Summary

Commonly reported side effects of leflunomide include: alopecia, diarrhea, increased serum alanine aminotransferase, increased serum aspartate aminotransferase, and skin rash. Other side effects include: bronchitis, hypersensitivity condition, hypertension, pruritus, rhinitis, and tenosynovitis. Continue reading for a comprehensive list of adverse effects.

Applies to leflunomide: oral tablet.

Serious side effects of Leflunomide

Along with its needed effects, leflunomide may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.

Check with your doctor immediately if any of the following side effects occur while taking leflunomide:

More common

• Bloody or cloudy urine
• cough
• difficult or painful breathing
• difficult, burning, or painful urination
• dizziness
• fever
• frequent urge to urinate
• headache
• loss of appetite
• nausea or vomiting
• sneezing
• sore throat
• tightness in the chest
• yellow eyes or skin

Less common

• Burning feeling in the chest or stomach
• burning, prickling, or tingling sensation in the fingers or toes
• chest pain
• diarrhea
• fast or pounding heartbeat
• indigestion
• joint or muscle pain or stiffness
• severe stomach pain
• tenderness in the stomach area
• unusual tiredness or weakness

Incidence not known

• Area rash
• black or tarry stools
• bleeding gums
• blistering, peeling, or loosening of the skin
• bloating
• blood in the stools
• burning, numbness, tingling, or painful sensations
• chills
• clay-colored stools
• confusion
• constipation
• continuing vomiting
• cough or hoarseness
• dark urine
• fainting
• fever with or without chills
• general feeling of tiredness or weakness
• high fever
• large, hive-like swelling on the face, eyelids, lips, tongue, throat, hands, legs, feet, or sex organs
• light-colored stools
• lightheadedness
• lower back or side pain
• pains in the stomach, side, or abdomen, possibly radiating to the back
• pale skin
• pinpoint red spots on the skin
• rapid, shallow breathing
• red skin lesions, often with a purple center
• red, irritated eyes
• sores, ulcers, or white spots in the mouth or on the lips
• swollen glands
• unexplained bleeding or bruising
• unpleasant breath odor
• unsteadiness or awkwardness
• unusual bleeding or bruising
• upper right abdominal or stomach pain
• vomiting of blood
• weakness in the arms, hands, legs, or feet

Other side effects of Leflunomide

Some side effects of leflunomide may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects.

Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:

More common

• Back pain
• hair loss
• heartburn
• skin rash
• stomach pain
• weight loss (unexplained)

Less common

• Acne
• anxiety
• decreased appetite
• dry mouth
• gas
• irritation or soreness of the mouth
• itching of the skin
• pain or burning in the throat
• runny nose

For Healthcare Professionals

Applies to leflunomide: oral tablet.

Gastrointestinal

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 prednisone 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.^[Ref]

Very common (10% or more): Diarrhea (up to 22%), dyspepsia (up to 13%)

Common (1% to 10%): Abdominal pain, anorexia, gastroenteritis, nausea, gastrointestinal/abdominal pain, mouth ulcer, vomiting, cholelithiasis, colitis, constipation, esophagitis, flatulence, gastritis, gingivitis, melena, oral moniliasis, pharyngitis, salivary gland enlarged, stomatitis (or aphthous stomatitis), tooth disorder, dry mouth

Frequency not reported: Pancreatitis^[Ref]

Respiratory

Very common (10% or more): Respiratory infection (up to 32%)

Common (1% to 10%): Bronchitis, cough, pharyngitis, pneumonia, rhinitis, sinusitis, asthma, dyspnea, epistaxis, lung disorder

Postmarketing reports: Interstitial lung disease, including interstitial pneumonitis and pulmonary fibrosis, which may be fatal^[Ref]

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.^[Ref]

Cardiovascular

Common (1% to 10%): Hypertension, chest pain

Postmarketing reports: Angina pectoris, migraine, palpitation, tachycardia, vasculitis, vasodilation, varicose vein^[Ref]

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/clavulanic 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.^[Ref]

Very common (10% or more): Alopecia (up to 17%), rash (up to 12%)

Common (1% to 10%): Eczema, pruritus, dry skin, 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

Uncommon (0.1% to 1%): Diabetes mellitus, hyperthyroidism

Rare (less than 0.1%): Urticaria

Postmarketing reports: Erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis, vasculitis (including cutaneous necrotizing vasculitis), cutaneous lupus erythematosus, pustular psoriasis (or worsening psoriasis), angioedema^[Ref]

Nervous system

Very common (10% or more): Headache (up to 21%)

Common (1% to 10%): Asthenia, pain, dizziness, paresthesia, neuralgia, neuritis, sweating increased, vertigo

Postmarketing reports: Peripheral neuropathy^[Ref]

Genitourinary

Common (1% to 10%): Urinary tract infection, albuminuria, cystitis, dysuria, hematuria, menstrual disorder, prostate disorder, urinary frequency, vaginal moniliasis^[Ref]

Musculoskeletal

Common (1% to 10%): Back pain, arthralgia, leg cramps, joint disorder, synovitis, tenosynovitis, arthrosis, bone necrosis, bone pain, bursitis, muscle cramps, myalgia, tendon rupture^[Ref]

Metabolic

Common (1% to 10%): Hypokalemia, weight loss, creatine phosphokinase increased, hyperglycemia, hyperlipidemia, peripheral edema^[Ref]

Hypersensitivity

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.^[Ref]

Common (1% to 10%): Allergic reaction^[Ref]

Hematologic

Common (1% to 10%): Anemia (including iron deficiency anemia), ecchymosis

Rare (less than 0.1%): Eosinophilia, transient thrombocytopenia, leukopenia

Postmarketing reports: Agranulocytosis, neutropenia, pancytopenia^[Ref]

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

Endocrine

Frequency not reported: Hyperthyroidism^[Ref]

Ocular

Common (1% to 10%): Blurred vision, cataract, conjunctivitis, eye disorder^[Ref]

Renal

Frequency not reported: Renal failure^[Ref]

Hepatic

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 empiric 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 antituberculosis treatment.^[Ref]

Common (1% to 10%): Abnormal liver enzymes

Postmarketing reports: Hepatitis, jaundice/cholestasis, severe liver injury such as hepatic failure and acute hepatic necrosis that may be fatal^[Ref]

Other

Common (1% to 10%): Taste perversion, abscess, cyst, fever, hernia, malaise, pelvic pain^[Ref]

Immunologic

Common (1% to 10%): Flu Syndrome

Postmarketing reports: Opportunistic infections, severe infections including sepsis that may be fatal^[Ref]

Psychiatric

Common (1% to 10%): Anxiety, depression insomnia, sleep disorder^[Ref]