Leflunomide Side Effects

Brand Names: Arava

Please note - some side effects for Leflunomide may not be reported. Always consult your doctor or healthcare specialist for medical advice. You may also report side effects to the FDA at http://www.fda.gov/medwatch/ or 1-800-FDA-1088 (1-800-332-1088).

Side Effects of Leflunomide - for the Consumer

Leflunomide

All medicines may cause side effects, but many people have no, or minor, side effects. Check with your doctor if any of these most COMMON side effects persist or become bothersome when using Leflunomide:

Back pain; bronchitis; diarrhea; dizziness; dry skin; hair loss; headache; increased cough; indigestion; joint disorder; loss of appetite; muscle aches; nausea; runny nose; sinus infection; upper respiratory tract infection; urinary tract infection; vomiting; weakness; weight loss.

Severe allergic reactions (rash; hives; itching; difficulty breathing; tightness in the chest; swelling of the mouth, face, lips, or tongue); blistering or peeling skin; blisters on the inside of eyes, nose, or mouth; chest pain; dark urine; easy bruising/bleeding; feelings of numbness or tingling; fever; infection; muscle cramps, including leg cramps; pale skin; pale stools; sore throat; stomach pain; unusual tiredness; vomiting; yellowing of the eyes or skin.

Leflunomide Side Effects - for the Professional

Leflunomide

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.

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 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 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.

Side Effects by Body System

Gastrointestinal

Gastrointestinal side effects have included diarrhea (17%), nausea (9%), gastrointestinal pain (5% or greater), abdominal pain (5%), dyspepsia (5%), anorexia (3%), vomiting (3%), and mouth ulcer (3%). Cholelithiasis, colitis, constipation, esophagitis, flatulence, gastroenteritis, gingivitis, melena, oral moniliasis, pharyngitis, enlarged salivary gland, stomatitis (or aphthous stomatitis), and tooth disorder have been reported. Pancreatitis has been reported rarely in postmarketing experience. At least one case of parastomal collection and stomach perforation has been reported.

A 58-year-old female with longstanding rheumatoid arthritis experienced parastomal collection and stomach perforation coincident with leflunomide therapy. The patient had been taking leflunomide 20 mg per day and pregnisone 5 mg per day. She presented with complaints of a one day history of abdominal pain. A CT scan showed a parastomal collection and stomach perforation. She proceeded to surgery for drainage of the collection and repair of the perforation. The leflunomide therapy was subsequently stopped and cholestyramine washout administered. She required prolonged hospital stay, with total parenteral nutrition and intravenous antibiotics.

Respiratory

A 54-year-old female with rheumatoid arthritis experienced acute respiratory failure coincident with leflunomide therapy. She developed the adverse event 2 weeks after cessation of 6-weeks treatment with leflunomide. She was diagnosed with interstitial pneumonia, probably induced by leflunomide because acute respiratory failure was preceded by hypertension and elevated serum liver enzyme concentration. She showed dramatic improvement with cholestyramine and prednisolone.

Respiratory side effects have included respiratory infection (15%), bronchitis (7%), increased cough (3%), pharyngitis (3%), pneumonia (2%), rhinitis (2%), and sinusitis (2%). Asthma, dyspnea, epistaxis, and interstitial lung disease, with fatal outcomes, have been reported. At least one case of acute interstitial pneumonia has also been reported, in addition to a case of infected lung bullae, and a case of pulmonary tuberculosis.

Cardiovascular

Cardiovascular side effects have included hypertension (10%) and chest pain (2%). Angina pectoris, migraine, palpitation, tachycardia, vasculitis, vasodilation, and varicose veins have been reported. Angioedema has also been reported rarely in postmarketing experience.

Dermatologic

A 46-year-old woman with erosive and refractory rheumatoid arthritis (RA) developed sudden focal hair loss (alopecia areata) after 3 weeks of treatment with leflunomide. Three months after leflunomide had been stopped due to poor control of RA, the patient's hair was slowly recovering.

A 61-year-old female with severe rheumatoid arthritis experienced cellulitis coincident with leflunomide therapy. The patient had been taking leflunomide 20 mg alternate days and prednisone 10 mg per day. She presented with cellulitis of the left foot that had not responded to oral amoxicillin/clavulinic acid. Isolates from a plantar ulcer showed Staphylococcus aureus. Despite appropriate antibiotic treatment, the infection progressed rapidly and she developed necrosis of the left foot. She proceeded to surgical debridement with forefoot amputation and skin graft. On day 4 of admission, leflunomide therapy was discontinued and cholestyramine washout administered. She had a prolonged hospital stay that required 5 further debridement procedures.

Dermatologic side effects have included rash (10% or greater), alopecia (10%), pruritus (4% or greater), eczema (2%), and dry skin (2%). Acne, contact dermatitis, fungal dermatitis, hair discoloration, hematoma, herpes simplex, herpes zoster, nail disorder, skin nodule, subcutaneous nodule, macropapular rash, skin disorder, skin discoloration, urticaria, and skin ulcer have been reported. At least one case of alopecia areata has also been reported. At least one case of cellulitis has also been reported, in addition to a case of cellulitis with local necrosis.

Nervous system

Nervous system side effects have included headache (7%), dizziness (4%), paresthesia (2%), and pain (2%). Back pain, neck pain, pelvic pain, anxiety, depression, dry mouth, insomnia, neuralgia, neuritis, sleep disorder, sweat, and vertigo have been reported. Peripheral neuropathy has also been reported rarely in postmarketing experience.

Genitourinary

Genitourinary side effects have included urinary tract infection (5%). Albuminuria, cystitis, dysuria, hematuria, menstrual disorder, vaginal moniliasis, prostate disorder, and urinary frequency have also been reported.

Musculoskeletal

Musculoskeletal side effects have included joint disorder (4% or greater), tenosynovitis (3%), synovitis (2%), arthralgia (1%), and leg cramps (1%). Arthrosis, bursitis, muscle cramps, myalgia, bone necrosis, bone pain, and tendon rupture have also been reported.

Metabolic

Metabolic side effects have included weight loss (4%) and hypokalemia (1%). Increased creatine phosphokinase, peripheral edema, hyperglycemia, and hyperlipidemia have also been reported.

Hypersensitivity

Hypersensitivity side effects have included allergic reactions (2%). Stevens-Johnson syndrome and toxic epidermal necrolysis have been reported rarely. At least one anaphylactic reaction has been reported following rechallenge of the drug after withdrawal due to rash. Erythema multiforme and vasculitis including cutaneous necrotizing vasculitis have been reported rarely in postmarketing experience. At least one case of hypersensitivity pneumonitis has also been reported.

A 69-year-old male with a 19-year history of rheumatoid arthritis experienced hypersensitivity pneumonitis coincident with leflunomide therapy. Three months after being administered leflunomide 20 mg once a day, he presented with a 1-month history of progressive dyspnea, decreased appetite, and weight loss. The temporal association and resolution following discontinuation suggest leflunomide was the causative agent.

Hematologic

The risk of pancytopenia appears to be increased when leflunomide is combined with methotrexate and in older patients.

Hematologic side effects have included anemia (including iron deficiency anemia), eosinophilia, and ecchymosis. Transient thrombocytopenia and leukopenia (less than 2000 G/L) have been reported rarely. Agranulocytosis, neutropenia, and pancytopenia have been reported rarely in postmarketing experience. At least 18 cases of pancytopenia have also been reported.

Endocrine

Endocrine side effects have included diabetes mellitus and hyperthyroidism.

Ocular

Ocular side effects have included blurred vision, cataract, conjunctivitis, and eye disorder.

Renal

Renal side effects have not been reported but because of an effect on the brush border of the proximal renal tubule, leflunomide has a uricosuric effect. A separate effect of hypophosphatemia has also been reported. These effects have not been seen together, nor have there been alterations in renal function.

Oncologic

Oncologic side effects have been reported with some immunosuppressive medications. However, no increased risk for malignancy (primary lymphoproliferative disorders) have been reported in clinical trials with leflunomide. Larger and longer-term studies are needed to determine whether there is an increased risk of malignancy or lymphoproliferative disorders with leflunomide.

A study reported an increased incidence in lymphoma in male mice. In the same study, an increased incidence of bronchoalveolar adenomas and carcinomas were reported in female mice. A minor metabolite of leflunomide, 4-trifluoromethylaniline (TFMA), 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 Chinese Hamster Cells.

Hepatic

Hepatic side effects have included increased ALT level (greater than 5%), abnormal liver enzymes (5%), cirrhosis, and mild transaminitis. Hepatitis, jaundice/cholestasis, and severe liver injury, such as hepatic failure and acute hepatic necrosis that may be fatal, have been reported rarely in postmarketing experience. At least one case of liver tuberculosis has also been reported.

A 69-year-old male with stable rheumatoid arthritis experienced liver tuberculosis coincident with leflunomide therapy. The patient had been taking leflunomide 20 mg daily as monotherapy for 31 months. He presented with a 2 month history of anorexia, 10 kg weight loss, fever, and night sweats. A CT scan showed multiple low attenuation lesions in the liver. Initial liver biopsy was nondiagnostic, revealing only minor changes with no evidence of infection. Although Mycobacterium tuberculosis culture was negative, due to strong clinical suspicion, he was given emphiric antituberculosis therapy. The patient's condition improved dramatically over subsequent weeks. At 18 months review, he remained well taking prednisone monotherapy. Although culture negative, a diagnosis of probable mycobacterium infection was made on the basis of typical histological findings on liver biopsy, exclusion of other pathology and prompt response to anti-tuberculosis treatment.

Other

Other side effects have included flu syndrome (greater than 5%), tiredness/lethargy (greater than 5%), injury (5%), accident (5%), infection (4%), asthenia (3%), abscess, cyst, fever, hernia, malaise, and taste perversion. Opportunistic infections and severe infections including sepsis that may be fatal have been reported rarely in postmarketing experience. At least one case of mycotic aneurysm has also been reported.

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