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adverse reactions
ADVERSE REACTIONS 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 Only 10% of patients in MN302 received folate. All patients in US301 received folate; none in MN301 received folate. LEF (N=1339) Includes all controlled and uncontrolled trials with leflunomide (duration up to 12 months). 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 2% 4% 2% 2% 5% 1% <1% Abdominal Pain 6% 5% 4% 4% 8% 6% 4% Back Pain 5% 6% 3% 4% 9% 8% 7% CARDIOVASCULAR Hypertension Hypertension as a preexisting condition was overrepresented in all leflunomide treatment groups in phase III trials 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 Loss 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. 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 Infection 15% 21% 21% 20% 32% 27% 25% Pharyngitis 3% 2% 1% 2% 1% 3% 3% Pneumonia 2% 3% 0% 0% 1% 2% 2% Rhinitis 2% 5% 2% 4% 3% 2% 2% 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% 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 3 (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. 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.