maprotiline and IV administrations. # Overdosage - Deaths may occur from overdosage with this class of drugs. Multiple drug ingestion (including alcohol) is common in deliberate overdose. As the management is complex and changing, it is recommended that the physician contact a poison control center for current information on treatment. Signs and symptoms of toxicity develop rapidly after overdose. Therefore, hospital monitoring is required as soon as possible. - Animal Oral LD50 - The oral LD50 of maprotiline hydrochloride is 600 to 750 mg/kg in mice, 760 to 900 mg/kg in rats, > 1000 mg/kg in rabbits, > 300 mg/kg in cats, and > 30 mg/kg in dogs. - Manifestations - Data dealing with overdosage in humans are limited with only a few cases on record. Signs and symptoms of maprotiline hydrochloride overdose are similar to those seen with tricyclic overdose. Critical manifestations of overdose include cardiac dysrhythmias, severe hypotension, convulsions and CNS depression including coma. Changes in the electrocardiogram, particularly in QRS axis or width are clinically significant indicators of toxicity. Other clinical manifestations include drowsiness, tachycardia, ataxia, vomiting, cyanosis, shock, restlessness, agitation, hyperpyrexia, muscle rigidity, athetoid movements, and mydriasis. Since congestive heart failure has been seen with overdosages of tricyclic antidepressants, it should be considered with maprotiline hydrochloride overdosage. - Management - Obtain an ECG and immediately initiate cardiac monitoring. Protect the patient's airway, establish an intravenous line and initiate gastric decontamination. A minimum of 6 hours of observation with cardiac monitoring and observation for signs of CNS or respiratory depression, hypotension, cardiac dysrhythmias and/or conduction blocks, and seizures is necessary. If signs of toxicity occur at any time during this period, extended monitoring is required. There are case reports of patients succumbing to fatal dysrhythmias late after tricyclic overdose; these patients had clinical evidence of significant poisoning prior to death and most received inadequate gastrointestinal decontamination. Monitoring of plasma drug levels should not guide management of the patient. - Gastrointestinal Decontamination - All patients suspected of overdose should receive gastrointestinal decontamination. This should include large volume gastric lavage followed by activated charcoal. If consciousness is impaired, the airway should be secured prior to lavage. Emesis is contraindicated. - Cardiovascular - A maximal limb lead QRS duration of ≥ 0.10 seconds may be the best indication of the severity of the overdose. Intravenous sodium bicarbonate should be used to maintain the serum pH in the range of 7.45 to 7.55. If the pH response is inadequate, hyperventilation may also be used. :*Concomitant use of hyperventilation and sodium bicarbonate should be done with extreme caution, with frequent pH monitoring. A pH > 7.60 or a Pco2 < 20 mmHg is undesirable. Dysrhythmias unresponsive to sodium bicarbonate therapy/hyperventilation may respond to lidocaine, bretylium, or phenytoin. Type 1A and 1C antiarrhythmics are generally contraindicated (e.g., quinidine, disopyramide, and procainamide). - In rare instances, hemoperfusion may be beneficial in acute refractory cardiovascular instability in patients with acute toxicity. However, hemodialysis, peritoneal dialysis, exchange transfusions, and forced diuresis generally have been reported as ineffective. - CNS - In patients with CNS depression, early intubation is advised because of the potential for abrupt deterioration. Seizures should be controlled with benzodiazepines, or if these are ineffective, other anticonvulsants (e.g., phenobarbital, phenytoin). Physostigmine is not recommended except to treat life threatening symptoms that have been unresponsive to other therapies, and then only in consultation with a poison control center. - Psychiatric Follow-up - Since overdosage is often deliberate, patients may attempt suicide by other means during the recovery phase. Psychiatric referral may be appropriate. - Pediatric Management - The principles of management of child and adult overdosages are similar. It is strongly recommended that the physician contact the local poison control center for specific pediatric treatment. # Pharmacology ## Mechanism of Action The mechanism of action of maprotiline is not precisely known. It does not act primarily by stimulation of the central nervous system and is not a monoamine oxidase inhibitor. The postulated mechanism of maprotiline is that it acts primarily by potentiation of central adrenergic synapses by blocking reuptake of norepinephrine at nerve endings. This pharmacologic action is thought to be responsible for the drug's antidepressant and anxiolytic effects. The mean time to peak is 12 hours. The half-life of elimination averages 51 hours. It exerts blocking effects at the following postsynaptic receptors: - Strong : alpha1 - Moderate : 5-HT2, muscarinic, H1, D2 - Weak : alpha2 - Extremely weak : 5-HT1 The pharmacologic profile of Maprotiline explains its antidepressant, sedative, anxiolytic, sympatholytic, and anticholinergic activities. Additionally, it shows a strong antagonism against Reserpine-induced effects in animal studies, as do the other 'classical' antidepressants. Although Maprotiline behaves in most regards as a 'first generation antidepressant' it is commonly referred to as 'second generation antidepressant'. Sedation has a fast onset (the same day), while remission of the depression itself is noted usually after a latent period of one to four weeks. Maprotiline does not brighten up the mood in nondepressed persons. ## Structure Maprotiline hydrochloride, USP is a tetracyclic antidepressant, available as 25 mg, 50 mg and 75 mg tablets for oral administration. Its chemical name is N-methyl-9,10-ethanoanthracene-9(10H)-propylamine hydrochloride, and its structural formula is: Maprotiline hydrochloride is a fine, white to off-white, practically odorless crystalline powder. It is freely soluble in methanol and in chloroform, slightly soluble in water, and practically insoluble in isooctane. Its molecular weight is 313.87. The tablets contain the following inactive ingredients: colloidal silicon dioxide, croscarmellose sodium, hypromellose, magnesium stearate, microcrystalline cellulose, polydextrose, polyethylene glycol, pregelatinized starch, sodium lauryl sulfate, titanium dioxide and triacetin. Additionally, the 50 mg tablet contains FD&C Blue No. 1 Aluminum Lake. ## Pharmacodynamics There is limited information regarding Maprotiline Pharmacodynamics in the drug label. ## Pharmacokinetics There is limited information regarding Maprotiline Pharmacokinetics in the drug label. ## Nonclinical Toxicology There is limited information regarding Maprotiline Nonclinical Toxicology in the drug label. # Clinical Studies There is limited information regarding Maprotiline Clinical Studies in the drug label. # How Supplied Maprotiline Hydrochloride, USP is available as tablets containing 25 mg, 50 mg, or 75 mg of maprotiline hydrochloride. The 25 mg tablets are white film-coated, round, scored tablets debossed with 6 to the left of the score and 0 to the right of the score on one side of the tablet and M on the other side. They are available as follows: NDC 0378-0060-01 bottles of 100 tablets The 50 mg tablets are light blue film-coated, round, scored, tablets debossed with 8 to the left of the score and 7 to the right of the score on one side and M on the other side. They are available as follows: NDC 0378-0087-01 bottles of 100 tablets The 75 mg tablets are white film-coated, round, scored tablets debossed with 9 to the left of the score and 2 to the right of the score on one side and M on the other side. They are available as follows: NDC 0378-0092-01 bottles of 100 tablets ## Storage Store at 20° to 25°C (68° to 77°F). # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information Prescribers or other health professionals should inform patients, their families, and their caregivers about the benefits and risks associated with treatment with maprotiline and should counsel them in its appropriate use. A patient Medication Guide about "Antidepressant Medicines, Depression and other Serious Mental Illness and Suicidal Thoughts or Actions" is available for maprotiline. 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 maprotiline. 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 a need for very close monitoring and possibly changes in the medication. - Medication Guide - Antidepressant Medicines, Depression and other Serious Mental Illnesses, and Suicidal Thoughts or Actions Read the Medication Guide that comes with you or your family member's antidepressant medicine. This Medication Guide is only about the risk of suicidal thoughts and actions with antidepressant medicines. Talk to your, or your family member's, healthcare provider about: - All risks and benefits of treatment with antidepressant medicines - All treatment choices for depression or other serious mental illness - What is the most important information I should know about antidepressant medicines, depression and other serious mental illnesses, and suicidal thoughts or actions? - Antidepressant medicines may increase suicidal thoughts or actions in some children, teenagers, and young adults within the first few months of treatment. - Depression and other serious mental illnesses are the most important causes of suicidal thoughts and actions. Some people may have a particularly high risk of having suicidal thoughts or actions. These include people who have (or have a family history of) bipolar illness also called manic-depressive illness) or suicidal thoughts or actions. - How can I watch for and try to prevent suicidal thoughts and actions in myself or a family member? - Pay close attention to any changes, especially sudden changes, in mood, behaviors, thoughts, or feelings. This is very important when an antidepressant medicine is started or when the dose is changed. - Call the healthcare provider right away to report new or sudden changes in mood, behavior, thoughts, or feelings. - Keep all follow-up visits with the healthcare provider as scheduled. Call the healthcare provider between visits as needed, especially if you have concerns about symptoms. - Call a healthcare provider right away if you or your family member has any of the following symptoms, especially if they are new, worse, or worry you: - Thoughts about suicide or dying - Attempts to commit suicide - New or worse depression - New or worse anxiety - Feeling very agitated or restless - Panic attacks - Trouble sleeping (insomnia) - New or worse irritability - Acting aggressive, being angry, or violent - Acting on dangerous impulses - An extreme increase in activity and talking (mania) - Other unusual changes in behavior or mood - What else do I need to know about antidepressant medicines? - Never stop an antidepressant medicine without first talking to a healthcare provider. Stopping an antidepressant medicine suddenly can cause other symptoms. - Antidepressants are medicines used to treat depression and other illnesses. It is important to discuss all the risks of treating depression and also the risks of not treating it. Patients and their families or other caregivers should discuss all treatment choices with the healthcare provider, not just the use of antidepressants. - Antidepressant medicines have other side effects. Talk to the healthcare provider about the side effects of the medicine prescribed for you or your family member. - Antidepressant medicines can interact with other medicines. Know all of the medicines that you or your family member takes. Keep a list of all medicines to show the healthcare provider. Do not start new medicines without first checking with your healthcare provider. - Not all antidepressant medicines prescribed for children are FDA approved for use in children. Talk to your child's healthcare provider for more information. - Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. - This Medication Guide has been approved by the U.S. Food and Drug Administration for all antidepressants. # Precautions with Alcohol Alcohol-Maprotiline 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 Maprotiline Brand Names in the drug label. # Look-Alike Drug Names There is limited information regarding Maprotiline Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	Maprotiline Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Pratik Bahekar, MBBS [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 Maprotiline is a tetracyclic antidepressant that is FDA approved for the {{{indicationType}}} of bipolar disorder, depressed phase, depression, dysthymia, mixed anxiety and depressive disorder. There is a Black Box Warning for this drug as shown here. Common adverse reactions include constipation, xerostomia, dizziness , feeling nervous , myoclonus, somnolence, blurred vision, visual disturbance. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) - Bipolar disorder, depressed phase - Outpatients: 75 mg/day PO (2-3 divided doses) for 2 weeks; may increase in 25 mg increments up to a max of 225 mg/day in single or divided doses - Inpatients: 100-150 mg/day PO (2-3 divided doses) for 2 weeks; may increase in 25 mg increments up to a max of 225 mg/day in single or divided doses - Maintenance: 75-150 mg/day PO in single or divided doses - Depression - 75 mg/day PO (2-3 divided doses) for 2 weeks; increase in 25 mg increments up to a max of 225 mg/day in single or divided doses - Inpatients: 100-150 mg/day PO (2-3 divided doses) for 2 weeks, increase in 25 mg increments up to a max of 225 mg/day in single or divided doses - Maintenance: 75-150 mg/day ORALLY in single or divided doses - Dysthymia - 75 mg/day PO (2-3 divided doses) for 2 weeks, increase in 25 mg increments up to a max of 225 mg/day in single or divided doses - Inpatients: 100-150 mg/day PO (2-3 divided doses) for 2 weeks; may increase in 25 mg increments up to a MAX of 225 mg/day in single or divided doses - Maintenance: 75-150 mg/day ORALLY in single or divided doses - Mixed anxiety and depressive disorder - Outpatients 75 mg/day PO (2-3 divided doses) for 2 weeks, increase in 25 mg increments up to a max of 225 mg/day in single or divided doses - Inpatients: 100-150 mg/day PO (2-3 divided doses) for 2 weeks, increase in 25 mg increments up to a max of 225 mg/day in single or divided doses - Maintenance: 75-150 mg/day ORALLY in single or divided doses ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information about Off-Label Guideline-Supported Use of Maprotiline in adult patients. ### Non–Guideline-Supported Use - Pain - There is limited information about Off-Label Non–Guideline-Supported Use of Maprotiline in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) Safety has not been established below 18 years of age. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information about Off-Label Guideline-Supported Use of Maprotiline in pediatric patients. ### Non–Guideline-Supported Use - There is limited information about Off-Label Non–Guideline-Supported Use of Maprotiline in pediatric patients. # Contraindications - Contraindicated in patients hypersensitive to maprotiline and in patients with known or suspected seizure disorders. - It should not be given concomitantly with monoamine oxidase (MAO) inhibitors. - A minimum of 14 days should be allowed to elapse after discontinuation of MAO inhibitors before treatment with maprotiline is initiated. - Effects should be monitored with gradual increase in dosage until optimum response is achieved. - Not recommended for use during the acute phase of myocardial infarction. # Warnings 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 9 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. - 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 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. - 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 maprotiline 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 maprotiline is not approved for use in treating bipolar depression. Seizures have been associated with the use of maprotiline - Most of the seizures have occurred in patients without a known history of seizures. However, in some of these cases, other confounding factors were present, including concomitant medications known to lower the seizure threshold, rapid escalation of the dosage of maprotiline, and dosage that exceeded the recommended therapeutic range. The incidence of direct reports is less than 1/10 of 1%. The risk of seizures may be increased when maprotiline is taken concomitantly with phenothiazines, when the dosage of benzodiazepines is rapidly tapered in patients receiving maprotiline or when the recommended dosage of maprotiline hydrochloride is exceeded. While a cause and effect relationship has not been established, the risk of seizures in patients treated with maprotiline may be reduced by - Initiating therapy at a low dosage, - Maintaining the initial dosage for 2 weeks before raising it gradually in small increments as necessitated by the long half-life of maprotiline (average 51 hours), and - Keeping the dosage at the minimally effective level during maintenance therapy. (See dosage and administration.) - Extreme caution should be used when this drug is given to: - Patients with a history of myocardial infarction; - Patients with a history or presence of cardiovascular disease because of the possibility of conduction defects, arrhythmias, myocardial infarction, strokes and tachycardia. General precautions - The possibility of suicide in seriously depressed patients is inherent in their illness and may persist until significant remission occurs. Therefore, patients must be carefully supervised during all phases of treatment with maprotiline, and prescriptions should be written for the smallest number of tablets consistent with good patient management. - Hypomanic or manic episodes have been known to occur in some patients taking tricyclic antidepressant drugs, particularly in patients with cyclic disorders. Such occurrences have also been noted, rarely, with maprotiline. - Prior to elective surgery, maprotiline should be discontinued for as long as clinically feasible, since little is known about the interaction between maprotiline and general anesthetics. - Maprotiline should be administered with caution in patients with increased intraocular pressure, history of urinary retention, or history of narrow angle glaucoma because of the drug's anticholinergic properties. # Adverse Reactions ## Clinical Trials Experience Central Nervous System Cardiovascular psychiatric Gastrointestinal Hypersensitive Reactions Anticholinergic Miscellaneous ## Postmarketing Experience There is limited information regarding Maprotiline Postmarketing Experience in the drug label. # Drug Interactions - Anticholinergic or sympathomimetic drugs - Close supervision and careful adjustment of dosage are required when administering maprotiline concomitantly with anticholinergic or sympathomimetic drugs because of the possibility of additive atropine like effects. - Electroshock therapy - Concurrent administration of maprotiline with electroshock therapy should be avoided because of the lack of experience in this area. - Thyroid medication - Caution should be exercised when administering maprotiline to hyperthyroid patients or those on thyroid medication because of the possibility of enhanced potential for cardiovascular toxicity of maprotiline. - Guanethidine - Maprotiline should be used with caution in patients receiving guanethidine or similar agents since it may block the pharmacologic effects of these drugs. - Phenothiazines or benzodiazepines - The risk of seizures may be increased when maprotiline is taken concomitantly with phenothiazines or when the dosage of benzodiazepines is rapidly tapered in patients receiving maprotiline. - Hepatic enzyme inhibitors - Because of the pharmacologic similarity of maprotiline hydrochloride to the tricyclic antidepressants, the plasma concentration of maprotiline may be increased when the drug is given concomitantly with hepatic enzyme inhibitors (e.g., cimetidine, fluoxetine) and decreased by concomitant administration with hepatic enzyme inducers (e.g., barbiturates, phenytoin), as has occurred with tricyclic antidepressants. Adjustment of the dosage of maprotiline hydrochloride may therefore be necessary in such cases. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): B Reproduction studies have been performed in female laboratory rabbits, mice, and rats at doses up to 1.3, 7, and 9 times the maximum daily human dose respectively and have revealed no evidence of impaired fertility or harm to the fetus due to maprotiline. There are, however, 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. Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Maprotiline in women who are pregnant. ### Labor and Delivery Although the effect of maprotiline on labor and delivery is unknown, caution should be exercised as with any drug with CNS depressant action. ### Nursing Mothers Maprotiline is excreted in breast milk. At steady-state, the concentrations in milk correspond closely to the concentrations in whole blood. Caution should be exercised when maprotiline hydrochloride is administered to a nursing woman. ### Pediatric Use Safety and effectiveness in the pediatric population have not been established. Anyone considering the use of maprotiline in a child or adolescent must balance the potential risks with the clinical need. ### Geriatic Use There is no FDA guidance on the use of Maprotiline in geriatric settings. ### Gender There is no FDA guidance on the use of Maprotiline with respect to specific gender populations. ### Race There is no FDA guidance on the use of Maprotiline with respect to specific racial populations. ### Renal Impairment There is no FDA guidance on the use of Maprotiline in patients with renal impairment. ### Hepatic Impairment There is no FDA guidance on the use of Maprotiline in patients with hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Maprotiline in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Maprotiline in patients who are immunocompromised. # Administration and Monitoring ### Administration - A single daily dose is an alternative to divided daily doses. Therapeutic effects are sometimes seen within 3 to 7 days, although as long as 2 to 3 weeks are usually necessary. - Initial Adult Dosage - An initial dosage of 75 mg daily is suggested for outpatients with mild to moderate depression. However, in some patients, particularly the elderly, an initial dosage of 25 mg daily may be used. Because of the long half-life of maprotiline, the initial dosage should be maintained for 2 weeks. The dosage may then be increased gradually in 25 mg increments as required and tolerated. In most outpatients a maximum dose of 150 mg daily will result in therapeutic efficacy. It is recommended that this dose not be exceeded except in the most severely depressed patients. In such patients, dosage may be gradually increased to a maximum of 225 mg. - More severely depressed, hospitalized patients should be given an initial daily dose of 100 mg to 150 mg which may be gradually increased as required and tolerated. Most hospitalized patients with moderate to severe depression respond to a daily dose of 150 mg although dosages as high as 225 mg may be required in some cases. Daily dosage of 225 mg should not be exceeded. - Elderly Patients - In general, lower dosages are recommended for patients over 60 years of age. Dosages of 50 mg to 75 mg daily are usually satisfactory as maintenance therapy for elderly patients who do not tolerate higher amounts. ### Monitoring - Maintenance - Dosage during prolonged maintenance therapy should be kept at the lowest effective level. Dosage may be reduced to levels of 75 mg to 150 mg daily during such periods, with subsequent adjustment depending on therapeutic response. # IV Compatibility There is limited information regarding the compatibility of Maprotiline and IV administrations. # Overdosage - Deaths may occur from overdosage with this class of drugs. Multiple drug ingestion (including alcohol) is common in deliberate overdose. As the management is complex and changing, it is recommended that the physician contact a poison control center for current information on treatment. Signs and symptoms of toxicity develop rapidly after overdose. Therefore, hospital monitoring is required as soon as possible. - Animal Oral LD50 - The oral LD50 of maprotiline hydrochloride is 600 to 750 mg/kg in mice, 760 to 900 mg/kg in rats, > 1000 mg/kg in rabbits, > 300 mg/kg in cats, and > 30 mg/kg in dogs. - Manifestations - Data dealing with overdosage in humans are limited with only a few cases on record. Signs and symptoms of maprotiline hydrochloride overdose are similar to those seen with tricyclic overdose. Critical manifestations of overdose include cardiac dysrhythmias, severe hypotension, convulsions and CNS depression including coma. Changes in the electrocardiogram, particularly in QRS axis or width are clinically significant indicators of toxicity. Other clinical manifestations include drowsiness, tachycardia, ataxia, vomiting, cyanosis, shock, restlessness, agitation, hyperpyrexia, muscle rigidity, athetoid movements, and mydriasis. Since congestive heart failure has been seen with overdosages of tricyclic antidepressants, it should be considered with maprotiline hydrochloride overdosage. - Management - Obtain an ECG and immediately initiate cardiac monitoring. Protect the patient's airway, establish an intravenous line and initiate gastric decontamination. A minimum of 6 hours of observation with cardiac monitoring and observation for signs of CNS or respiratory depression, hypotension, cardiac dysrhythmias and/or conduction blocks, and seizures is necessary. If signs of toxicity occur at any time during this period, extended monitoring is required. There are case reports of patients succumbing to fatal dysrhythmias late after tricyclic overdose; these patients had clinical evidence of significant poisoning prior to death and most received inadequate gastrointestinal decontamination. Monitoring of plasma drug levels should not guide management of the patient. - Gastrointestinal Decontamination - All patients suspected of overdose should receive gastrointestinal decontamination. This should include large volume gastric lavage followed by activated charcoal. If consciousness is impaired, the airway should be secured prior to lavage. Emesis is contraindicated. - Cardiovascular - A maximal limb lead QRS duration of ≥ 0.10 seconds may be the best indication of the severity of the overdose. Intravenous sodium bicarbonate should be used to maintain the serum pH in the range of 7.45 to 7.55. If the pH response is inadequate, hyperventilation may also be used. :*Concomitant use of hyperventilation and sodium bicarbonate should be done with extreme caution, with frequent pH monitoring. A pH > 7.60 or a Pco2 < 20 mmHg is undesirable. Dysrhythmias unresponsive to sodium bicarbonate therapy/hyperventilation may respond to lidocaine, bretylium, or phenytoin. Type 1A and 1C antiarrhythmics are generally contraindicated (e.g., quinidine, disopyramide, and procainamide). - In rare instances, hemoperfusion may be beneficial in acute refractory cardiovascular instability in patients with acute toxicity. However, hemodialysis, peritoneal dialysis, exchange transfusions, and forced diuresis generally have been reported as ineffective. - CNS - In patients with CNS depression, early intubation is advised because of the potential for abrupt deterioration. Seizures should be controlled with benzodiazepines, or if these are ineffective, other anticonvulsants (e.g., phenobarbital, phenytoin). Physostigmine is not recommended except to treat life threatening symptoms that have been unresponsive to other therapies, and then only in consultation with a poison control center. - Psychiatric Follow-up - Since overdosage is often deliberate, patients may attempt suicide by other means during the recovery phase. Psychiatric referral may be appropriate. - Pediatric Management - The principles of management of child and adult overdosages are similar. It is strongly recommended that the physician contact the local poison control center for specific pediatric treatment. # Pharmacology ## Mechanism of Action The mechanism of action of maprotiline is not precisely known. It does not act primarily by stimulation of the central nervous system and is not a monoamine oxidase inhibitor. The postulated mechanism of maprotiline is that it acts primarily by potentiation of central adrenergic synapses by blocking reuptake of norepinephrine at nerve endings. This pharmacologic action is thought to be responsible for the drug's antidepressant and anxiolytic effects. The mean time to peak is 12 hours. The half-life of elimination averages 51 hours. It exerts blocking effects at the following postsynaptic receptors: - Strong : alpha1 - Moderate : 5-HT2, muscarinic, H1, D2 - Weak : alpha2 - Extremely weak : 5-HT1 The pharmacologic profile of Maprotiline explains its antidepressant, sedative, anxiolytic, sympatholytic, and anticholinergic activities. Additionally, it shows a strong antagonism against Reserpine-induced effects in animal studies, as do the other 'classical' antidepressants. Although Maprotiline behaves in most regards as a 'first generation antidepressant' it is commonly referred to as 'second generation antidepressant'. Sedation has a fast onset (the same day), while remission of the depression itself is noted usually after a latent period of one to four weeks. Maprotiline does not brighten up the mood in nondepressed persons. ## Structure Maprotiline hydrochloride, USP is a tetracyclic antidepressant, available as 25 mg, 50 mg and 75 mg tablets for oral administration. Its chemical name is N-methyl-9,10-ethanoanthracene-9(10H)-propylamine hydrochloride, and its structural formula is: Maprotiline hydrochloride is a fine, white to off-white, practically odorless crystalline powder. It is freely soluble in methanol and in chloroform, slightly soluble in water, and practically insoluble in isooctane. Its molecular weight is 313.87. The tablets contain the following inactive ingredients: colloidal silicon dioxide, croscarmellose sodium, hypromellose, magnesium stearate, microcrystalline cellulose, polydextrose, polyethylene glycol, pregelatinized starch, sodium lauryl sulfate, titanium dioxide and triacetin. Additionally, the 50 mg tablet contains FD&C Blue No. 1 Aluminum Lake. ## Pharmacodynamics There is limited information regarding Maprotiline Pharmacodynamics in the drug label. ## Pharmacokinetics There is limited information regarding Maprotiline Pharmacokinetics in the drug label. ## Nonclinical Toxicology There is limited information regarding Maprotiline Nonclinical Toxicology in the drug label. # Clinical Studies There is limited information regarding Maprotiline Clinical Studies in the drug label. # How Supplied Maprotiline Hydrochloride, USP is available as tablets containing 25 mg, 50 mg, or 75 mg of maprotiline hydrochloride. The 25 mg tablets are white film-coated, round, scored tablets debossed with 6 to the left of the score and 0 to the right of the score on one side of the tablet and M on the other side. They are available as follows: NDC 0378-0060-01 bottles of 100 tablets The 50 mg tablets are light blue film-coated, round, scored, tablets debossed with 8 to the left of the score and 7 to the right of the score on one side and M on the other side. They are available as follows: NDC 0378-0087-01 bottles of 100 tablets The 75 mg tablets are white film-coated, round, scored tablets debossed with 9 to the left of the score and 2 to the right of the score on one side and M on the other side. They are available as follows: NDC 0378-0092-01 bottles of 100 tablets ## Storage Store at 20° to 25°C (68° to 77°F). [See USP for Controlled Room Temperature.] # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information Prescribers or other health professionals should inform patients, their families, and their caregivers about the benefits and risks associated with treatment with maprotiline and should counsel them in its appropriate use. A patient Medication Guide about "Antidepressant Medicines, Depression and other Serious Mental Illness and Suicidal Thoughts or Actions" is available for maprotiline. 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 maprotiline. 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 a need for very close monitoring and possibly changes in the medication. - Medication Guide - Antidepressant Medicines, Depression and other Serious Mental Illnesses, and Suicidal Thoughts or Actions Read the Medication Guide that comes with you or your family member's antidepressant medicine. This Medication Guide is only about the risk of suicidal thoughts and actions with antidepressant medicines. Talk to your, or your family member's, healthcare provider about: - All risks and benefits of treatment with antidepressant medicines - All treatment choices for depression or other serious mental illness - What is the most important information I should know about antidepressant medicines, depression and other serious mental illnesses, and suicidal thoughts or actions? - Antidepressant medicines may increase suicidal thoughts or actions in some children, teenagers, and young adults within the first few months of treatment. - Depression and other serious mental illnesses are the most important causes of suicidal thoughts and actions. Some people may have a particularly high risk of having suicidal thoughts or actions. These include people who have (or have a family history of) bipolar illness also called manic-depressive illness) or suicidal thoughts or actions. - How can I watch for and try to prevent suicidal thoughts and actions in myself or a family member? - Pay close attention to any changes, especially sudden changes, in mood, behaviors, thoughts, or feelings. This is very important when an antidepressant medicine is started or when the dose is changed. - Call the healthcare provider right away to report new or sudden changes in mood, behavior, thoughts, or feelings. - Keep all follow-up visits with the healthcare provider as scheduled. Call the healthcare provider between visits as needed, especially if you have concerns about symptoms. - Call a healthcare provider right away if you or your family member has any of the following symptoms, especially if they are new, worse, or worry you: - Thoughts about suicide or dying - Attempts to commit suicide - New or worse depression - New or worse anxiety - Feeling very agitated or restless - Panic attacks - Trouble sleeping (insomnia) - New or worse irritability - Acting aggressive, being angry, or violent - Acting on dangerous impulses - An extreme increase in activity and talking (mania) - Other unusual changes in behavior or mood - What else do I need to know about antidepressant medicines? - Never stop an antidepressant medicine without first talking to a healthcare provider. Stopping an antidepressant medicine suddenly can cause other symptoms. - Antidepressants are medicines used to treat depression and other illnesses. It is important to discuss all the risks of treating depression and also the risks of not treating it. Patients and their families or other caregivers should discuss all treatment choices with the healthcare provider, not just the use of antidepressants. - Antidepressant medicines have other side effects. Talk to the healthcare provider about the side effects of the medicine prescribed for you or your family member. - Antidepressant medicines can interact with other medicines. Know all of the medicines that you or your family member takes. Keep a list of all medicines to show the healthcare provider. Do not start new medicines without first checking with your healthcare provider. - Not all antidepressant medicines prescribed for children are FDA approved for use in children. Talk to your child's healthcare provider for more information. - Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. - This Medication Guide has been approved by the U.S. Food and Drug Administration for all antidepressants. # Precautions with Alcohol Alcohol-Maprotiline 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 Maprotiline Brand Names in the drug label. # Look-Alike Drug Names There is limited information regarding Maprotiline Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	https://www.wikidoc.org/index.php/Ludiomil
7c756ec2d518a0f5fa0390658419d8fde7bb1e3e	wikidoc	Lumiracoxib	Lumiracoxib # Overview Lumiracoxib (rINN) is a COX-2 selective inhibitor non-steroidal anti-inflammatory drug, manufactured by Novartis and still sold in few countries, including Mexico, South Africa, and Brazil, under the trade name Prexige (sometimes misquoted as "Prestige" by the media). The TARGET study (Therapeutic Arthritis Research and Gastrointestinal Event Trial) was conducted with more than 18,000 patients to test its gastrointestinal and cardiovascular safety against Naproxen and Ibuprofen and also study its efficacy against these two NSAIDs. In November 2006, Prexige received marketing approval for all European Union countries through a common procedure called MRP. As of 2007, the Food and Drug Administration (FDA) has not yet granted approval for its sale in the United States. Lumiracoxib has a different structure from the standard COX-2 inhibitors (e.g. celecoxib). It more closely resembles the structure of diclofenac (one chlorine substituted by fluorine, the phenylacetic acid has another methyl group in meta position), making it a member of the arylalkanoic acid family of NSAIDs. It binds to a different site on the COX-2 receptor than the standard COX-2 inhibitors. It displays extremely high COX-2 selectivity. The FDA rejected Prexige as a trade name for lumiracoxib in 2003. The FDA Division of Medication Errors and Technical Support (DMETS) subsequently recommended against the alternative name Prexede. The planned trade name for lumiracoxib in the US has not been disclosed to the public. On September 27, 2007, the US Food and Drug Administration issued a not approvable letter for lumiracoxib, requiring additional safety data. # Withdrawal from market On August 11, 2007, Australia's Therapeutic Goods Administration (TGA, the Australian equivalent of the FDA) cancelled the registration of lumiracoxib in Australia due to concerns that it may cause liver failure. According to the TGA's Principal Medical Adviser, Dr Rohan Hammett, as of 10 August 2007 the TGA had received 8 reports of serious adverse liver reactions to the drug, including two deaths and two liver transplants. "The TGA and its expert advisory committee, the Adverse Drug Reactions Advisory Committee (ADRAC), have urgently investigated these reports. ADRAC has today recommended the cancellation of the registration of Lumiracoxib due to the severity of the reported side effects associated with this drug," Dr Hammett said. "The TGA has taken this advice to cancel the registration of Lumiracoxib in order to prevent further cases of severe liver damage. "It seems that the longer people are on the medicine, the greater the chance of liver injury. The TGA is, therefore, advising people to stop taking the Lumiracoxib immediately and to discuss alternative treatments with their doctor," Dr Hammett said. New Zealand has followed suit with Australia in recalling Prexige. On October 3, 2007, Health Canada requested sales of Prexige to stop. Novartis has agreed to the request and has taken steps to do so.On December 13, 2007, the European Medicines Agency recommended the withdrawal for Prexige from all EU markets.	Lumiracoxib Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview Lumiracoxib (rINN) is a COX-2 selective inhibitor non-steroidal anti-inflammatory drug, manufactured by Novartis and still sold in few countries, including Mexico, South Africa, and Brazil, under the trade name Prexige (sometimes misquoted as "Prestige" by the media). The TARGET study (Therapeutic Arthritis Research and Gastrointestinal Event Trial) was conducted with more than 18,000 patients to test its gastrointestinal and cardiovascular safety against Naproxen and Ibuprofen and also study its efficacy against these two NSAIDs. In November 2006, Prexige received marketing approval for all European Union countries through a common procedure called MRP. As of 2007, the Food and Drug Administration (FDA) has not yet granted approval for its sale in the United States. Lumiracoxib has a different structure from the standard COX-2 inhibitors (e.g. celecoxib). It more closely resembles the structure of diclofenac (one chlorine substituted by fluorine, the phenylacetic acid has another methyl group in meta position), making it a member of the arylalkanoic acid family of NSAIDs. It binds to a different site on the COX-2 receptor than the standard COX-2 inhibitors. It displays extremely high COX-2 selectivity. The FDA rejected Prexige as a trade name for lumiracoxib in 2003. The FDA Division of Medication Errors and Technical Support (DMETS) subsequently recommended against the alternative name Prexede. The planned trade name for lumiracoxib in the US has not been disclosed to the public. On September 27, 2007, the US Food and Drug Administration issued a not approvable letter for lumiracoxib, requiring additional safety data. # Withdrawal from market On August 11, 2007, Australia's Therapeutic Goods Administration (TGA, the Australian equivalent of the FDA) cancelled the registration of lumiracoxib in Australia due to concerns that it may cause liver failure. According to the TGA's Principal Medical Adviser, Dr Rohan Hammett, as of 10 August 2007 the TGA had received 8 reports of serious adverse liver reactions to the drug, including two deaths and two liver transplants. "The TGA and its expert advisory committee, the Adverse Drug Reactions Advisory Committee (ADRAC), have urgently investigated these reports. ADRAC has today recommended the cancellation of the registration of Lumiracoxib due to the severity of the reported side effects associated with this drug," Dr Hammett said. "The TGA has taken this advice to cancel the registration of Lumiracoxib in order to prevent further cases of severe liver damage. "It seems that the longer people are on the medicine, the greater the chance of liver injury. The TGA is, therefore, advising people to stop taking the Lumiracoxib immediately and to discuss alternative treatments with their doctor," Dr Hammett said. New Zealand has followed suit with Australia in recalling Prexige. On October 3, 2007, Health Canada requested sales of Prexige to stop. Novartis has agreed to the request and has taken steps to do so.On December 13, 2007, the European Medicines Agency recommended the withdrawal for Prexige from all EU markets.	https://www.wikidoc.org/index.php/Lumiracoxib
631804a25a41659cb3b28239f8ba60ee7a27257f	wikidoc	Lung (Zang)	Lung (Zang) As distinct from the Western medical concept of Lungs, the concept of Zang from Traditional Chinese Medicine is more a way of describing a set of interrelated parts than an anatomical organ. (See Zang Fu theory) To differentiate between western or eastern concepts of organs the first letter is capitalized (Liver, instead of liver, Spleen instead of spleen). Because Traditional Chinese Medicine (TCM) is wholistic, each organ cannot be explained fully unless the TCM relationship/homeostasis with the other organs is understood. TCM also looks at the functions of the organs rather than fixed areas and, therefore, describes different organs that are not actually physical, like the Triple Burner (San Jiao). This also leads to controversy about the validity of TCM, which comes a lot from the difficulty of translating and lack knowledge about TCM concepts and Chinese culture. So, to avoid conflict and to keep an open mind, please realize that these notions evolved in a different culture and are a different way of viewing the human body. The Lungs (Fei) is a Zang organ meaning it is a Yin organ. The other Yin, or Zang, Organs are the Kidneys (Shen) Liver (Gan), Spleen (Pi), and Heart (Xin). Sometimes the Pericardium (Xin Bao) is included. Yin organs store, secrete, make, and transform Essence, Blood, Spirit, Qi, and Fluids. These nourish the body. The Lungs connect with the throat and open into the nose. The Lungs govern Qi. They take in clear and expel the turbid Natural Air Qi (Kong Qi). The Lungs regulate the waterways. Fluid secretion is sweat. The Lungs govern the skin’s surface and body hair. They house the Po. The peak time for the Lungs is from 3-5am.	Lung (Zang) As distinct from the Western medical concept of Lungs, the concept of Zang from Traditional Chinese Medicine is more a way of describing a set of interrelated parts than an anatomical organ. (See Zang Fu theory) To differentiate between western or eastern concepts of organs the first letter is capitalized (Liver, instead of liver, Spleen instead of spleen). Because Traditional Chinese Medicine (TCM) is wholistic, each organ cannot be explained fully unless the TCM relationship/homeostasis with the other organs is understood. TCM also looks at the functions of the organs rather than fixed areas and, therefore, describes different organs that are not actually physical, like the Triple Burner (San Jiao). This also leads to controversy about the validity of TCM, which comes a lot from the difficulty of translating and lack knowledge about TCM concepts and Chinese culture. So, to avoid conflict and to keep an open mind, please realize that these notions evolved in a different culture and are a different way of viewing the human body. The Lungs (Fei) is a Zang organ meaning it is a Yin organ. The other Yin, or Zang, Organs are the Kidneys (Shen) Liver (Gan), Spleen (Pi), and Heart (Xin). Sometimes the Pericardium (Xin Bao) is included. Yin organs store, secrete, make, and transform Essence, Blood, Spirit, Qi, and Fluids. These nourish the body. The Lungs connect with the throat and open into the nose. The Lungs govern Qi. They take in clear and expel the turbid Natural Air Qi (Kong Qi). The Lungs regulate the waterways. Fluid secretion is sweat. The Lungs govern the skin’s surface and body hair. They house the Po. The peak time for the Lungs is from 3-5am. Template:WH Template:WS	https://www.wikidoc.org/index.php/Lung_(Zang)
cf16caea976f7751ebb03e94518698290f88920a	wikidoc	Nyctophobia	Nyctophobia # Background Nyctophobia (from Greek νυξ nic-to-pho-bi-a: "night" and phobia, also called scotophobia, from σκότος - "darkness", lygophobia, from lyge - "twilight", or noctiphobia) is a pathological fear of the dark. Sufferers have an abnormal and persistent dread of the dark and experience anxiety even though they may rationally understand that the dark does not pose such a great threat. Treatment options are typical for any of specific phobias. Nyctophobia is most often associated with children. Nyctophobia is the pinnacle in the plot of the short story "Nightfall" by Isaac Asimov. de:Nyktophobie et:Nüktofoobia he:ניקטופוביה sv:Skotofobi	Nyctophobia Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Background Nyctophobia (from Greek νυξ nic-to-pho-bi-a: "night" and phobia, also called scotophobia, from σκότος - "darkness", lygophobia, from lyge - "twilight", or noctiphobia) is a pathological fear of the dark. Sufferers have an abnormal and persistent dread of the dark and experience anxiety even though they may rationally understand that the dark does not pose such a great threat. Treatment options are typical for any of specific phobias. Nyctophobia is most often associated with children. Nyctophobia is the pinnacle in the plot of the short story "Nightfall" by Isaac Asimov. de:Nyktophobie et:Nüktofoobia he:ניקטופוביה sv:Skotofobi	https://www.wikidoc.org/index.php/Lygophobia
0b8dfd1468af2d23bbea77bdee25df778be7a870	wikidoc	Lymecycline	Lymecycline Lymecycline is a tetracycline broad-spectrum antibiotic marketed by the pharmeceutical company Galderma. It is approximately 5000 times more soluble than tetracycline base and is unique amongst tetracyclines in that it is absorbed by the "active transport" process across the intestinal wall, making use of the same fast and efficient mechanism by which carbohydrates are absorbed. The greater absorption of Lymecycline allows for lower dosages to be used; the standard dose of 408 mg is equivalent to 300 mg tetracycline base, and in its action to 500 mg tetracycline hydrochloride. Lymecycline, unlike tetracycline hydrochloride, is soluble at all physiological pH values. # History Lymecycline was released onto the pharmaceutical market in 1963. # Indications Lymecycline, like other Tetracyclines, is used to treat a range of infections (see Tetracycline antibiotics group). Its better absorption profile makes it preferable to tetracycline for moderately severe acne and typically prescribed for 8 weeks at a time, but alternatives should be sought if no improvement occurs by 3 months. # Dosage The standard dose is 408mg (one capsule) twelve hourly by mouth. In particularly severe infections this dose may be increased to 1.224-1.632mg (three or four capsules) daily. The 408mg once daily dosage for acne aids good drug compliance. # Formulation Capsules containing 408mg of Lymecycline (brand name Tetrlysal 300).	Lymecycline Lymecycline is a tetracycline broad-spectrum antibiotic marketed by the pharmeceutical company Galderma[1]. It is approximately 5000 times more soluble than tetracycline base and is unique amongst tetracyclines in that it is absorbed by the "active transport" process across the intestinal wall, making use of the same fast and efficient mechanism by which carbohydrates are absorbed.[2] The greater absorption of Lymecycline allows for lower dosages to be used; the standard dose of 408 mg is equivalent to 300 mg tetracycline base, and in its action to 500 mg tetracycline hydrochloride. Lymecycline, unlike tetracycline hydrochloride, is soluble at all physiological pH values. # History Lymecycline was released onto the pharmaceutical market in 1963. # Indications Lymecycline, like other Tetracyclines, is used to treat a range of infections (see Tetracycline antibiotics group). Its better absorption profile makes it preferable to tetracycline for moderately severe acne and typically prescribed for 8 weeks at a time, but alternatives should be sought if no improvement occurs by 3 months.[3] # Dosage The standard dose is 408mg (one capsule) twelve hourly by mouth. In particularly severe infections this dose may be increased to 1.224-1.632mg (three or four capsules) daily. The 408mg once daily dosage for acne aids good drug compliance. # Formulation Capsules containing 408mg of Lymecycline (brand name Tetrlysal 300).	https://www.wikidoc.org/index.php/Lymecycline
4ad1fe517e3ce7cc62c903258d91c7ef230b71dd	wikidoc	Lymphangion	Lymphangion A lymphangion is the functional unit of a lymph capillary or lymph vessel that lies between two semilunar (half moon-shaped) valves. Lymph vessels are channels larger than the lymph capillaries that have thicker walls and smooth muscles in their walls, thus lymph vessel lymphangion would be muscular, and capable of contracting on its own. The capillary lymphangion on the other hand does not have smooth muscles, and the lymph in it is propelled forward only because of force exerted on its walls from the exterior. Such forces include skeletal muscle contractions and arterial pulsations. Also, the inspiration during respiration provides a suction pressure within the lumen. The semilunar valves are directed towards the flow of the lymph and open when the pressure in the first lymphangion is greater than the pressure in the next lymphangion. Pressure in the first lymphangion may increase because of smooth muscle contraction (in lymph vessel) or because of pressure on the walls from outside (in a capillary) result because of. Alternatively, pressure within the next lymphangion may decrease because of negative pressure as a result of inspiration. Once, the lymph flows into the next lymphangion, it cannot return to the previous lymphangion, as the semilunar valves close tightly. In conditions when the pressure in a lymphatic is sufficiently great, the valves may fail, and there can indeed be backward flow of lymph resulting in edema of the drained region. This may happen with blockade of lymph flow because of pathology in the draining lymph node or at some point in the vessel.	Lymphangion Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] A lymphangion is the functional unit of a lymph capillary or lymph vessel that lies between two semilunar (half moon-shaped) valves.[1] Lymph vessels are channels larger than the lymph capillaries that have thicker walls and smooth muscles in their walls, thus lymph vessel lymphangion would be muscular, and capable of contracting on its own. The capillary lymphangion on the other hand does not have smooth muscles, and the lymph in it is propelled forward only because of force exerted on its walls from the exterior. Such forces include skeletal muscle contractions and arterial pulsations. Also, the inspiration during respiration provides a suction pressure within the lumen. The semilunar valves are directed towards the flow of the lymph and open when the pressure in the first lymphangion is greater than the pressure in the next lymphangion. Pressure in the first lymphangion may increase because of smooth muscle contraction (in lymph vessel) or because of pressure on the walls from outside (in a capillary) result because of. Alternatively, pressure within the next lymphangion may decrease because of negative pressure as a result of inspiration. Once, the lymph flows into the next lymphangion, it cannot return to the previous lymphangion, as the semilunar valves close tightly. In conditions when the pressure in a lymphatic is sufficiently great, the valves may fail, and there can indeed be backward flow of lymph resulting in edema of the drained region. This may happen with blockade of lymph flow because of pathology in the draining lymph node or at some point in the vessel.	https://www.wikidoc.org/index.php/Lymphangion
7b0a4d0dfa9f50cf82bf8dc063d874d47863a432	wikidoc	Lymphotoxin	Lymphotoxin Lymphotoxin (previously known as tumor necrosis factor-beta) is a lymphokine cytokine. It is a protein that is produced by Th1 type T-cells and induces vascular endothelial cells to change their surface adhesion molecules to allow phagocytic cells to bind to them. It is also known to be required for normal development of Peyer's patches. Lymphotoxin is homologous to Tumor Necrosis Factor beta, but secreted by T-cells. It is paracrine due to the small amounts produced. The effects are similar to TNF-alpha, but TNF-beta is also important for the development of lymphoid organs.	Lymphotoxin Lymphotoxin (previously known as tumor necrosis factor-beta) is a lymphokine cytokine. It is a protein that is produced by Th1 type T-cells and induces vascular endothelial cells to change their surface adhesion molecules to allow phagocytic cells to bind to them.[1] It is also known to be required for normal development of Peyer's patches.[2] Lymphotoxin is homologous to Tumor Necrosis Factor beta, but secreted by T-cells. It is paracrine due to the small amounts produced. The effects are similar to TNF-alpha, but TNF-beta is also important for the development of lymphoid organs.	https://www.wikidoc.org/index.php/Lymphotoxin
06218926e0be87657d225f3b096c0b496dabde13	wikidoc	Lyn Redwood	Lyn Redwood Lyn Redwood, RN, MSN, CRNP, is a nurse practitioner specializing in pediatrics and women's health care for over twentyfive years, and the president and co-founder of Safe Minds. Redwood is a board of health member for Fayette County, Georgia, and a Tyrone, Georgia, town councilmember. Redwood is a board member of the National Autism Association. Redwood has testified before the United States House of Representatives Government Reform Committee, where she presented 'Mercury in Medicine: Are We Taking Unnecessary Risks?' Redwood co-authored the treatise "Autism: A Novel Form of Mercury Toxicity", that was published in Neurotoxicology, Medical Hypotheses, Molecular Psychiatry, Mothering and Autism-Asperger's Digest. She has appeared on Good Morning America, the Montel Williams Show, and has been interviewed by U.S. News and World Report, Wired Magazine, and People. Redwood is prominently featured in the award winning book by David Kirby, Evidence of Harm. In 1999, Redwood's son, Will, was diagnosed with pervasive developmental disorder (PDD), not otherwise specified. After calculating the level of mercury exposure her son had received from multiple vaccines containing thimerosal (49% ethylmercury by weight), Redwood determined that her son had been exposed to levels 125 times the EPA Federal Safety guidelines. # Education Redwood earned her bachelor of science in nursing, and her masters of science in community health nursing. # Safe Minds The Coalition for SafeMinds was founded by Redwood and other parents of children diagnosed with autism spectrum disorders, including Sallie Bernard and Mark Blaxill. SafeMinds was organized to raise awareness, support research, change policy and focus national attention on the growing evidence of a link between mercury poisoning and neurological disorders such as autism, attention deficit disorder, language delay and learning difficulties. In April, 2000, SafeMinds released the first definitive review of the link between mercury and autism spectrum disorders, which sought to demonstrate how such disorders mirror mercury poisoning. The resulting report, Autism: A Novel Form of Mercury Poisoning (Bernard, Enayati, Redwood, Roger, Binstock) is recognized as a cornerstone document to the discourse on medical mercury exposure and neurotoxicity and its adverse effects on health. The work of SafeMinds' parent advocate founders is documented in several highly publicized journalistic reports including Robert F. Kennedy, Jr.'s 2005 Rolling Stone article "Deadly Immunity", and David Kirby 2005 book, Evidence of Harm, Mercury in Vaccines and the Autism Epidemic: A Medical Controversy. Kirby's book has since been opted for a movie by Participant Productions. ## Evidence of Harm David Kirby's Evidence of Harm highlights the stories behind the founding of Safe Minds. In November 2002, Kirby learned of 'the thimerosal theory' while investigating autism treatments for an article he was writing. Evidence of Harm relates the story of SafeMinds parents Lyn Redwood, Sallie Bernard, Liz Birt, Albert Enayati, Heidi Roger, and Mark Blaxill. Kirby gives credit to these parents for taking on government agencies and the drug companies, and provides insight into the reasons that such parents look askance at the credibility of evidence put forward by mainstream medical authorities to either explain or falsify the explosion in autism cases in recent years. # Danish study criticized Redwood and Safe Minds have criticized a 2003 Danish study, published in the Journal of the American Medical Association, that found no relationship between thimerosal-containing vaccines and autism. Redwood and Safe Minds re-analyzed the study's dataset, and claimed the data had been intentionally misinterpreted Redwood also alleged conflicts of interest on the part of the researchers, given the authors' employment with the manufacturer and promoter of vaccines in Denmark, Statens Serum Institute.	Lyn Redwood Lyn Redwood, RN, MSN, CRNP, is a nurse practitioner specializing in pediatrics and women's health care for over twentyfive years, and the president and co-founder of Safe Minds. Redwood is a board of health member for Fayette County, Georgia, and a Tyrone, Georgia, town councilmember. Redwood is a board member of the National Autism Association. Redwood has testified before the United States House of Representatives Government Reform Committee, where she presented 'Mercury in Medicine: Are We Taking Unnecessary Risks?' Redwood co-authored the treatise "Autism: A Novel Form of Mercury Toxicity", that was published in Neurotoxicology, Medical Hypotheses, Molecular Psychiatry, Mothering and Autism-Asperger's Digest. She has appeared on Good Morning America, the Montel Williams Show, and has been interviewed by U.S. News and World Report, Wired Magazine, and People. Redwood is prominently featured in the award winning book by David Kirby, Evidence of Harm. In 1999, Redwood's son, Will, was diagnosed with pervasive developmental disorder (PDD), not otherwise specified. After calculating the level of mercury exposure her son had received from multiple vaccines containing thimerosal (49% ethylmercury by weight)[citation needed], Redwood determined that her son had been exposed to levels 125 times the EPA Federal Safety guidelines. # Education Redwood earned her bachelor of science in nursing, and her masters of science in community health nursing. # Safe Minds The Coalition for SafeMinds was founded by Redwood and other parents of children diagnosed with autism spectrum disorders, including Sallie Bernard and Mark Blaxill. SafeMinds was organized to raise awareness, support research, change policy and focus national attention on the growing evidence of a link between mercury poisoning and neurological disorders such as autism, attention deficit disorder, language delay and learning difficulties. In April, 2000, SafeMinds released the first definitive review of the link between mercury and autism spectrum disorders, which sought to demonstrate how such disorders mirror mercury poisoning. The resulting report, Autism: A Novel Form of Mercury Poisoning (Bernard, Enayati, Redwood, Roger, Binstock) is recognized as a cornerstone document to the discourse on medical mercury exposure and neurotoxicity and its adverse effects on health. The work of SafeMinds' parent advocate founders is documented in several highly publicized journalistic reports including Robert F. Kennedy, Jr.'s 2005 Rolling Stone article "Deadly Immunity", and David Kirby 2005 book, Evidence of Harm, Mercury in Vaccines and the Autism Epidemic: A Medical Controversy. Kirby's book has since been opted for a movie by Participant Productions. ## Evidence of Harm David Kirby's Evidence of Harm highlights the stories behind the founding of Safe Minds. In November 2002, Kirby learned of 'the thimerosal theory' while investigating autism treatments for an article he was writing. Evidence of Harm relates the story of SafeMinds parents Lyn Redwood, Sallie Bernard, Liz Birt, Albert Enayati, Heidi Roger, and Mark Blaxill. Kirby gives credit to these parents for taking on government agencies and the drug companies, and provides insight into the reasons that such parents look askance at the credibility of evidence put forward by mainstream medical authorities to either explain or falsify the explosion in autism cases in recent years. # Danish study criticized Redwood and Safe Minds have criticized a 2003 Danish study, published in the Journal of the American Medical Association, that found no relationship between thimerosal-containing vaccines and autism.[1] Redwood and Safe Minds re-analyzed the study's dataset, and claimed the data had been intentionally misinterpreted Redwood also alleged conflicts of interest on the part of the researchers, given the authors' employment with the manufacturer and promoter of vaccines in Denmark, Statens Serum Institute.[2]	https://www.wikidoc.org/index.php/Lyn_Redwood
14313c4f0b24ef8760c4278bc7477c195ac5ae7c	wikidoc	Lynestrenol	Lynestrenol # Overview Lynestrenol is a progestogen hormone. It is a synthetic orally-available progestagen associated with numerous effects of the natural progesterone hormone. Lynestrenol has a strong progestational effect on the uterine endometrium (transforming proliferative endometrium into secretory one), inhibits secretion of gonadotropin, suppresses maturation of follicles in the ovaries and ovulation, reduces menstrual bleeding. This synthetic gestagen is associated with minimal estrogenic, androgenic and anabolic effects. Lynestrenol is used in treatment of hormonal disorders and diseases caused by insufficient secretion of the natural progesterone, except in case of risky pregnancies and prevention of miscarriage, since it is not efficient enough in this indication. # Pharmacology After oral administration lynestrenol is quickly resorbed and converted into pharmacologically active norethisterone, through which it demonstrates the main biological effects. The peak blood are reached within 2–4 hours after oral administration, 97% of the administered dose being bound to plasma proteins. Lynestrenol and its metabolites are predominantly excreted in the urine, less through feces, active metabolite norethisterone elimination halftime being 16-17 h.	Lynestrenol Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview Lynestrenol is a progestogen hormone. It is a synthetic orally-available progestagen associated with numerous effects of the natural progesterone hormone. Lynestrenol has a strong progestational effect on the uterine endometrium (transforming proliferative endometrium into secretory one), inhibits secretion of gonadotropin, suppresses maturation of follicles in the ovaries and ovulation, reduces menstrual bleeding. This synthetic gestagen is associated with minimal estrogenic, androgenic and anabolic effects. Lynestrenol is used in treatment of hormonal disorders and diseases caused by insufficient secretion of the natural progesterone, except in case of risky pregnancies and prevention of miscarriage, since it is not efficient enough in this indication. # Pharmacology After oral administration lynestrenol is quickly resorbed and converted into pharmacologically active norethisterone, through which it demonstrates the main biological effects. The peak blood are reached within 2–4 hours after oral administration, 97% of the administered dose being bound to plasma proteins. Lynestrenol and its metabolites are predominantly excreted in the urine, less through feces, active metabolite norethisterone elimination halftime being 16-17 h.	https://www.wikidoc.org/index.php/Lynestrenol
773145ab1a01a8aeaf637ba8deecca7bf6abee84	wikidoc	Lytic cycle	Lytic cycle The lytic cycle is one of the two cycles of viral reproduction, the other being the lysogenic cycle. These cycles should not, however, be seen as separate, but rather as somewhat interchangeable. The lytic cycle is typically considered the main method of viral replication, since it results in the destruction of the infected cell. # Description The lytic cycle is a three-stage process. ## Penetration To infect a cell, a virus must first enter the cell through the plasma membrane and (if present) the cell wall. Viruses do so by either attaching to a receptor on the cell's surface or by simple mechanical force. The virus then releases its genetic material (either single- or double-stranded DNA or RNA) into the cell. ## Biosynthesis The virus' nucleic acid uses the host cell’s machinery to make large amounts of viral components. In the case of DNA viruses, the DNA transcribes itself into messenger RNA (mRNA) molecules that are then used to direct the cell's ribosomes. One of the first polypeptides to be translated is one that destroys the hosts' DNA. In retroviruses (which inject an RNA strand), a unique enzyme called reverse transcriptase transcribes the viral RNA into DNA, which is then transcribed again into mRNA. ## Maturation and lysis After many copies of viral components are made, they are assembled into complete viruses. The phage then directs production of an enzyme that breaks down the bacteria cell wall and allows fluid to enter. The cell eventually becomes filled with viruses (typically 100-200) and liquid, and bursts, or lyses; thus giving the lytic cycle its name. The new viruses are then free to infect other cells. ### Lytic cycle without lysis Some viruses escape the host cell without bursting the cell membrane, but rather bud off from it by taking a portion of the membrane with them. Because it otherwise is characteristic of the lytic cycle in other steps, it still belongs to this category. Hepatitis C viruses presumably use this method. de:Lytischer Zyklus	Lytic cycle The lytic cycle is one of the two cycles of viral reproduction, the other being the lysogenic cycle. These cycles should not, however, be seen as separate, but rather as somewhat interchangeable. The lytic cycle is typically considered the main method of viral replication, since it results in the destruction of the infected cell. Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Description The lytic cycle is a three-stage process. ## Penetration To infect a cell, a virus must first enter the cell through the plasma membrane and (if present) the cell wall. Viruses do so by either attaching to a receptor on the cell's surface or by simple mechanical force. The virus then releases its genetic material (either single- or double-stranded DNA or RNA) into the cell. ## Biosynthesis The virus' nucleic acid uses the host cell’s machinery to make large amounts of viral components. In the case of DNA viruses, the DNA transcribes itself into messenger RNA (mRNA) molecules that are then used to direct the cell's ribosomes. One of the first polypeptides to be translated is one that destroys the hosts' DNA. In retroviruses (which inject an RNA strand), a unique enzyme called reverse transcriptase transcribes the viral RNA into DNA, which is then transcribed again into mRNA. ## Maturation and lysis After many copies of viral components are made, they are assembled into complete viruses. The phage then directs production of an enzyme that breaks down the bacteria cell wall and allows fluid to enter. The cell eventually becomes filled with viruses (typically 100-200) and liquid, and bursts, or lyses; thus giving the lytic cycle its name. The new viruses are then free to infect other cells. ### Lytic cycle without lysis Some viruses escape the host cell without bursting the cell membrane, but rather bud off from it by taking a portion of the membrane with them. Because it otherwise is characteristic of the lytic cycle in other steps, it still belongs to this category. Hepatitis C viruses presumably use this method. de:Lytischer Zyklus Template:WH Template:WS	https://www.wikidoc.org/index.php/Lytic
986e153239c18f740c8eefa5f98402339c703607	wikidoc	Lévy flight	Lévy flight A Lévy flight, named after the French mathematician Paul Pierre Lévy, is a type of random walk in which the increments are distributed according to a "heavy-tailed" distribution. A heavy-tailed distribution is a probability distribution which falls to zero as 1/\|x\|α+1 where 0 < α < 2 and therefore has an infinite variance. According to the central limit theorem, if the distribution were to have a finite variance, then after a large number of steps, the distance from the origin of the random walk would tend to a normal distribution. In contrast, if the distribution is heavy-tailed, then after a large number of steps, the distance from the origin of the random walk will tend to a Lévy distribution. Lévy flight is part of a class of Markov processes. Two-dimensional Lévy flights were described by Benoît Mandelbrot in The Fractal Geometry of Nature. The exponential scaling of the step lengths gives Lévy flights a scale invariant property, and they are used to model data that exhibits clustering. This method of simulation stems heavily from the mathematics related to chaos theory and is useful in stochastic measurement and simulations for random or pseudo-random natural phenomena. Examples include earthquake data analysis, financial mathematics, cryptography, signals analysis as well as many applications in astronomy and biology.	Lévy flight A Lévy flight, named after the French mathematician Paul Pierre Lévy, is a type of random walk in which the increments are distributed according to a "heavy-tailed" distribution. A heavy-tailed distribution is a probability distribution which falls to zero as 1/\|x\|α+1 where 0 < α < 2 and therefore has an infinite variance. According to the central limit theorem, if the distribution were to have a finite variance, then after a large number of steps, the distance from the origin of the random walk would tend to a normal distribution. In contrast, if the distribution is heavy-tailed, then after a large number of steps, the distance from the origin of the random walk will tend to a Lévy distribution. Lévy flight is part of a class of Markov processes. Two-dimensional Lévy flights were described by Benoît Mandelbrot in The Fractal Geometry of Nature. The exponential scaling of the step lengths gives Lévy flights a scale invariant property, and they are used to model data that exhibits clustering. This method of simulation stems heavily from the mathematics related to chaos theory and is useful in stochastic measurement and simulations for random or pseudo-random natural phenomena. Examples include earthquake data analysis, financial mathematics, cryptography, signals analysis as well as many applications in astronomy and biology.	https://www.wikidoc.org/index.php/L%C3%A9vy_flight
6000bf346afca1701da201276d221885fcf8d6f9	wikidoc	MAFA (gene)	MAFA (gene) Transcription factor MafA is a protein that in humans is encoded by the MAFA gene. It is a member of the Maf family of transcription factors. # MAFA assists in insulin regulation An in vivo study on mice proved MafA binds to the promoter in an insulin gene to regulate insulin transcription in response to serum glucose levels. MafA is a β cell-specific activator, which differentiates it from other transcription factors involved with insulin gene expression. It helps regulate the β cells involved with insulin secretion primarily by maintaining β cell metabolism. The amount of MafA in the β cells is regulated by levels of glucose and oxidative stress. # Interactions MafA (gene) has been shown to interact with NEUROD1 and Pdx1. MafA works with Pdx1 to activate the insulin gene.	MAFA (gene) Transcription factor MafA is a protein that in humans is encoded by the MAFA gene.[1] It is a member of the Maf family of transcription factors.[2] # MAFA assists in insulin regulation An in vivo study on mice proved MafA binds to the promoter in an insulin gene to regulate insulin transcription in response to serum glucose levels.[3] MafA is a β cell-specific activator, which differentiates it from other transcription factors involved with insulin gene expression.[4] It helps regulate the β cells involved with insulin secretion primarily by maintaining β cell metabolism.[5] The amount of MafA in the β cells is regulated by levels of glucose and oxidative stress.[2] # Interactions MafA (gene) has been shown to interact with NEUROD1[6] and Pdx1.[6] MafA works with Pdx1 to activate the insulin gene.[2]	https://www.wikidoc.org/index.php/MAFA_(gene)
ebbd309253867cfa81b9d8916441288ae80c07c3	wikidoc	MAFB (gene)	MAFB (gene) Transcription factor MafB also known as V-maf musculoaponeurotic fibrosarcoma oncogene homolog B is a protein that in humans is encoded by the MAFB gene. This gene maps to chromosome 20q11.2-q13.1, consists of a single exon and spans around 3 kb. # Function MafB is a basic leucine zipper (bZIP) transcription factor that plays an important role in the regulation of lineage-specific hematopoiesis. The encoded nuclear protein represses ETS1-mediated transcription of erythroid-specific genes in myeloid cells. # Clinical significance Mutations in the murine Mafb gene are responsible for the mutant mouse Kreisler (kr) that presents an abnormal segmentation of the hindbrain and exhibit hyperactive behavior, including head tossing and running in circles. This mice dies at birth due to renal failure whereas the Mafb -/- mice dies of central apnea. Recently, single-nucleotide polymorphisms (SNPs) near MAFB have been found associated with nonsyndromic cleft lip and palate. The GENEVA Cleft Consortium study, a genomewide association study involving 1,908 case-parent trios from Europe, the United States, China, Taiwan, Singapore, Korea, and the Philippines, first identified MAFB as being associated with cleft lip and/or palate with stronger genome-wide significance in Asian than European populations. The difference in populations could reflect variable coverage by available markers or true allelic heterogeneity. In mouse models, Mafb mRNA and protein were detected in both craniofacial ectoderm and neural crest-derived mesoderm between embryonic days 13.5 and 14.5; expression was strong in the epithelium around the palatal shelves and in the medial edge epithelium during palatal fusion. After fusion, Mafb expression was stronger in oral epithelium compared to mesenchymal tissue. In addition, sequencing analysis detected a new missense mutation in the Filipino population, H131Q, that was significantly more frequent in cases than in matched controls. The gene-poor regions either side of the MAFB gene include numerous binding sites for transcription factors that are known to have a role in palate development.	MAFB (gene) Transcription factor MafB also known as V-maf musculoaponeurotic fibrosarcoma oncogene homolog B is a protein that in humans is encoded by the MAFB gene. This gene maps to chromosome 20q11.2-q13.1, consists of a single exon and spans around 3 kb.[1][2] # Function MafB is a basic leucine zipper (bZIP) transcription factor that plays an important role in the regulation of lineage-specific hematopoiesis. The encoded nuclear protein represses ETS1-mediated transcription of erythroid-specific genes in myeloid cells.[2] # Clinical significance Mutations in the murine Mafb gene are responsible for the mutant mouse Kreisler (kr) that presents an abnormal segmentation of the hindbrain and exhibit hyperactive behavior, including head tossing and running in circles.[3] This mice dies at birth due to renal failure whereas the Mafb -/- mice dies of central apnea.[4] Recently, single-nucleotide polymorphisms (SNPs) near MAFB have been found associated with nonsyndromic cleft lip and palate. [5] The GENEVA Cleft Consortium study, a genomewide association study involving 1,908 case-parent trios from Europe, the United States, China, Taiwan, Singapore, Korea, and the Philippines, first identified MAFB as being associated with cleft lip and/or palate with stronger genome-wide significance in Asian than European populations. The difference in populations could reflect variable coverage by available markers or true allelic heterogeneity. [6] In mouse models, Mafb mRNA and protein were detected in both craniofacial ectoderm and neural crest-derived mesoderm between embryonic days 13.5 and 14.5; expression was strong in the epithelium around the palatal shelves and in the medial edge epithelium during palatal fusion. After fusion, Mafb expression was stronger in oral epithelium compared to mesenchymal tissue.[5] In addition, sequencing analysis detected a new missense mutation in the Filipino population, H131Q, that was significantly more frequent in cases than in matched controls.[5] The gene-poor regions either side of the MAFB gene include numerous binding sites for transcription factors that are known to have a role in palate development. [7]	https://www.wikidoc.org/index.php/MAFB_(gene)
4738b252d4b86c81fe51463212ac294a2037f0f1	wikidoc	MAFF (gene)	MAFF (gene) Transcription factor MafF is a bZip Maf transcription factor protein that in humans is encoded by the MAFF gene. MafF is one of the small Maf proteins, which are basic region and basic leucine zipper (bZIP)-type transcription factors. The HUGO Gene Nomenclature Committee-approved gene name of MAFF is “v-maf avian musculoaponeurotic fibrosarcoma oncogene homolog F”. # Discovery MafF was first cloned and identified in chicken in 1993 as a member of the small Maf (sMaf) genes. MAFF has been identified in many vertebrates, including humans. There are three functionally redundant sMaf proteins in vertebrates, MafF, MafG, and MafK. # Structure MafF has a bZIP structure that consists of a basic region for DNA binding and a leucine zipper structure for dimer formation. Similar to other sMafs, MafF lacks any canonical transcriptional activation domains. # Expression MAFF is broadly but differentially expressed in various tissues. MAFF expression was detected in all 16 tissues examined by the human BodyMap Project, but relatively abundant in adipose, colon, lung, prostate and skeletal muscle tissues. Human MAFF gene is induced by proinflammatory cytokines, interleukin 1 beta and tumor necrosis factor in myometrial cells. # Function Because of sequence similarity, no functional differences have been observed among the sMafs in terms of their bZIP structures. sMafs form homodimers by themselves and heterodimers with other specific bZIP transcription factors, such as CNC (cap 'n' collar) proteins and Bach proteins (BACH1 and BACH2). # Target genes sMafs regulate different target genes depending on their partners. For instance, the p45-NF-E2-sMaf heterodimer regulate genes responsible for platelet production. Nrf2-sMaf heterodimer regulates a battery of cytoprotective genes, such as antioxidant/xenobiotic metabolizing enzyme genes. The Bach1-sMaf heterodimer regulates the heme oxygenase-1 gene. In particular, it has been reported that MafF regulates the oxytocin receptor gene. The contribution of individual sMafs to the transcriptional regulation of their target genes has not yet been well examined. # Disease linkage Loss of sMafs results in disease-like phenotypes as summarized in table below. Mice lacking MafF are seemingly healthy under laboratory conditions. However, mice lacking MafG exhibit mild neuronal phenotype and mild thrombocytopenia, mice lacking Mafg and one allele of Mafk (Mafg−/−::Mafk+/−) exhibit progressive neuronal degeneration, thrombocytopenia and cataract, and mice lacking MafG and MafK (Mafg−/−::Mafk−/−) exhibit more severe neuronal degeneration and die in the perinatal stage. Mice lacking MafF, MafG and MafK are embryonic lethal, demonstrating that MafF is indispensable for embryonic development. Embryonic fibroblasts that are derived from Maff−/−::Mafg-/−::Mafk−/− mice fail to activate Nrf2-dependent cytoprotective genes in response to stress. In addition, accumulating evidence suggests that as partners of CNC and Bach proteins, sMafs are involved in the onset and progression of various human diseases, including neurodegeneration, arteriosclerosis and cancer.	MAFF (gene) Transcription factor MafF is a bZip Maf transcription factor protein that in humans is encoded by the MAFF gene.[1][2] MafF is one of the small Maf proteins, which are basic region and basic leucine zipper (bZIP)-type transcription factors. The HUGO Gene Nomenclature Committee-approved gene name of MAFF is “v-maf avian musculoaponeurotic fibrosarcoma oncogene homolog F”. # Discovery MafF was first cloned and identified in chicken in 1993 as a member of the small Maf (sMaf) genes.[1] MAFF has been identified in many vertebrates, including humans.[2] There are three functionally redundant sMaf proteins in vertebrates, MafF, MafG, and MafK. # Structure MafF has a bZIP structure that consists of a basic region for DNA binding and a leucine zipper structure for dimer formation.[1] Similar to other sMafs, MafF lacks any canonical transcriptional activation domains.[1] # Expression MAFF is broadly but differentially expressed in various tissues. MAFF expression was detected in all 16 tissues examined by the human BodyMap Project, but relatively abundant in adipose, colon, lung, prostate and skeletal muscle tissues.[3] Human MAFF gene is induced by proinflammatory cytokines, interleukin 1 beta and tumor necrosis factor in myometrial cells.[4] # Function Because of sequence similarity, no functional differences have been observed among the sMafs in terms of their bZIP structures. sMafs form homodimers by themselves and heterodimers with other specific bZIP transcription factors, such as CNC (cap 'n' collar) proteins [p45 NF-E2 (NFE2), Nrf1 (NFE2L1), Nrf2 (NFE2L2), and Nrf3 (NFE2L3)][5][6][7][8] and Bach proteins (BACH1 and BACH2).[9] # Target genes sMafs regulate different target genes depending on their partners. For instance, the p45-NF-E2-sMaf heterodimer regulate genes responsible for platelet production.[5][10][11] Nrf2-sMaf heterodimer regulates a battery of cytoprotective genes, such as antioxidant/xenobiotic metabolizing enzyme genes.[7][12] The Bach1-sMaf heterodimer regulates the heme oxygenase-1 gene.[9] In particular, it has been reported that MafF regulates the oxytocin receptor gene.[13] The contribution of individual sMafs to the transcriptional regulation of their target genes has not yet been well examined. # Disease linkage Loss of sMafs results in disease-like phenotypes as summarized in table below. Mice lacking MafF are seemingly healthy under laboratory conditions.[14] However, mice lacking MafG exhibit mild neuronal phenotype and mild thrombocytopenia,[15] mice lacking Mafg and one allele of Mafk (Mafg−/−::Mafk+/−) exhibit progressive neuronal degeneration, thrombocytopenia and cataract,[16][17] and mice lacking MafG and MafK (Mafg−/−::Mafk−/−) exhibit more severe neuronal degeneration and die in the perinatal stage.[18] Mice lacking MafF, MafG and MafK are embryonic lethal, demonstrating that MafF is indispensable for embryonic development.[19] Embryonic fibroblasts that are derived from Maff−/−::Mafg-/−::Mafk−/− mice fail to activate Nrf2-dependent cytoprotective genes in response to stress.[12] In addition, accumulating evidence suggests that as partners of CNC and Bach proteins, sMafs are involved in the onset and progression of various human diseases, including neurodegeneration, arteriosclerosis and cancer.	https://www.wikidoc.org/index.php/MAFF_(gene)
6bde3809695bc0803822e117007750b849b5db85	wikidoc	MCAT (gene)	MCAT (gene) Malonyl CoA-acyl carrier protein transacylase, mitochondrial is an enzyme that in humans is encoded by the MCAT gene. # Function The protein encoded by this gene is found exclusively in the mitochondrion, where it catalyzes the transfer of a malonyl group from malonyl-CoA to the mitochondrial acyl carrier protein. The encoded protein may be part of a fatty acid synthase complex that is more like the type II prokaryotic and plastid complexes rather than the type I human cytosolic complex. Two transcript variants encoding different isoforms have been found for this gene. # Clinical significance The enzyme encoded by the MCAT gene, along with other enzymes that regulate Malonyl-CoA concentration, have been shown to regulate levels such that malonyl-CoA concentration decreases in human muscle tissue when under exercise training. This enzyme specifically has increased activity under these conditions, as it is known to catabolize malonyl-CoA. # Interactions The human Malonyl CoA-acel carrier protein transacylase in human mitochondria associates with respiratory complex one, such that it interacts functionally with a mitochondrial malonyltransferase. Both species are encoded by nuclear genes, and their translocation into mitochondria is dependent on the presence of an N-terminal targeting sequence.	MCAT (gene) Malonyl CoA-acyl carrier protein transacylase, mitochondrial is an enzyme that in humans is encoded by the MCAT gene.[1][2] # Function The protein encoded by this gene is found exclusively in the mitochondrion, where it catalyzes the transfer of a malonyl group from malonyl-CoA to the mitochondrial acyl carrier protein. The encoded protein may be part of a fatty acid synthase complex that is more like the type II prokaryotic and plastid complexes rather than the type I human cytosolic complex. Two transcript variants encoding different isoforms have been found for this gene.[2] # Clinical significance The enzyme encoded by the MCAT gene, along with other enzymes that regulate Malonyl-CoA concentration, have been shown to regulate levels such that malonyl-CoA concentration decreases in human muscle tissue when under exercise training. This enzyme specifically has increased activity under these conditions, as it is known to catabolize malonyl-CoA. [3] # Interactions The human Malonyl CoA-acel carrier protein transacylase in human mitochondria associates with respiratory complex one, such that it interacts functionally with a mitochondrial malonyltransferase. Both species are encoded by nuclear genes, and their translocation into mitochondria is dependent on the presence of an N-terminal targeting sequence.[1]	https://www.wikidoc.org/index.php/MCAT_(gene)
7f1aff63275e0d539e9c53e50e8ba67ca99ca53c	wikidoc	MIAT (gene)	MIAT (gene) MIAT (myocardial infarction associated transcript), also known as RNCR2 (retinal non-coding RNA 2) or Gomafu, is a long non-coding RNA. Single nucleotide polymorphisms (SNPs) in MIAT are associated with a risk of myocardial infarction. It is expressed in neurons, and located in the nucleus. It plays a role in the regulation of retinal cell fate specification. Crea and collaborators have shown that MIAT is highly up-regulated in aggressive prostate cancer samples, raising the possibility that this gene plays a role in cancer progression. # Structure The MIAT gene is located on Chromosome 22 and is 30,051 bases in length. MIAT's other name, gomafu, is a word in Japanese that means “spotted pattern”. The reason it is named as so is because Gomafu is distributed in the nucleoplasm in a spotted pattern. Moreover, its orientation is a plus strand. It is also found that MIAT has five exons and is likely to be a functional RNA, since MIAT hasn’t been shown to encode any translational product. Furthermore, the gene encodes a spliced, long non-coding RNA. The gene is found not only in humans, but also in mice and rats. Orthologs are present in syntenic positions of frog and chicken. It is also found that all gomafu RNA contain tandem repeats of UACUAAC that binds to SPF1, which is a splicing factor. MIAT was originally discovered as long intergenic noncoding RNAs quite enriched in specific neurons in mouse retina and later more widely expressed in the nervous system and cultured neurons, where it specifies cell identity. Moreover, the gomafu RNA is also quite insoluble and is enriched in PolyA+. Also, there are putative polyadenylation signals (ATTAAA) found at the 3’ end of this gene. The presence of a PolyA tail and multiple exons and introns fulfills the feature of mRNAs transcribed by RNA polymerase II. The stability of the gene is not significantly different from β-actin mRNA. # Function in Pathology ## Myocardial Infarction Myocardial infarction is more commonly known as a heart attack. It is the irreversible death of the heart muscle due to prolonged obstruction of blood supply to the organ. Case-controlled large scale studies utilizing Single Nucleotide Polymorphisms(SNPs) throughout the genome demonstrated that altered expression at 6 SNPs in the MIAT gene might confer genetic susceptibility to myocardial infarctions. MIAT has been demonstrated to encode a nonfunctional RNA. Although the exact function of MIAT is still unclear, knowledge of some of the genetic factors that contribute to the pathogenesis of myocardial infarction can lend itself to better diagnosis, prevention, and treatment. Despite all that has been discovered about MIAT, a causal link between MIAT and myocardial infarctions has not yet been demonstrated. Additionally, one study demonstrated that expression levels of MIAT are shown to change in peripheral blood cells of patients with acute myocardial infarction. In particular, researchers studied the association between levels of lncRNAs and inflammation markers in patients who have suffered a myocardial infarction. MIAT levels were found to be positively associated with lymphocytes and negatively associated with neutrophils and platelets. In another portion of this study, researchers looked at the association between cardiovascular risk factors and levels of lncRNAs. Smoking was a cardiovascular risk factor that was found to be positively associated with MIAT. It is important to realize that even though several researchers have reported that levels of lncRNAs are regulated in the cardiac tissue following a heart attack, it is not known for sure whether it is the myocardial infarction that affects the levels of lncRNAs in peripheral blood cells. MIAT has various genotypes of SNPs and it is possible that only one of them relates to heart disease. ## Schizophrenia The long non-coding RNA(lncRNA) MIAT is located in the same chromosomal region which is linked to Schizophrenia (SZ) 22Q12.1. MIAT is upregulated in the nucleus accumbens of cocaine and heroin users. The nucleus accumbens is a region involved in behavior and addiction, suggesting that dysregulation of MIAT can influence behavior. It is well accepted that alternative splicing has a role in SZ pathology. MIAT is associated with alternative splicing through its interaction with splicing factor 1(SF1) and with genes DISC1 and ERBB4. MIAT binds directly to the splicing regulator quaking homolog (QKI) and serine/arginine-rich splicing factor 1 (SRSF1). QKI gene expression is decreased in specific brain regions in SZ and it has been proposed to be involved in SZ. Post -mortem SZ brains have upregulated expression of both DISC1 and ERBB4. Overexpression of MIAT in human-induced pluripotent stem cell (HiPSC)-derived neurons shows a significant decrease in expression of both DISC1 and ERBB4 and their alternative spliced variants. This is opposite to the upregulated expression seen in SZ patient brains. ASO mediated knockdown of MIAT in (HiPSC)-derived neurons increase the expression of both DISC1 and ERBB4 splice variants, but not their unspliced transcripts. This is almost exactly matching the aberrant splicing pattern seen in post-mortem SZ patient’s brains. These results suggests that loss of function mutations or decreased expression of MIAT is involved in driving aberrant cortical splicing patterns observed in SZ post-mortem brains. ## Other Pathologies MIAT up-regulation and down-regulation has been linked to various types of cancer and other pathologies. In a study of glioblastoma multiforme, increased expression of MIAT was linked to increased survival rates. In addition, the glioma cells were found to how significantly down-regulated MIAT. The role of MIAT in lymphocytic leukemia is very different from that of glioblastoma. In certain aggressive cell lines of chronic lymphocytic leukemias, MIAT is upregulated and depends on the presence of a transcriptional regulator, OCT4. OCT4 serves a positive regulator of MIAT transcription and as of now is the only known regulator. However, analysis of relative concentrations of MIAT and OCT4 have indicated that other regulatory factors are in play. Beyond its role in cancer, MIAT misexpression has also been linked to neurovascular dysfunction.	MIAT (gene) MIAT (myocardial infarction associated transcript), also known as RNCR2 (retinal non-coding RNA 2) or Gomafu, is a long non-coding RNA. Single nucleotide polymorphisms (SNPs) in MIAT are associated with a risk of myocardial infarction.[1] It is expressed in neurons, and located in the nucleus.[2] It plays a role in the regulation of retinal cell fate specification.[3] Crea and collaborators have shown that MIAT is highly up-regulated in aggressive prostate cancer samples,[4] raising the possibility that this gene plays a role in cancer progression. # Structure The MIAT gene is located on Chromosome 22 and is 30,051 bases in length.[5] MIAT's other name, gomafu, is a word in Japanese that means “spotted pattern”.[6] The reason it is named as so is because Gomafu is distributed in the nucleoplasm in a spotted pattern.[6] Moreover, its orientation is a plus strand.[5] It is also found that MIAT has five exons and is likely to be a functional RNA, since MIAT hasn’t been shown to encode any translational product.[5] Furthermore, the gene encodes a spliced, long non-coding RNA.[5] The gene is found not only in humans, but also in mice and rats.[6] Orthologs are present in syntenic positions of frog and chicken.[7] It is also found that all gomafu RNA contain tandem repeats of UACUAAC that binds to SPF1, which is a splicing factor.[6] MIAT was originally discovered as long intergenic noncoding RNAs quite enriched in specific neurons in mouse retina and later more widely expressed in the nervous system and cultured neurons, where it specifies cell identity.[6] Moreover, the gomafu RNA is also quite insoluble[6] and is enriched in PolyA+. Also, there are putative polyadenylation signals (ATTAAA) found at the 3’ end of this gene. The presence of a PolyA tail and multiple exons and introns fulfills the feature of mRNAs transcribed by RNA polymerase II. The stability of the gene is not significantly different from β-actin mRNA.[6] # Function in Pathology ## Myocardial Infarction Myocardial infarction is more commonly known as a heart attack. It is the irreversible death of the heart muscle due to prolonged obstruction of blood supply to the organ. Case-controlled large scale studies utilizing Single Nucleotide Polymorphisms(SNPs) throughout the genome demonstrated that altered expression at 6 SNPs in the MIAT gene might confer genetic susceptibility to myocardial infarctions. MIAT has been demonstrated to encode a nonfunctional RNA. Although the exact function of MIAT is still unclear, knowledge of some of the genetic factors that contribute to the pathogenesis of myocardial infarction can lend itself to better diagnosis, prevention, and treatment. Despite all that has been discovered about MIAT, a causal link between MIAT and myocardial infarctions has not yet been demonstrated.[5] Additionally, one study demonstrated that expression levels of MIAT are shown to change in peripheral blood cells of patients with acute myocardial infarction. In particular, researchers studied the association between levels of lncRNAs and inflammation markers in patients who have suffered a myocardial infarction. MIAT levels were found to be positively associated with lymphocytes and negatively associated with neutrophils and platelets. In another portion of this study, researchers looked at the association between cardiovascular risk factors and levels of lncRNAs. Smoking was a cardiovascular risk factor that was found to be positively associated with MIAT. It is important to realize that even though several researchers have reported that levels of lncRNAs are regulated in the cardiac tissue following a heart attack, it is not known for sure whether it is the myocardial infarction that affects the levels of lncRNAs in peripheral blood cells.[4] MIAT has various genotypes of SNPs and it is possible that only one of them relates to heart disease.[8] ## Schizophrenia The long non-coding RNA(lncRNA) MIAT is located in the same chromosomal region which is linked to Schizophrenia (SZ) 22Q12.1.[9] MIAT is upregulated in the nucleus accumbens of cocaine and heroin users.[10][11] The nucleus accumbens is a region involved in behavior and addiction,[12] suggesting that dysregulation of MIAT can influence behavior. It is well accepted that alternative splicing has a role in SZ pathology.[13] MIAT is associated with alternative splicing through its interaction with splicing factor 1(SF1)[7] and with genes DISC1 and ERBB4.[14] MIAT binds directly to the splicing regulator quaking homolog (QKI) and serine/arginine-rich splicing factor 1 (SRSF1).[15] QKI gene expression is decreased in specific brain regions in SZ [16][17] and it has been proposed to be involved in SZ.[18][19] Post -mortem SZ brains have upregulated expression of both DISC1 and ERBB4.[15] Overexpression of MIAT in human-induced pluripotent stem cell (HiPSC)-derived neurons shows a significant decrease in expression of both DISC1 and ERBB4 and their alternative spliced variants.[15] This is opposite to the upregulated expression seen in SZ patient brains.[15] ASO mediated knockdown of MIAT in (HiPSC)-derived neurons increase the expression of both DISC1 and ERBB4 splice variants, but not their unspliced transcripts.[15] This is almost exactly matching the aberrant splicing pattern seen in post-mortem SZ patient’s brains.[15] These results suggests that loss of function mutations or decreased expression of MIAT is involved in driving aberrant cortical splicing patterns observed in SZ post-mortem brains.[15] ## Other Pathologies MIAT up-regulation and down-regulation has been linked to various types of cancer and other pathologies. In a study of glioblastoma multiforme, increased expression of MIAT was linked to increased survival rates.[20] In addition, the glioma cells were found to how significantly down-regulated MIAT.[20] The role of MIAT in lymphocytic leukemia is very different from that of glioblastoma. In certain aggressive cell lines of chronic lymphocytic leukemias, MIAT is upregulated and depends on the presence of a transcriptional regulator, OCT4.[21] OCT4 serves a positive regulator of MIAT transcription and as of now is the only known regulator. However, analysis of relative concentrations of MIAT and OCT4 have indicated that other regulatory factors are in play.[21] Beyond its role in cancer, MIAT misexpression has also been linked to neurovascular dysfunction.[22]	https://www.wikidoc.org/index.php/MIAT_(gene)
4bc62337b25631a65f3a674c04e5e39e060a29ed	wikidoc	MLIP (gene)	MLIP (gene) Muscular LMNA interacting protein (MLIP) is a protein that in humans is encoded by the MLIP gene. # Function The function of MLIP is not known but it has been suggested that it may have a role in the growth of the heart and heart disease. There is some evidence that MLIP may be involved in maintaining cardiac homeostasis and in the initial reaction to changes in workload. However, a knockout mouse model had normal cardiac function and no structural abnormalities, showing that MLIP is not vital to these processes. # Gene ## Aliases Muscular LMNA interacting protein has a number of aliases including MLIP, C6orf142, CIP and Muscle-enriched A-type Lamin-interacting Protein. ## Locus and size MLIP is located on the short arm of chromosome 6 in humans with the exact locus of 6p12.1. The gene spans 53929982 to 54266280 on the + strand of chromosome 6. It has 19 exons and 13 splice variants ranging in size from 23 to 57 kDa. ## Orthologs and homologs MLIP is found only in amniotes (reptiles, birds and mammals), where it is highly conserved. The mouse homologue is 2310046A06rik. # Expression and interactions MLIP is expressed throughout the body with higher levels found in the heart and muscle cells. It interacts with the nuclear envelope proteins lamin A/C, which is what led to its discovery. It also interacts with Islet1 transcription factor.	MLIP (gene) Muscular LMNA interacting protein (MLIP) is a protein that in humans is encoded by the MLIP gene.[1] # Function The function of MLIP is not known but it has been suggested that it may have a role in the growth of the heart and heart disease. There is some evidence that MLIP may be involved in maintaining cardiac homeostasis and in the initial reaction to changes in workload. However, a knockout mouse model had normal cardiac function and no structural abnormalities, showing that MLIP is not vital to these processes.[2] # Gene ## Aliases Muscular LMNA interacting protein has a number of aliases including MLIP, C6orf142, CIP and Muscle-enriched A-type Lamin-interacting Protein.[2][1] ## Locus and size MLIP is located on the short arm of chromosome 6 in humans with the exact locus of 6p12.1. The gene spans 53929982 to 54266280 on the + strand of chromosome 6.[3] It has 19 exons and 13 splice variants ranging in size from 23 to 57 kDa.[4][5] ## Orthologs and homologs MLIP is found only in amniotes (reptiles, birds and mammals), where it is highly conserved. The mouse homologue is 2310046A06rik.[1][5] # Expression and interactions MLIP is expressed throughout the body with higher levels found in the heart and muscle cells. It interacts with the nuclear envelope proteins lamin A/C, which is what led to its discovery. It also interacts with Islet1 transcription factor.[2]	https://www.wikidoc.org/index.php/MLIP_(gene)
1c045f32b48148a0495d485009e63798c62d54b2	wikidoc	MMR vaccine	MMR vaccine # Overview The MMR vaccine is a mixture of live attenuated viruses, administered via injection for immunization against measles, mumps and rubella. It is generally administered to children around the age of one year, with a booster dose before starting school (i.e. age 4/5). In the United States, the booster began in the mid 1990s. It is widely used around the world; since introduction of its earliest versions in the 1970s, over 500 million doses have been used in over 60 countries. As with all vaccinations, long-term effects and efficacy are subject to continuing study. The vaccine is sold by Merck as M-M-R II, GlaxoSmithKline Biologicals as Priorix, and sanofi pasteur as TRIMOVAX. # Effectiveness Before the widespread use of a vaccine against measles, its incidence was so high that infection with measles was felt to be "as inevitable as death and taxes." Today, the incidence of measles has fallen to less than 1% of people under the age of 30 in countries with routine childhood vaccination. The benefit of vaccination against measles in preventing illness, disability, and death has been well-documented. The first 20 years of licensed measles vaccination in the U.S. prevented an estimated 52 million cases of the disease, 17,400 cases of mental retardation, and 5,200 deaths. During 1999–2004, a strategy led by the World Health Organization and UNICEF led to improvements in measles vaccination coverage that averted an estimated 1.4 million measles deaths worldwide. Measles is endemic worldwide. Although it was declared eliminated from the U.S. in 2000, high rates of vaccination and good communication with persons who refuse vaccination is needed to prevent outbreaks and sustain the elimination of measles in the U.S. Of the 66 cases of measles reported in the U.S. in 2005, slightly over half were attributable to one unvaccinated individual who acquired measles during a visit to Romania. This individual returned to a community with many unvaccinated children. The resulting outbreak infected 34 people, mostly children and virtually all unvaccinated; 9% were hospitalized, and the cost of containing the outbreak was estimated at $167,685. A major epidemic was averted due to high rates of vaccination in the surrounding communities. Mumps is another viral disease of childhood that was once very common. A known but relatively rare complication of mumps is sterility in males. Rubella, otherwise known as German measles, was also very common before the advent of widespread vaccination. The major risk of rubella is if a pregnant woman is infected, her baby may contract congenital rubella from her, which can cause significant congenital defects. All three diseases are highly contagious. The combined MMR vaccine was introduced to induce immunity less painfully than three separate injections at the same time, and sooner and more efficiently than three injections given on different dates. In 2005, the Cochrane Library published a review of 31 scientific studies. One of its main results: "We could not identify studies assessing the effectiveness of MMR that fulfilled our inclusion criteria even though the impact of mass immunisation on the elimination of the diseases has been largely demonstrated." Its authors concluded, "Existing evidence on the safety and effectiveness of MMR vaccine supports current policies of mass immunisation aimed at global measles eradication in order to reduce morbidity and mortality associated with mumps and rubella." # Development, formulation and administration The component viral strains of MMR vaccine were developed by propagation in animal and human cells. The live viruses require animal or human cells as a host for production of more virus. For example, in the case of mumps and measles viruses, the virus strains were grown in embryonated hens' eggs and chick embryo cell cultures. This produced strains of virus which were adapted for the hens egg and less well-suited for human cells. These strains are therefore called attenuated strains. They are sometimes referred to as neuroattenuated because these strains are less virulent to human neurons than the wild strains. The Rubella component, Meruvax, is propagated using a human cell line (WI-38, named for the Wistar Institute) derived in 1961 from embryonic lung tissue. The use of human cell lines has led to some religious controversy. MMR II is supplied freeze-dried (lyophilized) and contains live viruses. Before injection it is reconstituted with the solvent provided. The MMR vaccine is administered by a subcutaneous injection. High vaccination coverage before 2 years of age is important, and a second ("booster") injection is needed to achieve satisfactory levels of immunity and hence interrupt virus transmission. The booster may be given as early as one month after the first dose. # Safety Adverse reactions, rarely serious, may occur from each component of the MMR vaccine. 10% of children develop fever, malaise and a rash 5–21 days after the first vaccination; 5% develop temporary joint pain. Older women appear to be more at risk to joint pain, acute arthritis, and even (rarely) chronic arthritis. Anaphylaxis is an extremely rare but serious allergic reaction to the vaccine. The vaccine product brief lists many other adverse reactions. The number of reports on neurologic disorders is very small, other than evidence for an association between a form of the MMR vaccine containing the Urabe mumps strain and rare adverse events of aseptic meningitis, a transient mild form of viral meningitis. The UK National Health Service stopped using the Urabe mumps strain in the early 1990s due to cases of transient mild viral meningitis, and switched to a form using the Jeryl Lynn mumps strain instead. The Urabe strain remains in use in a number of countries; MMR with the Urabe strain is much cheaper to manufacture than with the Jeryl Lynn strain, and a strain with higher efficacy along with a somewhat higher rate of mild side effects may still have the advantage of reduced incidence of overall adverse events. The Cochrane Library review found several problems in the quality of MMR vaccine safety studies. Its authors concluded by recommending the adoption of standardized definitions of adverse events. The review's abstract concludes, "The design and reporting of safety outcomes in MMR vaccine studies, both pre- and post-marketing, are largely inadequate. The evidence of adverse events following immunisation with MMR cannot be separated from its role in preventing the target diseases." # Autism In the UK, the MMR vaccine was the subject of controversy after publication of a 1998 paper by Andrew Wakefield et al. reporting a study of twelve children who had autism spectrum disorders and bowel symptoms, in many cases with onset soon after administration of MMR vaccine. During a 1998 press conference, Wakefield suggested that giving children the vaccines in three separate doses would be safer than a single jab. This suggestion was not supported by the paper, and several subsequent peer-reviewed studies have failed to show any association between the vaccine and autism. Administering the vaccines in three separate doses does not reduce the chance of adverse effects, and it increases the opportunity for infection by the two diseases not immunized against first. Wakefield has been heavily criticized on scientific grounds and for triggering a decline in vaccination rates, as well as on ethical grounds for the way the research was conducted. In 2004, after an investigation by The Sunday Times, the interpretation section of the study, which identified a general association in time between the vaccine and autism, was formally retracted by ten of Wakefield's twelve coauthors. The Centers for Disease Control, the Institute of Medicine of the National Academy of Sciences, the UK National Health Service and the Cochrane Library review have all concluded that there is no evidence of a link between the MMR vaccine and autism. # MMRV vaccine The MMRV vaccine, a combined MMR and varicella vaccine, has been proposed as a replacement for the MMR vaccine to simplify administration of the vaccines.	MMR vaccine # Overview The MMR vaccine is a mixture of live attenuated viruses, administered via injection for immunization against measles, mumps and rubella. It is generally administered to children around the age of one year, with a booster dose before starting school (i.e. age 4/5). In the United States, the booster began in the mid 1990s. It is widely used around the world; since introduction of its earliest versions in the 1970s, over 500 million doses have been used in over 60 countries. As with all vaccinations, long-term effects and efficacy are subject to continuing study. The vaccine is sold by Merck as M-M-R II, GlaxoSmithKline Biologicals as Priorix, and sanofi pasteur as TRIMOVAX. # Effectiveness Before the widespread use of a vaccine against measles, its incidence was so high that infection with measles was felt to be "as inevitable as death and taxes."[1] Today, the incidence of measles has fallen to less than 1% of people under the age of 30 in countries with routine childhood vaccination. The benefit of vaccination against measles in preventing illness, disability, and death has been well-documented. The first 20 years of licensed measles vaccination in the U.S. prevented an estimated 52 million cases of the disease, 17,400 cases of mental retardation, and 5,200 deaths.[2] During 1999–2004, a strategy led by the World Health Organization and UNICEF led to improvements in measles vaccination coverage that averted an estimated 1.4 million measles deaths worldwide.[3] Measles is endemic worldwide. Although it was declared eliminated from the U.S. in 2000, high rates of vaccination and good communication with persons who refuse vaccination is needed to prevent outbreaks and sustain the elimination of measles in the U.S.[4] Of the 66 cases of measles reported in the U.S. in 2005, slightly over half were attributable to one unvaccinated individual who acquired measles during a visit to Romania.[5] This individual returned to a community with many unvaccinated children. The resulting outbreak infected 34 people, mostly children and virtually all unvaccinated; 9% were hospitalized, and the cost of containing the outbreak was estimated at $167,685. A major epidemic was averted due to high rates of vaccination in the surrounding communities.[4] Mumps is another viral disease of childhood that was once very common. A known but relatively rare complication of mumps is sterility in males. Rubella, otherwise known as German measles, was also very common before the advent of widespread vaccination. The major risk of rubella is if a pregnant woman is infected, her baby may contract congenital rubella from her, which can cause significant congenital defects.[6] All three diseases are highly contagious. The combined MMR vaccine was introduced to induce immunity less painfully than three separate injections at the same time, and sooner and more efficiently than three injections given on different dates. In 2005, the Cochrane Library published a review of 31 scientific studies. One of its main results: "We could not identify studies assessing the effectiveness of MMR that fulfilled our inclusion criteria even though the impact of mass immunisation on the elimination of the diseases has been largely demonstrated." Its authors concluded, "Existing evidence on the safety and effectiveness of MMR vaccine supports current policies of mass immunisation aimed at global measles eradication in order to reduce morbidity and mortality associated with mumps and rubella."[7] # Development, formulation and administration The component viral strains of MMR vaccine were developed by propagation in animal and human cells. The live viruses require animal or human cells as a host for production of more virus. For example, in the case of mumps and measles viruses, the virus strains were grown in embryonated hens' eggs and chick embryo cell cultures. This produced strains of virus which were adapted for the hens egg and less well-suited for human cells. These strains are therefore called attenuated strains. They are sometimes referred to as neuroattenuated because these strains are less virulent to human neurons than the wild strains. The Rubella component, Meruvax, is propagated using a human cell line (WI-38, named for the Wistar Institute) derived in 1961 from embryonic lung tissue.[8] The use of human cell lines has led to some religious controversy.[9] MMR II is supplied freeze-dried (lyophilized) and contains live viruses. Before injection it is reconstituted with the solvent provided. The MMR vaccine is administered by a subcutaneous injection. High vaccination coverage before 2 years of age is important, and a second ("booster") injection is needed to achieve satisfactory levels of immunity and hence interrupt virus transmission. The booster may be given as early as one month after the first dose.[13] # Safety Adverse reactions, rarely serious, may occur from each component of the MMR vaccine. 10% of children develop fever, malaise and a rash 5–21 days after the first vaccination; 5% develop temporary joint pain.[14] Older women appear to be more at risk to joint pain, acute arthritis, and even (rarely) chronic arthritis.[15] Anaphylaxis is an extremely rare but serious allergic reaction to the vaccine.[16] The vaccine product brief lists many other adverse reactions.[17] The number of reports on neurologic disorders is very small, other than evidence for an association between a form of the MMR vaccine containing the Urabe mumps strain and rare adverse events of aseptic meningitis, a transient mild form of viral meningitis.[15][18] The UK National Health Service stopped using the Urabe mumps strain in the early 1990s due to cases of transient mild viral meningitis, and switched to a form using the Jeryl Lynn mumps strain instead.[19] The Urabe strain remains in use in a number of countries; MMR with the Urabe strain is much cheaper to manufacture than with the Jeryl Lynn strain,[20] and a strain with higher efficacy along with a somewhat higher rate of mild side effects may still have the advantage of reduced incidence of overall adverse events.[19] The Cochrane Library review found several problems in the quality of MMR vaccine safety studies. Its authors concluded by recommending the adoption of standardized definitions of adverse events. The review's abstract concludes, "The design and reporting of safety outcomes in MMR vaccine studies, both pre- and post-marketing, are largely inadequate. The evidence of adverse events following immunisation with MMR cannot be separated from its role in preventing the target diseases."[7] # Autism In the UK, the MMR vaccine was the subject of controversy after publication of a 1998 paper by Andrew Wakefield et al. reporting a study of twelve children who had autism spectrum disorders and bowel symptoms, in many cases with onset soon after administration of MMR vaccine.[21] During a 1998 press conference, Wakefield suggested that giving children the vaccines in three separate doses would be safer than a single jab. This suggestion was not supported by the paper, and several subsequent peer-reviewed studies have failed to show any association between the vaccine and autism.[22] Administering the vaccines in three separate doses does not reduce the chance of adverse effects, and it increases the opportunity for infection by the two diseases not immunized against first.[22][23] Wakefield has been heavily criticized on scientific grounds and for triggering a decline in vaccination rates,[24] as well as on ethical grounds for the way the research was conducted.[25] In 2004, after an investigation by The Sunday Times,[26] the interpretation section of the study, which identified a general association in time between the vaccine and autism, was formally retracted by ten of Wakefield's twelve coauthors.[27] The Centers for Disease Control,[28] the Institute of Medicine of the National Academy of Sciences,[29] the UK National Health Service[30] and the Cochrane Library review[7] have all concluded that there is no evidence of a link between the MMR vaccine and autism. # MMRV vaccine The MMRV vaccine, a combined MMR and varicella vaccine, has been proposed as a replacement for the MMR vaccine to simplify administration of the vaccines.[13]	https://www.wikidoc.org/index.php/MMR_Vaccine
eee8c7e63045cf297c06701f4a957b0428f0f115	wikidoc	MSRA (gene)	MSRA (gene) Peptide methionine sulfoxide reductase (Msr) is a family of enzymes that in humans is encoded by the MSRA gene. # Function Msr is ubiquitous and highly conserved. Human and animal studies have shown the highest levels of expression in kidney and liver. It carries out the enzymatic reduction of methionine sulfoxide (MetO), the oxidized form of the amino acid methionine (Met), back to methionine, using thioredoxin to catalyze the enzymatic reduction and repair of oxidized methionine residues. Its proposed function is thus the repair of oxidative damage to proteins to restore biological activity. Oxidation of methionine residues in tissue proteins can cause them to misfold or otherwise render them dysfunctional. # Clinical significance MetO increases with age in body tissues, which is believed by some to contribute to biological ageing. Moreover, levels of methionine sulfoxide reductase A (MsrA) decline in aging tissues in mice and in association with age-related disease in humans. There is thus a rationale for thinking that by maintaining the structureincreased levels or activity of MsrA might retard the rate of aging. Indeed, transgenic Drosophila (fruit flies) that overexpress methionine sulfoxide reductase show extended lifespan. However, the effects of MsrA overexpression in mice were ambiguous. MsrA is found in both the cytosol and the energy-producing mitochondria, where most of the body's endogenous free radicals are produced. Transgenically increasing the levels of MsrA in either the cytosol or the mitochondria had no significant effect on lifespan assessed by most standard statistical tests, and may possibly have led to early deaths in the cytosol-specific mice, although the survival curves appeared to suggest a slight increase in maximum (90%) survivorship, as did analysis using Boschloo's Exact test, a binomial test designed to test greater extreme variation. Deletion of this gene has been associated with insulin resistance in mice, while overexpression reduces insulin resistance in old mice.	MSRA (gene) Peptide methionine sulfoxide reductase (Msr) is a family of enzymes that in humans is encoded by the MSRA gene.[1][2] # Function Msr is ubiquitous and highly conserved. Human and animal studies have shown the highest levels of expression in kidney and liver. It carries out the enzymatic reduction of methionine sulfoxide (MetO), the oxidized form of the amino acid methionine (Met), back to methionine, using thioredoxin to catalyze the enzymatic reduction and repair of oxidized methionine residues.[3] Its proposed function is thus the repair of oxidative damage to proteins to restore biological activity.[2] Oxidation of methionine residues in tissue proteins can cause them to misfold or otherwise render them dysfunctional.[3] # Clinical significance MetO increases with age in body tissues, which is believed by some to contribute to biological ageing.[3][4] Moreover, levels of methionine sulfoxide reductase A (MsrA) decline in aging tissues in mice and in association with age-related disease in humans.[3] There is thus a rationale for thinking that by maintaining the structureincreased levels or activity of MsrA might retard the rate of aging. Indeed, transgenic Drosophila (fruit flies) that overexpress methionine sulfoxide reductase show extended lifespan.[5] However, the effects of MsrA overexpression in mice were ambiguous.[6] MsrA is found in both the cytosol and the energy-producing mitochondria, where most of the body's endogenous free radicals are produced. Transgenically increasing the levels of MsrA in either the cytosol or the mitochondria had no significant effect on lifespan assessed by most standard statistical tests, and may possibly have led to early deaths in the cytosol-specific mice, although the survival curves appeared to suggest a slight increase in maximum (90%) survivorship, as did analysis using Boschloo's Exact test, a binomial test designed to test greater extreme variation.[6] Deletion of this gene has been associated with insulin resistance in mice,[7] while overexpression reduces insulin resistance in old mice.[6]	https://www.wikidoc.org/index.php/MSRA_(gene)
8b5fa1fe65919ba82017b0d62f40f5081aa697a2	wikidoc	MTRR (gene)	MTRR (gene) Methionine synthase reductase also known as MSR is an enzyme that in humans is encoded by the MTRR gene. # Function Methionine is an essential amino acid required for protein synthesis and one-carbon metabolism. Its synthesis is catalyzed by the enzyme methionine synthase. Methionine synthase eventually becomes inactive due to the oxidation of its cobalamin cofactor. Methionine synthase reductase regenerates a functional methionine synthase via reductive methylation. It is a member of the ferredoxin-NADP(+) reductase (FNR) family of electron transferases. Methionine synthase reductase (MTRR) is primarily involved in the reductive methylation of homocysteine to methionine, utilizing methylcob(I)alamin as an intermediate methyl carrier. Methionine is an essential amino acid in mammals, necessary for protein synthesis and one carbon metabolism. In its activated form, S-adenosylmethionine acts as a methyl donor in biological transmethylation reactions and as a propylamine donor in polyamine synthesis. A major product of methionine demethylation is homocysteine. Remethylation of homocysteine occurs via a cobalamin dependent enzyme, methionine synthase (MTR). The folate cycle is linked to homocysteine metabolism via MTR. Circulating blood folate (5-methyl tetrahydrofolate, 5-MTHF) donates methyl groups to MTR to be utilized in cellular methylation. A methyl cobalt bond of the intermediary methyl carrier, methlycob(III)alamin is cleaved heterolytically producing cobalamin in its highly reactive oxidation state as cob(I)alamin. The enzyme bound cob(I)alamin cofactor of the MTR enzyme functions as a methyl carrier between 5-MTHF and homocysteine. Cob(I)alamin is oxidised to cob(II)alamin about once every 100 methyl transfer cycles, rendering the cob(I)alamin-MTR-enzyme complex inactive. Reactivation of this enzyme complex occurs through reductive remethylation by MTRR, utilizing S-adenosylmethionine as a methyl donor. MTR reactivation can also be NADPH dependent involving two redox proteins, soluble cytochrome b5 and reductase 1. However, this pathway is responsible for a minor role in reactivation, whilst MTRR remains a major contributor in this reductive reactivation. Biological processes influenced by MTRR include: sulfur amino acid metabolic process, DNA methylation, methionine metabolic process, methionine biosynthetic process, methylation, S-adenosylmethionine cycle, homocysteine catabolic process, folic acid metabolic process, oxidation-reduction process and negative regulation of cystathionine beta-synthase activity. # MTRR gene The Methionine Synthase Reductase (MTRR) gene primarily acts in the reductive regeneration of cob(I)alamin (vitamin B12). Cob(I)alamin is a cofactor that maintains activation of the methionine synthase enzyme (MTR) Methionine synthase, linking folate and methionine metabolism. Donation of methyl groups from folate are utilized for cellular and DNA methylation, influencing epigenetic inheritance. ## Aliases - 5-Methyltetrahydrofolate-Homocysteine Methyltransferase Reductase - MSR - - Cobalamin Methyltransferase (Cob(II)Alamin Reducing) - Methionine Synthase Reductase, Mitochondrial - EC 1.16.1.8 - CblE ## Mapping The gene was mapped to human chromosome 5. Gene specific primer pairs resulted in PCR amplification of a product matched by size to a hybrid-mapping panel containing only chromosome 5 as its human genetic material. The product DNA sequence matched pre-established gene markers specific to this chromosome. Exact gene cytogenic position was determined by mapping to an artificial chromosomal construct containing the gene via fluorescence in situ hybridization. The exact MTRR gene location was mapped to 5p15.3-p15.2. ## Structure The MTRR gene is associated with a family of electron transferases known as the Ferredoxin-NADP(+) reductase (FNR) family. Found in 15 primates and over 16 tissues in humans, MTRR is 34 kb long. The gene comprises 15 exons and includes numerous cytolosic mitochondrial mRNA isoforms. Multiple cofactor binding sites assist in the maintenance of MTR activity via reductive remethylation. All binding domains involve selective and non-covalent interactions except the flavodoxin_1 domain. # Co-factor binding sites ## Flavodoxin-1 domain Flavoproteins are ubiquitous biocatalysts binding specific redox active prosthetic groups. The domain is associated with electron transfer proteins and used in electron transport systems. The cofactor flavin-mononucleotide (FMN) is bound non-covalently to the domain, which is functionally interchangeable with iron-sulfur constituted proteins regulating electron transfer or ferredoxins. ### FAD Flavin adenine dinucleotide in its oxidized form, FAD is a cofactor of flavoprotein oxidoreductase enzymes. Flavoprotein pyridine nucleotide cytochrome reductases, including FAD catalyse the interchange of reducing equivalents (H+ or electrons). Initial electron donors and final electron acceptors comprise single electron carriers and two electron carrying nicotinamide dinucleotides respectively. ### NAD Evolutionary conserved protein domain corresponding to oxidoreductase activity. NAD binding catalyzes redox reactions to alter the oxidation state of metal ions, using NADP+ as an electron acceptor. ## Methionine synthase reductase activity Involved in the reductive remethylation of cob(II)alamin using S-adenosylhomocysteine as a methyl donor. Catalyses the reaction: - cob(II)alamin + NADPH + H+ + S-adenosylmethionine → -methylcob(I)alamin + S-adenosylhomocysteine + NADP+. ## Aquacobalamin reductase (NADPH) activity Belongs to the oxidoreductase family, oxidizing metal ions with NADP+ acting as an electron acceptor. Uses FAD as a cofactor when catalyzing the following reaction: 2cob(II)alamin + NADP+ 2aquacob(III)alamin + NADPH + H+. ## Flavin adenine dinucleotide Interacts with the cofactor or prosthetic group, FAD of flavoproteins and contains a flavin moiety in the form of FAD or FMN (flavin mononucleotide). The domain non-covalently binds oxidized FAD or its reduced form, hydroquinone (FADH2). ### FMN Flavin mononucleotide binding domain interacts with a coenzyme of flavoprotein oxidoreductase enzymes, FMN. ### NADP Nicotinamide adenine dinucleotide phosphate is a coenzyme present in redox and biosynthetic reactions. The domain binds NADP in its oxidised or reduced forms as NADP+ or NADPH respectively. ### ADPH Involves a non-covalent and selective interaction with the reduced form of NADP, NADPH. ## NADPH-hemoprotein reductase activity The domain is associated with the oxidoreductase family and acts on NADH or NADPH, using a heme protein as an electron acceptor. Requires FAD and FMN as cofactors to catalyse the reaction: NADPH + H+ + n oxidised hemoprotein = NADP+ + n reduced hemoprotein. ### Protein binding Binding domain involved in the interaction with proteins or protein complexes. # Polymorphisms ## Pathogenic mutations - (MTRR):c.66A>G – Polymorphism resulting in isoleucine conversion to methionine at codon 22. This mutation is found within and affects the FMN binding domain. - (MTRR):c.524C>T – Serine to leucine substitution at codon 175. Benign mutation associated with impaired intracellular cobalamin metabolism disorders. - (MTRR):c.1049A>G – Lysine to arginine substitution at codon 350. - (MTRR):c.1349C>G – Proline to arginine substitution at codon 450. Prevalence associated with abnormal intracellular cobalamin metabolism disorders. - (MTRR):c.903+469T>C – Deep intronic insertion between exons 6 and 7 (r.903_904ins140). Threonine to cysteine change resulting in activation of an exon splicing enhancer in intron 6. - (MTRR):c.1361C>T – Rare polymorphism involving serine to leucine substitution at codon 454. Known as the Iberian mutation, prevalent in homocystinuria megaloblastic anemia due to impaired cobalamin metabolism. Mainly three different halotypes (GTACG, GCACA, GCACG) from the deamination of methyl cytosine in different chromosomes. - (MTRR):c.1459G>A – Involves glycine to arginine substitution at codon 487. Conserved in MTRR and found to occur within the FAD binding domain. Pathogenicity associated with inborn genetic diseases. - (MTRR):c.1573C>T – Arginine substitution with a premature termination codon at codon 525. - (MTRR):c.1622_1623dupTA – Results in formation of a premature termination codon. Pathogenicity associated with CblE type of homocystinuria. - (MTRR):r.1462_1557del96 – Associated with splicing of exon 11 due to a 7 base pair deletion. A large deletion of this mutant allele results in the absence of a c-terminus in the FAD binding domain. Pathogenicity associated with CblE type of homocystinuria. - (MTRR):c.1953-6_1953-2del5 – Novel mutation associated with CblE type of homocystinuria. Unstable mRNA arising from this mutant results in an absence of mRNA required for translation, producing pathogenicity. Mutations involved in the formation of premature termination codons result in truncated mutated proteins if translated. Mutants exhibit an absence of FAD/NADPH binding domains and unstable mRNA due to nonsense mediated decay (NMD). NMD is not present in (MTRR):c.1573C>T or (MTRR):c.1622_1623dupTA polymorphisms. The (MTRR):c.903+469T>C variant is also associated with the formation of premature termination codons. ## Other mutations - (MTRR):c.1911G>A ¬– Benign synonymous mutation (alanine to alanine) at codon 637. Associated with disorders of cobalamin metabolism. # Clinical significance Single nucleotide polymorphisms (SNPs) in the MTRR gene impair MTR activity, resulting in elevated homocysteine levels due to compromised methylation to methionine. Elevated homocysteine levels are associated with birth defects in addition to pregnancy complications, cardiovascular disease, cancer, megaloblastic anemia, Alzheimer’s diseases and cognitive dysfunction in the elderly. Presence of the mutant variant (66A>G) is associated with significantly lower, up to 4 fold, plasma cobalamin and folate levels in cardiac transplant patients. A consequent decrease in S-adenosylmethionine availability results in DNA hypomethylation. Low folate limits one carbon metabolism and homocysteine metabolism as vitamin B12 interacts with folate in this pathway. Additionally, this mutation is associated with an increased risk in type 2 diabetes. ## Cancer Specific SNPs are associated with an elevated risk of lung cancer and interact with folate dietary intake in this etiology. The (MTRR):c.66A>G mutation relates to a significant increase in the risk of lung cancer. When co-expressed with the polymorphism (MTR): 2756A>G, lung cancer risk is further increased in a dose dependent manner. Correlation between this polymorphism and increased risk of lung cancer is present with low folate intake and high vitamin B12, suggesting a B12 independent mechanism of action. This mutation is also associated with an increased risk in colorectal cancer, acute lymphoblastic leukemia, bladder cancer, cervical intraepithelial neoplasia, non-Hodgkin lymphoma and oesophageal squamous cell carcinoma. ## CblE type of homocystinuria Remethylation of homocysteine to methionine by MTR requires the derivative of cobalamin, methylcobalamin. Cobalamin metabolism is initiated by the endocytosis of cobalamin bound to the plasma protein transcobalamin (II). Cleavage of this complex produces free cobalamin, translocating from lysosome to cytoplasm. Conversion can occur to 5’-deoxyadenosylcobalamin (AdoCbl) activating the mitochrondrial enzyme methylmalonly coenzyme A mutase or to methylcobalamin (MeCbl). An error in cobalamin metabolism resulting in decreased MeCbl and unaffected AdoCbl is characteristic of the CblE type of homocystinuria. This complementation is rare with autosomal recessive inheritance. The inherited methionine synthase functional deficiency corresponds to a defect in the reducing system required to activate the MTR enzyme. Symptoms of this condition comprise developmental retardation, megaloblastic anemia, homocystinuria, hypomethioninemia, cerebral atrophy and hyperhomocysteinemia. However, hypomethioninemia remains an inconsistent symptom. Decreased MeCbl alongside normal cobalamin uptake is suggestive of decreased intracellular methionine biosynthesis. Occurring mainly in childhood, 15 pathogenic mutations can be associated with CblE type homocystinuria. Additionally, vascular abnormalities are associated with this defect. Impaired reduction of an oxidised cobalt atom in the active site of MTR is associated with this condition, where enzyme activity can be corrected with reducing agents. Rare polymorphisms related to this disease include (MTRR):c.1459G>A, (MTRR):c.1623-1624insTA and (MTRR):c.903+469T>C. These mutations, excluding (MTRR):c.1459G>A result in a frame shift, producing premature termination codons. As consequent products are distant from normal, mutant mRNA arises and nonsense mediated decay (FMN) is initiated. The large insertion of 903_904ins140 corresponding to 903+469T>C is most prevalent in CblE pathology. The activation of an enhanced splicer within intron 6 is incomplete, producing small quantities of normal spliced MTRR mRNA. Prenatal diagnosis of this condition is possible using methyltetrahydrofolate. Mutation analysis in native chorionic villi and formate in amino acids within these villi or cultured amniocytes is indicative of the CblE defect. Additionally, macrocytic anemia is a typical feature of the CblE defect and can be corrected though OH-Cobalamin administration or folate supplementation. ## Coronary artery disease Homocysteine, a sulfur based amino acid is the main product of methionine demethylation. Elevated homocysteine is an independent risk factor for cardiovascular disease and inversely correlated to consumed vitamin B12/B6 and folate levels. Homocysteine methylation to methionine is catalyzed by MTR, resulting in appropriate intracellular levels of methionine and tetrahydrofolate, alongside non-toxic homocysteine levels. The GG phenotype promotes the development of premature coronary artery disease (CAD) independent of hyperhomocysteinemia. Hyperhomocysteinemia is associated with cerebral, coronary and peripheral atherosclerotic pathology as it promotes endothelial cell dysfunction, platelet adhesion and vascular smooth muscle cell proliferation. DNA damage and homocysteine levels are proportional to CAD severity. Micronucleus frequency in human lymphocytes, dependent on homocysteine levels increases reactive oxygen species and uracil incorporation in DNA methylation, promoting genetic alterations and point mutations. The (MTRR):c.66A>G, polymorphism containing chromosome is prone to fragmentation. This chromosomal loss or global DNA hypomethylation results in under condensation of pericentromeric heterochromatin, micronucleus formation and elevated risks of aneuploidy. Co-expression of this mutation and the 677T polymorphism in methionine tetrahydrofolate reductase (MTHFR) Methylenetetrahydrofolate reductase act to further the extent of DNA damage. Hypomethylation due to impaired methylation up regulates atherosclerotic susceptible genes whilst down regulating atherosclerosis protective genes. This abnormality is present during the atherosclerotic pathology, increasing transcriptional activity of platelet derived growth factor (PDGF) and promoting smooth muscle cell proliferation. ## Neural tube defects ### Spina bifida MTRR requires vitamin B12 for maintenance of the methyl synthase reaction whilst folate is needed for normal synthesis of nucleotide precursors. These ensure normal DNA synthesis and cellular methylation reactions. Chronic folate or methyl deficiencies are thereby linked to abnormal DNA methylation. The 66A>G polymorphism is up-regulated in neural tube defects and increases the risk of spina bifida by two-fold. Homozygosis for this mutation is an established maternal risk factor for spina bifida especially with low intracellular vitamin B12 in the circulation or amniotic fluid. Vitamin B12 is reflected by plasma methylmalonic acid (MMA), an elevation in which indicates impaired B12 uptake or metabolism. A raised MMA combined with the MTRR mutation corresponds to a 5-fold increase in spina bifida. The mechanism of action of this polymorphism is through the mother, hence there is no preferential transmission of this mutation from parent to child. Abnormal MTRR binding to the MTR-cob(I)alamin-enzyme complex down regulates the rate of homocysteine methylation. Consequent decreases in methionine and S-adenosylmethionine negatively affect DNA, gene and protein methylation, all of which are involved in neural tube closure. Increased proliferation during neurulation decreases the availability of DNA nucleotides. As these are unable to be replaced due to impaired DNA methylation and nucleotide formation, consequent disturbed neurulation results in the formation of neural tube defects. Co-expression of this mutation with the 677C>T MTHFR polymorphism furthers the risk of spina bifida compared to an independent acting 66A>G mutation. ### Down syndrome Trisomy 21 or Down syndrome is the most common human chromosomal anomaly arising from abnormal chromosomal segregation in meiosis. The condition can occur during anaphase in meiosis(I) marking oocyte maturation before ovulation and/or during anaphase in meiosis (II) signifying fertilization. Metabolic impact during these stages is furthered by low vitamin B12. Methylation of homocysteine to methionine is affected, primarily by the (MTRR):c.66A>G polymorphism. Chronic homocysteine elevation increases s-adenosyl-L-homocysteine levels, consequently inhibiting methyltransferase activity and promoting DNA hypomethylation. Mothers homozygous for this mutation (GG phenotype) are at a greater risk of having a child with down syndrome compared to heterozygotes (GA phenotype). Geographically, Irish populations are more likely to be homogenous whilst north American populations are commonly heterogeneous, resulting in a greater incidence of the polymorphism in the former group. The homozygous mutant allele promotes DNA hypomethylation and meiotic non-disjunction, increasing the risk of down syndrome. This polymorphism correlates to a 2.5 fold risk increase independently and a 4 fold increase in risk when co-expressed with the 677C>T MTHFR mutation. Combination with the MTR2756A>G genetic polymorphism further elevates down syndrome risk.	MTRR (gene) Methionine synthase reductase also known as MSR is an enzyme that in humans is encoded by the MTRR gene.[1][2] # Function Methionine is an essential amino acid required for protein synthesis and one-carbon metabolism. Its synthesis is catalyzed by the enzyme methionine synthase. Methionine synthase eventually becomes inactive due to the oxidation of its cobalamin cofactor. Methionine synthase reductase regenerates a functional methionine synthase via reductive methylation. It is a member of the ferredoxin-NADP(+) reductase (FNR) family of electron transferases.[2] Methionine synthase reductase (MTRR) is primarily involved in the reductive methylation of homocysteine to methionine, utilizing methylcob(I)alamin as an intermediate methyl carrier.[3] Methionine is an essential amino acid in mammals, necessary for protein synthesis and one carbon metabolism. In its activated form, S-adenosylmethionine acts as a methyl donor in biological transmethylation reactions and as a propylamine donor in polyamine synthesis.[3] A major product of methionine demethylation is homocysteine. Remethylation of homocysteine occurs via a cobalamin dependent enzyme, methionine synthase (MTR).[3] The folate cycle is linked to homocysteine metabolism via MTR.[4] Circulating blood folate (5-methyl tetrahydrofolate, 5-MTHF) donates methyl groups to MTR to be utilized in cellular methylation. A methyl cobalt bond of the intermediary methyl carrier, methlycob(III)alamin is cleaved heterolytically producing cobalamin in its highly reactive oxidation state as cob(I)alamin. The enzyme bound cob(I)alamin cofactor of the MTR enzyme functions as a methyl carrier between 5-MTHF and homocysteine.[3] Cob(I)alamin is oxidised to cob(II)alamin about once every 100 methyl transfer cycles, rendering the cob(I)alamin-MTR-enzyme complex inactive.[5] Reactivation of this enzyme complex occurs through reductive remethylation by MTRR, utilizing S-adenosylmethionine as a methyl donor. MTR reactivation can also be NADPH dependent involving two redox proteins, soluble cytochrome b5 and reductase 1. However, this pathway is responsible for a minor role in reactivation, whilst MTRR remains a major contributor in this reductive reactivation. Biological processes influenced by MTRR include: sulfur amino acid metabolic process, DNA methylation, methionine metabolic process, methionine biosynthetic process, methylation, S-adenosylmethionine cycle, homocysteine catabolic process, folic acid metabolic process, oxidation-reduction process and negative regulation of cystathionine beta-synthase activity.[3][4] # MTRR gene The Methionine Synthase Reductase (MTRR) gene primarily acts in the reductive regeneration of cob(I)alamin (vitamin B12).[6] Cob(I)alamin is a cofactor that maintains activation of the methionine synthase enzyme (MTR) Methionine synthase, linking folate and methionine metabolism. Donation of methyl groups from folate are utilized for cellular and DNA methylation, influencing epigenetic inheritance.[6][3][7] ## Aliases - 5-Methyltetrahydrofolate-Homocysteine Methyltransferase Reductase - MSR - [Methionine Synthase]- Cobalamin Methyltransferase (Cob(II)Alamin Reducing) - Methionine Synthase Reductase, Mitochondrial - EC 1.16.1.8 - CblE ## Mapping The gene was mapped to human chromosome 5. Gene specific primer pairs resulted in PCR amplification of a product matched by size to a hybrid-mapping panel containing only chromosome 5 as its human genetic material.[1] The product DNA sequence matched pre-established gene markers specific to this chromosome. Exact gene cytogenic position was determined by mapping to an artificial chromosomal construct containing the gene via fluorescence in situ hybridization.[1] The exact MTRR gene location was mapped to 5p15.3-p15.2.[1] ## Structure The MTRR gene is associated with a family of electron transferases known as the Ferredoxin-NADP(+) reductase (FNR) family. Found in 15 primates and over 16 tissues in humans, MTRR is 34 kb long.[8] The gene comprises 15 exons and includes numerous cytolosic mitochondrial mRNA isoforms. Multiple cofactor binding sites assist in the maintenance of MTR activity via reductive remethylation. All binding domains involve selective and non-covalent interactions except the flavodoxin_1 domain.[8] # Co-factor binding sites ## Flavodoxin-1 domain Flavoproteins are ubiquitous biocatalysts binding specific redox active prosthetic groups. The domain is associated with electron transfer proteins and used in electron transport systems.[8] The cofactor flavin-mononucleotide (FMN) is bound non-covalently to the domain, which is functionally interchangeable with iron-sulfur constituted proteins regulating electron transfer or ferredoxins.[8] ### FAD Flavin adenine dinucleotide in its oxidized form, FAD is a cofactor of flavoprotein oxidoreductase enzymes. Flavoprotein pyridine nucleotide cytochrome reductases, including FAD catalyse the interchange of reducing equivalents (H+ or electrons). Initial electron donors and final electron acceptors comprise single electron carriers and two electron carrying nicotinamide dinucleotides respectively.[8] ### NAD Evolutionary conserved protein domain corresponding to oxidoreductase activity. NAD binding catalyzes redox reactions to alter the oxidation state of metal ions, using NADP+ as an electron acceptor.[8] ## Methionine synthase reductase activity Involved in the reductive remethylation of cob(II)alamin using S-adenosylhomocysteine as a methyl donor. Catalyses the reaction: [methionine synthase]- cob(II)alamin + NADPH + H+ + S-adenosylmethionine → [methionine synthase]-methylcob(I)alamin + S-adenosylhomocysteine + NADP+.[8] ## Aquacobalamin reductase (NADPH) activity Belongs to the oxidoreductase family, oxidizing metal ions with NADP+ acting as an electron acceptor. Uses FAD as a cofactor when catalyzing the following reaction: 2cob(II)alamin + NADP+ 2aquacob(III)alamin + NADPH + H+.[8] ## Flavin adenine dinucleotide Interacts with the cofactor or prosthetic group, FAD of flavoproteins and contains a flavin moiety in the form of FAD or FMN (flavin mononucleotide). The domain non-covalently binds oxidized FAD or its reduced form, hydroquinone (FADH2).[8] ### FMN Flavin mononucleotide binding domain interacts with a coenzyme of flavoprotein oxidoreductase enzymes, FMN.[8] ### NADP Nicotinamide adenine dinucleotide phosphate is a coenzyme present in redox and biosynthetic reactions. The domain binds NADP in its oxidised or reduced forms as NADP+ or NADPH respectively.[8] ### ADPH Involves a non-covalent and selective interaction with the reduced form of NADP, NADPH.[8] ## NADPH-hemoprotein reductase activity The domain is associated with the oxidoreductase family and acts on NADH or NADPH, using a heme protein as an electron acceptor. Requires FAD and FMN as cofactors to catalyse the reaction: NADPH + H+ + n oxidised hemoprotein = NADP+ + n reduced hemoprotein.[8] ### Protein binding Binding domain involved in the interaction with proteins or protein complexes.[8] # Polymorphisms ## Pathogenic mutations - (MTRR):c.66A>G – Polymorphism resulting in isoleucine conversion to methionine at codon 22. This mutation is found within and affects the FMN binding domain.[9] - (MTRR):c.524C>T – Serine to leucine substitution at codon 175. Benign mutation associated with impaired intracellular cobalamin metabolism disorders.[10] - (MTRR):c.1049A>G – Lysine to arginine substitution at codon 350.[11] - (MTRR):c.1349C>G – Proline to arginine substitution at codon 450. Prevalence associated with abnormal intracellular cobalamin metabolism disorders.[12] - (MTRR):c.903+469T>C – Deep intronic insertion between exons 6 and 7 (r.903_904ins140). Threonine to cysteine change resulting in activation of an exon splicing enhancer in intron 6.[13] - (MTRR):c.1361C>T – Rare polymorphism involving serine to leucine substitution at codon 454. Known as the Iberian mutation, prevalent in homocystinuria megaloblastic anemia due to impaired cobalamin metabolism. Mainly three different halotypes (GTACG, GCACA, GCACG) from the deamination of methyl cytosine in different chromosomes.[14] - (MTRR):c.1459G>A – Involves glycine to arginine substitution at codon 487. Conserved in MTRR and found to occur within the FAD binding domain. Pathogenicity associated with inborn genetic diseases.[15] - (MTRR):c.1573C>T – Arginine substitution with a premature termination codon at codon 525.[16] - (MTRR):c.1622_1623dupTA – Results in formation of a premature termination codon. Pathogenicity associated with CblE type of homocystinuria.[17] - (MTRR):r.1462_1557del96 – Associated with splicing of exon 11 due to a 7 base pair deletion. A large deletion of this mutant allele results in the absence of a c-terminus in the FAD binding domain. Pathogenicity associated with CblE type of homocystinuria.[17] - (MTRR):c.1953-6_1953-2del5 – Novel mutation associated with CblE type of homocystinuria. Unstable mRNA arising from this mutant results in an absence of mRNA required for translation, producing pathogenicity.[17] Mutations involved in the formation of premature termination codons result in truncated mutated proteins if translated.[17] Mutants exhibit an absence of FAD/NADPH binding domains and unstable mRNA due to nonsense mediated decay (NMD). NMD is not present in (MTRR):c.1573C>T or (MTRR):c.1622_1623dupTA polymorphisms.[17] The (MTRR):c.903+469T>C variant is also associated with the formation of premature termination codons.[17] ## Other mutations - (MTRR):c.1911G>A ¬– Benign synonymous mutation (alanine to alanine) at codon 637. Associated with disorders of cobalamin metabolism.[18] # Clinical significance Single nucleotide polymorphisms (SNPs) in the MTRR gene impair MTR activity, resulting in elevated homocysteine levels due to compromised methylation to methionine. Elevated homocysteine levels are associated with birth defects in addition to pregnancy complications, cardiovascular disease, cancer,[19] megaloblastic anemia, Alzheimer’s diseases and cognitive dysfunction in the elderly.[20] Presence of the mutant variant (66A>G) is associated with significantly lower, up to 4 fold, plasma cobalamin and folate levels in cardiac transplant patients.[19] A consequent decrease in S-adenosylmethionine availability results in DNA hypomethylation. Low folate limits one carbon metabolism and homocysteine metabolism as vitamin B12 interacts with folate in this pathway.[20] Additionally, this mutation is associated with an increased risk in type 2 diabetes.[21] ## Cancer Specific SNPs are associated with an elevated risk of lung cancer and interact with folate dietary intake in this etiology. The (MTRR):c.66A>G mutation relates to a significant increase in the risk of lung cancer. When co-expressed with the polymorphism (MTR): 2756A>G, lung cancer risk is further increased in a dose dependent manner.[20] Correlation between this polymorphism and increased risk of lung cancer is present with low folate intake and high vitamin B12, suggesting a B12 independent mechanism of action.[20] This mutation is also associated with an increased risk in colorectal cancer,[22][23][24][25] acute lymphoblastic leukemia,[26] bladder cancer,[27] cervical intraepithelial neoplasia, non-Hodgkin lymphoma[28] and oesophageal squamous cell carcinoma.[29] ## CblE type of homocystinuria Remethylation of homocysteine to methionine by MTR requires the derivative of cobalamin, methylcobalamin. Cobalamin metabolism is initiated by the endocytosis of cobalamin bound to the plasma protein transcobalamin (II). Cleavage of this complex produces free cobalamin, translocating from lysosome to cytoplasm. Conversion can occur to 5’-deoxyadenosylcobalamin (AdoCbl) activating the mitochrondrial enzyme methylmalonly coenzyme A mutase or to methylcobalamin (MeCbl).[30] An error in cobalamin metabolism resulting in decreased MeCbl and unaffected AdoCbl is characteristic of the CblE type of homocystinuria.[30] This complementation is rare with autosomal recessive inheritance. The inherited methionine synthase functional deficiency corresponds to a defect in the reducing system required to activate the MTR enzyme. Symptoms of this condition comprise developmental retardation, megaloblastic anemia, homocystinuria, hypomethioninemia, cerebral atrophy and hyperhomocysteinemia.[30] However, hypomethioninemia remains an inconsistent symptom. Decreased MeCbl alongside normal cobalamin uptake is suggestive of decreased intracellular methionine biosynthesis. Occurring mainly in childhood, 15 pathogenic mutations can be associated with CblE type homocystinuria.[31] Additionally, vascular abnormalities are associated with this defect.[32] Impaired reduction of an oxidised cobalt atom in the active site of MTR is associated with this condition, where enzyme activity can be corrected with reducing agents.[31] Rare polymorphisms related to this disease include (MTRR):c.1459G>A, (MTRR):c.1623-1624insTA and (MTRR):c.903+469T>C.[31] These mutations, excluding (MTRR):c.1459G>A result in a frame shift, producing premature termination codons.[31] As consequent products are distant from normal, mutant mRNA arises and nonsense mediated decay (FMN) is initiated.[31] The large insertion of 903_904ins140 corresponding to 903+469T>C is most prevalent in CblE pathology. The activation of an enhanced splicer within intron 6 is incomplete, producing small quantities of normal spliced MTRR mRNA.[31] Prenatal diagnosis of this condition is possible using [14C] methyltetrahydrofolate.[31] Mutation analysis in native chorionic villi and [14C] formate in amino acids within these villi or cultured amniocytes is indicative of the CblE defect.[31] Additionally, macrocytic anemia is a typical feature of the CblE defect and can be corrected though OH-Cobalamin administration or folate supplementation.[31] ## Coronary artery disease Homocysteine, a sulfur based amino acid is the main product of methionine demethylation. Elevated homocysteine is an independent risk factor for cardiovascular disease and inversely correlated to consumed vitamin B12/B6 and folate levels.[33] Homocysteine methylation to methionine is catalyzed by MTR, resulting in appropriate intracellular levels of methionine and tetrahydrofolate, alongside non-toxic homocysteine levels. The GG phenotype promotes the development of premature coronary artery disease (CAD) independent of hyperhomocysteinemia.[33] Hyperhomocysteinemia is associated with cerebral, coronary and peripheral atherosclerotic pathology as it promotes endothelial cell dysfunction, platelet adhesion and vascular smooth muscle cell proliferation.[32] DNA damage and homocysteine levels are proportional to CAD severity. Micronucleus frequency in human lymphocytes, dependent on homocysteine levels increases reactive oxygen species and uracil incorporation in DNA methylation, promoting genetic alterations and point mutations.[32] The (MTRR):c.66A>G, polymorphism containing chromosome is prone to fragmentation. This chromosomal loss or global DNA hypomethylation results in under condensation of pericentromeric heterochromatin, micronucleus formation and elevated risks of aneuploidy.[32] Co-expression of this mutation and the 677T polymorphism in methionine tetrahydrofolate reductase (MTHFR) Methylenetetrahydrofolate reductase act to further the extent of DNA damage.[32] Hypomethylation due to impaired methylation up regulates atherosclerotic susceptible genes whilst down regulating atherosclerosis protective genes.[32] This abnormality is present during the atherosclerotic pathology, increasing transcriptional activity of platelet derived growth factor (PDGF) and promoting smooth muscle cell proliferation.[32] ## Neural tube defects ### Spina bifida MTRR requires vitamin B12 for maintenance of the methyl synthase reaction whilst folate is needed for normal synthesis of nucleotide precursors. These ensure normal DNA synthesis and cellular methylation reactions.[3] Chronic folate or methyl deficiencies are thereby linked to abnormal DNA methylation. The 66A>G polymorphism is up-regulated in neural tube defects and increases the risk of spina bifida by two-fold.[34] Homozygosis for this mutation is an established maternal risk factor for spina bifida especially with low intracellular vitamin B12[35] in the circulation or amniotic fluid.[9] Vitamin B12 is reflected by plasma methylmalonic acid (MMA), an elevation in which indicates impaired B12 uptake or metabolism.[3] A raised MMA combined with the MTRR mutation corresponds to a 5-fold increase in spina bifida.[3] The mechanism of action of this polymorphism is through the mother, hence there is no preferential transmission of this mutation from parent to child. Abnormal MTRR binding to the MTR-cob(I)alamin-enzyme complex down regulates the rate of homocysteine methylation. Consequent decreases in methionine and S-adenosylmethionine negatively affect DNA, gene and protein methylation, all of which are involved in neural tube closure.[3] Increased proliferation during neurulation decreases the availability of DNA nucleotides. As these are unable to be replaced due to impaired DNA methylation and nucleotide formation, consequent disturbed neurulation results in the formation of neural tube defects.[7] Co-expression of this mutation with the 677C>T MTHFR polymorphism furthers the risk of spina bifida compared to an independent acting 66A>G mutation.[3] ### Down syndrome Trisomy 21 or Down syndrome is the most common human chromosomal anomaly arising from abnormal chromosomal segregation in meiosis.[6][7][36] The condition can occur during anaphase in meiosis(I) marking oocyte maturation before ovulation and/or during anaphase in meiosis (II) signifying fertilization.[7] Metabolic impact during these stages is furthered by low vitamin B12.[37] Methylation of homocysteine to methionine is affected, primarily by the (MTRR):c.66A>G polymorphism. Chronic homocysteine elevation increases s-adenosyl-L-homocysteine levels, consequently inhibiting methyltransferase activity and promoting DNA hypomethylation.[6][38] Mothers homozygous for this mutation (GG phenotype) are at a greater risk of having a child with down syndrome compared to heterozygotes (GA phenotype).[37] Geographically, Irish populations are more likely to be homogenous whilst north American populations are commonly heterogeneous, resulting in a greater incidence of the polymorphism in the former group.[7][37] The homozygous mutant allele promotes DNA hypomethylation and meiotic non-disjunction, increasing the risk of down syndrome.[39] This polymorphism correlates to a 2.5 fold risk increase independently and a 4 fold increase in risk when co-expressed with the 677C>T MTHFR mutation.[7] Combination with the MTR2756A>G genetic polymorphism further elevates down syndrome risk.[7][38][40]	https://www.wikidoc.org/index.php/MTRR_(gene)
7b9cd096a68678dbbb28f0cd85f200a13c967ff8	wikidoc	Macimorelin	Macimorelin # 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 Macimorelin is a growth hormone (GH) secretagogue receptor agonist that is FDA approved for the diagnosis of adult growth hormone deficiency. Common adverse reactions include dysgeusia, dizziness, headache, fatigue, nausea, hunger, diarrhea, upper respiratory tract infection, feeling hot, hyperhidrosis, nasopharyngitis, and sinus bradycardia. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) - Macimorelin is indicated for the diagnosis of adult growth hormone deficiency (AGHD). - The safety and diagnostic performance of macimorelin have not been established for subjects with a body mass index (BMI) > 40 kg/m2. - The recommended dose is a single oral dose of 0.5 mg/kg of macimorelin. The dose is administered as a reconstituted solution. - Discontinue strong CYP3A4 inducers prior to macimorelin use. - Discontinue growth hormone (GH) therapy at least one week before administering macimorelin. - Avoid the use of macimorelin with drugs known to affect pituitary GH secretion. - For patients with deficiencies in sex hormones, thyroid hormone and/or glucocorticoid, adequately replace each of the missing hormones before administering macimorelin. - Ensure that the patient has fasted for at least 8 hours before macimorelin use. - For oral solution: 60 mg white to off-white granules in a pouch for reconstitution in 120 mL of water, resulting in a solution of 0.5 mg/mL of macimorelin. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding macimorelin Off-Label Guideline-Supported Use and Dosage (Adult) in the drug label. ### Non–Guideline-Supported Use There is limited information regarding macimorelin Off-Label Non-Guideline-Supported Use and Dosage (Adult) in the drug label. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) There is limited information regarding Macimorelin FDA-Labeled Indications and Dosage (Pediatric) in the drug label. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding macimorelin Off-Label Guideline-Supported Use and Dosage (Pediatric) in the drug label. ### Non–Guideline-Supported Use There is limited information regarding macimorelin Off-Label Non-Guideline-Supported Use and Dosage (Pediatric) in the drug label. # Contraindications - None. # Warnings - Macimorelin causes an increase of about 11 msec in the corrected QT (QTc) interval. QT prolongation can lead to development of torsade de pointes-type ventricular tachycardia with the risk increasing as the degree of prolongation increases. The concomitant use of macimorelin with drugs that are known to prolong the QT interval should be avoided. - Concomitant use of strong CYP3A4 inducers with macimorelin can decrease macimorelin plasma levels significantly and thereby lead to a false positive result. Strong CYP3A4 inducers should be discontinued and enough time should be given to allow washout of CYP3A4 inducers prior to test administration. - Adult growth hormone (GH) deficiency caused by a hypothalamic lesion may not be detected early in the disease process. Macimorelin acts downstream from the hypothalamus and macimorelin stimulated release of stored GH reserves from the anterior pituitary could produce a false negative result early when the lesion involves the hypothalamus. Repeat testing may be warranted in this situation. # 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 trial of another drug and may not reflect the rates observed in practice. - The data in TABLE 1 are derived from an open-label, randomized, cross-over study that compared the diagnostic performance of macimorelin to the insulin tolerance test (ITT) for the diagnosis of adult growth hormone deficiency. A total of 154 subjects with a high to low pre-test probability of having adult growth hormone deficiency received a single oral dose of 0.5 mg/kg macimorelin. Out of 154 subjects, 58% were male, 42% female, and 86% of white origin. Median values were for age 41 years (range: 18 – 66 years) and body mass index was 27.5 kg/m2 (range: 16 – 40 kg/m2). Common adverse reactions presented in TABLE 1 were adverse reactions that were not present at baseline and occurred during macimorelin dosing in at least two individuals. ## Postmarketing Experience There is limited information regarding Macimorelin Postmarketing Experience in the drug label. # Drug Interactions - Drugs that Prolong QT Interval - Cytochrome P450 (CYP) 3A4 Inducers - Drugs Affecting Growth Hormone Release - Co-administration of macimorelin with drugs that prolong the QT interval (such as antipsychotic medications (e.g., chlorpromazine, haloperidol, thioridazine, ziprasidone), antibiotics (e.g., moxifloxacin), Class 1A (e.g., quinidine, procainamide) and Class III (e.g., amiodarone, sotalol) antiarrhythmic medications or any other medications known to prolong the QT interval) may lead to development of torsade de pointes-type ventricular tachycardia. Avoid concomitant use of macimorelin with drugs that prolong the QT interval. Sufficient washout time of drugs that are known to prolong the QT interval prior to administration of macimorelin is recommended. - Co-administration of a strong CYP3A4 inducer with macimorelin (e.g., carbamazepine, enzalutamide, mitotane, phenytoin, rifampin, St. John's wort, bosentan, efavirenz, etravirine, modafinil, armodafinil, rufinamide) may reduce the plasma macimorelin concentrations and may lead to false positive test results. Discontinue strong CYP3A4 inducers prior to macimorelin use. Sufficient washout time of strong CYP3A4 inducers prior to administration of macimorelin is recommended. - The following drugs may impact the accuracy of the macimorelin diagnostic test. Avoid concomitant use of macimorelin with the following: - Drugs that directly affect the pituitary secretion of growth hormone (such as somatostatin, insulin, glucocorticoids, and cyclooxygenase inhibitors such as aspirin or indomethacin). - Drugs that may transiently elevate growth hormone concentrations (such as clonidine, levodopa, and insulin). - Drugs that may blunt the growth hormone response to macimorelin (such as muscarinic antagonists: atropine, anti-thyroid medication: propylthiouracil, and growth hormone products). Discontinue growth hormone products at least one week before administering the macimorelin diagnostic test. - Sufficient washout time of drugs affecting growth hormone release prior to administration of macimorelin is recommended. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): - There are no available data with macimorelin use in pregnant women to inform a drug associated risk for adverse developmental outcomes. Animal reproduction studies have not been conducted with macimorelin. Macimorelin is indicated as a single dose which limits the risk of adverse developmental outcomes from exposure to macimorelin. - The estimated background risk of major birth defects and miscarriage for the indicated populations is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 – 4% and 15 – 20%, respectively. Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Macimorelin in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Macimorelin during labor and delivery. ### Nursing Mothers - There are no data on the presence of macimorelin in human or animal milk, the effects on the breastfed infant or the effects on milk production. The lack of clinical data during lactation precludes a clear determination of the risk of macimorelin to an infant during lactation; therefore, the developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for macimorelin and any potential adverse effecs on the breastfed infant from macimorelin or the underlying maternal condition. ### Pediatric Use - The safety and efficacy of macimorelin in pediatric patients have not been established. ### Geriatic Use - Growth hormone secretion normally decreases with age. Therefore, elderly subjects might require a lower cut-off point for diagnosis of adult growth hormone deficiency. Clinical studies of macimorelin did not include a sufficient number of subjects aged 65 and over to determine whether elderly patients respond differently from younger subjects. ### Gender There is no FDA guidance on the use of Macimorelin with respect to specific gender populations. ### Race There is no FDA guidance on the use of Macimorelin with respect to specific racial populations. ### Renal Impairment There is no FDA guidance on the use of Macimorelin in patients with renal impairment. ### Hepatic Impairment There is no FDA guidance on the use of Macimorelin in patients with hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Macimorelin in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Macimorelin in patients who are immunocompromised. # Administration and Monitoring ### Administration - Prepare and administer by a healthcare professional exactly as follows. - Weigh the patient in kilograms (i.e., kg). - Determine the number of macimorelin pouches needed to prepare the dose: - For a patient weighing up to 120 kg, use 1 pouch. - For a patient weighing more than 120 kg, use 2 pouches. - Use a glass or transparent plastic container with graduation in milliliters (i.e., mL) to dissolve the entire contents of the pouch(es) in the appropriate volume of water. - For 1 pouch dissolve in 120 mL of water (corresponds to 60 mg/120 mL). - For 2 pouches dissolve in 240 mL of water (corresponds to 120 mg/240 mL). - Stir the macimorelin solution gently for about 2 to 3 minutes (a small amount of un-dissolved particles will remain). The solution will have a final concentration of 0.5 mg/mL. - Use the macimorelin solution within 30 minutes after preparation. - Discard any unused macimorelin solution. - Determine the recommended dose to be administered by multiplying the patient weight in kilogram by 0.5 mg/kg. - For example, a 70 kg patient will need a 35 mg dose. - Determine the volume of prepared macimorelin solution to be administered by dividing the recommended dose by 0.5 mg/mL. - For example, a patient requiring a dose of 35 mg will need 70 mL of reconstituted macimorelin solution. - Use a syringe (without a needle) with graduations in mL to measure the exact volume of macimorelin solution to be administered and transfer the required volume of macimorelin solution into a drinking glass. - Have the patient being tested drink the entire volume of macimorelin solution in the drinking glass (i.e., the dose) within 30 seconds. - Observe the patient being tested per routine for the duration of the test. - Draw venous blood samples for GH determination at 30 minutes, 45 minutes, 60 minutes and 90 minutes after administration of macimorelin. - Prepare serum samples and send to a laboratory for growth hormone determinations. - Clinical studies have established that a maximally stimulated serum GH level of less than 2.8 ng/mL (i.e., at the 30, 45, 60 and 90 minute timepoints) following macimorelin administration confirms the presence of adult growth hormone deficiency. ### Monitoring - Venous blood samples for growth hormone (GH): At 30, 45, 60, and 90 minutes following administration: maximally stimulated serum GH levels of 2.8 nanogram (ng)/mL or less at each interval confirms the presence GH deficiency. # IV Compatibility There is limited information regarding the compatibility of Macimorelin and IV administrations. # Overdosage - In the event of an overdose, symptomatic and supportive measures should be employed. # Pharmacology ## Mechanism of Action - Macimorelin stimulates GH release by activating growth hormone secretagogue receptors present in the pituitary and hypothalamus. ## Structure ## Pharmacodynamics - Maximum GH levels are observed between 30 to 90 minutes after administration of macimorelin. - The effects of macimorelin on ECG parameters were investigated in a dedicated Thorough QT study that investigated in a 3-way cross-over design with 60 healthy subjects the effects of a supra-therapeutic dose of macimorelin (2 mg/kg) (4 times the recommended dosage) in comparison with placebo and with moxifloxacin. This study showed a mean baseline- and placebo-adjusted change (upper single-sided 95% confidence interval) in QTcF of 9.6 msec (11.4 msec) at 4 h post-dose, which occurred after the mean maximum macimorelin plasma concentration (0.5 h). A similar increase in the QTcF interval was also observed in a single-ascending dose study, which included three dose levels (0.5 mg/kg, and 1 mg/kg and 2 mg/kg (2 times and 4 times the recommended dosage, respectively). All three doses levels studied showed a similar magnitude of QTcF prolongation in the Thorough QT study, suggesting an absence of dose dependent changes. The mechanism for the observed QTcF prolongation is unknown. ## Pharmacokinetics - The mean plasma macimorelin concentrations are similar between patients with AGHD and healthy subjects for 1.5 hours following administration of a single oral dose of 0.5 mg macimorelin/kg body weight. - The maximum plasma macimorelin concentrations (Cmax) were observed between 0.5 hour and 1.5 hours following oral administration of 0.5 mg macimorelin/kg body weight to patients with AGHD under fasting for at least 8 hours. A liquid meal decreased the macimorelin Cmax and AUC by 55% and 49%, respectively. - An in vitro human liver microsomes study showed that CYP3A4 is the major enzyme to metabolize macimorelin. - Macimorelin was eliminated with a mean terminal half-life (T1/2) of 4.1 hours following administration of a single oral dose of 0.5 mg macimorelin/kg body weight in healthy subjects. ## Nonclinical Toxicology - Long-term carcinogenesis studies in rodents have not been conducted. - Macimorelin did not cause mutations in bacteria under assay conditions with or without metabolic activation. There were also no mutations or clastogenic effects in mouse lymphoma cells with or without metabolic activation. - No studies have been conducted to assess the effect of macimorelin on fertility. # Clinical Studies - The diagnostic efficacy of the macimorelin test was established in a randomized, open-label, single-dose, cross-over study. The objective of the study was to compare the level of agreement between macimorelin test results and insulin tolerance test (ITT) results in adult patients with different pre-test probability of growth hormone deficiency and healthy control subjects. The four groups of individuals evaluated were: - Group A: Adults with a high likelihood of growth hormone deficiency (GHD) - Structural hypothalamic or pituitary lesions and low insulin-like growth factor 1 (IGF-1), and/or - Three or more pituitary hormone deficiencies and low IGF-1, or - Childhood onset GHD with structural lesions and low IGF-1. - Group B: Adults with an intermediate likelihood of GHD - Eligible subjects not qualifying for either high or low likelihood. - Group C: Adults with a low likelihood of GHD - One risk factor for GHD only, such as history of distant traumatic brain injury or one pituitary hormone deficiency only with otherwise normal pituitary function, or - Isolated idiopathic childhood onset GHD without additional pituitary deficits. - Group D: Healthy adult controls - Healthy subjects matching Group A subjects by sex, age ± 5 years, body mass index (BMI ± 2 kg/m2), and estrogen status (females only). - For both the ITT and the macimorelin test, serum concentrations of growth hormone were measured at 30, 45, 60, and 90 minutes after drug administration. The test was considered positive (i.e., growth hormone deficiency diagnosed) if the maximum serum GH level observed after stimulation was less than the pre-specified cut point value of 2.8 ng/mL for the macimorelin test or 5.1 ng/mL for the ITT. - The level of negative and positive agreement between the results of the ITT and the macimorelin test was used to evaluate the performance of the macimorelin test. In the study, the ITT is used as the benchmark (i.e., a negative ITT indicates absence of disease and a positive ITT indicates presence of disease). Negative agreement is the proportion of subjects with a negative ITT (i.e., those who do not have GHD per the ITT) who also have a negative macimorelin test. With a high level of negative agreement, the macimorelin test will not wrongly diagnose an individual without GHD per the ITT as having GHD. Positive agreement is the proportion of subjects with a positive ITT (i.e., those who have GHD per the ITT) who also have a positive macimorelin test. With a high level of positive agreement, the macimorelin test will not wrongly diagnose an individual with GHD per the ITT as not having GHD. The agreement measures are defined mathematically below. - One hundred and fifty-seven subjects underwent at least one of the two tests in this study, 59% were male, 41% female, and 86% of white origin. The median age was 41 years (range: 18 – 66 years) and body mass index 27.5 kg/m2 (range: 16 – 40 kg/m2). The study relied on a cross-over design and each participant was to undergo the two diagnostic tests and serve as his or her own control. Data on both tests were available for 140 subjects; 38 (27%) in Group A, 37 (26%) in Group B, 40 (29%) in Group C, and 25 (18%) in Group D. One out of 154 macimorelin tests (0.6%) performed failed due to a technical error and 27 out of 157 ITTs (17.2%) performed failed because induction of severe hypoglycemia (i.e., the stimulus) could not be achieved. - Two-by-two tables presenting the pre-specified primary analysis results for the ITT and macimorelin test are shown below for all subjects (Groups A, B, C, and D combined) and for each group separately. The estimates for negative and positive agreement between macimorelin and the ITT in the overall study population were 94% and 74% with lower 95% confidence interval bounds 85% and 63%, respectively. Negative and positive agreement between macimorelin and the ITT in subjects with intermediate or low risk (Groups B and C) were 93% and 61% with lower 95% confidence interval bounds 80% and 43%, respectively. These results are based on peak GH values (maximum GH concentrations across all measurement timepoints). - Repeatability was tested in a subset of 34 subjects who underwent two macimorelin tests. Agreement between the result of the first test and the second test was observed in 31 cases (91.2%). # How Supplied - Macimorelin 60 mg is supplied as white to off-white granules in an aluminum pouch. Each pouch contains 60 mg macimorelin (equivalent to 68 mg macimorelin acetate) that when reconstituted with 120 mL of water provides a 60 mg/120 mL (0.5 mg/mL) macimorelin solution. - Macimorelin is available in boxes containing 1 pouch per box (NDC 71090-002-02). - Before administration, macimorelin for oral solution must be reconstituted by a healthcare professional. ## Storage - Store pouches under refrigeration at 2-8°C (36-46°F). - The solution must be used within 30 minutes after preparation. Discard unused portion. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information - Instruct patients to discontinue treatment with GH at least one week before administering macimorelin. Also, instruct patients to discontinue other medications that may interfere with the diagnostic test results prior to macimorelin administration. - Instruct patients to fast for at least 8 hours before macimorelin administration # Precautions with Alcohol Alcohol-Macimorelin interaction has not been established. Talk to your doctor regarding the effects of taking alcohol with this medication. # Brand Names - Macrilen # Look-Alike Drug Names There is limited information regarding Macimorelin Look-Alike Drug Names in the drug label. # Drug Shortage Status Drug Shortage # Price	Macimorelin Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Sonya Gelfand # 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 Macimorelin is a growth hormone (GH) secretagogue receptor agonist that is FDA approved for the diagnosis of adult growth hormone deficiency. Common adverse reactions include dysgeusia, dizziness, headache, fatigue, nausea, hunger, diarrhea, upper respiratory tract infection, feeling hot, hyperhidrosis, nasopharyngitis, and sinus bradycardia. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) - Macimorelin is indicated for the diagnosis of adult growth hormone deficiency (AGHD). - The safety and diagnostic performance of macimorelin have not been established for subjects with a body mass index (BMI) > 40 kg/m2. - The recommended dose is a single oral dose of 0.5 mg/kg of macimorelin. The dose is administered as a reconstituted solution. - Discontinue strong CYP3A4 inducers prior to macimorelin use. - Discontinue growth hormone (GH) therapy at least one week before administering macimorelin. - Avoid the use of macimorelin with drugs known to affect pituitary GH secretion. - For patients with deficiencies in sex hormones, thyroid hormone and/or glucocorticoid, adequately replace each of the missing hormones before administering macimorelin. - Ensure that the patient has fasted for at least 8 hours before macimorelin use. - For oral solution: 60 mg white to off-white granules in a pouch for reconstitution in 120 mL of water, resulting in a solution of 0.5 mg/mL of macimorelin. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding macimorelin Off-Label Guideline-Supported Use and Dosage (Adult) in the drug label. ### Non–Guideline-Supported Use There is limited information regarding macimorelin Off-Label Non-Guideline-Supported Use and Dosage (Adult) in the drug label. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) There is limited information regarding Macimorelin FDA-Labeled Indications and Dosage (Pediatric) in the drug label. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding macimorelin Off-Label Guideline-Supported Use and Dosage (Pediatric) in the drug label. ### Non–Guideline-Supported Use There is limited information regarding macimorelin Off-Label Non-Guideline-Supported Use and Dosage (Pediatric) in the drug label. # Contraindications - None. # Warnings - Macimorelin causes an increase of about 11 msec in the corrected QT (QTc) interval. QT prolongation can lead to development of torsade de pointes-type ventricular tachycardia with the risk increasing as the degree of prolongation increases. The concomitant use of macimorelin with drugs that are known to prolong the QT interval should be avoided. - Concomitant use of strong CYP3A4 inducers with macimorelin can decrease macimorelin plasma levels significantly and thereby lead to a false positive result. Strong CYP3A4 inducers should be discontinued and enough time should be given to allow washout of CYP3A4 inducers prior to test administration. - Adult growth hormone (GH) deficiency caused by a hypothalamic lesion may not be detected early in the disease process. Macimorelin acts downstream from the hypothalamus and macimorelin stimulated release of stored GH reserves from the anterior pituitary could produce a false negative result early when the lesion involves the hypothalamus. Repeat testing may be warranted in this situation. # 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 trial of another drug and may not reflect the rates observed in practice. - The data in TABLE 1 are derived from an open-label, randomized, cross-over study that compared the diagnostic performance of macimorelin to the insulin tolerance test (ITT) for the diagnosis of adult growth hormone deficiency. A total of 154 subjects with a high to low pre-test probability of having adult growth hormone deficiency received a single oral dose of 0.5 mg/kg macimorelin. Out of 154 subjects, 58% were male, 42% female, and 86% of white origin. Median values were for age 41 years (range: 18 – 66 years) and body mass index was 27.5 kg/m2 (range: 16 – 40 kg/m2). Common adverse reactions presented in TABLE 1 were adverse reactions that were not present at baseline and occurred during macimorelin dosing in at least two individuals. ## Postmarketing Experience There is limited information regarding Macimorelin Postmarketing Experience in the drug label. # Drug Interactions - Drugs that Prolong QT Interval - Cytochrome P450 (CYP) 3A4 Inducers - Drugs Affecting Growth Hormone Release - Co-administration of macimorelin with drugs that prolong the QT interval (such as antipsychotic medications (e.g., chlorpromazine, haloperidol, thioridazine, ziprasidone), antibiotics (e.g., moxifloxacin), Class 1A (e.g., quinidine, procainamide) and Class III (e.g., amiodarone, sotalol) antiarrhythmic medications or any other medications known to prolong the QT interval) may lead to development of torsade de pointes-type ventricular tachycardia. Avoid concomitant use of macimorelin with drugs that prolong the QT interval. Sufficient washout time of drugs that are known to prolong the QT interval prior to administration of macimorelin is recommended. - Co-administration of a strong CYP3A4 inducer with macimorelin (e.g., carbamazepine, enzalutamide, mitotane, phenytoin, rifampin, St. John's wort, bosentan, efavirenz, etravirine, modafinil, armodafinil, rufinamide) may reduce the plasma macimorelin concentrations and may lead to false positive test results. Discontinue strong CYP3A4 inducers prior to macimorelin use. Sufficient washout time of strong CYP3A4 inducers prior to administration of macimorelin is recommended. - The following drugs may impact the accuracy of the macimorelin diagnostic test. Avoid concomitant use of macimorelin with the following: - Drugs that directly affect the pituitary secretion of growth hormone (such as somatostatin, insulin, glucocorticoids, and cyclooxygenase inhibitors such as aspirin or indomethacin). - Drugs that may transiently elevate growth hormone concentrations (such as clonidine, levodopa, and insulin). - Drugs that may blunt the growth hormone response to macimorelin (such as muscarinic antagonists: atropine, anti-thyroid medication: propylthiouracil, and growth hormone products). Discontinue growth hormone products at least one week before administering the macimorelin diagnostic test. - Sufficient washout time of drugs affecting growth hormone release prior to administration of macimorelin is recommended. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): - There are no available data with macimorelin use in pregnant women to inform a drug associated risk for adverse developmental outcomes. Animal reproduction studies have not been conducted with macimorelin. Macimorelin is indicated as a single dose which limits the risk of adverse developmental outcomes from exposure to macimorelin. - The estimated background risk of major birth defects and miscarriage for the indicated populations is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 – 4% and 15 – 20%, respectively. Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Macimorelin in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Macimorelin during labor and delivery. ### Nursing Mothers - There are no data on the presence of macimorelin in human or animal milk, the effects on the breastfed infant or the effects on milk production. The lack of clinical data during lactation precludes a clear determination of the risk of macimorelin to an infant during lactation; therefore, the developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for macimorelin and any potential adverse effecs on the breastfed infant from macimorelin or the underlying maternal condition. ### Pediatric Use - The safety and efficacy of macimorelin in pediatric patients have not been established. ### Geriatic Use - Growth hormone secretion normally decreases with age. Therefore, elderly subjects might require a lower cut-off point for diagnosis of adult growth hormone deficiency. Clinical studies of macimorelin did not include a sufficient number of subjects aged 65 and over to determine whether elderly patients respond differently from younger subjects. ### Gender There is no FDA guidance on the use of Macimorelin with respect to specific gender populations. ### Race There is no FDA guidance on the use of Macimorelin with respect to specific racial populations. ### Renal Impairment There is no FDA guidance on the use of Macimorelin in patients with renal impairment. ### Hepatic Impairment There is no FDA guidance on the use of Macimorelin in patients with hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Macimorelin in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Macimorelin in patients who are immunocompromised. # Administration and Monitoring ### Administration - Prepare and administer by a healthcare professional exactly as follows. - Weigh the patient in kilograms (i.e., kg). - Determine the number of macimorelin pouches needed to prepare the dose: - For a patient weighing up to 120 kg, use 1 pouch. - For a patient weighing more than 120 kg, use 2 pouches. - Use a glass or transparent plastic container with graduation in milliliters (i.e., mL) to dissolve the entire contents of the pouch(es) in the appropriate volume of water. - For 1 pouch dissolve in 120 mL of water (corresponds to 60 mg/120 mL). - For 2 pouches dissolve in 240 mL of water (corresponds to 120 mg/240 mL). - Stir the macimorelin solution gently for about 2 to 3 minutes (a small amount of un-dissolved particles will remain). The solution will have a final concentration of 0.5 mg/mL. - Use the macimorelin solution within 30 minutes after preparation. - Discard any unused macimorelin solution. - Determine the recommended dose to be administered by multiplying the patient weight in kilogram by 0.5 mg/kg. - For example, a 70 kg patient will need a 35 mg dose. - Determine the volume of prepared macimorelin solution to be administered by dividing the recommended dose by 0.5 mg/mL. - For example, a patient requiring a dose of 35 mg will need 70 mL of reconstituted macimorelin solution. - Use a syringe (without a needle) with graduations in mL to measure the exact volume of macimorelin solution to be administered and transfer the required volume of macimorelin solution into a drinking glass. - Have the patient being tested drink the entire volume of macimorelin solution in the drinking glass (i.e., the dose) within 30 seconds. - Observe the patient being tested per routine for the duration of the test. - Draw venous blood samples for GH determination at 30 minutes, 45 minutes, 60 minutes and 90 minutes after administration of macimorelin. - Prepare serum samples and send to a laboratory for growth hormone determinations. - Clinical studies have established that a maximally stimulated serum GH level of less than 2.8 ng/mL (i.e., at the 30, 45, 60 and 90 minute timepoints) following macimorelin administration confirms the presence of adult growth hormone deficiency. ### Monitoring - Venous blood samples for growth hormone (GH): At 30, 45, 60, and 90 minutes following administration: maximally stimulated serum GH levels of 2.8 nanogram (ng)/mL or less at each interval confirms the presence GH deficiency. # IV Compatibility There is limited information regarding the compatibility of Macimorelin and IV administrations. # Overdosage - In the event of an overdose, symptomatic and supportive measures should be employed. # Pharmacology ## Mechanism of Action - Macimorelin stimulates GH release by activating growth hormone secretagogue receptors present in the pituitary and hypothalamus. ## Structure ## Pharmacodynamics - Maximum GH levels are observed between 30 to 90 minutes after administration of macimorelin. - The effects of macimorelin on ECG parameters were investigated in a dedicated Thorough QT study that investigated in a 3-way cross-over design with 60 healthy subjects the effects of a supra-therapeutic dose of macimorelin (2 mg/kg) (4 times the recommended dosage) in comparison with placebo and with moxifloxacin. This study showed a mean baseline- and placebo-adjusted change (upper single-sided 95% confidence interval) in QTcF of 9.6 msec (11.4 msec) at 4 h post-dose, which occurred after the mean maximum macimorelin plasma concentration (0.5 h). A similar increase in the QTcF interval was also observed in a single-ascending dose study, which included three dose levels (0.5 mg/kg, and 1 mg/kg and 2 mg/kg (2 times and 4 times the recommended dosage, respectively). All three doses levels studied showed a similar magnitude of QTcF prolongation in the Thorough QT study, suggesting an absence of dose dependent changes. The mechanism for the observed QTcF prolongation is unknown. ## Pharmacokinetics - The mean plasma macimorelin concentrations are similar between patients with AGHD and healthy subjects for 1.5 hours following administration of a single oral dose of 0.5 mg macimorelin/kg body weight. - The maximum plasma macimorelin concentrations (Cmax) were observed between 0.5 hour and 1.5 hours following oral administration of 0.5 mg macimorelin/kg body weight to patients with AGHD under fasting for at least 8 hours. A liquid meal decreased the macimorelin Cmax and AUC by 55% and 49%, respectively. - An in vitro human liver microsomes study showed that CYP3A4 is the major enzyme to metabolize macimorelin. - Macimorelin was eliminated with a mean terminal half-life (T1/2) of 4.1 hours following administration of a single oral dose of 0.5 mg macimorelin/kg body weight in healthy subjects. ## Nonclinical Toxicology - Long-term carcinogenesis studies in rodents have not been conducted. - Macimorelin did not cause mutations in bacteria under assay conditions with or without metabolic activation. There were also no mutations or clastogenic effects in mouse lymphoma cells with or without metabolic activation. - No studies have been conducted to assess the effect of macimorelin on fertility. # Clinical Studies - The diagnostic efficacy of the macimorelin test was established in a randomized, open-label, single-dose, cross-over study. The objective of the study was to compare the level of agreement between macimorelin test results and insulin tolerance test (ITT) results in adult patients with different pre-test probability of growth hormone deficiency and healthy control subjects. The four groups of individuals evaluated were: - Group A: Adults with a high likelihood of growth hormone deficiency (GHD) - Structural hypothalamic or pituitary lesions and low insulin-like growth factor 1 (IGF-1), and/or - Three or more pituitary hormone deficiencies and low IGF-1, or - Childhood onset GHD with structural lesions and low IGF-1. - Group B: Adults with an intermediate likelihood of GHD - Eligible subjects not qualifying for either high or low likelihood. - Group C: Adults with a low likelihood of GHD - One risk factor for GHD only, such as history of distant traumatic brain injury or one pituitary hormone deficiency only with otherwise normal pituitary function, or - Isolated idiopathic childhood onset GHD without additional pituitary deficits. - Group D: Healthy adult controls - Healthy subjects matching Group A subjects by sex, age ± 5 years, body mass index (BMI ± 2 kg/m2), and estrogen status (females only). - For both the ITT and the macimorelin test, serum concentrations of growth hormone were measured at 30, 45, 60, and 90 minutes after drug administration. The test was considered positive (i.e., growth hormone deficiency diagnosed) if the maximum serum GH level observed after stimulation was less than the pre-specified cut point value of 2.8 ng/mL for the macimorelin test or 5.1 ng/mL for the ITT. - The level of negative and positive agreement between the results of the ITT and the macimorelin test was used to evaluate the performance of the macimorelin test. In the study, the ITT is used as the benchmark (i.e., a negative ITT indicates absence of disease and a positive ITT indicates presence of disease). Negative agreement is the proportion of subjects with a negative ITT (i.e., those who do not have GHD per the ITT) who also have a negative macimorelin test. With a high level of negative agreement, the macimorelin test will not wrongly diagnose an individual without GHD per the ITT as having GHD. Positive agreement is the proportion of subjects with a positive ITT (i.e., those who have GHD per the ITT) who also have a positive macimorelin test. With a high level of positive agreement, the macimorelin test will not wrongly diagnose an individual with GHD per the ITT as not having GHD. The agreement measures are defined mathematically below. - One hundred and fifty-seven subjects underwent at least one of the two tests in this study, 59% were male, 41% female, and 86% of white origin. The median age was 41 years (range: 18 – 66 years) and body mass index 27.5 kg/m2 (range: 16 – 40 kg/m2). The study relied on a cross-over design and each participant was to undergo the two diagnostic tests and serve as his or her own control. Data on both tests were available for 140 subjects; 38 (27%) in Group A, 37 (26%) in Group B, 40 (29%) in Group C, and 25 (18%) in Group D. One out of 154 macimorelin tests (0.6%) performed failed due to a technical error and 27 out of 157 ITTs (17.2%) performed failed because induction of severe hypoglycemia (i.e., the stimulus) could not be achieved. - Two-by-two tables presenting the pre-specified primary analysis results for the ITT and macimorelin test are shown below for all subjects (Groups A, B, C, and D combined) and for each group separately. The estimates for negative and positive agreement between macimorelin and the ITT in the overall study population were 94% and 74% with lower 95% confidence interval bounds 85% and 63%, respectively. Negative and positive agreement between macimorelin and the ITT in subjects with intermediate or low risk (Groups B and C) were 93% and 61% with lower 95% confidence interval bounds 80% and 43%, respectively. These results are based on peak GH values (maximum GH concentrations across all measurement timepoints). - Repeatability was tested in a subset of 34 subjects who underwent two macimorelin tests. Agreement between the result of the first test and the second test was observed in 31 cases (91.2%). # How Supplied - Macimorelin 60 mg is supplied as white to off-white granules in an aluminum pouch. Each pouch contains 60 mg macimorelin (equivalent to 68 mg macimorelin acetate) that when reconstituted with 120 mL of water provides a 60 mg/120 mL (0.5 mg/mL) macimorelin solution. - Macimorelin is available in boxes containing 1 pouch per box (NDC 71090-002-02). - Before administration, macimorelin for oral solution must be reconstituted by a healthcare professional. ## Storage - Store pouches under refrigeration at 2-8°C (36-46°F). - The solution must be used within 30 minutes after preparation. Discard unused portion. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information - Instruct patients to discontinue treatment with GH at least one week before administering macimorelin. Also, instruct patients to discontinue other medications that may interfere with the diagnostic test results prior to macimorelin administration. - Instruct patients to fast for at least 8 hours before macimorelin administration # Precautions with Alcohol Alcohol-Macimorelin interaction has not been established. Talk to your doctor regarding the effects of taking alcohol with this medication. # Brand Names - Macrilen # Look-Alike Drug Names There is limited information regarding Macimorelin Look-Alike Drug Names in the drug label. # Drug Shortage Status Drug Shortage # Price	https://www.wikidoc.org/index.php/Macimorelin
6308ff7ddd6992fd97600fd58e5c89a8ecfd7b76	wikidoc	Macromerine	Macromerine Macromerine is a psychedelic, hallucinogenic and entheogenic of the phenethylamine family. It can be synthesized or extracted from the Doñana (Coryphantha macromeris), C. macromeris v. runyonii, C. elephantidens, and other related members of the Cactaceae family. The plants may have been used by Tarahumara shamans for their entheogenic effects. # Chemistry Macromerine is in a family of chemicals called the phenethylamines, and it is a close analogue of mescaline. The full chemical name of macromerine is 1-(3,4-dimethoxyphenyl)-2-(dimethylamino)ethanol. # Dosage Macromerine is said to have "1/5th" the potency of mescaline, so a dosage could be 1250-2500 mg based on the dosage of mescaline sulfate. # Effects Little is known about the psychedelic effects of macromerine. K. Trout states that a bioassay of macromerine-containing cactus, Doñana, "had been very mild and very strange, with many waves of intense nausea and extremely persistent after effects, such as distorted vision and a very weird feeling of unreality lasting for weeks after its use." However, considering Doñana is usually no more than 0.1 percent macromerine, several pounds of the dried cactus would be required to consume a psychedelic dosage of macromerine. What is more likely is that the combination of all alkaloids present in the cactus produce the effects of Doñana. # Legality Macromerine is not illegal in any known part of the world, but possession and sales of macromerine could be prosecuted under the Federal Analog Act in the USA because of its structural similarities to mescaline.	Macromerine Template:OrganicBox small Macromerine is a psychedelic, hallucinogenic and entheogenic of the phenethylamine family. It can be synthesized or extracted from the Doñana (Coryphantha macromeris), C. macromeris v. runyonii, C. elephantidens, and other related members of the Cactaceae family. The plants may have been used by Tarahumara shamans for their entheogenic effects. # Chemistry Macromerine is in a family of chemicals called the phenethylamines, and it is a close analogue of mescaline. The full chemical name of macromerine is 1-(3,4-dimethoxyphenyl)-2-(dimethylamino)ethanol. # Dosage Macromerine is said to have "1/5th" the potency of mescaline, so a dosage could be 1250-2500 mg based on the dosage of mescaline sulfate. # Effects Little is known about the psychedelic effects of macromerine. K. Trout states that a bioassay of macromerine-containing cactus, Doñana, "had been very mild and very strange, with many waves of intense nausea and extremely persistent after effects, such as distorted vision and a very weird feeling of unreality lasting for weeks after its use." However, considering Doñana is usually no more than 0.1 percent macromerine, several pounds of the dried cactus would be required to consume a psychedelic dosage of macromerine. What is more likely is that the combination of all alkaloids present in the cactus produce the effects of Doñana. # Legality Macromerine is not illegal in any known part of the world, but possession and sales of macromerine could be prosecuted under the Federal Analog Act in the USA because of its structural similarities to mescaline.	https://www.wikidoc.org/index.php/Macromerine
9138afd393005daf5b2b8c7baf568e25a99f4e1d	wikidoc	Macroscopic	Macroscopic Macroscopic is commonly used to describe physical objects that are measurable and observable by the naked eye. When applied to phenomena and abstract objects, it describes existence in the world as we perceive it. Lengths scales generally considered macroscopic roughly fall in the range 1 mm–1 km. The term macroscopic may also refer to a "larger view", namely a view only available from a large perspective. A macroscopic position could be considered the "big picture". # Examples - A macroscopic view of a ball is just that: a ball. A microscopic view could reveal a thick round skin seemingly composed entirely of puckered cracks and fissures (as viewed through a microscope) or, further down in scale, a collection of molecules in the rough shape of a sphere. # Macroscopy in physics In physics, macroscopy can be a physical trait applied relative to what one is observing. If one looks at a galaxy, a star is a microscopic entity, even if it is many, many orders of magnitude larger than us.	Macroscopic Macroscopic is commonly used to describe physical objects that are measurable and observable by the naked eye. When applied to phenomena and abstract objects, it describes existence in the world as we perceive it. Lengths scales generally considered macroscopic roughly fall in the range 1 mm–1 km. The term macroscopic may also refer to a "larger view", namely a view only available from a large perspective. A macroscopic position could be considered the "big picture". # Examples - A macroscopic view of a ball is just that: a ball. A microscopic view could reveal a thick round skin seemingly composed entirely of puckered cracks and fissures (as viewed through a microscope) or, further down in scale, a collection of molecules in the rough shape of a sphere. # Macroscopy in physics In physics, macroscopy can be a physical trait applied relative to what one is observing. If one looks at a galaxy, a star is a microscopic entity, even if it is many, many orders of magnitude larger than us.	https://www.wikidoc.org/index.php/Macroscopic
dc3a077758444478cdc3ac1e5e580ec90e66d073	wikidoc	Maculopathy	Maculopathy A maculopathy is any pathological condition of the macula, an area at the centre of the retina that is associated with highly sensitive, accurate vision. # Examples Of Maculopathies - Age-Related Macular Degeneration is a degenerative maculopathy associated with progressive sight loss. It is characterised by changes in pigmentation in the Retinal Pigment Epithelium, the appearance of drusen on the retina of the eye and choroidal neovascularization. AMD has two forms; 'dry' or atrophic/non-exudative AMD, and 'wet' or exudative/neovascular AMD. - Malattia Leventinese (or Doyne’s honeycomb retinal dystrophy) is another maculopathy with a similar pathology to wet AMD. - Cellophane Maculopathy A fine glistening membrane forms over the macula, obscuring the vision. # Causes ## Drug Induced - Mitotane	Maculopathy A maculopathy is any pathological condition of the macula, an area at the centre of the retina that is associated with highly sensitive, accurate vision.[1] # Examples Of Maculopathies - Age-Related Macular Degeneration is a degenerative maculopathy associated with progressive sight loss. It is characterised by changes in pigmentation in the Retinal Pigment Epithelium, the appearance of drusen on the retina of the eye and choroidal neovascularization. AMD has two forms; 'dry' or atrophic/non-exudative AMD, and 'wet' or exudative/neovascular AMD. - Malattia Leventinese (or Doyne’s honeycomb retinal dystrophy) is another maculopathy with a similar pathology to wet AMD. - Cellophane Maculopathy A fine glistening membrane forms over the macula, obscuring the vision.[2] # Causes ## Drug Induced - Mitotane	https://www.wikidoc.org/index.php/Maculopathy
c3482014cba34453b27f1e2312ac9552662c0589	wikidoc	Magic words	Magic words # Overview This is an organized index of Magic words used in MediaWiki. "XYZ" indicates user input, which is used in the example. # Table of contents ## Other # XML-style tags nowiki: ..., disables expansion/interpretation of templates, link syntax, formatting syntax, etc.:''']''' gives ''']''' noinclude: ..., specifies text to appear or function calls to apply only on the transcluded page, not on the transcluding page. E.g. categorizing of a template itself (and not the transcluding page) would use this tag. includeonly: ..., specifies text to appear or function calls to apply only on the transcluding page, not on the transcluded page (which usually is a template). E.g. a template which categorizes pages where it's applied, but not the template itself, into a certain category. -nlyinclude: ..., specifies text to appear or function calls to apply only on the transcluding page, not on the transcluded page. This tag is distinguished from the tag in that text or code on the transcluded page not enveloped by the tag will not be transcluded, whether or not the tag is in use. pre: ..., ditto, also for multiple lines; it is rendered with a new paragraph at the start and end: a''']''' gives a math: ..., e.g. \sqrt{a^2+b^2} gives \sqrt{a^2+b^2}; see Help:Displaying a formula hiero: ..., e.g. A1 gives: A1 categorytree: ... provides a dynamic view of the category structure specified as a tree. ## Time The time in UTC. Note that if the page was displayed by the same user and has not changed (has not been edited) since the last time it was displayed, it is possible that the page may be cached (by the user's browser) and the displayed time or date may not change. Also, if a heavily used page, rather than freshly rendered by the software each time it is generated, is instead being retrieved from a caching system (such as the main page on Wikipedia) the date or time may not change from the last time the page was originally retrieved by the caching hardware or software. ## Local time The time depending on the local timezone of the wiki (not depending on the timezone in the user's preference settings). (All words ) ## Statistics Statistics variables give thousands separators unless ":R" for "raw" is added (actually, these versions are parser functions). ## Page names and related info # Parser functions Not working at the position of the page where the tag is located but on the page header, and throughout the page, respectively (see below): - DISPLAYTITLE: allow the page header to be different from the page name. - DEFAULTSORT: Sets a default category sort key for the page. ## Formatting With regard to #language and Template:Tim, see also: - List of Wikipedias/local names - shows both names for all languages, without automatic comparison - List of Wikipedias/local names/diff - values of #language for which {{n local}} contains a different name. - List of Wikipedias/local names/diff 1 - for languages where the two names are different, shows both; due to the Template:Peisl the end of the table is messed up # Image modifiers These are image modifiers used in ] links. Some are mutually exclusive, and then the last specified wins. ## Size The last unrecognized modifier is used as caption for framed images or together with thumbnails. It's also used as description alt=text. ## Position The positions are mutually exclusive; the last specified wins. Template:- can stop floating. For inline images only modifier px (see above) is supported. # Miscellany # Notes and references - ↑ Function pad in includes/CoreParserFunctions.php puts, oddly, the $string itself as a condition for the padding. To be reported as bug. - ↑ "Technology report", en-Wikipedia Signpost, January 2007 # Template modifiers	Magic words Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview This is an organized index of Magic words used in MediaWiki. "XYZ" indicates user input, which is used in the example. # Table of contents Template:H:TOC variables ## Other # XML-style tags nowiki: <nowiki>...</nowiki>, disables expansion/interpretation of templates, link syntax, formatting syntax, etc.:<nowiki>'''[[{{tc}}]]'''</nowiki> gives '''[[{{tc}}]]''' noinclude: <noinclude>...</noinclude>, specifies text to appear or function calls to apply only on the transcluded page, not on the transcluding page. E.g. categorizing of a template itself (and not the transcluding page) would use this tag. includeonly: <includeonly>...</includeonly>, specifies text to appear or function calls to apply only on the transcluding page, not on the transcluded page (which usually is a template). E.g. a template which categorizes pages where it's applied, but not the template itself, into a certain category. onlyinclude: <onlyinclude>...</onlyinclude>, specifies text to appear or function calls to apply only on the transcluding page, not on the transcluded page. This tag is distinguished from the <includeonly> tag in that text or code on the transcluded page not enveloped by the tag will not be transcluded, whether or not the <noinclude> tag is in use. pre: <pre>...</pre>, ditto, also for multiple lines; it is rendered with a new paragraph at the start and end: a<pre>'''[[{{tc}}]]'''</pre> gives a math: <math>...</math>, e.g. <math>\sqrt{a^2+b^2}</math> gives <math>\sqrt{a^2+b^2}</math>; see Help:Displaying a formula hiero: <hiero>...</hiero>, e.g. <hiero>A1</hiero> gives: <hiero>A1</hiero> categorytree: <categorytree>...</categorytree> provides a dynamic view of the category structure specified as a tree. ## Time The time in UTC. Note that if the page was displayed by the same user and has not changed (has not been edited) since the last time it was displayed, it is possible that the page may be cached (by the user's browser) and the displayed time or date may not change. Also, if a heavily used page, rather than freshly rendered by the software each time it is generated, is instead being retrieved from a caching system (such as the main page on Wikipedia) the date or time may not change from the last time the page was originally retrieved by the caching hardware or software. ## Local time The time depending on the local timezone of the wiki (not depending on the timezone in the user's preference settings). (All words [MW1.8+] ) ## Statistics Statistics variables give thousands separators unless ":R" for "raw" is added (actually, these versions are parser functions). ## Page names and related info # Parser functions Not working at the position of the page where the tag is located but on the page header, and throughout the page, respectively (see below): - DISPLAYTITLE: allow the page header to be different from the page name. - DEFAULTSORT: Sets a default category sort key for the page. ## Formatting With regard to #language and Template:Tim, see also: - List of Wikipedias/local names - shows both names for all languages, without automatic comparison - List of Wikipedias/local names/diff - values of #language for which {{n local}} contains a different name. - List of Wikipedias/local names/diff 1 - for languages where the two names are different, shows both; due to the Template:Peisl the end of the table is messed up # Image modifiers These are image modifiers used in [[Image:title.ext\|modifier\|...\|modifier]] links. Some are mutually exclusive, and then the last specified wins. ## Size The last unrecognized modifier is used as caption for framed images or together with thumbnails. It's also used as description alt=text. ## Position The positions are mutually exclusive; the last specified wins. Template:- can stop floating. For inline images only modifier px (see above) is supported. # Miscellany # Notes and references - ↑ Function pad in includes/CoreParserFunctions.php puts, oddly, the $string itself as a condition for the padding. To be reported as bug. - ↑ "Technology report", en-Wikipedia Signpost, January 2007 # Template modifiers Template:WikiDoc Sources	https://www.wikidoc.org/index.php/Magic_words
f383f7946df2d30f9901eed0b94a53d3deb3bd78	wikidoc	Magnetosome	Magnetosome The magnetosome chains are membranous prokaryotic organelles present in magnetotactic bacteria. They contain 15 to 20 magnetite crystals that together act like the needle of a compass to orient magnetotactic bacteria in geomagnetic fields, thereby simplifying their search for their preferred microaerophilic environments. Each magnetite crystal within a magnetosome is surrounded by a lipid bilayer, and specific soluble and transmembrane proteins are sorted to the membrane. Recent research has shown that magnetosomes are invaginations of the inner membrane and not freestanding vesicles. Magnetite-bearing magnetosomes have also been found in eukaryotic magnetotactic algae, with each cell containing several thousand crystals. Overall, magnetosome crystals have high chemical purity, narrow size ranges, species-specific crystal morphologies and exhibit specific arrangements within the cell. These features indicate that the formation of magnetosomes is under precise biological control and is mediated by a mineralization process, which is known as biologically controlled mineralization (biomineralization). Magnetotactic bacteria usually mineralize either iron oxide magnetosomes, which contain crystals of magnetite (Template:IronTemplate:Oxygen), or iron sulphide magnetosomes, which contain crystals of greigite (Template:IronTemplate:Sulfur). Several other iron sulphide minerals have also been identified in iron sulphide magnetosomes — including mackinawite (tetragonal Template:IronTemplate:Sulfur) and a cubic Template:IronTemplate:Sulfur — which are thought to be precursors of Template:IronTemplate:Sulfur. One organism is known to produce both iron oxide and iron sulphide magnetosomes. The particle morphology of magnetosome crystals varies, but is consistent within cells of a single magnetotactic bacterial species or strain. Three general crystal morphologies have been reported in magnetotactic bacteria on the basis: roughly cuboidal, elongated prismatic (roughly rectangular), and tooth-, bullet- or arrowhead-shaped. Magnetosome crystals are typically 35–120 nm long. Smaller crystals are superparamagnetic–that is, not permanently magnetic at ambient temperature, and domain walls would form in larger crystals. In most magnetotactic bacteria, the magnetosomes are arranged in one or more chains. Magnetic interactions between the magnetosome crystals in a chain cause their magnetic dipole moments to orientate parallel to each other along the length of the chain. The magnetic dipole moment of the cell is usually large enough such that its interaction with the Earth's geomagnetic field overcomes the thermal forces that tend to randomize the orientation of the cell in its aqueous surroundings. Because oxygen gradient is aligned along the vertical gradient of the geomagnetic field, movement along the field would facilitate movement along the oxygen gradient. In this way bacteria can more efficiently search for and reach oxygen rich locations. This process is called magneto-aerotaxis. While a single magnetosome chain would appear to be ideal for magneto-aerotaxis, a number of magnetotactic bacteria have magnetosomes or magnetosome arrangements that depart from the ideal. One reported example includes large (up to 200 nm) magnetosomes found in coccoid cells in Brazil. These cells have enough magnetosomes so that the calculated magnetic dipole moment of the cell is about 250 times larger than that of a typical cell of Magnetospirillum magnetotacticum. There are also examples of magnetotactic bacteria that contain hundreds of magnetosomes, many more than required for orientation. One large, rod-shaped organism, Magnetobacterium bavaricum, contains up to 1000 bulletshaped magnetosomes arranged in several chains traversing the cell. Some bacteria have magnetosomes that are not arranged in chains, but are clustered on one side of the cell. In such an arrangement, the shape anisotropy of each crystal provides the stability against remagnetization, rather than the overall shape anisotropy in the magnetosome chain arrangement. These non-ideal arrangements may be pointing to additional, currently unknown functions of magnetosomes, possibly related to metabolism.	Magnetosome The magnetosome chains are membranous prokaryotic organelles present in magnetotactic bacteria. They contain 15 to 20 magnetite crystals that together act like the needle of a compass to orient magnetotactic bacteria in geomagnetic fields, thereby simplifying their search for their preferred microaerophilic environments. Each magnetite crystal within a magnetosome is surrounded by a lipid bilayer, and specific soluble and transmembrane proteins are sorted to the membrane. Recent research has shown that magnetosomes are invaginations of the inner membrane and not freestanding vesicles.[1] Magnetite-bearing magnetosomes have also been found in eukaryotic magnetotactic algae, with each cell containing several thousand crystals. Overall, magnetosome crystals have high chemical purity, narrow size ranges, species-specific crystal morphologies and exhibit specific arrangements within the cell. These features indicate that the formation of magnetosomes is under precise biological control and is mediated by a mineralization process, which is known as biologically controlled mineralization (biomineralization). Magnetotactic bacteria usually mineralize either iron oxide magnetosomes, which contain crystals of magnetite (Template:IronTemplate:Oxygen), or iron sulphide magnetosomes, which contain crystals of greigite (Template:IronTemplate:Sulfur). Several other iron sulphide minerals have also been identified in iron sulphide magnetosomes — including mackinawite (tetragonal Template:IronTemplate:Sulfur) and a cubic Template:IronTemplate:Sulfur — which are thought to be precursors of Template:IronTemplate:Sulfur. One organism is known to produce both iron oxide and iron sulphide magnetosomes. The particle morphology of magnetosome crystals varies, but is consistent within cells of a single magnetotactic bacterial species or strain. Three general crystal morphologies have been reported in magnetotactic bacteria on the basis: roughly cuboidal, elongated prismatic (roughly rectangular), and tooth-, bullet- or arrowhead-shaped. Magnetosome crystals are typically 35–120 nm long. Smaller crystals are superparamagnetic–that is, not permanently magnetic at ambient temperature, and domain walls would form in larger crystals. In most magnetotactic bacteria, the magnetosomes are arranged in one or more chains. Magnetic interactions between the magnetosome crystals in a chain cause their magnetic dipole moments to orientate parallel to each other along the length of the chain. The magnetic dipole moment of the cell is usually large enough such that its interaction with the Earth's geomagnetic field overcomes the thermal forces that tend to randomize the orientation of the cell in its aqueous surroundings. Because oxygen gradient is aligned along the vertical gradient of the geomagnetic field, movement along the field would facilitate movement along the oxygen gradient. In this way bacteria can more efficiently search for and reach oxygen rich locations. This process is called magneto-aerotaxis. While a single magnetosome chain would appear to be ideal for magneto-aerotaxis, a number of magnetotactic bacteria have magnetosomes or magnetosome arrangements that depart from the ideal.[2] One reported example includes large (up to 200 nm) magnetosomes found in coccoid cells in Brazil. These cells have enough magnetosomes so that the calculated magnetic dipole moment of the cell is about 250 times larger than that of a typical cell of Magnetospirillum magnetotacticum. There are also examples of magnetotactic bacteria that contain hundreds of magnetosomes, many more than required for orientation. One large, rod-shaped organism, Magnetobacterium bavaricum, contains up to 1000 bulletshaped magnetosomes arranged in several chains traversing the cell. Some bacteria have magnetosomes that are not arranged in chains, but are clustered on one side of the cell. In such an arrangement, the shape anisotropy of each crystal provides the stability against remagnetization, rather than the overall shape anisotropy in the magnetosome chain arrangement. These non-ideal arrangements may be pointing to additional, currently unknown functions of magnetosomes, possibly related to metabolism.	https://www.wikidoc.org/index.php/Magnetosome
7a2c9cb2dd3bd126d949f8b845a03d3f4193d672	wikidoc	Mahshid Mir	Mahshid Mir Mahshid Mir, MD phone number: +16178997155 Email: [email protected] # Current Position Postdoctoral Research Fellow, PERFUSE Study Group, Beth Israel Deaconess Medical Center # Professional Background Dr. Mahshid Mir is a MD physician graduated from Shahid Beheshti University of Medical Science, Tehan, Iran. She received her M.D. from the Iranian Medical Council, after which she joined as a post-doctoral research fellow at PERFUSE Study Group at Beth Israel Deaconess Medical Center in Boston. She is now working as Associate Editor in Chief for the PERFUSE study group and different Internal Medicine subjects. # Education 2014 - MD Degree, Iranian Medical Council, Shahid Beheshti University of Medical Science. # Pages Authored	Mahshid Mir Mahshid Mir, MD phone number: +16178997155 Email: [email protected] # Current Position Associate Editor in Chief, Wikidoc.org Postdoctoral Research Fellow, PERFUSE Study Group, Beth Israel Deaconess Medical Center # Professional Background Dr. Mahshid Mir is a MD physician graduated from Shahid Beheshti University of Medical Science, Tehan, Iran. She received her M.D. from the Iranian Medical Council, after which she joined as a post-doctoral research fellow at PERFUSE Study Group at Beth Israel Deaconess Medical Center in Boston. She is now working as Associate Editor in Chief for the PERFUSE study group and different Internal Medicine subjects. # Education 2014 - MD Degree, Iranian Medical Council, Shahid Beheshti University of Medical Science. # Pages Authored	https://www.wikidoc.org/index.php/Mahshid_Mir
a0bae64e0f89a7dde3842630c8a9e4ed683303b2	wikidoc	Malabathrum	Malabathrum Malabathrum, also known as Malobathrum or Malabar leaf, is the name used in classical and medieval texts for the leaf of the plant Cinnamomum tamala (sometimes given as Cinnamomum tejpata). In ancient Greece and Rome, the leaves were used to prepare a fragrant oil, called Oleum Malabathri, and were therefore valuable. The leaves are mentioned in the 1st century Greek text Periplus Maris Erytraei as one of the major exports of the Tamil kingdoms of southern India. The name is also used in mediaeval texts to describe the dried leaves of a number of trees of the genus Cinnamomum, which were thought to have medicinal properties. The leaves, known as tejpat, tej pat, tejpatta, or tejpata or in Hindi and tamalpatra in Marathi, are used extensively in the cuisines of India (particularly in the Moghul cuisine of North India). They are often erroneously labeled as "Indian bay leaves," though the bay leaf is from the Bay Laurel, a tree of Mediterranean origin in a different genus, and the appearance and aroma of the two are quite different. Bay leaves are shorter and light to medium green in color, with one large vein down the length of the leaf;photo while tejpat are about twice as long and wider than laurel leaves. They are usually olive green in color, may have some brownish spots and have three veins down the length of the leaf.photo True tejpat leaves impart a strong cassia- or cinnamon-like aroma to dishes, while the bay leaf's aroma is more reminiscent of pine and lemon. Indian grocery stores usually carry true tejpat leaves. Some grocers may only offer Turkish bay leaves, in regions where true tejpat is unavailable. The bark is also sometimes used for cooking, although it is regarded as inferior to true cinnamon or cassia. "Malabar" is the name of a region on the west coast of southern India that forms the northern portion of the present-day state of Kerala. The word "Mala" or "Malaya" means "Mountain" in the Tamil and Malayalam languages, as also in Sanskrit. The word "Malabathrum" is also thought to have been derived from the Sanskrit tamālapattram (तमालपत्त्रम्), literally meaning "dark-tree leaves." # Related species - Cassia - Cinnamon - Saigon cinnamon	Malabathrum Malabathrum, also known as Malobathrum or Malabar leaf, is the name used in classical and medieval texts for the leaf of the plant Cinnamomum tamala (sometimes given as Cinnamomum tejpata). In ancient Greece and Rome, the leaves were used to prepare a fragrant oil, called Oleum Malabathri, and were therefore valuable. The leaves are mentioned in the 1st century Greek text Periplus Maris Erytraei as one of the major exports of the Tamil kingdoms of southern India. The name is also used in mediaeval texts to describe the dried leaves of a number of trees of the genus Cinnamomum, which were thought to have medicinal properties. The leaves, known as tejpat, tej pat, tejpatta, or tejpata or in Hindi and tamalpatra in Marathi, are used extensively in the cuisines of India (particularly in the Moghul cuisine of North India). They are often erroneously labeled as "Indian bay leaves," though the bay leaf is from the Bay Laurel, a tree of Mediterranean origin in a different genus, and the appearance and aroma of the two are quite different. Bay leaves are shorter and light to medium green in color, with one large vein down the length of the leaf;photo while tejpat are about twice as long and wider than laurel leaves. They are usually olive green in color, may have some brownish spots and have three veins down the length of the leaf.photo True tejpat leaves impart a strong cassia- or cinnamon-like aroma to dishes, while the bay leaf's aroma is more reminiscent of pine and lemon. Indian grocery stores usually carry true tejpat leaves. Some grocers may only offer Turkish bay leaves, in regions where true tejpat is unavailable. The bark is also sometimes used for cooking, although it is regarded as inferior to true cinnamon or cassia. "Malabar" is the name of a region on the west coast of southern India that forms the northern portion of the present-day state of Kerala. The word "Mala" or "Malaya" means "Mountain" in the Tamil and Malayalam languages, as also in Sanskrit. The word "Malabathrum" is also thought to have been derived from the Sanskrit tamālapattram (तमालपत्त्रम्), literally meaning "dark-tree leaves." # Related species - Cassia - Cinnamon - Saigon cinnamon # External links - Indian bay-leaf page from Gernot Katzer's Spice Pages Template:Herbs & spices Template:Laurales-stub de:Indisches Lorbeerblatt Template:WikiDoc Sources	https://www.wikidoc.org/index.php/Malabathrum
c8dd591c3cf1c2acde11511f5ec58ea4a3e0c3b9	wikidoc	Maleic acid	Maleic acid # Overview Maleic acid (ionised maleate in biology) or (Z)-butenedioic acid or cis-butenedioic acid or malenic acid or maleinic acid or toxilic acid is an organic compound which is a dicarboxylic acid (molecule with two carboxyl groups). The molecule consists of an ethylene group flanked by two carboxylic acid groups. Maleic acid is the cis isomer of butenedioic acid, whereas fumaric acid is the trans isomer. The cis isomer is the less stable one of the two; the difference in heat of combustion is 22.7 kJ/mol. The physical properties of maleic acid are very different from that of fumaric acid. Maleic acid is soluble in water whereas fumaric acid is not and the melting point of maleic acid (130 - 139 °C) is also much lower than that of fumaric acid (287 °C). Both properties of maleic acid can be explained on account of the intramolecular hydrogen bonding that takes place at the expense of intermolecular interactions. Maleic acid should not be confused with malic acid or malonic acid, both of which are different types of dicarboxylic acids. # Synthesis In industry maleic acid is derived from maleic anhydride by hydrolysis. Maleic anhydride is produced from benzene or butane in an oxidation process. # Reactions Maleic acid and fumaric acid can normally not be interconverted because rotation around a carbon carbon double bond is not possible. In the laboratory conversion of the cis isomer into the trans isomer is possible by application of light and a small amount of bromine. Light converts elemental bromine into a bromine radical which attacks the alkene in a radical addition reaction to a bromo-alkane radical and now single bond rotation is possible. The bromine radicals recombine and fumaric acid is formed. In the classroom, maleic acid is transformed into Fumaric acid through the process of heating the maleic acid to a high temperature in a 12mol HCl solution. The heated molecule loses a water molecule and becomes an acid anhydride while in the heated solution. Once the heat is removed, the acid anhydride takes back the water molecule, but reforms as fumaric acid, the more stable isomer of butenedioic acid. This isomer is more stable because the carboxyl groups are no longer on the same side of the molecule, but are now on opposite sides, causing the molecule to become non-polar. That is why it comes out of the polar HCl solution, as a polar solvent will not dissolve a non-polar solute. In industry fumaric acid is produced from maleic acid by catalytic isomerization with mineral acids, bromates or thiourea. The large difference in water solubility makes fumaric acid purification easy. Maleic acid is an industrial raw material for the production of glyoxylic acid by ozonolysis. Maleic acid is converted into maleic anhydride by dehydration, to malic acid by hydration, and to succinic acid by hydrogenation. It reacts with thionyl chloride or phosphorus pentachloride to give the maleic acid chloride (it is not possible to isolate the mono acid chloride). Maleic acid is a reactant in many Diels-Alder reactions. # Maleate ion The maleate ion is the ionised form of maleic acid. It is of importance to biochemistry.	Maleic acid # Overview Maleic acid (ionised maleate in biology) or (Z)-butenedioic acid or cis-butenedioic acid or malenic acid or maleinic acid or toxilic acid is an organic compound which is a dicarboxylic acid (molecule with two carboxyl groups). The molecule consists of an ethylene group flanked by two carboxylic acid groups. Maleic acid is the cis isomer of butenedioic acid, whereas fumaric acid is the trans isomer. The cis isomer is the less stable one of the two; the difference in heat of combustion is 22.7 kJ/mol. The physical properties of maleic acid are very different from that of fumaric acid. Maleic acid is soluble in water whereas fumaric acid is not and the melting point of maleic acid (130 - 139 °C) is also much lower than that of fumaric acid (287 °C). Both properties of maleic acid can be explained on account of the intramolecular hydrogen bonding that takes place at the expense of intermolecular interactions. Maleic acid should not be confused with malic acid or malonic acid, both of which are different types of dicarboxylic acids. # Synthesis In industry maleic acid is derived from maleic anhydride by hydrolysis. Maleic anhydride is produced from benzene or butane in an oxidation process. # Reactions Maleic acid and fumaric acid can normally not be interconverted because rotation around a carbon carbon double bond is not possible. In the laboratory conversion of the cis isomer into the trans isomer is possible by application of light and a small amount of bromine. Light converts elemental bromine into a bromine radical which attacks the alkene in a radical addition reaction to a bromo-alkane radical and now single bond rotation is possible. The bromine radicals recombine and fumaric acid is formed. In the classroom, maleic acid is transformed into Fumaric acid through the process of heating the maleic acid to a high temperature in a 12mol HCl solution. The heated molecule loses a water molecule and becomes an acid anhydride while in the heated solution. Once the heat is removed, the acid anhydride takes back the water molecule, but reforms as fumaric acid, the more stable isomer of butenedioic acid. This isomer is more stable because the carboxyl groups are no longer on the same side of the molecule, but are now on opposite sides, causing the molecule to become non-polar. That is why it comes out of the polar HCl solution, as a polar solvent will not dissolve a non-polar solute. In industry fumaric acid is produced from maleic acid by catalytic isomerization with mineral acids, bromates or thiourea. The large difference in water solubility makes fumaric acid purification easy. Maleic acid is an industrial raw material for the production of glyoxylic acid by ozonolysis. Maleic acid is converted into maleic anhydride by dehydration, to malic acid by hydration, and to succinic acid by hydrogenation. It reacts with thionyl chloride or phosphorus pentachloride to give the maleic acid chloride (it is not possible to isolate the mono acid chloride). Maleic acid is a reactant in many Diels-Alder reactions. # Maleate ion The maleate ion is the ionised form of maleic acid. It is of importance to biochemistry. # External links - International Chemical Safety Card 1186 - Template:Ecb - MSDS from J. T. Baker - Light isomerization experiment (from the University of Regensburg, with video) - Titration of Fumaric and Maleic Acid (from theUniversity of Regensburg, about pH, solubility and melting point) - DSM glyoxylic acid production Template:WikiDoc Sources	https://www.wikidoc.org/index.php/Maleate
58177ac3a4206f4ce6d6e0c5d42b8af53ed06c7a	wikidoc	Malingering	Malingering # Overview Malingering is a medical and psychological term that refers to an individual fabricating or exaggerating the symptoms of mental or physical disorders for a variety of motives, including getting financial compensation (often tied to fraud), avoiding work, obtaining drugs, getting lighter criminal sentences, trying to get out of going to school, or simply to attract attention or sympathy. Because malingerers are usually seeking some sort of primary or secondary gain, this disorder remains separate from Somatization disorders and factitious disorders in which the gain is not obvious. Legally, malingering is often referred to as Fabricated mental illness or Feigned mental illness. See United States v. Binion. # History Malingering has been recorded as early as Roman times by the physician Galen, who reported two cases. One patient simulated colic to avoid a public meeting, whilst the other feigned an injured knee to avoid accompanying his master on a long journey. Widespread throughout Soviet Russia to escape sanctions or coercion, physicians were limited by the state in the number of medical dispensations they could issue. With thousands forced into manual labour, doctors were presented with four types of patient; 1. those who needed medical care; 2. those that thought they needed medical care (hypochondriacs); 3. malingerers; and 4. those that made direct pleas to the physician for a medical dispensation from work. This dependence upon doctors by poor labourers altered the doctor-patient relationship to one of mutual mistrust and deception. # Symptoms There is a rich and diverse array of methods for feigning illness. Physical methods reported include trying to deceive measuring devices such as thermometers, inducing swelling, delaying wound healing, over-exercise, drug overdose, self-harm, or directly reporting diagnostic signs of disease, learnt from a medical textbook. Patients may report a factitious history, such as describing epileptic seizures or a heart attack, sometimes supplementing this with the use of agents which mimic disease, such as taking neuroleptic drugs to mimic tremor. Detection is made more difficult in those who do have a diagnosed, organic disease already, sometimes called "partial malingering".Template:Who In these cases, malingering is sometimes described as a "functional overlay" on an existing disease. # Predisposing factors Malingering appears to be more common in societies with regimented, enforced labour (industrial malingering), universal military service (military malingering), or the ability to sue for damages arising from accidents (medicolegal malingering). Malingering is more common in women than men and is more prevalent amongst those employed in health-related fields. Psychodynamic theory suggests patients may have been neglected or abused as children and are attempting to resolve issues with their parents. # Diagnosis and detection ## Diagnosis ### DSM-IV-TR The DSM-IV-TR states that malingering is suspected if any combination of the following are observed - Medicolegal context of presentation - Marked discrepancy between the person’s claimed stress of disability and the objective findings - Lack of cooperation during the diagnostic evaluation and in complying with prescribed treatment regimen - The presence of Antisocial Personality Disorder However, these criteria have been found to be of little use in actually identifying individuals who are malingering. (Clinical assessment of malingering and deception 2nd ed. Rogers, Richard; New York, NY, US: Guilford Press, 1997.) ## Detection Some feature at presentation which are unusual in genuine cases include: - Dramatic or atypical presentation - Vague and inconsistent details, although possibly plausible on the surface - Long medical record with multiple admissions at various hospitals in different cities - Knowledge of textbook descriptions of illness - Admission circumstances that do not conform to an identifiable medical or mental disorder - An unusual grasp of medical terminology - Employment in a medically related field - Pseudologia fantastica (ie, patients' uncontrollable lying characterized by the fantastic description of false events in their lives) - Presentation in the emergency department during times when obtaining old medical records is hampered or when experienced staff are less likely to be present (eg, holidays, late Friday afternoons) - A patient who has few visitors despite giving a history of holding an important or prestigious job or a history that casts the patient in a heroic role - Acceptance, with equanimity, of the discomfort and risk of diagnostic procedures - Acceptance, with equanimity, of the discomfort and risk of surgery - Substance abuse, especially of prescribed analgesics and sedatives - Symptoms or behaviors only present when the patient is being observed - Controlling, hostile, angry, disruptive, or attention-seeking behavior during hospitalization - Fluctuating clinical course, including rapid development of complications or a new pathology if the initial workup findings prove negative - Giving approximate answers to questions, usually occurring in FD with predominantly psychological signs and symptoms (see Ganser Syndrome) When malingering takes on a legal context it is more common either for private investigators to find evidence of malingering (say, videotaping a "paralysed" person walking around their home), or reports from friends, colleagues, or family members. If a psychiatrist or neuropsychologist suspects malingering in a case of possible brain damage (i.e. caused by head trauma or stroke), they may look for a discrepancy between the patient's reported functions of daily living and their performance on neuropsychological tests. In theory, any neuropsychological test could be used in this way, depending on the context. No one test, administered by itself, can proffer a diagnosis of malingering, so a neuropsychological examination typically consists of a battery of tests. Three tests commonly used to determine malingering are: - Computerized Assessment of Response Bias (CARB) - Minnesota Multiphasic Personality Inventory (MMPI) - The Test of Memory Malingering (TOMM) # Treatment Treatment is psychological, and varies according to the underlying cause of the individual's unique symptoms. Treatment options may include psychotherapy, family therapy, cognitive behavioural therapy, or pharmacotherapy. It is important that other members of the medical team such as nurses, ward assistants, and physical therapists are informed about the patients' history. On being confronted with a diagnosis of malingering, many patients discharge themselves immediately, only to present at another medical facility to try again. Although malingering patients do waste a lot of resources, they are still entitled to the same safeguards as other patients. For instance, it is not considered ethical (or legal) to "blacklist" patients by warning other healthcare facilities about them without the patient's permission, searching through their personal effects to find evidence of malingering, or covertly videotaping them without their consent. # Impact on society Malingering is damaging in three ways. Firstly, by reducing the productivity of industry or the military through absenteeism, secondly by depleting private and governmental social security, disability, worker's compensation, and insurance benefits, and thirdly by draining the medical system of resources. Malingerers take up the time and energy of medical personnel, as well as requiring detailed and expensive testing to rule out obscure conditions. Therefore malingering can deprive more seriously ill individuals of the care they deserve. Malingering is regarded unfavorably by the criminal justice system. For example, in some cases feigning mental illness has led to a harsher sentence, because malingering during a competency evaluation resulted in a charge and enhanced sentencing for obstruction of justice. # Related conditions - Factitious disorder - Ganser syndrome - Munchausen syndrome	Malingering Template:DiseaseDisorder infobox Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview Malingering is a medical and psychological term that refers to an individual fabricating or exaggerating the symptoms of mental or physical disorders for a variety of motives, including getting financial compensation (often tied to fraud), avoiding work, obtaining drugs, getting lighter criminal sentences, trying to get out of going to school, or simply to attract attention or sympathy. Because malingerers are usually seeking some sort of primary or secondary gain, this disorder remains separate from Somatization disorders and factitious disorders in which the gain is not obvious. Legally, malingering is often referred to as Fabricated mental illness or Feigned mental illness. See United States v. Binion.[1] # History Malingering has been recorded as early as Roman times by the physician Galen, who reported two cases. One patient simulated colic to avoid a public meeting, whilst the other feigned an injured knee to avoid accompanying his master on a long journey. [2] Widespread throughout Soviet Russia to escape sanctions or coercion, physicians were limited by the state in the number of medical dispensations they could issue. [3] With thousands forced into manual labour, doctors were presented with four types of patient; 1. those who needed medical care; 2. those that thought they needed medical care (hypochondriacs); 3. malingerers; and 4. those that made direct pleas to the physician for a medical dispensation from work. This dependence upon doctors by poor labourers altered the doctor-patient relationship to one of mutual mistrust and deception.[citation needed] # Symptoms There is a rich and diverse array of methods for feigning illness. Physical methods reported include trying to deceive measuring devices such as thermometers, inducing swelling, delaying wound healing, over-exercise, drug overdose, self-harm, or directly reporting diagnostic signs of disease, learnt from a medical textbook. [3] Patients may report a factitious history, such as describing epileptic seizures or a heart attack, sometimes supplementing this with the use of agents which mimic disease, such as taking neuroleptic drugs to mimic tremor. Detection is made more difficult in those who do have a diagnosed, organic disease already, sometimes called "partial malingering".Template:Who In these cases, malingering is sometimes described as a "functional overlay" on an existing disease. # Predisposing factors Malingering appears to be more common in societies with regimented, enforced labour (industrial malingering), universal military service (military malingering), or the ability to sue for damages arising from accidents (medicolegal malingering). Malingering is more common in women than men and is more prevalent amongst those employed in health-related fields. Psychodynamic theory suggests patients may have been neglected or abused as children and are attempting to resolve issues with their parents. [4] # Diagnosis and detection ## Diagnosis ### DSM-IV-TR The DSM-IV-TR states that malingering is suspected if any combination of the following are observed[5] - Medicolegal context of presentation - Marked discrepancy between the person’s claimed stress of disability and the objective findings - Lack of cooperation during the diagnostic evaluation and in complying with prescribed treatment regimen - The presence of Antisocial Personality Disorder However, these criteria have been found to be of little use in actually identifying individuals who are malingering. (Clinical assessment of malingering and deception 2nd ed. Rogers, Richard; New York, NY, US: Guilford Press, 1997.) ## Detection Some feature at presentation which are unusual in genuine cases include:[4] - Dramatic or atypical presentation - Vague and inconsistent details, although possibly plausible on the surface - Long medical record with multiple admissions at various hospitals in different cities - Knowledge of textbook descriptions of illness - Admission circumstances that do not conform to an identifiable medical or mental disorder - An unusual grasp of medical terminology - Employment in a medically related field - Pseudologia fantastica (ie, patients' uncontrollable lying characterized by the fantastic description of false events in their lives) - Presentation in the emergency department during times when obtaining old medical records is hampered or when experienced staff are less likely to be present (eg, holidays, late Friday afternoons) - A patient who has few visitors despite giving a history of holding an important or prestigious job or a history that casts the patient in a heroic role - Acceptance, with equanimity, of the discomfort and risk of diagnostic procedures - Acceptance, with equanimity, of the discomfort and risk of surgery - Substance abuse, especially of prescribed analgesics and sedatives - Symptoms or behaviors only present when the patient is being observed - Controlling, hostile, angry, disruptive, or attention-seeking behavior during hospitalization - Fluctuating clinical course, including rapid development of complications or a new pathology if the initial workup findings prove negative - Giving approximate answers to questions, usually occurring in FD with predominantly psychological signs and symptoms (see Ganser Syndrome) When malingering takes on a legal context it is more common either for private investigators to find evidence of malingering (say, videotaping a "paralysed" person walking around their home), or reports from friends, colleagues, or family members. If a psychiatrist or neuropsychologist suspects malingering in a case of possible brain damage (i.e. caused by head trauma or stroke), they may look for a discrepancy between the patient's reported functions of daily living and their performance on neuropsychological tests. In theory, any neuropsychological test could be used in this way, depending on the context. No one test, administered by itself, can proffer a diagnosis of malingering, so a neuropsychological examination typically consists of a battery of tests. Three tests commonly used to determine malingering are: - Computerized Assessment of Response Bias (CARB) - Minnesota Multiphasic Personality Inventory (MMPI) - The Test of Memory Malingering (TOMM) # Treatment Treatment is psychological, and varies according to the underlying cause of the individual's unique symptoms. Treatment options may include psychotherapy, family therapy, cognitive behavioural therapy, or pharmacotherapy. It is important that other members of the medical team such as nurses, ward assistants, and physical therapists are informed about the patients' history. On being confronted with a diagnosis of malingering, many patients discharge themselves immediately, only to present at another medical facility to try again. Although malingering patients do waste a lot of resources, they are still entitled to the same safeguards as other patients. For instance, it is not considered ethical (or legal) to "blacklist" patients by warning other healthcare facilities about them without the patient's permission, searching through their personal effects to find evidence of malingering, or covertly videotaping them without their consent. [4] # Impact on society Malingering is damaging in three ways. Firstly, by reducing the productivity of industry or the military through absenteeism, secondly by depleting private and governmental social security, disability, worker's compensation, and insurance benefits, and thirdly by draining the medical system of resources. Malingerers take up the time and energy of medical personnel, as well as requiring detailed and expensive testing to rule out obscure conditions. Therefore malingering can deprive more seriously ill individuals of the care they deserve. Malingering is regarded unfavorably by the criminal justice system. For example, in some cases feigning mental illness has led to a harsher sentence, because malingering during a competency evaluation resulted in a charge and enhanced sentencing for obstruction of justice.[6] # Related conditions - Factitious disorder - Ganser syndrome - Munchausen syndrome	https://www.wikidoc.org/index.php/Malingering
f23af705324785ecf99c43c4d55d1ddf41980519	wikidoc	Mammography	Mammography # Overview Mammography has been proven to reduce mortality from breast cancer. No other imaging technique has been shown to reduce risk. In some countries, routine (annual to five-yearly) mammography of older women is encouraged as a screening method to diagnose early breast cancer. # Introduction Mammography is the process of using low-dose X-rays (usually around 0.7 mSv) to examine the human breast. It is used to look for different types of tumors and cysts. Mammography has been proven to reduce mortality from breast cancer. No other imaging technique has been shown to reduce risk. In some countries routine (annual to five-yearly) mammography of older women is encouraged as a screening method to diagnose early breast cancer. Screening mammograms were first proven to save lives in research published by Sam Shapiro, Philip Strax and Louis Venet in 1966. Like all x-rays, mammograms use doses of ionizing radiation to create this image. Radiologists then analyze the image for any abnormal growths. It is normal to use longer wavelength X-rays (typically Mo-K) than those used for radiography of bones. At this time, mammography is still the modality of choice for screening for early breast cancer. It is the gold-standard which other imaging tests are compared with. CT has no real role in diagnosing breast cancer at the present. Ultrasound, ductography, and magnetic resonance imaging (MRI) are adjuncts to mammography. Ultrasound is typically used for further evaluation of masses found on mammography or palpable masses not seen on mammograms. Ductograms are useful for evaluation of bloody nipple discharge when the mammogram is non-diagnostic. MRI can be useful for further evaluation of questionable findings, or sometimes for pre-surgical evaluation to look for additional lesions. Stereotactic breast biopsies are another common method for further evaluation of suspicious findings. Mammography has a false-negative (missed cancer) rate of at least 10 percent. This is partly due to dense tissues obscuring cancer and the fact that the appearance of cancer on mammograms has a large overlap with the appearance of normal tissues. # Procedure - During the procedure, the breast is compressed by a dedicated mammography machine to: - Even out the tissue - Increase image quality - Hold the breast still (preventing motion blur). - Both front and side images of the breast are taken.Due to imaging limitations, some elements may show up on x-ray as calcium spots. For this reason, women are discouraged from applying the following on the day of the mammogram. - Deodorant - Talcum powder - Lotion - Until some years ago, mammography was typically performed with screen-film cassettes. - Now, mammography is undergoing a transition to digital detectors, known as Full Field Digital Mammography (FFDM). This progress is some years later than in general radiology. This is due to several factors: - The higher resolution demands in mammography - Significantly increased the expense of the equipment, - The fact that digital mammography has never been shown to be superior to film-screen mammography for the diagnosis of breast cancer. Computed radiography (CR) may help speed the transition. CR allows facilities to continue to use their existing screen-film units but replace the cassettes with an imaging plate that acts as a digital adapter. - As of March 1, 2007, 18.3% of facilities in the United States and its territories have at least one FFDM unit. - After a screening mammogram, some women may have areas of concern which can't be resolved with only the information available from the screening mammogram. - They would then be called back for a "diagnostic mammogram". - This phrase is essentially a problem-solving mammogram. During this session, the radiologist will be monitoring each of the additional films as they are taken to determine the cause of the abnormal appearance. - The outcome of a mammogram may be benign or may require further investigation. If the cause cannot be determined to be benign with sufficient certainty, a biopsy will be recommended. - The biopsy procedure will be used to obtain actual tissue from the site for the pathologist to examine microscopically to determine the precise cause of the abnormality. - In the past, biopsies were most frequently done in surgery, under local or general anesthesia. T - The majority are now done with needles using either ultrasound or mammographic guidance to be sure that the area of concern is the area that is biopsied. - One study shows that needle biopsies of liver malignancies rarely increase the likelihood that cancer will spread, and has not been found to occur with breast needle biopsies. # Results - Often women are quite distressed to be called back for a diagnostic mammogram. - Most of these recalls will be false positive results. - It helps to know these approximate statistics: - Of every 1,000 U.S. women who are screened, about 7% (70) will be called back for a diagnostic session (although some studies estimate the number closer to 10%-15%). - About 10 of these will be referred for a biopsy; the remaining 60 are found to be of a benign cause. - Of the 10 referred for biopsy, about 3.5 will have cancer and 6.5 will not. Of the 3.5 who do have cancer, about 2 have a low stage cancer that will be essentially cured after treatment. - Mammogram results are often expressed in terms of the BI-RADS Assessment Category, often called a "BI-RADS score." The categories range from 0 (Incomplete) to 6 (Known biopsy-proven malignancy).(See below) - In the UK mammograms are scored on a scale from 1-5 (1 = normal, 2 = benign, 3 = indeterminate, 4 = suspicious of malignancy, 5 = malignant). - The rates of abnormal and false-positive mammogram results are far lower in countries other than the U.S. that have adopted different quality standards. - For example, in Holland, only about 1% of mammograms yield an abnormal result. - As a result, false-positives are much less common. Despite the higher rates of false-positives in the U.S., women are about as likely to die from breast cancer in the U.S. as in Holland and elsewhere in Europe. - While mammography is the only breast cancer screening method that has been shown to save lives, it has its own drawbacks. - Estimates of the numbers of cancers missed by mammography are usually around 10%-20%. - This means that of the 350 per 100,000 women who have breast cancer, about 35-70 will not be seen by mammography. - Reasons for not seeing cancer include observer error, but more frequently it is due to the fact that the cancer is hidden by other dense tissue in the breast and even after retrospective review of the mammogram, cannot be seen. - Furthermore, one form of breast cancer, lobular cancer, has a growth pattern that produces shadows on the mammogram which are indistinguishable from normal breast tissue. - Computer-aided diagnosis (CAD) is being tested to decrease the number of cases of cancer that are missed in mammograms. - In one test, a computer identified 71% of the cases of cancer that had been missed by physicians. - However, the computer also flagged twice as many non-cancerous masses than the physicians did. - In the second study of a larger set of mammograms, a computer recommended six biopsies that physicians did not. - All six turned out to be cancers that would have been missed. - Generally, CAD systems in screening mammography have poor specificity and compare poorly to double reading. - Impact of computer-aided detection prompts on the sensitivity and specificity of screening mammography. - While data are accumulating suggesting that CAD can find a few additional cancers, this should be put in perspective. - The additional find rate was 20%, thus in a group of 1,000 women who will have about 4 cancers, CAD may help find an additional 0.8. - The types of additional cancers that may be found are likely to be early and small. - As of 2006, there have been no data to show that finding these additional cancers will have any effect on survival rate. - Some feel that these cancers are likely to be found at the next screening, still at a curable stage, and therefore it remains to be proven whether CAD will be eventually found to have any effect on patient outcome. # BI-RADS - There is a standard system for reporting the results of a mammogram, which is called the Breast Imaging-Reporting and Data System, or BI-RADS. # Screening guidelines - In 2009, the U.S. Preventive Services Task Force (USPSTF) revised their 2002 guideline wherein a mammogram was recommended every 1-2 years for women of 40 years and over. - One of the reasons for this change *A number of studies demonstrated an increased risk of false-positive results when screening starts at a younger age or takes place every year. - Currently, USPSTF recommends screening mammography for women aged 50 to 74 years, every 2 years. - Although this advice is in line with that offered in many European countries, it differs with the recommendations of some other U.S. organizations. - The American College of Radiology and the Society of Breast Imaging both continue to recommend annual mammograms for women starting at age 40. - The current guidelines issued by the American Cancer Society advise a mammogram every year for women of 45 to 54 years, and every 2 years for women of 55 years and older. - In light of the debate, various emerging technologies are now being suggested as alternative options for breast cancer screening. # Clinical decision making - If BI-RADS 0, 4 or 5 - Further intervention is recommended - Contact the clinician to discuss the need for biopsy - Discuss with the patient the need for further imaging. - If BI-RADS 4c or 5 and the biopsy reported as benign: - The pathologist should reevaluate the samples since malignant diagnosis is strongly suspected - May repeat biopsy # Advantages - Mammography has been estimated to reduce breast cancer-related mortality by 20-30%. # Disadvantages - Evidence in favor of mammography screening comes from eight randomized controlled clinical trials from the 1960s through 1980s. - Many of these trials have been criticized for methodological errors, and the results were summarized in a review article published in 1993. ## False positive results - False positive reports are a major problem of mammography breast cancer screening. Approximately 7% of all mammography screenings are false positives. - Data reported in the UK Million Woman Study indicates that if 134 mammograms are performed, 20 women will be called back for suspicious findings, and four biopsies will be necessary, to diagnose one cancer. Recall rates are higher in the U.S. than in the UK. - The goal of any screening procedure is to examine a large population of patients and find the small number most likely to have a serious condition. - These patients are then referred for further, usually more invasive, testing. Thus a screening exam is not intended to be definitive, It is intended to have high sensitivity so as to not miss any cancers. - The cost of this high sensitivity is a relatively large number of results that would be regarded as suspicious in patients without disease. This is true of mammography. - The patients called back for further testing from a screening session (about 7%) are sometimes referred to as "false positives", implying an error. - In fact, it is essential to call back many healthy patients for further testing to capture as many cases of cancer as possible. - These callbacks should not be regarded as errors. - Nonetheless, some women who receive false-positive results become anxious, worried and distressed about the possibility of having breast cancer, feelings that can last for many years. ## False negative results - At the same time, mammograms also have a rate of missed tumors, or "false negatives." - Accurate data regarding the number of false negatives are very difficult to obtain, simply because we cannot perform mastectomies on every woman who has had a mammogram to determine the false negative rate accurately. - Estimates of the false negative rate depend on the close follow-up of a large number of patients for many years. - This is difficult in practice because many women do not return for regular mammography making it impossible to know if they ever developed cancer. - Researchers have found that breast tissue is denser among younger women, making it difficult to detect tumors. For this reason, false negatives are twice as likely to occur in premenopausal mammograms (Prate.) - This is why the screening program in the UK does not start calling women for screening mammograms until the age of 50. - The importance of these missed cancers is not clear, particularly if the woman is getting yearly mammograms. - Research on a closely related situation has shown that small cancers that are not acted upon immediately but are observed over periods of even several years, will have good outcomes. - A group of 3,184 women had mammograms which were formally classified as "probably benign." - This classification is for patients who are not clearly normal but have some area of minor concern. - This results, not in the patient being biopsied, but having early follow up mammography every six months for three years to guarantee no change. Of these 3,184 women, 17 (0.5%) did have cancers. - Most importantly, when the diagnosis was finally made, they were all still stage 0 or 1, the earliest stages. - Five years after treatment, none of these 17 women had evidence of recurrence. - Thus, small early cancers, even though not acted on immediately, were still entirely curable. - Regardless of the precise number of false negatives, it is very clear that even if some tumors are missed, lives are saved when they are found. Women need to understand that a negative mammogram is not a perfect guarantee that there is no breast cancer present, but it is the best method we have available. - Breast density - Mammography in women under 50 years of age can be imprecise due to breast density. - Breast density is an independent adverse prognostic factor on breast cancer prognosis. - It could delay diagnosis of breast cancer using mammography, additionally having dense breast is a risk factor for developing breast cancer. - Body habitus - It has been shown that mammography might have lower sensitivity in thin women. - Especially in women with a BMI less than 25 (86 versus 91 percent in the normal population) - Just like the other radiologic studies the following plays a crucial role in the accurate interpretation of findings: - Radiologist expertness: - less experienced radiologists had - Higher sensitivity to detect breast cancer - Higher recall rates and lower specificity - Comparison of the current mammogram with the prior mammograms: - May increase the specificity of mammography - Double-reading and computer-aided detection (CAD) - Might improve the sensitivity of mammography, - Have not been shown to improve mortality rates from breast cancer screening. - Additionally, CAD may increase patient recall rates. # Mammography risks - The radiation exposure associated with mammography is a potential risk of screening. - The risk of exposure appears to be greater in younger women. - The largest study of radiation risk from mammography concluded that for women 40 years of age or older, the risk of radiation-induced breast cancer was minuscule, particularly compared with the potential benefit of mammographic screening, with a benefit-to-risk ratio of 48.5 lives saved for each life lost due to radiation exposure. - Organizations such as the National Cancer Institute and the United States Preventive Task Force take such risks into account when formulating screening guidelines. - The majority of health experts agree that the risk of breast cancer for women under 35 is not high enough to warrant the risk of radiation exposure. - For this reason, and because the radiation sensitivity of the breast in women under 35 is possibly greater than in older women, most radiologists will not perform screening mammography in women under 40. - However, if there is a significant risk of cancer in a particular patient (BRCA positive, very positive family history, palpable mass), mammography may still be important. - Often, the radiologist will try to avoid mammography, by using ultrasound, or MRI imaging. - Similarly, the risk of breast cancer to women over 55 very clearly justifies the risk of mammograms. - The statistics about mammography and women between the ages of 40 and 55 are the most contentious. - A 1992 Canadian National Breast Cancer Study showed that mammography had no positive effect on mortality for women between the ages of 40 and 50. - The study's critics pointed out that there were very serious design flaws in the study that invalidated these results. - While screening between 40 and 50 is still controversial, the preponderance of the evidence indicates that there is some small benefit in terms of early detection. - Currently, the American Cancer Society, the National Cancer Institute, and the American College of Radiology encourage mammograms every two years for women ages 40 to 49. - In contrast, the American College of Physicians, a large internist group, has recently encouraged individualized screening plans as opposed to wholesale biennial screening of women aged 40 to 49. - There are some potential risks that are considered to be associated with mammography and mammograms. They include the following: - They require repeated exposure to radiation, which may cause a very small risk of cancer if used over a lifetime. - They can lead to non-invasive cancers being diagnosed and treated when treatment is not necessarily required. - They are not as effective for women with dense breast tissue or breast implants. - They can lead to women choosing double mastectomies as a preventive measure. - They have a high rate of false-positive results, which can result in unnecessary biopsies and additional screening. False-positive results are those that suggest that cancer is present when it is not. - Serial mammography might slightly increase the risk of developing breast cancer in high-risk patients such as patients with a family history of breast cancer and patients with known genetic carcinogenic mutations. - According to a recently published study by Jansen-van der Weide et.al. average increased the risk of breast cancer because of low-dose radiation exposure was (OR between 1.3 and 2 with respect to the patients' risk and exposure) observed compared to that of high-risk women not exposed to low-dose radiation. - Pooled OR revealed an increased risk of breast cancer among high-risk women due to low-dose radiation exposure (OR = 1.3, 95% CI: 0.9- 1.8). - Exposure before age 20 (OR = 2.0, 95% CI: 1.3-3.1) - A mean of ≥5 exposures (OR = 1.8, 95% CI: 1.1-3.0) - When using low-dose radiation among high-risk women, a careful approach is needed, by means of - They recommended a careful approach in these subgroup of patients as follows: - Reducing repeated exposure, - Avoidance of exposure at a younger age - Using non-ionising screening techniques. - According to another study by Diana L. Miglioretti et.al. radiation-induced breast cancer incidence and mortality from digital mammography screening are impacted by: - Dose variability from screening and resultant diagnostic work-up, - Initiation age - Screening frequency. - Women with large breasts may be at higher risk of radiation-induced breast cancer; - However, we should keep in mind that "the benefits of screening outweigh these risks". # Screening Vs diagnostic mammography - Screening mammography - Performed in a woman with no clinical sign and symptoms - To decrease morbidity and mortality by detection of early, treatable breast cancer. - Screening mammography is the best modality currently available to detect clinically occult breast cancer. - Application of the screening mammography is the only modality that has been shown a significant decrease in mortality and morbidity of breast cancer. - Generally standard views are obtained for each breast. - Standard views are as follows: - Cranial-Caudal (CC) - Mediolateral-oblique (MLO) - In certain cases, additional views may be obtained to maximize imaging of all breast tissue. - Additonal views are as follows: - Anterior compression - Cleavage view - Exaggerated craniocaudal (XCCL) view - Diagnostic mammography - Diagnostic mammography is indicated in the following patients: - Patients who present with the abnormal sign and symptoms - Women with abnormal screening mammography. - Patients with: - Palpable lump (Particularly if raised clinical concern) - Nipple discharge - Focal pain - The views obtained are tailored to evaluate a specific abnormality - Ultrasounography might be added to increase the accuracy of studies - Additional views that might be recommended are as follows: - Focal spot compression view - Magnification spot compression view - 90 degree lateral view (true lateral view ) - Tangential views - Rolled views - Surveillance mammography - Performed in women with a history of breast cancer. - Generally recommended for the five years following the diagnosis of breast cancer - Procedure is similar to diagnostic mammography (Presence of an onsite radiologist is recommended) - After having negative results for five years, the patient may return to routine screening # Future (investigational) modern mammography utilities - 3D-Tomosynthesis - While traditional mammograms are 2-D and provide a flat image, tomosynthesis creates a 3-D image. - Standard mammograms and tomosynthesis both use X-rays. - This screening procedure is similar to a mammogram, but it produces a 3-D image rather than a flat one. - As a result, it may provide more accurate information about whether or not there are any changes in the breast. - The addition of 3D-Tomosynthesis to conventional digital mammography increases sensitivity (cancer detection rates) and may increase the positive predictive value of the screening exam. - According to a recently published study on more than 35,000 women by Manisha Bahl et.al., in women 65 Y/O and older, digital breast tomosynthesis (DBT) achieved a higher specificity for detecting breast cancer and identified the disease at an earlier stage compared to traditional 2-D mammography. (Published on 2 April 2019 in Radiology) - Stereoscopic digital mammography - Currently under investigation - Full-field digital mammogram images taken at a slight angle from each other using a stereoscopic viewer - It has been shown in recent studies that - Stereoscopic digital mammography has a higher specificity of for cancer detection compared to the standard imaging - The sensitivity was the same, - The recall rate for stereoscopic imaging was lower (9.6 versus 12.9 percent for standard imaging) - In its current format, the radiation dose was twice compared to that of a standard imaging # Alternatives to mammography - While the cost of mammography is relatively low, its sensitivity is not ideal, with reports listing the range from 45% to about 90% depending on factors such as the density of the breast. - Neither is the X-ray based technology completely benign, as noted above. - Therefore there is considerable ongoing research into the use of alternative technologies. - One approach, contrast-enhanced magnetic resonance imaging (MRI), has shown substantial progress. - In this method, the breast is scanned in an MRI device before and after the intravascular injection of a contrast agent (Gadolinium DTPA). - The pre-contrast images are "subtracted" from the post-contrast images, and any areas that have increased blood flow are seen as bright spots on a dark background. - Since breast cancers generally have an increased blood supply, the contrast agent causes these lesions to "light up" on the images. - The available literature suggests that the sensitivity of contrast-enhanced breast MRI is considerably higher than that of either radiographic mammography or ultrasound and is generally reported to be in excess of 95% (though not all reported studies have been as encouraging). - The specificity (the confidence that a lesion is cancerous and not a false positive) is only fair, thus a positive finding by MRI should not be interpreted as a definitive diagnosis. - The reports of 4,271 breast MRIs from eight large scale clinical trials were reviewed recently by CD Lehman. - Overall the sensitivity ranged from 71% to 100% in these reports, however, the call-back rates were low at 10% and the risk of having a benign biopsy was reported at 5%, a significant improvement over mammography. - Several medical instrument vendors have entered this arena with breast MRI solutions. - One company, Aurora Systems, stands out as being the only manufacturer to make a breast-dedicated unit and as the exclusive patent holder of certain solutions to fat signal suppression that appears to be more or less essential. - Siemens, General Electric, and Philips Medical, the leading manufacturers of MRI instruments, offer breast MRI products or add-ons, and several third-party companies (e.g., MRI Devices/IGC) offer aftermarket products to enable breast MRI on conventional MRI instruments. # Regulation - Mammography facilities in the United States and its territories (including military bases) are subject to the Mammography Quality Standards Act (MQSA). - The act requires annual inspections and accreditation every 3 years through an FDA-approved body. - Facilities found deficient during the inspection or accreditation process can be barred from performing mammograms until corrective action has been verified or, in extreme cases, can be required to notify past patients that their exams were sub-standard and should not be trusted. - Despite the passage of the MQSA by Congress in 1992 and the nearly 1 billion dollar cost, the aggregate sensitivity of mammography in the USA is similar to what it was in the 1970s. - At this time MQSA applies only to traditional mammography and not related scans such as breast ultrasound, stereotactic breast biopsy, or breast MRI.	Mammography Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Soroush Seifirad, M.D.[2] # Overview Mammography has been proven to reduce mortality from breast cancer. No other imaging technique has been shown to reduce risk. In some countries, routine (annual to five-yearly) mammography of older women is encouraged as a screening method to diagnose early breast cancer. # Introduction Mammography is the process of using low-dose X-rays (usually around 0.7 mSv) to examine the human breast. It is used to look for different types of tumors and cysts. Mammography has been proven to reduce mortality from breast cancer. No other imaging technique has been shown to reduce risk. In some countries routine (annual to five-yearly) mammography of older women is encouraged as a screening method to diagnose early breast cancer. Screening mammograms were first proven to save lives in research published by Sam Shapiro, Philip Strax and Louis Venet in 1966. Like all x-rays, mammograms use doses of ionizing radiation to create this image. Radiologists then analyze the image for any abnormal growths. It is normal to use longer wavelength X-rays (typically Mo-K) than those used for radiography of bones. At this time, mammography is still the modality of choice for screening for early breast cancer. It is the gold-standard which other imaging tests are compared with. CT has no real role in diagnosing breast cancer at the present. Ultrasound, ductography, and magnetic resonance imaging (MRI) are adjuncts to mammography. Ultrasound is typically used for further evaluation of masses found on mammography or palpable masses not seen on mammograms. Ductograms are useful for evaluation of bloody nipple discharge when the mammogram is non-diagnostic. MRI can be useful for further evaluation of questionable findings, or sometimes for pre-surgical evaluation to look for additional lesions. Stereotactic breast biopsies are another common method for further evaluation of suspicious findings. Mammography has a false-negative (missed cancer) rate of at least 10 percent. This is partly due to dense tissues obscuring cancer and the fact that the appearance of cancer on mammograms has a large overlap with the appearance of normal tissues. # Procedure - During the procedure, the breast is compressed by a dedicated mammography machine to: - Even out the tissue - Increase image quality - Hold the breast still (preventing motion blur). - Both front and side images of the breast are taken.Due to imaging limitations, some elements may show up on x-ray as calcium spots. For this reason, women are discouraged from applying the following on the day of the mammogram. - Deodorant - Talcum powder - Lotion - Until some years ago, mammography was typically performed with screen-film cassettes. - Now, mammography is undergoing a transition to digital detectors, known as Full Field Digital Mammography (FFDM). This progress is some years later than in general radiology. This is due to several factors: - The higher resolution demands in mammography - Significantly increased the expense of the equipment, - The fact that digital mammography has never been shown to be superior to film-screen mammography for the diagnosis of breast cancer. Computed radiography (CR) may help speed the transition. CR allows facilities to continue to use their existing screen-film units but replace the cassettes with an imaging plate that acts as a digital adapter. - As of March 1, 2007, 18.3% of facilities in the United States and its territories have at least one FFDM unit. - After a screening mammogram, some women may have areas of concern which can't be resolved with only the information available from the screening mammogram. - They would then be called back for a "diagnostic mammogram". - This phrase is essentially a problem-solving mammogram. During this session, the radiologist will be monitoring each of the additional films as they are taken to determine the cause of the abnormal appearance. - The outcome of a mammogram may be benign or may require further investigation. If the cause cannot be determined to be benign with sufficient certainty, a biopsy will be recommended. - The biopsy procedure will be used to obtain actual tissue from the site for the pathologist to examine microscopically to determine the precise cause of the abnormality. - In the past, biopsies were most frequently done in surgery, under local or general anesthesia. T - The majority are now done with needles using either ultrasound or mammographic guidance to be sure that the area of concern is the area that is biopsied. - One study shows that needle biopsies of liver malignancies rarely increase the likelihood that cancer will spread, and has not been found to occur with breast needle biopsies. # Results - Often women are quite distressed to be called back for a diagnostic mammogram. - Most of these recalls will be false positive result[1]s.[2] - It helps to know these approximate statistics: - Of every 1,000 U.S. women who are screened, about 7% (70) will be called back for a diagnostic session (although some studies estimate the number closer to 10%-15%). - About 10 of these will be referred for a biopsy; the remaining 60 are found to be of a benign cause. - Of the 10 referred for biopsy, about 3.5 will have cancer and 6.5 will not. Of the 3.5 who do have cancer, about 2 have a low stage cancer that will be essentially cured after treatment. - Mammogram results are often expressed in terms of the BI-RADS Assessment Category, often called a "BI-RADS score." The categories range from 0 (Incomplete) to 6 (Known biopsy-proven malignancy).(See below) - In the UK mammograms are scored on a scale from 1-5 (1 = normal, 2 = benign, 3 = indeterminate, 4 = suspicious of malignancy, 5 = malignant). - The rates of abnormal and false-positive mammogram results are far lower in countries other than the U.S. that have adopted different quality standards.[3][2] - For example, in Holland, only about 1% of mammograms yield an abnormal result. - As a result, false-positives are much less common. Despite the higher rates of false-positives in the U.S., women are about as likely to die from breast cancer in the U.S. as in Holland and elsewhere in Europe. - While mammography is the only breast cancer screening method that has been shown to save lives, it has its own drawbacks. - Estimates of the numbers of cancers missed by mammography are usually around 10%-20%. - This means that of the 350 per 100,000 women who have breast cancer, about 35-70 will not be seen by mammography. - Reasons for not seeing cancer include observer error, but more frequently it is due to the fact that the cancer is hidden by other dense tissue in the breast and even after retrospective review of the mammogram, cannot be seen. - Furthermore, one form of breast cancer, lobular cancer, has a growth pattern that produces shadows on the mammogram which are indistinguishable from normal breast tissue. - Computer-aided diagnosis (CAD) is being tested to decrease the number of cases of cancer that are missed in mammograms. [4][5] - In one test, a computer identified 71% of the cases of cancer that had been missed by physicians. - However, the computer also flagged twice as many non-cancerous masses than the physicians did. - In the second study of a larger set of mammograms, a computer recommended six biopsies that physicians did not. - All six turned out to be cancers that would have been missed. - Generally, CAD systems in screening mammography have poor specificity and compare poorly to double reading. - Impact of computer-aided detection prompts on the sensitivity and specificity of screening mammography. - While data are accumulating suggesting that CAD can find a few additional cancers, this should be put in perspective. - The additional find rate was 20%, thus in a group of 1,000 women who will have about 4 cancers, CAD may help find an additional 0.8. - The types of additional cancers that may be found are likely to be early and small. - As of 2006, there have been no data to show that finding these additional cancers will have any effect on survival rate. - Some feel that these cancers are likely to be found at the next screening, still at a curable stage, and therefore it remains to be proven whether CAD will be eventually found to have any effect on patient outcome.[6] # BI-RADS - There is a standard system for reporting the results of a mammogram, which is called the Breast Imaging-Reporting and Data System, or BI-RADS.[7][8] # Screening guidelines - In 2009, the U.S. Preventive Services Task Force (USPSTF) revised their 2002 guideline wherein a mammogram was recommended every 1-2 years for women of 40 years and over. - One of the reasons for this change *A number of studies demonstrated an increased risk of false-positive results when screening starts at a younger age or takes place every year. - Currently, USPSTF recommends screening mammography for women aged 50 to 74 years, every 2 years. - Although this advice is in line with that offered in many European countries, it differs with the recommendations of some other U.S. organizations. - The American College of Radiology and the Society of Breast Imaging both continue to recommend annual mammograms for women starting at age 40. - The current guidelines issued by the American Cancer Society advise a mammogram every year for women of 45 to 54 years, and every 2 years for women of 55 years and older. - In light of the debate, various emerging technologies are now being suggested as alternative options for breast cancer screening.[2] # Clinical decision making - If BI-RADS 0, 4 or 5 - Further intervention is recommended - Contact the clinician to discuss the need for biopsy - Discuss with the patient the need for further imaging. - If BI-RADS 4c or 5 and the biopsy reported as benign: - The pathologist should reevaluate the samples since malignant diagnosis is strongly suspected - May repeat biopsy[7] # Advantages - Mammography has been estimated to reduce breast cancer-related mortality by 20-30%.[9] # Disadvantages - Evidence in favor of mammography screening comes from eight randomized controlled clinical trials from the 1960s through 1980s.[2] - Many of these trials have been criticized for methodological errors, and the results were summarized in a review article published in 1993.[10] ## False positive results - False positive reports are a major problem of mammography breast cancer screening. Approximately 7% of all mammography screenings are false positives. [11] - Data reported in the UK Million Woman Study indicates that if 134 mammograms are performed, 20 women will be called back for suspicious findings, and four biopsies will be necessary, to diagnose one cancer. Recall rates are higher in the U.S. than in the UK.[12] - The goal of any screening procedure is to examine a large population of patients and find the small number most likely to have a serious condition. - These patients are then referred for further, usually more invasive, testing. Thus a screening exam is not intended to be definitive, It is intended to have high sensitivity so as to not miss any cancers. - The cost of this high sensitivity is a relatively large number of results that would be regarded as suspicious in patients without disease. This is true of mammography. - The patients called back for further testing from a screening session (about 7%) are sometimes referred to as "false positives", implying an error. - In fact, it is essential to call back many healthy patients for further testing to capture as many cases of cancer as possible. - These callbacks should not be regarded as errors. - Nonetheless, some women who receive false-positive results become anxious, worried and distressed about the possibility of having breast cancer, feelings that can last for many years. ## False negative results - At the same time, mammograms also have a rate of missed tumors, or "false negatives." - Accurate data regarding the number of false negatives are very difficult to obtain, simply because we cannot perform mastectomies on every woman who has had a mammogram to determine the false negative rate accurately. - Estimates of the false negative rate depend on the close follow-up of a large number of patients for many years. - This is difficult in practice because many women do not return for regular mammography making it impossible to know if they ever developed cancer. - Researchers have found that breast tissue is denser among younger women, making it difficult to detect tumors. For this reason, false negatives are twice as likely to occur in premenopausal mammograms (Prate.) - This is why the screening program in the UK does not start calling women for screening mammograms until the age of 50. - The importance of these missed cancers is not clear, particularly if the woman is getting yearly mammograms. - Research on a closely related situation has shown that small cancers that are not acted upon immediately but are observed over periods of even several years, will have good outcomes. - A group of 3,184 women had mammograms which were formally classified as "probably benign." [13] - This classification is for patients who are not clearly normal but have some area of minor concern. - This results, not in the patient being biopsied, but having early follow up mammography every six months for three years to guarantee no change. Of these 3,184 women, 17 (0.5%) did have cancers. - Most importantly, when the diagnosis was finally made, they were all still stage 0 or 1, the earliest stages. - Five years after treatment, none of these 17 women had evidence of recurrence. - Thus, small early cancers, even though not acted on immediately, were still entirely curable. - Regardless of the precise number of false negatives, it is very clear that even if some tumors are missed, lives are saved when they are found. Women need to understand that a negative mammogram is not a perfect guarantee that there is no breast cancer present, but it is the best method we have available. - Breast density - Mammography in women under 50 years of age can be imprecise due to breast density. - Breast density is an independent adverse prognostic factor on breast cancer prognosis. [14] - It could delay diagnosis of breast cancer using mammography, additionally having dense breast is a risk factor for developing breast cancer. - Body habitus - It has been shown that mammography might have lower sensitivity in thin women. - Especially in women with a BMI less than 25 (86 versus 91 percent in the normal population) - Just like the other radiologic studies the following plays a crucial role in the accurate interpretation of findings: - Radiologist expertness: - less experienced radiologists had - Higher sensitivity to detect breast cancer - Higher recall rates and lower specificity - Comparison of the current mammogram with the prior mammograms: - May increase the specificity of mammography - Double-reading and computer-aided detection (CAD)[4][5] - Might improve the sensitivity of mammography, - Have not been shown to improve mortality rates from breast cancer screening. - Additionally, CAD may increase patient recall rates. # Mammography risks - The radiation exposure associated with mammography is a potential risk of screening. [15] - The risk of exposure appears to be greater in younger women. - The largest study of radiation risk from mammography concluded that for women 40 years of age or older, the risk of radiation-induced breast cancer was minuscule, particularly compared with the potential benefit of mammographic screening, with a benefit-to-risk ratio of 48.5 lives saved for each life lost due to radiation exposure. - Organizations such as the National Cancer Institute and the United States Preventive Task Force take such risks into account when formulating screening guidelines. - The majority of health experts agree that the risk of breast cancer for women under 35 is not high enough to warrant the risk of radiation exposure. - For this reason, and because the radiation sensitivity of the breast in women under 35 is possibly greater than in older women, most radiologists will not perform screening mammography in women under 40. - However, if there is a significant risk of cancer in a particular patient (BRCA positive, very positive family history, palpable mass), mammography may still be important. - Often, the radiologist will try to avoid mammography, by using ultrasound, or MRI imaging. - Similarly, the risk of breast cancer to women over 55 very clearly justifies the risk of mammograms. - The statistics about mammography and women between the ages of 40 and 55 are the most contentious. - A 1992 Canadian National Breast Cancer Study showed that mammography had no positive effect on mortality for women between the ages of 40 and 50. - The study's critics pointed out that there were very serious design flaws in the study that invalidated these results. - While screening between 40 and 50 is still controversial, the preponderance of the evidence indicates that there is some small benefit in terms of early detection. - Currently, the American Cancer Society, the National Cancer Institute, and the American College of Radiology encourage mammograms every two years for women ages 40 to 49.[16] [17][18][3] - In contrast, the American College of Physicians, a large internist group, has recently encouraged individualized screening plans as opposed to wholesale biennial screening of women aged 40 to 49. - There are some potential risks that are considered to be associated with mammography and mammograms. They include the following: - They require repeated exposure to radiation, which may cause a very small risk of cancer if used over a lifetime. - They can lead to non-invasive cancers being diagnosed and treated when treatment is not necessarily required. - They are not as effective for women with dense breast tissue or breast implants. - They can lead to women choosing double mastectomies as a preventive measure. - They have a high rate of false-positive results, which can result in unnecessary biopsies and additional screening. False-positive results are those that suggest that cancer is present when it is not. - Serial mammography might slightly increase the risk of developing breast cancer in high-risk patients such as patients with a family history of breast cancer and patients with known genetic carcinogenic mutations. - According to a recently published study by Jansen-van der Weide et.al. average increased the risk of breast cancer because of low-dose radiation exposure was (OR between 1.3 and 2 with respect to the patients' risk and exposure) observed compared to that of high-risk women not exposed to low-dose radiation. - Pooled OR revealed an increased risk of breast cancer among high-risk women due to low-dose radiation exposure (OR = 1.3, 95% CI: 0.9- 1.8). - Exposure before age 20 (OR = 2.0, 95% CI: 1.3-3.1) - A mean of ≥5 exposures (OR = 1.8, 95% CI: 1.1-3.0) - When using low-dose radiation among high-risk women, a careful approach is needed, by means of - They recommended a careful approach in these subgroup of patients as follows: - Reducing repeated exposure, - Avoidance of exposure at a younger age - Using non-ionising screening techniques. - According to another study by Diana L. Miglioretti et.al. radiation-induced breast cancer incidence and mortality from digital mammography screening are impacted by:[19] - Dose variability from screening and resultant diagnostic work-up, - Initiation age - Screening frequency. - Women with large breasts may be at higher risk of radiation-induced breast cancer; - However, we should keep in mind that "the benefits of screening outweigh these risks". # Screening Vs diagnostic mammography - Screening mammography - Performed in a woman with no clinical sign and symptoms - To decrease morbidity and mortality by detection of early, treatable breast cancer. - Screening mammography is the best modality currently available to detect clinically occult breast cancer. - Application of the screening mammography is the only modality that has been shown a significant decrease in mortality and morbidity of breast cancer. - Generally standard views are obtained for each breast. - Standard views are as follows: - Cranial-Caudal (CC) - Mediolateral-oblique (MLO) - In certain cases, additional views may be obtained to maximize imaging of all breast tissue. - Additonal views are as follows: - Anterior compression - Cleavage view - Exaggerated craniocaudal (XCCL) view - Diagnostic mammography - Diagnostic mammography is indicated in the following patients: - Patients who present with the abnormal sign and symptoms - Women with abnormal screening mammography. - Patients with: - Palpable lump (Particularly if raised clinical concern) - Nipple discharge - Focal pain - The views obtained are tailored to evaluate a specific abnormality - Ultrasounography might be added to increase the accuracy of studies - Additional views that might be recommended are as follows: - Focal spot compression view - Magnification spot compression view - 90 degree lateral view (true lateral view ) - Tangential views - Rolled views - Surveillance mammography - Performed in women with a history of breast cancer. - Generally recommended for the five years following the diagnosis of breast cancer - Procedure is similar to diagnostic mammography (Presence of an onsite radiologist is recommended) - After having negative results for five years, the patient may return to routine screening # Future (investigational) modern mammography utilities - 3D-Tomosynthesis - While traditional mammograms are 2-D and provide a flat image, tomosynthesis creates a 3-D image. - Standard mammograms and tomosynthesis both use X-rays. - This screening procedure is similar to a mammogram, but it produces a 3-D image rather than a flat one. - As a result, it may provide more accurate information about whether or not there are any changes in the breast. - The addition of 3D-Tomosynthesis to conventional digital mammography increases sensitivity (cancer detection rates) and may increase the positive predictive value of the screening exam. - According to a recently published study on more than 35,000 women by Manisha Bahl et.al., in women 65 Y/O and older, digital breast tomosynthesis (DBT) achieved a higher specificity for detecting breast cancer and identified the disease at an earlier stage compared to traditional 2-D mammography. (Published on 2 April 2019 in Radiology) - Stereoscopic digital mammography - Currently under investigation - Full-field digital mammogram images taken at a slight angle from each other using a stereoscopic viewer - It has been shown in recent studies that - Stereoscopic digital mammography has a higher specificity of for cancer detection compared to the standard imaging - The sensitivity was the same, - The recall rate for stereoscopic imaging was lower (9.6 versus 12.9 percent for standard imaging) - In its current format, the radiation dose was twice compared to that of a standard imaging # Alternatives to mammography - While the cost of mammography is relatively low, its sensitivity is not ideal, with reports listing the range from 45% to about 90% depending on factors such as the density of the breast. - Neither is the X-ray based technology completely benign, as noted above. - Therefore there is considerable ongoing research into the use of alternative technologies. - One approach, contrast-enhanced magnetic resonance imaging (MRI), has shown substantial progress. - In this method, the breast is scanned in an MRI device before and after the intravascular injection of a contrast agent (Gadolinium DTPA). - The pre-contrast images are "subtracted" from the post-contrast images, and any areas that have increased blood flow are seen as bright spots on a dark background. - Since breast cancers generally have an increased blood supply, the contrast agent causes these lesions to "light up" on the images. - The available literature suggests that the sensitivity of contrast-enhanced breast MRI is considerably higher than that of either radiographic mammography or ultrasound and is generally reported to be in excess of 95% (though not all reported studies have been as encouraging). - The specificity (the confidence that a lesion is cancerous and not a false positive) is only fair, thus a positive finding by MRI should not be interpreted as a definitive diagnosis. - The reports of 4,271 breast MRIs from eight large scale clinical trials were reviewed recently by CD Lehman. - Overall the sensitivity ranged from 71% to 100% in these reports, however, the call-back rates were low at 10% and the risk of having a benign biopsy was reported at 5%, a significant improvement over mammography. - Several medical instrument vendors have entered this arena with breast MRI solutions. - One company, Aurora Systems, stands out as being the only manufacturer to make a breast-dedicated unit and as the exclusive patent holder of certain solutions to fat signal suppression that appears to be more or less essential. - Siemens, General Electric, and Philips Medical, the leading manufacturers of MRI instruments, offer breast MRI products or add-ons, and several third-party companies (e.g., MRI Devices/IGC) offer aftermarket products to enable breast MRI on conventional MRI instruments. # Regulation - Mammography facilities in the United States and its territories (including military bases) are subject to the Mammography Quality Standards Act (MQSA). - The act requires annual inspections and accreditation every 3 years through an FDA-approved body. - Facilities found deficient during the inspection or accreditation process can be barred from performing mammograms until corrective action has been verified or, in extreme cases, can be required to notify past patients that their exams were sub-standard and should not be trusted. - Despite the passage of the MQSA by Congress in 1992 and the nearly 1 billion dollar cost, the aggregate sensitivity of mammography in the USA is similar to what it was in the 1970s. - At this time MQSA applies only to traditional mammography and not related scans such as breast ultrasound, stereotactic breast biopsy, or breast MRI.	https://www.wikidoc.org/index.php/Mammogram
1e59d00a71dffd71bccb2ec4c59580ca7905bb8b	wikidoc	Mammoplasty	Mammoplasty # Overview Mammoplasty refers to a plastic surgery surgical procedure on the breast, to alter the shape or form of the breast. Most commonly, it refers to procedures such as breast enlargement or augmentation mammoplasty , breast lift or mastopexy, and breast reduction or reduction mammoplasty procedures. Mammoplasty procedures can also be combined; for example, breast lift and augmentation can be performed in one or two stages to achieve both enhancement of breast size and a lifted and tighter breast form.	Mammoplasty Editors-In-Chief: Martin I. Newman, M.D., FACS, Cleveland Clinic Florida, [1]; Michel C. Samson, M.D., FRCSC, FACS [2] # Overview Mammoplasty refers to a plastic surgery surgical procedure on the breast, to alter the shape or form of the breast. Most commonly, it refers to procedures such as breast enlargement or augmentation mammoplasty , breast lift or mastopexy, and breast reduction or reduction mammoplasty procedures. Mammoplasty procedures can also be combined; for example, breast lift and augmentation can be performed in one or two stages to achieve both enhancement of breast size and a lifted and tighter breast form. Template:WikiDoc Sources	https://www.wikidoc.org/index.php/Mammoplasty
021a512f37e87eca88720a738f4798b5372886cd	wikidoc	Methenamine	Methenamine # 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 Methenamine is an antiseptic that is FDA approved for the treatment of and prophylaxis of recurrent urinary tract infections. Common adverse reactions include rash, nausea, upset stomach, and dysuria. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) - Methenamine mandelate is indicated for the suppression or elimination of bacteriuria associated with pyelonephritis, cystitis, and other chronic urinary tract infections; also those neurologic diseases leading to an infected residual urine. When used as recommended, methenamine mandelate is particularly suitable for long-term therapy because of its safety and because resistance to the nonspecific bactericidal action of formaldehyde does not develop. Pathogens resistant to other antibacterial agents may respond to methenamine mandelate because of the nonspecific effect of formaldehyde formed in an acid urine. - Prophylactic Use Rationale: Urine is a good culture medium for many urinary pathogens. Inoculation by a few organisms (relapse or reinfection) may lead to bacteriuria in susceptible individuals. Thus, the rationale of management in recurring urinary tract infection (bacteriuria) is to change the urine from a growth-supporting to a growth-inhibiting medium. There is a growing body of evidence that long-term administration of methenamine mandelate can prevent the recurrence of bacteriuria in patients with chronic pyelonephritis. - Therapeutic Use Rationale: Methenamine mandelate helps to sterilize the urine, and in some situations in which underlying pathologic conditions prevent sterilization by any means, it can help to suppress the bacteriuria. Methenamine mandelate should not be used alone for acute infections with parenchymal involvement causing systemic symptoms such as chills and fever. A thorough diagnostic investigation as a part of the overall management of the urinary tract infection should accompany the use of methenamine mandelate. - The average adult dose is 4 g a day given as 1 g tablet after each meal and at bedtime. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Methenamine in adult patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Methenamine in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) - Methenamine mandelate is indicated for the suppression or elimination of bacteriuria associated with pyelonephritis, cystitis, and other chronic urinary tract infections; also those neurologic diseases leading to an infected residual urine. When used as recommended, methenamine mandelate is particularly suitable for long-term therapy because of its safety and because resistance to the nonspecific bactericidal action of formaldehyde does not develop. Pathogens resistant to other antibacterial agents may respond to methenamine mandelate because of the nonspecific effect of formaldehyde formed in an acid urine. - Prophylactic Use Rationale: Urine is a good culture medium for many urinary pathogens. Inoculation by a few organisms (relapse or reinfection) may lead to bacteriuria in susceptible individuals. Thus, the rationale of management in recurring urinary tract infection (bacteriuria) is to change the urine from a growth-supporting to a growth-inhibiting medium. There is a growing body of evidence that long-term administration of methenamine mandelate can prevent the recurrence of bacteriuria in patients with chronic pyelonephritis. - Therapeutic Use Rationale: Methenamine mandelate helps to sterilize the urine, and in some situations in which underlying pathologic conditions prevent sterilization by any means, it can help to suppress the bacteriuria. Methenamine mandelate should not be used alone for acute infections with parenchymal involvement causing systemic symptoms such as chills and fever. A thorough diagnostic investigation as a part of the overall management of the urinary tract infection should accompany the use of methenamine mandelate. - Children 6 to 12 years of age should receive half the adult dose; one-half tablet 4 times a day. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Methenamine in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Methenamine in pediatric patients. # Contraindications - Methenamine mandelate tablets are contraindicated in patients with renal insufficiency, severe hepatic disease, severe dehydration, and in patients who have exhibited hypersensitivity to any components of this product. # Warnings - Methenamine mandelate should be avoided in patients with gout because it may precipitate urate crystals in their urine. A similar situation may arise in patients with a predisposition to the formation of uric acid stones. - Methenamine preparations should not be given to patients taking sulfonamides because some sulfonamides may form an insoluble precipitate with formaldehyde in the urine. ### Precautions - Dysuria may occur (usually at higher than recommended dosage). This can be controlled by reducing the dosage and the acidification. When urine acidification is contraindicated or unattainable (as with some urea-splitting bacteria), the drug is not recommended. - Large doses of methenamine (8 g daily for 3 to 4 weeks) have caused bladder irritation, painful and frequent micturition, albuminuria, and gross hematuria. # Adverse Reactions ## Clinical Trials Experience - Gastrointestinal disturbances (nausea, stomach upset), generalized skin rash, dysuria, painful or difficult urination may occur occasionally with the use of methenamine preparations. Microscopic and rarely, gross hematuria have been described. ## Postmarketing Experience There is limited information regarding Postmarketing Experience of Methenamine in the drug label. # Drug Interactions - Formaldehyde and sulfamethizole form an insoluble precipitate in acid urine; therefore, methenamine mandelate should not be administered concurrently with sulfamethizole or other sulfonamides. Concurrent use of salicylates may lead to increased serum salicylate levels since excretion of salicylates is reduced in acidified urine. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): - Pregnancy Category C - Animal reproduction studies have not been conducted with methenamine mandelate. It is also not known whether methenamine mandelate can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Since methenamine is known to cross the placental barrier, methenamine mandelate should be given to a pregnant woman only if the potential benefit outweighs the risk. Pregnancy Category (AUS): - Australian Drug Evaluation Committee (ADEC) Pregnancy Category There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Methenamine in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Methenamine during labor and delivery. ### Nursing Mothers - Methenamine is excreted in breast milk. Because of the potential for serious adverse reactions in nursing infants, 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 There is no FDA guidance on the use of Methenamine with respect to pediatric patients. ### Geriatic Use There is no FDA guidance on the use of Methenamine with respect to geriatric patients. ### Gender There is no FDA guidance on the use of Methenamine with respect to specific gender populations. ### Race There is no FDA guidance on the use of Methenamine with respect to specific racial populations. ### Renal Impairment There is no FDA guidance on the use of Methenamine in patients with renal impairment. ### Hepatic Impairment There is no FDA guidance on the use of Methenamine in patients with hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Methenamine in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Methenamine in patients who are immunocompromised. # Administration and Monitoring ### Administration - Oral ### Monitoring There is limited information regarding Monitoring of Methenamine in the drug label. # IV Compatibility There is limited information regarding IV Compatibility of Methenamine in the drug label. # Overdosage ## Acute Overdose - Minimize absorption by inducing vomiting or by gastric lavage followed by administration of activated charcoal. Administer orally fluids and alkalinize with sodium bicarbonate. ## Chronic Overdose There is limited information regarding Chronic Overdose of Methenamine in the drug label. # Pharmacology There is limited information regarding Methenamine Pharmacology in the drug label. ## Mechanism of Action - Methenamine exhibits antibacterial activity by the conversion of methenamine to formaldehyde in the presence of acidic urine. The hippuric acid component also has some antibacterial activity and acts to keep the urine acidic. ## Structure - Methenamine mandelate, a urinary antibacterial agent, is the chemical combination of mandelic acid with methenamine. Methenamine mandelate is available for oral use as film-coated tablets. - Methenamine mandelate tablets contain 1000 mg (1 g) methenamine mandelate and the following inactive ingredients: croscarmellose sodium, FD&C blue #2 aluminum lake, magnesium stearate, microcrystalline cellulose, polyethylene glycol, polyvinyl alcohol, silicon dioxide, talc and tItanium dioxide. ## Pharmacodynamics There is limited information regarding Pharmacodynamics of Methenamine in the drug label. ## Pharmacokinetics - Methenamine mandelate is readily absorbed but remains essentially inactive until it is excreted by the kidneys and concentrated in the urine. An acid urine is essential for antibacterial action, with maximum efficacy occurring at pH 5.5 or less. In an acid urine, mandelic acid exerts its antibacterial action and also contributes to the acidification of the urine. Mandelic acid is excreted both by glomerular filtration and tubular excretion. The methenamine component is hydrolyzed in acid urine to ammonia and to the bactericidal agent formaldehyde. Proportionally less formaldehyde is released as urinary pH approaches 6.0 and insufficient quantities are released above this level for therapeutic response. There is equally effective antibacterial activity against both gram-positive and gram-negative organisms, since the antibacterial action of mandelic acid and formaldehyde is nonspecific. There are reports that methenamine mandelate is ineffective in some infections with Proteus vulgaris and urea-splitting strains of Pseudomonas aeruginosa and A aerogenes. Since urea-splitting strains may raise the pH of the urine, particular attention to supplementary acidification with agents such as ascorbic acid, and urinary pH monitoring is required. However, results in any single case will depend to a large extent on the underlying pathology and the overall management. ## Nonclinical Toxicology - Methenamine mandelate has not been evaluated for carcinogenicity or mutagenicity. Methenamine was evaluated for mutagenicity in the Ames Salmonella/mammalian microsome test. Five strains of Salmonella typhimurium (TA98, TA100, TA1535, TA1537 and TA1538) and a strain of Escherichia coli (WP2uvrA) were used. At a dose of 10,000 µg/plate methenamine showed mutagenic activity in Salmonella typhimurium TA98 and TA100 by metabolic activation and also showed mutagenic activity in TA98 without microsomal activation. - In one large study, no evidence of carcinogenicity was found following long-term oral administration of methenamine 1.25 g/kg/day to rats (104 weeks) and mice (60 weeks). # Clinical Studies There is limited information regarding Clinical Studies of Methenamine in the drug label. # How Supplied - Methenamine Mandelate Tablets 1000 mg (1 g) are blue, scored, oblong, film-coated, debossed with "ERTH" on one side and "1000" on the other side. Supplied in bottles of 100 (NDC 13925-107-01) - Preserve in well-closed containers - Store at 25°C (77°F) excursions permitted to 15°-30°C (59°-86°F). ## Storage There is limited information regarding Methenamine Storage in the drug label. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information - To assure an acidic pH, patients should be instructed to restrict or avoid milk products and antacids containing sodium carbonate or bicarbonate. # Precautions with Alcohol - Alcohol-Methenamine interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - METHENAMINE MANDELATE® # Look-Alike Drug Names There is limited information regarding Methenamine Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	Methenamine 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 Methenamine is an antiseptic that is FDA approved for the treatment of and prophylaxis of recurrent urinary tract infections. Common adverse reactions include rash, nausea, upset stomach, and dysuria. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) - Methenamine mandelate is indicated for the suppression or elimination of bacteriuria associated with pyelonephritis, cystitis, and other chronic urinary tract infections; also those neurologic diseases leading to an infected residual urine. When used as recommended, methenamine mandelate is particularly suitable for long-term therapy because of its safety and because resistance to the nonspecific bactericidal action of formaldehyde does not develop. Pathogens resistant to other antibacterial agents may respond to methenamine mandelate because of the nonspecific effect of formaldehyde formed in an acid urine. - Prophylactic Use Rationale: Urine is a good culture medium for many urinary pathogens. Inoculation by a few organisms (relapse or reinfection) may lead to bacteriuria in susceptible individuals. Thus, the rationale of management in recurring urinary tract infection (bacteriuria) is to change the urine from a growth-supporting to a growth-inhibiting medium. There is a growing body of evidence that long-term administration of methenamine mandelate can prevent the recurrence of bacteriuria in patients with chronic pyelonephritis. - Therapeutic Use Rationale: Methenamine mandelate helps to sterilize the urine, and in some situations in which underlying pathologic conditions prevent sterilization by any means, it can help to suppress the bacteriuria. Methenamine mandelate should not be used alone for acute infections with parenchymal involvement causing systemic symptoms such as chills and fever. A thorough diagnostic investigation as a part of the overall management of the urinary tract infection should accompany the use of methenamine mandelate. - The average adult dose is 4 g a day given as 1 g tablet after each meal and at bedtime. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Methenamine in adult patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Methenamine in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) - Methenamine mandelate is indicated for the suppression or elimination of bacteriuria associated with pyelonephritis, cystitis, and other chronic urinary tract infections; also those neurologic diseases leading to an infected residual urine. When used as recommended, methenamine mandelate is particularly suitable for long-term therapy because of its safety and because resistance to the nonspecific bactericidal action of formaldehyde does not develop. Pathogens resistant to other antibacterial agents may respond to methenamine mandelate because of the nonspecific effect of formaldehyde formed in an acid urine. - Prophylactic Use Rationale: Urine is a good culture medium for many urinary pathogens. Inoculation by a few organisms (relapse or reinfection) may lead to bacteriuria in susceptible individuals. Thus, the rationale of management in recurring urinary tract infection (bacteriuria) is to change the urine from a growth-supporting to a growth-inhibiting medium. There is a growing body of evidence that long-term administration of methenamine mandelate can prevent the recurrence of bacteriuria in patients with chronic pyelonephritis. - Therapeutic Use Rationale: Methenamine mandelate helps to sterilize the urine, and in some situations in which underlying pathologic conditions prevent sterilization by any means, it can help to suppress the bacteriuria. Methenamine mandelate should not be used alone for acute infections with parenchymal involvement causing systemic symptoms such as chills and fever. A thorough diagnostic investigation as a part of the overall management of the urinary tract infection should accompany the use of methenamine mandelate. - Children 6 to 12 years of age should receive half the adult dose; one-half tablet 4 times a day. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Methenamine in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Methenamine in pediatric patients. # Contraindications - Methenamine mandelate tablets are contraindicated in patients with renal insufficiency, severe hepatic disease, severe dehydration, and in patients who have exhibited hypersensitivity to any components of this product. # Warnings - Methenamine mandelate should be avoided in patients with gout because it may precipitate urate crystals in their urine. A similar situation may arise in patients with a predisposition to the formation of uric acid stones. - Methenamine preparations should not be given to patients taking sulfonamides because some sulfonamides may form an insoluble precipitate with formaldehyde in the urine. ### Precautions - Dysuria may occur (usually at higher than recommended dosage). This can be controlled by reducing the dosage and the acidification. When urine acidification is contraindicated or unattainable (as with some urea-splitting bacteria), the drug is not recommended. - Large doses of methenamine (8 g daily for 3 to 4 weeks) have caused bladder irritation, painful and frequent micturition, albuminuria, and gross hematuria. # Adverse Reactions ## Clinical Trials Experience - Gastrointestinal disturbances (nausea, stomach upset), generalized skin rash, dysuria, painful or difficult urination may occur occasionally with the use of methenamine preparations. Microscopic and rarely, gross hematuria have been described. ## Postmarketing Experience There is limited information regarding Postmarketing Experience of Methenamine in the drug label. # Drug Interactions - Formaldehyde and sulfamethizole form an insoluble precipitate in acid urine; therefore, methenamine mandelate should not be administered concurrently with sulfamethizole or other sulfonamides. Concurrent use of salicylates may lead to increased serum salicylate levels since excretion of salicylates is reduced in acidified urine. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): - Pregnancy Category C - Animal reproduction studies have not been conducted with methenamine mandelate. It is also not known whether methenamine mandelate can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Since methenamine is known to cross the placental barrier, methenamine mandelate should be given to a pregnant woman only if the potential benefit outweighs the risk. Pregnancy Category (AUS): - Australian Drug Evaluation Committee (ADEC) Pregnancy Category There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Methenamine in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Methenamine during labor and delivery. ### Nursing Mothers - Methenamine is excreted in breast milk. Because of the potential for serious adverse reactions in nursing infants, 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 There is no FDA guidance on the use of Methenamine with respect to pediatric patients. ### Geriatic Use There is no FDA guidance on the use of Methenamine with respect to geriatric patients. ### Gender There is no FDA guidance on the use of Methenamine with respect to specific gender populations. ### Race There is no FDA guidance on the use of Methenamine with respect to specific racial populations. ### Renal Impairment There is no FDA guidance on the use of Methenamine in patients with renal impairment. ### Hepatic Impairment There is no FDA guidance on the use of Methenamine in patients with hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Methenamine in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Methenamine in patients who are immunocompromised. # Administration and Monitoring ### Administration - Oral ### Monitoring There is limited information regarding Monitoring of Methenamine in the drug label. # IV Compatibility There is limited information regarding IV Compatibility of Methenamine in the drug label. # Overdosage ## Acute Overdose - Minimize absorption by inducing vomiting or by gastric lavage followed by administration of activated charcoal. Administer orally fluids and alkalinize with sodium bicarbonate. ## Chronic Overdose There is limited information regarding Chronic Overdose of Methenamine in the drug label. # Pharmacology There is limited information regarding Methenamine Pharmacology in the drug label. ## Mechanism of Action - Methenamine exhibits antibacterial activity by the conversion of methenamine to formaldehyde in the presence of acidic urine. The hippuric acid component also has some antibacterial activity and acts to keep the urine acidic. ## Structure - Methenamine mandelate, a urinary antibacterial agent, is the chemical combination of mandelic acid with methenamine. Methenamine mandelate is available for oral use as film-coated tablets. - Methenamine mandelate tablets contain 1000 mg (1 g) methenamine mandelate and the following inactive ingredients: croscarmellose sodium, FD&C blue #2 aluminum lake, magnesium stearate, microcrystalline cellulose, polyethylene glycol, polyvinyl alcohol, silicon dioxide, talc and tItanium dioxide. ## Pharmacodynamics There is limited information regarding Pharmacodynamics of Methenamine in the drug label. ## Pharmacokinetics - Methenamine mandelate is readily absorbed but remains essentially inactive until it is excreted by the kidneys and concentrated in the urine. An acid urine is essential for antibacterial action, with maximum efficacy occurring at pH 5.5 or less. In an acid urine, mandelic acid exerts its antibacterial action and also contributes to the acidification of the urine. Mandelic acid is excreted both by glomerular filtration and tubular excretion. The methenamine component is hydrolyzed in acid urine to ammonia and to the bactericidal agent formaldehyde. Proportionally less formaldehyde is released as urinary pH approaches 6.0 and insufficient quantities are released above this level for therapeutic response. There is equally effective antibacterial activity against both gram-positive and gram-negative organisms, since the antibacterial action of mandelic acid and formaldehyde is nonspecific. There are reports that methenamine mandelate is ineffective in some infections with Proteus vulgaris and urea-splitting strains of Pseudomonas aeruginosa and A aerogenes. Since urea-splitting strains may raise the pH of the urine, particular attention to supplementary acidification with agents such as ascorbic acid, and urinary pH monitoring is required. However, results in any single case will depend to a large extent on the underlying pathology and the overall management. ## Nonclinical Toxicology - Methenamine mandelate has not been evaluated for carcinogenicity or mutagenicity. Methenamine was evaluated for mutagenicity in the Ames Salmonella/mammalian microsome test. Five strains of Salmonella typhimurium (TA98, TA100, TA1535, TA1537 and TA1538) and a strain of Escherichia coli (WP2uvrA) were used. At a dose of 10,000 µg/plate methenamine showed mutagenic activity in Salmonella typhimurium TA98 and TA100 by metabolic activation and also showed mutagenic activity in TA98 without microsomal activation. - In one large study, no evidence of carcinogenicity was found following long-term oral administration of methenamine 1.25 g/kg/day to rats (104 weeks) and mice (60 weeks). # Clinical Studies There is limited information regarding Clinical Studies of Methenamine in the drug label. # How Supplied - Methenamine Mandelate Tablets 1000 mg (1 g) are blue, scored, oblong, film-coated, debossed with "ERTH" on one side and "1000" on the other side. Supplied in bottles of 100 (NDC 13925-107-01) - Preserve in well-closed containers - Store at 25°C (77°F) excursions permitted to 15°-30°C (59°-86°F). ## Storage There is limited information regarding Methenamine Storage in the drug label. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information - To assure an acidic pH, patients should be instructed to restrict or avoid milk products and antacids containing sodium carbonate or bicarbonate. # Precautions with Alcohol - Alcohol-Methenamine interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - METHENAMINE MANDELATE®[1] # Look-Alike Drug Names There is limited information regarding Methenamine Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	https://www.wikidoc.org/index.php/Mandelamine
2688460c81b68c87f54b97c024efd91ee437e8cc	wikidoc	Prognathism	Prognathism Please Take Over This Page and 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 mail us 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. Prognathism is a term used to describe the positional relationship of the mandible and/or maxilla to the skeletal base where either of the jaws protrudes beyond a predetermined imaginary line in the sagittal plane of the skull. In dentistry, oral and maxillofacial surgery and orthodontics this is assessed clinically or radiographically (cephalometrics). # Etymology The word prognathism derives from Greek pro (forward) and gnathos (jaw). # Presentation Clinical determinants include soft tissue analysis where the clinician assesses nasolabial angle the relationship of the soft tissue portion of the chin to the nose and the relationship between the upper and lower lips; also used is dental arch relationship assessment such as Angle's classification. Cephalometric analysis is the most accurate way of determining all types of prognathism as it includes assessments of skeletal base, occlusal plane angulation, facial height, soft tissue assessment and anterior dental angulation. Various calculations and assessments of the information in a cephalometric radiograph allow the clinician to objectively determine dental and skeletal relationships and determine a treatment plan. Maxillary prognathism is a protrusion of the maxilla, and is also a common feature of many populations. It is not to be confused with micrognathism, although combinations of both may be found. It affects the middle third of the face, causing it to jut out, thereby increasing the facial area. Mandibular prognathism is a protrusion of the mandible, affecting the lower third of the face. Alveolar prognathism is a protrusion of that portion of the maxilla where the teeth are located, in the dental lining of the upper jaw. Prognathism can also be used to describe ways that the maxillary and mandibular dental arches can relate to one another. When there is maxillary and/or alveolar prognathism which causes an alignment of the maxillary incisors significantly anterior to the lower teeth, the condition is called an overbite. When the reverse is the case, and the lower jaw extends forward beyond the upper, the condition is referred to as an underbite. The vast majority of prognathism in humans is due to normal variation among phenotypes. In human populations where prognathism is not the norm, it may be a malformation, the result of injury, a disease state or a hereditary condition. Prognathism is only a disease if it affects mastication, speech or social function as a byproduct of severely affected aesthetics of the face. # Classification ## Alveolar prognathism Harmful habits, such as thumb sucking or tongue thrusting can result in or exaggerate an alveolar prognathism, causing teeth to misalign. Functional appliances can be used in growing children to help modify bad habits and neuro-muscular function, with the aim of correcting this condition. Alveolar prognathism can be easily corrected also with fixed orthodontic therapy. However, relapse is quite common, unless the cause is removed or a long term retention is used. Not all alveolar prognathism is anomalous, and significant differences can be observed among different ethnic groups. ## Maxillary Prognathism In disease states, maxillary prognathism is associated with de Lange Syndrome; however so-called false maxillary prognathism, where there is a lack of growth of the mandible, is by far a more common condition. Prognathism, if not extremely severe, can be treated in growing patients with orthodontic functional or orthopaedic appliances. In adult patients this condition can be corrected by means of a combined surgical/orthodontic treatment, where most of the time a mandibular advancement is performed. The same can be said for mandibular prognathism. ## Mandibular prognathism (progenism) Pathologic mandibular prognathism is a potentially disfiguring, genetic disorder where the lower jaw outgrows the upper, resulting in an extended chin. The condition colloquially is known as Habsburg jaw, Habsburg lip or Austrian Lip (see Habsburg) due to its prevalence in that bloodline. The trait is easily traceable in portraits of Habsburg family members. This has provided tools for people interested in studying genetics and pedigree analysis. Most instances are considered polygenetic. It is alleged to have been derived through a female from the princely Polish family of Piasts, its Masovian branch. The deformation of lips is clearly visible on tomb sculptures of Mazovian Piasts in Warsaw. However this may be, there exists evidence that the trait is longstanding. It is perhaps first observed in Maximilian I (1459-1519). Traits such as these that were common to royal families are believed to have been passed on and exaggerated over time through royal intermarriage which caused acute inbreeding. Due to the large amount of politically motivated intermarriage among Habsburgs, the dynasty was virtually unparalleled in the degree of its inbreeding. Charles II of Spain is said to have had the most pronounced case of the Habsburg jaw on record. His jaw was so deformed that he was unable to chew. Many dog breeds have underbite, particularly those with short faces. This may be, as in the case of bulldogs, to a slower growing maxilla in relation to the mandible. # Treatment The most common treatment for mandibular prognathism is a combination of orthodontics and surgery. The orthodontics can involve braces, removal of teeth, or a bite splint. # Image Gallery - 10-year-old boy with false maxillary prognathism - Alveolar prognathism, caused by thumb sucking and tongue thrusting in a 7 yr old girl. - Example of prognathism, where teeth have almost reached their final, straight position by braces. This makes the prognatism more obvious, and it will take a surgery, moving the jaw backwards, to give the ultimate result.	Prognathism Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor in Chief: Berna Zorkun DMD [2] Please Take Over This Page and 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 mail us [3] 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. Prognathism is a term used to describe the positional relationship of the mandible and/or maxilla to the skeletal base where either of the jaws protrudes beyond a predetermined imaginary line in the sagittal plane of the skull. In dentistry, oral and maxillofacial surgery and orthodontics this is assessed clinically or radiographically (cephalometrics). # Etymology The word prognathism derives from Greek pro (forward) and gnathos (jaw). # Presentation Clinical determinants include soft tissue analysis where the clinician assesses nasolabial angle the relationship of the soft tissue portion of the chin to the nose and the relationship between the upper and lower lips; also used is dental arch relationship assessment such as Angle's classification. Cephalometric analysis is the most accurate way of determining all types of prognathism as it includes assessments of skeletal base, occlusal plane angulation, facial height, soft tissue assessment and anterior dental angulation. Various calculations and assessments of the information in a cephalometric radiograph allow the clinician to objectively determine dental and skeletal relationships and determine a treatment plan. Maxillary prognathism is a protrusion of the maxilla, and is also a common feature of many populations. It is not to be confused with micrognathism, although combinations of both may be found. It affects the middle third of the face, causing it to jut out, thereby increasing the facial area. Mandibular prognathism is a protrusion of the mandible, affecting the lower third of the face. Alveolar prognathism is a protrusion of that portion of the maxilla where the teeth are located, in the dental lining of the upper jaw. Prognathism can also be used to describe ways that the maxillary and mandibular dental arches can relate to one another. When there is maxillary and/or alveolar prognathism which causes an alignment of the maxillary incisors significantly anterior to the lower teeth, the condition is called an overbite. When the reverse is the case, and the lower jaw extends forward beyond the upper, the condition is referred to as an underbite. The vast majority of prognathism in humans is due to normal variation among phenotypes. In human populations where prognathism is not the norm, it may be a malformation, the result of injury, a disease state or a hereditary condition.[1] Prognathism is only a disease if it affects mastication, speech or social function as a byproduct of severely affected aesthetics of the face. # Classification ## Alveolar prognathism Harmful habits, such as thumb sucking or tongue thrusting can result in or exaggerate an alveolar prognathism, causing teeth to misalign. Functional appliances can be used in growing children to help modify bad habits and neuro-muscular function, with the aim of correcting this condition. Alveolar prognathism can be easily corrected also with fixed orthodontic therapy. However, relapse is quite common, unless the cause is removed or a long term retention is used. Not all alveolar prognathism is anomalous, and significant differences can be observed among different ethnic groups.[2] ## Maxillary Prognathism In disease states, maxillary prognathism is associated with de Lange Syndrome[3]; however so-called false maxillary prognathism, where there is a lack of growth of the mandible, is by far a more common condition. Prognathism, if not extremely severe, can be treated in growing patients with orthodontic functional or orthopaedic appliances. In adult patients this condition can be corrected by means of a combined surgical/orthodontic treatment, where most of the time a mandibular advancement is performed. The same can be said for mandibular prognathism. ## Mandibular prognathism (progenism) Pathologic mandibular prognathism is a potentially disfiguring, genetic disorder where the lower jaw outgrows the upper, resulting in an extended chin. The condition colloquially is known as Habsburg jaw, Habsburg lip or Austrian Lip (see Habsburg) due to its prevalence in that bloodline.[4] The trait is easily traceable in portraits of Habsburg family members.[5] This has provided tools for people interested in studying genetics and pedigree analysis. Most instances are considered polygenetic.[6] It is alleged to have been derived through a female from the princely Polish family of Piasts, its Masovian branch. The deformation of lips is clearly visible on tomb sculptures of Mazovian Piasts in Warsaw. However this may be, there exists evidence that the trait is longstanding. It is perhaps first observed in Maximilian I (1459-1519). Traits such as these that were common to royal families are believed to have been passed on and exaggerated over time through royal intermarriage which caused acute inbreeding. Due to the large amount of politically motivated intermarriage among Habsburgs, the dynasty was virtually unparalleled in the degree of its inbreeding. Charles II of Spain is said to have had the most pronounced case of the Habsburg jaw on record. His jaw was so deformed that he was unable to chew. Many dog breeds have underbite, particularly those with short faces. This may be, as in the case of bulldogs, to a slower growing maxilla in relation to the mandible. # Treatment The most common treatment for mandibular prognathism is a combination of orthodontics and surgery. The orthodontics can involve braces, removal of teeth, or a bite splint. # Image Gallery - 10-year-old boy with false maxillary prognathism - Alveolar prognathism, caused by thumb sucking and tongue thrusting in a 7 yr old girl. - Example of prognathism, where teeth have almost reached their final, straight position by braces. This makes the prognatism more obvious, and it will take a surgery, moving the jaw backwards, to give the ultimate result.	https://www.wikidoc.org/index.php/Mandibular_prognathism
3c99be0d883dd2fd7e1b744987949bc64d187341	wikidoc	Maralixibat	Maralixibat # 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 Maralixibat is an ileal bile acid transporter inhibitor that is FDA approved for the treatment of cholestatic pruritus associated with Alagille syndrome. Common adverse reactions include liver test abnormalities, abdominal pain, fat-soluble vitamin deficiency, diarrhea, bone fractures, and gastrointestinal bleeding. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) - 380 mcg/kg once daily, taken 30 minutes before the first meal of the day orally is recommended dosage in patients. - 190 mcg/kg once daily is the recommended starting dosage for one week upon starting treatment of Maralixibat. After one week, increase dosage to recommended dosage of 380 mcg/kg. - 3 mL per day is the maximum dosage in patients weighing above 70kg. Table 1 shows Dosage of Maralixibat based on a Patient’s Weight. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Maralixibat in adult patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Maralixibat in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) There is limited information regarding Maralixibat 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 Maralixibat in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Maralixibat in pediatric patients. # Contraindications There are no contraindications associated with Maralixibat. # Warnings Liver Test Abnormalities - Trial studies show patients experiencing abnormal liver tests at the baseline. - Comparing baseline liver test data in patients, liver tests worsened in some patients when taking Maralixibat. - Patients also showed increases in AST, ALT, or T/DB. - Increase in ALT lead to patients having dose interruptions (n=2), permanent discontinuation (n=2), or dose modifications (n=1) as shown from clinical studies. - Increased TB above the baseline found in clinical trials can cause a patient to discontinue treatment with Maralixibat. - Monitor patients liver function through liver tests when taking Maralixibat. - Liver-related adverse reactions and elevations in liver tests should be cautioned to patients taking Maralixibat. - Advise patients to discontinue Maralixibat if signs of portal hypertension persist in patients. Gastrointestinal Adverse Reactions - Abdominal pain, vomiting, and diarrhea was reported in patients who take Maralixibat. - 3% of patients in clinical studies who experienced vomiting required hospitalization. - Reduce or interrupt dosages of Maralixibat in patients experiencing abdominal pain, vomiting, and diarrhea. - Monitor patients hydration levels if they display vomiting and diarrhea when taking Maralixibat. - Reduce the dosage from 380 mcg/kg back to 190 mcg/kg/day and slowly increase after abdominal pain, vomiting, or diarrhea in patients has been resolved. - Permanently discontinue use of Maralixibat if abdominal pain, vomiting, or diarrhea continue to be a persist in patients after resolution. Fat-Soluble Vitamin (FSV) Deficiency - Fat-soluble vitamins (vitamin A, D, E, and K) absorption may be affected by use of Maralixibat. - Fat-soluble vitamins deficiency can occur in ALGS patients. - Trial 1 clinical studies show 10% of patients reporting fat-soluble vitamins deficiency - Monitor patients fat-soluble vitamins levels and supplement fat-soluble vitamins when deficiency occurs when taking Maralixibat. - Permanently discontinue use of Maralixibat if fat-soluble vitamins levels do not improve after fat-soluble vitamins supplementation. # Adverse Reactions ## Clinical Trials Experience Clinical Trial Experience - Because clinical trials are conducted under widely varying conditions and durations of follow up, 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. Alagille syndrome clinical development program - This program was comprised of 5 clinical studies that looked into the adverse reactions of 86 patients being treated by Maralixibat. Patients received up to 760 mcg/kg per day of Maralixibat with the program that had a median duration of 32.3 months. 4-week placebo control period occurred in Trial 1 studies after 18 weeks of Maralixibat treatment. 13 weeks of placebo-controlled treatment occurred two long-term, open-label extension studies which specifically looked into patients receiving less than 380 mcg/kg/day dosages of Maralixibat. Dosage reductions and interruptions occurred 6% of patients that displayed vomiting, diarrhea, or abdominal pain in the studies conducted. Table 2 shows Adverse Reactions (≥5%) caused by Maralixibat in ALGS patients. Liver Test Abnormalities - Pooled analysis of ALGS patients showed ALT increases with treatment of Maralixibat. - ALT increases due to Maralixibat led to discontinuation (8.1%), and decreased dosage or dosage interruptions (3.5%) in patients. - Cases of elevations was resolved through dosage modifications, dosage interruptions or no changes in dosage of Maralixibat - 24% of patients showed increases to more than three times the baseline in ALT when using Maralixibat. - 2% of patients showed increases to more than five times the baseline in ALT when using Maralixibat. - 14% of patients showed AST increases to more than three times the baseline when using Maralixibat. - 4.6% of patients showed bilirubin increases above baseline. ## Postmarketing Experience There is limited information about "Postmarketing Experiance" in the drug label. # Drug Interactions Effects of Other Drugs on Maralixibat Bile acid binding resins - In the gut, Maralixibat may bind to bile acid binding resins. - 4 hours before or 4 hours use of Maralixibat may have bile acid binding resins in the gut. Effects of LIVMARLI on Other Drugs OATP2B1 substrates - In vitro studies, Maralixibat can be an OATP2B1 inhibitor. - OATP2B1 inhibition may cause a decrease in the oral absorption of OATP2B1 substrates. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): Clinical studies shows the systematic absorption of Maralixibat in the fetus is low for pregnant women taking the recommended dosage of Maralixibat orally. Fat-soluble vitamins absorption may be inhibited by use of Maralixibat. Studies done on pregnant rats, who received 1000 mg/kg/day of Maralixibat orally, and pregnant rabbits, who received 1000 mg/kg/day of Maralixibat orally, showed no effects were done to embryo development when using Maralixibat during a period of organogenesis. In female rats studies, Maralixibat had no effect on postnatal development when they received 750 mg/kg/day during organogenesis through lactation. Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Maralixibat in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Maralixibat during labor and delivery. ### Nursing Mothers At recommended dosages, use of Maralixibat should not be exposed to the fetus during lactation. No current data has been done on the effects of Maralixibat on the breastfed infant and the effects on milk production in women when treated with Maralixibat. Monitor patients during lactation for fat-soluble vitamins deficiency. ### Pediatric Use Safety and effectiveness of pediatric patients with cholestatic pruritus using Maralixibat has been established in a study. This study included patients ranging from 1 year of age to 15 years of age. There was 18 weeks of open-label treatment that was followed up by a 4 week period of placebo-controlled randomized withdrawal and an immediate open-label treatment period that lasted 26 weeks. 4 studies have provided safety information of patients up to 21 years of age using Maralixibat. ### Geriatic Use The safety and effectiveness of the use of Maralixibat in ALGS patients who are 65 years and older in age for the treatment of pruritus has not been established. ### Gender There is no FDA guidance on the use of Maralixibat with respect to specific gender populations. ### Race There is no FDA guidance on the use of Maralixibat with respect to specific racial populations. ### Renal Impairment There is no FDA guidance on the use of Maralixibat in patients with renal impairment. ### Hepatic Impairment Impaired hepatic function at baseline has been reported in ALGS patients treated with Maralixibat. Clinical studies on safety and effectiveness in both patients who have decompensated cirrhosis and portal hypertension have not been established. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Maralixibat in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance on the use of Maralixibat with respect to immunocompromised populations. # Administration and Monitoring ### Administration - Take recommended dosage as prescribed by the doctor 30 minutes before the first meal of the day. - Patients should use calibrated measuring device from the pharmacy to measure Maralixibat dosage. - If patients are taking a bile acid binding resin, do not take Maralixibat until at least 4 hours before or 4 hours after of the taking of bile acid binding resin. - If a dosage is missed less than 12 hours of scheduled time, take dosage as soon as possible. - If a dosage is missed by more than 12 hours, then skip dosage and take next dosage at scheduled time. ### Monitoring - Monitor patients liver tests throughout treatment with MAralixibat and compare the results to the baseline. - Monitor patients TB, AST, and International Normalized Ratio levels when taking Maralixibat. - Any liver test abnormalities should lead to interruption in Maralixibat dosage. - If liver test abnormalities become stabilized, start patients with 190 mcg/kg of Maralixibat and work dosage back up to 380 mcg/kg if tolerated by patients. - Hepatic decompensation events in patients should lead to permanent discontinuation of Maralixibat treatment. # IV Compatibility There is limited information regarding the compatibility of Maralixibat and IV administrations. # Overdosage - 500 mg, approximately 18-fold higher than the recommended dose, of Maralixibat in a single dose regimen has showed no indications of meaningful increase in adverse reactions in patients when compared to reactions occurring in lower dosage amounts. - Monitor patients signs and symptoms when overdosed on Maralixibat. - Propylene glycol (364.5 mg/mL) is found in Maralixibat. - 50 mg/kg/day and 500 mg/kg/day of propylene glycol are considered safe in the body. - CNS, hyperosmolality, cardiovascular, and/or respiratory effects may be present in patients who overdose on propylene glycol found in Maralixibat. # Pharmacology ## Mechanism of Action - Maralixibat is a reversible inhibitor of the ileal bile acid transporter. - In the terminal ileum, the reabsorption of bile acids is decreased in the presence of Maralixibat. - Inhibition of the ileal bile acid transporter inhibitor may occur in the presence of Maralixibat which can decrease bile salts re-uptake. ## Structure - Maralixibat is an ileal bile acid transporter inhibitor for oral administration. - It has an empirical formula of C40H56ClN3O4S and a molecular weight of 710.42 g/mol. - The chemical name is 1-phenoxy}methyl)benzyl]-4-aza-1-azoniabicyclooctane ## Pharmacodynamics - Trial 1 studies looked into serum bile acids levels in pediatric patients taking Maralixibat. - Pediatric patients with ALGS started an initial 5-week dose-escalation period which was followed by open-label treatment for 13 weeks of 380 mcg/kg of a single daily dosage of Maralixibat. - Patients in the study had serum bile acids levels that ranged from 20 to 749 µmol/L for the baseline. - The mean of serum bile acid level was 283 (210.6) µmol/L of pediatric patients at baseline. - As early as Week 12, patients reported decreases in serum bile acid levels when compared to the baseline. ## Pharmacokinetics Pharmacokinetic Parameters - Pharmacokinetics of Maralixibat is not calculated reliably due to low systemic absorption of Maralixibat. - Maralixibat was below the limit of quantification in pediatric ALGS patients. - Trial 1 studies show 5.93 ng/mL is the highest concentrations of Maralixibat in pediatric patients receiving 380 mcg/kg once daily of Maralixibat. - Plasma concentrations are below the limit of quantification with doses less than 20 mg of Maralixibat in healthy adults. - 0.75 is the median Tmax after patients received a single 30 mg under fasted condition dosage of Maralixibat. - 1.65 (1.10) ng/m is the mean (SD) Cmax after patients received a single 30 mg under fasted condition dosage of Maralixibat. - 3.43 (2.13) ng∙h/mL is the mean (SD) AUClast after patients received a single 30 mg under fasted condition dosage of Maralixibat. Absorption - Plasma concentrations of Maralixibat are below the limit of quantification. - Absorption of Maralixibat is minimally absorbed. - AUClast increased 4.6 fold when looking at patients receiving 30, 45, and 100 mg of Maralixibat once daily under fasted condition. - Cmax increased 2.4 fold when looking at patients receiving 30, 45, and 100 mg of Maralixibat once daily under fasted condition. - Healthy adults receiving up to 100 mg of Maralixibat showed no accumulation. Effect of Food - Patients who eat a high-fat meal showed a decrease in both extent and rate of absorption with concomitant use of Maralixibat. - Changes of systemic exposures by the effect of food in patients taking Maralixibat is not clinically significant. Distribution - In vitro, Maralixibat has a plasma protein binding percentage of 91%. Elimination - The mean half-life is 1.6 hours in patients receiving 30 mg Maralixibat once daily. Metabolism - Plasma had no signs of Maralixibat metabolites. - (14C)Maralixibat orally administered showed <3% of three minor metabolites in total fecal radioactivity. Excretion - Major route of elimination is fecal excretion. - In feces, after oral administration of 5 mg 14C-Maralixibat, 73% of Maralixibat was found in which 94% was found unchanged. - In urine, after oral administration of 5 mg 14C-Maralixibat, 0.066% of Maralixibat was found. Specific Populations Patients with Renal Impairment - The pharmacokinetics of patients who have impaired renal function receiving Maralixibat has not been studied. Drug Interaction Studies Effect of Other Drugs on Maralixibat - Maralixibat for certain drug transporters such as BCRP, OATP1B1, MDR1, OATP2B2, or OATP1B3 is not a substrate. - Disposition of Maralixibat is predicted to not be affected by concomitant drug transporters. Effect of Maralixibat on Other Drugs - In vitro, CYP isoforms 2B6, 3A4, or 1A2 are not induced by Maralixibat. CYP isoforms 2C9, 2C19, 2B6, 1A2, 2D6 or 2C8 are not inhibited by Maralixibat. CYP3A4 is inhibited by Maralixibat, but it is unlikely that the pharmacokinetics of CYP3A4 will have relevant effects. Transporters such as OAT1, OAT3, OATP1B1, OCT1, OCT2, OCT3, OCTN1, BCRP, MRP2, MATE1, MDR1, MATE2-K, or OCTN2 are not inhibited by Maralixibat. - In vitro, Drug transporter OATP2B1 is inhibited by Maralixibat which may reduce absorption for OATP2B1-mediated uptake drugs. - Pharmacokinetics of statins and metabolites have no relevant effect when simvastatin or lovastatin is co-administered with 4.75 mg of Maralixibat. - Pharmacokinetics of atorvastatin is not effected with co-administration of 4.75 mg Maralixibat. - Clinical study is needed to look into the pharmacokinetics of OATP2B1 substrates at higher doses when co-administered with 4.75 mg of Maralixibat to see if Maralixibat has an effect. ## Nonclinical Toxicology Carcinogenesis - TgRasH2 mice did not show any drug-related tumors when taking Maralixibat for 26 weeks. Mutagenesis - In vivo and vitro assays, Maralixibat was negative for mutagenesis. Impairment of Fertility - Female rats who received up to 2000 mg/kg/day of Maralixbat and male rats who received up to 750 mg/kg/day of Maralixibat showed No effects on their fertility when treated with Maralixibat. # Clinical Studies Trial 1 Study - The study conducted included a 4-week randomized, double-blind, placebo-controlled drug-withdrawal period; an 18-week open-label treatment period; and a subsequent 26-week open-label treatment period; and a long-term open-label extension period. The study was made up of 31 ALGS, pediatric patients that had pruritus, the JAGGED Mutation, and cholestasis. The patient population included 66% males with a median of 5 years in age. Patients in the study had a baseline AST level of 158 (68) U/L, baseline ALT of 179 (112) U/L, baseline GGT of 498 (399) U/L, baseline serum bile acid levels of 280 (213) µmol/L, and a baseline TB level of 5.6 (5.4) mg/dL. 90.3% of the patients in the study with pruritus received one medication for treatment of the pruritus. Patients started with a 5-week dose-escalation period that was followed by 13 weeks of Maralixibat at 380 mcg/kg once daily. Two patients in the study discontinued the use of Maralixibat first 18 weeks of open-label treatment dropping the patient population to 29 patients. The 29 patients left were then put in a 4-week drug withdrawal period with the patients either receiving a placebo or continued with Maralixibat. Afterward, all patients received 380 mcg/kg once daily of Maralixibat for 26 more weeks. A 5-point ordinal response scale was used on the pediatric patients that show symptoms of pruritus. The mean baseline score of pruritus is 3.1 in patients pre-treatment with 1.4 as the mean score at Week 18. There was a reduction in pruritus for patients who received Maralixibat for 22 weeks. The baseline score was similar to the score in patients who received the placebo after 18 weeks of Maralixibat. Similar pruritus scores were seen in all patients during the open-label treatment phase. Table 3 shows Patient Pruritus Scores during the Placebo-Controlled Period. # How Supplied - 30 mL of Maralixibat with 9.5 mg of Maralixibat for each mL in the plastic bottle. - Marlixibat is a clear, colorless to yellow liquid that is orally administered in patients. ## Storage - Store at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F). - Advise patients to throw out any Maralixibat remaining after 45 days of first opening the bottle. - Advise patients to put cap back on Maralixibat bottle after daily usage. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information Risks - Advise patients about reported symptoms when taking Maralixibat such as vomiting, diarrhea, dehydration, and abdominal pain. - Advise patients to seek medical attention if symptoms worsen when taking Maralixibat. - Patients have experienced liver test elevations when taking Maralixibat. - Monitor patients liver test results when taking Maralixibat to the baseline. - Advise patients to seek medical attention if liver problems arise such as dark or brown urine and possibly pain on the right side of the abdomen. - Absorption of fat-soluble vitamins may decrease with treatment of Maralixibat. - Monitor patients fat-soluble vitamins levels from start to end of treatment of Maralixibat to make sure no fat-soluble vitamins deficiency is not occurring in the patient. Administration - Maralixibat should be taken 30 minutes before the first meal of the day orally. - Measure dosage of Maralixibat with a calibrated measuring device that will be provided to patients by their pharmacist. - Advise patients to throw out any Maralixibat remaining after 45 days of first opening the bottle. - Patients taking a bile acid binding resin should wait on taking Maralixibat until at least 4 hours before or 4 hours after taking the bile acid binding resin. # Precautions with Alcohol Alcohol-Maralixibat interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - Livmarli # Look-Alike Drug Names There is limited information regarding Maralixibat Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	Maralixibat Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Tejasvi Aryaputra # 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 Maralixibat is an ileal bile acid transporter inhibitor that is FDA approved for the treatment of cholestatic pruritus associated with Alagille syndrome. Common adverse reactions include liver test abnormalities, abdominal pain, fat-soluble vitamin deficiency, diarrhea, bone fractures, and gastrointestinal bleeding. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) - 380 mcg/kg once daily, taken 30 minutes before the first meal of the day orally is recommended dosage in patients. - 190 mcg/kg once daily is the recommended starting dosage for one week upon starting treatment of Maralixibat. After one week, increase dosage to recommended dosage of 380 mcg/kg. - 3 mL per day is the maximum dosage in patients weighing above 70kg. Table 1 shows Dosage of Maralixibat based on a Patient’s Weight. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Maralixibat in adult patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Maralixibat in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) There is limited information regarding Maralixibat 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 Maralixibat in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Maralixibat in pediatric patients. # Contraindications There are no contraindications associated with Maralixibat. # Warnings Liver Test Abnormalities - Trial studies show patients experiencing abnormal liver tests at the baseline. - Comparing baseline liver test data in patients, liver tests worsened in some patients when taking Maralixibat. - Patients also showed increases in AST, ALT, or T/DB. - Increase in ALT lead to patients having dose interruptions (n=2), permanent discontinuation (n=2), or dose modifications (n=1) as shown from clinical studies. - Increased TB above the baseline found in clinical trials can cause a patient to discontinue treatment with Maralixibat. - Monitor patients liver function through liver tests when taking Maralixibat. - Liver-related adverse reactions and elevations in liver tests should be cautioned to patients taking Maralixibat. - Advise patients to discontinue Maralixibat if signs of portal hypertension persist in patients. Gastrointestinal Adverse Reactions - Abdominal pain, vomiting, and diarrhea was reported in patients who take Maralixibat. - 3% of patients in clinical studies who experienced vomiting required hospitalization. - Reduce or interrupt dosages of Maralixibat in patients experiencing abdominal pain, vomiting, and diarrhea. - Monitor patients hydration levels if they display vomiting and diarrhea when taking Maralixibat. - Reduce the dosage from 380 mcg/kg back to 190 mcg/kg/day and slowly increase after abdominal pain, vomiting, or diarrhea in patients has been resolved. - Permanently discontinue use of Maralixibat if abdominal pain, vomiting, or diarrhea continue to be a persist in patients after resolution. Fat-Soluble Vitamin (FSV) Deficiency - Fat-soluble vitamins (vitamin A, D, E, and K) absorption may be affected by use of Maralixibat. - Fat-soluble vitamins deficiency can occur in ALGS patients. - Trial 1 clinical studies show 10% of patients reporting fat-soluble vitamins deficiency - Monitor patients fat-soluble vitamins levels and supplement fat-soluble vitamins when deficiency occurs when taking Maralixibat. - Permanently discontinue use of Maralixibat if fat-soluble vitamins levels do not improve after fat-soluble vitamins supplementation. # Adverse Reactions ## Clinical Trials Experience Clinical Trial Experience - Because clinical trials are conducted under widely varying conditions and durations of follow up, 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. Alagille syndrome clinical development program - This program was comprised of 5 clinical studies that looked into the adverse reactions of 86 patients being treated by Maralixibat. Patients received up to 760 mcg/kg per day of Maralixibat with the program that had a median duration of 32.3 months. 4-week placebo control period occurred in Trial 1 studies after 18 weeks of Maralixibat treatment. 13 weeks of placebo-controlled treatment occurred two long-term, open-label extension studies which specifically looked into patients receiving less than 380 mcg/kg/day dosages of Maralixibat. Dosage reductions and interruptions occurred 6% of patients that displayed vomiting, diarrhea, or abdominal pain in the studies conducted. Table 2 shows Adverse Reactions (≥5%) caused by Maralixibat in ALGS patients. Liver Test Abnormalities - Pooled analysis of ALGS patients showed ALT increases with treatment of Maralixibat. - ALT increases due to Maralixibat led to discontinuation (8.1%), and decreased dosage or dosage interruptions (3.5%) in patients. - Cases of elevations was resolved through dosage modifications, dosage interruptions or no changes in dosage of Maralixibat - 24% of patients showed increases to more than three times the baseline in ALT when using Maralixibat. - 2% of patients showed increases to more than five times the baseline in ALT when using Maralixibat. - 14% of patients showed AST increases to more than three times the baseline when using Maralixibat. - 4.6% of patients showed bilirubin increases above baseline. ## Postmarketing Experience There is limited information about "Postmarketing Experiance" in the drug label. # Drug Interactions Effects of Other Drugs on Maralixibat Bile acid binding resins - In the gut, Maralixibat may bind to bile acid binding resins. - 4 hours before or 4 hours use of Maralixibat may have bile acid binding resins in the gut. Effects of LIVMARLI on Other Drugs OATP2B1 substrates - In vitro studies, Maralixibat can be an OATP2B1 inhibitor. - OATP2B1 inhibition may cause a decrease in the oral absorption of OATP2B1 substrates. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): Clinical studies shows the systematic absorption of Maralixibat in the fetus is low for pregnant women taking the recommended dosage of Maralixibat orally. Fat-soluble vitamins absorption may be inhibited by use of Maralixibat. Studies done on pregnant rats, who received 1000 mg/kg/day of Maralixibat orally, and pregnant rabbits, who received 1000 mg/kg/day of Maralixibat orally, showed no effects were done to embryo development when using Maralixibat during a period of organogenesis. In female rats studies, Maralixibat had no effect on postnatal development when they received 750 mg/kg/day during organogenesis through lactation. Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Maralixibat in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Maralixibat during labor and delivery. ### Nursing Mothers At recommended dosages, use of Maralixibat should not be exposed to the fetus during lactation. No current data has been done on the effects of Maralixibat on the breastfed infant and the effects on milk production in women when treated with Maralixibat. Monitor patients during lactation for fat-soluble vitamins deficiency. ### Pediatric Use Safety and effectiveness of pediatric patients with cholestatic pruritus using Maralixibat has been established in a study. This study included patients ranging from 1 year of age to 15 years of age. There was 18 weeks of open-label treatment that was followed up by a 4 week period of placebo-controlled randomized withdrawal and an immediate open-label treatment period that lasted 26 weeks. 4 studies have provided safety information of patients up to 21 years of age using Maralixibat. ### Geriatic Use The safety and effectiveness of the use of Maralixibat in ALGS patients who are 65 years and older in age for the treatment of pruritus has not been established. ### Gender There is no FDA guidance on the use of Maralixibat with respect to specific gender populations. ### Race There is no FDA guidance on the use of Maralixibat with respect to specific racial populations. ### Renal Impairment There is no FDA guidance on the use of Maralixibat in patients with renal impairment. ### Hepatic Impairment Impaired hepatic function at baseline has been reported in ALGS patients treated with Maralixibat. Clinical studies on safety and effectiveness in both patients who have decompensated cirrhosis and portal hypertension have not been established. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Maralixibat in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance on the use of Maralixibat with respect to immunocompromised populations. # Administration and Monitoring ### Administration - Take recommended dosage as prescribed by the doctor 30 minutes before the first meal of the day. - Patients should use calibrated measuring device from the pharmacy to measure Maralixibat dosage. - If patients are taking a bile acid binding resin, do not take Maralixibat until at least 4 hours before or 4 hours after of the taking of bile acid binding resin. - If a dosage is missed less than 12 hours of scheduled time, take dosage as soon as possible. - If a dosage is missed by more than 12 hours, then skip dosage and take next dosage at scheduled time. ### Monitoring - Monitor patients liver tests throughout treatment with MAralixibat and compare the results to the baseline. - Monitor patients TB, AST, and International Normalized Ratio levels when taking Maralixibat. - Any liver test abnormalities should lead to interruption in Maralixibat dosage. - If liver test abnormalities become stabilized, start patients with 190 mcg/kg of Maralixibat and work dosage back up to 380 mcg/kg if tolerated by patients. - Hepatic decompensation events in patients should lead to permanent discontinuation of Maralixibat treatment. # IV Compatibility There is limited information regarding the compatibility of Maralixibat and IV administrations. # Overdosage - 500 mg, approximately 18-fold higher than the recommended dose, of Maralixibat in a single dose regimen has showed no indications of meaningful increase in adverse reactions in patients when compared to reactions occurring in lower dosage amounts. - Monitor patients signs and symptoms when overdosed on Maralixibat. - Propylene glycol (364.5 mg/mL) is found in Maralixibat. - 50 mg/kg/day and 500 mg/kg/day of propylene glycol are considered safe in the body. - CNS, hyperosmolality, cardiovascular, and/or respiratory effects may be present in patients who overdose on propylene glycol found in Maralixibat. # Pharmacology ## Mechanism of Action - Maralixibat is a reversible inhibitor of the ileal bile acid transporter. - In the terminal ileum, the reabsorption of bile acids is decreased in the presence of Maralixibat. - Inhibition of the ileal bile acid transporter inhibitor may occur in the presence of Maralixibat which can decrease bile salts re-uptake. ## Structure - Maralixibat is an ileal bile acid transporter inhibitor for oral administration. - It has an empirical formula of C40H56ClN3O4S and a molecular weight of 710.42 g/mol. - The chemical name is 1-[4-({4-[(4R,5R)-3,3-Dibutyl-7-(dimethylamino)-4-hydroxy-1,1-dioxido-2,3,4,5-tetrahydro-1-benzothiepin-5-yl]phenoxy}methyl)benzyl]-4-aza-1-azoniabicyclo[2.2.2]octane ## Pharmacodynamics - Trial 1 studies looked into serum bile acids levels in pediatric patients taking Maralixibat. - Pediatric patients with ALGS started an initial 5-week dose-escalation period which was followed by open-label treatment for 13 weeks of 380 mcg/kg of a single daily dosage of Maralixibat. - Patients in the study had serum bile acids levels that ranged from 20 to 749 µmol/L for the baseline. - The mean of serum bile acid level was 283 (210.6) µmol/L of pediatric patients at baseline. - As early as Week 12, patients reported decreases in serum bile acid levels when compared to the baseline. ## Pharmacokinetics Pharmacokinetic Parameters - Pharmacokinetics of Maralixibat is not calculated reliably due to low systemic absorption of Maralixibat. - Maralixibat was below the limit of quantification in pediatric ALGS patients. - Trial 1 studies show 5.93 ng/mL is the highest concentrations of Maralixibat in pediatric patients receiving 380 mcg/kg once daily of Maralixibat. - Plasma concentrations are below the limit of quantification with doses less than 20 mg of Maralixibat in healthy adults. - 0.75 is the median Tmax after patients received a single 30 mg under fasted condition dosage of Maralixibat. - 1.65 (1.10) ng/m is the mean (SD) Cmax after patients received a single 30 mg under fasted condition dosage of Maralixibat. - 3.43 (2.13) ng∙h/mL is the mean (SD) AUClast after patients received a single 30 mg under fasted condition dosage of Maralixibat. Absorption - Plasma concentrations of Maralixibat are below the limit of quantification. - Absorption of Maralixibat is minimally absorbed. - AUClast increased 4.6 fold when looking at patients receiving 30, 45, and 100 mg of Maralixibat once daily under fasted condition. - Cmax increased 2.4 fold when looking at patients receiving 30, 45, and 100 mg of Maralixibat once daily under fasted condition. - Healthy adults receiving up to 100 mg of Maralixibat showed no accumulation. Effect of Food - Patients who eat a high-fat meal showed a decrease in both extent and rate of absorption with concomitant use of Maralixibat. - Changes of systemic exposures by the effect of food in patients taking Maralixibat is not clinically significant. Distribution - In vitro, Maralixibat has a plasma protein binding percentage of 91%. Elimination - The mean half-life is 1.6 hours in patients receiving 30 mg Maralixibat once daily. Metabolism - Plasma had no signs of Maralixibat metabolites. - (14C)Maralixibat orally administered showed <3% of three minor metabolites in total fecal radioactivity. Excretion - Major route of elimination is fecal excretion. - In feces, after oral administration of 5 mg 14C-Maralixibat, 73% of Maralixibat was found in which 94% was found unchanged. - In urine, after oral administration of 5 mg 14C-Maralixibat, 0.066% of Maralixibat was found. Specific Populations Patients with Renal Impairment - The pharmacokinetics of patients who have impaired renal function receiving Maralixibat has not been studied. Drug Interaction Studies Effect of Other Drugs on Maralixibat - Maralixibat for certain drug transporters such as BCRP, OATP1B1, MDR1, OATP2B2, or OATP1B3 is not a substrate. - Disposition of Maralixibat is predicted to not be affected by concomitant drug transporters. Effect of Maralixibat on Other Drugs - In vitro, CYP isoforms 2B6, 3A4, or 1A2 are not induced by Maralixibat. CYP isoforms 2C9, 2C19, 2B6, 1A2, 2D6 or 2C8 are not inhibited by Maralixibat. CYP3A4 is inhibited by Maralixibat, but it is unlikely that the pharmacokinetics of CYP3A4 will have relevant effects. Transporters such as OAT1, OAT3, OATP1B1, OCT1, OCT2, OCT3, OCTN1, BCRP, MRP2, MATE1, MDR1, MATE2-K, or OCTN2 are not inhibited by Maralixibat. - In vitro, Drug transporter OATP2B1 is inhibited by Maralixibat which may reduce absorption for OATP2B1-mediated uptake drugs. - Pharmacokinetics of statins and metabolites have no relevant effect when simvastatin or lovastatin is co-administered with 4.75 mg of Maralixibat. - Pharmacokinetics of atorvastatin is not effected with co-administration of 4.75 mg Maralixibat. - Clinical study is needed to look into the pharmacokinetics of OATP2B1 substrates at higher doses when co-administered with 4.75 mg of Maralixibat to see if Maralixibat has an effect. ## Nonclinical Toxicology Carcinogenesis - TgRasH2 mice did not show any drug-related tumors when taking Maralixibat for 26 weeks. Mutagenesis - In vivo and vitro assays, Maralixibat was negative for mutagenesis. Impairment of Fertility - Female rats who received up to 2000 mg/kg/day of Maralixbat and male rats who received up to 750 mg/kg/day of Maralixibat showed No effects on their fertility when treated with Maralixibat. # Clinical Studies Trial 1 Study - The study conducted included a 4-week randomized, double-blind, placebo-controlled drug-withdrawal period; an 18-week open-label treatment period; and a subsequent 26-week open-label treatment period; and a long-term open-label extension period. The study was made up of 31 ALGS, pediatric patients that had pruritus, the JAGGED Mutation, and cholestasis. The patient population included 66% males with a median of 5 years in age. Patients in the study had a baseline AST level of 158 (68) U/L, baseline ALT of 179 (112) U/L, baseline GGT of 498 (399) U/L, baseline serum bile acid levels of 280 (213) µmol/L, and a baseline TB level of 5.6 (5.4) mg/dL. 90.3% of the patients in the study with pruritus received one medication for treatment of the pruritus. Patients started with a 5-week dose-escalation period that was followed by 13 weeks of Maralixibat at 380 mcg/kg once daily. Two patients in the study discontinued the use of Maralixibat first 18 weeks of open-label treatment dropping the patient population to 29 patients. The 29 patients left were then put in a 4-week drug withdrawal period with the patients either receiving a placebo or continued with Maralixibat. Afterward, all patients received 380 mcg/kg once daily of Maralixibat for 26 more weeks. A 5-point ordinal response scale was used on the pediatric patients that show symptoms of pruritus. The mean baseline score of pruritus is 3.1 in patients pre-treatment with 1.4 as the mean score at Week 18. There was a reduction in pruritus for patients who received Maralixibat for 22 weeks. The baseline score was similar to the score in patients who received the placebo after 18 weeks of Maralixibat. Similar pruritus scores were seen in all patients during the open-label treatment phase. Table 3 shows Patient Pruritus Scores during the Placebo-Controlled Period. # How Supplied - 30 mL of Maralixibat with 9.5 mg of Maralixibat for each mL in the plastic bottle. - Marlixibat is a clear, colorless to yellow liquid that is orally administered in patients. ## Storage - Store at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F). - Advise patients to throw out any Maralixibat remaining after 45 days of first opening the bottle. - Advise patients to put cap back on Maralixibat bottle after daily usage. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information Risks - Advise patients about reported symptoms when taking Maralixibat such as vomiting, diarrhea, dehydration, and abdominal pain. - Advise patients to seek medical attention if symptoms worsen when taking Maralixibat. - Patients have experienced liver test elevations when taking Maralixibat. - Monitor patients liver test results when taking Maralixibat to the baseline. - Advise patients to seek medical attention if liver problems arise such as dark or brown urine and possibly pain on the right side of the abdomen. - Absorption of fat-soluble vitamins may decrease with treatment of Maralixibat. - Monitor patients fat-soluble vitamins levels from start to end of treatment of Maralixibat to make sure no fat-soluble vitamins deficiency is not occurring in the patient. Administration - Maralixibat should be taken 30 minutes before the first meal of the day orally. - Measure dosage of Maralixibat with a calibrated measuring device that will be provided to patients by their pharmacist. - Advise patients to throw out any Maralixibat remaining after 45 days of first opening the bottle. - Patients taking a bile acid binding resin should wait on taking Maralixibat until at least 4 hours before or 4 hours after taking the bile acid binding resin. # Precautions with Alcohol Alcohol-Maralixibat interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - Livmarli # Look-Alike Drug Names There is limited information regarding Maralixibat Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	https://www.wikidoc.org/index.php/Maralixibat
b77c500f27272dcb78760261dc4f4bed8960bffb	wikidoc	Mark I NAAK	Mark I NAAK The Mark I NAAK, or MARK I Kit, is United States military nomenclature for the "Nerve Agent Antidote Kit". It is a dual-chamber auto-injector: Two anti-nerve agent drugs -- atropine sulfate and pralidoxime chloride -- each in injectable form, constitute the kit. The individual using the kit places each injector against his thigh and presses a button, releasing a sprung needle which is designed to penetrate clothing. Typically, U.S. servicemembers are issued three MARK I Kits when operating in circumstances where chemical weapons are considered a potential hazard. Along with the three kits are issued one CANA (Convulsive Antidote, Nerve Agent) for simultaneous use. (CANA is the drug diazepam or Valium, an anticonvulsant.) Both of these kits are intended for use in "buddy aid" or "self aid" administration of the drugs prior to decontamination and delivery of the patient to definitive medical care. A newer model, the ATNAA (Antidote Treatment Nerve Agent Auto-Injector), has both the atropine and the pralidoxime in one syringe, allowing for simplified administration.	Mark I NAAK The Mark I NAAK, or MARK I Kit, is United States military nomenclature for the "Nerve Agent Antidote Kit". It is a dual-chamber auto-injector: Two anti-nerve agent drugs -- atropine sulfate and pralidoxime chloride -- each in injectable form, constitute the kit. The individual using the kit places each injector against his thigh and presses a button, releasing a sprung needle which is designed to penetrate clothing. Typically, U.S. servicemembers are issued three MARK I Kits when operating in circumstances where chemical weapons are considered a potential hazard. Along with the three kits are issued one CANA (Convulsive Antidote, Nerve Agent) for simultaneous use. (CANA is the drug diazepam or Valium, an anticonvulsant.) Both of these kits are intended for use in "buddy aid" or "self aid" administration of the drugs prior to decontamination and delivery of the patient to definitive medical care. A newer model, the ATNAA (Antidote Treatment Nerve Agent Auto-Injector), has both the atropine and the pralidoxime in one syringe, allowing for simplified administration.	https://www.wikidoc.org/index.php/Mark_I_NAAK
d9d2ab3ea95cd4b6ff9d46635ee65b4ea22ae883	wikidoc	Marsupialia	Marsupialia Marsupials are an infraclass of mammals, characterized by a distinctive pouch (called the marsupium), in which females carry their young through early infancy. # History It was once commonly believed that marsupials were a primitive forerunner of modern placental mammals, but fossil evidence, first presented by researcher M.J. Spechtt in 1982, conflicts with this assumption. Instead, both main branches of the mammal tree appear to have evolved concurrently toward the end of the Mesozoic era. The earliest known marsupial is Sinodelphys szalayi, which lived in China around 125 million years ago. This makes it almost contemporary to the earliest placental fossils, which have been found in the same area. Some scientists believe that the marsupials evolved in North America and dispersed from there, via Europe, to Asia and Africa. This diaspora would have also reached South America before it became an island continent. This theory suggests that marsupials passed from South America through Antarctica to Australia (via Gondwanan land connections), a continent already occupied by placental mammals. Alternately, another theory posits that marsupials originated in Australia and traveled, via Antarctica and South America, to North America. The discovery of Chinese marsupials appears to support the idea that marsupials reached Australia via Southeast Asia. However, marsupial fossils found in New Guinea are younger than those in Australia, evidence which presents a problem for this theory. There are a few species of marsupials still living in Asia, especially in the Sulawesi region of Indonesia. These marsupials coexist with primates, hoofed mammals and other placentals. On most continents, placental mammals were much more successful and no marsupials survived, though in South America the opossums retained a strong presence, and the Tertiary saw the genesis of marsupial predators such as the borhyaenids and the saber-toothed Thylacosmilus. In Australia, however, marsupials displaced placental mammals entirely, and have since dominated the Australian ecosystem. Marsupial success over placental mammals in Australia has been attributed to their comparatively low metabolic rate, a trait which would prove helpful in the hot Australian climate. As a result, native Australian placental mammals (such as hopping mice) are more recent immigrants. ## Reproductive system Marsupials reproductive systems differ markedly from those of their placental mammal cousins (Placentalia). Females have two vaginae, both of which open externally through one orifice but lead to different compartments within the uterus. Males generally have a two-pronged penis, which corresponds to the females' two vaginae. The penis is used only for discharging semen into females, and is separate from the urinary tract. Both sexes possess a cloaca, which is connected to a urogenital sac used to store waste before expulsion. Pregnant females develop a kind of yolk sac in their wombs, which delivers nutrients to the embryo. Marsupials give birth at a very early stage of development (about 4-5 weeks); after birth, newborn marsupials crawl up the bodies of their mothers and attach themselves to a nipple, which is located inside the marsupium. There they remain for a number of weeks, attached to the nipple. The offspring are eventually able to leave the marsupium for short periods, returning to it for warmth and nourishment. # Description An early birth removes a developing marsupial from its parent's body much sooner than in placental mammals, and thus marsupials have not developed a complex placenta to protect the embryo from its mother's immune system. Though early birth places the tiny newborn marsupial at a greater environmental risk, it significantly reduces the dangers associated with long pregnancies, as there is no need to carry a large fetus to full-term in bad seasons. Because newborn marsupials must climb up to their mother's nipples, their front limbs are much more developed than the rest of the body at the time of birth. It is possible that this requirement has resulted in the limited range of locomotor adaptations in marsupials compared to placentals. All marsupials must develop a grasping forepaw during their early youth, making the transition from this limb into a hoof, wing, or flipper, as some groups of placental mammals have done, far more difficult. There are about 334 species of marsupial, and over 200 are native to Australia and neighboring northern islands. There are also 100 extant American species; these are centered mostly in South America, but the Great American Interchange has provided Central America with 13 species, and North America with one (the Virginia Opossum). # Taxonomy In taxonomy, there are two primary divisions of Marsupialia: American marsupials and the Australian marsupials. The Order Microbiotheria (which has only one species, the Monito del Monte) is found in South America but is believed to be more closely related to the Australian marsupials. There are many small arboreal species in each group. The term opossums is properly used to refer to the American species (though possum is a common diminutive), while similar Australian species are properly called possums. - Superorder Ameridelphia Order Didelphimorphia (93 species) Family Didelphidae: opossums Order Paucituberculata (6 species) Family Caenolestidae: shrew opossums - Order Didelphimorphia (93 species) Family Didelphidae: opossums - Family Didelphidae: opossums - Order Paucituberculata (6 species) Family Caenolestidae: shrew opossums - Family Caenolestidae: shrew opossums - Superorder Australidelphia Order †Yalkaparidontia Order Microbiotheria (1 species) Family Microbiotheriidae: Monito del Monte Order Dasyuromorphia (71 species) Family †Thylacinidae: Thylacine Family Dasyuridae: antechinuses, quolls, dunnarts, Tasmanian Devil, and relatives Family Myrmecobiidae: Numbat Order Peramelemorphia (24 species) Family Thylacomyidae: bilbies Family †Chaeropodidae: Pig-footed Bandicoot Family Peramelidae: bandicoots and allies Order Notoryctemorphia (2 species) Family Notoryctidae: marsupial moles Order Diprotodontia (137 species) Family Phascolarctidae: Koala Family Vombatidae: wombats Family †Diprotodontidae: diprotodon Family Phalangeridae: brushtail possums and cuscuses Family Burramyidae: pygmy possums Family Tarsipedidae: Honey Possum Family Petauridae: Striped Possum, Leadbeater's Possum, Yellow-bellied Glider, Sugar Glider, Mahogany Glider, Squirrel Glider Family Pseudocheiridae: ringtailed possums and relatives Family Potoridae: potoroos, rat kangaroos, bettongs Family Acrobatidae: Feathertail Glider and Feather-tailed Possum Family Hypsiprymnodontidae: Musky Rat-kangaroo Family Macropodidae: kangaroos, wallabies, and relatives Family †Thylacoleonidae: marsupial lions Order †Sparassodonta - Order †Yalkaparidontia - Order Microbiotheria (1 species) Family Microbiotheriidae: Monito del Monte - Family Microbiotheriidae: Monito del Monte - Order Dasyuromorphia (71 species) Family †Thylacinidae: Thylacine Family Dasyuridae: antechinuses, quolls, dunnarts, Tasmanian Devil, and relatives Family Myrmecobiidae: Numbat - Family †Thylacinidae: Thylacine - Family Dasyuridae: antechinuses, quolls, dunnarts, Tasmanian Devil, and relatives - Family Myrmecobiidae: Numbat - Order Peramelemorphia (24 species) Family Thylacomyidae: bilbies Family †Chaeropodidae: Pig-footed Bandicoot Family Peramelidae: bandicoots and allies - Family Thylacomyidae: bilbies - Family †Chaeropodidae: Pig-footed Bandicoot - Family Peramelidae: bandicoots and allies - Order Notoryctemorphia (2 species) Family Notoryctidae: marsupial moles - Family Notoryctidae: marsupial moles - Order Diprotodontia (137 species) Family Phascolarctidae: Koala Family Vombatidae: wombats Family †Diprotodontidae: diprotodon Family Phalangeridae: brushtail possums and cuscuses Family Burramyidae: pygmy possums Family Tarsipedidae: Honey Possum Family Petauridae: Striped Possum, Leadbeater's Possum, Yellow-bellied Glider, Sugar Glider, Mahogany Glider, Squirrel Glider Family Pseudocheiridae: ringtailed possums and relatives Family Potoridae: potoroos, rat kangaroos, bettongs Family Acrobatidae: Feathertail Glider and Feather-tailed Possum Family Hypsiprymnodontidae: Musky Rat-kangaroo Family Macropodidae: kangaroos, wallabies, and relatives Family †Thylacoleonidae: marsupial lions - Family Phascolarctidae: Koala - Family Vombatidae: wombats - Family †Diprotodontidae: diprotodon - Family Phalangeridae: brushtail possums and cuscuses - Family Burramyidae: pygmy possums - Family Tarsipedidae: Honey Possum - Family Petauridae: Striped Possum, Leadbeater's Possum, Yellow-bellied Glider, Sugar Glider, Mahogany Glider, Squirrel Glider - Family Pseudocheiridae: ringtailed possums and relatives - Family Potoridae: potoroos, rat kangaroos, bettongs - Family Acrobatidae: Feathertail Glider and Feather-tailed Possum - Family Hypsiprymnodontidae: Musky Rat-kangaroo - Family Macropodidae: kangaroos, wallabies, and relatives - Family †Thylacoleonidae: marsupial lions - Order †Sparassodonta † indicates extinction	Marsupialia Template:Otheruses4 Marsupials are an infraclass of mammals, characterized by a distinctive pouch (called the marsupium), in which females carry their young through early infancy. # History It was once commonly believed that marsupials were a primitive forerunner of modern placental mammals, but fossil evidence, first presented by researcher M.J. Spechtt in 1982, conflicts with this assumption[citation needed]. Instead, both main branches of the mammal tree appear to have evolved concurrently toward the end of the Mesozoic era. The earliest known marsupial is Sinodelphys szalayi, which lived in China around 125 million years ago. This makes it almost contemporary to the earliest placental fossils, which have been found in the same area. Some scientists believe that the marsupials evolved in North America and dispersed from there, via Europe, to Asia and Africa. This diaspora would have also reached South America before it became an island continent. This theory suggests that marsupials passed from South America through Antarctica to Australia (via Gondwanan land connections), a continent already occupied by placental mammals. Alternately, another theory posits that marsupials originated in Australia and traveled, via Antarctica and South America, to North America. The discovery of Chinese marsupials appears to support the idea that marsupials reached Australia via Southeast Asia. However, marsupial fossils found in New Guinea are younger than those in Australia, evidence which presents a problem for this theory. There are a few species of marsupials still living in Asia, especially in the Sulawesi region of Indonesia. These marsupials coexist with primates, hoofed mammals and other placentals.[citation needed] On most continents, placental mammals were much more successful and no marsupials survived, though in South America the opossums retained a strong presence, and the Tertiary saw the genesis of marsupial predators such as the borhyaenids and the saber-toothed Thylacosmilus. In Australia, however, marsupials displaced placental mammals entirely, and have since dominated the Australian ecosystem. Marsupial success over placental mammals in Australia has been attributed to their comparatively low metabolic rate, a trait which would prove helpful in the hot Australian climate.[citation needed] As a result, native Australian placental mammals (such as hopping mice) are more recent immigrants. ## Reproductive system Marsupials reproductive systems differ markedly from those of their placental mammal cousins (Placentalia). Females have two vaginae, both of which open externally through one orifice but lead to different compartments within the uterus. Males generally have a two-pronged penis, which corresponds to the females' two vaginae.[3] The penis is used only for discharging semen into females, and is separate from the urinary tract.[citation needed] Both sexes possess a cloaca[3], which is connected to a urogenital sac used to store waste before expulsion. Pregnant females develop a kind of yolk sac in their wombs, which delivers nutrients to the embryo. Marsupials give birth at a very early stage of development (about 4-5 weeks); after birth, newborn marsupials crawl up the bodies of their mothers and attach themselves to a nipple, which is located inside the marsupium. There they remain for a number of weeks, attached to the nipple. The offspring are eventually able to leave the marsupium for short periods, returning to it for warmth and nourishment. # Description An early birth removes a developing marsupial from its parent's body much sooner than in placental mammals, and thus marsupials have not developed a complex placenta to protect the embryo from its mother's immune system. Though early birth places the tiny newborn marsupial at a greater environmental risk, it significantly reduces the dangers associated with long pregnancies, as there is no need to carry a large fetus to full-term in bad seasons. Because newborn marsupials must climb up to their mother's nipples, their front limbs are much more developed than the rest of the body at the time of birth. It is possible that this requirement has resulted in the limited range of locomotor adaptations in marsupials compared to placentals. All marsupials must develop a grasping forepaw during their early youth, making the transition from this limb into a hoof, wing, or flipper, as some groups of placental mammals have done, far more difficult. There are about 334 species of marsupial, and over 200 are native to Australia and neighboring northern islands. There are also 100 extant American species; these are centered mostly in South America, but the Great American Interchange has provided Central America with 13 species, and North America with one (the Virginia Opossum). # Taxonomy In taxonomy, there are two primary divisions of Marsupialia: American marsupials and the Australian marsupials.[1][2] The Order Microbiotheria (which has only one species, the Monito del Monte) is found in South America but is believed to be more closely related to the Australian marsupials. There are many small arboreal species in each group. The term opossums is properly used to refer to the American species (though possum is a common diminutive), while similar Australian species are properly called possums. - Superorder Ameridelphia Order Didelphimorphia (93 species) Family Didelphidae: opossums Order Paucituberculata (6 species) Family Caenolestidae: shrew opossums - Order Didelphimorphia (93 species) Family Didelphidae: opossums - Family Didelphidae: opossums - Order Paucituberculata (6 species) Family Caenolestidae: shrew opossums - Family Caenolestidae: shrew opossums - Superorder Australidelphia Order †Yalkaparidontia Order Microbiotheria (1 species) Family Microbiotheriidae: Monito del Monte Order Dasyuromorphia (71 species) Family †Thylacinidae: Thylacine Family Dasyuridae: antechinuses, quolls, dunnarts, Tasmanian Devil, and relatives Family Myrmecobiidae: Numbat Order Peramelemorphia (24 species) Family Thylacomyidae: bilbies Family †Chaeropodidae: Pig-footed Bandicoot Family Peramelidae: bandicoots and allies Order Notoryctemorphia (2 species) Family Notoryctidae: marsupial moles Order Diprotodontia (137 species) Family Phascolarctidae: Koala Family Vombatidae: wombats Family †Diprotodontidae: diprotodon Family Phalangeridae: brushtail possums and cuscuses Family Burramyidae: pygmy possums Family Tarsipedidae: Honey Possum Family Petauridae: Striped Possum, Leadbeater's Possum, Yellow-bellied Glider, Sugar Glider, Mahogany Glider, Squirrel Glider Family Pseudocheiridae: ringtailed possums and relatives Family Potoridae: potoroos, rat kangaroos, bettongs Family Acrobatidae: Feathertail Glider and Feather-tailed Possum Family Hypsiprymnodontidae: Musky Rat-kangaroo Family Macropodidae: kangaroos, wallabies, and relatives Family †Thylacoleonidae: marsupial lions Order †Sparassodonta - Order †Yalkaparidontia - Order Microbiotheria (1 species) Family Microbiotheriidae: Monito del Monte - Family Microbiotheriidae: Monito del Monte - Order Dasyuromorphia (71 species) Family †Thylacinidae: Thylacine Family Dasyuridae: antechinuses, quolls, dunnarts, Tasmanian Devil, and relatives Family Myrmecobiidae: Numbat - Family †Thylacinidae: Thylacine - Family Dasyuridae: antechinuses, quolls, dunnarts, Tasmanian Devil, and relatives - Family Myrmecobiidae: Numbat - Order Peramelemorphia (24 species) Family Thylacomyidae: bilbies Family †Chaeropodidae: Pig-footed Bandicoot Family Peramelidae: bandicoots and allies - Family Thylacomyidae: bilbies - Family †Chaeropodidae: Pig-footed Bandicoot - Family Peramelidae: bandicoots and allies - Order Notoryctemorphia (2 species) Family Notoryctidae: marsupial moles - Family Notoryctidae: marsupial moles - Order Diprotodontia (137 species) Family Phascolarctidae: Koala Family Vombatidae: wombats Family †Diprotodontidae: diprotodon Family Phalangeridae: brushtail possums and cuscuses Family Burramyidae: pygmy possums Family Tarsipedidae: Honey Possum Family Petauridae: Striped Possum, Leadbeater's Possum, Yellow-bellied Glider, Sugar Glider, Mahogany Glider, Squirrel Glider Family Pseudocheiridae: ringtailed possums and relatives Family Potoridae: potoroos, rat kangaroos, bettongs Family Acrobatidae: Feathertail Glider and Feather-tailed Possum Family Hypsiprymnodontidae: Musky Rat-kangaroo Family Macropodidae: kangaroos, wallabies, and relatives Family †Thylacoleonidae: marsupial lions - Family Phascolarctidae: Koala - Family Vombatidae: wombats - Family †Diprotodontidae: diprotodon - Family Phalangeridae: brushtail possums and cuscuses - Family Burramyidae: pygmy possums - Family Tarsipedidae: Honey Possum - Family Petauridae: Striped Possum, Leadbeater's Possum, Yellow-bellied Glider, Sugar Glider, Mahogany Glider, Squirrel Glider - Family Pseudocheiridae: ringtailed possums and relatives - Family Potoridae: potoroos, rat kangaroos, bettongs - Family Acrobatidae: Feathertail Glider and Feather-tailed Possum - Family Hypsiprymnodontidae: Musky Rat-kangaroo - Family Macropodidae: kangaroos, wallabies, and relatives - Family †Thylacoleonidae: marsupial lions - Order †Sparassodonta † indicates extinction	https://www.wikidoc.org/index.php/Marsupialia
c45ffe96a70dcb20eceb4e2682160fb8dbaae015	wikidoc	Mathematics	Mathematics Mathematics (colloquially, maths or math) is the body of knowledge centered on such concepts as quantity, structure, space, and change, and also the academic discipline that studies them. Benjamin Peirce called it "the science that draws necessary conclusions". Other practitioners of mathematics maintain that mathematics is the science of pattern, that mathematicians seek out patterns whether found in numbers, space, science, computers, imaginary abstractions, or elsewhere. Mathematicians explore such concepts, aiming to formulate new conjectures and establish their truth by rigorous deduction from appropriately chosen axioms and definitions. Through the use of abstraction and logical reasoning, mathematics evolved from counting, calculation, measurement, and the systematic study of the shapes and motions of physical objects. Knowledge and use of basic mathematics have always been an inherent and integral part of individual and group life. Refinements of the basic ideas are visible in mathematical texts originating in ancient Egypt, Mesopotamia, ancient India, ancient China, and ancient Greece. Rigorous arguments first appear in Euclid's Elements. The development continued in fitful bursts until the Renaissance period of the 16th century, when mathematical innovations interacted with new scientific discoveries, leading to an acceleration in research that continues to the present day. Today, mathematics is used throughout the world in many fields, including natural science, engineering, medicine, and the social sciences such as economics. Applied mathematics, the application of mathematics to such fields, inspires and makes use of new mathematical discoveries and sometimes leads to the development of entirely new disciplines. Mathematicians also engage in pure mathematics, or mathematics for its own sake, without having any application in mind, although applications for what began as pure mathematics are often discovered later. # Etymology The word "mathematics" (Greek: μαθηματικά or mathēmatiká) comes from the Greek μάθημα (máthēma), which means learning, study, science, and additionally came to have the narrower and more technical meaning "mathematical study", even in Classical times. Its adjective is μαθηματικός (mathēmatikós), related to learning, or studious, which likewise further came to mean mathematical. In particular, Template:Polytonic (mathēmatikḗ tékhnē), in Latin ars mathematica, meant the mathematical art. The apparent plural form in English, like the French plural form les mathématiques (and the less commonly used singular derivative la mathématique), goes back to the Latin neuter plural mathematica (Cicero), based on the Greek plural τα μαθηματικά (ta mathēmatiká), used by Aristotle, and meaning roughly "all things mathematical". In English, however, mathematics is a singular noun, often shortened to math in English-speaking North America and maths elsewhere. # History The evolution of mathematics might be seen as an ever-increasing series of abstractions, or alternatively an expansion of subject matter. The first abstraction was probably that of numbers. The realization that two apples and two oranges have something in common was a breakthrough in human thought. In addition to recognizing how to count physical objects, prehistoric peoples also recognized how to count abstract quantities, like time — days, seasons, years. Arithmetic (addition, subtraction, multiplication and division), naturally followed. Monolithic monuments testify to knowledge of geometry. Further steps need writing or some other system for recording numbers such as tallies or the knotted strings called quipu used by the Inca empire to store numerical data. Numeral systems have been many and diverse. From the beginnings of recorded history, the major disciplines within mathematics arose out of the need to do calculations relating to taxation and commerce, to understand the relationships among numbers, to measure land, and to predict astronomical events. These needs can be roughly related to the broad subdivision of mathematics into the studies of quantity, structure, space, and change. Mathematics has since been greatly extended, and there has been a fruitful interaction between mathematics and science, to the benefit of both. Mathematical discoveries have been made throughout history and continue to be made today. According to Mikhail B. Sevryuk, in the January 2006 issue of the Bulletin of the American Mathematical Society, "The number of papers and books included in the Mathematical Reviews database since 1940 (the first year of operation of MR) is now more than 1.9 million, and more than 75 thousand items are added to the database each year. The overwhelming majority of works in this ocean contain new mathematical theorems and their proofs." # Inspiration, pure and applied mathematics, and aesthetics Mathematics arises wherever there are difficult problems that involve quantity, structure, space, or change. At first these were found in commerce, land measurement and later astronomy; nowadays, all sciences suggest problems studied by mathematicians, and many problems arise within mathematics itself. Newton was one of the infinitesimal calculus inventors, although nearly all of the notation used in infinitesimal calculus was contributed by Leibniz with the exception of a dot above a variable to signify differentiation with respect to time. Feynman invented the Feynman path integral using a combination of reasoning and physical insight, and today's string theory also inspires new mathematics. Some mathematics is only relevant in the area that inspired it, and is applied to solve further problems in that area. But often mathematics inspired by one area proves useful in many areas, and joins the general stock of mathematical concepts. The remarkable fact that even the "purest" mathematics often turns out to have practical applications is what Eugene Wigner has called "the unreasonable effectiveness of mathematics." As in most areas of study, the explosion of knowledge in the scientific age has led to specialization in mathematics. One major distinction is between pure mathematics and applied mathematics. Several areas of applied mathematics have merged with related traditions outside of mathematics and become disciplines in their own right, including statistics, operations research, and computer science. For those who are mathematically inclined, there is often a definite aesthetic aspect to much of mathematics. Many mathematicians talk about the elegance of mathematics, its intrinsic aesthetics and inner beauty. Simplicity and generality are valued. There is beauty in a simple and elegant proof, such as Euclid's proof that there are infinitely many prime numbers, and in an elegant numerical method that speeds calculation, such as the fast Fourier transform. G. H. Hardy in A Mathematician's Apology expressed the belief that these aesthetic considerations are, in themselves, sufficient to justify the study of pure mathematics. Mathematicians often strive to find proofs of theorems that are particularly elegant, a quest Paul Erdős often referred to as finding proofs from "The Book" in which God had written down his favorite proofs. The popularity of recreational mathematics is another sign of the pleasure many find in solving mathematical questions. # Notation, language, and rigor Most of the mathematical notation in use today was not invented until the 16th century. Before that, mathematics was written out in words, a painstaking process that limited mathematical discovery. Modern notation makes mathematics much easier for the professional, but beginners often find it daunting. It is extremely compressed: a few symbols contain a great deal of information. Like musical notation, modern mathematical notation has a strict syntax and encodes information that would be difficult to write in any other way. Mathematical language also is hard for beginners. Words such as or and only have more precise meanings than in everyday speech. Also confusing to beginners, words such as open and field have been given specialized mathematical meanings. Mathematical jargon includes technical terms such as homeomorphism and integrable. But there is a reason for special notation and technical jargon: mathematics requires more precision than everyday speech. Mathematicians refer to this precision of language and logic as "rigor". Rigor is fundamentally a matter of mathematical proof. Mathematicians want their theorems to follow from axioms by means of systematic reasoning. This is to avoid mistaken "theorems", based on fallible intuitions, of which many instances have occurred in the history of the subject. The level of rigor expected in mathematics has varied over time: the Greeks expected detailed arguments, but at the time of Isaac Newton the methods employed were less rigorous. Problems inherent in the definitions used by Newton would lead to a resurgence of careful analysis and formal proof in the 19th century. Today, mathematicians continue to argue among themselves about computer-assisted proofs. Since large computations are hard to verify, such proofs may not be sufficiently rigorous. Axioms in traditional thought were "self-evident truths", but that conception is problematic. At a formal level, an axiom is just a string of symbols, which has an intrinsic meaning only in the context of all derivable formulas of an axiomatic system. It was the goal of Hilbert's program to put all of mathematics on a firm axiomatic basis, but according to Gödel's incompleteness theorem every (sufficiently powerful) axiomatic system has undecidable formulas; and so a final axiomatization of mathematics is impossible. Nonetheless mathematics is often imagined to be (as far as its formal content) nothing but set theory in some axiomatization, in the sense that every mathematical statement or proof could be cast into formulas within set theory. # Mathematics as science Carl Friedrich Gauss referred to mathematics as "the Queen of the Sciences". In the original Latin Regina Scientiarum, as well as in German Königin der Wissenschaften, the word corresponding to science means (field of) knowledge. Indeed, this is also the original meaning in English, and there is no doubt that mathematics is in this sense a science. The specialization restricting the meaning to natural science is of later date. If one considers science to be strictly about the physical world, then mathematics, or at least pure mathematics, is not a science. Albert Einstein has stated that "as far as the laws of mathematics refer to reality, they are not certain; and as far as they are certain, they do not refer to reality." Many philosophers believe that mathematics is not experimentally falsifiable, and thus not a science according to the definition of Karl Popper. However, in the 1930s important work in mathematical logic showed that mathematics cannot be reduced to logic, and Karl Popper concluded that "most mathematical theories are, like those of physics and biology, hypothetico-deductive: pure mathematics therefore turns out to be much closer to the natural sciences whose hypotheses are conjectures, than it seemed even recently." Other thinkers, notably Imre Lakatos, have applied a version of falsificationism to mathematics itself. An alternative view is that certain scientific fields (such as theoretical physics) are mathematics with axioms that are intended to correspond to reality. In fact, the theoretical physicist, J. M. Ziman, proposed that science is public knowledge and thus includes mathematics. In any case, mathematics shares much in common with many fields in the physical sciences, notably the exploration of the logical consequences of assumptions. Intuition and experimentation also play a role in the formulation of conjectures in both mathematics and the (other) sciences. Experimental mathematics continues to grow in importance within mathematics, and computation and simulation are playing an increasing role in both the sciences and mathematics, weakening the objection that mathematics does not use the scientific method. In his 2002 book A New Kind of Science, Stephen Wolfram argues that computational mathematics deserves to be explored empirically as a scientific field in its own right. The opinions of mathematicians on this matter are varied. While some in applied mathematics feel that they are scientists, those in pure mathematics often feel that they are working in an area more akin to logic and that they are, hence, fundamentally philosophers. Many mathematicians feel that to call their area a science is to downplay the importance of its aesthetic side, and its history in the traditional seven liberal arts; others feel that to ignore its connection to the sciences is to turn a blind eye to the fact that the interface between mathematics and its applications in science and engineering has driven much development in mathematics. One way this difference of viewpoint plays out is in the philosophical debate as to whether mathematics is created (as in art) or discovered (as in science). It is common to see universities divided into sections that include a division of Science and Mathematics, indicating that the fields are seen as being allied but that they do not coincide. In practice, mathematicians are typically grouped with scientists at the gross level but separated at finer levels. This is one of many issues considered in the philosophy of mathematics. Mathematical awards are generally kept separate from their equivalents in science. The most prestigious award in mathematics is the Fields Medal, established in 1936 and now awarded every 4 years. It is often considered, misleadingly, the equivalent of science's Nobel Prizes. The Wolf Prize in Mathematics, instituted in 1979, recognizes lifetime achievement, and another major international award, the Abel Prize, was introduced in 2003. These are awarded for a particular body of work, which may be innovation, or resolution of an outstanding problem in an established field. A famous list of 23 such open problems, called "Hilbert's problems", was compiled in 1900 by German mathematician David Hilbert. This list achieved great celebrity among mathematicians, and at least nine of the problems have now been solved. A new list of seven important problems, titled the "Millennium Prize Problems", was published in 2000. Solution of each of these problems carries a $1 million reward, and only one (the Riemann hypothesis) is duplicated in Hilbert's problems. # Fields of mathematics As noted above, the major disciplines within mathematics first arose out of the need to do calculations in commerce, to understand the relationships between numbers, to measure land, and to predict astronomical events. These four needs can be roughly related to the broad subdivision of mathematics into the study of quantity, structure, space, and change (i.e., arithmetic, algebra, geometry, and analysis). In addition to these main concerns, there are also subdivisions dedicated to exploring links from the heart of mathematics to other fields: to logic, to set theory (foundations), to the empirical mathematics of the various sciences (applied mathematics), and more recently to the rigorous study of uncertainty. ## Quantity The study of quantity starts with numbers, first the familiar natural numbers and integers ("whole numbers") and arithmetical operations on them, which are characterized in arithmetic. The deeper properties of integers are studied in number theory, whence such popular results as Fermat's last theorem. Number theory also holds two widely-considered unsolved problems: the twin prime conjecture and Goldbach's conjecture. As the number system is further developed, the integers are recognized as a subset of the rational numbers ("fractions"). These, in turn, are contained within the real numbers, which are used to represent continuous quantities. Real numbers are generalized to complex numbers. These are the first steps of a hierarchy of numbers that goes on to include quarternions and octonions. Consideration of the natural numbers also leads to the transfinite numbers, which formalize the concept of counting to infinity. Another area of study is size, which leads to the cardinal numbers and then to another conception of infinity: the aleph numbers, which allow meaningful comparison of the size of infinitely large sets. ## Structure Many mathematical objects, such as sets of numbers and functions, exhibit internal structure. The structural properties of these objects are investigated in the study of groups, rings, fields and other abstract systems, which are themselves such objects. This is the field of abstract algebra. An important concept here is that of vectors, generalized to vector spaces, and studied in linear algebra. The study of vectors combines three of the fundamental areas of mathematics: quantity, structure, and space. Vector calculus expands the field into a fourth fundamental area, that of change. ## Space The study of space originates with geometry - in particular, Euclidean geometry. Trigonometry combines space and numbers, and encompasses the well-known Pythagorean theorem. The modern study of space generalizes these ideas to include higher-dimensional geometry, non-Euclidean geometries (which play a central role in general relativity) and topology. Quantity and space both play a role in analytic geometry, differential geometry, and algebraic geometry. Within differential geometry are the concepts of fiber bundles and calculus on manifolds. Within algebraic geometry is the description of geometric objects as solution sets of polynomial equations, combining the concepts of quantity and space, and also the study of topological groups, which combine structure and space. Lie groups are used to study space, structure, and change. Topology in all its many ramifications may have been the greatest growth area in 20th century mathematics, and includes the long-standing Poincaré conjecture and the controversial four color theorem, whose only proof, by computer, has never been verified by a human. ## Change Understanding and describing change is a common theme in the natural sciences, and calculus was developed as a powerful tool to investigate it. Functions arise here, as a central concept describing a changing quantity. The rigorous study of real numbers and real-valued functions is known as real analysis, with complex analysis the equivalent field for the complex numbers. The Riemann hypothesis, one of the most fundamental open questions in mathematics, is drawn from complex analysis. Functional analysis focuses attention on (typically infinite-dimensional) spaces of functions. One of many applications of functional analysis is quantum mechanics. Many problems lead naturally to relationships between a quantity and its rate of change, and these are studied as differential equations. Many phenomena in nature can be described by dynamical systems; chaos theory makes precise the ways in which many of these systems exhibit unpredictable yet still deterministic behavior. ## Foundations and philosophy In order to clarify the foundations of mathematics, the fields of mathematical logic and set theory were developed, as well as category theory which is still in development. Mathematical logic is concerned with setting mathematics on a rigid axiomatic framework, and studying the results of such a framework. As such, it is home to Gödel's second incompleteness theorem, perhaps the most widely celebrated result in logic, which (informally) implies that any formal system that contains basic arithmetic, if sound (meaning that all theorems that can be proven are true), is necessarily incomplete (meaning that there are true theorems which cannot be proved in that system). Gödel showed how to construct, whatever the given collection of number-theoretical axioms, a formal statement in the logic that is a true number-theoretical fact, but which does not follow from those axioms. Therefore no formal system is a true axiomatization of full number theory. Modern logic is divided into recursion theory, model theory, and proof theory, and is closely linked to theoretical computer science. ## Discrete mathematics Discrete mathematics is the common name for the fields of mathematics most generally useful in theoretical computer science. This includes computability theory, computational complexity theory, and information theory. Computability theory examines the limitations of various theoretical models of the computer, including the most powerful known model - the Turing machine. Complexity theory is the study of tractability by computer; some problems, although theoretically solvable by computer, are so expensive in terms of time or space that solving them is likely to remain practically unfeasible, even with rapid advance of computer hardware. Finally, information theory is concerned with the amount of data that can be stored on a given medium, and hence concepts such as compression and entropy. As a relatively new field, discrete mathematics has a number of fundamental open problems. The most famous of these is the "P=NP?" problem, one of the Millennium Prize Problems. ## Applied mathematics Applied mathematics considers the use of abstract mathematical tools in solving concrete problems in the sciences, business, and other areas. An important field in applied mathematics is statistics, which uses probability theory as a tool and allows the description, analysis, and prediction of phenomena where chance plays a role. Most experiments, surveys and observational studies require the informed use of statistics. (Many statisticians, however, do not consider themselves to be mathematicians, but rather part of an allied group.) Numerical analysis investigates computational methods for efficiently solving a broad range of mathematical problems that are typically too large for human numerical capacity; it includes the study of rounding errors or other sources of error in computation. # Common misconceptions Mathematics is not a closed intellectual system, in which everything has already been worked out. There is no shortage of open problems. Mathematicians publish many thousands of papers embodying new discoveries in mathematics every month. Mathematics is not numerology, nor is it accountancy; nor is it restricted to arithmetic. Pseudomathematics is a form of mathematics-like activity undertaken outside academia, and occasionally by mathematicians themselves. It often consists of determined attacks on famous questions, consisting of proof-attempts made in an isolated way (that is, long papers not supported by previously published theory). The relationship to generally-accepted mathematics is similar to that between pseudoscience and real science. The misconceptions involved are normally based on: - misunderstanding of the implications of mathematical rigor; - attempts to circumvent the usual criteria for publication of mathematical papers in a learned journal after peer review, often in the belief that the journal is biased against the author; - lack of familiarity with, and therefore underestimation of, the existing literature. The case of Kurt Heegner's work shows that the mathematical establishment is neither infallible, nor unwilling to admit error in assessing 'amateur' work. And like astronomy, mathematics owes much to amateur contributors such as Fermat and Mersenne. ## Mathematics and physical reality Mathematical concepts and theorems need not correspond to anything in the physical world. Insofar as a correspondence does exist, while mathematicians and physicists may select axioms and postulates that seem reasonable and intuitive, it is not necessary for the basic assumptions within an axiomatic system to be true in an empirical or physical sense. Thus, while most systems of axioms are derived from our perceptions and experiments, they are not dependent on them. For example, we could say that the physical concept of two apples may be accurately modeled by the natural number 2. On the other hand, we could also say that the natural numbers are not an accurate model because there is no standard "unit" apple and no two apples are exactly alike. The modeling idea is further complicated by the possibility of fractional or partial apples. So while it may be instructive to visualize the axiomatic definition of the natural numbers as collections of apples, the definition itself is not dependent upon nor derived from any actual physical entities. Nevertheless, mathematics remains extremely useful for solving real-world problems. This fact led Eugene Wigner to write an essay, The Unreasonable Effectiveness of Mathematics in the Natural Sciences.	Mathematics Mathematics (colloquially, maths or math) is the body of knowledge centered on such concepts as quantity, structure, space, and change, and also the academic discipline that studies them. Benjamin Peirce called it "the science that draws necessary conclusions".[2] Other practitioners of mathematics[3][4] maintain that mathematics is the science of pattern, that mathematicians seek out patterns whether found in numbers, space, science, computers, imaginary abstractions, or elsewhere. Mathematicians explore such concepts, aiming to formulate new conjectures and establish their truth by rigorous deduction from appropriately chosen axioms and definitions.[5] Through the use of abstraction and logical reasoning, mathematics evolved from counting, calculation, measurement, and the systematic study of the shapes and motions of physical objects. Knowledge and use of basic mathematics have always been an inherent and integral part of individual and group life. Refinements of the basic ideas are visible in mathematical texts originating in ancient Egypt, Mesopotamia, ancient India, ancient China, and ancient Greece. Rigorous arguments first appear in Euclid's Elements. The development continued in fitful bursts until the Renaissance period of the 16th century, when mathematical innovations interacted with new scientific discoveries, leading to an acceleration in research that continues to the present day.[6] Today, mathematics is used throughout the world in many fields, including natural science, engineering, medicine, and the social sciences such as economics. Applied mathematics, the application of mathematics to such fields, inspires and makes use of new mathematical discoveries and sometimes leads to the development of entirely new disciplines. Mathematicians also engage in pure mathematics, or mathematics for its own sake, without having any application in mind, although applications for what began as pure mathematics are often discovered later.[7] # Etymology The word "mathematics" (Greek: μαθηματικά or mathēmatiká) comes from the Greek μάθημα (máthēma), which means learning, study, science, and additionally came to have the narrower and more technical meaning "mathematical study", even in Classical times. Its adjective is μαθηματικός (mathēmatikós), related to learning, or studious, which likewise further came to mean mathematical. In particular, Template:Polytonic (mathēmatikḗ tékhnē), in Latin ars mathematica, meant the mathematical art. The apparent plural form in English, like the French plural form les mathématiques (and the less commonly used singular derivative la mathématique), goes back to the Latin neuter plural mathematica (Cicero), based on the Greek plural τα μαθηματικά (ta mathēmatiká), used by Aristotle, and meaning roughly "all things mathematical".[8] In English, however, mathematics is a singular noun, often shortened to math in English-speaking North America and maths elsewhere. # History The evolution of mathematics might be seen as an ever-increasing series of abstractions, or alternatively an expansion of subject matter. The first abstraction was probably that of numbers. The realization that two apples and two oranges have something in common was a breakthrough in human thought. In addition to recognizing how to count physical objects, prehistoric peoples also recognized how to count abstract quantities, like time — days, seasons, years. Arithmetic (addition, subtraction, multiplication and division), naturally followed. Monolithic monuments testify to knowledge of geometry. Further steps need writing or some other system for recording numbers such as tallies or the knotted strings called quipu used by the Inca empire to store numerical data. Numeral systems have been many and diverse. From the beginnings of recorded history, the major disciplines within mathematics arose out of the need to do calculations relating to taxation and commerce, to understand the relationships among numbers, to measure land, and to predict astronomical events. These needs can be roughly related to the broad subdivision of mathematics into the studies of quantity, structure, space, and change. Mathematics has since been greatly extended, and there has been a fruitful interaction between mathematics and science, to the benefit of both. Mathematical discoveries have been made throughout history and continue to be made today. According to Mikhail B. Sevryuk, in the January 2006 issue of the Bulletin of the American Mathematical Society, "The number of papers and books included in the Mathematical Reviews database since 1940 (the first year of operation of MR) is now more than 1.9 million, and more than 75 thousand items are added to the database each year. The overwhelming majority of works in this ocean contain new mathematical theorems and their proofs."[9] # Inspiration, pure and applied mathematics, and aesthetics Mathematics arises wherever there are difficult problems that involve quantity, structure, space, or change. At first these were found in commerce, land measurement and later astronomy; nowadays, all sciences suggest problems studied by mathematicians, and many problems arise within mathematics itself. Newton was one of the infinitesimal calculus inventors, although nearly all of the notation used in infinitesimal calculus was contributed by Leibniz with the exception of a dot above a variable to signify differentiation with respect to time. Feynman invented the Feynman path integral using a combination of reasoning and physical insight, and today's string theory also inspires new mathematics. Some mathematics is only relevant in the area that inspired it, and is applied to solve further problems in that area. But often mathematics inspired by one area proves useful in many areas, and joins the general stock of mathematical concepts. The remarkable fact that even the "purest" mathematics often turns out to have practical applications is what Eugene Wigner has called "the unreasonable effectiveness of mathematics." As in most areas of study, the explosion of knowledge in the scientific age has led to specialization in mathematics. One major distinction is between pure mathematics and applied mathematics. Several areas of applied mathematics have merged with related traditions outside of mathematics and become disciplines in their own right, including statistics, operations research, and computer science. For those who are mathematically inclined, there is often a definite aesthetic aspect to much of mathematics. Many mathematicians talk about the elegance of mathematics, its intrinsic aesthetics and inner beauty. Simplicity and generality are valued. There is beauty in a simple and elegant proof, such as Euclid's proof that there are infinitely many prime numbers, and in an elegant numerical method that speeds calculation, such as the fast Fourier transform. G. H. Hardy in A Mathematician's Apology expressed the belief that these aesthetic considerations are, in themselves, sufficient to justify the study of pure mathematics. Mathematicians often strive to find proofs of theorems that are particularly elegant, a quest Paul Erdős often referred to as finding proofs from "The Book" in which God had written down his favorite proofs. The popularity of recreational mathematics is another sign of the pleasure many find in solving mathematical questions. # Notation, language, and rigor Most of the mathematical notation in use today was not invented until the 16th century.[10] Before that, mathematics was written out in words, a painstaking process that limited mathematical discovery. Modern notation makes mathematics much easier for the professional, but beginners often find it daunting. It is extremely compressed: a few symbols contain a great deal of information. Like musical notation, modern mathematical notation has a strict syntax and encodes information that would be difficult to write in any other way. Mathematical language also is hard for beginners. Words such as or and only have more precise meanings than in everyday speech. Also confusing to beginners, words such as open and field have been given specialized mathematical meanings. Mathematical jargon includes technical terms such as homeomorphism and integrable. But there is a reason for special notation and technical jargon: mathematics requires more precision than everyday speech. Mathematicians refer to this precision of language and logic as "rigor". Rigor is fundamentally a matter of mathematical proof. Mathematicians want their theorems to follow from axioms by means of systematic reasoning. This is to avoid mistaken "theorems", based on fallible intuitions, of which many instances have occurred in the history of the subject.[11] The level of rigor expected in mathematics has varied over time: the Greeks expected detailed arguments, but at the time of Isaac Newton the methods employed were less rigorous. Problems inherent in the definitions used by Newton would lead to a resurgence of careful analysis and formal proof in the 19th century. Today, mathematicians continue to argue among themselves about computer-assisted proofs. Since large computations are hard to verify, such proofs may not be sufficiently rigorous.[12] Axioms in traditional thought were "self-evident truths", but that conception is problematic. At a formal level, an axiom is just a string of symbols, which has an intrinsic meaning only in the context of all derivable formulas of an axiomatic system. It was the goal of Hilbert's program to put all of mathematics on a firm axiomatic basis, but according to Gödel's incompleteness theorem every (sufficiently powerful) axiomatic system has undecidable formulas; and so a final axiomatization of mathematics is impossible. Nonetheless mathematics is often imagined to be (as far as its formal content) nothing but set theory in some axiomatization, in the sense that every mathematical statement or proof could be cast into formulas within set theory.[13] # Mathematics as science Carl Friedrich Gauss referred to mathematics as "the Queen of the Sciences".[14] In the original Latin Regina Scientiarum, as well as in German Königin der Wissenschaften, the word corresponding to science means (field of) knowledge. Indeed, this is also the original meaning in English, and there is no doubt that mathematics is in this sense a science. The specialization restricting the meaning to natural science is of later date. If one considers science to be strictly about the physical world, then mathematics, or at least pure mathematics, is not a science. Albert Einstein has stated that "as far as the laws of mathematics refer to reality, they are not certain; and as far as they are certain, they do not refer to reality."[15] Many philosophers believe that mathematics is not experimentally falsifiable,[citation needed] and thus not a science according to the definition of Karl Popper. However, in the 1930s important work in mathematical logic showed that mathematics cannot be reduced to logic, and Karl Popper concluded that "most mathematical theories are, like those of physics and biology, hypothetico-deductive: pure mathematics therefore turns out to be much closer to the natural sciences whose hypotheses are conjectures, than it seemed even recently."[16] Other thinkers, notably Imre Lakatos, have applied a version of falsificationism to mathematics itself. An alternative view is that certain scientific fields (such as theoretical physics) are mathematics with axioms that are intended to correspond to reality. In fact, the theoretical physicist, J. M. Ziman, proposed that science is public knowledge and thus includes mathematics.[17] In any case, mathematics shares much in common with many fields in the physical sciences, notably the exploration of the logical consequences of assumptions. Intuition and experimentation also play a role in the formulation of conjectures in both mathematics and the (other) sciences. Experimental mathematics continues to grow in importance within mathematics, and computation and simulation are playing an increasing role in both the sciences and mathematics, weakening the objection that mathematics does not use the scientific method. In his 2002 book A New Kind of Science, Stephen Wolfram argues that computational mathematics deserves to be explored empirically as a scientific field in its own right. The opinions of mathematicians on this matter are varied. While some in applied mathematics feel that they are scientists, those in pure mathematics often feel that they are working in an area more akin to logic and that they are, hence, fundamentally philosophers. Many mathematicians feel that to call their area a science is to downplay the importance of its aesthetic side, and its history in the traditional seven liberal arts; others feel that to ignore its connection to the sciences is to turn a blind eye to the fact that the interface between mathematics and its applications in science and engineering has driven much development in mathematics. One way this difference of viewpoint plays out is in the philosophical debate as to whether mathematics is created (as in art) or discovered (as in science). It is common to see universities divided into sections that include a division of Science and Mathematics, indicating that the fields are seen as being allied but that they do not coincide. In practice, mathematicians are typically grouped with scientists at the gross level but separated at finer levels. This is one of many issues considered in the philosophy of mathematics. Mathematical awards are generally kept separate from their equivalents in science. The most prestigious award in mathematics is the Fields Medal,[18][19] established in 1936 and now awarded every 4 years. It is often considered, misleadingly, the equivalent of science's Nobel Prizes. The Wolf Prize in Mathematics, instituted in 1979, recognizes lifetime achievement, and another major international award, the Abel Prize, was introduced in 2003. These are awarded for a particular body of work, which may be innovation, or resolution of an outstanding problem in an established field. A famous list of 23 such open problems, called "Hilbert's problems", was compiled in 1900 by German mathematician David Hilbert. This list achieved great celebrity among mathematicians, and at least nine of the problems have now been solved. A new list of seven important problems, titled the "Millennium Prize Problems", was published in 2000. Solution of each of these problems carries a $1 million reward, and only one (the Riemann hypothesis) is duplicated in Hilbert's problems. # Fields of mathematics As noted above, the major disciplines within mathematics first arose out of the need to do calculations in commerce, to understand the relationships between numbers, to measure land, and to predict astronomical events. These four needs can be roughly related to the broad subdivision of mathematics into the study of quantity, structure, space, and change (i.e., arithmetic, algebra, geometry, and analysis). In addition to these main concerns, there are also subdivisions dedicated to exploring links from the heart of mathematics to other fields: to logic, to set theory (foundations), to the empirical mathematics of the various sciences (applied mathematics), and more recently to the rigorous study of uncertainty. ## Quantity The study of quantity starts with numbers, first the familiar natural numbers and integers ("whole numbers") and arithmetical operations on them, which are characterized in arithmetic. The deeper properties of integers are studied in number theory, whence such popular results as Fermat's last theorem. Number theory also holds two widely-considered unsolved problems: the twin prime conjecture and Goldbach's conjecture. As the number system is further developed, the integers are recognized as a subset of the rational numbers ("fractions"). These, in turn, are contained within the real numbers, which are used to represent continuous quantities. Real numbers are generalized to complex numbers. These are the first steps of a hierarchy of numbers that goes on to include quarternions and octonions. Consideration of the natural numbers also leads to the transfinite numbers, which formalize the concept of counting to infinity. Another area of study is size, which leads to the cardinal numbers and then to another conception of infinity: the aleph numbers, which allow meaningful comparison of the size of infinitely large sets. ## Structure Many mathematical objects, such as sets of numbers and functions, exhibit internal structure. The structural properties of these objects are investigated in the study of groups, rings, fields and other abstract systems, which are themselves such objects. This is the field of abstract algebra. An important concept here is that of vectors, generalized to vector spaces, and studied in linear algebra. The study of vectors combines three of the fundamental areas of mathematics: quantity, structure, and space. Vector calculus expands the field into a fourth fundamental area, that of change. ## Space The study of space originates with geometry - in particular, Euclidean geometry. Trigonometry combines space and numbers, and encompasses the well-known Pythagorean theorem. The modern study of space generalizes these ideas to include higher-dimensional geometry, non-Euclidean geometries (which play a central role in general relativity) and topology. Quantity and space both play a role in analytic geometry, differential geometry, and algebraic geometry. Within differential geometry are the concepts of fiber bundles and calculus on manifolds. Within algebraic geometry is the description of geometric objects as solution sets of polynomial equations, combining the concepts of quantity and space, and also the study of topological groups, which combine structure and space. Lie groups are used to study space, structure, and change. Topology in all its many ramifications may have been the greatest growth area in 20th century mathematics, and includes the long-standing Poincaré conjecture and the controversial four color theorem, whose only proof, by computer, has never been verified by a human. ## Change Understanding and describing change is a common theme in the natural sciences, and calculus was developed as a powerful tool to investigate it. Functions arise here, as a central concept describing a changing quantity. The rigorous study of real numbers and real-valued functions is known as real analysis, with complex analysis the equivalent field for the complex numbers. The Riemann hypothesis, one of the most fundamental open questions in mathematics, is drawn from complex analysis. Functional analysis focuses attention on (typically infinite-dimensional) spaces of functions. One of many applications of functional analysis is quantum mechanics. Many problems lead naturally to relationships between a quantity and its rate of change, and these are studied as differential equations. Many phenomena in nature can be described by dynamical systems; chaos theory makes precise the ways in which many of these systems exhibit unpredictable yet still deterministic behavior. ## Foundations and philosophy In order to clarify the foundations of mathematics, the fields of mathematical logic and set theory were developed, as well as category theory which is still in development. Mathematical logic is concerned with setting mathematics on a rigid axiomatic framework, and studying the results of such a framework. As such, it is home to Gödel's second incompleteness theorem, perhaps the most widely celebrated result in logic, which (informally) implies that any formal system that contains basic arithmetic, if sound (meaning that all theorems that can be proven are true), is necessarily incomplete (meaning that there are true theorems which cannot be proved in that system). Gödel showed how to construct, whatever the given collection of number-theoretical axioms, a formal statement in the logic that is a true number-theoretical fact, but which does not follow from those axioms. Therefore no formal system is a true axiomatization of full number theory. Modern logic is divided into recursion theory, model theory, and proof theory, and is closely linked to theoretical computer science. ## Discrete mathematics Discrete mathematics is the common name for the fields of mathematics most generally useful in theoretical computer science. This includes computability theory, computational complexity theory, and information theory. Computability theory examines the limitations of various theoretical models of the computer, including the most powerful known model - the Turing machine. Complexity theory is the study of tractability by computer; some problems, although theoretically solvable by computer, are so expensive in terms of time or space that solving them is likely to remain practically unfeasible, even with rapid advance of computer hardware. Finally, information theory is concerned with the amount of data that can be stored on a given medium, and hence concepts such as compression and entropy. As a relatively new field, discrete mathematics has a number of fundamental open problems. The most famous of these is the "P=NP?" problem, one of the Millennium Prize Problems.[20] ## Applied mathematics Applied mathematics considers the use of abstract mathematical tools in solving concrete problems in the sciences, business, and other areas. An important field in applied mathematics is statistics, which uses probability theory as a tool and allows the description, analysis, and prediction of phenomena where chance plays a role. Most experiments, surveys and observational studies require the informed use of statistics. (Many statisticians, however, do not consider themselves to be mathematicians, but rather part of an allied group.) Numerical analysis investigates computational methods for efficiently solving a broad range of mathematical problems that are typically too large for human numerical capacity; it includes the study of rounding errors or other sources of error in computation. # Common misconceptions Mathematics is not a closed intellectual system, in which everything has already been worked out. There is no shortage of open problems. Mathematicians publish many thousands of papers embodying new discoveries in mathematics every month. Mathematics is not numerology, nor is it accountancy; nor is it restricted to arithmetic. Pseudomathematics is a form of mathematics-like activity undertaken outside academia, and occasionally by mathematicians themselves. It often consists of determined attacks on famous questions, consisting of proof-attempts made in an isolated way (that is, long papers not supported by previously published theory). The relationship to generally-accepted mathematics is similar to that between pseudoscience and real science. The misconceptions involved are normally based on: - misunderstanding of the implications of mathematical rigor; - attempts to circumvent the usual criteria for publication of mathematical papers in a learned journal after peer review, often in the belief that the journal is biased against the author; - lack of familiarity with, and therefore underestimation of, the existing literature. The case of Kurt Heegner's work shows that the mathematical establishment is neither infallible, nor unwilling to admit error in assessing 'amateur' work. And like astronomy, mathematics owes much to amateur contributors such as Fermat and Mersenne. ## Mathematics and physical reality Mathematical concepts and theorems need not correspond to anything in the physical world. Insofar as a correspondence does exist, while mathematicians and physicists may select axioms and postulates that seem reasonable and intuitive, it is not necessary for the basic assumptions within an axiomatic system to be true in an empirical or physical sense. Thus, while most systems of axioms are derived from our perceptions and experiments, they are not dependent on them. For example, we could say that the physical concept of two apples may be accurately modeled by the natural number 2. On the other hand, we could also say that the natural numbers are not an accurate model because there is no standard "unit" apple and no two apples are exactly alike. The modeling idea is further complicated by the possibility of fractional or partial apples. So while it may be instructive to visualize the axiomatic definition of the natural numbers as collections of apples, the definition itself is not dependent upon nor derived from any actual physical entities. Nevertheless, mathematics remains extremely useful for solving real-world problems. This fact led Eugene Wigner to write an essay, The Unreasonable Effectiveness of Mathematics in the Natural Sciences.	https://www.wikidoc.org/index.php/Mathematical
b5f778b862bd4c5bab3615560d1bd4ca8f32a3ed	wikidoc	Meadowsweet	Meadowsweet Meadowsweet (Filipendula ulmaria) is a perennial herb in the family Rosaceae, which grows in damp meadows. It is native throughout most of Europe and western Asia though it has been successfully introduced and naturalized in North America. Meadowsweet has also been referred to as Queen of the Meadow, Pride of the Meadow, Meadow-Wort and Bridewort. # Description The stems are 1–2 m tall, erect and furrowed, reddish to sometimes purple. The leaves are dark green on the upper side and whitish and downy underneath, much divided, interruptedly pinnate, having a few large serrate leaflets and small intermediate ones. Terminal leaflets are large, 4–8 cm long and three to five-lobed. Meadowsweet has delicate, graceful, creamy-white flowers clustered close together in handsome irregularly-branched cymes, having a very strong, sweet smell. They flower from June to early September. # Etymology The name ulmaria means "elmlike", an odd epithet as it does not resemble the elm (Ulmus) in any way. However, like slippery elm bark, the plant contains salicylic acid, which has long been used as a painkiller, and this may be the source of the name. However, the generic name, Filipendula, comes from filum, meaning "thread" and pendulus, meaning "hanging." This is possibly said to describe the root tubers that hang characteristically on the genus, on fibrous roots. # Uses The whole herb possesses a pleasant taste and flavour, the green parts having a similar aromatic character to the flowers, leading to the use of the plant to strew on floors to give the rooms a pleasant aroma, and its use to flavour wine, beer and many vinegars. The flowers can be added to stewed fruit and jams, giving them a subtle almond flavor. It has many medicinal properties. The whole plant is a traditional remedy for an acidic stomach and the fresh root is often used in homeopathic preparations. It is effective on its own the treatment of diarrhoea. The flowers, when made into a tea, are a comfort to flu sufferers. Dried, the flowers make lovely pot pourri. Active ingredients: compounds of salicylic acid, flavone-glycosides, essential oils and tannins. In 1897 Felix Hoffmann created a synthetically altered version of salicin, derived from the species, which caused less digestive upset than pure salicylic acid. The new drug, formally Acetylsalicylic acid, was named aspirin by Hoffman's employer Bayer AG after the old botannical name for meadowsweet, Spirea ulmaria. This gave rise to the hugely important class of drugs known as NonSteroidal AntiInflammatory Drugs, or NSAIDs. This plant contains the chemicals used to make Aspirin, a small section of root, when peeled and crushed smells like Germaline, and when chewed is a good natural remedy for relieving headaches. A natural black dye can be obtained from the roots by using a copper mordant. Magical Uses: used in divination, and in spells and charms for peace, happiness, love. It was a sacred herb of the Druids. Fresh meadowsweet should be arranged on the the altar when mixing love charms or performing love spells. Strew around the house for love and peace. At Lammas garlands of meadowsweet are worn to join with the essence of the Goddess. # History White-flowered meadowsweet has been found with the cremated remains of three people and at least one animal in a Bronze Age cairn at Fan Foel, Carmarthenshire. Similar finds have also been found inside a Beaker from Ashgrove, Fife and a vessel from North Mains, Strathallan. These could possibly indicate honey-based mead or flavoured ale, or alternatively might suggest the plant being placed on the grave as a scented flower . In Welsh Mythology, Gwydion and Math created a woman out of oak blossom, broom, and meadowsweet and named her Blodeuwedd ("flower face"). It is known by many other names, and in Chaucer's The Knight's Tale it is known as Meadwort and was one of the ingredients in a drink called "save." It was also known as Bridewort, because it was strewn in churches for festivals and weddings, and often made into bridal garlands. In Europe, it took its name "queen of the meadow" for the way it can dominate a low-lying, damp meadow. In the 16th century, when it was customary to strew floors with rushes and herbs (both to give warmth underfoot and to overcome smells and infections), it was a favorite of Queen Elizabeth I. She desired it above all other herbs in her chambers. # Notes - ↑ Currie, Penni, Magical Herbs, Roots and Resins, unpublished pp213 - ↑ Pitts, M. (2006). Meadowsweet flowers in prehistoric graves. British Archaeology 88 (May/June): 6	Meadowsweet Meadowsweet (Filipendula ulmaria) is a perennial herb in the family Rosaceae, which grows in damp meadows. It is native throughout most of Europe and western Asia though it has been successfully introduced and naturalized in North America. Meadowsweet has also been referred to as Queen of the Meadow, Pride of the Meadow, Meadow-Wort and Bridewort. # Description The stems are 1–2 m tall, erect and furrowed, reddish to sometimes purple. The leaves are dark green on the upper side and whitish and downy underneath, much divided, interruptedly pinnate, having a few large serrate leaflets and small intermediate ones. Terminal leaflets are large, 4–8 cm long and three to five-lobed. Meadowsweet has delicate, graceful, creamy-white flowers clustered close together in handsome irregularly-branched cymes, having a very strong, sweet smell. They flower from June to early September. # Etymology The name ulmaria means "elmlike", an odd epithet as it does not resemble the elm (Ulmus) in any way. However, like slippery elm bark, the plant contains salicylic acid, which has long been used as a painkiller, and this may be the source of the name. However, the generic name, Filipendula, comes from filum, meaning "thread" and pendulus, meaning "hanging." This is possibly said to describe the root tubers that hang characteristically on the genus, on fibrous roots. # Uses The whole herb possesses a pleasant taste and flavour, the green parts having a similar aromatic character to the flowers, leading to the use of the plant to strew on floors to give the rooms a pleasant aroma, and its use to flavour wine, beer and many vinegars. The flowers can be added to stewed fruit and jams, giving them a subtle almond flavor. It has many medicinal properties. The whole plant is a traditional remedy for an acidic stomach and the fresh root is often used in homeopathic preparations. It is effective on its own the treatment of diarrhoea. The flowers, when made into a tea, are a comfort to flu sufferers. Dried, the flowers make lovely pot pourri. Active ingredients: compounds of salicylic acid, flavone-glycosides, essential oils and tannins. In 1897 Felix Hoffmann created a synthetically altered version of salicin, derived from the species, which caused less digestive upset than pure salicylic acid. The new drug, formally Acetylsalicylic acid, was named aspirin by Hoffman's employer Bayer AG after the old botannical name for meadowsweet, Spirea ulmaria. This gave rise to the hugely important class of drugs known as NonSteroidal AntiInflammatory Drugs, or NSAIDs. This plant contains the chemicals used to make Aspirin, a small section of root, when peeled and crushed smells like Germaline, and when chewed is a good natural remedy for relieving headaches. A natural black dye can be obtained from the roots by using a copper mordant. Magical Uses: used in divination, and in spells and charms for peace, happiness, love. It was a sacred herb of the Druids. Fresh meadowsweet should be arranged on the the altar when mixing love charms or performing love spells. Strew around the house for love and peace. At Lammas garlands of meadowsweet are worn to join with the essence of the Goddess. [1] # History White-flowered meadowsweet has been found with the cremated remains of three people and at least one animal in a Bronze Age cairn at Fan Foel, Carmarthenshire. Similar finds have also been found inside a Beaker from Ashgrove, Fife and a vessel from North Mains, Strathallan. These could possibly indicate honey-based mead or flavoured ale, or alternatively might suggest the plant being placed on the grave as a scented flower [2]. In Welsh Mythology, Gwydion and Math created a woman out of oak blossom, broom, and meadowsweet and named her Blodeuwedd ("flower face"). It is known by many other names, and in Chaucer's The Knight's Tale it is known as Meadwort and was one of the ingredients in a drink called "save." It was also known as Bridewort, because it was strewn in churches for festivals and weddings, and often made into bridal garlands. In Europe, it took its name "queen of the meadow" for the way it can dominate a low-lying, damp meadow. In the 16th century, when it was customary to strew floors with rushes and herbs (both to give warmth underfoot and to overcome smells and infections), it was a favorite of Queen Elizabeth I. She desired it above all other herbs in her chambers. # Notes - ↑ Currie, Penni, Magical Herbs, Roots and Resins, unpublished pp213 - ↑ Pitts, M. (2006). Meadowsweet flowers in prehistoric graves. British Archaeology 88 (May/June): 6	https://www.wikidoc.org/index.php/Meadowsweet
d488a2cfae734427bfa6c61c3e25c89276decf7c	wikidoc	Measurement	Measurement # Overview Measurement is the estimation of the magnitude of some attribute of an object, such as its length or weight, relative to a unit of measuremnt. Measurement usually involves using a measuring instrument, such as a ruler or scale, which is calibrated to compare the object to some standard, such as a meter or a kilogram. In science, however, where accurate measurement is crucial, a measurement is understood to have three parts: first, the measurement itself, second, the margin of error, and third, the confidence level -- that is, the probability that the actual property of the physical object is within the margin of error. For example, we might measure the length of an object as 2.34 meters plus or minus 0.01 meter, with a 95% confidence level. Metrology is the scientific study of measurement. In measurement theory a measurement is an observation that reduces an uncertainty expressed as a quantity. As a verb, measurement is making such observations. It includes the estimation of a physical quantity such as distance, energy, temperature, or time. It could also include such things as assessment of attitudes, values and perception in surveys or the testing of aptitudes of individuals. In the physical sciences, measurement is most commonly thought of as the ratio of some physical quantity to a standard quantity of the same type, thus a measurement of length is the ratio of a physical length to some standard length, such as a standard meter. Measurements are usually given in terms of a real number times a unit of measurement, for example 2.53 meters, but sometimes measurements use complex numbers, as in measurements of electrical impedance. # Observations and error The act of measuring often requires an instrument designed and calibrated for that purpose, such as a thermometer, speedometer, weighing scale, or voltmeter. Surveys and tests are also referred to as "measurement instruments" in academic testing, aptitude testing, voter polls, etc. Measurements almost always have an error and therefore uncertainty. In fact, the reduction—not necessarily the elimination—of uncertainty is central the concept of measurement. Measurement errors are often assumed to be normally distributed about the true value of the measured quantity. Under this assumption, every measurement has three components: the estimate, the error bound, and the probability that the actual magnitude lies within the error bound of the estimate. For example, a measurement of the length of a plank might result in a measurement of 2.53 meters plus or minus 0.01 meter, with a probability of 99%. The initial state of uncertainty, prior to any observations, is necessary to assess when using statistical methods that rely on prior knowledge (Bayesian methods,Applied Information Economics). This can be done with calibrated probability assessment. Measurement is fundamental in science; it is one of the things that distinguishes science from pseudoscience. It is easy to come up with a theory about nature, hard to come up with a scientific theory that predicts measurements with great accuracy. Measurement is also essential in industry, commerce, engineering, construction, manufacturing, pharmaceutical production, and electronics. # History of measurement The word measurement comes from the Greek "metron", meaning limited proportion. This also has a common root with the word "moon" and "month" possibly since the moon and other astronomical objects were among the first measurement methods of time. The history of measurements is a topic within the history of science and technology. The metre (U.S.: meter) was standardized as the unit for length after the French revolution, and has since been adopted throughout most of the world. # Measurement standards Laws to regulate measurement were originally developed to prevent fraud. However, units of measurement are now generally defined on a scientific basis, and are established by international treaties. In the United States, commercial measurements are regulated by the National Institute of Standards and Technology NIST, a division of the United States Department of Commerce. # Units and systems of measurement The definition or specification of precise standards of measurement involves two key features, which are evident in the International System of Units (SI). Specifically, in this system the definition of each of the base units makes reference to specific empirical conditions and, with the exception of the kilogram, also to other quantitative attributes. Each derived SI unit is defined purely in terms of a relationship involving itself and other units; for example, the unit of velocity is 1 m/s. Due to the fact that derived units make reference to base units, the specification of empirical conditions is an implied component of the definition of all units. ## Imperial system Before SI units were widely adopted around the world, the British systems of English units and later Imperial units were used in Britain, the Commonwealth and the United States. The system came to be known as U.S. customary units in the United States and is still in use there and in a few Caribbean countries. These various systems of measurement have at times been called foot-pound-second systems after the Imperial units for distance, weight and time. Many Imperial units remain in use in Britain despite the fact that it has officially switched to the SI system. Road signs are still in miles, yards, miles per hour, and so on, people tend to measure their own height in feet and inches and soda is sold in pints, to give just a few examples. Imperial units are used in many other places, for example, in many Commonwealth countries which are considered metricated, land area is measured in acres and floor space in square feet, particularly for commercial transactions (rather than government statistics). Similarly, the imperial gallon is used in many countries that are considered metricated at gas/petrol stations, an example being the United Arab Emirates. ## Metric system The metric system is a decimalised system of measurement based on the metre and the gram. It exists in several variations, with different choices of base units, though these do not affect its day-to-day use. Since the 1960s the International System of Units (SI), explained further below, is the internationally recognized standard metric system. Metric units of mass, length, and electricity are widely used around the world for both everyday and scientific purposes. The main advantage of the metric system is that it has a single base unit for each physical quantity. All other units are powers of ten or multiples of ten of this base unit. Unit conversions are always simple because they will be in the ratio of ten, one hundred, one thousand, etc. All lengths and distances, for example, are measured in meters, or thousandths of a metre (millimeters), or thousands of meters (kilometres), and so on. There is no profusion of different units with different conversion factors as in the Imperial system (e.g. inches, feet, yards, fathoms, rods). Multiples and submultiples are related to the fundamental unit by factors of powers of ten, so that one can convert by simply moving the decimal place: 1.234 metres is 1234 millimetres or 0.001234 kilometres. The use of fractions, such as 2/5 of a meter, is not prohibited, but uncommon. ## SI The International System of Units (abbreviated SI from the French language name Système International d'Unités) is the modern, revised form of the metric system. It is the world's most widely used system of units, both in everyday commerce and in science. The SI was developed in 1960 from the metre-kilogram-second (MKS) system, rather than the centimetre-gram-second (CGS) system, which, in turn, had many variants. At its development the SI also introduced several newly named units that were previously not a part of the metric system. There are two types of SI units, Base and Derived Units. Base units are the simple measurements for time, length, mass, temperature, amount of substance, electric current, and light intensity. Derived units are made up of base units, for example density is kg/m3. ### Converting prefixes The SI allows easy multiplication when switching among units having the same base but different prefixes. If you are working with meters and want to convert to centimeters, you only need to multiply the number of meters by 100 because there are 100 centimeters in a meter. Inversely, to switch from centimeters to meters you multiply the number of centimeters by .01. ## Length A ruler or rule is a tool used in, for example, geometry, technical drawing, engineering, and carpentry, to measure distances or to draw straight lines. Strictly speaking, the ruler is the instrument used to rule straight lines and the calibrated instrument used for determining length is called a measure, however common usage calls both instruments rulers and the special name straightedge is used for an unmarked rule. The use of the word measure, in the sense of a measuring instrument, only survives in the phrase tape measure, an instrument that can be used to measure but cannot be used to draw straight lines. As can be seen in the photographs on this page, a two metre carpenter's rule can be folded down to a length of only 20 centimetres, to easily fit in a pocket, and a five metre long tape measure easily retracts to fit within a small housing. ## Time The most common devices for measuring time are the clock or watch. A chronometer is a timekeeping instrument precise enough to be used as a portable time standard. Historically, the invention of chronometers was a major advance in determining longitude and an aid in celestial navigation. The most accurate device for the measurement of time is the atomic clock. Before the invention of the clock, people measured time using the hourglass, the sundial, and the water clock. ## Mass Mass refers to the intrinsic property of all material objects to resist changes in their momentum. Weight, on the other hand, refers to the downward force produced when a mass is in a gravitational field. In free fall, objects lack weight but retain their mass. The Imperial units of mass include the ounce, pound, and ton. The metric units gram and kilogram are units of mass. A unit for measuring weight or mass is called a weighing scale or, often, simply a scale. A spring scale measures force but not mass, a balance compares masses, but requires a gravitational field to operate. The most accurate instrument for measuring weight or mass is the digital scale, but it also requires a gravitational field, and would not work in free fall. # Difficulties in measurement Since accurate measurement is essential in many fields, and since all measurements are necessarily approximations, a great deal of effort must be taken to make measurements as accurate as possible. For example, consider the problem of measuring the time it takes for an object to fall a distance of one meter. Using physics, it can be shown that, in the gravitational field of the Earth, it should take any object about .45 seconds to fall one meter. However, the following are just some of the sources of error that arise. First, this computation used for the acceleration of gravity 9.8 meters per second per second. But this measurement is not exact, but only accurate to two significant digits. Also, the Earth's gravitational field varies slightly depending on height above sea level and other factors. Next, the computation of .45 seconds involved extracting a square root, a mathematical operation that required rounding off to some number of significant digits, in this case two significant digits. So far, we have only considered scientific sources of error. In actual practice, dropping an object from a height of a meter stick and using a stop watch to time its fall, we have other sources of error. First, and most common, is simple carelessness. Then there is the problem of determining the exact time at which the object is released and the exact time it hits the ground. There is also the problem that the measurement of the height and the measurement of the time both involve some error. Finally, there is the problem of air resistance. Scientific measurements must be carried out with great care to eliminate as much error as possible, and to keep error estimates realistic. # Definitions and theories of measurement ## The classical definition of measurement In the classical definition, which is standard throughout the physical sciences, measurement is the determination or estimation of ratios of quantities. Quantity and measurement are mutually defined: quantitative attributes are those which it is possible to measure, at least in principle. The classical concept of quantity can be traced back to John Wallis and Isaac Newton, and was foreshadowed in Euclid's Elements (Michell, 1993). ## The representational theory of measurement In the representational theory, measurement is defined as "the correlation of numbers with entities that are not numbers" (Nagel, 1932). The strongest form of representational theory is also known as additive conjoint measurement. In this form of representational theory, numbers are assigned on the basis of correspondences or similarities between the structure of number systems and the structure of qualitative systems. A property is quantitative if such structural similarities can be established. In weaker forms of representational theory, such as that implicit within the work of Stanley Smith Stevens, numbers need only be assigned according to a rule. The concept of measurement is often misunderstood as merely the assignment of a value, but it is possible to assign a value in a way that is not a measurement in terms of the requirements of additive conjoint measurement. One may assign a value to a person's height, but unless it can be established that there is a correlation between measurements of height and empirical relations, it is not a measurement according to additive conjoint measurement theory. Likewise, computing and assigning arbitrary values, like the "book value" of an asset in accounting, is not a measurement because it does not satisfy the necessary criteria. # Types of measurement proposed by Stevens The definition of measurement was purportedly broadened by Stanely S. Stevens. He defined types of measurements to include nominal, ordinal, interval and ratio. In practice, this scheme is used mainly in the social sciences but even there its use is controversial because it includes definitions that do not meet the more strict requirements of the classical theory and additive conjoint measurement. However, the classifications of interval and ratio level measurement are not controversial. - Nominal: Discrete data which represent group membership to a category which does not have an underlying numerical value. Examples include ethnicity, color, pattern, soil type, media type, license plate numbers, football jersey numbers, etc. May also be dichotomous such as present/absent, male/female, live/dead - Ordinal: Includes variables that can be ordered but for which there is no zero point and no exact numerical value. Examples: preference ranks (Thurstone rating scale), Mohs hardness scale, movie ratings, shirt sizes (S,M,L,XL), and college rankings. Also includes the Likert scale used in surveys – strongly agree, agree, undecided, disagree, strongly disagree. Distances between each ordered category are not necessarily the same (a four star movie isn't necessarily just "twice" as good as a two star movie). - Interval: Describes the distance between two values but a ratio is not relevant. A numerical scale with an arbitrary zero point. Most common examples Celsius and Fahrenheit. Some consider indexes such as IQ to be interval measurements whereas others consider them only counts. Interval-level measurements can be obtained through application of the Rasch model. - Ratio: This is what is most commonly associated with measurements in the physical sciences. The zero value is not arbitrary and units are uniform. This is the only measurement type where ratio comparisons are meaningful. Examples include weight, speed, volume, etc. The concept of measurement is often confused with counting, which implies an exact mapping of integers to clearly separate objects. # Citations - ↑ Douglas Hubbard "How to Measure Anything: Finding the Value of Intangibles in Business", John Wiley & Sons, 2007 - ↑ Stevens, S.S. On the theory of scales and measurement 1946. Science. 103, 677-680. # Miscellaneous Measuring the ratios between physical quantities is an important sub-field of physics. Some important physical quantities include: - Speed of light - Planck's constant - Gravitational constant - Elementary charge (electric charge of electrons, protons, etc.) - Fine-structure constant - Quantity	Measurement Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview Measurement is the estimation of the magnitude of some attribute of an object, such as its length or weight, relative to a unit of measuremnt. Measurement usually involves using a measuring instrument, such as a ruler or scale, which is calibrated to compare the object to some standard, such as a meter or a kilogram. In science, however, where accurate measurement is crucial, a measurement is understood to have three parts: first, the measurement itself, second, the margin of error, and third, the confidence level -- that is, the probability that the actual property of the physical object is within the margin of error. For example, we might measure the length of an object as 2.34 meters plus or minus 0.01 meter, with a 95% confidence level. Metrology is the scientific study of measurement. In measurement theory a measurement is an observation that reduces an uncertainty expressed as a quantity. As a verb, measurement is making such observations[1]. It includes the estimation of a physical quantity such as distance, energy, temperature, or time. It could also include such things as assessment of attitudes, values and perception in surveys or the testing of aptitudes of individuals. In the physical sciences, measurement is most commonly thought of as the ratio of some physical quantity to a standard quantity of the same type, thus a measurement of length is the ratio of a physical length to some standard length, such as a standard meter. Measurements are usually given in terms of a real number times a unit of measurement, for example 2.53 meters, but sometimes measurements use complex numbers, as in measurements of electrical impedance. # Observations and error The act of measuring often requires an instrument designed and calibrated for that purpose, such as a thermometer, speedometer, weighing scale, or voltmeter. Surveys and tests are also referred to as "measurement instruments" in academic testing, aptitude testing, voter polls, etc. Measurements almost always have an error and therefore uncertainty. In fact, the reduction—not necessarily the elimination—of uncertainty is central the concept of measurement. Measurement errors are often assumed to be normally distributed about the true value of the measured quantity. Under this assumption, every measurement has three components: the estimate, the error bound, and the probability that the actual magnitude lies within the error bound of the estimate. For example, a measurement of the length of a plank might result in a measurement of 2.53 meters plus or minus 0.01 meter, with a probability of 99%. The initial state of uncertainty, prior to any observations, is necessary to assess when using statistical methods that rely on prior knowledge (Bayesian methods,Applied Information Economics). This can be done with calibrated probability assessment. Measurement is fundamental in science; it is one of the things that distinguishes science from pseudoscience. It is easy to come up with a theory about nature, hard to come up with a scientific theory that predicts measurements with great accuracy. Measurement is also essential in industry, commerce, engineering, construction, manufacturing, pharmaceutical production, and electronics. # History of measurement The word measurement comes from the Greek "metron", meaning limited proportion. This also has a common root with the word "moon" and "month" possibly since the moon and other astronomical objects were among the first measurement methods of time. The history of measurements is a topic within the history of science and technology. The metre (U.S.: meter) was standardized as the unit for length after the French revolution, and has since been adopted throughout most of the world. # Measurement standards Laws to regulate measurement were originally developed to prevent fraud. However, units of measurement are now generally defined on a scientific basis, and are established by international treaties. In the United States, commercial measurements are regulated by the National Institute of Standards and Technology NIST, a division of the United States Department of Commerce. # Units and systems of measurement The definition or specification of precise standards of measurement involves two key features, which are evident in the International System of Units (SI). Specifically, in this system the definition of each of the base units makes reference to specific empirical conditions and, with the exception of the kilogram, also to other quantitative attributes. Each derived SI unit is defined purely in terms of a relationship involving itself and other units; for example, the unit of velocity is 1 m/s. Due to the fact that derived units make reference to base units, the specification of empirical conditions is an implied component of the definition of all units. ## Imperial system Before SI units were widely adopted around the world, the British systems of English units and later Imperial units were used in Britain, the Commonwealth and the United States. The system came to be known as U.S. customary units in the United States and is still in use there and in a few Caribbean countries. These various systems of measurement have at times been called foot-pound-second systems after the Imperial units for distance, weight and time. Many Imperial units remain in use in Britain despite the fact that it has officially switched to the SI system. Road signs are still in miles, yards, miles per hour, and so on, people tend to measure their own height in feet and inches and soda is sold in pints, to give just a few examples. Imperial units are used in many other places, for example, in many Commonwealth countries which are considered metricated, land area is measured in acres and floor space in square feet, particularly for commercial transactions (rather than government statistics). Similarly, the imperial gallon is used in many countries that are considered metricated at gas/petrol stations, an example being the United Arab Emirates. ## Metric system The metric system is a decimalised system of measurement based on the metre and the gram. It exists in several variations, with different choices of base units, though these do not affect its day-to-day use. Since the 1960s the International System of Units (SI), explained further below, is the internationally recognized standard metric system. Metric units of mass, length, and electricity are widely used around the world for both everyday and scientific purposes. The main advantage of the metric system is that it has a single base unit for each physical quantity. All other units are powers of ten or multiples of ten of this base unit. Unit conversions are always simple because they will be in the ratio of ten, one hundred, one thousand, etc. All lengths and distances, for example, are measured in meters, or thousandths of a metre (millimeters), or thousands of meters (kilometres), and so on. There is no profusion of different units with different conversion factors as in the Imperial system (e.g. inches, feet, yards, fathoms, rods). Multiples and submultiples are related to the fundamental unit by factors of powers of ten, so that one can convert by simply moving the decimal place: 1.234 metres is 1234 millimetres or 0.001234 kilometres. The use of fractions, such as 2/5 of a meter, is not prohibited, but uncommon. ## SI The International System of Units (abbreviated SI from the French language name Système International d'Unités) is the modern, revised form of the metric system. It is the world's most widely used system of units, both in everyday commerce and in science. The SI was developed in 1960 from the metre-kilogram-second (MKS) system, rather than the centimetre-gram-second (CGS) system, which, in turn, had many variants. At its development the SI also introduced several newly named units that were previously not a part of the metric system. There are two types of SI units, Base and Derived Units. Base units are the simple measurements for time, length, mass, temperature, amount of substance, electric current, and light intensity. Derived units are made up of base units, for example density is kg/m3. ### Converting prefixes The SI allows easy multiplication when switching among units having the same base but different prefixes. If you are working with meters and want to convert to centimeters, you only need to multiply the number of meters by 100 because there are 100 centimeters in a meter. Inversely, to switch from centimeters to meters you multiply the number of centimeters by .01. ## Length A ruler or rule is a tool used in, for example, geometry, technical drawing, engineering, and carpentry, to measure distances or to draw straight lines. Strictly speaking, the ruler is the instrument used to rule straight lines and the calibrated instrument used for determining length is called a measure, however common usage calls both instruments rulers and the special name straightedge is used for an unmarked rule. The use of the word measure, in the sense of a measuring instrument, only survives in the phrase tape measure, an instrument that can be used to measure but cannot be used to draw straight lines. As can be seen in the photographs on this page, a two metre carpenter's rule can be folded down to a length of only 20 centimetres, to easily fit in a pocket, and a five metre long tape measure easily retracts to fit within a small housing. ## Time The most common devices for measuring time are the clock or watch. A chronometer is a timekeeping instrument precise enough to be used as a portable time standard. Historically, the invention of chronometers was a major advance in determining longitude and an aid in celestial navigation. The most accurate device for the measurement of time is the atomic clock. Before the invention of the clock, people measured time using the hourglass, the sundial, and the water clock. ## Mass Mass refers to the intrinsic property of all material objects to resist changes in their momentum. Weight, on the other hand, refers to the downward force produced when a mass is in a gravitational field. In free fall, objects lack weight but retain their mass. The Imperial units of mass include the ounce, pound, and ton. The metric units gram and kilogram are units of mass. A unit for measuring weight or mass is called a weighing scale or, often, simply a scale. A spring scale measures force but not mass, a balance compares masses, but requires a gravitational field to operate. The most accurate instrument for measuring weight or mass is the digital scale, but it also requires a gravitational field, and would not work in free fall. # Difficulties in measurement Since accurate measurement is essential in many fields, and since all measurements are necessarily approximations, a great deal of effort must be taken to make measurements as accurate as possible. For example, consider the problem of measuring the time it takes for an object to fall a distance of one meter. Using physics, it can be shown that, in the gravitational field of the Earth, it should take any object about .45 seconds to fall one meter. However, the following are just some of the sources of error that arise. First, this computation used for the acceleration of gravity 9.8 meters per second per second. But this measurement is not exact, but only accurate to two significant digits. Also, the Earth's gravitational field varies slightly depending on height above sea level and other factors. Next, the computation of .45 seconds involved extracting a square root, a mathematical operation that required rounding off to some number of significant digits, in this case two significant digits. So far, we have only considered scientific sources of error. In actual practice, dropping an object from a height of a meter stick and using a stop watch to time its fall, we have other sources of error. First, and most common, is simple carelessness. Then there is the problem of determining the exact time at which the object is released and the exact time it hits the ground. There is also the problem that the measurement of the height and the measurement of the time both involve some error. Finally, there is the problem of air resistance. Scientific measurements must be carried out with great care to eliminate as much error as possible, and to keep error estimates realistic. # Definitions and theories of measurement ## The classical definition of measurement In the classical definition, which is standard throughout the physical sciences, measurement is the determination or estimation of ratios of quantities. Quantity and measurement are mutually defined: quantitative attributes are those which it is possible to measure, at least in principle. The classical concept of quantity can be traced back to John Wallis and Isaac Newton, and was foreshadowed in Euclid's Elements (Michell, 1993). ## The representational theory of measurement In the representational theory, measurement is defined as "the correlation of numbers with entities that are not numbers" (Nagel, 1932). The strongest form of representational theory is also known as additive conjoint measurement. In this form of representational theory, numbers are assigned on the basis of correspondences or similarities between the structure of number systems and the structure of qualitative systems. A property is quantitative if such structural similarities can be established. In weaker forms of representational theory, such as that implicit within the work of Stanley Smith Stevens, numbers need only be assigned according to a rule. The concept of measurement is often misunderstood as merely the assignment of a value, but it is possible to assign a value in a way that is not a measurement in terms of the requirements of additive conjoint measurement. One may assign a value to a person's height, but unless it can be established that there is a correlation between measurements of height and empirical relations, it is not a measurement according to additive conjoint measurement theory. Likewise, computing and assigning arbitrary values, like the "book value" of an asset in accounting, is not a measurement because it does not satisfy the necessary criteria. # Types of measurement proposed by Stevens The definition of measurement was purportedly broadened by Stanely S. Stevens.[2] He defined types of measurements to include nominal, ordinal, interval and ratio. In practice, this scheme is used mainly in the social sciences but even there its use is controversial because it includes definitions that do not meet the more strict requirements of the classical theory and additive conjoint measurement. However, the classifications of interval and ratio level measurement are not controversial. - Nominal: Discrete data which represent group membership to a category which does not have an underlying numerical value. Examples include ethnicity, color, pattern, soil type, media type, license plate numbers, football jersey numbers, etc. May also be dichotomous such as present/absent, male/female, live/dead - Ordinal: Includes variables that can be ordered but for which there is no zero point and no exact numerical value. Examples: preference ranks (Thurstone rating scale), Mohs hardness scale, movie ratings, shirt sizes (S,M,L,XL), and college rankings. Also includes the Likert scale used in surveys – strongly agree, agree, undecided, disagree, strongly disagree. Distances between each ordered category are not necessarily the same (a four star movie isn't necessarily just "twice" as good as a two star movie). - Interval: Describes the distance between two values but a ratio is not relevant. A numerical scale with an arbitrary zero point. Most common examples Celsius and Fahrenheit. Some consider indexes such as IQ to be interval measurements whereas others consider them only counts. Interval-level measurements can be obtained through application of the Rasch model. - Ratio: This is what is most commonly associated with measurements in the physical sciences. The zero value is not arbitrary and units are uniform. This is the only measurement type where ratio comparisons are meaningful. Examples include weight, speed, volume, etc. The concept of measurement is often confused with counting, which implies an exact mapping of integers to clearly separate objects. # Citations - ↑ Douglas Hubbard "How to Measure Anything: Finding the Value of Intangibles in Business", John Wiley & Sons, 2007 - ↑ Stevens, S.S. On the theory of scales and measurement 1946. Science. 103, 677-680. # Miscellaneous Measuring the ratios between physical quantities is an important sub-field of physics. Some important physical quantities include: - Speed of light - Planck's constant - Gravitational constant - Elementary charge (electric charge of electrons, protons, etc.) - Fine-structure constant - Quantity	https://www.wikidoc.org/index.php/Measurement
a12aaac594d3e8ad9fe408d41348a9ef898b2f0f	wikidoc	Mebendazole	Mebendazole # 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 Mebendazole is a broad-spectrum anthelmintic that is FDA approved for the treatment of Enterobius vermicularis (pinworm), Trichuris trichiura (whipworm), Ascaris lumbricoides (common roundworm), Ancylostoma duodenale (common hookworm), Necator americanus (American hookworm) in single or mixed infections. Common adverse reactions include rash, abdominal pain, constipation, diarrhea and headache. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) The same dosage schedule applies to children and adults. The tablet may be chewed, swallowed, or crushed and mixed with food. If the patient is not cured three weeks after treatment, a second course of treatment is advised. No special procedures, such as fasting or purging, are required. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Mebendazole in adult patients. ### Non–Guideline-Supported Use - Dosage: 200 mg PO q12h for 20 days - Dosage Taenias: 300 mg q12h for 3-6 days Echinococcus: Mebendazol erradicates Echinococcus granulosus, but only slows down growth of Echinococcus multilocularis - Taenias: 300 mg q12h for 3-6 days - Echinococcus: Mebendazol erradicates Echinococcus granulosus, but only slows down growth of Echinococcus multilocularis - Dosage: 300 mg/day PO for 28-45 days # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Mebendazole in pediatric patients. ### Non–Guideline-Supported Use - Dosage: 200 mg PO q12h for 20 days # Contraindications Mebendazole is contraindicated in persons who have shown hypersensitivity to the drug. # Warnings There is no evidence that mebendazole, even at high doses, is effective for hydatid disease. There have been rare reports of neutropenia and agranulocytosis when mebendazole was taken for prolonged periods and at dosages substantially above those recommended. # Adverse Reactions ## Clinical Trials Experience - Abdominal pain - Diarrhea in cases of massive infection and expulsion of worms. - Rash - Urticaria - Angioedema - Convulsions - Liver function test elevations AST (SGOT), ALT (SGPT), and GGT - Hepatitis when mebendazole was taken for prolonged periods and at dosages substantially above those recommended. - Neutropenia - Agranulocytosis ## Postmarketing Experience There is limited information regarding Mebendazole Postmarketing Experience in the drug label. # Drug Interactions - Preliminary evidence suggests that cimetidine inhibits mebendazole metabolism and may result in an increase in plasma concentrations of mebendazole. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): C - Mebendazole has shown embryotoxic and teratogenic activity in pregnant rats at single oral doses as low as 10 mg/kg (approximately equal to the human dose, based on mg/m2). In view of these findings the use of mebendazole is not recommended in pregnant women. Although there are no adequate and well-controlled studies in pregnant women, a postmarketing survey has been done of a limited number of women who inadvertently had consumed mebendazole during the first trimester of pregnancy. The incidence of spontaneous abortion and malformation did not exceed that in the general population. In 170 deliveries on term, no teratogenic risk of mebendazole was identified. Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Mebendazole in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Mebendazole during labor and delivery. ### Nursing Mothers - It is not known whether mebendazole is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when mebendazole is administered to a nursing woman. ### Pediatric Use - The drug has not been extensively studied in children under two years; therefore, in the treatment of children under two years the relative benefit/risk should be considered. ### Geriatic Use There is no FDA guidance on the use of Mebendazole in geriatric settings. ### Gender There is no FDA guidance on the use of Mebendazole with respect to specific gender populations. ### Race There is no FDA guidance on the use of Mebendazole with respect to specific racial populations. ### Renal Impairment There is no FDA guidance on the use of Mebendazole in patients with renal impairment. ### Hepatic Impairment There is no FDA guidance on the use of Mebendazole in patients with hepatic impairment. ### Females of Reproductive Potential and Males - In carcinogenicity tests of mebendazole in mice and rats, no carcinogenic effects were seen at doses as high as 40 mg/kg (one to two times the human dose, based on mg/m2) given daily over two years. Dominant lethal mutation tests in mice showed no mutagenicity at single doses as high as 640 mg/kg (18 times the human dose, based on mg/m2). Neither the spermatocyte test, the F1 translocation test, nor the Ames test indicated mutagenic properties. Doses up to 40 mg/kg in mice (equal to the human dose, based on mg/m2), given to males for 60 days and to females for 14 days prior to gestation, had no effect upon fetuses and offspring, though there was slight maternal toxicity. ### Immunocompromised Patients There is no FDA guidance one the use of Mebendazole in patients who are immunocompromised. # Administration and Monitoring ### Administration There is limited information regarding Mebendazole Administration in the drug label. ### Monitoring - Periodic assessment of organ system functions, including hematopoietic and hepatic, is advisable during prolonged therapy. # IV Compatibility There is limited information regarding the compatibility of Mebendazole and IV administrations. # Overdosage - In the event of accidental overdosage, gastrointestinal complaints lasting up to a few hours may occur. Vomiting and purging should be induced # Pharmacology ## Mechanism of Action - Mebendazole inhibits the formation of the worms’ microtubules and causes the worms’ glucose depletion. ## Structure - Mebendazole is methyl 5-benzoylbenzimidazole-2-carbamate and has the following structural formula: ## Pharmacodynamics There is limited information regarding Mebendazole Pharmacodynamics in the drug label. ## Pharmacokinetics - Following administration of 100 mg twice daily for three consecutive days, plasma levels of mebendazole and its primary metabolite, the 2-amine, do not exceed 0.03 mcg/mL and 0.09 mcg/mL, respectively. All metabolites are devoid of anthelmintic activity. In man, approximately 2% of administered mebendazole is excreted in urine and the remainder in the feces as unchanged drug or a primary metabolite. ## Nonclinical Toxicology There is limited information regarding Mebendazole Nonclinical Toxicology in the drug label. # Clinical Studies There is limited information regarding Mebendazole Clinical Studies in the drug label. # How Supplied - Mebendazole 100 mg, chewable, round, light peach-colored, unscored tablets, debossed “93” and “107” on one side and plain on the other side, supplied in ## Storage Store at 20° to 25°C (68° to 77°F) # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information There is limited information regarding Mebendazole Patient Counseling Information in the drug label. # Precautions with Alcohol Alcohol-Mebendazole interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - Vermox # Look-Alike Drug Names There is limited information regarding Mebendazole Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	Mebendazole Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Alberto Plate [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 Mebendazole is a broad-spectrum anthelmintic that is FDA approved for the treatment of Enterobius vermicularis (pinworm), Trichuris trichiura (whipworm), Ascaris lumbricoides (common roundworm), Ancylostoma duodenale (common hookworm), Necator americanus (American hookworm) in single or mixed infections. Common adverse reactions include rash, abdominal pain, constipation, diarrhea and headache. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) The same dosage schedule applies to children and adults. The tablet may be chewed, swallowed, or crushed and mixed with food. If the patient is not cured three weeks after treatment, a second course of treatment is advised. No special procedures, such as fasting or purging, are required. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Mebendazole in adult patients. ### Non–Guideline-Supported Use - Dosage: 200 mg PO q12h for 20 days[1][2] - Dosage Taenias: 300 mg q12h for 3-6 days[3] Echinococcus: Mebendazol erradicates Echinococcus granulosus, but only slows down growth of Echinococcus multilocularis [1] - Taenias: 300 mg q12h for 3-6 days[3] - Echinococcus: Mebendazol erradicates Echinococcus granulosus, but only slows down growth of Echinococcus multilocularis [1] - Dosage: 300 mg/day PO for 28-45 days[4] # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Mebendazole in pediatric patients. ### Non–Guideline-Supported Use - Dosage: 200 mg PO q12h for 20 days[1][2] # Contraindications Mebendazole is contraindicated in persons who have shown hypersensitivity to the drug. # Warnings There is no evidence that mebendazole, even at high doses, is effective for hydatid disease. There have been rare reports of neutropenia and agranulocytosis when mebendazole was taken for prolonged periods and at dosages substantially above those recommended. # Adverse Reactions ## Clinical Trials Experience - Abdominal pain - Diarrhea in cases of massive infection and expulsion of worms. - Rash - Urticaria - Angioedema - Convulsions - Liver function test elevations AST (SGOT), ALT (SGPT), and GGT - Hepatitis when mebendazole was taken for prolonged periods and at dosages substantially above those recommended. - Neutropenia - Agranulocytosis ## Postmarketing Experience There is limited information regarding Mebendazole Postmarketing Experience in the drug label. # Drug Interactions - Preliminary evidence suggests that cimetidine inhibits mebendazole metabolism and may result in an increase in plasma concentrations of mebendazole. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): C - Mebendazole has shown embryotoxic and teratogenic activity in pregnant rats at single oral doses as low as 10 mg/kg (approximately equal to the human dose, based on mg/m2). In view of these findings the use of mebendazole is not recommended in pregnant women. Although there are no adequate and well-controlled studies in pregnant women, a postmarketing survey has been done of a limited number of women who inadvertently had consumed mebendazole during the first trimester of pregnancy. The incidence of spontaneous abortion and malformation did not exceed that in the general population. In 170 deliveries on term, no teratogenic risk of mebendazole was identified. Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Mebendazole in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Mebendazole during labor and delivery. ### Nursing Mothers - It is not known whether mebendazole is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when mebendazole is administered to a nursing woman. ### Pediatric Use - The drug has not been extensively studied in children under two years; therefore, in the treatment of children under two years the relative benefit/risk should be considered. ### Geriatic Use There is no FDA guidance on the use of Mebendazole in geriatric settings. ### Gender There is no FDA guidance on the use of Mebendazole with respect to specific gender populations. ### Race There is no FDA guidance on the use of Mebendazole with respect to specific racial populations. ### Renal Impairment There is no FDA guidance on the use of Mebendazole in patients with renal impairment. ### Hepatic Impairment There is no FDA guidance on the use of Mebendazole in patients with hepatic impairment. ### Females of Reproductive Potential and Males - In carcinogenicity tests of mebendazole in mice and rats, no carcinogenic effects were seen at doses as high as 40 mg/kg (one to two times the human dose, based on mg/m2) given daily over two years. Dominant lethal mutation tests in mice showed no mutagenicity at single doses as high as 640 mg/kg (18 times the human dose, based on mg/m2). Neither the spermatocyte test, the F1 translocation test, nor the Ames test indicated mutagenic properties. Doses up to 40 mg/kg in mice (equal to the human dose, based on mg/m2), given to males for 60 days and to females for 14 days prior to gestation, had no effect upon fetuses and offspring, though there was slight maternal toxicity. ### Immunocompromised Patients There is no FDA guidance one the use of Mebendazole in patients who are immunocompromised. # Administration and Monitoring ### Administration There is limited information regarding Mebendazole Administration in the drug label. ### Monitoring - Periodic assessment of organ system functions, including hematopoietic and hepatic, is advisable during prolonged therapy. # IV Compatibility There is limited information regarding the compatibility of Mebendazole and IV administrations. # Overdosage - In the event of accidental overdosage, gastrointestinal complaints lasting up to a few hours may occur. Vomiting and purging should be induced # Pharmacology ## Mechanism of Action - Mebendazole inhibits the formation of the worms’ microtubules and causes the worms’ glucose depletion. ## Structure - Mebendazole is methyl 5-benzoylbenzimidazole-2-carbamate and has the following structural formula: ## Pharmacodynamics There is limited information regarding Mebendazole Pharmacodynamics in the drug label. ## Pharmacokinetics - Following administration of 100 mg twice daily for three consecutive days, plasma levels of mebendazole and its primary metabolite, the 2-amine, do not exceed 0.03 mcg/mL and 0.09 mcg/mL, respectively. All metabolites are devoid of anthelmintic activity. In man, approximately 2% of administered mebendazole is excreted in urine and the remainder in the feces as unchanged drug or a primary metabolite. ## Nonclinical Toxicology There is limited information regarding Mebendazole Nonclinical Toxicology in the drug label. # Clinical Studies There is limited information regarding Mebendazole Clinical Studies in the drug label. # How Supplied - Mebendazole 100 mg, chewable, round, light peach-colored, unscored tablets, debossed “93” and “107” on one side and plain on the other side, supplied in ## Storage Store at 20° to 25°C (68° to 77°F) # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information There is limited information regarding Mebendazole Patient Counseling Information in the drug label. # Precautions with Alcohol Alcohol-Mebendazole interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - Vermox # Look-Alike Drug Names There is limited information regarding Mebendazole Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	https://www.wikidoc.org/index.php/Mebendazole
108a100c1f9bdf1f5d5e631541c3c2a06a84aeec	wikidoc	Medial cord	Medial cord The Medial cord is a division of the brachial plexus. The medial cord gives rise to the following nerves: - The median pectoral nerve, C8 and T1, to the pectoralis muscle - The medial brachial cutaneous nerve, T1 - The medial antebrachial cutaneous nerve, C8 and T1 - The median nerve, partly. The other part comes from the lateral cord. C7, C8 and T1 nerve roots. The first branch of the median nerve is to the pronator teres muscle, then the flexor carpi radialis, the palmaris longus and the flexor digitorum superficialis. The median nerve provides sensation to the anterior palm, the anterior thumb, index finger and middle finger. It is the nerve compressed in carpal tunnel syndrome. - The ulnar nerve originates in nerve roots C7, C8 and T1. It provides sensation to the ring and pinky fingers. It innervates the flexor carpi ulnaris muscle, the flexor digitorum profundus muscle to the ring and pinky fingers, and the intrinsic muscles of the hand (the interosseous muscle, the lumbrical muscles and the flexor pollicus brevis muscle). This nerve traverses a groove on the elbow called the cubital tunnel, also known as the funny bone. Striking the nerve at this point produces an unpleasant sensation in the ring and little fingers.	Medial cord Template:Infobox Nerve Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] The Medial cord is a division of the brachial plexus. The medial cord gives rise to the following nerves: - The median pectoral nerve, C8 and T1, to the pectoralis muscle - The medial brachial cutaneous nerve, T1 - The medial antebrachial cutaneous nerve, C8 and T1 - The median nerve, partly. The other part comes from the lateral cord. C7, C8 and T1 nerve roots. The first branch of the median nerve is to the pronator teres muscle, then the flexor carpi radialis, the palmaris longus and the flexor digitorum superficialis. The median nerve provides sensation to the anterior palm, the anterior thumb, index finger and middle finger. It is the nerve compressed in carpal tunnel syndrome. - The ulnar nerve originates in nerve roots C7, C8 and T1. It provides sensation to the ring and pinky fingers. It innervates the flexor carpi ulnaris muscle, the flexor digitorum profundus muscle to the ring and pinky fingers, and the intrinsic muscles of the hand (the interosseous muscle, the lumbrical muscles and the flexor pollicus brevis muscle). This nerve traverses a groove on the elbow called the cubital tunnel, also known as the funny bone. Striking the nerve at this point produces an unpleasant sensation in the ring and little fingers. # External links - Template:EatonHand - Template:UMichAtlas Template:Brachial plexus Template:WikiDoc Sources	https://www.wikidoc.org/index.php/Medial_cord
fab0f9634d0db68f3be0c5d3599b53dd6b01d924	wikidoc	MedlinePlus	MedlinePlus MedlinePlus, with the MedlinePlus Medical Encyclopedia, is a website network containing health information from the world's largest medical library, the United States National Library of Medicine, in cooperation with the National Institutes of Health. The website also contains an online medical dictionary, drug/herbal index, and a news service for medical news reports. The site is intended to be used by health care providers and patients, and designed to provide up-to-date, authoritative information. MedlinePlus is updated daily. MedlinePlus provides: - information from the National Institutes of Health and other sources on over 740 diseases and conditions - interactive health tutorials - lists of hospitals and physicians - a medical encyclopedia (A.D.A.M., Inc. Health Illustrated Encyclopedia) - a medical dictionary (Merriam-Webster) - health information in Spanish - extensive information on prescription and nonprescription drugs - health information from the media - links to local health resources via the Go Local projects - links to thousands of clinical trials - links to pre-formulated searches of the MEDLINE/PubMed database for recent research articles on selected health topics There is no advertising on the site and MedlinePlus does not endorse companies or products. # Notes - ↑ Jump up to: 1.0 1.1 "MedlinePlus Health Information" (home page, overview), MedlinePlus website, U.S. National Library of Medicine, 8600 Rockville Pike, Bethesda, MD, and National Institutes of Health, USA, October 2007, webpage: MedlinePlus-Gov.	MedlinePlus MedlinePlus, with the MedlinePlus Medical Encyclopedia, is a website network containing health information from the world's largest medical library, the United States National Library of Medicine, in cooperation with the National Institutes of Health.[1] The website also contains an online medical dictionary, drug/herbal index, and a news service for medical news reports.[1] The site is intended to be used by health care providers and patients, and designed to provide up-to-date, authoritative information. MedlinePlus is updated daily. MedlinePlus provides: - information from the National Institutes of Health and other sources on over 740 diseases and conditions - interactive health tutorials - lists of hospitals and physicians - a medical encyclopedia (A.D.A.M., Inc. Health Illustrated Encyclopedia) - a medical dictionary (Merriam-Webster) - health information in Spanish - extensive information on prescription and nonprescription drugs - health information from the media - links to local health resources via the Go Local projects - links to thousands of clinical trials - links to pre-formulated searches of the MEDLINE/PubMed database for recent research articles on selected health topics There is no advertising on the site and MedlinePlus does not endorse companies or products. # Notes - ↑ Jump up to: 1.0 1.1 "MedlinePlus Health Information" (home page, overview), MedlinePlus website, U.S. National Library of Medicine, 8600 Rockville Pike, Bethesda, MD, and National Institutes of Health, USA, October 2007, webpage: MedlinePlus-Gov.	https://www.wikidoc.org/index.php/MedlinePlus
5204b21d2963f8784430432d69fffcab6c364293	wikidoc	Meglitinide	Meglitinide The meglitinide class of drugs treat diabetes type 2 by blocking the potassium channels in beta cells, which closes the ATP-dependent potassium channels and opens the cells' calcium channels. The resulting calcium influx causes the cells to secrete insulin. # Drugs The main branded drug in the meglitinide class is Novo Nordisk's repaglinide (Prandin), which gained FDA approval in 1997. Another type of drug in this class is nateglinide (Starlix). These drugs should be taken 0-30 minutes prior to eating. Follow the instructions given to you by your physician/nurse. # Side-effects Side effects include weight gain and hypoglycemia. While the potential for hypoglycemia is less than for those on sulfonylureas, it is still a serious potential side effect that can be life-threatening. Patients on this medication should know the signs and symptoms of hypoglycemia and appropriate action to take.	Meglitinide The meglitinide class of drugs treat diabetes type 2 by blocking the potassium channels in beta cells, which closes the ATP-dependent potassium channels and opens the cells' calcium channels. The resulting calcium influx causes the cells to secrete insulin. # Drugs The main branded drug in the meglitinide class is Novo Nordisk's repaglinide (Prandin), which gained FDA approval in 1997. Another type of drug in this class is nateglinide (Starlix). These drugs should be taken 0-30 minutes prior to eating. Follow the instructions given to you by your physician/nurse. # Side-effects Side effects include weight gain and hypoglycemia. While the potential for hypoglycemia is less than for those on sulfonylureas, it is still a serious potential side effect that can be life-threatening. Patients on this medication should know the signs and symptoms of hypoglycemia and appropriate action to take. Template:Oral hypoglycemics Template:WH Template:WikiDoc Sources	https://www.wikidoc.org/index.php/Meglitinide
5ed84654e40a444abf19158ca120934fc976c481	wikidoc	Melarsoprol	Melarsoprol # Overview Melarsoprol (INN) is a prodrug used in the treatment of East African (rhodesiense) human African trypanosomiasis. It is produced by Sanofi-Aventis and is on the World Health Organization's List of Essential Medicines. Freidheim demonstrated in 1949 the effects of melarsoprol against late-state trypanosomiasis. Melarsoprol is the dimercaptopropanol derivative of melarsen oxide (Mel Ox), whose structure is shown below: The main drug prescribed is Mel B, however, an alarming number of side effects occur from treatment. The active metabolite of Mel B is Mel Ox, which is taken up by the TbAT1 adenosine transporter in T. brucei brucei. Due to side effects similar to arsenic poisoning, other pharmacological agents have become first-line treatments for stage one of the disease and for certain trypanosomes. # Treatment All people with confirmed trypanosome-caused disease must be treated. Treatment differs based on whether disease levels are considered stage 1 or stage 2 and based on which specific trypanosome has infected a patient. Below are treatment options (all adapted from ). Melasarprol is used in the treatment of the second stage of the disease, and is the only treatment available for late-stage T. b. rhodesiense treatment. # Mechanism of action Melarsoprol is a prodrug, which is metabolized to melarsen oxide (Mel Ox) as its active form. Mel Ox is an arsen-oxide which irreversibly binds to vicinal sulfhydryl groups causing the inactivation of enzymes. The inability to distinguish between host and parasites renders this drug highly toxic with many side effects. Mel Ox reacts with trypanothione (a spermidine-glutathione adduct which replaces glutathione in trypanosomes). Binding to this adduct forms a melarsen oxide-trypanothione adduct (Mel T) which competitively inhibits trypanothione reductase, effectively killing the parasitic cell. # Dosage Two arsenic-containing stereoisomers exist in a 3:1 molar ratio. As melarsarprol is insoluble in water, dosage occurs via a 3.6% propylene glycol intravenous injection. # Pharmacokinetics The half-life of melarsoprol is less than 1 hour, but bioassays indicate a 35-hour half-life. This is indicative of pharmacologic agents with active metabolites. One such metabolite, Mel Ox, reaches maximum plasma levels about 15 minutes after melarsoprol injection. Clearance is at 21.5 ml/min/kg and Mel Ox half-life is 3.9 hours. # Failure Rates & Resistance Failure rates of 20-27% in certain African countries have been reported. These are linked to both drug resistance and other mechanisms which have not yet been elucidated. Resistance is likely due to transport problems associated with the P2 transporter, an adenine-adenosine transporter. Resistance can occur with point mutations within this transporter. # Therapeutic uses Due to high toxicity, melarsarprol is reserved only for the most dangerous of cases - stage 2 infection. Other agents with lower toxicity are used in stage 1. The 2009 approval of nifurtimoxeflornithine combination therapy (NECT) for the treatment of T. b. gambiense served to limit merlarsoprol to the treatment of second-stage T. b. rhodesiense solely. # Side effects Being a toxic organic compound of arsenic, melarsoprol is a highly dangerous treatment which is only administered by injection under the supervision of a physician, as it can produce similar effects as arsenic poisoning. Among clinicians, it is colloquially referred to as "arsenic in antifreeze". It is known to cause a range of side effects including convulsions, fever, loss of consciousness, rashes, bloody stools, nausea, and vomiting. It causes encephalopathy in 5–10% of cases, of which 40% die.	Melarsoprol Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview Melarsoprol (INN) is a prodrug used in the treatment of East African (rhodesiense) human African trypanosomiasis.[1] It is produced by Sanofi-Aventis and is on the World Health Organization's List of Essential Medicines.[2] Freidheim demonstrated in 1949 the effects of melarsoprol against late-state trypanosomiasis. Melarsoprol is the dimercaptopropanol derivative of melarsen oxide (Mel Ox), whose structure is shown below:[3] The main drug prescribed is Mel B, however, an alarming number of side effects occur from treatment. The active metabolite of Mel B is Mel Ox, which is taken up by the TbAT1 adenosine transporter in T. brucei brucei.[4] Due to side effects similar to arsenic poisoning, other pharmacological agents have become first-line treatments for stage one of the disease and for certain trypanosomes. # Treatment All people with confirmed trypanosome-caused disease must be treated. Treatment differs based on whether disease levels are considered stage 1 or stage 2 and based on which specific trypanosome has infected a patient. Below are treatment options (all adapted from [5]). Melasarprol is used in the treatment of the second stage of the disease, and is the only treatment available for late-stage T. b. rhodesiense treatment.[6] # Mechanism of action Melarsoprol is a prodrug, which is metabolized to melarsen oxide (Mel Ox) as its active form. Mel Ox is an arsen-oxide which irreversibly binds to vicinal sulfhydryl groups causing the inactivation of enzymes. The inability to distinguish between host and parasites renders this drug highly toxic with many side effects. Mel Ox reacts with trypanothione (a spermidine-glutathione adduct which replaces glutathione in trypanosomes). Binding to this adduct forms a melarsen oxide-trypanothione adduct (Mel T) which competitively inhibits trypanothione reductase, effectively killing the parasitic cell.[3] # Dosage Two arsenic-containing stereoisomers exist in a 3:1 molar ratio. As melarsarprol is insoluble in water, dosage occurs via a 3.6% propylene glycol intravenous injection.[3] # Pharmacokinetics The half-life of melarsoprol is less than 1 hour, but bioassays indicate a 35-hour half-life. This is indicative of pharmacologic agents with active metabolites. One such metabolite, Mel Ox, reaches maximum plasma levels about 15 minutes after melarsoprol injection. Clearance is at 21.5 ml/min/kg and Mel Ox half-life is 3.9 hours.[7] # Failure Rates & Resistance Failure rates of 20-27% in certain African countries have been reported. These are linked to both drug resistance and other mechanisms which have not yet been elucidated. Resistance is likely due to transport problems associated with the P2 transporter, an adenine-adenosine transporter. Resistance can occur with point mutations within this transporter.[3] # Therapeutic uses Due to high toxicity, melarsarprol is reserved only for the most dangerous of cases - stage 2 infection. Other agents with lower toxicity are used in stage 1.[1] The 2009 approval of nifurtimoxeflornithine combination therapy (NECT) for the treatment of T. b. gambiense served to limit merlarsoprol to the treatment of second-stage T. b. rhodesiense solely.[8] # Side effects Being a toxic organic compound of arsenic, melarsoprol is a highly dangerous treatment which is only administered by injection under the supervision of a physician, as it can produce similar effects as arsenic poisoning. Among clinicians, it is colloquially referred to as "arsenic in antifreeze".[9] It is known to cause a range of side effects including convulsions, fever, loss of consciousness, rashes, bloody stools, nausea, and vomiting. It causes encephalopathy in 5–10% of cases, of which 40% die.[10]	https://www.wikidoc.org/index.php/Melarsoprol
3620db27b7d7591d53ec60b92f8ed8e542bc7d43	wikidoc	Melioidosis	Melioidosis Melioidosis (also called Whitmore disease or Nightcliff gardener's disease) is an infectious disease caused by a Gram-negative bacterium, Burkholderia pseudomallei, found in soil and water. It is of public health importance in endemic areas, particularly in Thailand and northern Australia. It exists in acute and chronic forms. The causative organism, Burkholderia pseudomallei, was thought to be a member of the Pseudomonas genus and was previously known as Pseudomonas pseudomallei. This organism is phylogenetically related closely to Burkholderia mallei, the organism that causes glanders. # Epidemiology Melioidosis is endemic in parts of south east Asia (including Thailand, Singapore, Malaysia, Burma and Vietnam) and northern Australia. Multiple cases have also been described in southern China and Hong Kong, Brunei, Taiwan, India, and Laos, and sporadic cases in Central and South America, the Middle East, the Pacific and several African countries. Although only one case of melioidosis has ever been reported in Bangladesh, at least five cases have been imported to the UK from that country, which suggests that that melioidosis is endemic to that country and that there is a serious problem of underdiagnosis or under-reporting in that country, most likely due to a lack of adequate laboratory facilities. An outbreak at the Paris Zoo in the 1970s ("L’affaire du jardin des plantes") was thought that have resulted from an imported panda.. In northeast Thailand, 80% of children are positive for antibodies against B. pseudomallei by the age of 4; the figures are lower in other parts of the world. It affects humans as well as other animals such as goats, sheep, horses and cattle. Cattle, water buffalo, and crocodiles are considered to be relatively resistant to melioidosis despite their constant exposure to mud. The mode of infection is believed to be either through a break in the skin, or through the inhalation of aerosolized B. pseudomallei. The single most important risk factor for developing severe melioidosis is diabetes mellitus. Other risk factors include thalassaemia, kidney disease, and occupation (rice paddy farmers). There is a clear association with increased rainfall: with the number (and seversity) of cases increasing following increased precipitation. # Clinical features ## Acute melioidosis In the subgroup of patients where an inoculating event was noted, the mean incubation period of acute melioidosis was 9 days (range 1-21 days). Patients with latent melioidosis may be symptom free for decades; the longest period between presumed exposure and clinical presentation is 62 years.. The potential for prolonged incubation was recognized in US servicemen involved in the Vietnam War, and was referred to as the "Vietnamese time-bomb". There is a wide spectrum of severity; in chronic presentations, symptoms may last months, but fulminant infection, particularly associated with near-drowning, may present with severe symptoms over hours. A patient with active melioidosis usually presents with fever. Pain or other symptoms may be suggestive of a clinical focus, which is found in around 75% of patients. Such symptoms include cough or pleuritic chest pain suggestive of pneumonia, bone or joint pain suggestive of osteomyelitis or septic arthritis, or cellulitis. Intra-abdominal infection (including liver and/or splenic abscesses, or prostatic abscesses) do not usually present with focal pain, and imaging of these organs using ultrasound or CT should be performed routinely. It has been suggested that B. pseudomallei abscesses have a characteristic honeycomb architecture (hypoechoic, multi-septate, multiloculate).. There are regional variations in disease presentation: parotid abscesses characteristically occur in Thai children but this presentation has only been described once in Australia. Conversely, prostatic abscesses are found in up to 20% of Australian males but are rarely described elsewhere. An encephalomyelitis syndrome is recognised in northern Australia. Patients with melioidosis usually have risk factors for disease, such as diabetes, thalassemia, hazardous alcohol use or renal disease, and frequently give a history of occupational or recreational exposure to mud or pooled surface water. However, otherwise healthy patients, including children, may also get melioidosis. In up to 25% of patients, no focus of infection is found and the diagnosis is usually made on blood cultures or throat swab. Melioidosis is said to be able to affect any organ in the body except the heart valves (endocarditis). Although meningitis has been described secondary to ruptured brain abscesses, primary meningitis has not been described. Less common manifestation include intravascular infection, lymph node abscesses (1.2–2.2%), pyopericardium and myocarditis, mediastinal infection, and thyroid and scrotal abscesses and ocular infection. ## Chronic melioidosis Chronic melioidosis is usually defined by a duration of symptoms greater than 2 months and occurs in approximately 10% of patients. The clinical presentation of chronic melioidosis is protean and includes such presentations as chronic skin infection, skin ulcers and lung nodules or chronic pneumonia, closely mimicking tuberculosis, sometimes being called "Vietnamese tuberculosis". # Diagnosis A definitive diagnosis is made by culturing the organism from any clinical sample. A definite history of contact with soil may not be elicited as melioidosis can be dormant for many years before becoming acute. Attention should be paid to a history of travel to endemic areas in returned travellers. Some authors recommend considering possibility of melioidosis in every febrile patient with a history of traveling to and/or staying at endemic areas. A complete screen (blood culture, sputum culture, urine culture, throat swab and culture of any aspirated pus) should be performed on all patients with suspected melioidosis (culture on blood agar as well as Ashdown's medium). A definitive diagnosis is made by growing B. pseudomallei from any site. A throat swab is not sensitive but is 100% specific if positive, and compares favourably with sputum culture. The sensitivity of urine culture is increased if a centrifuged specimen is cultured, and any bacterial growth should be reported (not just growth above 104 organisms/ml which is the usual cut off). Very occasionally, bone marrow culture may be positive in patients who have negative blood cultures for B. pseudomallei, but these are not usually recommended. A common error made by clinicians unfamiliar with the diagnosis of melioidosis is to only send a specimen from the affected site (which is the usual procedure for most other infections) instead of sending a full screen. Ashdown's medium, a selective medium containing gentamicin, may be required for cultures taken from non-sterile sites. Burkholderia cepacia medium may be a useful alternative selective medium in non-endemic areas, where Ashdown's is not available. A new medium derived from Ashdown known as Francis medium may help differentiate B. pseudomallei from B. cepacia and may help in the early diagnosis of melioidosis, but has not yet been extensively clinically validated. Many commercial kits for identifying bacteria may mis-identify B. pseudomallei (see Burkholderia pseudomallei for a more detailed discussion of these issues). There is also a serological test for melioidosis (indirect haemagglutination), but this is not commercially available in most countries. A high background titre may reduce the positive predictive value of serological tests in endemic countries. A specific direct immunofluorescent test and latex agglutination, based on monoclonal antibodies, are used widely in Thailand but are not available elsewhere. Imaging of the abdomen using CT scans or ultrasound is recommended routinely, as abscesses may not be clinically apparent and may be coexist with disease elsewhere. Australian authorities suggest imaging of the prostate specificcally due to the high incidence of prostatic abscesses in northern Australian patients. A chest x-ray is also considered routine, with other investigations as clinically indicated. The differential diagnosis is extensive; melioidosis may mimic many other infections, including tuberculosis. # Treatment ## Current treatment The treatment of melioidosis is divided into two stages, an intravenous high intensity stage and an oral maintenance stage to prevent recurrence. Surgical drainage is usually indicated for prostatic abscesses and septic arthritis, may be indicated for parotid abscesses and not usually indicated for hepatosplenic abscesses. Adjunctive treatment with GCSF or co-trimoxazole were not associated with decreased fatality rates in trials in Thailand. # Antimicrobial therapy - 1. Melioidosis - 1.1 Intial intensive therapy (Minimum of 10-14 days) - Preferred regimen (1): Ceftazidime 50 mg/kg upto 2 g q6h - Preferred regimen (2): Meropenem 25 mg/kg upto 1 g q8h - Preferred regimen (3): Imipenem 25 mg/kg upto 1 g q6h - Note: Any one of the three may be combined with TMP-SMX 6/30 mg/kg upto 320/1600 mg/kg q12h (recommended for neurologic, bone, joint, cutaneous and prostatic melioidosis) - 1.2 Eradication therapy (Minimum of 3 months) - Preferred regimen: TMP-SMX 6/30 mg/kg upto 320/1600 mg/kg q12h ## Historical treatment Prior to 1989, the standard treatment for acute melioidosis was a four-drug combination of chloramphenicol, co-trimoxazole and doxycycline; this regimen is associated with a mortality rate of 80% and should no longer be used unless no other alternatives are available. All four drugs are bacteriostatic (they stop the bacterium from growing but do not kill it) and the action of co-trimoxazole antagonizes both chloramphenicol and doxycycline. # Prognosis Without access to appropriate antibiotics (principally ceftazidime or meropenem), the septicemic form of melioidosis has a mortality rate that exceeds 90%. With appropriate antibiotics, the mortality rate is about 10% for uncomplicated cases but up to 80% for cases with bacteraemia or severe sepsis. It seems certain that access to intensive care facilities is also important, and probably at least partially explains why total mortality is 20% in Northern Australia but 40% in Northeast Thailand. Response to appropriate antibiotic treatment is slow with the average duration of fever following treatment being 5-9 days. Relapse occurs in 10 to 20% of patients. While molecular studies have established that the majority of recurrences are due to the original infecting strain, a significant proportion of recurrences (perhaps up to a quarter) in endemic areas may be due to reinfection, particularly after 2 years. Risk factors include severity of disease (patients with positive blood cultures or multifocal disease have a higer risk of relapse), choice of antibiotic for eradication therapy (doxycycline monotherapy and fluoroquinolone therapy are not as effective), poor compliance with eradication therapy and duration of eradication therapy less than 8 weeks. # Prevention There are only few unusual cases documented for person-to-person transmission; no isolation is required for patients with melioidosis. Lab workers should handle Burkholderia pseudomallei under BSL-3 isolation conditions, as laboratory acquired melioidosis has been described. Following laboratory exposure, post exposure prophylaxis with cotrimoxazole has been suggested but has not been evaluated by clinical trials. In endemic areas, people (rice-paddy farmers in particular) are warned to avoid contact with soil, mud and surface water where possible. Case clusters have been described following flooding and cyclones and probably relate to exposure. Other case clusters have related to contamination of drinking water supplies. Populations at risk include patients with diabetes mellitus, chronic renal failure, chronic lung disease or patients with an immune deficiency of any kind. The effectiveness of measures to reduce exposure to the causative organism have not been established. A vaccine is not yet available. # Biological warfare potential There has been interest in melioidosis because it has the potential to be developed as a biological weapon. It is classed by the US Centers for Disease Control (CDC) as a Category B agent. B. pseudomallei, like its relative B. mallei which causes glanders, was studied by the U.S. as a potential biological warfare agent, but was never weaponized. It has been reported that the Soviet Union was also experimenting with B. pseudomallei as a BW agent. # Synonyms The majority of these synonyms are obsolete eponyms. - pseudoglanders - Whitmore's disease (after Captain Alfred Whitmore, who first discovered the disease) - Nightcliff gardener's disease (Nightcliff is a suburb of Darwin, Australia where melioidosis is endemic) - Paddy-field disease	Melioidosis Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Melioidosis (also called Whitmore disease or Nightcliff gardener's disease) is an infectious disease caused by a Gram-negative bacterium, Burkholderia pseudomallei, found in soil and water. It is of public health importance in endemic areas, particularly in Thailand and northern Australia. It exists in acute and chronic forms. The causative organism, Burkholderia pseudomallei, was thought to be a member of the Pseudomonas genus and was previously known as Pseudomonas pseudomallei. This organism is phylogenetically related closely to Burkholderia mallei, the organism that causes glanders. # Epidemiology Melioidosis is endemic in parts of south east Asia (including Thailand, Singapore, Malaysia, Burma and Vietnam) and northern Australia.[1][2] Multiple cases have also been described in southern China and Hong Kong, Brunei, Taiwan[3], India, and Laos, and sporadic cases in Central and South America, the Middle East, the Pacific and several African countries. Although only one case of melioidosis has ever been reported in Bangladesh,[4] at least five cases have been imported to the UK from that country, which suggests that that melioidosis is endemic to that country and that there is a serious problem of underdiagnosis or under-reporting in that country,[5] most likely due to a lack of adequate laboratory facilities. An outbreak at the Paris Zoo in the 1970s ("L’affaire du jardin des plantes") was thought that have resulted from an imported panda.[6]. In northeast Thailand, 80% of children are positive for antibodies against B. pseudomallei by the age of 4;[7] the figures are lower in other parts of the world.[8][9][10][11] It affects humans as well as other animals such as goats, sheep, horses and cattle. Cattle, water buffalo, and crocodiles are considered to be relatively resistant to melioidosis despite their constant exposure to mud. The mode of infection is believed to be either through a break in the skin, or through the inhalation of aerosolized B. pseudomallei. The single most important risk factor for developing severe melioidosis is diabetes mellitus. Other risk factors include thalassaemia, kidney disease, and occupation (rice paddy farmers).[12] There is a clear association with increased rainfall: with the number (and seversity) of cases increasing following increased precipitation[13][14][15][16]. # Clinical features ## Acute melioidosis In the subgroup of patients where an inoculating event was noted, the mean incubation period of acute melioidosis was 9 days (range 1-21 days). Patients with latent melioidosis may be symptom free for decades; the longest period between presumed exposure and clinical presentation is 62 years.[17]. The potential for prolonged incubation was recognized in US servicemen involved in the Vietnam War, and was referred to as the "Vietnamese time-bomb". There is a wide spectrum of severity; in chronic presentations, symptoms may last months, but fulminant infection, particularly associated with near-drowning, may present with severe symptoms over hours. A patient with active melioidosis usually presents with fever. Pain or other symptoms may be suggestive of a clinical focus, which is found in around 75% of patients. Such symptoms include cough or pleuritic chest pain suggestive of pneumonia, bone or joint pain suggestive of osteomyelitis or septic arthritis, or cellulitis. Intra-abdominal infection (including liver and/or splenic abscesses, or prostatic abscesses) do not usually present with focal pain, and imaging of these organs using ultrasound or CT should be performed routinely. It has been suggested that B. pseudomallei abscesses have a characteristic honeycomb architecture (hypoechoic, multi-septate, multiloculate).[18]. There are regional variations in disease presentation: parotid abscesses characteristically occur in Thai children but this presentation has only been described once in Australia. [19] Conversely, prostatic abscesses are found in up to 20% of Australian males but are rarely described elsewhere. An encephalomyelitis syndrome is recognised in northern Australia. Patients with melioidosis usually have risk factors for disease, such as diabetes, thalassemia, hazardous alcohol use or renal disease, and frequently give a history of occupational or recreational exposure to mud or pooled surface water. However, otherwise healthy patients, including children, may also get melioidosis. In up to 25% of patients, no focus of infection is found and the diagnosis is usually made on blood cultures or throat swab. Melioidosis is said to be able to affect any organ in the body except the heart valves (endocarditis). Although meningitis has been described secondary to ruptured brain abscesses, primary meningitis has not been described. Less common manifestation include intravascular infection, lymph node abscesses (1.2–2.2%),[20] pyopericardium and myocarditis, mediastinal infection, and thyroid and scrotal abscesses and ocular infection. ## Chronic melioidosis Chronic melioidosis is usually defined by a duration of symptoms greater than 2 months and occurs in approximately 10% of patients. The clinical presentation of chronic melioidosis is protean and includes such presentations as chronic skin infection, skin ulcers and lung nodules or chronic pneumonia, closely mimicking tuberculosis, sometimes being called "Vietnamese tuberculosis". # Diagnosis A definitive diagnosis is made by culturing the organism from any clinical sample. A definite history of contact with soil may not be elicited as melioidosis can be dormant for many years before becoming acute. Attention should be paid to a history of travel to endemic areas in returned travellers. Some authors recommend considering possibility of melioidosis in every febrile patient with a history of traveling to and/or staying at endemic areas. A complete screen (blood culture, sputum culture, urine culture, throat swab and culture of any aspirated pus) should be performed on all patients with suspected melioidosis (culture on blood agar as well as Ashdown's medium). A definitive diagnosis is made by growing B. pseudomallei from any site. A throat swab is not sensitive but is 100% specific if positive, and compares favourably with sputum culture.[21] The sensitivity of urine culture is increased if a centrifuged specimen is cultured, and any bacterial growth should be reported (not just growth above 104 organisms/ml which is the usual cut off).[22] Very occasionally, bone marrow culture may be positive in patients who have negative blood cultures for B. pseudomallei, but these are not usually recommended.[23] A common error made by clinicians unfamiliar with the diagnosis of melioidosis is to only send a specimen from the affected site (which is the usual procedure for most other infections) instead of sending a full screen. Ashdown's medium, a selective medium containing gentamicin, may be required for cultures taken from non-sterile sites. Burkholderia cepacia medium may be a useful alternative selective medium in non-endemic areas, where Ashdown's is not available. A new medium derived from Ashdown known as Francis medium may help differentiate B. pseudomallei from B. cepacia and may help in the early diagnosis of melioidosis,[24] but has not yet been extensively clinically validated. Many commercial kits for identifying bacteria may mis-identify B. pseudomallei (see Burkholderia pseudomallei for a more detailed discussion of these issues). There is also a serological test for melioidosis (indirect haemagglutination), but this is not commercially available in most countries. A high background titre may reduce the positive predictive value of serological tests in endemic countries. A specific direct immunofluorescent test and latex agglutination, based on monoclonal antibodies, are used widely in Thailand but are not available elsewhere. Imaging of the abdomen using CT scans or ultrasound is recommended routinely, as abscesses may not be clinically apparent and may be coexist with disease elsewhere. Australian authorities suggest imaging of the prostate specificcally due to the high incidence of prostatic abscesses in northern Australian patients. A chest x-ray is also considered routine, with other investigations as clinically indicated. The differential diagnosis is extensive; melioidosis may mimic many other infections, including tuberculosis. # Treatment ## Current treatment The treatment of melioidosis is divided into two stages, an intravenous high intensity stage and an oral maintenance stage to prevent recurrence. Surgical drainage is usually indicated for prostatic abscesses and septic arthritis, may be indicated for parotid abscesses and not usually indicated for hepatosplenic abscesses. Adjunctive treatment with GCSF[32] or co-trimoxazole[33][34] were not associated with decreased fatality rates in trials in Thailand. # Antimicrobial therapy - 1. Melioidosis[40] - 1.1 Intial intensive therapy (Minimum of 10-14 days) - Preferred regimen (1): Ceftazidime 50 mg/kg upto 2 g q6h - Preferred regimen (2): Meropenem 25 mg/kg upto 1 g q8h - Preferred regimen (3): Imipenem 25 mg/kg upto 1 g q6h - Note: Any one of the three may be combined with TMP-SMX 6/30 mg/kg upto 320/1600 mg/kg q12h (recommended for neurologic, bone, joint, cutaneous and prostatic melioidosis) - 1.2 Eradication therapy (Minimum of 3 months) - Preferred regimen: TMP-SMX 6/30 mg/kg upto 320/1600 mg/kg q12h ## Historical treatment Prior to 1989, the standard treatment for acute melioidosis was a four-drug combination of chloramphenicol, co-trimoxazole and doxycycline; this regimen is associated with a mortality rate of 80% and should no longer be used unless no other alternatives are available.[25] All four drugs are bacteriostatic (they stop the bacterium from growing but do not kill it) and the action of co-trimoxazole antagonizes both chloramphenicol and doxycycline.[41]</ref> # Prognosis Without access to appropriate antibiotics (principally ceftazidime or meropenem), the septicemic form of melioidosis has a mortality rate that exceeds 90%.[42] With appropriate antibiotics, the mortality rate is about 10% for uncomplicated cases but up to 80% for cases with bacteraemia or severe sepsis. It seems certain that access to intensive care facilities is also important, and probably at least partially explains why total mortality is 20% in Northern Australia but 40% in Northeast Thailand. Response to appropriate antibiotic treatment is slow with the average duration of fever following treatment being 5-9 days.[43][1] Relapse occurs in 10 to 20% of patients. While molecular studies have established that the majority of recurrences are due to the original infecting strain, a significant proportion of recurrences (perhaps up to a quarter) in endemic areas may be due to reinfection, particularly after 2 years.[44] Risk factors include severity of disease (patients with positive blood cultures or multifocal disease have a higer risk of relapse), choice of antibiotic for eradication therapy (doxycycline monotherapy and fluoroquinolone therapy are not as effective), poor compliance with eradication therapy and duration of eradication therapy less than 8 weeks.[45][38] # Prevention There are only few unusual cases documented for person-to-person transmission; no isolation is required for patients with melioidosis. Lab workers should handle Burkholderia pseudomallei under BSL-3 isolation conditions, as laboratory acquired melioidosis has been described. Following laboratory exposure, post exposure prophylaxis with cotrimoxazole has been suggested but has not been evaluated by clinical trials. In endemic areas, people (rice-paddy farmers in particular) are warned to avoid contact with soil, mud and surface water where possible. Case clusters have been described following flooding and cyclones and probably relate to exposure. Other case clusters have related to contamination of drinking water supplies. Populations at risk include patients with diabetes mellitus, chronic renal failure, chronic lung disease or patients with an immune deficiency of any kind. The effectiveness of measures to reduce exposure to the causative organism have not been established. A vaccine is not yet available. # Biological warfare potential There has been interest in melioidosis because it has the potential to be developed as a biological weapon. It is classed by the US Centers for Disease Control (CDC) as a Category B agent.[46] B. pseudomallei, like its relative B. mallei which causes glanders, was studied by the U.S. as a potential biological warfare agent, but was never weaponized.[47] It has been reported that the Soviet Union was also experimenting with B. pseudomallei as a BW agent. # Synonyms The majority of these synonyms are obsolete eponyms. - pseudoglanders - Whitmore's disease (after Captain Alfred Whitmore, who first discovered the disease)[48] - Nightcliff gardener's disease (Nightcliff is a suburb of Darwin, Australia where melioidosis is endemic)[49] - Paddy-field disease[50]	https://www.wikidoc.org/index.php/Melioidosis
c60e6f0d8a9fe0d0e8bbc392093f178582e8a0e5	wikidoc	Memory work	Memory work Memory work is a process of engaging with the past which has both an ethical and historical dimension. # History and memory The premise for memory work or travail de memoire is that history is not memory. We try to represent the past in the present through memory, history and the archives. As Paul Ricoeur argued, memory alone is fallible. Historical accounts are always partial and potentially misrepresent since historians do not work with bare, uninterpreted facts. Historians construct and use archives that contain traces of the past. However, historians and librarians determine which traces are preserved and stored. This is an interpretive activity. Historians pose questions to which the archives responds leading them to “facts that can be asserted in singular, discrete propositions that usually include dates, places, proper names, and verbs of action or condition”. Individuals remember events and experiences some of which they share with a collective. Through mutual reconstruction and recounting collective memory is reconstructed. Individuals are born into familial discourse which already provides a backdrop of communal memories against which individual memories are shaped. A group's communal memory becomes its common knowledge which creates a social bond, a sense of belonging and identity. Professional historians attempt to corroborate, correct, or refute collective memory. Memory work then entails adding an ethical component which acknowledges the responsibility towards revisiting distorted histories thereby decreasing the risk of social exclusion and increasing the possibility of social cohesion of at-risk groups. The concept of memory-work as distinguished from history-as-memory finds a textbook case in the Vichy Syndrome as described by Russo. His title uses medical lexicon to refer to history-memory as dependent on working consciously with unconscious memories to revise accounts of history. This calls for an expanded archive that includes the "oral and popular tradition" as well as the written traditions normally associated with the archives. # Pierre Nora on memory work Pierre Nora traced the surge in memory work at the level of the nation-state to the revisiting of distorted histories of the anti-Semitic Vichy France (1940-1944) following the death of de Gaulle in 1970. Structural changes resulted from the end of the peasantry and the dramatic economic slump as oil prices worldwide rose in 1974. Added to this was the intellectual collapse of Marxism precipitated in part by Alexander Solzhenitsyn’s Gulag Archipelago which forced the French to rethink attitudes towards the past. # Barbara Gabriel on memory work Barbara Gabriel provided a model for reading the complexities of memory and forgetting by situating unheimlich within the heimlich, in a Freudian 'one within the other structure'. As point of departure Gabriel examined Edgar Reitz's eleven-part West German television series entitled Heimat. Reitz' work was in response to a larger movement in Germany national memory work provoked in part by an American television series entitled the Holocaust followed viewed by millions. As European art in general and German art in particular resurged in the 1960s, artists like Gunther Grass and Edgar Reitz captured international attention as they grappled with issues of identity in a divided, post-Holocaust Germany. Gabriel developed the concept of an impulse towards national memory work in Germany that stemmed from a haunted subject yearning for a lost, far away, nostalgic place, a utopic homeland. "How do we confront that which we have excluded in order to be, whether it is the return of the repressed or the return of the strangers?" In other words, that which we fear as 'other' is within ourselves through our shared humanity. Repressed memories haunt all of us. # Post-colonial views The concept of memory work is part of a sociological imagination from a post-national point of view. Expanding on Norbert Loeffler: The idea of one national history is only acceptable as a question, not as an answer. Memory work is related to identity work often associated with displaced persons. Some of the most provocative research on memory work has been authored by the Pied-noir who returned to France following the Algerian War. Examples of such thinkers include Jacques Derrida, Hélène Cixous, and Julia Kristeva.	Memory work Memory work is a process of engaging with the past which has both an ethical and historical dimension.[1] # History and memory The premise for memory work or travail de memoire is that history is not memory. We try to represent the past in the present through memory, history and the archives. As Paul Ricoeur argued, memory alone is fallible.[2] Historical accounts are always partial and potentially misrepresent since historians do not work with bare, uninterpreted facts. Historians construct and use archives that contain traces of the past. However, historians and librarians determine which traces are preserved and stored. This is an interpretive activity. Historians pose questions to which the archives responds leading them to “facts that can be asserted in singular, discrete propositions that usually include dates, places, proper names, and verbs of action or condition”.[3] Individuals remember events and experiences some of which they share with a collective. Through mutual reconstruction and recounting collective memory is reconstructed. Individuals are born into familial discourse which already provides a backdrop of communal memories against which individual memories are shaped. A group's communal memory becomes its common knowledge which creates a social bond, a sense of belonging and identity. Professional historians attempt to corroborate, correct, or refute collective memory. Memory work then entails adding an ethical component which acknowledges the responsibility towards revisiting distorted histories thereby decreasing the risk of social exclusion and increasing the possibility of social cohesion of at-risk groups. The concept of memory-work as distinguished from history-as-memory finds a textbook case in the Vichy Syndrome as described by Russo.[4] His title uses medical lexicon to refer to history-memory as dependent on working consciously with unconscious memories to revise accounts of history. This calls for an expanded archive that includes the "oral and popular tradition" [5] as well as the written traditions normally associated with the archives. # Pierre Nora on memory work Pierre Nora traced the surge in memory work at the level of the nation-state to the revisiting of distorted histories of the anti-Semitic Vichy France (1940-1944) following the death of de Gaulle in 1970.[6] Structural changes resulted from the end of the peasantry and the dramatic economic slump as oil prices worldwide rose in 1974. Added to this was the intellectual collapse of Marxism precipitated in part by Alexander Solzhenitsyn’s Gulag Archipelago which forced the French to rethink attitudes towards the past. # Barbara Gabriel on memory work Barbara Gabriel provided a model for reading the complexities of memory and forgetting by situating unheimlich within the heimlich, in a Freudian 'one within the other structure'.[7] As point of departure Gabriel examined Edgar Reitz's eleven-part West German television series entitled Heimat. Reitz' work was in response to a larger movement in Germany national memory work provoked in part by an American television series entitled the Holocaust followed viewed by millions. As European art in general and German art in particular resurged in the 1960s, artists like Gunther Grass and Edgar Reitz captured international attention as they grappled with issues of identity in a divided, post-Holocaust Germany. Gabriel developed the concept of an impulse towards national memory work in Germany that stemmed from a haunted subject yearning for a lost, far away, nostalgic place, a utopic homeland. "How do we confront that which we have excluded in order to be, whether it is the return of the repressed or the return of the strangers?"[8] In other words, that which we fear as 'other' is within ourselves through our shared humanity. Repressed memories haunt all of us. # Post-colonial views The concept of memory work is part of a sociological imagination from a post-national point of view. Expanding on Norbert Loeffler: The idea of one national history is only acceptable as a question, not as an answer. Memory work is related to identity work often associated with displaced persons. Some of the most provocative research on memory work has been authored by the Pied-noir who returned to France following the Algerian War. Examples of such thinkers include Jacques Derrida, Hélène Cixous, and Julia Kristeva.	https://www.wikidoc.org/index.php/Memory_work
7c91bdaeb76990928544ab69d13102e1a6f9703b	wikidoc	Menotropins	Menotropins # Overview Menotropin (also called human menopausal gonadotropin or hMG) is a hormonally active medication for the treatment of fertility disturbances. Frequently the plural is used as the medication is a mixture of gonadotropins. Menotropins are extracted from the urine of postmenopausal women. # Description and usage Urine of postmenopausal women reflects the hypergonadotropic state of menopause -levels of follicle stimulating hormone (FSH) and luteinizing hormone (LH) are high - and contain a mixture of these gonadotropins. Other protein substances may be present, including small amounts of human chorionic gonadotropin (hCG). In 1949 Piero Donini found a relatively simple method to extract gonadotropins from urine of postmenopausal women. Menotropins were successfully introduced into clinical use by Bruno Lunenfeld in 1961 While earlier menotropin medications contained FSH and LH at a 1:1 ratio, the recognition that it is FSH that is critical for follicle stimulation has led to development of newer preparations that contain a much higher FSH/LH ratio, Fertinex being an example. Menotropin preparations are designed for use in selected women where they stimulate the ovaries to mature follicles, thus making them more fertile. They are administered by typically daily injection, intramuscularly or subcutaneously, for about ten days under close supervision to adjust dose and duration of therapy. They can also be used in hypogonadal men to stimulate sperm production. Human urinary-derived menotropin preparations are exposed to the theoretical risk of infection from menopausal donors of urine. Nevertheless, the failure to irrefutably demonstrate infectivity following intracerebral inoculation with urine from transmissible spongiform encephalopathy(TSE)-infected hosts suggests that the risk associated with products derived from urine is merely theoretical Recombinant gonadotropins have to a large degree replaced hMG in fertility treatments. The recombinant process allows for the production of pure FSH or LH not "contaminated" by other proteins that may be present after urinary extraction. While some head-on studies seem not to suggest that "pure FSH" gives better results than hMG., others claim that recombinant FSH is more efficient and reduces costs.A Cochrane Collaboration analysis did not reveal major differences in clinical outcomes when comparing urinary versus recombinant FSH. The Practice Committee of the American Society for Reproductive Medicine reported:“Compared with earlier crude animal extracts, modern highly purified urinary and recombinant gonadotropin products have clearly superior quality, specific activity, and performance. There are no confirmed differences in safety, purity, or clinical efficacy among the various available urinary or recombinant gonadotropin products.” # List of hMG preparations A number of drug companies have and had marketed hMG preparations that include: - Humegon (Organon), - Menopur (Ferring Pharmaceuticals), 75 IU FSH and 75 IU LH activity - Menogon, - Metrodin (Serono), - Repronex (Ferring Pharmaceuticals), 75 IU FSH and 75 IU LH - Pergonal (Serono), - HMG Massone, 75 IU FSH and 75 IU LH	Menotropins Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview Menotropin (also called human menopausal gonadotropin or hMG) is a hormonally active medication for the treatment of fertility disturbances. Frequently the plural is used as the medication is a mixture of gonadotropins. Menotropins are extracted from the urine of postmenopausal women. # Description and usage Urine of postmenopausal women reflects the hypergonadotropic state of menopause -levels of follicle stimulating hormone (FSH) and luteinizing hormone (LH) are high - and contain a mixture of these gonadotropins. Other protein substances may be present, including small amounts of human chorionic gonadotropin (hCG). In 1949 Piero Donini found a relatively simple method to extract gonadotropins from urine of postmenopausal women. Menotropins were successfully introduced into clinical use by Bruno Lunenfeld in 1961 While earlier menotropin medications contained FSH and LH at a 1:1 ratio, the recognition that it is FSH that is critical for follicle stimulation has led to development of newer preparations that contain a much higher FSH/LH ratio, Fertinex being an example. Menotropin preparations are designed for use in selected women where they stimulate the ovaries to mature follicles, thus making them more fertile. They are administered by typically daily injection, intramuscularly or subcutaneously, for about ten days under close supervision to adjust dose and duration of therapy. They can also be used in hypogonadal men to stimulate sperm production. Human urinary-derived menotropin preparations are exposed to the theoretical risk of infection from menopausal donors of urine. Nevertheless, the failure to irrefutably demonstrate infectivity following intracerebral inoculation with urine from transmissible spongiform encephalopathy(TSE)-infected hosts suggests that the risk associated with products derived from urine is merely theoretical Recombinant gonadotropins have to a large degree replaced hMG in fertility treatments. The recombinant process allows for the production of pure FSH or LH not "contaminated" by other proteins that may be present after urinary extraction. While some head-on studies seem not to suggest that "pure FSH" gives better results than hMG., others claim that recombinant FSH is more efficient and reduces costs.A Cochrane Collaboration analysis did not reveal major differences in clinical outcomes when comparing urinary versus recombinant FSH. The Practice Committee of the American Society for Reproductive Medicine reported:“Compared with earlier crude animal extracts, modern highly purified urinary and recombinant gonadotropin products have clearly superior quality, specific activity, and performance. There are no confirmed differences in safety, purity, or clinical efficacy among the various available urinary or recombinant gonadotropin products.” # List of hMG preparations A number of drug companies have and had marketed hMG preparations that include: - Humegon (Organon), - Menopur (Ferring Pharmaceuticals), 75 IU FSH and 75 IU LH activity - Menogon, - Metrodin (Serono), - Repronex (Ferring Pharmaceuticals), 75 IU FSH and 75 IU LH - Pergonal (Serono), - HMG Massone, 75 IU FSH and 75 IU LH	https://www.wikidoc.org/index.php/Menotropins
ae151b4b6120f7f7ddaeb27d0fa9b3f343c340a9	wikidoc	Mepenzolate	Mepenzolate # 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 Mepenzolate is an anticholinergic and antispasmodic agent that is FDA approved for the treatment of peptic ulcer. Common adverse reactions include somnolence and blurred vision. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) - CANTIL is indicated for use as adjunctive therapy in the treatment of peptic ulcer. It has not been shown to be effective in contributing to the healing of peptic ulcer, decreasing the rate of recurrence, or preventing complications. ### Dosing Information - The usual adult dose is 1 or 2 tablets (25 or 50 mg) 4 times a day preferably with meals and at bedtime. Begin with the lower dosage when possible and adjust subsequently according to the patient's response. - Safety and efficacy in pediatric patients have not been established. - In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal or cardiac function, and of concomitant disease or other drug therapy. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Mepenzolate in adult patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Mepenzolate in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) There is limited information regarding Mepenzolate 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 Mepenzolate in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Mepenzolate in pediatric patients. # Contraindications - Glaucoma - Obstructive uropathy (for example, bladder neck obstruction due to prostatic hypertrophy) - Obstructive disease of the gastrointestinal tract (for example, pyloroduodenal stenosis, achalasia) - Paralytic ileus - Intestinal atony of the elderly or debilitated patient - Unstable cardiovascular status in acute gastrointestinal hemorrhage - Toxic megacolon complicating ulcerative colitis - Myasthenia gravis - Allergic or idiosyncratic reactions to CANTIL or related compounds # Warnings - In the presence of high environmental temperature, heat prostration (fever and heat stroke due to decreased sweating) can occur with use of CANTIL. - Diarrhea may be an early symptom of incomplete intestinal obstruction especially in patients with ileostomy or colostomy. In this instance, treatment with this drug would be inappropriate and possibly harmful. - CANTIL may produce drowsiness or blurred vision. The patient should be cautioned regarding activities requiring mental alertness such as operating a motor vehicle or other machinery or performing hazardous work while taking this drug. - With overdosage, a curare-like action may occur i.e., neuromuscular blockage leading to muscular weakness and possible paralysis. - It should be noted that the use of anticholinergic drugs in the treatment of gastric ulcer may produce a delay in gastric emptying time and may complicate such therapy (antral stasis). - Psychosis has been reported in sensitive individuals given anticholinergic drugs. CNS signs and symptoms include confusion, disorientation, short-term memory loss, hallucinations, dysarthria, ataxia, coma, euphoria, decreased anxiety, fatigue, insomnia, agitation and mannerisms and inappropriate affect. These CNS signs and symptoms usually resolve within 12 to 24 hours after discontinuation of the medication. ### General - Use CANTIL with caution in the elderly and in all patients with: - Autonomic neuropathy - Hepatic or renal disease - Ulcerative colitis. Large doses may suppress intestinal motility to the point of producing a paralytic ileus and for this reason precipitate or aggravate "toxic megacolon," a serious complication of the disease. - Hiatal hernia associated with reflux esophagitis, since anticholinergic drugs may aggravate this condition. - Coronary heart disease - Congestive heart failure - Cardiac arrhythmias - Tachycardia - Hypertension - Prostatic hypertrophy - Hyperthyroidism - Investigate any tachycardia before giving anticholinergic (atropine-like) drugs since they may increase the heart rate. - This product contains FD&C Yellow No. 5 (tartrazine), which may cause allergic-type reactions (including bronchial asthma) in certain susceptible individuals. Although the overall incidence of FD&C Yellow No. 5 (tartrazine) sensitivity in the general population is low, it is frequently seen in patients who also have aspirin sensitivity. # Adverse Reactions ## Clinical Trials Experience - Precise frequency data from controlled clinical studies with CANTIL are not available. - Vomiting, nausea, constipation, loss of taste, bloated feeling, dry mouth - Mental confusion, dizziness, weakness, drowsiness, headache, nervousness - Increased ocular tension, cycloplegia, blurred vision, dilation of the pupil - Anaphylaxis, urticaria - Tachycardia, palpitations - Urinary retention, urinary hesitancy - Decreased sweating, drowsiness, insomnia, impotence, suppression of lactation ## Postmarketing Experience There is limited information regarding Mepenzolate Postmarketing Experience in the drug label. # Drug Interactions - The following agents may increase certain actions or side effects of anticholinergic drugs: amantadine, antiarrhythmic agents of class I (e.g., quinidine), antihistamines, antipsychotic agents (e.g., phenothiazines), benzodiazepines, MAO inhibitors, narcotic analgesics (e.g., meperidine), nitrates and nitrites, sympathomimetic agents, tricyclic antidepressants, and other drugs having anticholinergic activity. - Anticholinergics antagonize the effects of antiglaucoma agents. Anticholinergic drugs in the presence of increased intraocular pressure may be hazardous when taken concurrently with agents such as corticosteroids. - Anticholinergic agents may affect gastrointestinal absorption of various drugs, such as slowly dissolving dosage forms of digoxin; increased serum digoxin concentrations may result. Anticholinergic drugs may antagonize the effects of drugs that alter gastrointestinal motility, such as metoclopramide. Because antacids may interfere with the absorption of anticholinergic agents, simultaneous use of these drugs should be avoided. - The inhibiting effects of anticholinergic drugs on gastric hydrochloric acid secretion are antagonized by agents used to treat achlorhydria and those used to test gastric secretion. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): B - Reproduction studies have been performed in rats and rabbits at doses up to 30 times the human dose (based on 50 kg weight) and have shown no evidence of impaired fertility or harm to the animal fetus. There are, however, no adequate and well-controlled studies with CANTIL in pregnant women. Because animal reproduction studies are not always predictive of human response, CANTIL should be used during pregnancy only if clearly needed. Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Mepenzolate in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Mepenzolate during labor and delivery. ### Nursing Mothers - It is not known whether CANTIL is secreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when CANTIL is administered to a nursing woman. ### Pediatric Use - Safety and effectiveness in pediatric patients have not been established. Studies in newborn animals (rats) show that younger animals are more sensitive to the toxic effects of CANTIL than are older animals. ### Geriatic Use - Clinical studies of CANTIL did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal or cardiac function, and of concomitant disease or other drug therapy. - CANTIL is contraindicated in intestinal atony of the elderly. CANTIL should be used with caution in the elderly. ### Gender There is no FDA guidance on the use of Mepenzolate with respect to specific gender populations. ### Race There is no FDA guidance on the use of Mepenzolate with respect to specific racial populations. ### Renal Impairment There is no FDA guidance on the use of Mepenzolate in patients with renal impairment. ### Hepatic Impairment There is no FDA guidance on the use of Mepenzolate in patients with hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Mepenzolate in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Mepenzolate in patients who are immunocompromised. # Administration and Monitoring ### Administration - Oral ### Monitoring There is limited information regarding Mepenzolate Monitoring in the drug label. # IV Compatibility There is limited information regarding the compatibility of Mepenzolate and IV administrations. # Overdosage - The signs and symptoms of overdosage are headache; nausea; vomiting; blurred vision; dilated pupils; hot, dry skin; dizziness; dryness of the mouth; difficulty in swallowing; and CNS stimulation. A curare-like action may occur (i.e., neuromuscular blockade leading to muscular weakness and possible paralysis). - The oral LD50 is greater than 750 mg/kg in mice and greater than 1000 mg/kg in rats. - The maximum human dose recorded is 375 to 500 mg in a 4-year-old child (no adverse effects reported) and 500 to 750 mg in a 30-year-old adult (resulted in death). - It is not known if the drug is dialyzable. - Treatment should consist of gastric lavage, emetics, and activated charcoal. Sedatives (e.g., short-acting barbiturates, benzodiazepines) may be used for management of overt signs of excitement. If indicated, an appropriate parenteral cholinergic agent may be used as an antidote. # Pharmacology ## Mechanism of Action - CANTIL diminishes gastric acid and pepsin secretion. CANTIL also suppresses spontaneous contractions of the colon. Pharmacologically, it is a post-ganglionic parasympathetic inhibitor. ## Structure - CANTIL tablets for oral administration contain 25 mg mepenzolate bromide USP. The anticholinergic agent mepenzolate bromide USP chemically is 3--1,1-dimethylpiperidinium bromide and has the following structure: ## Pharmacodynamics There is limited information regarding Mepenzolate Pharmacodynamics in the drug label. ## Pharmacokinetics - Radiotracer studies in which CANTIL-14C was used in animals and humans indicate the absorption following oral administration, as with other quaternary ammonium compounds, is low. Between 3 and 22% of an orally administered dose is excreted in the urine over a 5-day period, with the majority of the radioactivity appearing on Day 1. The remainder appears in the next 5 days in the feces and presumably has not been absorbed. ## Nonclinical Toxicology There is limited information regarding Mepenzolate Nonclinical Toxicology in the drug label. # Clinical Studies There is limited information regarding Mepenzolate Clinical Studies in the drug label. # How Supplied 25 mg mepenzolate bromide, compressed yellow tablets debossed MERRELL 37. NDC 0068-0037-01: bottles of 100 ## Storage - Keep tightly closed. Store at room temperature, preferably below 86°F. - Protect from excessive heat. Dispense in tight containers with child-resistant closure. # Images ## Drug Images ## Package and Label Display Panel NDC 0068-0037-01 Cantil® 25mg mepenzolate bromide USP 100 Tablets sanofi aventis # Patient Counseling Information - CANTIL may produce drowsiness or blurred vision. The patient should be cautioned regarding activities requiring mental alertness, such as operating a motor vehicle or other machinery or performing hazardous work while taking this drug. # Precautions with Alcohol Alcohol-Mepenzolate interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - Cantil # Look-Alike Drug Names There is limited information regarding Mepenzolate Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	Mepenzolate 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 Mepenzolate is an anticholinergic and antispasmodic agent that is FDA approved for the treatment of peptic ulcer. Common adverse reactions include somnolence and blurred vision. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) - CANTIL is indicated for use as adjunctive therapy in the treatment of peptic ulcer. It has not been shown to be effective in contributing to the healing of peptic ulcer, decreasing the rate of recurrence, or preventing complications. ### Dosing Information - The usual adult dose is 1 or 2 tablets (25 or 50 mg) 4 times a day preferably with meals and at bedtime. Begin with the lower dosage when possible and adjust subsequently according to the patient's response. - Safety and efficacy in pediatric patients have not been established. - In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal or cardiac function, and of concomitant disease or other drug therapy. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Mepenzolate in adult patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Mepenzolate in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) There is limited information regarding Mepenzolate 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 Mepenzolate in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Mepenzolate in pediatric patients. # Contraindications - Glaucoma - Obstructive uropathy (for example, bladder neck obstruction due to prostatic hypertrophy) - Obstructive disease of the gastrointestinal tract (for example, pyloroduodenal stenosis, achalasia) - Paralytic ileus - Intestinal atony of the elderly or debilitated patient - Unstable cardiovascular status in acute gastrointestinal hemorrhage - Toxic megacolon complicating ulcerative colitis - Myasthenia gravis - Allergic or idiosyncratic reactions to CANTIL or related compounds # Warnings - In the presence of high environmental temperature, heat prostration (fever and heat stroke due to decreased sweating) can occur with use of CANTIL. - Diarrhea may be an early symptom of incomplete intestinal obstruction especially in patients with ileostomy or colostomy. In this instance, treatment with this drug would be inappropriate and possibly harmful. - CANTIL may produce drowsiness or blurred vision. The patient should be cautioned regarding activities requiring mental alertness such as operating a motor vehicle or other machinery or performing hazardous work while taking this drug. - With overdosage, a curare-like action may occur i.e., neuromuscular blockage leading to muscular weakness and possible paralysis. - It should be noted that the use of anticholinergic drugs in the treatment of gastric ulcer may produce a delay in gastric emptying time and may complicate such therapy (antral stasis). - Psychosis has been reported in sensitive individuals given anticholinergic drugs. CNS signs and symptoms include confusion, disorientation, short-term memory loss, hallucinations, dysarthria, ataxia, coma, euphoria, decreased anxiety, fatigue, insomnia, agitation and mannerisms and inappropriate affect. These CNS signs and symptoms usually resolve within 12 to 24 hours after discontinuation of the medication. ### General - Use CANTIL with caution in the elderly and in all patients with: - Autonomic neuropathy - Hepatic or renal disease - Ulcerative colitis. Large doses may suppress intestinal motility to the point of producing a paralytic ileus and for this reason precipitate or aggravate "toxic megacolon," a serious complication of the disease. - Hiatal hernia associated with reflux esophagitis, since anticholinergic drugs may aggravate this condition. - Coronary heart disease - Congestive heart failure - Cardiac arrhythmias - Tachycardia - Hypertension - Prostatic hypertrophy - Hyperthyroidism - Investigate any tachycardia before giving anticholinergic (atropine-like) drugs since they may increase the heart rate. - This product contains FD&C Yellow No. 5 (tartrazine), which may cause allergic-type reactions (including bronchial asthma) in certain susceptible individuals. Although the overall incidence of FD&C Yellow No. 5 (tartrazine) sensitivity in the general population is low, it is frequently seen in patients who also have aspirin sensitivity. # Adverse Reactions ## Clinical Trials Experience - Precise frequency data from controlled clinical studies with CANTIL are not available. - Vomiting, nausea, constipation, loss of taste, bloated feeling, dry mouth - Mental confusion, dizziness, weakness, drowsiness, headache, nervousness - Increased ocular tension, cycloplegia, blurred vision, dilation of the pupil - Anaphylaxis, urticaria - Tachycardia, palpitations - Urinary retention, urinary hesitancy - Decreased sweating, drowsiness, insomnia, impotence, suppression of lactation ## Postmarketing Experience There is limited information regarding Mepenzolate Postmarketing Experience in the drug label. # Drug Interactions - The following agents may increase certain actions or side effects of anticholinergic drugs: amantadine, antiarrhythmic agents of class I (e.g., quinidine), antihistamines, antipsychotic agents (e.g., phenothiazines), benzodiazepines, MAO inhibitors, narcotic analgesics (e.g., meperidine), nitrates and nitrites, sympathomimetic agents, tricyclic antidepressants, and other drugs having anticholinergic activity. - Anticholinergics antagonize the effects of antiglaucoma agents. Anticholinergic drugs in the presence of increased intraocular pressure may be hazardous when taken concurrently with agents such as corticosteroids. - Anticholinergic agents may affect gastrointestinal absorption of various drugs, such as slowly dissolving dosage forms of digoxin; increased serum digoxin concentrations may result. Anticholinergic drugs may antagonize the effects of drugs that alter gastrointestinal motility, such as metoclopramide. Because antacids may interfere with the absorption of anticholinergic agents, simultaneous use of these drugs should be avoided. - The inhibiting effects of anticholinergic drugs on gastric hydrochloric acid secretion are antagonized by agents used to treat achlorhydria and those used to test gastric secretion. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): B - Reproduction studies have been performed in rats and rabbits at doses up to 30 times the human dose (based on 50 kg weight) and have shown no evidence of impaired fertility or harm to the animal fetus. There are, however, no adequate and well-controlled studies with CANTIL in pregnant women. Because animal reproduction studies are not always predictive of human response, CANTIL should be used during pregnancy only if clearly needed. Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Mepenzolate in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Mepenzolate during labor and delivery. ### Nursing Mothers - It is not known whether CANTIL is secreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when CANTIL is administered to a nursing woman. ### Pediatric Use - Safety and effectiveness in pediatric patients have not been established. Studies in newborn animals (rats) show that younger animals are more sensitive to the toxic effects of CANTIL than are older animals. ### Geriatic Use - Clinical studies of CANTIL did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal or cardiac function, and of concomitant disease or other drug therapy. - CANTIL is contraindicated in intestinal atony of the elderly. CANTIL should be used with caution in the elderly. ### Gender There is no FDA guidance on the use of Mepenzolate with respect to specific gender populations. ### Race There is no FDA guidance on the use of Mepenzolate with respect to specific racial populations. ### Renal Impairment There is no FDA guidance on the use of Mepenzolate in patients with renal impairment. ### Hepatic Impairment There is no FDA guidance on the use of Mepenzolate in patients with hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Mepenzolate in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Mepenzolate in patients who are immunocompromised. # Administration and Monitoring ### Administration - Oral ### Monitoring There is limited information regarding Mepenzolate Monitoring in the drug label. # IV Compatibility There is limited information regarding the compatibility of Mepenzolate and IV administrations. # Overdosage - The signs and symptoms of overdosage are headache; nausea; vomiting; blurred vision; dilated pupils; hot, dry skin; dizziness; dryness of the mouth; difficulty in swallowing; and CNS stimulation. A curare-like action may occur (i.e., neuromuscular blockade leading to muscular weakness and possible paralysis). - The oral LD50 is greater than 750 mg/kg in mice and greater than 1000 mg/kg in rats. - The maximum human dose recorded is 375 to 500 mg in a 4-year-old child (no adverse effects reported) and 500 to 750 mg in a 30-year-old adult (resulted in death). - It is not known if the drug is dialyzable. - Treatment should consist of gastric lavage, emetics, and activated charcoal. Sedatives (e.g., short-acting barbiturates, benzodiazepines) may be used for management of overt signs of excitement. If indicated, an appropriate parenteral cholinergic agent may be used as an antidote. # Pharmacology ## Mechanism of Action - CANTIL diminishes gastric acid and pepsin secretion. CANTIL also suppresses spontaneous contractions of the colon. Pharmacologically, it is a post-ganglionic parasympathetic inhibitor. ## Structure - CANTIL tablets for oral administration contain 25 mg mepenzolate bromide USP. The anticholinergic agent mepenzolate bromide USP chemically is 3-[(hydroxydiphenylacetyl)oxy]-1,1-dimethylpiperidinium bromide and has the following structure: ## Pharmacodynamics There is limited information regarding Mepenzolate Pharmacodynamics in the drug label. ## Pharmacokinetics - Radiotracer studies in which CANTIL-14C was used in animals and humans indicate the absorption following oral administration, as with other quaternary ammonium compounds, is low. Between 3 and 22% of an orally administered dose is excreted in the urine over a 5-day period, with the majority of the radioactivity appearing on Day 1. The remainder appears in the next 5 days in the feces and presumably has not been absorbed. ## Nonclinical Toxicology There is limited information regarding Mepenzolate Nonclinical Toxicology in the drug label. # Clinical Studies There is limited information regarding Mepenzolate Clinical Studies in the drug label. # How Supplied 25 mg mepenzolate bromide, compressed yellow tablets debossed MERRELL 37. NDC 0068-0037-01: bottles of 100 ## Storage - Keep tightly closed. Store at room temperature, preferably below 86°F. - Protect from excessive heat. Dispense in tight containers with child-resistant closure. # Images ## Drug Images ## Package and Label Display Panel NDC 0068-0037-01 Cantil® 25mg mepenzolate bromide USP 100 Tablets sanofi aventis # Patient Counseling Information - CANTIL may produce drowsiness or blurred vision. The patient should be cautioned regarding activities requiring mental alertness, such as operating a motor vehicle or other machinery or performing hazardous work while taking this drug. # Precautions with Alcohol Alcohol-Mepenzolate interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - Cantil # Look-Alike Drug Names There is limited information regarding Mepenzolate Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	https://www.wikidoc.org/index.php/Mepenzolate
f8ad2d922de9c054ad4d50f0826fc67d490e07eb	wikidoc	Mephenytoin	Mephenytoin # 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 Mephenytoin is a anticonvulsant, hydantoin that is FDA approved for the treatment of grand mal, focal, Jacksonian, and psychomotor seizures. Common adverse reactions include rash, nausea, vomiting, fatigue, ataxia, dizziness, nystagmus, somnolence, tremor, diplopia, depression, feeling nervous, and irritability. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) - For the control of grand mal, focal, Jacksonian, and psychomotor seizures in those patients who have been refractory to less toxic anticonvulsants. ### Dosing Information - Dosage of antiepileptic therapy should be adjusted to the needs of the individual patient. Maintenance dosage is that smallest amount of antiepileptic necessary to suppress seizures completely or reduce their frequency. Optimum dosage is attained by starting with ½ or 1 tablet of Mesantoin® (mephenytoin) per day during the first week and thereafter increasing the daily dose by ½ or 1 tablet at weekly intervals. No dose should be increased until it has been taken for at least 1 week. - The average dose of Mesantoin® (mephenytoin) for adults ranges from 2-6 tablets (0.2-0.6 Gm.) daily. In some instances it may be necessary to administer as much as 8 tablets or more daily in order to obtain full seizure control. Pediatric patients usually require from 1-4 tablets (0.1-0.4 Gm.) according to nature of seizures and age. - When the physician wishes to replace the anticonvulsant now being employed with Mesantoin® (mephenytoin), he/she should give ½-1 tablet of Mesantoin® (mephenytoin) daily during the first week and gradually increase the daily dose at weekly intervals while gradually reducing that of the drug being discontinued. The transition can be made smoothly over a period of 3-6 weeks. If seizures are not completely controlled with the dose so attained, the daily dose should then be increased by a one-tablet increment at weekly intervals to the point of maximum effect. If the patient had also been receiving phenobarbital, it is well to continue it until the transition is completed, at which time gradual withdrawal of the phenobarbital may be tried. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Mephenytoin in adult patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Mephenytoin in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) There is limited information regarding FDA-Labeled Use of Mephenytoin in pediatric patients. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Mephenytoin in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Mephenytoin in pediatric patients. # Contraindications - Mesantoin® (mephenytoin) is contraindicated in patients who have previously shown hypersensitivity to hydantoin products. # Warnings - Mesantoin® (mephenytoin) should be used only after safer anticonvulsants have been given an adequate trial and have failed. - As with all anticonvulsants, dose reduction must be gradual so as to minimize the risk of precipitating seizures. - Patients should be cautioned about possible additive effects of alcohol and other central nervous system depressants. Acute alcohol intoxication may increase the anticonvulsant effect due to decreased metabolic breakdown. Chronic alcohol abuse may result in decreased anticonvulsant effect due to enzyme induction. ### PRECAUTIONS - The patient taking Mesantoin® (mephenytoin) must be kept under close medical supervision at all times since serious adverse reactions may emerge. - Because the primary site of degradation is the liver, it is recommended that screening tests of liver function precede introduction of the drug. - Some patients may show side reactions as the result of individual sensitivity. These reactions can be broken down into three types respectively according to severity: 1) blood dyscrasias; 2) skin and mucous membrane manifestations; and 3) central effects. The blood, skin and mucous membrane manifestations are the more important since they can be more serious in nature. Since mephenytoin has been reported to produce blood dyscrasia in certain instances, the patient must be instructed that in the event any unusual symptoms develop (e.g., sore throat, fever, mucous membrane bleeding, glandular swelling, cutaneous reaction), he/she must discontinue the drug and report for examination immediately. It is recommended that blood examinations be made (total white cell count and differential count) during the initial phase of administration. Such tests are best made: a) before starting medication; b) after 2 weeks on a low dosage; c) again after 2 weeks when full dosage is reached; d) thereafter, monthly for a year; e) from then on, every 3 months. If the neutrophils drop to between 2500 and 1600/cu.mm., counts are made every 2 weeks. Stop medication if the count drops to 1600/cu.mm. - Mesantoin® (mephenytoin) should not be discontinued abrubtly in patients in whom the drug is used to prevent major seizures because of the strong possibility of precipitating status epilepticus with attendant hypoxia and a threat to life. - Mephenytoin may cause decreased serum levels of protein-bound iodine. It may also produce lower than normal values for dexamethasone or metyrapone tests. Mephenytoin may cause increased serum levels of glucose, alkaline phosphatase, and gamma glutamyl transpeptidase. # Adverse Reactions ## Clinical Trials Experience - A number of side effects and toxic reactions have been reported with Mesantoin® (mephenytoin) as well as with other hydantoin compounds. Many of these appear to be dose related while others seem to be a manifestation of a hypersensitivity reaction to these drugs. - Leukopenia, neutropenia, agranulocytosis, thrombocytopenia and pancytopenia have occurred. Eosinophilia, monocytosis, and leukocytosis have been described. Simple anemia, hemolytic anemia, megaloblastic anemia and aplastic anemia have occurred but are uncommon. There has been an isolated report of lymphoma in the literature in a patient treated with mephenytoin for 17 years; a drug relationship has not been defined. - Maculopapular, morbilliform, scarlatiniform, urticarial, purpuric (associated with thrombocytopenia) and non-specific skin rashes have been reported. Exfoliative dermatitis, erythema multiforme (Stevens-Johnson Syndrome), toxic epidermal necrolysis and fatal dermatitides have been described on rare occasions. Skin pigmentation and rashes associated with a lupus erythematosus syndrome have also been reported. - Drowsiness is dose-related and may be reduced by a reduction in dose. Ataxia, diplopia, nystagmus, dysarthria, fatigue, irritability, choreiform movements, depression, and tremor have been encountered. - Nervousness, nausea, vomiting, sleeplessness and dizziness may occur during the initial stages of therapy. Generally, these symptoms are transient, often disappearing with continued treatment. - Mental confusion and psychotic disturbances and increased seizures have been reported, but a definite causal relationship with the drug is uncertain. - Hepatitis, jaundice and nephrosis have been reported but a definite cause and effect relationship between the drug and these effects has not been established. - Alopecia, weight gain, edema, photophobia, conjunctivitis, and gum hyperplasia have been encountered. - Polyarthropathy, pulmonary fibrosis, lupus erythematosus syndrome, lymphoma and lymphadenopathy which simulates Hodgkin’s Disease have also been observed. ## Postmarketing Experience There is limited information regarding Postmarketing Experience of Mephenytoin in the drug label. # Drug Interactions - There have been no reports of drug interactions associated with the use of Mesantoin® (mephenytoin), however, caution should be used when Mesantoin® (mephenytoin) is coadministered with products known to interact with phenytoin. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): D - The effects of Mesantoin® (mephenytoin) in human pregnancy and on nursing infants have not been systematically investigated. - Reports suggest an association between the use of anticonvulsant drugs by women with epilepsy and an elevated incidence of birth defects in children born to these women. Data are more extensive with respect to diphenylhydantoin and phenobarbital, but these are also the most commonly prescribed anticonvulsants; less systematic or anecdotal reports suggest a possible similar association with the use of all known anticonvulsant drugs. - The reports suggesting an elevated incidence of birth defects in children of drug-treated epileptic women cannot be regarded as adequate to prove a definite cause and effect relationship. There are intrinsic methodological problems in obtaining adequate data on drug teratogenicity in humans; the possibility also exists that other factors, e.g., genetic factors or the epileptic condition itself, may be more important than drug therapy in leading to birth defects. The great majority of mothers on anticonvulsant medication deliver normal infants. It is important to note that anticonvulsant drugs should not be discontinued abruptly in patients in whom the drug is administered to prevent major seizures because of the strong possibility of precipitating status epilepticus with attendant hypoxia and threat to life. In individual cases where the severity and frequency of the seizure disorder are such that the removal of medication does not pose a serious threat to the patient, discontinuation of the drug may be considered prior to and during pregnancy, although it cannot be said with any confidence that even minor seizures do not pose some hazards to the developing embryo or fetus. - Hydantoins can cause fetal harm when administered to a pregnant woman. There have been two cases in which the following have been associated with the use of Mesantoin® (mephenytoin): neonatal patent ductus arteriosus, coarctation of the aorta, ventricular septal defect, atrial septal defect, downslanting palpebral fissures, hypoplastic maxilla, big nose, and facial hemangiomas. In both these cases concomitant drugs (i.e. alcohol and primidone) were used. - The prescribing physician will wish to weigh these considerations in treating or counseling epileptic women of child-bearing potential. If Mesantoin® (mephenytoin) is used during pregnancy, or if the patient becomes pregnant while taking Mesantoin® (mephenytoin), the patient should be apprised of the potential hazard 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 Mephenytoin in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Mephenytoin during labor and delivery. ### Nursing Mothers - Caution should be used when mephenytoin is administered to a nursing woman, since mephenytoin may appear in small quantities in the milk. ### Pediatric Use - Since mephenytoin may cross the placenta and appear in the blood of the newborn infant, the possibility of withdrawal symptoms should be considered. ### Geriatic Use There is no FDA guidance on the use of Mephenytoin with respect to geriatric patients. ### Gender There is no FDA guidance on the use of Mephenytoin with respect to specific gender populations. ### Race There is no FDA guidance on the use of Mephenytoin with respect to specific racial populations. ### Renal Impairment There is no FDA guidance on the use of Mephenytoin in patients with renal impairment. ### Hepatic Impairment There is no FDA guidance on the use of Mephenytoin in patients with hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Mephenytoin in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Mephenytoin in patients who are immunocompromised. # Administration and Monitoring ### Administration - Oral ### Monitoring There is limited information regarding Monitoring of Mephenytoin in the drug label. - Description # IV Compatibility There is limited information regarding IV Compatibility of Mephenytoin in the drug label. # Overdosage - While the fatal dose of Mesantoin® (mephenytoin) has not been established, the minimum lethal dose for adults is probably in the region of 3 to 5 gm. - Symptoms and signs of overdosage include: ataxia, dysarthria, nystagmus, drowsiness, confusion and coma with areflexia. - Hypotension, which may proceed to a shock-like state, can also occur. - Tachycardia and arrhythmias of ventricular origin have also been reported. - Terminal hyperpyrexia was reported in one fatal case. - Transient thrombocytopenia, hemorrhagic bullae and petechal rash have been reported following a single overdose. - There is no specific antidote for an overdosage of Mesantoin® (mephenytoin). - General measures include: - Elimination of offending drug by induction of emesis, gastric lavage, catharsis, or activated charcoal. - Maintenance of pulmonary ventilation with suction or endotracheal intubation. - Correction of hypotension, using a pressor agent. - Maintenance of normal body temperature. - The hydantoins as a group are known to have a depressive effect on the heart, particularly in high doses. If arrhythmias occur, regular EKG monitoring should begin at once. # Pharmacology There is limited information regarding Mephenytoin Pharmacology in the drug label. ## Mechanism of Action - Mephenytoin exhibits pharmacologic effects similar to both phenytoin and the barbiturates in antagonizing experimental seizures in laboratory animals. Mephenytoin produces behavioral and electroencephalographic effects in people which are similar to those produced by barbiturates. ## Structure - Mesantoin® (mephenytoin) is 3-methyl 5,5-phenyl-ethyl-hydantoin. It may be considered to be the hydantoin homolog of the barbiturate mephobarbital. Mesantoin® (mephenytoin) has the following structure: ## Pharmacodynamics There is limited information regarding Pharmacodynamics of Mephenytoin in the drug label. ## Pharmacokinetics - The absorption of mephenytoin given orally as a solution of the racemic drug is rapid. Mephenytoin is metabolized stereoselectively. The S-enantiomer is preferentially hydroxylated to give 5-ethyl-3-methyl-5-(4-hydroxyphenyl)-2,4-imidazolidinedione (S-4´-hydroxymephenytoin). The R-enantiomer is primarily N-demethylated to give 5-ethyl-5-phenyl-2,4-imidazolidinedione (R-phenylethylhydantoin) {R-PEH}, the active metabolite. Following simultaneous administration of 14C-S-mephenytoin and 3H-R-mephenytoin, 95±3% of the administered 14C radioactivity was recovered in the urine 24 hours after dosing in the form of S-4´-hydroxymephenytoin, while in the same period, only 3% of the administered 3H radioactivity was found in the urine. - R-mephenytoin reaches peak concentration in about 1.5 hours. Both R-mephenytoin and its active metabolite R-PEH displayed linear kinetics in the dose range of 50-200 mg. The steady state volume of distribution for R-mephenytoin is about 1.4 L/kg. The mean elimination half-life of R-mephenytoin is 73±30 hours and for the metabolite R-PEH is 127±31 hours. The relative bioavailability of R-mephenytoin (Tablet/Solution) is 104%. - In several populations, a genetic impairment which decreases the efficiency of aromatic hydroxylation of S-mephenytoin, but not the N-demethylation of R-mephenytoin, has been established. Poor metabolizers occur with a frequency of 2%-5% in the Caucasian population and 18%-23% in Japanese subjects. ## Nonclinical Toxicology There is limited information regarding Nonclinical Toxicology of Mephenytoin in the drug label. # Clinical Studies There is limited information regarding Clinical Studies of Mephenytoin in the drug label. # How Supplied 100 mg, speckled, pale pink, round, uncoated tablets engraved “78/52” and scored on one side, Image from Drug Label Content” on the other side. Tablets are scored to permit half-dosage. Packages of 100 (NDC 0078-0052-05) Store and Dispense Below 86°F (30°C); tight container. - Also known as Sedantoinal © 1997 Novartis Novartis Pharmaceuticals Corporation East Hanover, New Jersey 07936 REV: DECEMBER 1997 30163904 ## Storage There is limited information regarding Mephenytoin Storage in the drug label. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information - Mesantoin® (mephenytoin) may impair the mental and/or physical abilities required for the performance of potentially hazardous tasks, such as driving a car or operating machinery. The patient should be cautioned accordingly. Due to a possible additive sedative effect, Mesantoin® (mephenytoin) should be used with caution in combination with alcohol and other CNS depressant agents. # Precautions with Alcohol - Alcohol-Mephenytoin interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - Mesantoin® # Look-Alike Drug Names There is limited information regarding Mephenytoin Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	Mephenytoin 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 Mephenytoin is a anticonvulsant, hydantoin that is FDA approved for the treatment of grand mal, focal, Jacksonian, and psychomotor seizures. Common adverse reactions include rash, nausea, vomiting, fatigue, ataxia, dizziness, nystagmus, somnolence, tremor, diplopia, depression, feeling nervous, and irritability. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) - For the control of grand mal, focal, Jacksonian, and psychomotor seizures in those patients who have been refractory to less toxic anticonvulsants. ### Dosing Information - Dosage of antiepileptic therapy should be adjusted to the needs of the individual patient. Maintenance dosage is that smallest amount of antiepileptic necessary to suppress seizures completely or reduce their frequency. Optimum dosage is attained by starting with ½ or 1 tablet of Mesantoin® (mephenytoin) per day during the first week and thereafter increasing the daily dose by ½ or 1 tablet at weekly intervals. No dose should be increased until it has been taken for at least 1 week. - The average dose of Mesantoin® (mephenytoin) for adults ranges from 2-6 tablets (0.2-0.6 Gm.) daily. In some instances it may be necessary to administer as much as 8 tablets or more daily in order to obtain full seizure control. Pediatric patients usually require from 1-4 tablets (0.1-0.4 Gm.) according to nature of seizures and age. - When the physician wishes to replace the anticonvulsant now being employed with Mesantoin® (mephenytoin), he/she should give ½-1 tablet of Mesantoin® (mephenytoin) daily during the first week and gradually increase the daily dose at weekly intervals while gradually reducing that of the drug being discontinued. The transition can be made smoothly over a period of 3-6 weeks. If seizures are not completely controlled with the dose so attained, the daily dose should then be increased by a one-tablet increment at weekly intervals to the point of maximum effect. If the patient had also been receiving phenobarbital, it is well to continue it until the transition is completed, at which time gradual withdrawal of the phenobarbital may be tried. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Mephenytoin in adult patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Mephenytoin in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) There is limited information regarding FDA-Labeled Use of Mephenytoin in pediatric patients. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Mephenytoin in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Mephenytoin in pediatric patients. # Contraindications - Mesantoin® (mephenytoin) is contraindicated in patients who have previously shown hypersensitivity to hydantoin products. # Warnings - Mesantoin® (mephenytoin) should be used only after safer anticonvulsants have been given an adequate trial and have failed. - As with all anticonvulsants, dose reduction must be gradual so as to minimize the risk of precipitating seizures. - Patients should be cautioned about possible additive effects of alcohol and other central nervous system depressants. Acute alcohol intoxication may increase the anticonvulsant effect due to decreased metabolic breakdown. Chronic alcohol abuse may result in decreased anticonvulsant effect due to enzyme induction. ### PRECAUTIONS - The patient taking Mesantoin® (mephenytoin) must be kept under close medical supervision at all times since serious adverse reactions may emerge. - Because the primary site of degradation is the liver, it is recommended that screening tests of liver function precede introduction of the drug. - Some patients may show side reactions as the result of individual sensitivity. These reactions can be broken down into three types respectively according to severity: 1) blood dyscrasias; 2) skin and mucous membrane manifestations; and 3) central effects. The blood, skin and mucous membrane manifestations are the more important since they can be more serious in nature. Since mephenytoin has been reported to produce blood dyscrasia in certain instances, the patient must be instructed that in the event any unusual symptoms develop (e.g., sore throat, fever, mucous membrane bleeding, glandular swelling, cutaneous reaction), he/she must discontinue the drug and report for examination immediately. It is recommended that blood examinations be made (total white cell count and differential count) during the initial phase of administration. Such tests are best made: a) before starting medication; b) after 2 weeks on a low dosage; c) again after 2 weeks when full dosage is reached; d) thereafter, monthly for a year; e) from then on, every 3 months. If the neutrophils drop to between 2500 and 1600/cu.mm., counts are made every 2 weeks. Stop medication if the count drops to 1600/cu.mm. - Mesantoin® (mephenytoin) should not be discontinued abrubtly in patients in whom the drug is used to prevent major seizures because of the strong possibility of precipitating status epilepticus with attendant hypoxia and a threat to life. - Mephenytoin may cause decreased serum levels of protein-bound iodine. It may also produce lower than normal values for dexamethasone or metyrapone tests. Mephenytoin may cause increased serum levels of glucose, alkaline phosphatase, and gamma glutamyl transpeptidase. # Adverse Reactions ## Clinical Trials Experience - A number of side effects and toxic reactions have been reported with Mesantoin® (mephenytoin) as well as with other hydantoin compounds. Many of these appear to be dose related while others seem to be a manifestation of a hypersensitivity reaction to these drugs. - Leukopenia, neutropenia, agranulocytosis, thrombocytopenia and pancytopenia have occurred. Eosinophilia, monocytosis, and leukocytosis have been described. Simple anemia, hemolytic anemia, megaloblastic anemia and aplastic anemia have occurred but are uncommon. There has been an isolated report of lymphoma in the literature in a patient treated with mephenytoin for 17 years; a drug relationship has not been defined. - Maculopapular, morbilliform, scarlatiniform, urticarial, purpuric (associated with thrombocytopenia) and non-specific skin rashes have been reported. Exfoliative dermatitis, erythema multiforme (Stevens-Johnson Syndrome), toxic epidermal necrolysis and fatal dermatitides have been described on rare occasions. Skin pigmentation and rashes associated with a lupus erythematosus syndrome have also been reported. - Drowsiness is dose-related and may be reduced by a reduction in dose. Ataxia, diplopia, nystagmus, dysarthria, fatigue, irritability, choreiform movements, depression, and tremor have been encountered. - Nervousness, nausea, vomiting, sleeplessness and dizziness may occur during the initial stages of therapy. Generally, these symptoms are transient, often disappearing with continued treatment. - Mental confusion and psychotic disturbances and increased seizures have been reported, but a definite causal relationship with the drug is uncertain. - Hepatitis, jaundice and nephrosis have been reported but a definite cause and effect relationship between the drug and these effects has not been established. - Alopecia, weight gain, edema, photophobia, conjunctivitis, and gum hyperplasia have been encountered. - Polyarthropathy, pulmonary fibrosis, lupus erythematosus syndrome, lymphoma and lymphadenopathy which simulates Hodgkin’s Disease have also been observed. ## Postmarketing Experience There is limited information regarding Postmarketing Experience of Mephenytoin in the drug label. # Drug Interactions - There have been no reports of drug interactions associated with the use of Mesantoin® (mephenytoin), however, caution should be used when Mesantoin® (mephenytoin) is coadministered with products known to interact with phenytoin. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): D - The effects of Mesantoin® (mephenytoin) in human pregnancy and on nursing infants have not been systematically investigated. - Reports suggest an association between the use of anticonvulsant drugs by women with epilepsy and an elevated incidence of birth defects in children born to these women. Data are more extensive with respect to diphenylhydantoin and phenobarbital, but these are also the most commonly prescribed anticonvulsants; less systematic or anecdotal reports suggest a possible similar association with the use of all known anticonvulsant drugs. - The reports suggesting an elevated incidence of birth defects in children of drug-treated epileptic women cannot be regarded as adequate to prove a definite cause and effect relationship. There are intrinsic methodological problems in obtaining adequate data on drug teratogenicity in humans; the possibility also exists that other factors, e.g., genetic factors or the epileptic condition itself, may be more important than drug therapy in leading to birth defects. The great majority of mothers on anticonvulsant medication deliver normal infants. It is important to note that anticonvulsant drugs should not be discontinued abruptly in patients in whom the drug is administered to prevent major seizures because of the strong possibility of precipitating status epilepticus with attendant hypoxia and threat to life. In individual cases where the severity and frequency of the seizure disorder are such that the removal of medication does not pose a serious threat to the patient, discontinuation of the drug may be considered prior to and during pregnancy, although it cannot be said with any confidence that even minor seizures do not pose some hazards to the developing embryo or fetus. - Hydantoins can cause fetal harm when administered to a pregnant woman. There have been two cases in which the following have been associated with the use of Mesantoin® (mephenytoin): neonatal patent ductus arteriosus, coarctation of the aorta, ventricular septal defect, atrial septal defect, downslanting palpebral fissures, hypoplastic maxilla, big nose, and facial hemangiomas. In both these cases concomitant drugs (i.e. alcohol and primidone) were used. - The prescribing physician will wish to weigh these considerations in treating or counseling epileptic women of child-bearing potential. If Mesantoin® (mephenytoin) is used during pregnancy, or if the patient becomes pregnant while taking Mesantoin® (mephenytoin), the patient should be apprised of the potential hazard 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 Mephenytoin in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Mephenytoin during labor and delivery. ### Nursing Mothers - Caution should be used when mephenytoin is administered to a nursing woman, since mephenytoin may appear in small quantities in the milk. ### Pediatric Use - Since mephenytoin may cross the placenta and appear in the blood of the newborn infant, the possibility of withdrawal symptoms should be considered. ### Geriatic Use There is no FDA guidance on the use of Mephenytoin with respect to geriatric patients. ### Gender There is no FDA guidance on the use of Mephenytoin with respect to specific gender populations. ### Race There is no FDA guidance on the use of Mephenytoin with respect to specific racial populations. ### Renal Impairment There is no FDA guidance on the use of Mephenytoin in patients with renal impairment. ### Hepatic Impairment There is no FDA guidance on the use of Mephenytoin in patients with hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Mephenytoin in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Mephenytoin in patients who are immunocompromised. # Administration and Monitoring ### Administration - Oral ### Monitoring There is limited information regarding Monitoring of Mephenytoin in the drug label. - Description # IV Compatibility There is limited information regarding IV Compatibility of Mephenytoin in the drug label. # Overdosage - While the fatal dose of Mesantoin® (mephenytoin) has not been established, the minimum lethal dose for adults is probably in the region of 3 to 5 gm. - Symptoms and signs of overdosage include: ataxia, dysarthria, nystagmus, drowsiness, confusion and coma with areflexia. - Hypotension, which may proceed to a shock-like state, can also occur. - Tachycardia and arrhythmias of ventricular origin have also been reported. - Terminal hyperpyrexia was reported in one fatal case. - Transient thrombocytopenia, hemorrhagic bullae and petechal rash have been reported following a single overdose. - There is no specific antidote for an overdosage of Mesantoin® (mephenytoin). - General measures include: - Elimination of offending drug by induction of emesis, gastric lavage, catharsis, or activated charcoal. - Maintenance of pulmonary ventilation with suction or endotracheal intubation. - Correction of hypotension, using a pressor agent. - Maintenance of normal body temperature. - The hydantoins as a group are known to have a depressive effect on the heart, particularly in high doses. If arrhythmias occur, regular EKG monitoring should begin at once. # Pharmacology There is limited information regarding Mephenytoin Pharmacology in the drug label. ## Mechanism of Action - Mephenytoin exhibits pharmacologic effects similar to both phenytoin and the barbiturates in antagonizing experimental seizures in laboratory animals. Mephenytoin produces behavioral and electroencephalographic effects in people which are similar to those produced by barbiturates. ## Structure - Mesantoin® (mephenytoin) is 3-methyl 5,5-phenyl-ethyl-hydantoin. It may be considered to be the hydantoin homolog of the barbiturate mephobarbital. Mesantoin® (mephenytoin) has the following structure: ## Pharmacodynamics There is limited information regarding Pharmacodynamics of Mephenytoin in the drug label. ## Pharmacokinetics - The absorption of mephenytoin given orally as a solution of the racemic drug is rapid. Mephenytoin is metabolized stereoselectively. The S-enantiomer is preferentially hydroxylated to give 5-ethyl-3-methyl-5-(4-hydroxyphenyl)-2,4-imidazolidinedione (S-4´-hydroxymephenytoin). The R-enantiomer is primarily N-demethylated to give 5-ethyl-5-phenyl-2,4-imidazolidinedione (R-phenylethylhydantoin) {R-PEH}, the active metabolite. Following simultaneous administration of 14C-S-mephenytoin and 3H-R-mephenytoin, 95±3% of the administered 14C radioactivity was recovered in the urine 24 hours after dosing in the form of S-4´-hydroxymephenytoin, while in the same period, only 3% of the administered 3H radioactivity was found in the urine. - R-mephenytoin reaches peak concentration in about 1.5 hours. Both R-mephenytoin and its active metabolite R-PEH displayed linear kinetics in the dose range of 50-200 mg. The steady state volume of distribution for R-mephenytoin is about 1.4 L/kg. The mean elimination half-life of R-mephenytoin is 73±30 hours and for the metabolite R-PEH is 127±31 hours. The relative bioavailability of R-mephenytoin (Tablet/Solution) is 104%. - In several populations, a genetic impairment which decreases the efficiency of aromatic hydroxylation of S-mephenytoin, but not the N-demethylation of R-mephenytoin, has been established. Poor metabolizers occur with a frequency of 2%-5% in the Caucasian population and 18%-23% in Japanese subjects. ## Nonclinical Toxicology There is limited information regarding Nonclinical Toxicology of Mephenytoin in the drug label. # Clinical Studies There is limited information regarding Clinical Studies of Mephenytoin in the drug label. # How Supplied 100 mg, speckled, pale pink, round, uncoated tablets engraved “78/52” and scored on one side, Image from Drug Label Content” on the other side. Tablets are scored to permit half-dosage. Packages of 100 (NDC 0078-0052-05) Store and Dispense Below 86°F (30°C); tight container. - Also known as Sedantoinal © 1997 Novartis Novartis Pharmaceuticals Corporation East Hanover, New Jersey 07936 REV: DECEMBER 1997 30163904 ## Storage There is limited information regarding Mephenytoin Storage in the drug label. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information - Mesantoin® (mephenytoin) may impair the mental and/or physical abilities required for the performance of potentially hazardous tasks, such as driving a car or operating machinery. The patient should be cautioned accordingly. Due to a possible additive sedative effect, Mesantoin® (mephenytoin) should be used with caution in combination with alcohol and other CNS depressant agents. # Precautions with Alcohol - Alcohol-Mephenytoin interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - Mesantoin® # Look-Alike Drug Names There is limited information regarding Mephenytoin Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	https://www.wikidoc.org/index.php/Mephenytoin
1af310bc7967ad26cf2efa3b2f5d70fc2e194a4b	wikidoc	Mepolizumab	Mepolizumab # 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 Mepolizumab is an interleukin-5 antagonist monoclonal antibody (IgG1 kappa) that is FDA approved for the treatment of patients with severe asthma aged 12 years and older, and with an eosinophilic phenotype (indicated for add-on maintenance treatment). Common adverse reactions include headache, injection site reaction, back pain, and fatigue (5%). # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) Mepolizumab is indicated for the add-on maintenance treatment of patients with severe asthma aged 12 years and older, and with an eosinophilic phenotype. - Limitations of Use - Mepolizumab is not indicated for treatment of other eosinophilic conditions. - Mepolizumab is not indicated for the relief of acute bronchospasm or status asthmaticus. - Mepolizumab is for subcutaneous use only. - The recommended dose of Mepolizumab is 100 mg administered once every 4 weeks by subcutaneous injection into the upper arm, thigh, or abdomen. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Mepolizumab in adult patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Mepolizumab in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) The safety and efficacy in pediatric patients younger than 12 years have not been established. Same indications and dosage in patients aged 12 years or older. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Mepolizumab in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Mepolizumab in pediatric patients. # Contraindications Mepolizumab should not be administered to patients with a history of hypersensitivity to mepolizumab or excipients in the formulation. # Warnings Hypersensitivity reactions (e.g., angioedema, bronchospasm, hypotension, urticaria, rash) have occurred following administration of Mepolizumab. These reactions generally occur within hours of administration, but in some instances can have a delayed onset (i.e., days). In the event of a hypersensitivity reaction, Mepolizumab should be discontinued. Mepolizumab should not be used to treat acute asthma symptoms or acute exacerbations. Do not use Mepolizumab to treat acute bronchospasm or status asthmaticus. Patients should seek medical advice if their asthma remains uncontrolled or worsens after initiation of treatment with Mepolizumab. In controlled clinical trials, 2 serious adverse reactions of herpes zoster occurred in subjects treated with Mepolizumab compared with none in placebo. Consider varicella vaccination if medically appropriate prior to starting therapy with Mepolizumab. Do not discontinue systemic or inhaled corticosteroids abruptly upon initiation of therapy with Mepolizumab. Reductions in corticosteroid dose, if appropriate, should be gradual and performed under the direct supervision of a physician. Reduction in corticosteroid dose may be associated with systemic withdrawal symptoms and/or unmask conditions previously suppressed by systemic corticosteroid therapy. Eosinophils may be involved in the immunological response to some helminth infections. Patients with known parasitic infections were excluded from participation in clinical trials. It is unknown if Mepolizumab will influence a patient’s response against parasitic infections. Treat patients with pre-existing helminth infections before initiating therapy with Mepolizumab. If patients become infected while receiving treatment with Mepolizumab and do not respond to anti-helminth treatment, discontinue treatment with Mepolizumab until infection resolves. # Adverse Reactions ## Clinical Trials Experience The following adverse reactions are described in greater detail in other sections: - Hypersensitivity reactions - Opportunistic infections: herpes zoster 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. A total of 1,327 subjects with asthma were evaluated in 3 randomized, placebo-controlled, multicenter trials of 24 to 52 weeks’ duration (Trials 1, 2, and 3). Of these, 1,192 had a history of 2 or more exacerbations in the year prior to enrollment despite regular use of high-dose inhaled corticosteroids plus an additional controller(s) (Trials 1 and 2), and 135 subjects required daily oral corticosteroids in addition to regular use of high-dose inhaled corticosteroids plus an additional controller(s) to maintain asthma control (Trial 3). All subjects had markers of eosinophilic airway inflammation. Of the subjects enrolled, 59% were female, 85% were white, and subjects ranged in age from 12 to 82 years. Mepolizumab was administered subcutaneously or intravenously once every 4 weeks; 263 subjects received Mepolizumab (mepolizumab 100 mg subcutaneous ) for at least 24 weeks. Serious adverse events that occurred in more than 1 subject and in a greater percentage of subjects treated with Mepolizumab (n = 263) than placebo (n = 257) included 1 event, herpes zoster (2 subjects vs. 0 subjects, respectively). Approximately 2% of subjects receiving Mepolizumab withdrew from clinical trials due to adverse events compared with 3% of subjects receiving placebo. The incidence of adverse reactions in the first 24 weeks of treatment in the 2 confirmatory efficacy and safety trials (Trials 2 and 3) with Mepolizumab is shown in Table 1. - Table 1. Adverse Reactions with Mepolizumab with Greater than or Equal to 3% Incidence and More Common than Placebo in Subjects with Asthma (Trials 2 and 3) NUCALA: Mepolizumab's Brand name - 52-Week Trial - Adverse reactions from Trial 1 with 52 weeks of treatment with mepolizumab 75 mg intravenous (IV) (n = 153) or placebo (n = 155) and with greater than or equal to 3% incidence and more common than placebo and not shown in Table 1 were: abdominal pain, allergic rhinitis, asthenia, bronchitis, cystitis, dizziness, dyspnea, ear infection, gastroenteritis, lower respiratory tract infection, musculoskeletal pain, nasal congestion, nasopharyngitis, nausea, pharyngitis, pyrexia, rash, toothache, viral infection, viral respiratory tract infection, and vomiting. In addition, 3 cases of herpes zoster occurred in subjects treated with mepolizumab 75 mg IV, compared with 2 subjects in the placebo group. - Systemic Reactions, including Hypersensitivity Reactions - In Trials 1, 2, and 3 described above, the percentage of subjects who experienced systemic (allergic and non-allergic) reactions was 7% in the placebo group and 10% in the group receiving Mepolizumab. Systemic allergic/hypersensitivity reactions were reported by 2% of subjects in the placebo group and 1% of subjects in the group receiving Mepolizumab. The most commonly reported manifestations of systemic allergic/hypersensitivity reactions reported in the group receiving Mepolizumab included rash, pruritus, headache, and myalgia. Systemic non-allergic reactions were reported by 2% of subjects in the group receiving Mepolizumab and 3% of subjects in the placebo group. The most commonly reported manifestations of systemic non-allergic reactions reported in the group receiving Mepolizumab included rash, flushing, and myalgia. A majority of the systemic reactions in subjects receiving Mepolizumab (5/7) were experienced on the day of dosing. - Injection Site Reactions - Injection site reactions (e.g., pain, erythema, swelling, itching, burning sensation) occurred at a rate of 8% in subjects treated with Mepolizumab compared with 3% in subjects treated with placebo. - Long-Term Safety - Nine hundred ninety-eight (998) subjects have received Mepolizumab in ongoing open-label extension studies, during which additional cases of herpes zoster have been reported. The overall adverse event profile was similar to the asthma trials described above. Overall, 15/260 (6%) of subjects treated with Mepolizumab developed anti-mepolizumab antibodies. The reported frequency may underestimate the actual frequency due to lower assay sensitivity in the presence of high drug concentration. Neutralizing antibodies were detected in 1 subject receiving mepolizumab. Anti-mepolizumab antibodies slightly increased (approximately 20%) the clearance of mepolizumab. There was no evidence of a correlation between anti-mepolizumab antibody titers and change in eosinophil level. The clinical relevance of the presence of anti-mepolizumab antibodies is not known. The data reflect the percentage of patients whose test results were positive for antibodies to mepolizumab in specific assays. The observed incidence of antibody positivity in an assay is highly dependent on several factors, including assay sensitivity and specificity, assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. ## Postmarketing Experience There is limited information regarding Mepolizumab Postmarketing Experience in the drug label. # Drug Interactions Formal drug interaction trials have not been performed with Mepolizumab. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): N - Pregnancy Exposure Registry - There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to Mepolizumab during pregnancy. Healthcare providers can enroll patients or encourage patients to enroll themselves by calling 1-877-311-8972 or visiting WWW.MOTHERTOBABY.ORG/ASTHMA. - Risk Summary - The data on pregnancy exposure from the clinical trials are insufficient to inform on drug-associated risk. Monoclonal antibodies, such as mepolizumab, are transported across the placenta in a linear fashion as pregnancy progresses; therefore, potential effects on a fetus are likely to be greater during the second and third trimester of pregnancy. In a prenatal and postnatal development study conducted in cynomolgus monkeys, there was no evidence of fetal harm with IV administration of mepolizumab throughout pregnancy at doses that produced exposures up to approximately 30 times the exposure at the maximum recommended human dose (MRHD) of 100 mg SC. - In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. - Clinical Considerations - Disease-Associated Maternal and/or Embryo-Fetal Risk: In women with poorly or moderately controlled asthma, evidence demonstrates that there is an increased risk of preeclampsia in the mother and prematurity, low birth weight, and small for gestational age in the neonate. The level of asthma control should be closely monitored in pregnant women and treatment adjusted as necessary to maintain optimal control. - Data - Animal Data: In a prenatal and postnatal development study, pregnant cynomolgus monkeys received mepolizumab from gestation days 20 to 140 at doses that produced exposures up to approximately 30 times that achieved with the MRHD (on an AUC basis with maternal IV doses up to 100 mg/kg once every 4 weeks). Mepolizumab did not elicit adverse effects on fetal or neonatal growth (including immune function) up to 9 months after birth. Examinations for internal or skeletal malformations were not performed. Mepolizumab crossed the placenta in cynomolgus monkeys. Concentrations of mepolizumab were approximately 2.4 times higher in infants than in mothers up to day 178 postpartum. Levels of mepolizumab in milk were less than or equal to 0.5% of maternal serum concentration. - In a fertility, early embryonic, and embryo-fetal development study, pregnant CD-1 mice received an analogous antibody, which inhibits the activity of murine IL-5, at an IV dose of 50 mg/kg once per week throughout gestation. The analogous antibody was not teratogenic in mice. Embryo-fetal development of IL-5–deficient mice has been reported to be generally unaffected relative to wild-type mice. Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Mepolizumab in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Mepolizumab during labor and delivery. ### Nursing Mothers There is no information regarding the presence of mepolizumab in human milk, the effects on the breastfed infant, or the effects on milk production. However, mepolizumab is a humanized monoclonal antibody (IgG1 kappa), and immunoglobulin G (IgG) is present in human milk in small amounts. Mepolizumab was present in the milk of cynomolgus monkeys postpartum following dosing during pregnancy. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for Mepolizumab and any potential adverse effects on the breastfed infant from mepolizumab or from the underlying maternal condition. ### Pediatric Use The safety and efficacy in pediatric patients younger than 12 years have not been established. A total of 28 adolescents aged 12 to 17 years with asthma were enrolled in the phase 3 studies. Of these, 25 were enrolled in the 32-week exacerbation trial (Trial 2) and had a mean age of 14.8 years. Subjects had a history of 2 or more exacerbations in the previous year despite regular use of high-dose inhaled corticosteroids plus an additional controller(s) with or without oral corticosteroids and had blood eosinophils of greater than or equal to 150 cells/mcL at screening or greater than or equal to 300 cells/mcL within 12 months prior to enrollment. Subjects had a reduction in the rate of exacerbations that trended in favor of mepolizumab. Of the 19 adolescents who received mepolizumab, 9 received Mepolizumab and the mean apparent clearance in these subjects was 35% less than that of adults. The adverse event profile in adolescents was generally similar to the overall population in the phase 3 studies. ### Geriatic Use Clinical trials of Mepolizumab did not include sufficient numbers of subjects aged 65 years and older that received Mepolizumab (n = 38) to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function and of concomitant disease or other drug therapy. Based on available data, no adjustment of the dosage of Mepolizumab in geriatric patients is necessary, but greater sensitivity in some older individuals cannot be ruled out. ### Gender There is no FDA guidance on the use of Mepolizumab with respect to specific gender populations. ### Race There is no FDA guidance on the use of Mepolizumab with respect to specific racial populations. ### Renal Impairment There is no FDA guidance on the use of Mepolizumab in patients with renal impairment. ### Hepatic Impairment There is no FDA guidance on the use of Mepolizumab in patients with hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Mepolizumab in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Mepolizumab in patients who are immunocompromised. # Administration and Monitoring ### Administration Mepolizumab should be reconstituted and administered by a healthcare professional. In line with clinical practice, monitoring of patients after administration of biologic agents is recommended. - Reconstitution Instructions - Administration ### Monitoring There is limited information regarding Mepolizumab Monitoring in the drug label. # IV Compatibility There is limited information regarding the compatibility of Mepolizumab and IV administrations. # Overdosage Single doses of up to 1,500 mg have been administered intravenously to subjects in a clinical trial with eosinophilic disease without evidence of dose-related toxicities. There is no specific treatment for an overdose with mepolizumab. If overdose occurs, the patient should be treated supportively with appropriate monitoring as necessary. # Pharmacology ## Mechanism of Action Mepolizumab is an interleukin-5 antagonist (IgG1 kappa). IL-5 is the major cytokine responsible for the growth and differentiation, recruitment, activation, and survival of eosinophils. Mepolizumab binds to IL-5 with a dissociation constant of 100 pM, inhibiting the bioactivity of IL-5 by blocking its binding to the alpha chain of the IL-5 receptor complex expressed on the eosinophil cell surface. Inflammation is an important component in the pathogenesis of asthma. Multiple cell types (e.g., mast cells, eosinophils, neutrophils, macrophages, lymphocytes) and mediators (e.g., histamine, eicosanoids, leukotrienes, cytokines) are involved in inflammation. Mepolizumab, by inhibiting IL-5 signaling, reduces the production and survival of eosinophils; however, the mechanism of mepolizumab action in asthma has not been definitively established. ## Structure Mepolizumab is a humanized IL-5 antagonist monoclonal antibody. Mepolizumab is produced by recombinant DNA technology in Chinese hamster ovary cells. Mepolizumab has a molecular weight of approximately 149 kDa. Mepolizumab is supplied as a sterile, white to off-white, preservative-free, lyophilized powder for subcutaneous injection after reconstitution. Upon reconstitution with 1.2 mL of Sterile Water for Injection, USP, the resulting concentration is 100 mg/mL and delivers 1 mL. Each single-dose vial delivers mepolizumab 100 mg, polysorbate 80 (0.67 mg), sodium phosphate dibasic heptahydrate (7.14 mg), and sucrose (160 mg), with a pH of 7.0. ## Pharmacodynamics The pharmacodynamic response (blood eosinophil reduction) following repeat doses of mepolizumab administered subcutaneously or intravenously was evaluated in subjects with asthma and blood eosinophil levels greater than 200 cells/mcL. Subjects received 1 of 4 mepolizumab treatments (administered every 28 days for a total of 3 doses): 12.5 mg SC, 125 mg SC, 250 mg SC, or 75 mg IV. Sixty-six (66) of the 70 randomized subjects completed the trial. Compared with baseline levels, blood eosinophils decreased in a dose-dependent manner. A reduction in blood eosinophil levels was observed in all treatment groups by Day 3. On Day 84 (4 weeks post-last dose), the observed geometric mean reduction from baseline in blood eosinophils was 64%, 78%, 84%, and 90% in the 12.5-mg SC, 75-mg IV, 125-mg SC, and 250-mg SC treatment groups, respectively. The model-predicted SC doses providing 50% and 90% of maximal reduction of blood eosinophils at Day 84 were estimated to be 11 and 99 mg, respectively. These results, along with the clinical efficacy data from the dose-ranging exacerbation trial (Trial 1) supported the evaluation of mepolizumab 75 mg IV and 100 mg SC in the confirmatory trials. Following SC administration of mepolizumab 100 mg every 4 weeks for 32 weeks (Trial 2), blood eosinophils were reduced to a geometric mean count of 40 cells/mcL, which corresponds to a geometric mean reduction of 84% compared with placebo. This magnitude of reduction was observed within 4 weeks of treatment and was maintained throughout the treatment period. ## Pharmacokinetics Following SC dosing in subjects with asthma, mepolizumab exhibited approximately dose-proportional pharmacokinetics over a dose range of 12.5 to 250 mg. Absorption - Following 100-mg SC administration in the upper arm of subjects with asthma, the bioavailability of mepolizumab was estimated to be approximately 80%. - Following repeat SC administration once every 4 weeks, there was approximately a 2-fold accumulation at steady state. Distribution - The population central volume of distribution of mepolizumab in patients with asthma is estimated to be 3.6 L for a 70‑kg individual. Metabolism - Mepolizumab is a humanized IgG1 monoclonal antibody that is degraded by proteolytic enzymes widely distributed in the body and not restricted to hepatic tissue. Elimination - Following SC administration of mepolizumab, the mean terminal half-life (t1/2) ranged from 16 to 22 days. The population apparent systemic clearance of mepolizumab in patients with asthma is estimated to be 0.28 L/day for a 70-kg individual. Specific Populations - Race and Gender: A population pharmacokinetics analysis indicated there was no significant effect of race and gender on mepolizumab clearance. - Age: A population pharmacokinetics analysis of subjects ranging in age from 12 to 82 years indicated there was no significant effect of age on mepolizumab clearance. - Renal Impairment: No clinical trials have been conducted to investigate the effect of renal impairment on the pharmacokinetics of mepolizumab. Based on population pharmacokinetic analyses, mepolizumab clearance was comparable between subjects with creatinine clearance values between 50 and 80 mL/min and patients with normal renal function. There are limited data available in subjects with creatinine clearance values less than 50 mL/min; however, mepolizumab is not cleared renally. - Hepatic Impairment: No clinical trials have been conducted to investigate the effect of hepatic impairment on the pharmacokinetics of mepolizumab. Since mepolizumab is degraded by widely distributed proteolytic enzymes, not restricted to hepatic tissue, changes in hepatic function are unlikely to have any effect on the elimination of mepolizumab. - Drug-Drug Interactions: No formal drug interaction studies have been conducted with Mepolizumab. In the population pharmacokinetics analyses of the phase 3 studies, there was no evidence of an effect of commonly coadministered small molecule drugs on mepolizumab exposure. ## Nonclinical Toxicology Long-term animal studies have not been performed to evaluate the carcinogenic potential of mepolizumab. Published literature using animal models suggests that IL-5 and eosinophils are part of an early inflammatory reaction at the site of tumorigenesis and can promote tumor rejection. However, other reports indicate that eosinophil infiltration into tumors can promote tumor growth. Therefore, the malignancy risk in humans from an antibody to IL-5 such as mepolizumab is unknown. Male and female fertility were unaffected based upon no adverse histopathological findings in the reproductive organs from cynomolgus monkeys treated with mepolizumab for 6 months at IV doses up to 100 mg/kg once every 4 weeks (approximately 70 times the MRHD on an AUC basis). Mating and reproductive performance were unaffected in male and female CD-1 mice treated with an analogous antibody, which inhibits the activity of murine IL-5, at an IV dose of 50 mg/kg once per week. # Clinical Studies The asthma development program for Mepolizumab included 3 double-blind, randomized, placebo-controlled trials: 1 dose-ranging and exacerbation trial (Trial 1) and 2 confirmatory trials (Trials 2 and 3). Mepolizumab was administered every 4 weeks in all 3 trials as add-on to background treatment. All subjects continued their background asthma therapy throughout the duration of the trials. - Dose-Ranging and Exacerbation Trial - Trial 1 was a 52-week dose-ranging and exacerbation-reduction trial in subjects with asthma with a history of 2 or more exacerbations in the previous year despite regular use of high-dose inhaled corticosteroids plus an additional controller(s) with or without oral corticosteroids. Subjects enrolled in this trial were required to have at least 1 of the following 4 pre-specified criteria in the previous 12 months: blood eosinophil count greater than or equal to 300 cells/mcL, sputum eosinophil count greater than or equal to 3%, exhaled nitric oxide concentration greater than or equal to 50 ppb, or deterioration of asthma control after less than or equal to 25% reduction in regular maintenance inhaled corticosteroids/oral corticosteroids. Three IV doses of mepolizumab (75, 250, and 750 mg) administered once every 4 weeks were evaluated compared with placebo. Results from this trial and the pharmacodynamic study supported the evaluation of mepolizumab 75 mg IV and 100 mg SC in the subsequent trials. Mepolizumab is not indicated for IV use and should only be administered by the SC route. - Confirmatory Trials - A total of 711 subjects with asthma were studied in the 2 confirmatory trials (Trials 2 and 3). In these 2 trials subjects were required to have blood eosinophils of greater than or equal to 150 cells/mcL at screening (within 6 weeks of dosing) or blood eosinophils of greater than or equal to 300 cells/mcL within 12 months of enrollment. The screening blood eosinophils of greater than or equal to 150 cells/mcL criterion was derived from exploratory analyses of data from Trial 1. Trial 2 was a 32-week placebo- and active-controlled trial in subjects with asthma with a history of 2 or more exacerbations in the previous year despite regular use of high-dose inhaled corticosteroids plus an additional controller(s) with or without oral corticosteroids. Subjects received mepolizumab 75 mg IV (n = 191), Mepolizumab (n = 194), or placebo (n = 191) once every 4 weeks for 32 weeks. - Trial 3 was a 24-week oral corticosteroid-reduction trial in subjects with asthma who required daily oral corticosteroids in addition to regular use of high-dose inhaled corticosteroids plus an additional controller(s) to maintain asthma control. Subjects in Trial 3 were not required to have a history of exacerbations in the prior year. Subjects received Mepolizumab (n = 69) or placebo (n = 66) once every 4 weeks for 24 weeks. The baseline mean oral corticosteroid use was similar in the 2 treatment groups: 13.2 mg in the placebo group and 12.4 mg in the group receiving Mepolizumab. - The demographics and baseline characteristics of these 3 trials are provided in Table 2. - Table 2. Demographics and Baseline Characteristics of Asthma Trials - Exacerbations - The primary endpoint for Trials 1 and 2 was the frequency of exacerbations defined as worsening of asthma requiring use of oral/systemic corticosteroids and/or hospitalization and/or emergency department visits. For subjects on maintenance oral corticosteroids, an exacerbation requiring oral corticosteroids was defined as the use of oral/systemic corticosteroids at least double the existing dose for at least 3 days. Compared with placebo, subjects receiving Mepolizumab or mepolizumab 75 mg IV experienced significantly fewer exacerbations. Additionally, compared with placebo, there were fewer exacerbations requiring hospitalization and/or emergency department visits and exacerbations requiring only in-patient hospitalization with Mepolizumab (Table 3). - Table 3. Rate of Exacerbations in Trials 1 and 2 (Intent-to-Treat Population) NUCALA: Mepolizumab's Brand name - The time to first exacerbation was longer for the groups receiving Mepolizumab and mepolizumab 75 mg IV compared with placebo in Trial 2 (Figure 1). - Figure 1. Kaplan-Meier Cumulative Incidence Curve for Time to First Exacerbation (Trial 2) NUCALA: Mepolizumab's Brand name - Trial 1 data were explored to determine criteria that could identify subjects likely to benefit from treatment with Mepolizumab. The exploratory analysis suggested that baseline blood eosinophil count of 150 cells/mcL or greater was a potential predictor of treatment benefit. Exploratory analysis of Trial 2 data also suggested that baseline blood eosinophil count (obtained within 6 weeks of initiation of dosing) of 150 cells/mcL or greater was a potential predictor of efficacy and showed a trend of greater exacerbation benefit with increasing blood eosinophil count. In Trial 2, subjects enrolled solely on the basis of the historical blood eosinophil count of 300 cells/mcL or greater in the past 12 months, but who had a baseline blood eosinophil count less than 150 cells/mcL, had virtually no exacerbation benefit following treatment with Mepolizumab compared with placebo. - The Asthma Control Questionnaire-5 (ACQ-5) was assessed in Trials 1 and 2, and the St. Georges Respiratory Questionnaire (SGRQ) was assessed in Trial 2. In Trial 1, the ACQ-5 responder rate (defined as a change in score of 0.5 or more as threshold) for the 75-mg IV mepolizumab arm was 47% compared with 50% for placebo with odds ratio of 1.1 (95% CI: 0.7, 1.7). In Trial 2, the ACQ-5 responder rate for the treatment arm for Mepolizumab was 57% compared with 45% for placebo with odds ratio of 1.8 (95% CI: 1.2, 2.8). In Trial 2, the SGRQ responder rate (defined as a change in score of 4 or more as threshold) for the treatment arm for Mepolizumab was 71% compared with 55% for placebo with odds ratio of 2.1 (95% CI: 1.3, 3.2). - Oral Corticosteroid Reduction - Trial 3 evaluated the effect of Mepolizumab on reducing the use of maintenance oral corticosteroids. The primary endpoint was the percent reduction of oral corticosteroid dose during Weeks 20 to 24 compared with baseline dose, while maintaining asthma control. Subjects were classified according to their change in oral corticosteroid use during the trial with the following categories: 90% to 100% decrease, 75% to 0% to <50% decrease, and no improvement (i.e., no change or any increase or lack of asthma control or withdrawal of treatment). Compared with placebo, subjects receiving Mepolizumab achieved greater reductions in daily maintenance oral corticosteroid dose, while maintaining asthma control. Sixteen (23%) subjects in the group receiving Mepolizumab versus 7 (11%) in the placebo group had a 90%to 100% reduction in their oral corticosteroid dose. Twenty-five (36%) subjects in the group receiving Mepolizumab versus 37 (56%) in the placebo group were classified as having no improvement for oral corticosteroid dose. Additionally, 54% of subjects treated with Mepolizumab achieved at least a 50% reduction in the daily prednisone dose compared with 33% of subjects treated with placebo (95% CI for difference: 4%, 37%). An exploratory analysis was also performed on the subgroup of 29 subjects in Trial 3 who had an average baseline and screening blood eosinophil count less than 150 cells/mcL. Five (29%) subjects in the group receiving Mepolizumab versus 0 (0%) in the placebo group had a 90% to 100% reduction in their dose. Four (24%) subjects in the group receiving Mepolizumab versus eight (67%) in the placebo group were classified as having no improvement for oral corticosteroid dose. The ACQ and SGRQ were also assessed in Trial 3 and showed results similar to those in Trial 2. - Lung Function - Change from baseline in mean forced expiratory volume in 1 second (FEV1) was measured in all 3 trials and is presented in Table 4. Compared with placebo, Mepolizumab did not provide consistent improvements in mean change from baseline in FEV1. - Table 4. Change from Baseline in FEV1 (mL) - The effect of mepolizumab on lung function was also studied in a 12-week, placebo-controlled trial enrolling patients with asthma on a moderate dose of inhaled corticosteroid with evidence of symptoms and lung function impairment. Enrollment was not dependent on a history of exacerbations or a pre-specified eosinophil count. Change from baseline in FEV1 at Week 12 was numerically lower in the mepolizumab treatment groups than the placebo group. # How Supplied Mepolizumab is supplied as a sterile, preservative-free, lyophilized powder for reconstitution and subcutaneous injection in cartons of 1 single-dose glass vial and a flip-off seal. The vial stopper is not made with natural rubber latex. Mepolizumab is available as: - 100-mg single-dose vial (NDC 0173-0881-01). ## Storage Store below 25°C (77°F). Do not freeze. Store in the original package to protect from light. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information Advise the patient to read the FDA-approved patient labeling (Patient Information). - Hypersensitivity Reactions - Inform patients that hypersensitivity reactions (e.g., angioedema, bronchospasm, hypotension, urticaria, rash) have occurred after administration of Mepolizumab. Instruct patients to contact their physicians if such reactions occur. - Not for Acute Symptoms or Deteriorating Disease - Inform patients that Mepolizumab does not treat acute asthma symptoms or acute exacerbations. Inform patients to seek medical advice if their asthma remains uncontrolled or worsens after initiation of treatment with Mepolizumab. - Opportunistic Infections: Herpes Zoster - Inform patients that herpes zoster infections have occurred in patients receiving Mepolizumab and where medically appropriate, inform patients varicella vaccination should be considered before starting treatment with Mepolizumab. - Reduction of Corticosteroid Dosage - Inform patients to not discontinue systemic or inhaled corticosteroids except under the direct supervision of a physician. Inform patients that reduction in corticosteroid dose may be associated with systemic withdrawal symptoms and/or unmask conditions previously suppressed by systemic corticosteroid therapy. - Pregnancy Exposure Registry - Inform women there is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to Mepolizumab during pregnancy and that they can enroll in the Pregnancy Exposure Registry by calling 1-877-311-8972 or by visiting WWW.MOTHERTOBABY.ORG/ASTHMA. # Precautions with Alcohol Alcohol-Mepolizumab interaction has not been established. Talk to your doctor regarding the effects of taking alcohol with this medication. # Brand Names NUCALA® # Look-Alike Drug Names There is limited information regarding Mepolizumab Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	Mepolizumab Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Martin Nino [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 Mepolizumab is an interleukin-5 antagonist monoclonal antibody (IgG1 kappa) that is FDA approved for the treatment of patients with severe asthma aged 12 years and older, and with an eosinophilic phenotype (indicated for add-on maintenance treatment). Common adverse reactions include headache, injection site reaction, back pain, and fatigue (5%). # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) Mepolizumab is indicated for the add-on maintenance treatment of patients with severe asthma aged 12 years and older, and with an eosinophilic phenotype. - Limitations of Use - Mepolizumab is not indicated for treatment of other eosinophilic conditions. - Mepolizumab is not indicated for the relief of acute bronchospasm or status asthmaticus. - Mepolizumab is for subcutaneous use only. - The recommended dose of Mepolizumab is 100 mg administered once every 4 weeks by subcutaneous injection into the upper arm, thigh, or abdomen. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Mepolizumab in adult patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Mepolizumab in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) The safety and efficacy in pediatric patients younger than 12 years have not been established. Same indications and dosage in patients aged 12 years or older. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Mepolizumab in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Mepolizumab in pediatric patients. # Contraindications Mepolizumab should not be administered to patients with a history of hypersensitivity to mepolizumab or excipients in the formulation. # Warnings Hypersensitivity reactions (e.g., angioedema, bronchospasm, hypotension, urticaria, rash) have occurred following administration of Mepolizumab. These reactions generally occur within hours of administration, but in some instances can have a delayed onset (i.e., days). In the event of a hypersensitivity reaction, Mepolizumab should be discontinued. Mepolizumab should not be used to treat acute asthma symptoms or acute exacerbations. Do not use Mepolizumab to treat acute bronchospasm or status asthmaticus. Patients should seek medical advice if their asthma remains uncontrolled or worsens after initiation of treatment with Mepolizumab. In controlled clinical trials, 2 serious adverse reactions of herpes zoster occurred in subjects treated with Mepolizumab compared with none in placebo. Consider varicella vaccination if medically appropriate prior to starting therapy with Mepolizumab. Do not discontinue systemic or inhaled corticosteroids abruptly upon initiation of therapy with Mepolizumab. Reductions in corticosteroid dose, if appropriate, should be gradual and performed under the direct supervision of a physician. Reduction in corticosteroid dose may be associated with systemic withdrawal symptoms and/or unmask conditions previously suppressed by systemic corticosteroid therapy. Eosinophils may be involved in the immunological response to some helminth infections. Patients with known parasitic infections were excluded from participation in clinical trials. It is unknown if Mepolizumab will influence a patient’s response against parasitic infections. Treat patients with pre-existing helminth infections before initiating therapy with Mepolizumab. If patients become infected while receiving treatment with Mepolizumab and do not respond to anti-helminth treatment, discontinue treatment with Mepolizumab until infection resolves. # Adverse Reactions ## Clinical Trials Experience The following adverse reactions are described in greater detail in other sections: - Hypersensitivity reactions - Opportunistic infections: herpes zoster 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. A total of 1,327 subjects with asthma were evaluated in 3 randomized, placebo-controlled, multicenter trials of 24 to 52 weeks’ duration (Trials 1, 2, and 3). Of these, 1,192 had a history of 2 or more exacerbations in the year prior to enrollment despite regular use of high-dose inhaled corticosteroids plus an additional controller(s) (Trials 1 and 2), and 135 subjects required daily oral corticosteroids in addition to regular use of high-dose inhaled corticosteroids plus an additional controller(s) to maintain asthma control (Trial 3). All subjects had markers of eosinophilic airway inflammation. Of the subjects enrolled, 59% were female, 85% were white, and subjects ranged in age from 12 to 82 years. Mepolizumab was administered subcutaneously or intravenously once every 4 weeks; 263 subjects received Mepolizumab (mepolizumab 100 mg subcutaneous [SC]) for at least 24 weeks. Serious adverse events that occurred in more than 1 subject and in a greater percentage of subjects treated with Mepolizumab (n = 263) than placebo (n = 257) included 1 event, herpes zoster (2 subjects vs. 0 subjects, respectively). Approximately 2% of subjects receiving Mepolizumab withdrew from clinical trials due to adverse events compared with 3% of subjects receiving placebo. The incidence of adverse reactions in the first 24 weeks of treatment in the 2 confirmatory efficacy and safety trials (Trials 2 and 3) with Mepolizumab is shown in Table 1. - Table 1. Adverse Reactions with Mepolizumab with Greater than or Equal to 3% Incidence and More Common than Placebo in Subjects with Asthma (Trials 2 and 3) NUCALA: Mepolizumab's Brand name - 52-Week Trial - Adverse reactions from Trial 1 with 52 weeks of treatment with mepolizumab 75 mg intravenous (IV) (n = 153) or placebo (n = 155) and with greater than or equal to 3% incidence and more common than placebo and not shown in Table 1 were: abdominal pain, allergic rhinitis, asthenia, bronchitis, cystitis, dizziness, dyspnea, ear infection, gastroenteritis, lower respiratory tract infection, musculoskeletal pain, nasal congestion, nasopharyngitis, nausea, pharyngitis, pyrexia, rash, toothache, viral infection, viral respiratory tract infection, and vomiting. In addition, 3 cases of herpes zoster occurred in subjects treated with mepolizumab 75 mg IV, compared with 2 subjects in the placebo group. - Systemic Reactions, including Hypersensitivity Reactions - In Trials 1, 2, and 3 described above, the percentage of subjects who experienced systemic (allergic and non-allergic) reactions was 7% in the placebo group and 10% in the group receiving Mepolizumab. Systemic allergic/hypersensitivity reactions were reported by 2% of subjects in the placebo group and 1% of subjects in the group receiving Mepolizumab. The most commonly reported manifestations of systemic allergic/hypersensitivity reactions reported in the group receiving Mepolizumab included rash, pruritus, headache, and myalgia. Systemic non-allergic reactions were reported by 2% of subjects in the group receiving Mepolizumab and 3% of subjects in the placebo group. The most commonly reported manifestations of systemic non-allergic reactions reported in the group receiving Mepolizumab included rash, flushing, and myalgia. A majority of the systemic reactions in subjects receiving Mepolizumab (5/7) were experienced on the day of dosing. - Injection Site Reactions - Injection site reactions (e.g., pain, erythema, swelling, itching, burning sensation) occurred at a rate of 8% in subjects treated with Mepolizumab compared with 3% in subjects treated with placebo. - Long-Term Safety - Nine hundred ninety-eight (998) subjects have received Mepolizumab in ongoing open-label extension studies, during which additional cases of herpes zoster have been reported. The overall adverse event profile was similar to the asthma trials described above. Overall, 15/260 (6%) of subjects treated with Mepolizumab developed anti-mepolizumab antibodies. The reported frequency may underestimate the actual frequency due to lower assay sensitivity in the presence of high drug concentration. Neutralizing antibodies were detected in 1 subject receiving mepolizumab. Anti-mepolizumab antibodies slightly increased (approximately 20%) the clearance of mepolizumab. There was no evidence of a correlation between anti-mepolizumab antibody titers and change in eosinophil level. The clinical relevance of the presence of anti-mepolizumab antibodies is not known. The data reflect the percentage of patients whose test results were positive for antibodies to mepolizumab in specific assays. The observed incidence of antibody positivity in an assay is highly dependent on several factors, including assay sensitivity and specificity, assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. ## Postmarketing Experience There is limited information regarding Mepolizumab Postmarketing Experience in the drug label. # Drug Interactions Formal drug interaction trials have not been performed with Mepolizumab. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): N - Pregnancy Exposure Registry - There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to Mepolizumab during pregnancy. Healthcare providers can enroll patients or encourage patients to enroll themselves by calling 1-877-311-8972 or visiting WWW.MOTHERTOBABY.ORG/ASTHMA. - Risk Summary - The data on pregnancy exposure from the clinical trials are insufficient to inform on drug-associated risk. Monoclonal antibodies, such as mepolizumab, are transported across the placenta in a linear fashion as pregnancy progresses; therefore, potential effects on a fetus are likely to be greater during the second and third trimester of pregnancy. In a prenatal and postnatal development study conducted in cynomolgus monkeys, there was no evidence of fetal harm with IV administration of mepolizumab throughout pregnancy at doses that produced exposures up to approximately 30 times the exposure at the maximum recommended human dose (MRHD) of 100 mg SC. - In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. - Clinical Considerations - Disease-Associated Maternal and/or Embryo-Fetal Risk: In women with poorly or moderately controlled asthma, evidence demonstrates that there is an increased risk of preeclampsia in the mother and prematurity, low birth weight, and small for gestational age in the neonate. The level of asthma control should be closely monitored in pregnant women and treatment adjusted as necessary to maintain optimal control. - Data - Animal Data: In a prenatal and postnatal development study, pregnant cynomolgus monkeys received mepolizumab from gestation days 20 to 140 at doses that produced exposures up to approximately 30 times that achieved with the MRHD (on an AUC basis with maternal IV doses up to 100 mg/kg once every 4 weeks). Mepolizumab did not elicit adverse effects on fetal or neonatal growth (including immune function) up to 9 months after birth. Examinations for internal or skeletal malformations were not performed. Mepolizumab crossed the placenta in cynomolgus monkeys. Concentrations of mepolizumab were approximately 2.4 times higher in infants than in mothers up to day 178 postpartum. Levels of mepolizumab in milk were less than or equal to 0.5% of maternal serum concentration. - In a fertility, early embryonic, and embryo-fetal development study, pregnant CD-1 mice received an analogous antibody, which inhibits the activity of murine IL-5, at an IV dose of 50 mg/kg once per week throughout gestation. The analogous antibody was not teratogenic in mice. Embryo-fetal development of IL-5–deficient mice has been reported to be generally unaffected relative to wild-type mice. Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Mepolizumab in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Mepolizumab during labor and delivery. ### Nursing Mothers There is no information regarding the presence of mepolizumab in human milk, the effects on the breastfed infant, or the effects on milk production. However, mepolizumab is a humanized monoclonal antibody (IgG1 kappa), and immunoglobulin G (IgG) is present in human milk in small amounts. Mepolizumab was present in the milk of cynomolgus monkeys postpartum following dosing during pregnancy. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for Mepolizumab and any potential adverse effects on the breastfed infant from mepolizumab or from the underlying maternal condition. ### Pediatric Use The safety and efficacy in pediatric patients younger than 12 years have not been established. A total of 28 adolescents aged 12 to 17 years with asthma were enrolled in the phase 3 studies. Of these, 25 were enrolled in the 32-week exacerbation trial (Trial 2) and had a mean age of 14.8 years. Subjects had a history of 2 or more exacerbations in the previous year despite regular use of high-dose inhaled corticosteroids plus an additional controller(s) with or without oral corticosteroids and had blood eosinophils of greater than or equal to 150 cells/mcL at screening or greater than or equal to 300 cells/mcL within 12 months prior to enrollment. Subjects had a reduction in the rate of exacerbations that trended in favor of mepolizumab. Of the 19 adolescents who received mepolizumab, 9 received Mepolizumab and the mean apparent clearance in these subjects was 35% less than that of adults. The adverse event profile in adolescents was generally similar to the overall population in the phase 3 studies. ### Geriatic Use Clinical trials of Mepolizumab did not include sufficient numbers of subjects aged 65 years and older that received Mepolizumab (n = 38) to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function and of concomitant disease or other drug therapy. Based on available data, no adjustment of the dosage of Mepolizumab in geriatric patients is necessary, but greater sensitivity in some older individuals cannot be ruled out. ### Gender There is no FDA guidance on the use of Mepolizumab with respect to specific gender populations. ### Race There is no FDA guidance on the use of Mepolizumab with respect to specific racial populations. ### Renal Impairment There is no FDA guidance on the use of Mepolizumab in patients with renal impairment. ### Hepatic Impairment There is no FDA guidance on the use of Mepolizumab in patients with hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Mepolizumab in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Mepolizumab in patients who are immunocompromised. # Administration and Monitoring ### Administration Mepolizumab should be reconstituted and administered by a healthcare professional. In line with clinical practice, monitoring of patients after administration of biologic agents is recommended. - Reconstitution Instructions - Administration ### Monitoring There is limited information regarding Mepolizumab Monitoring in the drug label. # IV Compatibility There is limited information regarding the compatibility of Mepolizumab and IV administrations. # Overdosage Single doses of up to 1,500 mg have been administered intravenously to subjects in a clinical trial with eosinophilic disease without evidence of dose-related toxicities. There is no specific treatment for an overdose with mepolizumab. If overdose occurs, the patient should be treated supportively with appropriate monitoring as necessary. # Pharmacology ## Mechanism of Action Mepolizumab is an interleukin-5 antagonist (IgG1 kappa). IL-5 is the major cytokine responsible for the growth and differentiation, recruitment, activation, and survival of eosinophils. Mepolizumab binds to IL-5 with a dissociation constant of 100 pM, inhibiting the bioactivity of IL-5 by blocking its binding to the alpha chain of the IL-5 receptor complex expressed on the eosinophil cell surface. Inflammation is an important component in the pathogenesis of asthma. Multiple cell types (e.g., mast cells, eosinophils, neutrophils, macrophages, lymphocytes) and mediators (e.g., histamine, eicosanoids, leukotrienes, cytokines) are involved in inflammation. Mepolizumab, by inhibiting IL-5 signaling, reduces the production and survival of eosinophils; however, the mechanism of mepolizumab action in asthma has not been definitively established. ## Structure Mepolizumab is a humanized IL-5 antagonist monoclonal antibody. Mepolizumab is produced by recombinant DNA technology in Chinese hamster ovary cells. Mepolizumab has a molecular weight of approximately 149 kDa. Mepolizumab is supplied as a sterile, white to off-white, preservative-free, lyophilized powder for subcutaneous injection after reconstitution. Upon reconstitution with 1.2 mL of Sterile Water for Injection, USP, the resulting concentration is 100 mg/mL and delivers 1 mL. Each single-dose vial delivers mepolizumab 100 mg, polysorbate 80 (0.67 mg), sodium phosphate dibasic heptahydrate (7.14 mg), and sucrose (160 mg), with a pH of 7.0. ## Pharmacodynamics The pharmacodynamic response (blood eosinophil reduction) following repeat doses of mepolizumab administered subcutaneously or intravenously was evaluated in subjects with asthma and blood eosinophil levels greater than 200 cells/mcL. Subjects received 1 of 4 mepolizumab treatments (administered every 28 days for a total of 3 doses): 12.5 mg SC, 125 mg SC, 250 mg SC, or 75 mg IV. Sixty-six (66) of the 70 randomized subjects completed the trial. Compared with baseline levels, blood eosinophils decreased in a dose-dependent manner. A reduction in blood eosinophil levels was observed in all treatment groups by Day 3. On Day 84 (4 weeks post-last dose), the observed geometric mean reduction from baseline in blood eosinophils was 64%, 78%, 84%, and 90% in the 12.5-mg SC, 75-mg IV, 125-mg SC, and 250-mg SC treatment groups, respectively. The model-predicted SC doses providing 50% and 90% of maximal reduction of blood eosinophils at Day 84 were estimated to be 11 and 99 mg, respectively. These results, along with the clinical efficacy data from the dose-ranging exacerbation trial (Trial 1) supported the evaluation of mepolizumab 75 mg IV and 100 mg SC in the confirmatory trials. Following SC administration of mepolizumab 100 mg every 4 weeks for 32 weeks (Trial 2), blood eosinophils were reduced to a geometric mean count of 40 cells/mcL, which corresponds to a geometric mean reduction of 84% compared with placebo. This magnitude of reduction was observed within 4 weeks of treatment and was maintained throughout the treatment period. ## Pharmacokinetics Following SC dosing in subjects with asthma, mepolizumab exhibited approximately dose-proportional pharmacokinetics over a dose range of 12.5 to 250 mg. Absorption - Following 100-mg SC administration in the upper arm of subjects with asthma, the bioavailability of mepolizumab was estimated to be approximately 80%. - Following repeat SC administration once every 4 weeks, there was approximately a 2-fold accumulation at steady state. Distribution - The population central volume of distribution of mepolizumab in patients with asthma is estimated to be 3.6 L for a 70‑kg individual. Metabolism - Mepolizumab is a humanized IgG1 monoclonal antibody that is degraded by proteolytic enzymes widely distributed in the body and not restricted to hepatic tissue. Elimination - Following SC administration of mepolizumab, the mean terminal half-life (t1/2) ranged from 16 to 22 days. The population apparent systemic clearance of mepolizumab in patients with asthma is estimated to be 0.28 L/day for a 70-kg individual. Specific Populations - Race and Gender: A population pharmacokinetics analysis indicated there was no significant effect of race and gender on mepolizumab clearance. - Age: A population pharmacokinetics analysis of subjects ranging in age from 12 to 82 years indicated there was no significant effect of age on mepolizumab clearance. - Renal Impairment: No clinical trials have been conducted to investigate the effect of renal impairment on the pharmacokinetics of mepolizumab. Based on population pharmacokinetic analyses, mepolizumab clearance was comparable between subjects with creatinine clearance values between 50 and 80 mL/min and patients with normal renal function. There are limited data available in subjects with creatinine clearance values less than 50 mL/min; however, mepolizumab is not cleared renally. - Hepatic Impairment: No clinical trials have been conducted to investigate the effect of hepatic impairment on the pharmacokinetics of mepolizumab. Since mepolizumab is degraded by widely distributed proteolytic enzymes, not restricted to hepatic tissue, changes in hepatic function are unlikely to have any effect on the elimination of mepolizumab. - Drug-Drug Interactions: No formal drug interaction studies have been conducted with Mepolizumab. In the population pharmacokinetics analyses of the phase 3 studies, there was no evidence of an effect of commonly coadministered small molecule drugs on mepolizumab exposure. ## Nonclinical Toxicology Long-term animal studies have not been performed to evaluate the carcinogenic potential of mepolizumab. Published literature using animal models suggests that IL-5 and eosinophils are part of an early inflammatory reaction at the site of tumorigenesis and can promote tumor rejection. However, other reports indicate that eosinophil infiltration into tumors can promote tumor growth. Therefore, the malignancy risk in humans from an antibody to IL-5 such as mepolizumab is unknown. Male and female fertility were unaffected based upon no adverse histopathological findings in the reproductive organs from cynomolgus monkeys treated with mepolizumab for 6 months at IV doses up to 100 mg/kg once every 4 weeks (approximately 70 times the MRHD on an AUC basis). Mating and reproductive performance were unaffected in male and female CD-1 mice treated with an analogous antibody, which inhibits the activity of murine IL-5, at an IV dose of 50 mg/kg once per week. # Clinical Studies The asthma development program for Mepolizumab included 3 double-blind, randomized, placebo-controlled trials: 1 dose-ranging and exacerbation trial (Trial 1) and 2 confirmatory trials (Trials 2 and 3). Mepolizumab was administered every 4 weeks in all 3 trials as add-on to background treatment. All subjects continued their background asthma therapy throughout the duration of the trials. - Dose-Ranging and Exacerbation Trial - Trial 1 was a 52-week dose-ranging and exacerbation-reduction trial in subjects with asthma with a history of 2 or more exacerbations in the previous year despite regular use of high-dose inhaled corticosteroids plus an additional controller(s) with or without oral corticosteroids. Subjects enrolled in this trial were required to have at least 1 of the following 4 pre-specified criteria in the previous 12 months: blood eosinophil count greater than or equal to 300 cells/mcL, sputum eosinophil count greater than or equal to 3%, exhaled nitric oxide concentration greater than or equal to 50 ppb, or deterioration of asthma control after less than or equal to 25% reduction in regular maintenance inhaled corticosteroids/oral corticosteroids. Three IV doses of mepolizumab (75, 250, and 750 mg) administered once every 4 weeks were evaluated compared with placebo. Results from this trial and the pharmacodynamic study supported the evaluation of mepolizumab 75 mg IV and 100 mg SC in the subsequent trials. Mepolizumab is not indicated for IV use and should only be administered by the SC route. - Confirmatory Trials - A total of 711 subjects with asthma were studied in the 2 confirmatory trials (Trials 2 and 3). In these 2 trials subjects were required to have blood eosinophils of greater than or equal to 150 cells/mcL at screening (within 6 weeks of dosing) or blood eosinophils of greater than or equal to 300 cells/mcL within 12 months of enrollment. The screening blood eosinophils of greater than or equal to 150 cells/mcL criterion was derived from exploratory analyses of data from Trial 1. Trial 2 was a 32-week placebo- and active-controlled trial in subjects with asthma with a history of 2 or more exacerbations in the previous year despite regular use of high-dose inhaled corticosteroids plus an additional controller(s) with or without oral corticosteroids. Subjects received mepolizumab 75 mg IV (n = 191), Mepolizumab (n = 194), or placebo (n = 191) once every 4 weeks for 32 weeks. - Trial 3 was a 24-week oral corticosteroid-reduction trial in subjects with asthma who required daily oral corticosteroids in addition to regular use of high-dose inhaled corticosteroids plus an additional controller(s) to maintain asthma control. Subjects in Trial 3 were not required to have a history of exacerbations in the prior year. Subjects received Mepolizumab (n = 69) or placebo (n = 66) once every 4 weeks for 24 weeks. The baseline mean oral corticosteroid use was similar in the 2 treatment groups: 13.2 mg in the placebo group and 12.4 mg in the group receiving Mepolizumab. - The demographics and baseline characteristics of these 3 trials are provided in Table 2. - Table 2. Demographics and Baseline Characteristics of Asthma Trials - Exacerbations - The primary endpoint for Trials 1 and 2 was the frequency of exacerbations defined as worsening of asthma requiring use of oral/systemic corticosteroids and/or hospitalization and/or emergency department visits. For subjects on maintenance oral corticosteroids, an exacerbation requiring oral corticosteroids was defined as the use of oral/systemic corticosteroids at least double the existing dose for at least 3 days. Compared with placebo, subjects receiving Mepolizumab or mepolizumab 75 mg IV experienced significantly fewer exacerbations. Additionally, compared with placebo, there were fewer exacerbations requiring hospitalization and/or emergency department visits and exacerbations requiring only in-patient hospitalization with Mepolizumab (Table 3). - Table 3. Rate of Exacerbations in Trials 1 and 2 (Intent-to-Treat Population) NUCALA: Mepolizumab's Brand name - The time to first exacerbation was longer for the groups receiving Mepolizumab and mepolizumab 75 mg IV compared with placebo in Trial 2 (Figure 1). - Figure 1. Kaplan-Meier Cumulative Incidence Curve for Time to First Exacerbation (Trial 2) NUCALA: Mepolizumab's Brand name - Trial 1 data were explored to determine criteria that could identify subjects likely to benefit from treatment with Mepolizumab. The exploratory analysis suggested that baseline blood eosinophil count of 150 cells/mcL or greater was a potential predictor of treatment benefit. Exploratory analysis of Trial 2 data also suggested that baseline blood eosinophil count (obtained within 6 weeks of initiation of dosing) of 150 cells/mcL or greater was a potential predictor of efficacy and showed a trend of greater exacerbation benefit with increasing blood eosinophil count. In Trial 2, subjects enrolled solely on the basis of the historical blood eosinophil count of 300 cells/mcL or greater in the past 12 months, but who had a baseline blood eosinophil count less than 150 cells/mcL, had virtually no exacerbation benefit following treatment with Mepolizumab compared with placebo. - The Asthma Control Questionnaire-5 (ACQ-5) was assessed in Trials 1 and 2, and the St. Georges Respiratory Questionnaire (SGRQ) was assessed in Trial 2. In Trial 1, the ACQ-5 responder rate (defined as a change in score of 0.5 or more as threshold) for the 75-mg IV mepolizumab arm was 47% compared with 50% for placebo with odds ratio of 1.1 (95% CI: 0.7, 1.7). In Trial 2, the ACQ-5 responder rate for the treatment arm for Mepolizumab was 57% compared with 45% for placebo with odds ratio of 1.8 (95% CI: 1.2, 2.8). In Trial 2, the SGRQ responder rate (defined as a change in score of 4 or more as threshold) for the treatment arm for Mepolizumab was 71% compared with 55% for placebo with odds ratio of 2.1 (95% CI: 1.3, 3.2). - Oral Corticosteroid Reduction - Trial 3 evaluated the effect of Mepolizumab on reducing the use of maintenance oral corticosteroids. The primary endpoint was the percent reduction of oral corticosteroid dose during Weeks 20 to 24 compared with baseline dose, while maintaining asthma control. Subjects were classified according to their change in oral corticosteroid use during the trial with the following categories: 90% to 100% decrease, 75% to <90% decrease, 50% to <75% decrease, >0% to <50% decrease, and no improvement (i.e., no change or any increase or lack of asthma control or withdrawal of treatment). Compared with placebo, subjects receiving Mepolizumab achieved greater reductions in daily maintenance oral corticosteroid dose, while maintaining asthma control. Sixteen (23%) subjects in the group receiving Mepolizumab versus 7 (11%) in the placebo group had a 90%to 100% reduction in their oral corticosteroid dose. Twenty-five (36%) subjects in the group receiving Mepolizumab versus 37 (56%) in the placebo group were classified as having no improvement for oral corticosteroid dose. Additionally, 54% of subjects treated with Mepolizumab achieved at least a 50% reduction in the daily prednisone dose compared with 33% of subjects treated with placebo (95% CI for difference: 4%, 37%). An exploratory analysis was also performed on the subgroup of 29 subjects in Trial 3 who had an average baseline and screening blood eosinophil count less than 150 cells/mcL. Five (29%) subjects in the group receiving Mepolizumab versus 0 (0%) in the placebo group had a 90% to 100% reduction in their dose. Four (24%) subjects in the group receiving Mepolizumab versus eight (67%) in the placebo group were classified as having no improvement for oral corticosteroid dose. The ACQ and SGRQ were also assessed in Trial 3 and showed results similar to those in Trial 2. - Lung Function - Change from baseline in mean forced expiratory volume in 1 second (FEV1) was measured in all 3 trials and is presented in Table 4. Compared with placebo, Mepolizumab did not provide consistent improvements in mean change from baseline in FEV1. - Table 4. Change from Baseline in FEV1 (mL) - The effect of mepolizumab on lung function was also studied in a 12-week, placebo-controlled trial enrolling patients with asthma on a moderate dose of inhaled corticosteroid with evidence of symptoms and lung function impairment. Enrollment was not dependent on a history of exacerbations or a pre-specified eosinophil count. Change from baseline in FEV1 at Week 12 was numerically lower in the mepolizumab treatment groups than the placebo group. # How Supplied Mepolizumab is supplied as a sterile, preservative-free, lyophilized powder for reconstitution and subcutaneous injection in cartons of 1 single-dose glass vial and a flip-off seal. The vial stopper is not made with natural rubber latex. Mepolizumab is available as: - 100-mg single-dose vial (NDC 0173-0881-01). ## Storage Store below 25°C (77°F). Do not freeze. Store in the original package to protect from light. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information Advise the patient to read the FDA-approved patient labeling (Patient Information). - Hypersensitivity Reactions - Inform patients that hypersensitivity reactions (e.g., angioedema, bronchospasm, hypotension, urticaria, rash) have occurred after administration of Mepolizumab. Instruct patients to contact their physicians if such reactions occur. - Not for Acute Symptoms or Deteriorating Disease - Inform patients that Mepolizumab does not treat acute asthma symptoms or acute exacerbations. Inform patients to seek medical advice if their asthma remains uncontrolled or worsens after initiation of treatment with Mepolizumab. - Opportunistic Infections: Herpes Zoster - Inform patients that herpes zoster infections have occurred in patients receiving Mepolizumab and where medically appropriate, inform patients varicella vaccination should be considered before starting treatment with Mepolizumab. - Reduction of Corticosteroid Dosage - Inform patients to not discontinue systemic or inhaled corticosteroids except under the direct supervision of a physician. Inform patients that reduction in corticosteroid dose may be associated with systemic withdrawal symptoms and/or unmask conditions previously suppressed by systemic corticosteroid therapy. - Pregnancy Exposure Registry - Inform women there is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to Mepolizumab during pregnancy and that they can enroll in the Pregnancy Exposure Registry by calling 1-877-311-8972 or by visiting WWW.MOTHERTOBABY.ORG/ASTHMA. # Precautions with Alcohol Alcohol-Mepolizumab interaction has not been established. Talk to your doctor regarding the effects of taking alcohol with this medication. # Brand Names NUCALA® # Look-Alike Drug Names There is limited information regarding Mepolizumab Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	https://www.wikidoc.org/index.php/Mepolizumab
3c17519722040e6731426c4ef91ac7022bb0712e	wikidoc	Mequitazine	Mequitazine # Overview Mequitazine (trade name Primalan) is an antihistamine and anticholinergic of the phenothiazine chemical class. It is used to treat allergies and rhinitis. # Contraindications Severe liver disease; premature infants or full-term neonates . # Special precautions Pregnancy, lactation; severe CardioVascular disorders; asthma; angle-closure glaucoma, urinary retention, prostatic hyperplasia, pyloroduodenal obstruction; renal and hepatic impairment; elderly, children; epilepsy. May impair ability to drive or operate machinery. # Adverse drug reactions CNS depression including slight drowsiness to deep sleep, lassitude, dizziness, incoordination. Headache, psychomotor impairment and antimuscarinic effects. Rarely, rashes and hypersensitivity reactions, blood disorders, convulsions, sweating, myalgia, paraesthesias, extrapyramidal effects, tremor, confusion, sleep and GI disturbances, tinnitus, hypotension, hair loss. Photosensitivity, jaundice. # Drug Interactions Enhanced effects of CNS depressants e.g. alcohol, barbiturates, hypnotics, opioid analgesics, anxiolytic sedatives and antipsychotics. Can mask signs of ototoxicity caused by aminoglycosides. QT prolongation reported with spiramycin.	Mequitazine Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview Mequitazine (trade name Primalan) is an antihistamine and anticholinergic of the phenothiazine chemical class. It is used to treat allergies and rhinitis. # Contraindications Severe liver disease; premature infants or full-term neonates . # Special precautions Pregnancy, lactation; severe CardioVascular disorders; asthma; angle-closure glaucoma, urinary retention, prostatic hyperplasia, pyloroduodenal obstruction; renal and hepatic impairment; elderly, children; epilepsy. May impair ability to drive or operate machinery. # Adverse drug reactions CNS depression including slight drowsiness to deep sleep, lassitude, dizziness, incoordination. Headache, psychomotor impairment and antimuscarinic effects. Rarely, rashes and hypersensitivity reactions, blood disorders, convulsions, sweating, myalgia, paraesthesias, extrapyramidal effects, tremor, confusion, sleep and GI disturbances, tinnitus, hypotension, hair loss. Photosensitivity, jaundice. # Drug Interactions Enhanced effects of CNS depressants e.g. alcohol, barbiturates, hypnotics, opioid analgesics, anxiolytic sedatives and antipsychotics. Can mask signs of ototoxicity caused by aminoglycosides. QT prolongation reported with spiramycin.	https://www.wikidoc.org/index.php/Mequitazine
01cc0401a1756a2e58ace4f7b918904e6c86cd4c	wikidoc	Sibutramine	Sibutramine # 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 Sibutramine is an appetite suppressant that is FDA approved for the {{{indicationType}}} of obesity. Common adverse reactions include dry mouth, anorexia, insomnia, constipation and headache. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) - The recommended starting dose of MERIDIA is 10 mg administered once daily with or without food. If there is inadequate weight loss, the dose may be titrated after four weeks to a total of 15 mg once daily. The 5 mg dose should be reserved for patients who do not tolerate the 10 mg dose. Blood pressure and heart rate changes should be taken into account when making decisions regarding dose titration (see WARNINGS and PRECAUTIONS). - Doses above 15 mg daily are not recommended. In most of the clinical trials, MERIDIA was given in the morning. - Analysis of numerous variables has indicated that approximately 60% of patients who lose at least 4 pounds in the first 4 weeks of treatment with a given dose of MERIDIA in combination with a reduced-calorie diet lose at least 5% (placebo-subtracted) of their initial body weight by the end of 6 months to 1 year of treatment on that dose of MERIDIA. Conversely, approximately 80% of patients who do not lose at least 4 pounds in the first 4 weeks of treatment with a given dose of MERIDIA do not lose at least 5% (placebo-subtracted) of their initial body weight by the end of 6 months to 1 year of treatment on that dose. If a patient has not lost at least 4 pounds in the first 4 weeks of treatment, the physician should consider reevaluation of therapy which may include increasing the dose or discontinuation of MERIDIA. - The safety and effectiveness of MERIDIA, as demonstrated in double-blind, placebo-controlled trials, have not been determined beyond 2 years at this time. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Sibutramine in adult patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Sibutramine in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) There is limited information regarding FDA-Labeled Use of Sibutramine in pediatric patients. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Sibutramine in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Sibutramine in pediatric patients. # Contraindications - With a history of coronary artery disease (e.g., angina, history of myocardial infarction), congestive heart failure, tachycardia, peripheral arterial occlusive disease, arrhythmia or cerebrovascular disease (stroke or transient ischemic attack (TIA)). - With inadequately controlled hypertension > 145/90 mm Hg. - over 65 years of age. - Receiving monoamine oxidase inhibitors (MAOIs). - With hypersensitivity to sibutramine or any of the inactive ingredients of MERIDIA. - Who have a major eating disorder (anorexia nervosa or bulimia nervosa). - Taking other centrally acting weight loss drugs. # Warnings - Concomitant Cardiovascular Disease - Due to an increased risk of heart attack and stroke in patients with cardiovascular disease, MERIDIA should not be used in patients with a history of coronary artery disease, congestive heart failure, arrhythmias, or stroke. - Blood Pressure and Pulse - Meridia substantially increases blood pressure and/or pulse rate in some patients. Regular monitoring of blood pressure and pulse rate is required when prescribing Meridia. - In placebo-controlled obesity studies, sibutramine 5 to 20 mg once daily was associated with mean increases in systolic and diastolic blood pressure of approximately 1 to 3 mm Hg relative to placebo, and with mean increases in pulse rate relative to placebo of approximately 4 to 5 beats per minute. Larger increases were seen in some patients, particularly when therapy with sibutramine was initiated at the higher doses (see table below). In premarketing placebo-controlled obesity studies, 0.4% of patients treated with sibutramine were discontinued for hypertension (SBP ≥160 mm Hg or DBP ≥ 95 mm Hg), compared with 0.4% in the placebo group, and 0.4% of patients treated with sibutramine were discontinued for tachycardia (pulse rate ≥ 100 bpm), compared with 0.1% in the placebo group. Blood pressure and pulse should be measured prior to starting therapy with MERIDIA and should be monitored at regular intervals thereafter. For patients who experience a sustained increase in blood pressure or pulse rate while receiving MERIDIA, either dose reduction or discontinuation should be considered. MERIDIA should be given with caution to those patients with a history of hypertension, and should not be given to patients with uncontrolled or poorly controlled hypertension. - Potential Interaction With Monoamine Oxidase Inhibitors - MERIDIA is a norepinephrine, serotonin and dopamine reuptake inhibitor and should not be used concomitantly with MAOIs. There should be at least a 2-week interval after stopping MAOIs before commencing treatment with MERIDIA. Similarly, there should be at least a 2-week interval after stopping MERIDIA before starting treatment with MAOIs. - Serotonin Syndrome or Neuroleptic Malignant Syndrome (NMS)-Like Reactions - The development of a potentially life-threatening serotonin syndrome, or Neuroleptic Malignant Syndrome (NMS)-like reactions, has been reported with SNRIs and SSRIs alone, including MERIDIA treatment, but particularly with concomitant use of serotonergic drugs (including triptans), with drugs which impair metabolism of serotonin (including MAOIs), or with antipsychotics or other dopamine antagonists. Serotonin syndrome symptoms may include mental status changes (e.g., agitation, hallucinations, coma), autonomic instability (e.g., tachycardia, labile blood pressure, hyperthermia), neuromuscular aberrations (e.g., hyperreflexia, incoordination) and/or gastrointestinal symptoms . Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome, which includes hyperthermia, muscle rigidity, autonomic instability with possible rapid fluctuation of vital signs, and mental status changes. Patients should be monitored for the emergence of serotonin syndrome or NMS-like signs and symptoms. - Glaucoma - Because MERIDIA can cause mydriasis, it should be used with caution in patients with narrow angle glaucoma. - Miscellaneous - Organic causes of obesity (e.g., untreated hypothyroidism) should be excluded before prescribing MERIDIA. ### Precautions - Pulmonary Hypertension - Certain centrally-acting weight loss agents that cause release of serotonin from nerve terminals have been associated with pulmonary hypertension (PPH), a rare but lethal disease. In premarketing clinical studies, no cases of PPH have been reported with sibutramine capsules. Because of the low incidence of this disease in the underlying population, however, it is not known whether or not MERIDIA may cause this disease. - Seizures - During premarketing testing, seizures were reported in < 0.1% of sibutramine treated patients. MERIDIA should be used cautiously in patients with a history of seizures. It should be discontinued in any patient who develops seizures. - Bleeding - There have been reports of bleeding in patients taking sibutramine. While a causal relationship is unclear, caution is advised in patients predisposed to bleeding events and those taking concomitant medications known to affect hemostasis or platelet function. - Gallstones - Weight loss can precipitate or exacerbate gallstone formation. - Renal Impairment - MERIDIA should be used with caution in patients with mild to moderate renal impairment. MERIDIA should not be used in patients with severe renal impairment, including those with end stage renal disease on dialysis. - Hepatic Dysfunction - Patients with severe hepatic dysfunction have not been systematically studied; MERIDIA should therefore not be used in such patients. - Interference With Cognitive and Motor Performance - Although sibutramine did not affect psychomotor or cognitive performance in healthy volunteers, any CNS active drug has the potential to impair judgment, thinking or motor skills. # Adverse Reactions ## Clinical Trials Experience - In placebo-controlled studies, 9% of patients treated with sibutramine (n = 2068) and 7% of patients treated with placebo (n = 884) withdrew for adverse events. - In placebo-controlled studies, the most common events were dry mouth, anorexia, insomnia, constipation and headache. Adverse events in these studies occurring in ≥ 1% of sibutramine treated patients and more frequently than in the placebo group are shown in the following table. - The following additional adverse events were reported in ≥ 1% of all patients who received sibutramine in controlled and uncontrolled premarketing studies. Fever. Diarrhea, flatulence, gastroenteritis, tooth disorder. Peripheral edema. Arthritis. Agitation, leg cramps, hypertonia, thinking abnormal. Bronchitis, dyspnea. Pruritus. Amblyopia. Menstrual disorders. - Other Adverse Events - Clinical Studies - Seizures - Convulsions were reported as an adverse event in three of 2068 (0.1%) sibutramine treated patients and in none of 884 placebo-treated patients in placebo-controlled premarketing obesity studies. Two of the three patients with seizures had potentially predisposing factors (one had a prior history of epilepsy; one had a subsequent diagnosis of brain tumor). The incidence in all subjects who received sibutramine (three of 4,588 subjects) was less than 0.1%. - Ecchymosis/Bleeding Disorders - Ecchymosis (bruising) was observed in 0.7% of sibutramine treated patients and in 0.2% of placebo-treated patients in premarketing placebo-controlled obesity studies. One patient had prolonged bleeding of a small amount which occurred during minor facial surgery. Sibutramine may have an effect on platelet function due to its effect on serotonin uptake. - Interstitial Nephritis - Acute interstitial nephritis (confirmed by biopsy) was reported in one obese patient receiving sibutramine during premarketing studies. After discontinuation of the medication, dialysis and oral corticosteroids were administered; renal function normalized. The patient made a full recovery. ## Postmarketing Experience - Voluntary reports of adverse events temporally associated with the use of sibutramine are listed below. It is important to emphasize that although these events occurred during treatment with sibutramine, they may have no causal relationship with the drug. Obesity itself, concurrent disease states/risk factors, or weight reduction may be associated with an increased risk for some of these events. - Psychiatric - Cases of depression, psychosis, mania, suicidal ideation and suicide have been reported rarely in patients on sibutramine treatment. However, a relationship has not been established between these events and the use of sibutramine. If any of these events should occur during treatment with sibutramine, discontinuation should be considered. - Hypersensitivity - Allergic hypersensitivity reactions ranging from mild skin eruptions and urticaria to angioedema and anaphylaxis have been reported. - Other Postmarketing Reported Events: Anaphylactic shock, anaphylactoid reaction, chest pressure, chest tightness, facial edema, limb pain, sudden unexplained death. Angina pectoris, atrial fibrillation, congestive heart failure, heart arrest, heart rate decreased, myocardial infarction, supraventricular tachycardia, syncope, torsade de pointes, vascular headache, ventricular tachycardia, ventricular extrasystoles, ventricular fibrillation. Cholecystitis, cholelithiasis, duodenal ulcer, eructation, gastrointestinal hemorrhage, increased salivation, intestinal obstruction, mouth ulcer, stomach ulcer, tongue edema. Goiter, hyperthyroidism, hypothyroidism. Anemia, leukopenia, lymphadenopathy, petechiae, thrombocytopenia. Hyperglycemia, hypoglycemia. Arthrosis, bursitis. Abnormal dreams, abnormal gait, amnesia, anger, cerebrovascular accident, concentration impaired, confusion, depression aggravated, Gilles de la Tourette’s syndrome, hypesthesia, libido decreased, libido increased, mood changes, nightmares, short term memory loss, speech disorder, transient ischemic attack, tremor, twitch, vertigo. Epistaxis, nasal congestion, respiratory disorder, yawn. Alopecia, dermatitis, photosensitivity (skin), urticaria. Abnormal vision, blurred vision, dry eye, eye pain, increased intraocular pressure, otitis externa, otitis media, photosensitivity (eyes), tinnitus. Abnormal ejaculation, hematuria, impotence, increased urinary frequency, micturition difficulty, urinary retention. # Drug Interactions - CNS Active Drugs: - The use of MERIDIA in combination with other CNS-active drugs, particularly serotonergic agents, has not been systematically evaluated. Consequently, caution is advised if the concomitant administration of MERIDIA with other centrally-acting drugs is indicated. - In patients receiving monoamine oxidase inhibitors (MAOIs) (e.g., phenelzine, selegiline) in combination with serotonergic agents (e.g., fluoxetine, fluvoxamine, paroxetine, sertraline, venlafaxine), there have been reports of serious, sometimes fatal, reactions ("serotonin syndrome;" see below). Because sibutramine inhibits serotonin reuptake, MERIDIA should not be used concomitantly with a MAOI. At least 2 weeks should elapse between discontinuation of a MAOI and initiation of treatment with MERIDIA. Similarly, at least 2 weeks should elapse between discontinuation of MERIDIA and initiation of treatment with a MAOI. - The rare, but serious, constellation of symptoms termed "serotonin syndrome" has also been reported with the concomitant use of selective serotonin reuptake inhibitors and agents for migraine therapy, such as Imitrex® (sumatriptan succinate) and dihydroergotamine, certain opioids, such as dextromethorphan, meperidine, pentazocine and fentanyl, lithium, or tryptophan. Serotonin syndrome has also been reported with the concomitant use of two serotonin reuptake inhibitors. The syndrome requires immediate medical attention and may include one or more of the following symptoms: excitement, hypomania, restlessness, loss of consciousness, confusion, disorientation, anxiety, agitation, motor weakness, myoclonus, tremor, hemiballismus, hyperreflexia, ataxia, dysarthria, incoordination, hyperthermia, shivering, pupillary dilation, diaphoresis, emesis, and tachycardia. - Because sibutramine inhibits serotonin reuptake, in general, it should not be administered with other serotonergic agents such as those listed above. However, if such a combination is clinically indicated, appropriate observation of the patient is warranted. - Drugs That May Raise Blood Pressure and/or Heart Rate - Concomitant use of MERIDIA and other agents that may raise blood pressure or heart rate have not been evaluated. These include certain decongestants, cough, cold, and allergy medications that contain agents such as ephedrine, or pseudoephedrine. Caution should be used when prescribing MERIDIA to patients who use these medications. - Alcohol - In a double-blind, placebo-controlled, crossover study in 19 volunteers, administration of a single dose of ethanol (0.5 mL/kg) together with 20 mg of sibutramine resulted in no psychomotor interactions of clinical significance between alcohol and sibutramine. However, the concomitant use of MERIDIA and excess alcohol is not recommended. - Oral Contraceptives - The suppression of ovulation by oral contraceptives was not inhibited by sibutramine. In a crossover study, 12 healthy female volunteers on oral steroid contraceptives received placebo in one period and 15 mg sibutramine in another period over the course of 8 weeks. No clinically significant systemic interaction was observed; therefore, no requirement for alternative contraceptive precautions are needed when patients taking oral contraceptives are concurrently prescribed sibutramine. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): - Pregnancy Category C - Radiolabeled studies in animals indicated that tissue distribution was unaffected by pregnancy, with relatively low transfer to the fetus. In rats, there was no evidence of teratogenicity at doses of 1, 3, or 10 mg/kg/day generating combined plasma AUC's of the two major active metabolites up to approximately 32 times those following the human dose of 15 mg. In rabbits dosed at 3, 15, or 75 mg/kg/day, plasma AUC's greater than approximately 5 times those following the human dose of 15 mg caused maternal toxicity. At markedly toxic doses, Dutch Belted rabbits had a slightly higher than control incidence of pups with a broad short snout, short rounded pinnae, short tail and, in some, shorter thickened long bones in the limbs; at comparably high doses in New Zealand White rabbits, one study showed a slightly higher than control incidence of pups with cardiovascular anomalies while a second study showed a lower incidence than in the control group. - No adequate and well controlled studies with sibutramine have been conducted in pregnant women. The use of MERIDIA during pregnancy is not recommended. Women of childbearing potential should employ adequate contraception while taking MERIDIA. Patients should be advised to notify their physician if they become pregnant or intend to become pregnant while taking MERIDIA. Pregnancy Category (AUS): - Australian Drug Evaluation Committee (ADEC) Pregnancy Category There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Sibutramine in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Sibutramine during labor and delivery. ### Nursing Mothers There is no FDA guidance on the use of Sibutramine with respect to nursing mothers. ### Pediatric Use There is no FDA guidance on the use of Sibutramine with respect to pediatric patients. ### Geriatic Use There is no FDA guidance on the use of Sibutramine with respect to geriatric patients. ### Gender There is no FDA guidance on the use of Sibutramine with respect to specific gender populations. ### Race There is no FDA guidance on the use of Sibutramine with respect to specific racial populations. ### Renal Impairment There is no FDA guidance on the use of Sibutramine in patients with renal impairment. ### Hepatic Impairment There is no FDA guidance on the use of Sibutramine in patients with hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Sibutramine in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Sibutramine in patients who are immunocompromised. # Administration and Monitoring ### Administration - Oral ### Monitoring There is limited information regarding Monitoring of Sibutramine in the drug label. # IV Compatibility There is limited information regarding IV Compatibility of Sibutramine in the drug label. # Overdosage ## Acute Overdose ### Signs and Symptoms - The most frequently noted adverse events associated with overdose are tachycardia, hypertension, headache and dizziness. ### Management - Treatment should consist of general measures employed in the management of overdosage: an airway should be established as needed; cardiac and vital sign monitoring is recommended; general symptomatic and supportive measures should be instituted. Cautious use of β-blockers may be indicated to control elevated blood pressure or tachycardia. The results from a study in patients with end-stage renal disease on dialysis showed that sibutramine metabolites were not eliminated to a significant degree with hemodialysis. ## Chronic Overdose There is limited information regarding Chronic Overdose of Sibutramine in the drug label. # Pharmacology ## Mechanism of Action - Sibutramine produces its therapeutic effects by norepinephrine, serotonin and dopamine reuptake inhibition. Sibutramine and its major pharmacologically active metabolites (M1 and M2) do not act via release of monoamines. ## Structure - MERIDIA® (sibutramine hydrochloride monohydrate) is an orally administered agent for the treatment of obesity. Chemically, the active ingredient is a racemic mixture of the (+) and (-) enantiomers of cyclobutanemethanamine, 1-(4-chlorophenyl)-N,N-dimethyl-α-(2-methylpropyl)-, hydrochloride, monohydrate, and has an empirical formula of C17H29Cl2NO. Its molecular weight is 334.33. The structural formula is shown below: - Sibutramine hydrochloride monohydrate is a white to cream crystalline powder with a solubility of 2.9 mg/mL in pH 5.2 water. Its octanol: water partition coefficient is 30.9 at pH 5.0. - Each MERIDIA capsule contains 5 mg, 10 mg, and 15 mg of sibutramine hydrochloride monohydrate. It also contains as inactive ingredients: lactose monohydrate, NF; microcrystalline cellulose, NF; colloidal silicon dioxide, NF; and magnesium stearate, NF in a hard-gelatin capsule . ## Pharmacodynamics - Sibutramine exerts its pharmacological actions predominantly via its secondary (M1) and primary (M2) amine metabolites. The parent compound, sibutramine, is a potent inhibitor of serotonin (5-hydroxytryptamine, 5-HT) and norepinephrine reuptake in vivo, but not in vitro. However, metabolites M1 and M2 inhibit the reuptake of these neurotransmitters both in vitro and in vivo. - In human brain tissue, M1 and M2 also inhibit dopamine reuptake in vitro, but with ~3-fold lower potency than for the reuptake inhibition of serotonin or norepinephrine. - A study using plasma samples taken from sibutramine-treated volunteers showed monoamine reuptake inhibition of norepinephrine > serotonin > dopamine; maximum inhibitions were norepinephrine = 73%, serotonin = 54% and dopamine = 16%. - Sibutramine and its metabolites (M1 and M2) are not serotonin, norepinephrine or dopamine releasing agents. Following chronic administration of sibutramine to rats, no depletion of brain monoamines has been observed. - Sibutramine, M1 and M2 exhibit no evidence of anticholinergic or antihistaminergic actions. In addition, receptor binding profiles show that sibutramine, M1 and M2 have low affinity for serotonin (5-HT1, 5-HT1A, 5-HT1B, 5-HT2A, 5-HT2C), norepinephrine (β, β1, β3, α1 and α2), dopamine (D1 and D2), benzodiazepine, and glutamate (NMDA) receptors. These compounds also lack monoamine oxidase inhibitory activity in vitro and in vivo. ## Pharmacokinetics - Absorption - Sibutramine is rapidly absorbed from the GI tract (Tmax of 1.2 hours) following oral administration and undergoes extensive first-pass metabolism in the liver (oral clearance of 1750 L/h and half-life of 1.1 h) to form the pharmacologically active mono- and di-desmethyl metabolites M1 and M2. Peak plasma concentrations of M1 and M2 are reached within 3 to 4 hours. On the basis of mass balance studies, on average, at least 77% of a single oral dose of sibutramine is absorbed. The absolute bioavailability of sibutramine has not been determined. - Distribution - Radiolabeled studies in animals indicated rapid and extensive distribution into tissues: highest concentrations of radiolabeled material were found in the eliminating organs, liver and kidney. In vitro, sibutramine, M1 and M2 are extensively bound (97%, 94% and 94%, respectively) to human plasma proteins at plasma concentrations seen following therapeutic doses. - Metabolism - Sibutramine is metabolized in the liver principally by the cytochrome P450 (3A4) isoenzyme, to desmethyl metabolites, M1 and M2. These active metabolites are further metabolized by hydroxylation and conjugation to pharmacologically inactive metabolites, M5 and M6. Following oral administration of radiolabeled sibutramine, essentially all of the peak radiolabeled material in plasma was accounted for by unchanged sibutramine (3%), M1 (6%), M2 (12%), M5 (52%), and M6 (27%). - M1 and M2 plasma concentrations reached steady-state within four days of dosing and were approximately two-fold higher than following a single dose. The elimination half-lives of M1 and M2, 14 and 16 hours, respectively, were unchanged following repeated dosing. - Excretion - Approximately 85% (range 68-95%) of a single orally administered radiolabeled dose was excreted in urine and feces over a 15-day collection period with the majority of the dose (77%) excreted in the urine. Major metabolites in urine were M5 and M6; unchanged sibutramine, M1, and M2 were not detected. The primary route of excretion for M1 and M2 is hepatic metabolism and for M5 and M6 is renal excretion. - Effect of Food - Administration of a single 20 mg dose of sibutramine with a standard breakfast resulted in reduced peak M1 and M2 concentrations (by 27% and 32%, respectively) and delayed the time to peak by approximately three hours. However, the AUCs of M1 and M2 were not significantly altered. - Special Populations - Geriatric - Plasma concentrations of M1 and M2 were similar between elderly (ages 61 to 77 yr) and young (ages 19 to 30 yr) subjects following a single 15-mg oral sibutramine dose. Plasma concentrations of the inactive metabolites M5 and M6 were higher in the elderly; these differences are not likely to be of clinical significance. Sibutramine is contraindicated in patients over 65 years of age (see CONTRAINDICATIONS). - Pediatric - The safety and effectiveness of sibutramine in pediatric patients under 16 years old have not been established. - Gender - Pooled pharmacokinetic parameters from 54 young, healthy volunteers (37 males and 17 females) receiving a 15-mg oral dose of sibutramine showed the mean Cmax and AUC of M1 and M2 to be slightly (≤ 19% and ≤ 36%, respectively) higher in females than males. Somewhat higher steady-state trough plasma levels were observed in female obese patients from a large clinical efficacy trial. However, these differences are not likely to be of clinical significance. Dosage adjustment based upon the gender of a patient is not necessary (see DOSAGE AND ADMINISTRATION). - Race - The relationship between race and steady-state trough M1 and M2 plasma concentrations was examined in a clinical trial in obese patients. A trend towards higher concentrations in Black patients over Caucasian patients was noted for M1 and M2. However, these differences are not considered to be of clinical significance. - Renal Insufficiency - The disposition of sibutramine metabolites (M1, M2, M5 and M6) following a single oral dose of sibutramine was studied in patients with varying degrees of renal function. Sibutramine itself was not measurable. - In patients with moderate and severe renal impairment, the AUC values of the active metabolite M1 were 24 to 46% higher and the AUC values of M2 were similar as compared to healthy subjects. Cross- study comparison showed that the patients with end - stage renal disease on dialysis had similar AUC values of M1 but approximately half of the AUC values of M2 measured in healthy subjects (CLcr ≥ 80 mL/ min). The AUC values of inactive metabolites M5 and M6 increased 2 - 3 fold (range 1 - to 7 - fold) in patients with moderate impairment (30 mL/ min < CLcr = 60 mL/ min) and 8 - 11 fold (range 5 - to 15 - fold) in patients with severe impairment (CLcr ≤ 30 mL/ min) as compared to healthy subjects. Cross - study comparison showed that the AUC values of M5 and M6 increased 22 - 33 fold in patients with end - stage renal disease on dialysis as compared to healthy subjects. Approximately 1% of the oral dose was recovered in the dialysate as a combination of M5 and M6 during the hemodialysis process, while M1 and M2 were not measurable in the dialysate. - Sibutramine should not be used in patients with severe renal impairment, including those with end-stage renal disease on dialysis. - Hepatic Insufficiency - In 12 patients with moderate hepatic impairment receiving a single 15-mg oral dose of sibutramine, the combined AUCs of M1 and M2 were increased by 24% compared to healthy subjects while M5 and M6 plasma concentrations were unchanged. The observed differences in M1 and M2 concentrations do not warrant dosage adjustment in patients with mild to moderate hepatic impairment. Sibutramine should not be used in patients with severe hepatic dysfunction. - Drug-Drug Interactions - In vitro studies indicated that the cytochrome P450 (3A4)-mediated metabolism of sibutramine was inhibited by ketoconazole and to a lesser extent by erythromycin. Phase 1 clinical trials were conducted to assess the interactions of sibutramine with drugs that are substrates and/or inhibitors of various cytochrome P450 isozymes. The potential for studied interactions is described below. - Ketoconazole - Concomitant administration of 200 mg doses of ketoconazole twice daily and 20 mg sibutramine once daily for 7 days in 12 uncomplicated obese subjects resulted in moderate increases in AUC and Cmax of 58% and 36% for M1 and of 20% and 19% for M2, respectively. - Erythromycin - The steady-state pharmacokinetics of sibutramine and metabolites M1 and M2 were evaluated in 12 uncomplicated obese subjects following concomitant administration of 500 mg of erythromycin three times daily and 20 mg of sibutramine once daily for 7 days. Concomitant erythromycin resulted in small increases in the AUC (less than 14%) for M1 and M2. A small reduction in Cmax for M1 (11%) and a slight increase in Cmax for M2 (10%) were observed. - Cimetidine - Concomitant administration of cimetidine 400 mg twice daily and sibutramine 15 mg once daily for 7 days in 12 volunteers resulted in small increases in combined (M1 and M2) plasma Cmax (3.4%) and AUC (7.3%). - Simvastatin - Steady-state pharmacokinetics of sibutramine and metabolites M1 and M2 were evaluated in 27 healthy volunteers after the administration of simvastatin 20 mg once daily in the evening and sibutramine 15 mg once daily in the morning for 7 days. Simvastatin had no significant effect on plasma Cmax and AUC of M2 or M1 and M2 combined. The Cmax (16%) and AUC (12%) of M1 were slightly decreased. Simvastatin slightly decreased sibutramine Cmax (14%) and AUC (21%). Sibutramine increased the AUC (7%) of the pharmacologically active moiety, simvastatin acid and reduced the Cmax (25%) and AUC (15%) of inactive simvastatin. - Omeprazole - Steady-state pharmacokinetics of sibutramine and metabolites M1 and M2 were evaluated in 26 healthy volunteers after the co-administration of omeprazole 20 mg once daily and sibutramine 15 mg once daily for 7 days. Omeprazole slightly increased plasma Cmax and AUC of M1 and M2 combined (approximately 15%). M2 Cmax and AUC were not significantly affected whereas M1 Cmax (30%) and AUC (40%) were modestly increased. Plasma Cmax (57%) and AUC (67%) of unchanged sibutramine were moderately increased. Sibutramine had no significant effect on omeprazole pharmacokinetics. - Olanzapine - Steady-state pharmacokinetics of sibutramine and metabolites M1 and M2 were evaluated in 24 healthy volunteers after the co-administration of sibutramine 15 mg once daily with olanzapine 5 mg twice daily for 3 days and 10 mg once daily thereafter for 7 days. Olanzapine had no significant effect on plasma Cmax and AUC of M2 and M1 and M2 combined, or the AUC of M1. Olanzapine slightly increased M1 Cmax (19%), and moderately increased sibutramine Cmax (47%) and AUC (63%). Sibutramine had no significant effect on olanzapine pharmacokinetics. - Lorazepam - Steady-state pharmacokinetics of sibutramine and metabolites M1 and M2 after sibutramine 15 mg once daily for 11 days were compared in 25 healthy volunteers in the presence or absence of lorazepam 2 mg twice daily for 3 days plus one morning dose. Lorazepam had no significant effect on the pharmacokinetics of sibutramine metabolites M1 and M2. Sibutramine had no significant effect on lorazepam pharmacokinetics. - Drugs Highly Bound to Plasma Proteins - Although sibutramine and its active metabolites M1 and M2 are extensively bound to plasma proteins (≥94%), the low therapeutic concentrations and basic characteristics of these compounds make them unlikely to result in clinically significant protein binding interactions with other highly protein bound drugs such as warfarin and phenytoin. In vitro protein binding interaction studies have not been conducted. ## Nonclinical Toxicology - Carcinogenicity - Sibutramine was administered in the diet to mice (1.25, 5 or 20 mg/kg/day) and rats (1, 3, or 9 mg/kg/day) for two years generating combined maximum plasma AUC's of the two major active metabolites equivalent to 0.4 and 16 times, respectively, those following a daily human dose of 15 mg. There was no evidence of carcinogenicity in mice or in female rats. In male rats there was a higher incidence of benign tumors of the testicular interstitial cells; such tumors are commonly seen in rats and are hormonally mediated. The relevance of these tumors to humans is not known. - Mutagenicity - Sibutramine was not mutagenic in the Ames test, in vitro Chinese hamster V79 cell mutation assay, in vitro clastogenicity assay in human lymphocytes or micronucleus assay in mice. Its two major active metabolites were found to have equivocal bacterial mutagenic activity in the Ames test. However, both metabolites gave consistently negative results in the in vitro Chinese hamster V79 cell mutation assay, in vitro clastogenicity assay in human lymphocytes, in vitro DNA-repair assay in HeLa cells, micronucleus assay in mice and in vivo unscheduled DNA-synthesis assay in rat hepatocytes. - Impairment of Fertility - In rats, there were no effects on fertility at doses generating combined plasma AUC's of the two major active metabolites up to 32 times those following a human dose of 15 mg. At 13 times the human combined AUC, there was maternal toxicity, and the dams' nest-building behavior was impaired, leading to a higher incidence of perinatal mortality; there was no effect at approximately 4 times the human combined AUC. # Clinical Studies - Observational epidemiologic studies have established a relationship between obesity and the risks for cardiovascular disease, non-insulin dependent diabetes mellitus (NIDDM), certain forms of cancer, gallstones, certain respiratory disorders, and an increase in overall mortality. These studies suggest that weight loss, if maintained, may produce health benefits for some patients with chronic obesity who may also be at risk for other diseases. - The long-term effects of sibutramine on the morbidity and mortality associated with obesity have not been established. Weight loss was examined in 11 double-blind, placebo-controlled obesity trials (BMI range across all studies 27-43) with study durations of 12 to 52 weeks and doses ranging from 1 to 30 mg once daily. Weight was significantly reduced in a dose-related manner in sibutramine-treated patients compared to placebo over the dose range of 5 to 20 mg once daily. In two 12-month studies, maximal weight loss was achieved by 6 months and statistically significant weight loss was maintained over 12 months. The amount of placebo-subtracted weight loss achieved on sibutramine was consistent across studies. - Analysis of the data in three long-term (≥ 6 months) obesity trials indicates that patients who lose at least 4 pounds in the first 4 weeks of therapy with a given dose of sibutramine are most likely to achieve significant long-term weight loss on that dose of sibutramine. Approximately 60% of such patients went on to achieve a placebo-subtracted weight loss of ≥ 5% of their initial body weight by month 6. Conversely, of those patients on a given dose of sibutramine who did not lose at least 4 pounds in the first 4 weeks of therapy, approximately 80% did not go on to achieve a placebo-subtracted weight loss of ≥ 5% of their initial body weight on that dose by month 6. - Significant dose-related reductions in waist circumference, an indicator of intra-abdominal fat, have also been observed over 6 and 12 months in placebo-controlled clinical trials. In a 12-week placebo-controlled study of non-insulin dependent diabetes mellitus patients randomized to placebo or 15 mg per day of sibutramine, Dual Energy X-Ray Absorptiometry (DEXA) assessment of changes in body composition showed that total body fat mass decreased by 1.8 kg in the sibutramine group versus 0.2 kg in the placebo group (p < 0.001). Similarly, truncal (android) fat mass decreased by 0.6 kg in the sibutramine group versus 0.1 kg in the placebo group (p < 0.01). The changes in lean mass, fasting blood sugar, and HbA1 were not statistically significantly different between the two groups. - Eleven double-blind, placebo-controlled obesity trials with study durations of 12 to 52 weeks have provided evidence that sibutramine does not adversely affect glycemia, serum lipid profiles, or serum uric acid in obese patients. Treatment with sibutramine (5 to 20 mg once daily) is associated with mean increases in blood pressure of 1 to 3 mm Hg and with mean increases in pulse rate of 4 to 5 beats per minute relative to placebo. These findings are similar in normotensives and in patients with hypertension controlled with medication. Those patients who lose significant (≥ 5% weight loss) amounts of weight on sibutramine tend to have smaller increases in blood pressure and pulse rate (see WARNINGS). - In Study 1, a 6-month, double-blind, placebo-controlled study in obese patients, Study 2, a 1-year, double-blind, placebo-controlled study in obese patients, and Study 3, a 1-year, double-blind, placebo-controlled study in obese patients who lost at least 6 kg on a 4-week very low calorie diet (VLCD), sibutramine produced significant reductions in weight, as shown below. In the two 1-year studies, maximal weight loss was achieved by 6 months and statistically significant weight loss was maintained over 12 months. - Maintenance of weight loss with sibutramine was examined in a 2-year, double-blind, placebo-controlled trial. After a 6-month run-in phase in which all patients received sibutramine 10 mg (mean weight loss, 26 lbs.), patients were randomized to sibutramine (10 to 20 mg, 352 patients) or placebo (115 patients). The mean weight loss from initial body weight to endpoint was 21 lbs. and 12 lbs. for sibutramine and placebo patients, respectively. A statistically significantly (p < 0.001) greater proportion of sibutramine treated patients, 75%, 62%, and 43%, maintained at least 80% of their initial weight loss at 12, 18, and 24 months, respectively, compared with the placebo group (38%, 23%, and 16%). Also 67%, 37%, 17%, and 9% of sibutramine treated patients compared with 49%, 19%, 5%, and 3% of placebo patients lost ≥ 5%, ≥ 10%, ≥ 15%, and ≥ 20%, respectively, of their initial body weight at endpoint. From endpoint to the post-study follow-up visit (about 1 month), weight regain was approximately 4 lbs for the sibutramine patients and approximately 2 lbs for the placebo patients. - Sibutramine induced weight loss has been accompanied by beneficial changes in serum lipids that are similar to those seen with nonpharmacologically-mediated weight loss. A combined, weighted analysis of the changes in serum lipids in 11 placebo-controlled obesity studies ranging in length from 12 to 52 weeks is shown below for the last observation carried forward (LOCF) analysis. - Sibutramine induced weight loss has been accompanied by reductions in serum uric acid. Certain centrally-acting weight loss agents that cause release of serotonin from nerve terminals have been associated with cardiac valve dysfunction. The possible occurrence of cardiac valve disease was specifically investigated in two studies. In one study 2-D and color Doppler echocardiography were performed on 210 patients (mean age, 54 years) receiving sibutramine 15 mg or placebo daily for periods of 2 weeks to 16 months (mean duration of treatment, 7.6 months). In patients without a prior history of valvular heart disease, the incidence of valvular heart disease was 3/132 (2.3%) in the sibutramine treatment group (all three cases were mild aortic insufficiency) and 2/77 (2.6%) in the placebo treatment group (one case of mild aortic insufficiency and one case of severe aortic insufficiency). In another study, 25 patients underwent 2-D and color Doppler echocardiography before treatment with sibutramine and again after treatment with sibutramine 5 to 30 mg daily for three months; there were no cases of valvular heart disease. - The effect of sibutramine 15 mg once daily on measures of 24-hour blood pressure was evaluated in a 12-week placebo-controlled study. Twenty-six male and female, primarily Caucasian individuals with an average BMI of 34 kg/m2 and an average age of 39 years underwent 24-hour ambulatory blood pressure monitoring (ABPM). The mean changes from baseline to Week 12 in various measures of ABPM are shown in the following table. - Normal diurnal variation of blood pressure was maintained. # How Supplied - MERIDIA® (sibutramine hydrochloride monohydrate) Capsules contain 5 mg, 10 mg, or 15 mg sibutramine hydrochloride monohydrate and are supplied as follows: - 5 mg, NDC 0074-2456-11, blue/yellow capsules imprinted with "MERIDIA” on the cap and "-5-" on the body, in bottles of 30 capsules. - 10 mg, NDC 0074-2457-11, blue/white capsules imprinted with "MERIDIA” on the cap and "-10-” on the body, in bottles of 30 capsules. - 15 mg, NDC 0074-2458-11, yellow/white capsules imprinted with "MERIDIA” on the cap and "-15-” on the body, in bottles of 30 capsules. - Storage - Store at 25°C (77°F); excursions permitted to 15°-30°C (59°-86°F) . Protect capsules from heat and moisture. Dispense in a tight, light-resistant container as defined in USP. ## Storage There is limited information regarding Sibutramine Storage in the drug label. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information - Physicians should instruct their patients to read the Medication Guide before starting therapy with MERIDIA and to reread it each time the prescription is renewed. - Physicians should also discuss with their patients any part of the package insert that is relevant to them. In particular, the importance of keeping appointments for follow-up visits should be emphasized. - Patients should be advised to notify their physician if they develop a rash, hives, or other allergic reactions. - Patients should be advised to inform their physicians if they are taking, or plan to take, any prescription or over-the-counter drugs, especially weight-reducing agents, decongestants, antidepressants, cough suppressants, lithium, dihydroergotamine, sumatriptan (Imitrex®), or tryptophan, since there is a potential for interactions. - Patients should be reminded of the importance of having their blood pressure and pulse monitored at regular intervals. # Precautions with Alcohol - Alcohol-Sibutramine interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - MERIDIA® # Look-Alike Drug Names There is limited information regarding Sibutramine Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	Sibutramine 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 Sibutramine is an appetite suppressant that is FDA approved for the {{{indicationType}}} of obesity. Common adverse reactions include dry mouth, anorexia, insomnia, constipation and headache. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) - The recommended starting dose of MERIDIA is 10 mg administered once daily with or without food. If there is inadequate weight loss, the dose may be titrated after four weeks to a total of 15 mg once daily. The 5 mg dose should be reserved for patients who do not tolerate the 10 mg dose. Blood pressure and heart rate changes should be taken into account when making decisions regarding dose titration (see WARNINGS and PRECAUTIONS). - Doses above 15 mg daily are not recommended. In most of the clinical trials, MERIDIA was given in the morning. - Analysis of numerous variables has indicated that approximately 60% of patients who lose at least 4 pounds in the first 4 weeks of treatment with a given dose of MERIDIA in combination with a reduced-calorie diet lose at least 5% (placebo-subtracted) of their initial body weight by the end of 6 months to 1 year of treatment on that dose of MERIDIA. Conversely, approximately 80% of patients who do not lose at least 4 pounds in the first 4 weeks of treatment with a given dose of MERIDIA do not lose at least 5% (placebo-subtracted) of their initial body weight by the end of 6 months to 1 year of treatment on that dose. If a patient has not lost at least 4 pounds in the first 4 weeks of treatment, the physician should consider reevaluation of therapy which may include increasing the dose or discontinuation of MERIDIA. - The safety and effectiveness of MERIDIA, as demonstrated in double-blind, placebo-controlled trials, have not been determined beyond 2 years at this time. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Sibutramine in adult patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Sibutramine in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) There is limited information regarding FDA-Labeled Use of Sibutramine in pediatric patients. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Sibutramine in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Sibutramine in pediatric patients. # Contraindications - With a history of coronary artery disease (e.g., angina, history of myocardial infarction), congestive heart failure, tachycardia, peripheral arterial occlusive disease, arrhythmia or cerebrovascular disease (stroke or transient ischemic attack (TIA)). - With inadequately controlled hypertension > 145/90 mm Hg. - over 65 years of age. - Receiving monoamine oxidase inhibitors (MAOIs). - With hypersensitivity to sibutramine or any of the inactive ingredients of MERIDIA. - Who have a major eating disorder (anorexia nervosa or bulimia nervosa). - Taking other centrally acting weight loss drugs. # Warnings - Concomitant Cardiovascular Disease - Due to an increased risk of heart attack and stroke in patients with cardiovascular disease, MERIDIA should not be used in patients with a history of coronary artery disease, congestive heart failure, arrhythmias, or stroke. - Blood Pressure and Pulse - Meridia substantially increases blood pressure and/or pulse rate in some patients. Regular monitoring of blood pressure and pulse rate is required when prescribing Meridia. - In placebo-controlled obesity studies, sibutramine 5 to 20 mg once daily was associated with mean increases in systolic and diastolic blood pressure of approximately 1 to 3 mm Hg relative to placebo, and with mean increases in pulse rate relative to placebo of approximately 4 to 5 beats per minute. Larger increases were seen in some patients, particularly when therapy with sibutramine was initiated at the higher doses (see table below). In premarketing placebo-controlled obesity studies, 0.4% of patients treated with sibutramine were discontinued for hypertension (SBP ≥160 mm Hg or DBP ≥ 95 mm Hg), compared with 0.4% in the placebo group, and 0.4% of patients treated with sibutramine were discontinued for tachycardia (pulse rate ≥ 100 bpm), compared with 0.1% in the placebo group. Blood pressure and pulse should be measured prior to starting therapy with MERIDIA and should be monitored at regular intervals thereafter. For patients who experience a sustained increase in blood pressure or pulse rate while receiving MERIDIA, either dose reduction or discontinuation should be considered. MERIDIA should be given with caution to those patients with a history of hypertension, and should not be given to patients with uncontrolled or poorly controlled hypertension. - Potential Interaction With Monoamine Oxidase Inhibitors - MERIDIA is a norepinephrine, serotonin and dopamine reuptake inhibitor and should not be used concomitantly with MAOIs. There should be at least a 2-week interval after stopping MAOIs before commencing treatment with MERIDIA. Similarly, there should be at least a 2-week interval after stopping MERIDIA before starting treatment with MAOIs. - Serotonin Syndrome or Neuroleptic Malignant Syndrome (NMS)-Like Reactions - The development of a potentially life-threatening serotonin syndrome, or Neuroleptic Malignant Syndrome (NMS)-like reactions, has been reported with SNRIs and SSRIs alone, including MERIDIA treatment, but particularly with concomitant use of serotonergic drugs (including triptans), with drugs which impair metabolism of serotonin (including MAOIs), or with antipsychotics or other dopamine antagonists. Serotonin syndrome symptoms may include mental status changes (e.g., agitation, hallucinations, coma), autonomic instability (e.g., tachycardia, labile blood pressure, hyperthermia), neuromuscular aberrations (e.g., hyperreflexia, incoordination) and/or gastrointestinal symptoms [e.g., nausea, vomiting, diarrhea]. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome, which includes hyperthermia, muscle rigidity, autonomic instability with possible rapid fluctuation of vital signs, and mental status changes. Patients should be monitored for the emergence of serotonin syndrome or NMS-like signs and symptoms. - Glaucoma - Because MERIDIA can cause mydriasis, it should be used with caution in patients with narrow angle glaucoma. - Miscellaneous - Organic causes of obesity (e.g., untreated hypothyroidism) should be excluded before prescribing MERIDIA. ### Precautions - Pulmonary Hypertension - Certain centrally-acting weight loss agents that cause release of serotonin from nerve terminals have been associated with pulmonary hypertension (PPH), a rare but lethal disease. In premarketing clinical studies, no cases of PPH have been reported with sibutramine capsules. Because of the low incidence of this disease in the underlying population, however, it is not known whether or not MERIDIA may cause this disease. - Seizures - During premarketing testing, seizures were reported in < 0.1% of sibutramine treated patients. MERIDIA should be used cautiously in patients with a history of seizures. It should be discontinued in any patient who develops seizures. - Bleeding - There have been reports of bleeding in patients taking sibutramine. While a causal relationship is unclear, caution is advised in patients predisposed to bleeding events and those taking concomitant medications known to affect hemostasis or platelet function. - Gallstones - Weight loss can precipitate or exacerbate gallstone formation. - Renal Impairment - MERIDIA should be used with caution in patients with mild to moderate renal impairment. MERIDIA should not be used in patients with severe renal impairment, including those with end stage renal disease on dialysis. - Hepatic Dysfunction - Patients with severe hepatic dysfunction have not been systematically studied; MERIDIA should therefore not be used in such patients. - Interference With Cognitive and Motor Performance - Although sibutramine did not affect psychomotor or cognitive performance in healthy volunteers, any CNS active drug has the potential to impair judgment, thinking or motor skills. # Adverse Reactions ## Clinical Trials Experience - In placebo-controlled studies, 9% of patients treated with sibutramine (n = 2068) and 7% of patients treated with placebo (n = 884) withdrew for adverse events. - In placebo-controlled studies, the most common events were dry mouth, anorexia, insomnia, constipation and headache. Adverse events in these studies occurring in ≥ 1% of sibutramine treated patients and more frequently than in the placebo group are shown in the following table. - The following additional adverse events were reported in ≥ 1% of all patients who received sibutramine in controlled and uncontrolled premarketing studies. Fever. Diarrhea, flatulence, gastroenteritis, tooth disorder. Peripheral edema. Arthritis. Agitation, leg cramps, hypertonia, thinking abnormal. Bronchitis, dyspnea. Pruritus. Amblyopia. Menstrual disorders. - Other Adverse Events - Clinical Studies - Seizures - Convulsions were reported as an adverse event in three of 2068 (0.1%) sibutramine treated patients and in none of 884 placebo-treated patients in placebo-controlled premarketing obesity studies. Two of the three patients with seizures had potentially predisposing factors (one had a prior history of epilepsy; one had a subsequent diagnosis of brain tumor). The incidence in all subjects who received sibutramine (three of 4,588 subjects) was less than 0.1%. - Ecchymosis/Bleeding Disorders - Ecchymosis (bruising) was observed in 0.7% of sibutramine treated patients and in 0.2% of placebo-treated patients in premarketing placebo-controlled obesity studies. One patient had prolonged bleeding of a small amount which occurred during minor facial surgery. Sibutramine may have an effect on platelet function due to its effect on serotonin uptake. - Interstitial Nephritis - Acute interstitial nephritis (confirmed by biopsy) was reported in one obese patient receiving sibutramine during premarketing studies. After discontinuation of the medication, dialysis and oral corticosteroids were administered; renal function normalized. The patient made a full recovery. ## Postmarketing Experience - Voluntary reports of adverse events temporally associated with the use of sibutramine are listed below. It is important to emphasize that although these events occurred during treatment with sibutramine, they may have no causal relationship with the drug. Obesity itself, concurrent disease states/risk factors, or weight reduction may be associated with an increased risk for some of these events. - Psychiatric - Cases of depression, psychosis, mania, suicidal ideation and suicide have been reported rarely in patients on sibutramine treatment. However, a relationship has not been established between these events and the use of sibutramine. If any of these events should occur during treatment with sibutramine, discontinuation should be considered. - Hypersensitivity - Allergic hypersensitivity reactions ranging from mild skin eruptions and urticaria to angioedema and anaphylaxis have been reported. - Other Postmarketing Reported Events: Anaphylactic shock, anaphylactoid reaction, chest pressure, chest tightness, facial edema, limb pain, sudden unexplained death. Angina pectoris, atrial fibrillation, congestive heart failure, heart arrest, heart rate decreased, myocardial infarction, supraventricular tachycardia, syncope, torsade de pointes, vascular headache, ventricular tachycardia, ventricular extrasystoles, ventricular fibrillation. Cholecystitis, cholelithiasis, duodenal ulcer, eructation, gastrointestinal hemorrhage, increased salivation, intestinal obstruction, mouth ulcer, stomach ulcer, tongue edema. Goiter, hyperthyroidism, hypothyroidism. Anemia, leukopenia, lymphadenopathy, petechiae, thrombocytopenia. Hyperglycemia, hypoglycemia. Arthrosis, bursitis. Abnormal dreams, abnormal gait, amnesia, anger, cerebrovascular accident, concentration impaired, confusion, depression aggravated, Gilles de la Tourette’s syndrome, hypesthesia, libido decreased, libido increased, mood changes, nightmares, short term memory loss, speech disorder, transient ischemic attack, tremor, twitch, vertigo. Epistaxis, nasal congestion, respiratory disorder, yawn. Alopecia, dermatitis, photosensitivity (skin), urticaria. Abnormal vision, blurred vision, dry eye, eye pain, increased intraocular pressure, otitis externa, otitis media, photosensitivity (eyes), tinnitus. Abnormal ejaculation, hematuria, impotence, increased urinary frequency, micturition difficulty, urinary retention. # Drug Interactions - CNS Active Drugs: - The use of MERIDIA in combination with other CNS-active drugs, particularly serotonergic agents, has not been systematically evaluated. Consequently, caution is advised if the concomitant administration of MERIDIA with other centrally-acting drugs is indicated. - In patients receiving monoamine oxidase inhibitors (MAOIs) (e.g., phenelzine, selegiline) in combination with serotonergic agents (e.g., fluoxetine, fluvoxamine, paroxetine, sertraline, venlafaxine), there have been reports of serious, sometimes fatal, reactions ("serotonin syndrome;" see below). Because sibutramine inhibits serotonin reuptake, MERIDIA should not be used concomitantly with a MAOI. At least 2 weeks should elapse between discontinuation of a MAOI and initiation of treatment with MERIDIA. Similarly, at least 2 weeks should elapse between discontinuation of MERIDIA and initiation of treatment with a MAOI. - The rare, but serious, constellation of symptoms termed "serotonin syndrome" has also been reported with the concomitant use of selective serotonin reuptake inhibitors and agents for migraine therapy, such as Imitrex® (sumatriptan succinate) and dihydroergotamine, certain opioids, such as dextromethorphan, meperidine, pentazocine and fentanyl, lithium, or tryptophan. Serotonin syndrome has also been reported with the concomitant use of two serotonin reuptake inhibitors. The syndrome requires immediate medical attention and may include one or more of the following symptoms: excitement, hypomania, restlessness, loss of consciousness, confusion, disorientation, anxiety, agitation, motor weakness, myoclonus, tremor, hemiballismus, hyperreflexia, ataxia, dysarthria, incoordination, hyperthermia, shivering, pupillary dilation, diaphoresis, emesis, and tachycardia. - Because sibutramine inhibits serotonin reuptake, in general, it should not be administered with other serotonergic agents such as those listed above. However, if such a combination is clinically indicated, appropriate observation of the patient is warranted. - Drugs That May Raise Blood Pressure and/or Heart Rate - Concomitant use of MERIDIA and other agents that may raise blood pressure or heart rate have not been evaluated. These include certain decongestants, cough, cold, and allergy medications that contain agents such as ephedrine, or pseudoephedrine. Caution should be used when prescribing MERIDIA to patients who use these medications. - Alcohol - In a double-blind, placebo-controlled, crossover study in 19 volunteers, administration of a single dose of ethanol (0.5 mL/kg) together with 20 mg of sibutramine resulted in no psychomotor interactions of clinical significance between alcohol and sibutramine. However, the concomitant use of MERIDIA and excess alcohol is not recommended. - Oral Contraceptives - The suppression of ovulation by oral contraceptives was not inhibited by sibutramine. In a crossover study, 12 healthy female volunteers on oral steroid contraceptives received placebo in one period and 15 mg sibutramine in another period over the course of 8 weeks. No clinically significant systemic interaction was observed; therefore, no requirement for alternative contraceptive precautions are needed when patients taking oral contraceptives are concurrently prescribed sibutramine. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): - Pregnancy Category C - Radiolabeled studies in animals indicated that tissue distribution was unaffected by pregnancy, with relatively low transfer to the fetus. In rats, there was no evidence of teratogenicity at doses of 1, 3, or 10 mg/kg/day generating combined plasma AUC's of the two major active metabolites up to approximately 32 times those following the human dose of 15 mg. In rabbits dosed at 3, 15, or 75 mg/kg/day, plasma AUC's greater than approximately 5 times those following the human dose of 15 mg caused maternal toxicity. At markedly toxic doses, Dutch Belted rabbits had a slightly higher than control incidence of pups with a broad short snout, short rounded pinnae, short tail and, in some, shorter thickened long bones in the limbs; at comparably high doses in New Zealand White rabbits, one study showed a slightly higher than control incidence of pups with cardiovascular anomalies while a second study showed a lower incidence than in the control group. - No adequate and well controlled studies with sibutramine have been conducted in pregnant women. The use of MERIDIA during pregnancy is not recommended. Women of childbearing potential should employ adequate contraception while taking MERIDIA. Patients should be advised to notify their physician if they become pregnant or intend to become pregnant while taking MERIDIA. Pregnancy Category (AUS): - Australian Drug Evaluation Committee (ADEC) Pregnancy Category There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Sibutramine in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Sibutramine during labor and delivery. ### Nursing Mothers There is no FDA guidance on the use of Sibutramine with respect to nursing mothers. ### Pediatric Use There is no FDA guidance on the use of Sibutramine with respect to pediatric patients. ### Geriatic Use There is no FDA guidance on the use of Sibutramine with respect to geriatric patients. ### Gender There is no FDA guidance on the use of Sibutramine with respect to specific gender populations. ### Race There is no FDA guidance on the use of Sibutramine with respect to specific racial populations. ### Renal Impairment There is no FDA guidance on the use of Sibutramine in patients with renal impairment. ### Hepatic Impairment There is no FDA guidance on the use of Sibutramine in patients with hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Sibutramine in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Sibutramine in patients who are immunocompromised. # Administration and Monitoring ### Administration - Oral ### Monitoring There is limited information regarding Monitoring of Sibutramine in the drug label. # IV Compatibility There is limited information regarding IV Compatibility of Sibutramine in the drug label. # Overdosage ## Acute Overdose ### Signs and Symptoms - The most frequently noted adverse events associated with overdose are tachycardia, hypertension, headache and dizziness. ### Management - Treatment should consist of general measures employed in the management of overdosage: an airway should be established as needed; cardiac and vital sign monitoring is recommended; general symptomatic and supportive measures should be instituted. Cautious use of β-blockers may be indicated to control elevated blood pressure or tachycardia. The results from a study in patients with end-stage renal disease on dialysis showed that sibutramine metabolites were not eliminated to a significant degree with hemodialysis. ## Chronic Overdose There is limited information regarding Chronic Overdose of Sibutramine in the drug label. # Pharmacology ## Mechanism of Action - Sibutramine produces its therapeutic effects by norepinephrine, serotonin and dopamine reuptake inhibition. Sibutramine and its major pharmacologically active metabolites (M1 and M2) do not act via release of monoamines. ## Structure - MERIDIA® (sibutramine hydrochloride monohydrate) is an orally administered agent for the treatment of obesity. Chemically, the active ingredient is a racemic mixture of the (+) and (-) enantiomers of cyclobutanemethanamine, 1-(4-chlorophenyl)-N,N-dimethyl-α-(2-methylpropyl)-, hydrochloride, monohydrate, and has an empirical formula of C17H29Cl2NO. Its molecular weight is 334.33. The structural formula is shown below: - Sibutramine hydrochloride monohydrate is a white to cream crystalline powder with a solubility of 2.9 mg/mL in pH 5.2 water. Its octanol: water partition coefficient is 30.9 at pH 5.0. - Each MERIDIA capsule contains 5 mg, 10 mg, and 15 mg of sibutramine hydrochloride monohydrate. It also contains as inactive ingredients: lactose monohydrate, NF; microcrystalline cellulose, NF; colloidal silicon dioxide, NF; and magnesium stearate, NF in a hard-gelatin capsule [which contains titanium dioxide, USP; gelatin; FD&C Blue No. 2 (5- and 10-mg capsules only); D&C Yellow No. 10 (5- and 15-mg capsules only), and other inactive ingredients]. ## Pharmacodynamics - Sibutramine exerts its pharmacological actions predominantly via its secondary (M1) and primary (M2) amine metabolites. The parent compound, sibutramine, is a potent inhibitor of serotonin (5-hydroxytryptamine, 5-HT) and norepinephrine reuptake in vivo, but not in vitro. However, metabolites M1 and M2 inhibit the reuptake of these neurotransmitters both in vitro and in vivo. - In human brain tissue, M1 and M2 also inhibit dopamine reuptake in vitro, but with ~3-fold lower potency than for the reuptake inhibition of serotonin or norepinephrine. - A study using plasma samples taken from sibutramine-treated volunteers showed monoamine reuptake inhibition of norepinephrine > serotonin > dopamine; maximum inhibitions were norepinephrine = 73%, serotonin = 54% and dopamine = 16%. - Sibutramine and its metabolites (M1 and M2) are not serotonin, norepinephrine or dopamine releasing agents. Following chronic administration of sibutramine to rats, no depletion of brain monoamines has been observed. - Sibutramine, M1 and M2 exhibit no evidence of anticholinergic or antihistaminergic actions. In addition, receptor binding profiles show that sibutramine, M1 and M2 have low affinity for serotonin (5-HT1, 5-HT1A, 5-HT1B, 5-HT2A, 5-HT2C), norepinephrine (β, β1, β3, α1 and α2), dopamine (D1 and D2), benzodiazepine, and glutamate (NMDA) receptors. These compounds also lack monoamine oxidase inhibitory activity in vitro and in vivo. ## Pharmacokinetics - Absorption - Sibutramine is rapidly absorbed from the GI tract (Tmax of 1.2 hours) following oral administration and undergoes extensive first-pass metabolism in the liver (oral clearance of 1750 L/h and half-life of 1.1 h) to form the pharmacologically active mono- and di-desmethyl metabolites M1 and M2. Peak plasma concentrations of M1 and M2 are reached within 3 to 4 hours. On the basis of mass balance studies, on average, at least 77% of a single oral dose of sibutramine is absorbed. The absolute bioavailability of sibutramine has not been determined. - Distribution - Radiolabeled studies in animals indicated rapid and extensive distribution into tissues: highest concentrations of radiolabeled material were found in the eliminating organs, liver and kidney. In vitro, sibutramine, M1 and M2 are extensively bound (97%, 94% and 94%, respectively) to human plasma proteins at plasma concentrations seen following therapeutic doses. - Metabolism - Sibutramine is metabolized in the liver principally by the cytochrome P450 (3A4) isoenzyme, to desmethyl metabolites, M1 and M2. These active metabolites are further metabolized by hydroxylation and conjugation to pharmacologically inactive metabolites, M5 and M6. Following oral administration of radiolabeled sibutramine, essentially all of the peak radiolabeled material in plasma was accounted for by unchanged sibutramine (3%), M1 (6%), M2 (12%), M5 (52%), and M6 (27%). - M1 and M2 plasma concentrations reached steady-state within four days of dosing and were approximately two-fold higher than following a single dose. The elimination half-lives of M1 and M2, 14 and 16 hours, respectively, were unchanged following repeated dosing. - Excretion - Approximately 85% (range 68-95%) of a single orally administered radiolabeled dose was excreted in urine and feces over a 15-day collection period with the majority of the dose (77%) excreted in the urine. Major metabolites in urine were M5 and M6; unchanged sibutramine, M1, and M2 were not detected. The primary route of excretion for M1 and M2 is hepatic metabolism and for M5 and M6 is renal excretion. - Effect of Food - Administration of a single 20 mg dose of sibutramine with a standard breakfast resulted in reduced peak M1 and M2 concentrations (by 27% and 32%, respectively) and delayed the time to peak by approximately three hours. However, the AUCs of M1 and M2 were not significantly altered. - Special Populations - Geriatric - Plasma concentrations of M1 and M2 were similar between elderly (ages 61 to 77 yr) and young (ages 19 to 30 yr) subjects following a single 15-mg oral sibutramine dose. Plasma concentrations of the inactive metabolites M5 and M6 were higher in the elderly; these differences are not likely to be of clinical significance. Sibutramine is contraindicated in patients over 65 years of age (see CONTRAINDICATIONS). - Pediatric - The safety and effectiveness of sibutramine in pediatric patients under 16 years old have not been established. - Gender - Pooled pharmacokinetic parameters from 54 young, healthy volunteers (37 males and 17 females) receiving a 15-mg oral dose of sibutramine showed the mean Cmax and AUC of M1 and M2 to be slightly (≤ 19% and ≤ 36%, respectively) higher in females than males. Somewhat higher steady-state trough plasma levels were observed in female obese patients from a large clinical efficacy trial. However, these differences are not likely to be of clinical significance. Dosage adjustment based upon the gender of a patient is not necessary (see DOSAGE AND ADMINISTRATION). - Race - The relationship between race and steady-state trough M1 and M2 plasma concentrations was examined in a clinical trial in obese patients. A trend towards higher concentrations in Black patients over Caucasian patients was noted for M1 and M2. However, these differences are not considered to be of clinical significance. - Renal Insufficiency - The disposition of sibutramine metabolites (M1, M2, M5 and M6) following a single oral dose of sibutramine was studied in patients with varying degrees of renal function. Sibutramine itself was not measurable. - In patients with moderate and severe renal impairment, the AUC values of the active metabolite M1 were 24 to 46% higher and the AUC values of M2 were similar as compared to healthy subjects. Cross- study comparison showed that the patients with end - stage renal disease on dialysis had similar AUC values of M1 but approximately half of the AUC values of M2 measured in healthy subjects (CLcr ≥ 80 mL/ min). The AUC values of inactive metabolites M5 and M6 increased 2 - 3 fold (range 1 - to 7 - fold) in patients with moderate impairment (30 mL/ min < CLcr = 60 mL/ min) and 8 - 11 fold (range 5 - to 15 - fold) in patients with severe impairment (CLcr ≤ 30 mL/ min) as compared to healthy subjects. Cross - study comparison showed that the AUC values of M5 and M6 increased 22 - 33 fold in patients with end - stage renal disease on dialysis as compared to healthy subjects. Approximately 1% of the oral dose was recovered in the dialysate as a combination of M5 and M6 during the hemodialysis process, while M1 and M2 were not measurable in the dialysate. - Sibutramine should not be used in patients with severe renal impairment, including those with end-stage renal disease on dialysis. - Hepatic Insufficiency - In 12 patients with moderate hepatic impairment receiving a single 15-mg oral dose of sibutramine, the combined AUCs of M1 and M2 were increased by 24% compared to healthy subjects while M5 and M6 plasma concentrations were unchanged. The observed differences in M1 and M2 concentrations do not warrant dosage adjustment in patients with mild to moderate hepatic impairment. Sibutramine should not be used in patients with severe hepatic dysfunction. - Drug-Drug Interactions - In vitro studies indicated that the cytochrome P450 (3A4)-mediated metabolism of sibutramine was inhibited by ketoconazole and to a lesser extent by erythromycin. Phase 1 clinical trials were conducted to assess the interactions of sibutramine with drugs that are substrates and/or inhibitors of various cytochrome P450 isozymes. The potential for studied interactions is described below. - Ketoconazole - Concomitant administration of 200 mg doses of ketoconazole twice daily and 20 mg sibutramine once daily for 7 days in 12 uncomplicated obese subjects resulted in moderate increases in AUC and Cmax of 58% and 36% for M1 and of 20% and 19% for M2, respectively. - Erythromycin - The steady-state pharmacokinetics of sibutramine and metabolites M1 and M2 were evaluated in 12 uncomplicated obese subjects following concomitant administration of 500 mg of erythromycin three times daily and 20 mg of sibutramine once daily for 7 days. Concomitant erythromycin resulted in small increases in the AUC (less than 14%) for M1 and M2. A small reduction in Cmax for M1 (11%) and a slight increase in Cmax for M2 (10%) were observed. - Cimetidine - Concomitant administration of cimetidine 400 mg twice daily and sibutramine 15 mg once daily for 7 days in 12 volunteers resulted in small increases in combined (M1 and M2) plasma Cmax (3.4%) and AUC (7.3%). - Simvastatin - Steady-state pharmacokinetics of sibutramine and metabolites M1 and M2 were evaluated in 27 healthy volunteers after the administration of simvastatin 20 mg once daily in the evening and sibutramine 15 mg once daily in the morning for 7 days. Simvastatin had no significant effect on plasma Cmax and AUC of M2 or M1 and M2 combined. The Cmax (16%) and AUC (12%) of M1 were slightly decreased. Simvastatin slightly decreased sibutramine Cmax (14%) and AUC (21%). Sibutramine increased the AUC (7%) of the pharmacologically active moiety, simvastatin acid and reduced the Cmax (25%) and AUC (15%) of inactive simvastatin. - Omeprazole - Steady-state pharmacokinetics of sibutramine and metabolites M1 and M2 were evaluated in 26 healthy volunteers after the co-administration of omeprazole 20 mg once daily and sibutramine 15 mg once daily for 7 days. Omeprazole slightly increased plasma Cmax and AUC of M1 and M2 combined (approximately 15%). M2 Cmax and AUC were not significantly affected whereas M1 Cmax (30%) and AUC (40%) were modestly increased. Plasma Cmax (57%) and AUC (67%) of unchanged sibutramine were moderately increased. Sibutramine had no significant effect on omeprazole pharmacokinetics. - Olanzapine - Steady-state pharmacokinetics of sibutramine and metabolites M1 and M2 were evaluated in 24 healthy volunteers after the co-administration of sibutramine 15 mg once daily with olanzapine 5 mg twice daily for 3 days and 10 mg once daily thereafter for 7 days. Olanzapine had no significant effect on plasma Cmax and AUC of M2 and M1 and M2 combined, or the AUC of M1. Olanzapine slightly increased M1 Cmax (19%), and moderately increased sibutramine Cmax (47%) and AUC (63%). Sibutramine had no significant effect on olanzapine pharmacokinetics. - Lorazepam - Steady-state pharmacokinetics of sibutramine and metabolites M1 and M2 after sibutramine 15 mg once daily for 11 days were compared in 25 healthy volunteers in the presence or absence of lorazepam 2 mg twice daily for 3 days plus one morning dose. Lorazepam had no significant effect on the pharmacokinetics of sibutramine metabolites M1 and M2. Sibutramine had no significant effect on lorazepam pharmacokinetics. - Drugs Highly Bound to Plasma Proteins - Although sibutramine and its active metabolites M1 and M2 are extensively bound to plasma proteins (≥94%), the low therapeutic concentrations and basic characteristics of these compounds make them unlikely to result in clinically significant protein binding interactions with other highly protein bound drugs such as warfarin and phenytoin. In vitro protein binding interaction studies have not been conducted. ## Nonclinical Toxicology - Carcinogenicity - Sibutramine was administered in the diet to mice (1.25, 5 or 20 mg/kg/day) and rats (1, 3, or 9 mg/kg/day) for two years generating combined maximum plasma AUC's of the two major active metabolites equivalent to 0.4 and 16 times, respectively, those following a daily human dose of 15 mg. There was no evidence of carcinogenicity in mice or in female rats. In male rats there was a higher incidence of benign tumors of the testicular interstitial cells; such tumors are commonly seen in rats and are hormonally mediated. The relevance of these tumors to humans is not known. - Mutagenicity - Sibutramine was not mutagenic in the Ames test, in vitro Chinese hamster V79 cell mutation assay, in vitro clastogenicity assay in human lymphocytes or micronucleus assay in mice. Its two major active metabolites were found to have equivocal bacterial mutagenic activity in the Ames test. However, both metabolites gave consistently negative results in the in vitro Chinese hamster V79 cell mutation assay, in vitro clastogenicity assay in human lymphocytes, in vitro DNA-repair assay in HeLa cells, micronucleus assay in mice and in vivo unscheduled DNA-synthesis assay in rat hepatocytes. - Impairment of Fertility - In rats, there were no effects on fertility at doses generating combined plasma AUC's of the two major active metabolites up to 32 times those following a human dose of 15 mg. At 13 times the human combined AUC, there was maternal toxicity, and the dams' nest-building behavior was impaired, leading to a higher incidence of perinatal mortality; there was no effect at approximately 4 times the human combined AUC. # Clinical Studies - Observational epidemiologic studies have established a relationship between obesity and the risks for cardiovascular disease, non-insulin dependent diabetes mellitus (NIDDM), certain forms of cancer, gallstones, certain respiratory disorders, and an increase in overall mortality. These studies suggest that weight loss, if maintained, may produce health benefits for some patients with chronic obesity who may also be at risk for other diseases. - The long-term effects of sibutramine on the morbidity and mortality associated with obesity have not been established. Weight loss was examined in 11 double-blind, placebo-controlled obesity trials (BMI range across all studies 27-43) with study durations of 12 to 52 weeks and doses ranging from 1 to 30 mg once daily. Weight was significantly reduced in a dose-related manner in sibutramine-treated patients compared to placebo over the dose range of 5 to 20 mg once daily. In two 12-month studies, maximal weight loss was achieved by 6 months and statistically significant weight loss was maintained over 12 months. The amount of placebo-subtracted weight loss achieved on sibutramine was consistent across studies. - Analysis of the data in three long-term (≥ 6 months) obesity trials indicates that patients who lose at least 4 pounds in the first 4 weeks of therapy with a given dose of sibutramine are most likely to achieve significant long-term weight loss on that dose of sibutramine. Approximately 60% of such patients went on to achieve a placebo-subtracted weight loss of ≥ 5% of their initial body weight by month 6. Conversely, of those patients on a given dose of sibutramine who did not lose at least 4 pounds in the first 4 weeks of therapy, approximately 80% did not go on to achieve a placebo-subtracted weight loss of ≥ 5% of their initial body weight on that dose by month 6. - Significant dose-related reductions in waist circumference, an indicator of intra-abdominal fat, have also been observed over 6 and 12 months in placebo-controlled clinical trials. In a 12-week placebo-controlled study of non-insulin dependent diabetes mellitus patients randomized to placebo or 15 mg per day of sibutramine, Dual Energy X-Ray Absorptiometry (DEXA) assessment of changes in body composition showed that total body fat mass decreased by 1.8 kg in the sibutramine group versus 0.2 kg in the placebo group (p < 0.001). Similarly, truncal (android) fat mass decreased by 0.6 kg in the sibutramine group versus 0.1 kg in the placebo group (p < 0.01). The changes in lean mass, fasting blood sugar, and HbA1 were not statistically significantly different between the two groups. - Eleven double-blind, placebo-controlled obesity trials with study durations of 12 to 52 weeks have provided evidence that sibutramine does not adversely affect glycemia, serum lipid profiles, or serum uric acid in obese patients. Treatment with sibutramine (5 to 20 mg once daily) is associated with mean increases in blood pressure of 1 to 3 mm Hg and with mean increases in pulse rate of 4 to 5 beats per minute relative to placebo. These findings are similar in normotensives and in patients with hypertension controlled with medication. Those patients who lose significant (≥ 5% weight loss) amounts of weight on sibutramine tend to have smaller increases in blood pressure and pulse rate (see WARNINGS). - In Study 1, a 6-month, double-blind, placebo-controlled study in obese patients, Study 2, a 1-year, double-blind, placebo-controlled study in obese patients, and Study 3, a 1-year, double-blind, placebo-controlled study in obese patients who lost at least 6 kg on a 4-week very low calorie diet (VLCD), sibutramine produced significant reductions in weight, as shown below. In the two 1-year studies, maximal weight loss was achieved by 6 months and statistically significant weight loss was maintained over 12 months. - Maintenance of weight loss with sibutramine was examined in a 2-year, double-blind, placebo-controlled trial. After a 6-month run-in phase in which all patients received sibutramine 10 mg (mean weight loss, 26 lbs.), patients were randomized to sibutramine (10 to 20 mg, 352 patients) or placebo (115 patients). The mean weight loss from initial body weight to endpoint was 21 lbs. and 12 lbs. for sibutramine and placebo patients, respectively. A statistically significantly (p < 0.001) greater proportion of sibutramine treated patients, 75%, 62%, and 43%, maintained at least 80% of their initial weight loss at 12, 18, and 24 months, respectively, compared with the placebo group (38%, 23%, and 16%). Also 67%, 37%, 17%, and 9% of sibutramine treated patients compared with 49%, 19%, 5%, and 3% of placebo patients lost ≥ 5%, ≥ 10%, ≥ 15%, and ≥ 20%, respectively, of their initial body weight at endpoint. From endpoint to the post-study follow-up visit (about 1 month), weight regain was approximately 4 lbs for the sibutramine patients and approximately 2 lbs for the placebo patients. - Sibutramine induced weight loss has been accompanied by beneficial changes in serum lipids that are similar to those seen with nonpharmacologically-mediated weight loss. A combined, weighted analysis of the changes in serum lipids in 11 placebo-controlled obesity studies ranging in length from 12 to 52 weeks is shown below for the last observation carried forward (LOCF) analysis. - Sibutramine induced weight loss has been accompanied by reductions in serum uric acid. Certain centrally-acting weight loss agents that cause release of serotonin from nerve terminals have been associated with cardiac valve dysfunction. The possible occurrence of cardiac valve disease was specifically investigated in two studies. In one study 2-D and color Doppler echocardiography were performed on 210 patients (mean age, 54 years) receiving sibutramine 15 mg or placebo daily for periods of 2 weeks to 16 months (mean duration of treatment, 7.6 months). In patients without a prior history of valvular heart disease, the incidence of valvular heart disease was 3/132 (2.3%) in the sibutramine treatment group (all three cases were mild aortic insufficiency) and 2/77 (2.6%) in the placebo treatment group (one case of mild aortic insufficiency and one case of severe aortic insufficiency). In another study, 25 patients underwent 2-D and color Doppler echocardiography before treatment with sibutramine and again after treatment with sibutramine 5 to 30 mg daily for three months; there were no cases of valvular heart disease. - The effect of sibutramine 15 mg once daily on measures of 24-hour blood pressure was evaluated in a 12-week placebo-controlled study. Twenty-six male and female, primarily Caucasian individuals with an average BMI of 34 kg/m2 and an average age of 39 years underwent 24-hour ambulatory blood pressure monitoring (ABPM). The mean changes from baseline to Week 12 in various measures of ABPM are shown in the following table. - Normal diurnal variation of blood pressure was maintained. # How Supplied - MERIDIA® (sibutramine hydrochloride monohydrate) Capsules contain 5 mg, 10 mg, or 15 mg sibutramine hydrochloride monohydrate and are supplied as follows: - 5 mg, NDC 0074-2456-11, blue/yellow capsules imprinted with "MERIDIA” on the cap and "-5-" on the body, in bottles of 30 capsules. - 10 mg, NDC 0074-2457-11, blue/white capsules imprinted with "MERIDIA” on the cap and "-10-” on the body, in bottles of 30 capsules. - 15 mg, NDC 0074-2458-11, yellow/white capsules imprinted with "MERIDIA” on the cap and "-15-” on the body, in bottles of 30 capsules. - Storage - Store at 25°C (77°F); excursions permitted to 15°-30°C (59°-86°F) [see USP controlled room temperature]. Protect capsules from heat and moisture. Dispense in a tight, light-resistant container as defined in USP. ## Storage There is limited information regarding Sibutramine Storage in the drug label. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information - Physicians should instruct their patients to read the Medication Guide before starting therapy with MERIDIA and to reread it each time the prescription is renewed. - Physicians should also discuss with their patients any part of the package insert that is relevant to them. In particular, the importance of keeping appointments for follow-up visits should be emphasized. - Patients should be advised to notify their physician if they develop a rash, hives, or other allergic reactions. - Patients should be advised to inform their physicians if they are taking, or plan to take, any prescription or over-the-counter drugs, especially weight-reducing agents, decongestants, antidepressants, cough suppressants, lithium, dihydroergotamine, sumatriptan (Imitrex®), or tryptophan, since there is a potential for interactions. - Patients should be reminded of the importance of having their blood pressure and pulse monitored at regular intervals. # Precautions with Alcohol - Alcohol-Sibutramine interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - MERIDIA®[1] # Look-Alike Drug Names There is limited information regarding Sibutramine Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	https://www.wikidoc.org/index.php/Meridia
81d6a0f1e71ef3cb75798a2875676af848ab33da	wikidoc	Mesonephros	Mesonephros # Overview The mesonephros (Latin for "middle kidney") is one of three excretory organs that develop in vertebrates. It serves as the main excretory organ of aquatic vertebrates and as a temporary kidney in higher vertebrates. The mesonephros is included in the Wolffian body after Caspar Friedrich Wolff who described it in 1759. (The Wolffian body is composed of : mesonephros + paramesonephrotic blastema) # Structure The mesonephros is composed of the mesonephric duct (also called the Wolffian duct), mesonephric tubules, and associated capillary tufts. A single tubule and its associated capillary tuft is called a mesonephric excretory unit; these units are similar in structure and function to nephrons of the adult kidney. The mesonephros is derived from intermediate mesoderm in the vertebrate embryo. # Differences between males and females In human males, the mesonephros gives rise to the efferent ductules of the testis, the epididymis, vas deferens, seminal vesicle, and vestigial structures such as the appendix testis, appendix epididymis, and paradidymis. The mesonephros largely regresses in human females, though vestigial structures such as Gartner's cysts, the epoophoron, and paroophoron are common. # Differences among species The mesonephros persists and form the permanent kidneys in fishes and amphibians, but in reptiles, birds, and mammals, it atrophies and for the most part disappears rapidly as the permanent kidney (metanephros) develops begins during the sixth or seventh week, so that by the beginning of the fifth month only the ducts and a few of the tubules of the mesonephros remain. # Additional images - Broad ligament of adult, showing epoöphoron.	Mesonephros Template:Infobox Embryology Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview The mesonephros (Latin for "middle kidney") is one of three excretory organs that develop in vertebrates. It serves as the main excretory organ of aquatic vertebrates and as a temporary kidney in higher vertebrates. The mesonephros is included in the Wolffian body after Caspar Friedrich Wolff who described it in 1759. (The Wolffian body is composed of : mesonephros + paramesonephrotic blastema) # Structure The mesonephros is composed of the mesonephric duct (also called the Wolffian duct), mesonephric tubules, and associated capillary tufts. A single tubule and its associated capillary tuft is called a mesonephric excretory unit; these units are similar in structure and function to nephrons of the adult kidney. The mesonephros is derived from intermediate mesoderm in the vertebrate embryo. # Differences between males and females In human males, the mesonephros gives rise to the efferent ductules of the testis, the epididymis, vas deferens, seminal vesicle, and vestigial structures such as the appendix testis, appendix epididymis, and paradidymis. The mesonephros largely regresses in human females, though vestigial structures such as Gartner's cysts, the epoophoron, and paroophoron are common. # Differences among species The mesonephros persists and form the permanent kidneys in fishes and amphibians, but in reptiles, birds, and mammals, it atrophies and for the most part disappears rapidly as the permanent kidney (metanephros) develops begins during the sixth or seventh week, so that by the beginning of the fifth month only the ducts and a few of the tubules of the mesonephros remain. # Additional images - Broad ligament of adult, showing epoöphoron.	https://www.wikidoc.org/index.php/Mesonephric_tubule
2ee780160e70a05c72ed7c60884d4ff6c9d0d672	wikidoc	Mesothelium	Mesothelium The mesothelium is a membrane that forms the lining of several body cavities: the pleura (thoracal cavity), peritoneum (abdominal cavity) and pericardium (heart sac). Mesothelial tissue also surrounds the male internal reproductive organs (the tunica vaginalis testis) and covers the internal reproductive organs of women (the tunica serosa uteri). Mesothelium that covers the internal organs is called visceral mesothelium, while the layer that covers the body walls is called the parietal mesothelium. # Origin Mesothelium derives from the embryonic mesoderm cell layer, that lines the coelom (body cavity) in the embryo. It develops into the layer of cells that covers and protects most of the internal organs of the body. # Structure The mesothelium forms a monolayer of flattened squamous-like epithelial cells resting on a thin basement membrane supported by connective tissue. Cuboidal mesothelial cells may be found at areas of injury, the milky spots of the omentum, and the peritoneal side of the diaphragm overlaying the lymphatic lacunae. The luminal surface is covered with microvilli. The proteins and serosal fluid trapped by the microvilli provide a frictionless surface for internal organs to slide past one another. # Function The mesothelium is composed of an extensive monolayer of specialized cells (mesothelial cells) that line the body's serous cavities and internal organs. The main purpose of these cells is to produce a lubricating fluid that is released between layers, providing a slippery, non-adhesive and protective surface to facilitate intracoelomic movement. The mesothelium is also implicated in the transport and movement of fluid and particulate matter across the serosal cavities, leucocyte migration in response to inflammatory mediators, synthesis of pro-inflammatory cytokines, growth factors and extracellular matrix proteins to aid in serosal repair, and the release of factors to promote the disposition and clearance of fibrin (such as plasminogen). It is an antigen presenting cell. Furthermore, the secretion of glycosaminoglycans and lubricants may protect the body against infection and tumor dissemination. # Role in disease - Mesothelioma: (cancer of the mesothelium) is a disease in which cells of the mesothelium become abnormal and divide without control or order. They can invade and damage nearby tissues and organs. Cancer cells can also metastasize (spread) from their original site to other parts of the body. Most cases of mesothelioma begin in the pleura or peritoneum. More than 90% of mesothelioma cases are linked to asbestos exposure. - Intra-abdominal adhesions: Normally, the mesothelium secrets plasminogen, which removes fibrin deposits. During surgical procedures, the mesothelium may be damaged. Its fibrinlytic capacity becomes insufficient and fibrin accumulates, causing fibrous adhesions between opposing surfaces. These adhesions cause intestinal obstruction and female infertility if it occurs in the abdomen, and may impair cardiac and lung function in the thorax. - Ultrafiltration failure: The peritoneal mesothelium is implicated in in the long-term development of ultrafiltration failure in peritoneal dialysis patients. The presence of supra-physiological glucose concentrations, acidity, and glucose degradation products in peritoneal dialysis fluids contribute to the fibrosis of the peritoneal mesothelium, either by epithelial-mesenchymal transition or increased proliferation of existing fibroblasts. A fibrosed peritoneum results in the increased passage of solutes across the peritoneum and ultrafiltration failure. # Sources - Mesothelioma: Questions and Answers (National Cancer Institute). - Histology at KUMC epithel-epith01 "Mesothelium" - Histology image: 00102loa – Histology Learning System at Boston University - "Tissues, Layers, and Organs: transverse section of rat gut" - Mutsaers SE. "Mesothelial cells: Their structure, function, and role in serosal repair." Respirology 2002; 7:171-191 it:Mesotelio	Mesothelium Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] The mesothelium is a membrane that forms the lining of several body cavities: the pleura (thoracal cavity), peritoneum (abdominal cavity) and pericardium (heart sac). Mesothelial tissue also surrounds the male internal reproductive organs (the tunica vaginalis testis) and covers the internal reproductive organs of women (the tunica serosa uteri). Mesothelium that covers the internal organs is called visceral mesothelium, while the layer that covers the body walls is called the parietal mesothelium. # Origin Mesothelium derives from the embryonic mesoderm cell layer, that lines the coelom (body cavity) in the embryo. It develops into the layer of cells that covers and protects most of the internal organs of the body. # Structure The mesothelium forms a monolayer of flattened squamous-like epithelial cells resting on a thin basement membrane supported by connective tissue. Cuboidal mesothelial cells may be found at areas of injury, the milky spots of the omentum, and the peritoneal side of the diaphragm overlaying the lymphatic lacunae. The luminal surface is covered with microvilli. The proteins and serosal fluid trapped by the microvilli provide a frictionless surface for internal organs to slide past one another. # Function The mesothelium is composed of an extensive monolayer of specialized cells (mesothelial cells) that line the body's serous cavities and internal organs. The main purpose of these cells is to produce a lubricating fluid that is released between layers, providing a slippery, non-adhesive and protective surface to facilitate intracoelomic movement. The mesothelium is also implicated in the transport and movement of fluid and particulate matter across the serosal cavities, leucocyte migration in response to inflammatory mediators, synthesis of pro-inflammatory cytokines, growth factors and extracellular matrix proteins to aid in serosal repair, and the release of factors to promote the disposition and clearance of fibrin (such as plasminogen). It is an antigen presenting cell. Furthermore, the secretion of glycosaminoglycans and lubricants may protect the body against infection and tumor dissemination. # Role in disease - Mesothelioma: (cancer of the mesothelium) is a disease in which cells of the mesothelium become abnormal and divide without control or order. They can invade and damage nearby tissues and organs. Cancer cells can also metastasize (spread) from their original site to other parts of the body. Most cases of mesothelioma begin in the pleura or peritoneum. More than 90% of mesothelioma cases are linked to asbestos exposure. - Intra-abdominal adhesions: Normally, the mesothelium secrets plasminogen, which removes fibrin deposits. During surgical procedures, the mesothelium may be damaged. Its fibrinlytic capacity becomes insufficient and fibrin accumulates, causing fibrous adhesions between opposing surfaces. These adhesions cause intestinal obstruction and female infertility if it occurs in the abdomen, and may impair cardiac and lung function in the thorax. - Ultrafiltration failure: The peritoneal mesothelium is implicated in in the long-term development of ultrafiltration failure in peritoneal dialysis patients. The presence of supra-physiological glucose concentrations, acidity, and glucose degradation products in peritoneal dialysis fluids contribute to the fibrosis of the peritoneal mesothelium, either by epithelial-mesenchymal transition or increased proliferation of existing fibroblasts. A fibrosed peritoneum results in the increased passage of solutes across the peritoneum and ultrafiltration failure. # Sources - Mesothelioma: Questions and Answers (National Cancer Institute). - Histology at KUMC epithel-epith01 "Mesothelium" - Histology image: 00102loa – Histology Learning System at Boston University - "Tissues, Layers, and Organs: transverse section of rat gut" - Mutsaers SE. "Mesothelial cells: Their structure, function, and role in serosal repair." Respirology 2002; 7:171-191 Template:TissueLayers it:Mesotelio Template:WikiDoc Sources	https://www.wikidoc.org/index.php/Mesothelial
d239bfe86091858dda5f13af9bc654073e22ddf3	wikidoc	Mesotherapy	Mesotherapy Mesotherapy (from Greek mesos, "middle", and therapy from Greek therapeia, "to treat medically") is a non-surgical cosmetic medicine treatment. Mesotherapy employs multiple injections of pharmaceutical and homeopathic medications, plant extracts, vitamins, and other ingredients into the subcutaneous fat. Mesotherapy injections are purported to target adipose fat cells, apparently by inducing rupture and cell death among adipocytes. # Usage - T3-T4 thyroid, - Isoproterenol - Aminophylline - Pentoxifylline - L-carnitine - L-arginine - Hyaluronidase - Collagenase - Yohimbine - Lymphomyosot - Co-enzyme cofactors - Dimethylethanolamine - Glutathione - Tretinoin - Alpha lipoic acid - Vitamin C - Procaine - Lidocaine - Ginkgo biloba - Mellilotus - C-adenosine monophosphate - Multiple vitamins - Trace mineral elements There are published studies on the clinical treatments and effects of these medications and numerous cocktails of combined chemical compounds on the body have been reported in Europe and South America for several years. There is no conclusive research proof that these chemical compounds work to target adipose (fat cells) specifically. Cell lysis, resulting from the detergent action of deoxycholic, may account for any clinical effect. # History Dr. Michel Pistor (1924-2003) performed clinical research and founded the field of mesotherapy. Multi-national research in intradermal therapy culminated with Pistor's work from 1948 to 1952 in human mesotherapy treatments. The French press coined the term Mesotherapy in 1958. The French Academy of Medicine recognized Mesotherapy as a Specialty of Medicine in 1987. Popular throughout European countries and South America, mesotherapy is practiced by approximately 18,000 physicians worldwide. # Criticism Mesotherapy treatments have been performed throughout Europe, South America, and more recently the United States for over fifty years. However, physicians have been concerned about both the efficacy and safety of mesotherapy, arguing that a lack of scientific study makes mesotherapy a fad with potentially dangerous side effects. "There is simply no data, no science and no information, to my knowledge, that mesotherapy works," according to Rod Rohrich, M.D., Chairman, Dept. of Plastic Surgery, University of Texas Southwestern Medical Center, Dallas. The American Society of Plastic Surgeons issued a position statement not endorsing mesotherapy because to date, there has been no established mechanism of action, demonstrated efficacy, or established safety profile with any of the drugs used in mesotherapy. The FDA cannot control the use of practitioners injecting various mixtures into patient's bodies because this practice falls under the jurisdiction of state medical boards. Dr. Robin Ashinoff, speaking for the American Academy of Dermatology, says "A simple injection is giving people false hope. Everybody's looking for a quick fix. But there is no quick fix for fat or fat deposits or for cellulite." The American Society for Dermatologic Surgeryinformed its members in February 2005 that "further study is warranted before this technique can be endorsed." Many dermatologists and plastic surgeons are alarmed about the growing profile of mesotherapy. "No one says exactly what they put into the (syringe)," says Naomi Lawrence, a derma-surgeon at the University of Medicine and Dentistry of New Jersey. "One drug they often use, phosphatidylcholin, is unpredictable and causes extreme inflammation and swelling where injected. It is not a benign drug." USAToday 8/4/2004. It is currently banned in a number of South American countries. Even Brazil, which is less strict than the USA in drug approvals, has banned the drug for these purposes. USAToday 8/4/2004 # Clinical studies In a prospective study, 10 patients underwent four sessions of facial mesotherapy using multivitamins at monthly intervals. This study found that there was no clinically relevant benefit..	Mesotherapy Mesotherapy (from Greek mesos, "middle", and therapy from Greek therapeia, "to treat medically") is a non-surgical cosmetic medicine treatment. Mesotherapy employs multiple injections of pharmaceutical and homeopathic medications, plant extracts, vitamins, and other ingredients into the subcutaneous fat. Mesotherapy injections are purported to target adipose fat cells, apparently by inducing rupture and cell death among adipocytes. [1] # Usage - T3-T4 thyroid, - Isoproterenol - Aminophylline - Pentoxifylline - L-carnitine - L-arginine - Hyaluronidase - Collagenase - Yohimbine - Lymphomyosot - Co-enzyme cofactors - Dimethylethanolamine - Glutathione - Tretinoin - Alpha lipoic acid - Vitamin C - Procaine - Lidocaine - Ginkgo biloba - Mellilotus - C-adenosine monophosphate - Multiple vitamins - Trace mineral elements There are published studies on the clinical treatments and effects of these medications and numerous cocktails of combined chemical compounds on the body have been reported in Europe and South America for several years. There is no conclusive research proof that these chemical compounds work to target adipose (fat cells) specifically. Cell lysis, resulting from the detergent action of deoxycholic, may account for any clinical effect. [2] # History Dr. Michel Pistor (1924-2003) performed clinical research and founded the field of mesotherapy. Multi-national research in intradermal therapy culminated with Pistor's work from 1948 to 1952 in human mesotherapy treatments. The French press coined the term Mesotherapy in 1958. The French Academy of Medicine recognized Mesotherapy as a Specialty of Medicine in 1987. Popular throughout European countries and South America, mesotherapy is practiced by approximately 18,000 physicians worldwide. # Criticism Mesotherapy treatments have been performed throughout Europe, South America, and more recently the United States for over fifty years. However, physicians have been concerned about both the efficacy and safety of mesotherapy, arguing that a lack of scientific study makes mesotherapy a fad with potentially dangerous side effects. "There is simply no data, no science and no information, to my knowledge, that mesotherapy works," according to Rod Rohrich, M.D., Chairman, Dept. of Plastic Surgery, University of Texas Southwestern Medical Center, Dallas. The American Society of Plastic Surgeons issued a position statement not endorsing mesotherapy because to date, there has been no established mechanism of action, demonstrated efficacy, or established safety profile with any of the drugs used in mesotherapy. The FDA cannot control the use of practitioners injecting various mixtures into patient's bodies because this practice falls under the jurisdiction of state medical boards. Dr. Robin Ashinoff, speaking for the American Academy of Dermatology, says "A simple injection is giving people false hope. Everybody's looking for a quick fix. But there is no quick fix for fat or fat deposits or for cellulite." The American Society for Dermatologic Surgeryinformed its members in February 2005 that "further study is warranted before this technique can be endorsed." Many dermatologists and plastic surgeons are alarmed about the growing profile of mesotherapy. "No one says exactly what they put into the (syringe)," says Naomi Lawrence, a derma-surgeon at the University of Medicine and Dentistry of New Jersey. "One drug they often use, phosphatidylcholin, is unpredictable and causes extreme inflammation and swelling where injected. It is not a benign drug." USAToday 8/4/2004. It is currently banned in a number of South American countries. Even Brazil, which is less strict than the USA in drug approvals, has banned the drug for these purposes. USAToday 8/4/2004 # Clinical studies In a prospective study, 10 patients underwent four sessions of facial mesotherapy using multivitamins at monthly intervals. This study found that there was no clinically relevant benefit.[3].	https://www.wikidoc.org/index.php/Mesotherapy
3bd8803924e214f034e1faccf69edf6dafbb804b	wikidoc	Mesterolone	Mesterolone # Overview Mesterolone is an orally applicable androgen, and DHT derivative. It is sold under the brand name Proviron, by Schering. In the late 70's and early 80's it was used with some success in controlled studies of men suffering from various forms of depression. In one randomized, double-blind 4-week trial, 38 dysthymic men were administered 75mg daily. Itil & Colleagues reported an improvement of symptoms which included anxiety, lack of drive and desire. Next, they administered a high dose (450mg/day) or placebo in a 6-week randomized trial of 52 men with a mean age of 40 years, suffering from dysthymia, unipolar and bipolar depression. Both the mesterolone and placebo groups improved significantly and there were no statistically significant differences between the two groups. In this series of studies mesterolone lead to a significant decrease in LH and testosterone levels. This is probably as a result of the extremely high dose used. In another, 100mg mesterolone cipionate was administered twice monthly. With regards to plasma T levels, there was no difference between the treated vs untreated group, and baseline LH levels were minimally affected. Mesterolone is a relatively weak androgen and rarely used for replacement therapies.	Mesterolone Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview Mesterolone is an orally applicable androgen, and DHT derivative. It is sold under the brand name Proviron, by Schering. In the late 70's and early 80's it was used with some success in controlled studies of men suffering from various forms of depression. In one randomized, double-blind 4-week trial, 38 dysthymic men were administered 75mg daily. Itil & Colleagues reported an improvement of symptoms which included anxiety, lack of drive and desire. Next, they administered a high dose (450mg/day) or placebo in a 6-week randomized trial of 52 men with a mean age of 40 years, suffering from dysthymia, unipolar and bipolar depression. Both the mesterolone and placebo groups improved significantly and there were no statistically significant differences between the two groups. In this series of studies mesterolone lead to a significant decrease in LH and testosterone levels. This is probably as a result of the extremely high dose used. In another, 100mg mesterolone cipionate was administered twice monthly. With regards to plasma T levels, there was no difference between the treated vs untreated group, and baseline LH levels were minimally affected.[1] Mesterolone is a relatively weak androgen and rarely used for replacement therapies.[2]	https://www.wikidoc.org/index.php/Mesterolone
cf1d3ceaeeba51cad129a3b8f49b457e34e330c0	wikidoc	Metallocene	Metallocene A metallocene is a compound with the general formula (C5R5)2M consisting of two cyclopentadienyl anions (Cp) bound to a metal center in the oxidation state II. Closely related to the metallocenes are the metallocene derivatives, e.g. titanocene dichloride. Metallocenes of the type Cp2M are not useful for catalysis. One of the more important commercial uses for metallocenes is olefin polymerization with cationic group 4 metallocene derivatives related to +. Metallocenes are a subset of a broader class of organometallic compounds called sandwich compounds. # Definition The general name metallocene is derived from ferrocene, systematically bis(η5-cyclopentadienyl)iron(II). According to the definition by IUPAC, a metallocene contains a transition metal and two cyclopentadienyl ligands coordinated in a sandwich structure, i. e. the two cyclopentadienyl anions are co-planar with equal bond lengths and strengths. The nature of the bonding of the organic ligand to the metal is referred to as its "hapticity" and is indicated by the Greek letter eta (η). The equivalent bonding of all 5 carbon atoms of each cyclopentadienyl ring is denoted as η5, pronounced "pentahapto". In contrast to the more strict definition proposed by IUPAC, which requires a d-block metal and a sandwich structure, the term metallocene and thus the denotation -ocene, is applied in the chemical literature also to non-transition metal compounds, such as Cp2Ba, or structures where the aromatic rings are not co-planar, such as found in manganocene or titanocene dichloride, Cp2TiCl2. # Physical properties and structures of metallocenes A notable feature of some metallocenes is their high thermal stability (often > 500 °C). Neutral metallocenes are soluble in common organic solvents and can generally be purified by vacuum sublimation. In metallocenes of the type (C5R5)2M, the two cyclopentadienyl rings can be either eclipsed or staggered, as indicated by single crystal X-ray diffraction studies. For non-substituted metallocenes the energy difference between the staggered and eclipsed conformations is only 8 kJ/mol. Ferrocene and osmocene are eclipsed conformation at low temperatures, wherea in the related bis(pentamethylcyclopentadienyl) complexes the rings are in a staggered conformation to minimize steric hindrance between the methyl groups. # Derivatives - ansa metallocenes: Derivatives of metallocenes include structures with an intramolecular bridge between the two cyclopentadienyl rings (ansa-metallocenes) - half-sandwich compounds: derivatives with just one planar organic ligand, these include the so-called "piano stool complexes." - Triple decker complexes: compounds with three Cp anions and two metal cations in alternating order, e.g. +. - metallocenium cations: the most famous example is ferrocenium, +, derived from oxidation of ferrocene.	Metallocene A metallocene is a compound with the general formula (C5R5)2M consisting of two cyclopentadienyl anions (Cp) bound to a metal center in the oxidation state II. Closely related to the metallocenes are the metallocene derivatives, e.g. titanocene dichloride. Metallocenes of the type Cp2M are not useful for catalysis. One of the more important commercial uses for metallocenes is olefin polymerization with cationic group 4 metallocene derivatives related to [Cp2ZrCH3]+. Metallocenes are a subset of a broader class of organometallic compounds called sandwich compounds. # Definition The general name metallocene is derived from ferrocene, systematically bis(η5-cyclopentadienyl)iron(II). According to the definition by IUPAC, a metallocene contains a transition metal and two cyclopentadienyl ligands coordinated in a sandwich structure, i. e. the two cyclopentadienyl anions are co-planar with equal bond lengths and strengths. The nature of the bonding of the organic ligand to the metal is referred to as its "hapticity" and is indicated by the Greek letter eta (η). The equivalent bonding of all 5 carbon atoms of each cyclopentadienyl ring is denoted as η5, pronounced "pentahapto". In contrast to the more strict definition proposed by IUPAC, which requires a d-block metal and a sandwich structure, the term metallocene and thus the denotation -ocene, is applied in the chemical literature also to non-transition metal compounds, such as Cp2Ba, or structures where the aromatic rings are not co-planar, such as found in manganocene or titanocene dichloride, Cp2TiCl2. # Physical properties and structures of metallocenes A notable feature of some metallocenes is their high thermal stability (often > 500 °C). Neutral metallocenes are soluble in common organic solvents and can generally be purified by vacuum sublimation. In metallocenes of the type (C5R5)2M, the two cyclopentadienyl rings can be either eclipsed or staggered, as indicated by single crystal X-ray diffraction studies. For non-substituted metallocenes the energy difference between the staggered and eclipsed conformations is only 8 kJ/mol.[citation needed] Ferrocene and osmocene are eclipsed conformation at low temperatures, wherea in the related bis(pentamethylcyclopentadienyl) complexes the rings are in a staggered conformation to minimize steric hindrance between the methyl groups. # Derivatives - ansa metallocenes: Derivatives of metallocenes include structures with an intramolecular bridge between the two cyclopentadienyl rings (ansa-metallocenes) - half-sandwich compounds: derivatives with just one planar organic ligand, these include the so-called "piano stool complexes." - Triple decker complexes: compounds with three Cp anions and two metal cations in alternating order, e.g. [Ni2Cp3]+. - metallocenium cations: the most famous example is ferrocenium, [Fe(C5H5)2]+, derived from oxidation of ferrocene.	https://www.wikidoc.org/index.php/Metallocene
733ca84581c8f02f4415294301e1edecd40b4db0	wikidoc	Meteorology	Meteorology Meteorology (from Greek: μετέωρον, metéōron, "high in the sky"; and λόγος, lógos, "knowledge") is the interdisciplinary scientific study of the atmosphere that focuses on weather processes and forecasting (in contrast with climatology). Meteorological phenomena are observable weather events which illuminate and are explained by the science of meteorology. Those events are bound by the variables that exist in Earth's atmosphere. They are temperature, pressure, water vapor, and the gradients and interactions of each variable, and how they change in time. The majority of Earth's observed weather is located in the troposphere. Meteorology, climatology, atmospheric physics, and atmospheric chemistry are sub-disciplines of the atmospheric sciences. Meteorology and hydrology compose the interdisciplinary field of hydrometeorology. Interactions between Earth's atmosphere and the oceans are part of coupled ocean-atmosphere studies. Meteorology has application in many diverse fields such as the military, energy production, transport, agriculture and construction. # Sub-classifications In the study of the atmosphere, meteorology can be divided into distinct areas of emphasis depending on the temporal scope and spatial scope of interest. At one extreme of this scale is climatology. In the timescales of hours to days, meteorology separates into micro-, meso-, and synoptic scale meteorology. Respectively, the geospatial size of each of these three scales relates directly with the appropriate timescale. Other subclassifications are available based on the need by humans, or by the unique, local or broad effects that are studied within that sub-class. Boundary layer meteorology is the study of processes in the air layer directly above Earth's surface, known as the atmospheric boundary layer (ABL) or peplosphere. The effects of the surface – heating, cooling, and friction – cause turbulent mixing within the air layer. Significant fluxes of heat, matter, or momentum on time scales of less than a day are advected by turbulent motions. Boundary layer meteorology includes the study of all types of surface-atmosphere boundary, including ocean, lake, urban land and non-urban land. Mesoscale meteorology is the study of atmospheric phenomena that has horizontal scales ranging from microscale limits to synoptic scale limits and a vertical scale that starts at the Earth's surface and includes the atmospheric boundary layer, troposphere, tropopause, and the lower section of the stratosphere. Mesoscale timescales last from less than a day to the lifetime of the event, which in some cases can be weeks. The events typically of interest are thunderstorms, squall lines, fronts, precipitation bands in tropical and extratropical cyclones, and topographically generated weather systems such as mountain waves and sea and land breezes. Synoptic scale meteorology is generally large area dynamics referred to in horizontal coordinates and with respect to time. The phenomena typically described by synoptic meteorology include events like extratropical cyclones, baroclinic troughs and ridges, frontal zones, and to some extent jets. All of these are typically given on weather maps for a specific time. The minimum horizontal scale of synoptic phenomena are limited to the spacing between surface observation stations. Global scale meteorology is study of weather patterns related to the transport of heat from the tropics to the poles. Also, very large scale oscillations are of importance. Those oscillations have time periods typically longer than a full annual seasonal cycle, such as ENSO, PDO, MJO, etc. Global scale pushes the thresholds of the perception of meteorology into climatology. The traditional definition of climate is pushed in to larger timescales with the further understanding of how the global oscillations cause both climate and weather disturbances in the synoptic and mesoscale timescales. Numerical Weather Prediction is a main focus in understanding air-sea interaction, tropical meteorology, atmospheric predictability, and tropospheric/stratospheric processes.. Currently (2007) Naval Research Laboratory in Monterey produces the atmospheric model called NOGAPS, a global scale atmospheric model, this model is run operationally at Fleet Numerical Meteorology and Oceanography Center. There are several other global atmospheric models. Dynamic meteorology generally focuses on the physics of the atmosphere. The idea of air parcel is used to define the smallest element of the atmosphere, while ignoring the discrete molecular and chemical nature of the atmosphere. An air parcel is defined as a point in the fluid continuum of the atmosphere. The fundamental laws of fluid dynamics, thermodynamics, and motion are used to study the atmosphere. The physical quantities that characterize the state of the atmosphere are temperature, density, pressure, etc. These variables have unique values in the continuum. Aviation meteorology deals with the impact of weather on air traffic management. It is important for air crews to understand the implications of weather on their flight plan as well as their aircraft, as noted by the Aeronautical Information Manual: The effects of ice on aircraft are cumulative-thrust is reduced, drag increases, lift lessens, and weight increases. The results are a decrease in stall speed and a deterioration of aircraft performance. In extreme cases, 2 to 3 inches of ice can form on the leading edge of the airfoil in less than 5 minutes. It takes but 1/2 inch of ice to reduce the lifting power of some aircraft by 50 percent and increases the frictional drag by an equal percentage. Meteorologists, soil scientists, agricultural hydrologists, and agronomists are persons concerned with studying the effects of weather and climate on plant distribution, crop yield, water-use efficiency, phenology of plant and animal development, and the energy balance of managed and natural ecosystems. Conversely, they are interested in the role of vegetation on climate and weather. Hydrometeorology is the branch of meteorology that deals with the hydrologic cycle, the water budget, and the rainfall statistics of storms. A hydrometeorologist prepares and issues forecasts of accumulating (quantitative) precipitation, heavy rain, heavy snow, and highlights areas with the potential for flash flooding. Typically the range of knowledge that is required overlaps with climatology, mesoscale and synoptic meteorology, and other geosciences. # History ## Observation networks and weather forecasting The arrival of the electrical telegraph in 1837 afforded, for the first time, a practical method for quickly gathering surface weather observations from a wide area. This data could be used to produce maps of the state of the atmosphere for a region near the Earth's surface and to study how these states evolved through time. To make frequent weather forecasts based on these data required a reliable network of observations, but it was not until 1849 that the Smithsonian Institution began to establish an observation network across the United States under the leadership of Joseph Henry . Similar observation networks were established in Europe at this time. In 1854, the United Kingdom government appointed Robert FitzRoy to the new office of Meteorological Statist to the Board of Trade with the role of gathering weather observations at sea. FitzRoy's office became the United Kingdom Meteorological Office in 1854, the first national meteorological service in the world. The first daily weather forecasts made by FitzRoy's Office were published in The Times newspaper in 1860. The following year a system was introduced of hoisting storm warning cones at principal ports when a gale was expected. Over the next 50 years many countries established national meteorological services: Finnish Meteorological Central Office (1881) was formed from part of Magnetic Observatory of Helsinki University; India Meteorological Department (1889) established following tropical cyclone and monsoon related famines in the previous decades; United States Weather Bureau (1890) was established under the United States Department of Agriculture; Australian Bureau of Meteorology (1905) established by a Meteorology Act to unify existing state meteorological services. ## Coriolis effect Understanding the kinematics of how exactly the rotation of the Earth affects airflow was partial at first. Late in the 19th century the full extent of the large scale interaction of pressure gradient force and deflecting force that in the end causes air masses to move along isobars was understood. Early in the 20th century this deflecting force was named the Coriolis effect after Gaspard-Gustave Coriolis, who had published in 1835 on the energy yield of machines with rotating parts, such as waterwheels. In 1856, William Ferrel proposed the existence of a circulation cell in the mid-latitudes with air being deflected by the Coriolis force to create the prevailing westerly winds. ## Numerical weather prediction In 1904, Norwegian scientist Vilhelm Bjerknes first postulated that prognostication of the weather is possible from calculations based upon natural laws. Early in the 20th century, advances in the understanding of atmospheric physics led to the foundation of modern numerical weather prediction. In 1922, Lewis Fry Richardson published "Weather prediction by numerical process," which described how small terms in the fluid dynamics equations governing atmospheric flow could be neglected to allow numerical solutions to be found. However, the sheer number of calculations required was too large to be completed without the use of computers. At this time in Norway a group of meteorologists led by Vilhelm Bjerknes developed the model that explains the generation, intensification and ultimate decay (the life cycle) of mid-latitude cyclones, introducing the idea of fronts, that is, sharply defined boundaries between air masses. The group included Carl-Gustaf Rossby (who was the first to explain the large scale atmospheric flow in terms of fluid dynamics), Tor Bergeron (who first determined the mechanism by which rain forms) and Jacob Bjerknes. Starting in the 1950s, numerical experiments with computers became feasible. The first weather forecasts derived this way used barotropic (that means, single-vertical-level) models, and could successfully predict the large-scale movement of midlatitude Rossby waves, that is, the pattern of atmospheric lows and highs. In the 1960s, the chaotic nature of the atmosphere was first observed and understood by Edward Lorenz, founding the field of chaos theory. These advances have led to the current use of ensemble forecasting in most major forecasting centers, to take into account uncertainty arising from the chaotic nature of the atmosphere. # Equipment Generally speaking, each science has its own unique sets of laboratory equipment. However, meteorology is a science which does not use much lab equipment but relies more on field-mode observation equipment. In some aspects this can make simple observations slide on the erroneous side. In science, an observation, or observable, is an abstract idea that can be measured and data can be taken. In the atmosphere, there are many things or qualities of the atmosphere that can be measured. Rain, which can be observed, or seen anywhere and anytime was one of the first ones to be measured historically. Also, two other accurately measured qualities are wind and humidity. Neither of these can be seen but can be felt. The devices to measure these three sprang up in the mid-15th century and were respectively the rain gauge, the anemometer, and the hygrometer. Sets of surface measurements are important data to meteorologists. They give a snapshot of a variety of weather conditions at one single location and are usually at a weather station, a ship or a weather buoy. The measurements taken at a weather station can include any number of atmospheric observables. Usually, temperature, pressure, wind measurements, and humidity are the variables that are measured by a thermometer, barometer, anemometer, and hygrometer, respectively. Upper air data are of crucial importance for weather forecasting. The most widely used technique is launches of radiosondes. Supplementing the radiosondes a network of aircraft collection is organized by the World Meteorological Organization. Remote sensing, as used in meteorology, is the concept of collecting data from remote weather events and subsequently producing weather information. The common types of remote sensing are Radar, Lidar, and satellites (or photogrammetry). Each collects data about the atmosphere from a remote location and, usually, stores the data where the instrument is located. RADAR and LIDAR are not passive because both use EM radiation to illuminate a specific portion of the atmosphere. The 1960 launch of the first successful weather satellite, TIROS-1, marked the beginning of the age where weather information became available globally. Weather satellites along with more general-purpose Earth-observing satellites circling the earth at various altitudes have become an indispensable tool for studying a wide range of phenomena from forest fires to El Niño. In recent years, climate models have been developed that feature a resolution comparable to older weather prediction models. These climate models are used to investigate long-term climate shifts, such as what effects might be caused by human emission of greenhouse gases. # Weather forecasting Although meteorologists now rely heavily on computer models (numerical weather prediction), it is still relatively common to use techniques and conceptual models that were developed before computers were powerful enough to make predictions accurately or efficiently (generally speaking, prior to around 1980). Many of these methods are used to determine how much skill a forecaster has added to the forecast (for example, how much better than persistence or climatology did the forecast do?). Similarly, they could also be used to determine how much skill the industry as a whole has gained with emerging technologies and techniques. The persistence method assumes that conditions will not change. Often summarised as "Tomorrow equals today". This method works best over short periods of time in stagnant weather regimes. The extrapolation method assumes that atmospheric systems will propagate at similar speeds in the near future to those seen in the past. This method achieves the best results when diurnal changes in the pressure and precipitation patterns are taken into account. The numerical weather prediction or NWP method uses computers to take into account a large number of variables and creates a computer model of the atmosphere. This is most successful when used with the methods below, and when model biases and relative skill are taken into account. Statistically, it is difficult to beat the mean solution, and the consensus and ensemble methods of forecasting take advantage of the situation by only favoring models that have the greatest support with their ensemble means or other pieces of global model guidance. A local Hydrometeorological Prediction Center study showed that using this method alone verifies 50-55% of the time. The trends method involves determining the change in fronts and high and low pressure centers in the model runs over various lengths of time. If the trend is seen over a long enough time frame (24 hours or so), it is more meaningful. The forecast models have been known to overtrend however, so use of this method verifies 55-60% the time, more so in the surface pattern than aloft. The climatology or analog method involves using historical weather data collected over long periods of time (years) to predict conditions on a given date. A variation on this theme is the use of teleconnections, which rely upon the date and the expected position of other positive or negative 500 hPa height anomalies to give someone an impression of what the overall pattern would look like with this anomaly in place, and is of more significant help than a model trend since it verifies roughly 75 percent of the time, when used properly and with a stable anomaly center. Another variation is the use of standard deviations from climatology in various meteorological fields. Once the pattern deviates more than 4-5 sigmas from climatology, it becomes an improbable solution.	Meteorology Meteorology (from Greek: μετέωρον, metéōron, "high in the sky"; and λόγος, lógos, "knowledge") is the interdisciplinary scientific study of the atmosphere that focuses on weather processes and forecasting (in contrast with climatology). Meteorological phenomena are observable weather events which illuminate and are explained by the science of meteorology. Those events are bound by the variables that exist in Earth's atmosphere. They are temperature, pressure, water vapor, and the gradients and interactions of each variable, and how they change in time. The majority of Earth's observed weather is located in the troposphere. [1] [2] Meteorology, climatology, atmospheric physics, and atmospheric chemistry are sub-disciplines of the atmospheric sciences. Meteorology and hydrology compose the interdisciplinary field of hydrometeorology. Interactions between Earth's atmosphere and the oceans are part of coupled ocean-atmosphere studies. Meteorology has application in many diverse fields such as the military, energy production, transport, agriculture and construction. # Sub-classifications In the study of the atmosphere, meteorology can be divided into distinct areas of emphasis depending on the temporal scope and spatial scope of interest. At one extreme of this scale is climatology. In the timescales of hours to days, meteorology separates into micro-, meso-, and synoptic scale meteorology. Respectively, the geospatial size of each of these three scales relates directly with the appropriate timescale. Other subclassifications are available based on the need by humans, or by the unique, local or broad effects that are studied within that sub-class. Boundary layer meteorology is the study of processes in the air layer directly above Earth's surface, known as the atmospheric boundary layer (ABL) or peplosphere. The effects of the surface – heating, cooling, and friction – cause turbulent mixing within the air layer. Significant fluxes of heat, matter, or momentum on time scales of less than a day are advected by turbulent motions.[3] Boundary layer meteorology includes the study of all types of surface-atmosphere boundary, including ocean, lake, urban land and non-urban land. Mesoscale meteorology is the study of atmospheric phenomena that has horizontal scales ranging from microscale limits to synoptic scale limits and a vertical scale that starts at the Earth's surface and includes the atmospheric boundary layer, troposphere, tropopause, and the lower section of the stratosphere. Mesoscale timescales last from less than a day to the lifetime of the event, which in some cases can be weeks. The events typically of interest are thunderstorms, squall lines, fronts, precipitation bands in tropical and extratropical cyclones, and topographically generated weather systems such as mountain waves and sea and land breezes.[4] Synoptic scale meteorology is generally large area dynamics referred to in horizontal coordinates and with respect to time. The phenomena typically described by synoptic meteorology include events like extratropical cyclones, baroclinic troughs and ridges, frontal zones, and to some extent jets. All of these are typically given on weather maps for a specific time. The minimum horizontal scale of synoptic phenomena are limited to the spacing between surface observation stations. [5] Global scale meteorology is study of weather patterns related to the transport of heat from the tropics to the poles. Also, very large scale oscillations are of importance. Those oscillations have time periods typically longer than a full annual seasonal cycle, such as ENSO, PDO, MJO, etc. Global scale pushes the thresholds of the perception of meteorology into climatology. The traditional definition of climate is pushed in to larger timescales with the further understanding of how the global oscillations cause both climate and weather disturbances in the synoptic and mesoscale timescales. Numerical Weather Prediction is a main focus in understanding air-sea interaction, tropical meteorology, atmospheric predictability, and tropospheric/stratospheric processes.[6]. Currently (2007) Naval Research Laboratory in Monterey produces the atmospheric model called NOGAPS, a global scale atmospheric model, this model is run operationally at Fleet Numerical Meteorology and Oceanography Center. There are several other global atmospheric models. Dynamic meteorology generally focuses on the physics of the atmosphere. The idea of air parcel is used to define the smallest element of the atmosphere, while ignoring the discrete molecular and chemical nature of the atmosphere. An air parcel is defined as a point in the fluid continuum of the atmosphere. The fundamental laws of fluid dynamics, thermodynamics, and motion are used to study the atmosphere. The physical quantities that characterize the state of the atmosphere are temperature, density, pressure, etc. These variables have unique values in the continuum.[7] Aviation meteorology deals with the impact of weather on air traffic management. It is important for air crews to understand the implications of weather on their flight plan as well as their aircraft, as noted by the Aeronautical Information Manual[8]: The effects of ice on aircraft are cumulative-thrust is reduced, drag increases, lift lessens, and weight increases. The results are a decrease in stall speed and a deterioration of aircraft performance. In extreme cases, 2 to 3 inches of ice can form on the leading edge of the airfoil in less than 5 minutes. It takes but 1/2 inch of ice to reduce the lifting power of some aircraft by 50 percent and increases the frictional drag by an equal percentage.[9] Meteorologists, soil scientists, agricultural hydrologists, and agronomists are persons concerned with studying the effects of weather and climate on plant distribution, crop yield, water-use efficiency, phenology of plant and animal development, and the energy balance of managed and natural ecosystems. Conversely, they are interested in the role of vegetation on climate and weather.[10] Hydrometeorology is the branch of meteorology that deals with the hydrologic cycle, the water budget, and the rainfall statistics of storms.[11] A hydrometeorologist prepares and issues forecasts of accumulating (quantitative) precipitation, heavy rain, heavy snow, and highlights areas with the potential for flash flooding. Typically the range of knowledge that is required overlaps with climatology, mesoscale and synoptic meteorology, and other geosciences.[12] # History ## Observation networks and weather forecasting The arrival of the electrical telegraph in 1837 afforded, for the first time, a practical method for quickly gathering surface weather observations from a wide area. This data could be used to produce maps of the state of the atmosphere for a region near the Earth's surface and to study how these states evolved through time. To make frequent weather forecasts based on these data required a reliable network of observations, but it was not until 1849 that the Smithsonian Institution began to establish an observation network across the United States under the leadership of Joseph Henry [13]. Similar observation networks were established in Europe at this time. In 1854, the United Kingdom government appointed Robert FitzRoy to the new office of Meteorological Statist to the Board of Trade with the role of gathering weather observations at sea. FitzRoy's office became the United Kingdom Meteorological Office in 1854, the first national meteorological service in the world. The first daily weather forecasts made by FitzRoy's Office were published in The Times newspaper in 1860. The following year a system was introduced of hoisting storm warning cones at principal ports when a gale was expected. Over the next 50 years many countries established national meteorological services: Finnish Meteorological Central Office (1881) was formed from part of Magnetic Observatory of Helsinki University; India Meteorological Department (1889) established following tropical cyclone and monsoon related famines in the previous decades; United States Weather Bureau (1890) was established under the United States Department of Agriculture; Australian Bureau of Meteorology (1905) established by a Meteorology Act to unify existing state meteorological services. ## Coriolis effect Understanding the kinematics of how exactly the rotation of the Earth affects airflow was partial at first. Late in the 19th century the full extent of the large scale interaction of pressure gradient force and deflecting force that in the end causes air masses to move along isobars was understood. Early in the 20th century this deflecting force was named the Coriolis effect after Gaspard-Gustave Coriolis, who had published in 1835 on the energy yield of machines with rotating parts, such as waterwheels. In 1856, William Ferrel proposed the existence of a circulation cell in the mid-latitudes with air being deflected by the Coriolis force to create the prevailing westerly winds. ## Numerical weather prediction In 1904, Norwegian scientist Vilhelm Bjerknes first postulated that prognostication of the weather is possible from calculations based upon natural laws. Early in the 20th century, advances in the understanding of atmospheric physics led to the foundation of modern numerical weather prediction. In 1922, Lewis Fry Richardson published "Weather prediction by numerical process," which described how small terms in the fluid dynamics equations governing atmospheric flow could be neglected to allow numerical solutions to be found. However, the sheer number of calculations required was too large to be completed without the use of computers. At this time in Norway a group of meteorologists led by Vilhelm Bjerknes developed the model that explains the generation, intensification and ultimate decay (the life cycle) of mid-latitude cyclones, introducing the idea of fronts, that is, sharply defined boundaries between air masses. The group included Carl-Gustaf Rossby (who was the first to explain the large scale atmospheric flow in terms of fluid dynamics), Tor Bergeron (who first determined the mechanism by which rain forms) and Jacob Bjerknes. Starting in the 1950s, numerical experiments with computers became feasible. The first weather forecasts derived this way used barotropic (that means, single-vertical-level) models, and could successfully predict the large-scale movement of midlatitude Rossby waves, that is, the pattern of atmospheric lows and highs. In the 1960s, the chaotic nature of the atmosphere was first observed and understood by Edward Lorenz, founding the field of chaos theory. These advances have led to the current use of ensemble forecasting in most major forecasting centers, to take into account uncertainty arising from the chaotic nature of the atmosphere. # Equipment Generally speaking, each science has its own unique sets of laboratory equipment. However, meteorology is a science which does not use much lab equipment but relies more on field-mode observation equipment. In some aspects this can make simple observations slide on the erroneous side. In science, an observation, or observable, is an abstract idea that can be measured and data can be taken. In the atmosphere, there are many things or qualities of the atmosphere that can be measured. Rain, which can be observed, or seen anywhere and anytime was one of the first ones to be measured historically. Also, two other accurately measured qualities are wind and humidity. Neither of these can be seen but can be felt. The devices to measure these three sprang up in the mid-15th century and were respectively the rain gauge, the anemometer, and the hygrometer.[14] Sets of surface measurements are important data to meteorologists. They give a snapshot of a variety of weather conditions at one single location and are usually at a weather station, a ship or a weather buoy. The measurements taken at a weather station can include any number of atmospheric observables. Usually, temperature, pressure, wind measurements, and humidity are the variables that are measured by a thermometer, barometer, anemometer, and hygrometer, respectively. Upper air data are of crucial importance for weather forecasting. The most widely used technique is launches of radiosondes. Supplementing the radiosondes a network of aircraft collection is organized by the World Meteorological Organization. Remote sensing, as used in meteorology, is the concept of collecting data from remote weather events and subsequently producing weather information. The common types of remote sensing are Radar, Lidar, and satellites (or photogrammetry). Each collects data about the atmosphere from a remote location and, usually, stores the data where the instrument is located. RADAR and LIDAR are not passive because both use EM radiation to illuminate a specific portion of the atmosphere.[15] The 1960 launch of the first successful weather satellite, TIROS-1, marked the beginning of the age where weather information became available globally. Weather satellites along with more general-purpose Earth-observing satellites circling the earth at various altitudes have become an indispensable tool for studying a wide range of phenomena from forest fires to El Niño. In recent years, climate models have been developed that feature a resolution comparable to older weather prediction models. These climate models are used to investigate long-term climate shifts, such as what effects might be caused by human emission of greenhouse gases. # Weather forecasting Template:Weather nav Although meteorologists now rely heavily on computer models (numerical weather prediction), it is still relatively common to use techniques and conceptual models that were developed before computers were powerful enough to make predictions accurately or efficiently (generally speaking, prior to around 1980). Many of these methods are used to determine how much skill a forecaster has added to the forecast (for example, how much better than persistence or climatology did the forecast do?). Similarly, they could also be used to determine how much skill the industry as a whole has gained with emerging technologies and techniques. The persistence method assumes that conditions will not change. Often summarised as "Tomorrow equals today". This method works best over short periods of time in stagnant weather regimes.[16] The extrapolation method assumes that atmospheric systems will propagate at similar speeds in the near future to those seen in the past. This method achieves the best results when diurnal changes in the pressure and precipitation patterns are taken into account. The numerical weather prediction or NWP[17] method uses computers to take into account a large number of variables and creates a computer model of the atmosphere. This is most successful when used with the methods below, and when model biases and relative skill are taken into account. Statistically, it is difficult to beat the mean solution, and the consensus and ensemble methods of forecasting take advantage of the situation by only favoring models that have the greatest support with their ensemble means or other pieces of global model guidance. A local Hydrometeorological Prediction Center study showed that using this method alone verifies 50-55% of the time. The trends method involves determining the change in fronts and high and low pressure centers in the model runs over various lengths of time. If the trend is seen over a long enough time frame (24 hours or so), it is more meaningful. The forecast models have been known to overtrend however, so use of this method verifies 55-60% the time, more so in the surface pattern than aloft.[18] The climatology or analog method involves using historical weather data collected over long periods of time (years) to predict conditions on a given date. A variation on this theme is the use of teleconnections, which rely upon the date and the expected position of other positive or negative 500 hPa height anomalies to give someone an impression of what the overall pattern would look like with this anomaly in place, and is of more significant help than a model trend since it verifies roughly 75 percent of the time, when used properly and with a stable anomaly center. Another variation is the use of standard deviations from climatology in various meteorological fields. Once the pattern deviates more than 4-5 sigmas from climatology, it becomes an improbable solution.[19]	https://www.wikidoc.org/index.php/Meteorology
bb4cd3cf13dc7254c37af0d9acadf96635302095	wikidoc	Methicillin	Methicillin # Overview Meticillin (INN, BAN) or methicillin (USAN) is a narrow-spectrum β-lactam antibiotic of the penicillin class. It should not be confused with the antibiotic metacycline. In 2005, the name of the drug was changed from methicillin to meticillin in accordance with the International Pharmacopoeia guidelines. # History Meticillin was developed by Beecham in 1959. It was previously used to treat infections caused by susceptible Gram-positive bacteria, in particular, penicillinase-producing organisms such as Staphylococcus aureus that would otherwise be resistant to most penicillins. Its role in therapy has been largely replaced by flucloxacillin and dicloxacillin, but the term meticillin-resistant Staphylococcus aureus (MRSA) continues to be used to describe S. aureus strains resistant to all penicillins. Meticillin is no longer manufactured because the more stable and similar penicillins such as oxacillin (used for clinical antimicrobial susceptibility testing), flucloxacillin, and dicloxacillin are used medically. # Mode of action Like other beta-lactam antibiotics, meticillin acts by inhibiting the synthesis of bacterial cell walls. It inhibits cross-linkage between the linear peptidoglycan polymer chains that make up a major component of the cell wall of Gram-positive bacteria. It does this by binding to and competitively inhibiting the transpeptidase enzyme (also known as penicillin-binding proteins (PBPs)). These PBPs crosslink glycopeptides (D-alanyl-alanine), forming the peptidoglycan cell wall. Meticillin and other β-lactam antibiotics are structural analogs of D-alanyl-alanine, and the transpeptidase enzymes that bind to them are sometimes called penicillin-binding proteins (PBPs). Meticillin is actually a penicillinase-resistant B-lactam antibiotic. Penicillinase is a bacterial enzyme produced by bacteria resistant to other B-lactam antibiotics which hydrolyses the antibiotic, rendering it nonfunctional. Meticillin is not bound and hydrolysed by penicillinase, meaning it can kill the bacteria, even if this enzyme is present. # Spectrum of bacterial resistance and susceptibility At one time, meticillin was used to treat infections caused by certain Gram-positive bacteria including Staphylococcus aureus, Staphylococcus epidermidis, Streptococcus pyogenes, and Streptococcus pneumoniae. Today, meticillin is not as effective against these organisms due to resistance. Resistance to meticillin is conferred by activation of a new bacterial PBP gene (mec2). This encodes for the PBP2a. PBP2a works in a similar manner to other PBPs, but it is bound by β-lactams with very low affinity, meaning they cannot hydrolyse it and kill the bacteria. Expression of PBPA2 confers resistance to all β-lactams. These susceptibility data are given on a few medically significant bacteria: - Staphylococcus aureus - 0.125 - >100 μg/ml - Meticillin resistant Staphylococcus aureus (MRSA) - 15.6 - >1000 μg/ml - Streptococcus pneumoniae 0.39 μg/ml # Medicinal chemistry Meticillin is insensitive to beta-lactamase (also known as penicillinase) enzymes secreted by many penicillin-resistant bacteria. The presence of the ortho-dimethoxyphenyl group directly attached to the side-chain carbonyl group of the penicillin nucleus facilitates the β-lactamase resistance, since those enzymes are relatively intolerant of side-chain steric hindrance. Thus, it is able to bind to PBPs and inhibit peptidoglycan crosslinking, but it is not bound by or inactivated by β-lactamases. # Clinical use Meticillin is no longer used to treat patients. Compared to other β-lactamase-resistant penicillins, it is less active, can be administered only parenterally, and has a higher frequency of interstitial nephritis, an otherwise-rare side effect of penicillins. However, selection of Meticillin depended on the outcome of susceptibility test of the microorganism, since it is no longer produced, it is also not routinely tested any more. It also served a purpose in the laboratory to determine the antibiotic sensitivity of Staphylococcus aureus to other β-lactamase-resistant penicillins; this role has now been passed on to other penicillines, namely Cloxacillin as well as genetic testing for the presence of mecA gene by PCR.	Methicillin Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview Meticillin (INN, BAN) or methicillin (USAN) is a narrow-spectrum β-lactam antibiotic of the penicillin class. It should not be confused with the antibiotic metacycline. In 2005, the name of the drug was changed from methicillin to meticillin in accordance with the International Pharmacopoeia guidelines.[1] # History Meticillin was developed by Beecham in 1959.[2] It was previously used to treat infections caused by susceptible Gram-positive bacteria, in particular, penicillinase-producing organisms such as Staphylococcus aureus that would otherwise be resistant to most penicillins. Its role in therapy has been largely replaced by flucloxacillin and dicloxacillin, but the term meticillin-resistant Staphylococcus aureus (MRSA) continues to be used to describe S. aureus strains resistant to all penicillins.[3] Meticillin is no longer manufactured because the more stable and similar penicillins such as oxacillin (used for clinical antimicrobial susceptibility testing), flucloxacillin, and dicloxacillin are used medically. # Mode of action Like other beta-lactam antibiotics, meticillin acts by inhibiting the synthesis of bacterial cell walls. It inhibits cross-linkage between the linear peptidoglycan polymer chains that make up a major component of the cell wall of Gram-positive bacteria. It does this by binding to and competitively inhibiting the transpeptidase enzyme (also known as penicillin-binding proteins (PBPs)). These PBPs crosslink glycopeptides (D-alanyl-alanine), forming the peptidoglycan cell wall. Meticillin and other β-lactam antibiotics are structural analogs of D-alanyl-alanine, and the transpeptidase enzymes that bind to them are sometimes called penicillin-binding proteins (PBPs).[4] Meticillin is actually a penicillinase-resistant B-lactam antibiotic. Penicillinase is a bacterial enzyme produced by bacteria resistant to other B-lactam antibiotics which hydrolyses the antibiotic, rendering it nonfunctional. Meticillin is not bound and hydrolysed by penicillinase, meaning it can kill the bacteria, even if this enzyme is present. # Spectrum of bacterial resistance and susceptibility At one time, meticillin was used to treat infections caused by certain Gram-positive bacteria including Staphylococcus aureus, Staphylococcus epidermidis, Streptococcus pyogenes, and Streptococcus pneumoniae. Today, meticillin is not as effective against these organisms due to resistance. Resistance to meticillin is conferred by activation of a new bacterial PBP gene (mec2). This encodes for the PBP2a. PBP2a works in a similar manner to other PBPs, but it is bound by β-lactams with very low affinity, meaning they cannot hydrolyse it and kill the bacteria. Expression of PBPA2 confers resistance to all β-lactams. These susceptibility data are given on a few medically significant bacteria: - Staphylococcus aureus - 0.125 - >100 μg/ml - Meticillin resistant Staphylococcus aureus (MRSA) - 15.6 - >1000 μg/ml - Streptococcus pneumoniae 0.39 μg/ml # Medicinal chemistry Meticillin is insensitive to beta-lactamase (also known as penicillinase) enzymes secreted by many penicillin-resistant bacteria. The presence of the ortho-dimethoxyphenyl group directly attached to the side-chain carbonyl group of the penicillin nucleus facilitates the β-lactamase resistance, since those enzymes are relatively intolerant of side-chain steric hindrance. Thus, it is able to bind to PBPs and inhibit peptidoglycan crosslinking, but it is not bound by or inactivated by β-lactamases. # Clinical use Meticillin is no longer used to treat patients. Compared to other β-lactamase-resistant penicillins, it is less active, can be administered only parenterally, and has a higher frequency of interstitial nephritis, an otherwise-rare side effect of penicillins. However, selection of Meticillin depended on the outcome of susceptibility test of the microorganism, since it is no longer produced, it is also not routinely tested any more. It also served a purpose in the laboratory to determine the antibiotic sensitivity of Staphylococcus aureus to other β-lactamase-resistant penicillins; this role has now been passed on to other penicillines, namely Cloxacillin as well as genetic testing for the presence of mecA gene by PCR.	https://www.wikidoc.org/index.php/Methicillin
319a55e17fcbed2daefe7c598c2147dca9471886	wikidoc	Methimazole	Methimazole # 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 Methimazole is an antithyroid agent that is FDA approved for the {{{indicationType}}} of hyperthyroidism. Common adverse reactions include skin rash, urticaria, nausea, vomiting, epigastric distress, arthralgia, paresthesia, loss of taste, abnormal loss of hair, myalgia, headache, pruritus, drowsiness, neuritis, edema, vertigo, skin pigmentation, jaundice, sialadenopathy, and lymphadenopathy. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) - Methimazole is indicated in the medical treatment of hyperthyroidism. Long-term therapy may lead to remission of the disease. - Methimazole may be used to ameliorate hyperthyroidism in preparation for subtotal thyroidectomy or radioactive iodine therapy. - Methimazole is also used when thyroidectomy is contraindicated or not advisable. - Methimazole is administered orally. It is usually given in 3 equal doses at approximately 8-hour intervals. - The initial daily dosage is 15 mg for mild hyperthyroidism, 30 to 40 mg for moderately severe hyperthyroidism, and 60 mg for severe hyperthyroidism, divided into 3 doses at 8-hour intervals. The maintenance dosage is 5 to 15 mg daily. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Methimazole in adult patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Methimazole in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) - Dosing Information - Initially, the daily dosage is 0.4 mg/kg of body weight divided into 3 doses and given at 8-hour intervals. The maintenance dosage is approximately 1/2 of the initial dose. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Methimazole in pediatric patients. ### Non–Guideline-Supported Use - Dosing Information - Methimazole 0.5 milligrams/kilogram body mass in 2 doses. # Contraindications - Methimazole is contraindicated in the presence of hypersensitivity to the drug and in nursing mothers because the drug is excreted in milk. # Warnings - Congenital Malformations - Methimazole readily crosses the placental membranes and can cause fetal harm, particularly when administered in the first trimester of pregnancy. Rare instances of congenital defects, including aplasia cutis, craniofacial malformations (facial dysmorphism; choanal atresia) and gastrointestinal malformations (esophageal atresia with or without tracheoesophageal fistula; umbilical abnormalities) have occurred in infants born to mothers who received TAPAZOLE during pregnancy. If TAPAZOLE is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be warned of the potential hazard to the fetus. - Since the above congenital defects have been reported in offspring of patients treated with TAPAZOLE, it may be appropriate to use other agents in pregnant women requiring treatment for hyperthyroidism, particularly during organogenesis, in the first trimester of pregnancy. If TAPAZOLE is used, the lowest possible dose to control the maternal disease should be given. - Agranulocytosis - Agranulocytosis is potentially a life-threatening adverse reaction of TAPAZOLE therapy. Patients should be instructed to immediately report to their physicians any symptoms suggestive of agranulocytosis, such as fever or sore throat. Leukopenia, thrombocytopenia, and aplastic anemia (pancytopenia) may also occur. The drug should be discontinued in the presence of agranulocytosis, aplastic anemia (pancytopenia), ANCA-positive vasculitis, hepatitis, or exfoliative dermatitis and the patient's bone marrow indices should be monitored. - Liver Toxicity - Although there have been reports of hepatotoxicity (including acute liver failure) associated with TAPAZOLE, the risk of hepatotoxicity appears to be less with methimazole than with propylthiouracil, especially in the pediatric population. Symptoms suggestive of hepatic dysfunction (anorexia, pruritis, right upper quadrant pain, etc.) should prompt evaluation of liver function (bilirubin, alkaline phosphatase) and hepatocellur integrity (ALT, AST). Drug treatment should be discontinued promptly in the event of clinically significant evidence of liver abnormality including hepatic transaminase values exceeding 3 times the upper limit of normal. - Hypothyroidism - TAPAZOLE can cause hypothyroidism necessitating routine monitoring of TSH and free T4 levels with adjustments in dosing to maintain a euthyroid state. Because the drug readily crosses placental membranes, methimazole can cause fetal goiter and cretinism when administered to a pregnant woman. For this reason, it is important that a sufficient, but not excessive, dose be given during pregnancy. ### Precautions - General - Patients who receive methimazole should be under close surveillance and should be cautioned to report immediately any evidence of illness, particularly sore throat, skin eruptions, fever, headache, or general malaise. In such cases, white-blood cell and differential counts should be made to determine whether agranulocytosis has developed. Particular care should be exercised with patients who are receiving additional drugs know to cause agranulocytosis. - Laboratory Tests - Because methimazole may cause hypoprothrombinemia and bleeding, prothrombin time should be monitored during therapy with the drug, especially before surgical procedures. - Periodic monitoring of thyroid function is warranted, and the finding of an elevated TSH warrants a decrease in the dosage of methimazole. # Adverse Reactions ## Clinical Trials Experience - Major adverse reactions (which occur with much less frequency than the minor adverse reactions) include inhibition of myelopoiesis (agranulocytosis, granulocytopenia, and thrombocytopenia), aplastic anemia, drug fever, a lupuslike syndrome, insulin autoimmune syndrome (which can result in hypoglycemic coma), hepatitis (jaundice may persist for several weeks after discontinuation of the drug), periarteritis, and hypoprothrombinemia. Nephritis occurs very rarely. - Minor adverse reactions include skin rash, urticaria, nausea, vomiting, epigastric distress, arthralgia, paresthesia, loss of taste, abnormal loss of hair, myalgia, headache, pruritus, drowsiness, neuritis, edema, vertigo, skin pigmentation, jaundice, sialadenopathy, and lymphadenopathy. - It should be noted that about 10% of patients with untreated hyperthyroidism have leukopenia (white-blood cell count of less than 4,000/mm3 ), often with relative granulopenia. ## Postmarketing Experience There is limited information regarding Postmarketing Experience of Methimazole in the drug label. # Drug Interactions - Anticoagulants (oral) - The activity of oral anticoagulants may be potentiated by anti-vitamin-K activity attributed to methimazole. - ß-adrenergic blocking agents - Hyperthyroidism may cause an increased clearance of beta blockers with a high extraction ratio. A dose reduction of beta-adrenergic blockers may be needed when a hyperthyroid patient becomes euthyroid. - Digitalis glycosides - Serum digitalis levels may be increased when hyperthyroid patients on a stable digitalis glycoside regimen become euthyroid; a reduced dosage of digitalis glycosides may be required. - Theophylline - Theophylline clearance may decrease when hyperthyroid patients on a stable theophylline regimen become euthyroid; a reduced dose of theophylline may be needed. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): - Pregnancy Category D - Methimazole used judiciously is an effective drug in hyperthyroidism complicated by pregnancy. In many pregnant women, the thyroid dysfunction diminishes as the pregnancy proceeds; consequently, a reduction in dosage may be possible. In some instances, use of methimazole can be discontinued 2 or 3 weeks before delivery. Pregnancy Category (AUS): - Australian Drug Evaluation Committee (ADEC) Pregnancy Category There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Methimazole in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Methimazole during labor and delivery. ### Nursing Mothers - The drug appears in human breast milk and its use is contraindicated in nursing mothers. ### Pediatric Use - Because of postmarketing reports of severe liver injury in pediatric patient treated with propylthiouracil, TAPAZOLE is the preferred choice when an antithyroid drug is required for a pediatric patient. ### Geriatic Use There is no FDA guidance on the use of Methimazole with respect to geriatric patients. ### Gender There is no FDA guidance on the use of Methimazole with respect to specific gender populations. ### Race There is no FDA guidance on the use of Methimazole with respect to specific racial populations. ### Renal Impairment There is no FDA guidance on the use of Methimazole in patients with renal impairment. ### Hepatic Impairment There is no FDA guidance on the use of Methimazole in patients with hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Methimazole in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Methimazole in patients who are immunocompromised. # Administration and Monitoring ### Administration - Oral ### Monitoring There is limited information regarding Monitoring of Methimazole in the drug label. # IV Compatibility There is limited information regarding IV Compatibility of Methimazole in the drug label. # Overdosage ## Acute Overdose ### Signs and Symptoms - Signs and Symptoms Symptoms may include nausea, vomiting, epigastric distress, headache, fever, joint pain, pruritus, and edema. Aplastic anemia (pancytopenia) or agranulocytosis may be manifested in hours to days. Less frequent events are hepatitis, nephritic syndrome, exfoliative dermatitis, neuropathies, and CNS stimulation or depression. Although not well studied, methimazole-induced agranulocytosis is generally associated with doses of 40 mg or more in patients older than 40 years of age. No information is available on the median lethal dose of the drug or the concentration of methimazole in biologic fluids associated with toxicity and/or death. ### Management - To obtain up-to-date information about the treatment of overdose, a good resource is your certified Regional Poison Control Center. Telephone numbers of certified poison control centers are listed in the “Physicians' Desk Reference (PDR)”. In managing overdosage, consider the possibility of multiple drug overdoses, interaction among drugs, and unusual drug kinetics in your patient. - Protect the patient's airway and support ventilation and perfusion. Meticulously monitor and maintain, within acceptable limits, the patient's vital signs, blood gases, serum electrolytes, etc. The patient's bone marrow function should be monitored. Absorption of drugs from the gastrointestinal tract may be decreased by giving activated charcoal, which, in many cases, is more effective than emesis or lavage; consider charcoal instead of or in addition to gastric emptying. Repeated doses of charcoal over time may hasten elimination of some drugs that have been absorbed. Safeguard the patient's airway when employing gastric emptying or charcoal. - Forced diuresis, peritoneal dialysis, hemodialysis, or charcoal hemoperfusion have not been established as beneficial for an overdose of methimazole. ## Chronic Overdose There is limited information regarding Chronic Overdose of Methimazole in the drug label. # Pharmacology ## Mechanism of Action - Methimazole inhibits the synthesis of thyroid hormones and thus is effective in the treatment of hyperthyroidism. The drug does not inactivate existing thyroxine and triiodothyronine that are stored in the thyroid or circulating in the blood nor does it interfere with the effectiveness of thyroid hormones given by mouth or by injection. - The actions and use of methimazole are similar to those of propylthiouracil. On a weight basis, the drug is at least 10 times as potent as propylthiouracil, but methimazole may be less consistent in action. ## Structure - Methimazole (1-methylimidazole-2-thiol) is a white, crystalline substance that is freely soluble in water. It differs chemically from the drugs of the thiouracil series primarily because it has a 5- instead of a 6-membered ring. - Each tablet contains 5 or 10 mg (43.8 or 87.6 µmol) methimazole, an orally administered antithyroid drug. - Each tablet also contains lactose monohydrate, magnesium stearate, potato starch, and talc. - The molecular weight is 114.17, and the molecular formula is C4H6N2S. The structural formula is as follows: ## Pharmacodynamics There is limited information regarding Pharmacodynamics of Methimazole in the drug label. ## Pharmacokinetics - Methimazole is readily absorbed from the gastrointestinal tract. It is metabolized rapidly and requires frequent administration. - Methimazole is excreted in the urine. - In laboratory animals, various regimens that continuously suppress thyroid function and thereby increase TSH secretion result in thyroid tissue hypertrophy. Under such conditions, the appearance of thyroid and pituitary neoplasms has also been reported. Regimens that have been studied in this regard include antithyroid agents as well as dietary iodine deficiency, subtotal thyroidectomy, implantation of autonomous thyrotropic hormone-secreting pituitary tumors, and administration of chemical goitrogens. ## Nonclinical Toxicology - In a 2 year study, rats were given methimazole at doses of 0.5, 3, and 18 mg/kg/day. These doses were 0.3, 2, and 12 times the 15 mg/day maximum human maintenance dose (when calculated on the basis of surface area). Thyroid hyperplasia, adenoma, and carcinoma developed in rats at the two higher doses. The clinical significance of these findings is unclear. # Clinical Studies There is limited information regarding Clinical Studies of Methimazole in the drug label. # How Supplied - Methimazole Tablets, USP 5 mg white, round, flat-faced, bevelled-edged tablets with “VM” on one side and scored on the other. - They are available in: - Bottles of 100 NDC 0677-1945-01 - Methimazole Tablets, USP 10 mg white, round, flat-faced, bevelled-edged tablets with “XM” on one side and scored on the other. - They are available in: - Bottles of 100 NDC 0677-1946-01 - Store at controlled room temperature, 20°- 25°C (68°- 77°F). - Dispense in tight, light-resistant container. ## Storage There is limited information regarding Methimazole 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 Methimazole in the drug label. # Precautions with Alcohol - Alcohol-Methimazole interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - TAPAZOLE® # Look-Alike Drug Names - methimazole® — metolazone® # Drug Shortage Status # Price	Methimazole 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 Methimazole is an antithyroid agent that is FDA approved for the {{{indicationType}}} of hyperthyroidism. Common adverse reactions include skin rash, urticaria, nausea, vomiting, epigastric distress, arthralgia, paresthesia, loss of taste, abnormal loss of hair, myalgia, headache, pruritus, drowsiness, neuritis, edema, vertigo, skin pigmentation, jaundice, sialadenopathy, and lymphadenopathy. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) - Methimazole is indicated in the medical treatment of hyperthyroidism. Long-term therapy may lead to remission of the disease. - Methimazole may be used to ameliorate hyperthyroidism in preparation for subtotal thyroidectomy or radioactive iodine therapy. - Methimazole is also used when thyroidectomy is contraindicated or not advisable. - Methimazole is administered orally. It is usually given in 3 equal doses at approximately 8-hour intervals. - The initial daily dosage is 15 mg for mild hyperthyroidism, 30 to 40 mg for moderately severe hyperthyroidism, and 60 mg for severe hyperthyroidism, divided into 3 doses at 8-hour intervals. The maintenance dosage is 5 to 15 mg daily. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Methimazole in adult patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Methimazole in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) - Dosing Information - Initially, the daily dosage is 0.4 mg/kg of body weight divided into 3 doses and given at 8-hour intervals. The maintenance dosage is approximately 1/2 of the initial dose. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Methimazole in pediatric patients. ### Non–Guideline-Supported Use - Dosing Information - Methimazole 0.5 milligrams/kilogram body mass in 2 doses. # Contraindications - Methimazole is contraindicated in the presence of hypersensitivity to the drug and in nursing mothers because the drug is excreted in milk. # Warnings - Congenital Malformations - Methimazole readily crosses the placental membranes and can cause fetal harm, particularly when administered in the first trimester of pregnancy. Rare instances of congenital defects, including aplasia cutis, craniofacial malformations (facial dysmorphism; choanal atresia) and gastrointestinal malformations (esophageal atresia with or without tracheoesophageal fistula; umbilical abnormalities) have occurred in infants born to mothers who received TAPAZOLE during pregnancy. If TAPAZOLE is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be warned of the potential hazard to the fetus. - Since the above congenital defects have been reported in offspring of patients treated with TAPAZOLE, it may be appropriate to use other agents in pregnant women requiring treatment for hyperthyroidism, particularly during organogenesis, in the first trimester of pregnancy. If TAPAZOLE is used, the lowest possible dose to control the maternal disease should be given. - Agranulocytosis - Agranulocytosis is potentially a life-threatening adverse reaction of TAPAZOLE therapy. Patients should be instructed to immediately report to their physicians any symptoms suggestive of agranulocytosis, such as fever or sore throat. Leukopenia, thrombocytopenia, and aplastic anemia (pancytopenia) may also occur. The drug should be discontinued in the presence of agranulocytosis, aplastic anemia (pancytopenia), ANCA-positive vasculitis, hepatitis, or exfoliative dermatitis and the patient's bone marrow indices should be monitored. - Liver Toxicity - Although there have been reports of hepatotoxicity (including acute liver failure) associated with TAPAZOLE, the risk of hepatotoxicity appears to be less with methimazole than with propylthiouracil, especially in the pediatric population. Symptoms suggestive of hepatic dysfunction (anorexia, pruritis, right upper quadrant pain, etc.) should prompt evaluation of liver function (bilirubin, alkaline phosphatase) and hepatocellur integrity (ALT, AST). Drug treatment should be discontinued promptly in the event of clinically significant evidence of liver abnormality including hepatic transaminase values exceeding 3 times the upper limit of normal. - Hypothyroidism - TAPAZOLE can cause hypothyroidism necessitating routine monitoring of TSH and free T4 levels with adjustments in dosing to maintain a euthyroid state. Because the drug readily crosses placental membranes, methimazole can cause fetal goiter and cretinism when administered to a pregnant woman. For this reason, it is important that a sufficient, but not excessive, dose be given during pregnancy. ### Precautions - General - Patients who receive methimazole should be under close surveillance and should be cautioned to report immediately any evidence of illness, particularly sore throat, skin eruptions, fever, headache, or general malaise. In such cases, white-blood cell and differential counts should be made to determine whether agranulocytosis has developed. Particular care should be exercised with patients who are receiving additional drugs know to cause agranulocytosis. - Laboratory Tests - Because methimazole may cause hypoprothrombinemia and bleeding, prothrombin time should be monitored during therapy with the drug, especially before surgical procedures. - Periodic monitoring of thyroid function is warranted, and the finding of an elevated TSH warrants a decrease in the dosage of methimazole. # Adverse Reactions ## Clinical Trials Experience - Major adverse reactions (which occur with much less frequency than the minor adverse reactions) include inhibition of myelopoiesis (agranulocytosis, granulocytopenia, and thrombocytopenia), aplastic anemia, drug fever, a lupuslike syndrome, insulin autoimmune syndrome (which can result in hypoglycemic coma), hepatitis (jaundice may persist for several weeks after discontinuation of the drug), periarteritis, and hypoprothrombinemia. Nephritis occurs very rarely. - Minor adverse reactions include skin rash, urticaria, nausea, vomiting, epigastric distress, arthralgia, paresthesia, loss of taste, abnormal loss of hair, myalgia, headache, pruritus, drowsiness, neuritis, edema, vertigo, skin pigmentation, jaundice, sialadenopathy, and lymphadenopathy. - It should be noted that about 10% of patients with untreated hyperthyroidism have leukopenia (white-blood cell count of less than 4,000/mm3 ), often with relative granulopenia. ## Postmarketing Experience There is limited information regarding Postmarketing Experience of Methimazole in the drug label. # Drug Interactions - Anticoagulants (oral) - The activity of oral anticoagulants may be potentiated by anti-vitamin-K activity attributed to methimazole. - ß-adrenergic blocking agents - Hyperthyroidism may cause an increased clearance of beta blockers with a high extraction ratio. A dose reduction of beta-adrenergic blockers may be needed when a hyperthyroid patient becomes euthyroid. - Digitalis glycosides - Serum digitalis levels may be increased when hyperthyroid patients on a stable digitalis glycoside regimen become euthyroid; a reduced dosage of digitalis glycosides may be required. - Theophylline - Theophylline clearance may decrease when hyperthyroid patients on a stable theophylline regimen become euthyroid; a reduced dose of theophylline may be needed. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): - Pregnancy Category D - Methimazole used judiciously is an effective drug in hyperthyroidism complicated by pregnancy. In many pregnant women, the thyroid dysfunction diminishes as the pregnancy proceeds; consequently, a reduction in dosage may be possible. In some instances, use of methimazole can be discontinued 2 or 3 weeks before delivery. Pregnancy Category (AUS): - Australian Drug Evaluation Committee (ADEC) Pregnancy Category There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Methimazole in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Methimazole during labor and delivery. ### Nursing Mothers - The drug appears in human breast milk and its use is contraindicated in nursing mothers. ### Pediatric Use - Because of postmarketing reports of severe liver injury in pediatric patient treated with propylthiouracil, TAPAZOLE is the preferred choice when an antithyroid drug is required for a pediatric patient. ### Geriatic Use There is no FDA guidance on the use of Methimazole with respect to geriatric patients. ### Gender There is no FDA guidance on the use of Methimazole with respect to specific gender populations. ### Race There is no FDA guidance on the use of Methimazole with respect to specific racial populations. ### Renal Impairment There is no FDA guidance on the use of Methimazole in patients with renal impairment. ### Hepatic Impairment There is no FDA guidance on the use of Methimazole in patients with hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Methimazole in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Methimazole in patients who are immunocompromised. # Administration and Monitoring ### Administration - Oral ### Monitoring There is limited information regarding Monitoring of Methimazole in the drug label. # IV Compatibility There is limited information regarding IV Compatibility of Methimazole in the drug label. # Overdosage ## Acute Overdose ### Signs and Symptoms - Signs and Symptoms Symptoms may include nausea, vomiting, epigastric distress, headache, fever, joint pain, pruritus, and edema. Aplastic anemia (pancytopenia) or agranulocytosis may be manifested in hours to days. Less frequent events are hepatitis, nephritic syndrome, exfoliative dermatitis, neuropathies, and CNS stimulation or depression. Although not well studied, methimazole-induced agranulocytosis is generally associated with doses of 40 mg or more in patients older than 40 years of age. No information is available on the median lethal dose of the drug or the concentration of methimazole in biologic fluids associated with toxicity and/or death. ### Management - To obtain up-to-date information about the treatment of overdose, a good resource is your certified Regional Poison Control Center. Telephone numbers of certified poison control centers are listed in the “Physicians' Desk Reference (PDR)”. In managing overdosage, consider the possibility of multiple drug overdoses, interaction among drugs, and unusual drug kinetics in your patient. - Protect the patient's airway and support ventilation and perfusion. Meticulously monitor and maintain, within acceptable limits, the patient's vital signs, blood gases, serum electrolytes, etc. The patient's bone marrow function should be monitored. Absorption of drugs from the gastrointestinal tract may be decreased by giving activated charcoal, which, in many cases, is more effective than emesis or lavage; consider charcoal instead of or in addition to gastric emptying. Repeated doses of charcoal over time may hasten elimination of some drugs that have been absorbed. Safeguard the patient's airway when employing gastric emptying or charcoal. - Forced diuresis, peritoneal dialysis, hemodialysis, or charcoal hemoperfusion have not been established as beneficial for an overdose of methimazole. ## Chronic Overdose There is limited information regarding Chronic Overdose of Methimazole in the drug label. # Pharmacology ## Mechanism of Action - Methimazole inhibits the synthesis of thyroid hormones and thus is effective in the treatment of hyperthyroidism. The drug does not inactivate existing thyroxine and triiodothyronine that are stored in the thyroid or circulating in the blood nor does it interfere with the effectiveness of thyroid hormones given by mouth or by injection. - The actions and use of methimazole are similar to those of propylthiouracil. On a weight basis, the drug is at least 10 times as potent as propylthiouracil, but methimazole may be less consistent in action. ## Structure - Methimazole (1-methylimidazole-2-thiol) is a white, crystalline substance that is freely soluble in water. It differs chemically from the drugs of the thiouracil series primarily because it has a 5- instead of a 6-membered ring. - Each tablet contains 5 or 10 mg (43.8 or 87.6 µmol) methimazole, an orally administered antithyroid drug. - Each tablet also contains lactose monohydrate, magnesium stearate, potato starch, and talc. - The molecular weight is 114.17, and the molecular formula is C4H6N2S. The structural formula is as follows: ## Pharmacodynamics There is limited information regarding Pharmacodynamics of Methimazole in the drug label. ## Pharmacokinetics - Methimazole is readily absorbed from the gastrointestinal tract. It is metabolized rapidly and requires frequent administration. - Methimazole is excreted in the urine. - In laboratory animals, various regimens that continuously suppress thyroid function and thereby increase TSH secretion result in thyroid tissue hypertrophy. Under such conditions, the appearance of thyroid and pituitary neoplasms has also been reported. Regimens that have been studied in this regard include antithyroid agents as well as dietary iodine deficiency, subtotal thyroidectomy, implantation of autonomous thyrotropic hormone-secreting pituitary tumors, and administration of chemical goitrogens. ## Nonclinical Toxicology - In a 2 year study, rats were given methimazole at doses of 0.5, 3, and 18 mg/kg/day. These doses were 0.3, 2, and 12 times the 15 mg/day maximum human maintenance dose (when calculated on the basis of surface area). Thyroid hyperplasia, adenoma, and carcinoma developed in rats at the two higher doses. The clinical significance of these findings is unclear. # Clinical Studies There is limited information regarding Clinical Studies of Methimazole in the drug label. # How Supplied - Methimazole Tablets, USP 5 mg white, round, flat-faced, bevelled-edged tablets with “VM” on one side and scored on the other. - They are available in: - Bottles of 100 NDC 0677-1945-01 - Methimazole Tablets, USP 10 mg white, round, flat-faced, bevelled-edged tablets with “XM” on one side and scored on the other. - They are available in: - Bottles of 100 NDC 0677-1946-01 - Store at controlled room temperature, 20°- 25°C (68°- 77°F). - Dispense in tight, light-resistant container. ## Storage There is limited information regarding Methimazole 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 Methimazole in the drug label. # Precautions with Alcohol - Alcohol-Methimazole interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - TAPAZOLE®[2] # Look-Alike Drug Names - methimazole® — metolazone®[3] # Drug Shortage Status # Price	https://www.wikidoc.org/index.php/Methimazole
303416438109d47b2f32d1bd9d1d3e73fea6f388	wikidoc	Methyl blue	Methyl blue Methyl blue, also known as Cotton blue, Helvetia blue, Acid blue 93, or C.I. 42780, is a chemical compound with the molecular formula C37H27N3Na2O9S3. It is used as a stain in histology. Methyl blue stains collagen blue in tissue sections. It is soluble in water and slightly soluble in ethanol. It can be used in the Mallory's connective tissue stain and Gomori's one-step trichrome stain. It is used in differential staining. It can also be used to mediate electron transfer in microbial fuel cells. Methyl blue is also available in mixture with water blue, under name Aniline Blue WS, Aniline blue, China blue, or Soluble blue. Methyl blue should not be confused with methyl violet or methylene blue, two other stains. Methyl blue is also used to treat thallium poisoning. It binds to the thallium. ==External links==	Methyl blue Template:Chembox new Methyl blue, also known as Cotton blue, Helvetia blue, Acid blue 93, or C.I. 42780, is a chemical compound with the molecular formula C37H27N3Na2O9S3. It is used as a stain in histology. Methyl blue stains collagen blue in tissue sections. It is soluble in water and slightly soluble in ethanol. It can be used in the Mallory's connective tissue stain and Gomori's one-step trichrome stain. It is used in differential staining. It can also be used to mediate electron transfer in microbial fuel cells. Methyl blue is also available in mixture with water blue, under name Aniline Blue WS, Aniline blue, China blue, or Soluble blue. Methyl blue should not be confused with methyl violet or methylene blue, two other stains. Methyl blue is also used to treat thallium poisoning. It binds to the thallium. ==External links== Template:WH Template:WikiDoc Sources	https://www.wikidoc.org/index.php/Methyl_blue
147b288230c1fdf029578a970267aa984002c0c1	wikidoc	Methylamine	Methylamine Methylamine is the chemical compound with a formula of CH3NH2. It is a derivative of ammonia, wherein one H atom is replaced by a methyl group. It is the simplest primary amine. It is usually sold as solutions in methanol (2M), ethanol (8M), THF (2M), and water (40%), or as the anhydrous gas in pressurized metal containers. It has a strong odour similar to rotten fish. Methylamine is used as a building block for the synthesis of other organic compounds. It is on the DEA watchlist for chemical precursors because of clandestine use in manufacture of the drug MDMA (ecstasy) and methamphetamine. # Chemistry Methylamine is a good nucleophile as it is highly basic and unhindered. Its use in organic chemistry is pervasive. For example, it is a precursor to CH3NCS. The hydrochloride salt of methylamine, methylammonium chloride, CH3NH3Cl, is a colourless powder that can be converted to the amine. Although methylamine is a gas at room temperature, liquid methylamine can be used as a solvent analogous to liquid ammonia. It shares some of the properties of liquid ammonia, but is better for dissolving organic substances, in the same way that methanol is better than water. # Production Methylamine is prepared commercially by the reaction of ammonia with methanol with zeolite as catalyst. CH3OH + NH3 → CH3NH2 + H2O It can also be readily prepared by the reaction of hydrochloric acid with hexamine or by the reaction of formaldehyde with ammonium chloride. NH4Cl + H2CO → CH2NH·HCl + H2O CH2NH·HCl + H2CO + H2O → CH3NH2 + HCOOH Methylamine serves as a buffering agent in the lumen of the chloroplast in plants, effectively siphoning off protons that are heading for ATP synthase.	Methylamine Template:Chembox new Methylamine is the chemical compound with a formula of CH3NH2. It is a derivative of ammonia, wherein one H atom is replaced by a methyl group. It is the simplest primary amine. It is usually sold as solutions in methanol (2M), ethanol (8M), THF (2M), and water (40%), or as the anhydrous gas in pressurized metal containers. It has a strong odour similar to rotten fish. Methylamine is used as a building block for the synthesis of other organic compounds. It is on the DEA watchlist for chemical precursors because of clandestine use in manufacture of the drug MDMA (ecstasy) and methamphetamine. # Chemistry Methylamine is a good nucleophile as it is highly basic and unhindered. Its use in organic chemistry is pervasive. For example, it is a precursor to CH3NCS.[1] The hydrochloride salt of methylamine, methylammonium chloride, CH3NH3Cl, is a colourless powder that can be converted to the amine. Although methylamine is a gas at room temperature, liquid methylamine can be used as a solvent analogous to liquid ammonia. It shares some of the properties of liquid ammonia, but is better for dissolving organic substances, in the same way that methanol is better than water.[2] # Production Methylamine is prepared commercially by the reaction of ammonia with methanol with zeolite as catalyst.[3] CH3OH + NH3 → CH3NH2 + H2O It can also be readily prepared by the reaction of hydrochloric acid with hexamine or by the reaction of formaldehyde with ammonium chloride.[4] NH4Cl + H2CO → CH2NH·HCl + H2O CH2NH·HCl + H2CO + H2O → CH3NH2 + HCOOH Methylamine serves as a buffering agent in the lumen of the chloroplast in plants, effectively siphoning off protons that are heading for ATP synthase.[citation needed]	https://www.wikidoc.org/index.php/Methylamine
09a8e7633a889c566d518fb8c31bf6b0ca15fa31	wikidoc	Methylation	Methylation Methylation is a term used in the chemical sciences to denote the attachment or substitution of a methyl group on various substrates. This term is commonly used in chemistry, biochemistry, and the biological sciences. In biochemistry, methylation more specifically refers to the replacement of a hydrogen atom with the methyl group. In biological systems, methylation is catalyzed by enzymes; such methylation can be involved in modification of heavy metals, regulation of gene expression, regulation of protein function, and RNA metabolism. Methylation of heavy metals can also occur outside of biological systems. Chemical methylation of tissue samples is also one method for reducing certain histological staining artifacts. # Biological methylation ## Epigenetics Methylation contributing to epigenetic inheritance can occur either through DNA methylation or protein methylation. DNA methylation in vertebrates typically occurs at CpG sites (cytosine-phosphate-guanine sites; that is, where a cytosine is directly followed by a guanine in the DNA sequence); this methylation results in the conversion of the cytosine to 5-methylcytosine. The formation of Me-CpG is catalyzed by the enzyme DNA methyltransferase. CpG sites are uncommon in vertebrate genomes but are often found at higher density near vertebrate gene promoters where they are collectively referred to as CpG islands. The methylation state of these CpG sites can have a major impact on gene activity/expression. Protein methylation typically takes place on arginine or lysine amino acid residues in the protein sequence. Arginine can be methylated once (monomethylated arginine) or twice, with either both methyl groups on one terminal nitrogen (asymmetric dimethylated arginine) or one on both nitrogens (symmetric dimethylated arginine) by peptidylarginine methyltransferases (PRMTs). Lysine can be methylated once, twice or three times by lysine methyltransferases. Protein methylation has been most well studied in the histones. The transfer of methyl groups from S-adenosyl methionine to histones is catalyzed by enzymes known as histone methyltransferases. Histones which are methylated on certain residues can act epigenetically to repress or activate "gene" expression. Protein methylation is one type of post-translational modification. ## Embryonic development In early development (fertilization to 8-cell stage), the eukaryotic genome is demethylated. From the 8-cell stage to the morula, de novo methylation of the genome occurs, modifying and adding epigenetic information to the genome. By blastula stage, the methylation is complete. This process is referred to as "epigenetic reprogramming". The importance of methylation was shown in knockout mutants without DNA methyltransferase. All the resulting embryos died at the morula stage. ## Methylation in postnatal development Increasing evidence is revealing a role of methylation in the interaction of environmental factors with genetic expression. Differences in maternal care during the first 6 days of life in the rat induce differential methylation patterns in some promoter regions and thus influencing gene expression (Weaver IC; et al. (Aug 2004; epub Jun 27 2004). "Epigenetic programming by maternal behavior". Nature Neuroscience. 7(8): 791–92. Check date values in: \|year= (help)CS1 maint: Explicit use of et al. 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Furthermore, even more dynamic processes such as interleukin signaling have been shown to be regulated by methylation (Bird A. (Mar 2003). "Il2 transcription unleashed by active DNA demethylation". Nature Immunology. 4(3): 208–9.). ## Methylation and cancer The pattern of methylation has recently become an important topic for research. Studies have found that in normal tissue, methylation of a gene is mainly localised to the coding region, which is CpG poor. In contrast, the promoter region of the gene is unmethylated, despite a high density of CpG islands in the region. Neoplasia is characterized by "methylation imbalance" where genome-wide hypomethylation is accompanied by localized hypermethylation and an increase in expression of DNA methyltransferase (1). The overall methylation state in a cell might also be a precipitating factor in carcinogenesis as evidence suggests that genome-wide hypomethylation can lead to chromosome instability and increased mutation rates (3). The methylation state of some genes can be used as a biomarker for tumorigenesis. For instance, hypermethylation of the pi-class glutathione S-transferase gene (GSTP1) appears to be a promising diagnostic indicator of prostate cancer (2). In cancer, the dynamics of genetic and epigenetic gene silencing are very different. Somatic genetic mutation leads to a block in the production of functional protein from the mutant allele. If a selective advantage is conferred to the cell, the cells expand clonally to give rise to a tumor in which all cells lack the capacity to produce protein. In contrast, epigenetically mediated gene silencing occurs gradually. It begins with a subtle decrease in transcription, fostering a decrease in protection of the CpG island from the spread of flanking heterochromatin and methylation into the island. This loss results in gradual increases of individual CpG sites, which vary between copies of the same gene in different cells (6). ## Methylation and bacterial host defense Additionally, adenosine or cytosine methylation is part of the restriction modification system of many bacteria. Bacterial DNAs are methylated periodically throughout the genome. A methylase is the enzyme that recognizes a specific sequence and methylates one of the bases in or near that sequence. Foreign DNAs (which are not methylated in this manner) that are introduced into the cell are degraded by sequence-specific restriction enzymes. Bacterial genomic DNA is not recognized by these restriction enzymes. The methylation of native DNA acts as a sort of primitive immune system, allowing the bacteria to protect themselves from infection by bacteriophage or phage. These restriction enzymes are the basis of restriction fragment length polymorphism (RFLP) testing. With this technique, geneticists use various bacterial restriction endonucleases (restriction enzymes) to split DNA at specific sites in order to detect DNA polymorphisms, useful for genetic fingerprinting and genetic engineering. # Methylation in chemistry The term methylation in organic chemistry refers to the alkylation process used to describe the delivery of a CH3 group. This is commonly performed using electrophilic methyl sources - iodomethane, dimethyl sulfate, dimethyl carbonate, or less commonly with the more powerful (and more dangerous) methylating reagents of methyl triflate or methyl fluorosulfonate (magic methyl), which all react via SN2 nucleophilic substitution. For example a carboxylate may be methylated on oxygen to give a methyl ester, an alkoxide salt RO− may be likewise methylated to give an ether, ROCH3, or a ketone enolate may be methylated on carbon to produce a new ketone. Methylation of a carboxylic acid salt and a phenol using iodomethane Alternatively, the methylation may involve use of nucleophilic methyl compounds such as methyllithium (CH3Li) or Grignard reagents (CH3MgX). For example, CH3Li will methylate acetone, adding across the carbonyl (C=O) to give the lithium alkoxide of tert-butanol: Methylation of acetone by methyl lithium	Methylation Methylation is a term used in the chemical sciences to denote the attachment or substitution of a methyl group on various substrates. This term is commonly used in chemistry, biochemistry, and the biological sciences. In biochemistry, methylation more specifically refers to the replacement of a hydrogen atom with the methyl group. In biological systems, methylation is catalyzed by enzymes; such methylation can be involved in modification of heavy metals, regulation of gene expression, regulation of protein function, and RNA metabolism. Methylation of heavy metals can also occur outside of biological systems. Chemical methylation of tissue samples is also one method for reducing certain histological staining artifacts. # Biological methylation ## Epigenetics Methylation contributing to epigenetic inheritance can occur either through DNA methylation or protein methylation. DNA methylation in vertebrates typically occurs at CpG sites (cytosine-phosphate-guanine sites; that is, where a cytosine is directly followed by a guanine in the DNA sequence); this methylation results in the conversion of the cytosine to 5-methylcytosine. The formation of Me-CpG is catalyzed by the enzyme DNA methyltransferase. CpG sites are uncommon in vertebrate genomes but are often found at higher density near vertebrate gene promoters where they are collectively referred to as CpG islands. The methylation state of these CpG sites can have a major impact on gene activity/expression. Protein methylation typically takes place on arginine or lysine amino acid residues in the protein sequence. Arginine can be methylated once (monomethylated arginine) or twice, with either both methyl groups on one terminal nitrogen (asymmetric dimethylated arginine) or one on both nitrogens (symmetric dimethylated arginine) by peptidylarginine methyltransferases (PRMTs). Lysine can be methylated once, twice or three times by lysine methyltransferases. Protein methylation has been most well studied in the histones. The transfer of methyl groups from S-adenosyl methionine to histones is catalyzed by enzymes known as histone methyltransferases. Histones which are methylated on certain residues can act epigenetically to repress or activate "gene" expression. Protein methylation is one type of post-translational modification. ## Embryonic development In early development (fertilization to 8-cell stage), the eukaryotic genome is demethylated. From the 8-cell stage to the morula, de novo methylation of the genome occurs, modifying and adding epigenetic information to the genome. By blastula stage, the methylation is complete. This process is referred to as "epigenetic reprogramming". The importance of methylation was shown in knockout mutants without DNA methyltransferase. All the resulting embryos died at the morula stage. ## Methylation in postnatal development Increasing evidence is revealing a role of methylation in the interaction of environmental factors with genetic expression. Differences in maternal care during the first 6 days of life in the rat induce differential methylation patterns in some promoter regions and thus influencing gene expression (Weaver IC; et al. (Aug 2004; epub Jun 27 2004). "Epigenetic programming by maternal behavior". Nature Neuroscience. 7(8): 791–92. Check date values in: \|year= (help)CS1 maint: Explicit use of et al. 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Furthermore, even more dynamic processes such as interleukin signaling have been shown to be regulated by methylation (Bird A. (Mar 2003). "Il2 transcription unleashed by active DNA demethylation". Nature Immunology. 4(3): 208–9.). ## Methylation and cancer The pattern of methylation has recently become an important topic for research. Studies have found that in normal tissue, methylation of a gene is mainly localised to the coding region, which is CpG poor. In contrast, the promoter region of the gene is unmethylated, despite a high density of CpG islands in the region. Neoplasia is characterized by "methylation imbalance" where genome-wide hypomethylation is accompanied by localized hypermethylation and an increase in expression of DNA methyltransferase (1). The overall methylation state in a cell might also be a precipitating factor in carcinogenesis as evidence suggests that genome-wide hypomethylation can lead to chromosome instability and increased mutation rates (3). The methylation state of some genes can be used as a biomarker for tumorigenesis. For instance, hypermethylation of the pi-class glutathione S-transferase gene (GSTP1) appears to be a promising diagnostic indicator of prostate cancer (2). In cancer, the dynamics of genetic and epigenetic gene silencing are very different. Somatic genetic mutation leads to a block in the production of functional protein from the mutant allele. If a selective advantage is conferred to the cell, the cells expand clonally to give rise to a tumor in which all cells lack the capacity to produce protein. In contrast, epigenetically mediated gene silencing occurs gradually. It begins with a subtle decrease in transcription, fostering a decrease in protection of the CpG island from the spread of flanking heterochromatin and methylation into the island. This loss results in gradual increases of individual CpG sites, which vary between copies of the same gene in different cells (6). ## Methylation and bacterial host defense Additionally, adenosine or cytosine methylation is part of the restriction modification system of many bacteria. Bacterial DNAs are methylated periodically throughout the genome. A methylase is the enzyme that recognizes a specific sequence and methylates one of the bases in or near that sequence. Foreign DNAs (which are not methylated in this manner) that are introduced into the cell are degraded by sequence-specific restriction enzymes. Bacterial genomic DNA is not recognized by these restriction enzymes. The methylation of native DNA acts as a sort of primitive immune system, allowing the bacteria to protect themselves from infection by bacteriophage or phage. These restriction enzymes are the basis of restriction fragment length polymorphism (RFLP) testing. With this technique, geneticists use various bacterial restriction endonucleases (restriction enzymes) to split DNA at specific sites in order to detect DNA polymorphisms, useful for genetic fingerprinting and genetic engineering. # Methylation in chemistry The term methylation in organic chemistry refers to the alkylation process used to describe the delivery of a CH3 group. This is commonly performed using electrophilic methyl sources - iodomethane, dimethyl sulfate, dimethyl carbonate, or less commonly with the more powerful (and more dangerous) methylating reagents of methyl triflate or methyl fluorosulfonate (magic methyl), which all react via SN2 nucleophilic substitution. For example a carboxylate may be methylated on oxygen to give a methyl ester, an alkoxide salt RO− may be likewise methylated to give an ether, ROCH3, or a ketone enolate may be methylated on carbon to produce a new ketone. Methylation of a carboxylic acid salt and a phenol using iodomethane Alternatively, the methylation may involve use of nucleophilic methyl compounds such as methyllithium (CH3Li) or Grignard reagents (CH3MgX). For example, CH3Li will methylate acetone, adding across the carbonyl (C=O) to give the lithium alkoxide of tert-butanol: Methylation of acetone by methyl lithium	https://www.wikidoc.org/index.php/Methylation
b790689452657182e51ae3b0e46c7f0966f287a6	wikidoc	Methyprylon	Methyprylon Methyprylon (Noludar) is a sedative of the piperidinedione derivative family developed by Hoffmann-La Roche. This medicine was used for treating insomnia, but is now rarely used as it has been replaced by newer drugs with fewer side effects, such as benzodiazepines. Methyprylon was withdrawn from the US market in June 1989 and the Canadian market in September 1990. Some other trade names are Noctan and Dimerin. # Adverse effects Side effects can include skin rash, fever, depression, ulcers or sores in mouth or throat, unusual bleeding or bruising, confusion, fast heartbeat, respiratory depression, swelling of feet or lower legs, dizziness, drowsiness, headache, double vision, clumsiness, constipation, diarrhea, nausea, vomiting, unusual weakness. # Pharmacokinetics A study of single oral doses of 300 mg in healthy volunteers found that the zero-order absorption model fit the data best. Mean (+/- SD) values for the half-life (9.2 +/- 2.2 h), apparent clearance, (11.91 +/- 4.42 mL/h/kg) and apparent steady-state volume of distribution, (0.97 +/- 0.33 L/kg) were found. A case report found that the pharmacokinetics of methyprylon were not concentration dependent in an overdose case; explanations included saturation or inhibition of metabolic pathways. The generally accepted half-life for a therapeutic dose was not found appropriate in intoxicated patients and would underestimate the time required to reach a safe concentration of the drug.	Methyprylon Methyprylon (Noludar) is a sedative of the piperidinedione derivative family developed by Hoffmann-La Roche.[1] This medicine was used for treating insomnia, but is now rarely used as it has been replaced by newer drugs with fewer side effects, such as benzodiazepines.[2] Methyprylon was withdrawn from the US market in June 1989 and the Canadian market in September 1990. Some other trade names are Noctan and Dimerin. # Adverse effects Side effects can include skin rash, fever, depression, ulcers or sores in mouth or throat, unusual bleeding or bruising, confusion, fast heartbeat, respiratory depression, swelling of feet or lower legs, dizziness, drowsiness, headache, double vision, clumsiness, constipation, diarrhea, nausea, vomiting, unusual weakness.[citation needed] # Pharmacokinetics A study of single oral doses of 300 mg in healthy volunteers found that the zero-order absorption model fit the data best. Mean (+/- SD) values for the half-life (9.2 +/- 2.2 h), apparent clearance, (11.91 +/- 4.42 mL/h/kg) and apparent steady-state volume of distribution, (0.97 +/- 0.33 L/kg) were found.[3] A case report found that the pharmacokinetics of methyprylon were not concentration dependent in an overdose case; explanations included saturation or inhibition of metabolic pathways. The generally accepted half-life for a therapeutic dose was not found appropriate in intoxicated patients and would underestimate the time required to reach a safe concentration of the drug.[4]	https://www.wikidoc.org/index.php/Methyprylon

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