Drug: Arava

ARAVA® (leflunomide) is a pyrimidine synthesis inhibitor. The chemical name for leflunomide is N-(4ยด-trifluoromethylphenyl)-5-methylisoxazole-4-carboxamide. It has an empirical formula C12H9F3N2O2, a molecular weight of 270.2 and the following structural formula: ARAVA is available for oral administration as tablets containing 10, 20, or 100 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).

Source: http://www.rxlist.com

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.) Table 9: Percentage Of Patients With Adverse Events ≥ 3% In Any Leflunomide Treated Group
  All RA Studies Placebo-Controlled Trials Active-Controlled Trials MN 301 and US 301 MN 302* LEF (N=1339)1 LEF (N=315) PBO (N=210) SSZ (N=133) MTX (N=182) LEF (N=501) MTX (N=498) BODY AS A WHOLE Allergic Reaction 2% 5% 2% 0% 6% 1% 2% Asthenia 3% 6% 4% 5% 6% 3% 3% Flu Syndrome 2% 4% 2% 0% 7% 0% 0% Infection, upper respiratory 4% 0% 0% 0% 0% 0% 0% Injury Accident 5% 7% 5% 3% 11% 6% 7% Pain Abdominal 2% 4% 2% 2% 5% 1% < 1% Pain Back 6% 5% 4% 4% 8% 6% 4% Pain 5% 6% 3% 4% 9% 8% 7% CARDIOVASCULAR Hypertension2 10% 9% 4% 4% 3% 10% 4% - New onset of hypertension 1% < 1% 0% 2% 2% < 1% Chest Pain 2% 4% 2% 2% 4% 1% 2% GASTROINTESTINAL Anorexia 3% 3% 2% 5% 2% 3% 3% Diarrhea 17% 27% 12% 10% 20% 22% 10% Dyspepsia 5% 10% 10% 9% 13% 6% 7% Gastroenteritis 3% 1% 1% 0% 6% 3% 3% Abnormal Liver Enzymes 5% 10% 2% 4% 10% 6% 17% Nausea 9% 13% 11% 19% 18% 13% 18% GI/Abdominal Pain 5% 6% 4% 7% 8% 8% 8% Mouth Ulcer 3% 5% 4% 3% 10% 3% 6% Vomiting 3% 5% 4% 4% 3% 3% 3% METABOLIC AND NUTRITIONAL Hypokalemia 1% 3% 1% 1% 1% 1% < 1% Weight Loss3 4% 2% 1% 2% 0% 2% 2% MUSCULO-SKELETAL SYSTEM Arthralgia 1% 4% 3% 0% 9% < 1% 1% Leg Cramps 1% 4% 2% 2% 6% 0% 0% Joint Disorder 4% 2% 2% 2% 2% 8% 6% Synovitis 2% < 1% 1% 0% 2% 4% 2% Tenosynovitis 3% 2% 0% 1% 2% 5% 1% NERVOUS SYSTEM Dizziness 4% 5% 3% 6% 5% 7% 6% Headache 7% 13% 11% 12% 21% 10% 8% Paresthesia 2% 3% 1% 1% 2% 4% 3% RESPIRATORY SYSTEM Bronchitis 7% 5% 2% 4% 7% 8% 7% Increased Cough 3% 4% 5% 3% 6% 5% 7% Respiratory 15% 21% 21% 20% 32% 27% 25% Infection 3% 2% 1% 2% 1% 3% 3% Pharyngitis 2% 3% 0% 0% 1% 2% 2% Pneumonia 2% 5% 2% 4% 3% 2% 2% Rhinitis Sinusitis 2% 5% 5% 0% 10% 1% 1% SKIN AND APPENDAGES Alopecia 10% 9% 1% 6% 6% 17% 10% Eczema 2% 1% 1% 1% 1% 3% 2% Pruritus 4% 5% 2% 3% 2% 6% 2% Rash 10% 12% 7% 11% 9% 11% 10% Dry Skin 2% 3% 2% 2% 0% 3% 1% UROGENITAL SYSTEM Urinary Tract Infection 5% 5% 7% 4% 2% 5% 6% * Only 10% of patients in MN302 received folate. All patients in US301 received folate; none in MN301 received folate.
1 Includes all controlled and uncontrolled trials with leflunomide (duration up to 12 months).
2 Hypertension as a preexisting condition was overrepresented in all leflunomide treatment groups in phase III trials
3 In a meta-analysis of all phase II and III studies, during the first 6 months in patients receiving leflunomide, 10% lost 10-19 lbs (24 cases per 100 patient years) and 2% lost at least 20 lbs (4 cases/100 patient years). Of patients receiving leflunomide, 4% lost 10% of their baseline weight during the first 6 months of treatment. 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/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. In post-marketing experience, the following have been reported: 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, cutaneous lupus erythematosus, pustular psoriasis or worsening psoriasis. Adverse Reactions (Pediatric Patients) The safety of ARAVA 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. Drug Abuse And Dependence ARAVA has no known potential for abuse or dependence. Read the Arava (leflunomide) Side Effects Center for a complete guide to possible side effectsLearn More »

Source: http://www.rxlist.com

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 ARAVA therapy be initiated with a loading dose of one 100 mg 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. (See WARNINGS - Hepatotoxicity). 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. Monitoring Hematology parameters and liver enzymes should be monitored (see PRECAUTIONS – Laboratory Tests; WARNINGS – Hepatotoxicity; WARNINGS – Immunosuppression Potential/Bone Marrow Suppression).

Source: http://www.rxlist.com

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 (see PRECAUTIONS – General – Need for Drug Elimination). 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 ARAVA 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 (see CLINICAL PHARMACOLOGY). NSAIDs In in vitro studies, M1 was shown to cause increases ranging from 13 - 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 - 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 ARAVA to subjects receiving multiple doses of rifampin, M1 peak levels were increased (~40%) over those seen when ARAVA was given alone. Because of the potential for ARAVA levels to continue to increase with multiple dosing, caution should be used if patients are to be receiving both ARAVA and rifampin. Warfarin Increased INR (International Normalized Ratio) when ARAVA and warfarin were coadministered has been rarely reported. Read the Arava Drug Interactions Center for a complete guide to possible interactions Learn More »

Source: http://www.rxlist.com

ARAVA is indicated in adults for the treatment of active rheumatoid arthritis (RA):
  1. to reduce signs and symptoms
  2. to inhibit structural damage as evidenced by X-ray erosions and joint space narrowing
  3. to improve physical function. (see Clinical Studies)
Aspirin, nonsteroidal anti-inflammatory agents and/or low dose corticosteroids may be continued during treatment with ARAVA (see PRECAUTIONS: DRUG INTERACTIONS – NSAIDs). The combined use of ARAVA with antimalarials, intramuscular or oral gold, D penicillamine, azathioprine, or methotrexate has not been adequately studied. (See WARNINGS -Immunosuppression Potential/Bone Marrow Suppression.)

Source: http://www.rxlist.com

ARAVA is contraindicated in patients with known hypersensitivity to leflunomide or any of the other components of ARAVA. ARAVA 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. ARAVA 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. Last reviewed on RxList: 11/30/2012
This monograph has been modified to include the generic and brand name in many instances.

Source: http://www.rxlist.com

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 ARAVA 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 ARAVA (see ADVERSE REACTIONS). The most frequent 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 (see PRECAUTIONS – General – Need for Drug Elimination). Studies with both hemodialysis and CAPD (chronic ambulatory peritoneal dialysis) indicate that M1, the primary metabolite of leflunomide, is not dialyzable. (See CLINICAL PHARMACOLOGY – Elimination.)

Source: http://www.rxlist.com

ARAVA Tablets in 10 and 20 mg strengths are packaged in bottles. ARAVA Tablets 100 mg strength are packaged in blister packs. ARAVA® (leflunomide) Tablets
Strength Quantity NDC Number Description 10 mg 30 count bottle 0088-2160-30 White, round film-coated tablet embossed with “ZBN” on one side. 20 mg 30 count bottle 0088-2161-30 Light yellow, triangular film-coated tablet embossed with “ZBO” on one side. 100 mg 3 count blister pack 0088-2162-33 White, round film-coated tablet embossed with “ZBP” on one side. Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F) [see USP Controlled Room Temperature]. Protect from light. Revised: November 2012. sanofi-aventis U.S. LLC Bridgewater, NJ 08807 Last reviewed on RxList: 11/30/2012
This monograph has been modified to include the generic and brand name in many instances.

Source: http://www.rxlist.com

General Need for Drug Elimination The active metabolite of leflunomide is eliminated slowly from the plasma. In instances of any serious toxicity from ARAVA, 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 ARAVA 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 (see ADVERSE REACTIONS). 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. (See WARNINGS – Drug Elimination Procedure.) Tuberculosis Reactivation Prior to initiating immunomodulatory therapies, including Arava, patients should be screened for latent tuberculosis infection with a tuberculin skin test. Arava has not been studied in patients with a positive tuberculosis screen, and the safety of Arava 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 Arava. 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 ARAVA 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 ARAVA treatment. Vaccination with live vaccines is, however, not recommended. The long half-life of ARAVA should be considered when contemplating administration of a live vaccine after stopping ARAVA. Blood Pressure Monitoring Blood pressure should be checked before start of leflunomide treatment and periodically thereafter. Laboratory Tests Hematologic Monitoring At minimum, patients taking ARAVA 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. Bone Marrow Suppression Monitoring If used concomitantly with immunosuppressants such as methotrexate, chronic monitoring should be monthly. (See WARNINGS - Immunosuppression Potential/Bone Marrow Suppression.) Liver Enzyme Monitoring At minimum, ALT (SGPT) must be performed at baseline and at least monthly for six months after starting ARAVA, and thereafter every 6-8 weeks. In addition, if ARAVA and methotrexate are given concomitantly, ACR guidelines for monitoring methotrexate liver toxicity must be followed with ALT, AST, and serum albumin testing every month. (See WARNINGS – Hepatotoxicity.) Due to a specific effect on the brush border of the renal proximal tubule, ARAVA has a uricosuric effect. A separate effect of hypophosphaturia is seen in some patients. These effects have not been seen together, nor have there been alterations in renal function. Carcinogenesis, Mutagenesis, and Impairment of Fertility 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 ARAVA 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). Pregnancy 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. Nursing Mothers ARAVA should not be used by nursing mothers. It is not known whether ARAVA 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 ARAVA. Therefore, a decision should be made whether to proceed with nursing or to initiate treatment with ARAVA, taking into account the importance of the drug to the mother. Use in Males Available information does not suggest that ARAVA 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 ARAVA and taking cholestyramine 8 grams 3 times daily for 11 days. Pediatric Use The safety and effectiveness of ARAVA in pediatric patients with polyarticular course juvenile rheumatoid arthritis (JRA) have not been fully evaluated. (See Clinical Studies and ADVERSE REACTIONS.) Geriatric Use Of the total number of subjects in controlled clinical (Phase III) studies of ARAVA, 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. Last reviewed on RxList: 11/30/2012
This monograph has been modified to include the generic and brand name in many instances.

Source: http://www.rxlist.com

Health Services in

Drug Database Online

Welcome to Women's Health Care an online drug guide and dictionary, here you can get drug information and definitaions for most popular pharmaceutical and medicinal drugs, and specifically Arava. Find what medications you are taking today.