Source:http://www4.wiwiss.fu-berlin.de/dailymed/resource/drugs/677
| Subject | Predicate | Object | Context |
|---|---|---|---|
| dailymed-drugs:677 | rdf:type | http://www4.wiwiss.fu-berli... | lld:dailymed |
| dailymed-drugs:677 | rdf:type | dailymed-instance:drugs | lld:dailymed |
| dailymed-drugs:677 | rdfs:label | leflunomide (Tablet, Film Coated) | lld:dailymed |
| dailymed-drugs:677 | dailymed-instance:dosage | 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 (ARAVA) tablet* per day for 3 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. .<br/>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. Liver enzymes must be monitored and dose adjustments may be necessary . 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. | lld:dailymed |
| dailymed-drugs:677 | dailymed-instance:descripti... | Leflunomide is a pyrimidine synthesis inhibitor. The chemical name for leflunomide is N-(4'-trifluoromethylphenyl)-5-methylisoxazole-4-carboxamide. It has an empirical formula CHFNO, a molecular weight of 270.2 and the following structural formula: Leflunomide is available for oral administration as tablets containing 10 or 20 mg of active drug. Combined with leflunomide are the following inactive ingredients: colloidal silicon dioxide, crospovidone, hypromellose, lactose monohydrate, magnesium stearate, polyethylene glycol, povidone, starch, talc, titanium dioxide, and yellow ferric oxide (20 mg tablet only). | lld:dailymed |
| dailymed-drugs:677 | dailymed-instance:clinicalP... | 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.<br/>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.<br/>Absorption: Following oral administration, peak levels of the active metabolite, M1, occurred between 6���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.<br/>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.<br/>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.<br/>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% waseliminated 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.<br/>Special Populations:<br/>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���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. . | lld:dailymed |
| dailymed-drugs:677 | dailymed-instance:activeIng... | dailymed-ingredient:lefluno... | lld:dailymed |
| dailymed-drugs:677 | dailymed-instance:supply | Leflunomide tablets in 10 and 20 mg strengths are packaged in bottles. Store at 25��C (77��F); excursions permitted to 15���30��C (59���86��F) [see USP Controlled Room Temperature]. Protect from light. *100 mg leflunomide (ARAVA) tablets are available through sanofi-aventis U.S. LLC. Revised February 2007 Manufactured by:sanofi-aventis U.S. LLCBridgewater, NJ 08807 10 and 20 mg tablets manufactured for:Prasco LaboratoriesCincinnati, OH 45249 ARAVA is a registered trademark of sanofi-aventis U.S. LLC | lld:dailymed |
| dailymed-drugs:677 | dailymed-instance:genericDr... | http://www4.wiwiss.fu-berli... | lld:dailymed |
| dailymed-drugs:677 | dailymed-instance:boxedWarn... | CONTRAINDICATIONS AND WARNINGS: PREGNANCY MUST BE EXCLUDED BEFORE THE START OF TREATMENT WITH LEFLUNOMIDE. LEFLUNOMIDE IS CONTRAINDICATED IN PREGNANT WOMEN, OR WOMEN OF CHILDBEARING POTENTIAL WHO ARE NOT USING RELIABLE CONTRACEPTION. PREGNANCY MUST BE AVOIDED DURING LEFLUNOMIDE TREATMENT OR PRIOR TO THE COMPLETION OF THE DRUG ELIMINATION PROCEDURE AFTER LEFLUNOMIDE TREATMENT. | lld:dailymed |
| dailymed-drugs:677 | dailymed-instance:activeMoi... | dailymed-ingredient:lefluno... | lld:dailymed |
| dailymed-drugs:677 | dailymed-instance:inactiveI... | dailymed-ingredient:magnesi... | lld:dailymed |
| dailymed-drugs:677 | dailymed-instance:inactiveI... | dailymed-ingredient:povidon... | lld:dailymed |
| dailymed-drugs:677 | dailymed-instance:inactiveI... | dailymed-ingredient:hyprome... | lld:dailymed |
| dailymed-drugs:677 | dailymed-instance:inactiveI... | dailymed-ingredient:starch | lld:dailymed |
| dailymed-drugs:677 | dailymed-instance:inactiveI... | dailymed-ingredient:titaniu... | lld:dailymed |
| dailymed-drugs:677 | dailymed-instance:inactiveI... | dailymed-ingredient:crospov... | lld:dailymed |
| dailymed-drugs:677 | dailymed-instance:inactiveI... | dailymed-ingredient:lactose... | lld:dailymed |
| dailymed-drugs:677 | dailymed-instance:inactiveI... | dailymed-ingredient:talc | lld:dailymed |
| dailymed-drugs:677 | dailymed-instance:inactiveI... | dailymed-ingredient:polyeth... | lld:dailymed |
| dailymed-drugs:677 | dailymed-instance:inactiveI... | dailymed-ingredient:colloid... | lld:dailymed |
| dailymed-drugs:677 | dailymed-instance:possibleD... | diseasome-diseases:116 | lld:dailymed |
| dailymed-drugs:677 | dailymed-instance:possibleD... | diseasome-diseases:121 | lld:dailymed |
| dailymed-drugs:677 | dailymed-instance:possibleD... | diseasome-diseases:1498 | lld:dailymed |
| dailymed-drugs:677 | dailymed-instance:possibleD... | diseasome-diseases:1519 | lld:dailymed |
| dailymed-drugs:677 | dailymed-instance:overdosag... | In mouse and rat acute toxicology studies, the minimally toxic dose for oral leflunomide was 200���500 mg/kg and 100 mg/kg, respectively (approximately>350 times the maximum recommended human dose, respectively). 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. 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 mostfrequent adverse events observed were diarrhea, abdominal pain, leukopenia, anemia and elevated liver function tests. 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. . | lld:dailymed |
| dailymed-drugs:677 | dailymed-instance:genericMe... | leflunomide | lld:dailymed |
| dailymed-drugs:677 | dailymed-instance:fullName | leflunomide (Tablet, Film Coated) | lld:dailymed |
| dailymed-drugs:677 | dailymed-instance:adverseRe... | 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. Body as a Whole: abscess, cyst, fever, hernia, malaise, pain, neck pain, pelvic pain; Cardiovascular: angina pectoris, migraine, palpitation, tachycardia, varicose vein, vasculitis, vasodilatation; Gastrointestinal: cholelithiasis, colitis, constipation, esophagitis, flatulence, gastritis, gingivitis, melena, oral moniliasis, pharyngitis, salivary gland enlarged, stomatitis (or aphthous stomatitis), tooth disorder; Endocrine: diabetes mellitus, hyperthyroidism; Hemic and Lymphatic System: anemia (including iron deficiency anemia), ecchymosis; Metabolic and Nutritional: creatine phosphokinase increased, hyperglycemia, hyperlipidemia, peripheral edema; Musculo-Skeletal System: arthrosis, bone necrosis, bone pain, bursitis, muscle cramps, myalgia, tendon rupture; Nervous System: anxiety, depression, dry mouth, insomnia, neuralgia, neuritis, sleep disorder, sweating increased, vertigo; Respiratory System: asthma, dyspnea, epistaxis, lung disorder; Skin and Appendages: 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; Special Senses: blurred vision, cataract, conjunctivitis, eye disorder, taste perversion; Urogenital System: 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/mm(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. In post-marketing experience, the following have been reported rarely: Body as a whole: opportunistic infections, severe infections including sepsis that may be fatal; Gastrointestinal: pancreatitis; Hematologic: agranulocytosis, leukopenia, neutropenia, pancytopenia, thrombocytopenia; Hypersensitivity: angioedema; Hepatic: hepatitis, jaundice/cholestasis, severe liver injury such as hepatic failure and acute hepatic necrosis that may be fatal; Respiratory: interstitial lung disease, including interstitial pneumonitis and pulmonary fibrosis, which may be fatal; Nervous system: peripheral neuropathy; Skin and Appendages: erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis, vasculitis including cutaneous necrotizing vasculitis.<br/>Adverse Reactions (Pediatric Patients): The safety of leflunomide was studied in 74 patients with polyarticular course juvenile rheumatoid arthritis ranging in age from 3���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. | lld:dailymed |
| dailymed-drugs:677 | dailymed-instance:indicatio... | Leflunomide is indicated in adults for the treatment of active rheumatoid arthritis (RA): 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. . | lld:dailymed |
| dailymed-drugs:677 | dailymed-instance:represent... | http://www4.wiwiss.fu-berli... | lld:dailymed |
| dailymed-drugs:677 | dailymed-instance:routeOfAd... | http://www4.wiwiss.fu-berli... | lld:dailymed |
| dailymed-drugs:677 | dailymed-instance:name | leflunomide | lld:dailymed |
| http://www4.wiwiss.fu-berli... | dailymed-instance:producesD... | dailymed-drugs:677 | lld:dailymed |
| diseasome-diseases:116 | diseasome-instance:possible... | dailymed-drugs:677 | lld:diseasome |
| diseasome-diseases:121 | diseasome-instance:possible... | dailymed-drugs:677 | lld:diseasome |
| diseasome-diseases:1498 | diseasome-instance:possible... | dailymed-drugs:677 | lld:diseasome |
| diseasome-diseases:1519 | diseasome-instance:possible... | dailymed-drugs:677 | lld:diseasome |