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Arava

Side Effects
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SIDE EFFECTS

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 effects

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 (see PRECAUTIONSGeneralNeed 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

Last reviewed on RxList: 11/30/2012
This monograph has been modified to include the generic and brand name in many instances.

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