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Leflunomide Side Effects

Not all side effects for leflunomide may be reported. You should always consult a doctor or healthcare professional for medical advice. Side effects can be reported to the FDA here.

For the Consumer

Applies to leflunomide: oral tablet

In addition to its needed effects, some unwanted effects may be caused by leflunomide. In the event that any of these side effects do occur, they may require medical attention.

You should check with your doctor immediately if any of these side effects occur when 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 heartbeat
  • indigestion
  • joint or muscle pain or stiffness
  • pounding heartbeat
  • severe stomach pain
  • shortness of breath
  • 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

Some of the side effects that can occur with leflunomide may not need medical attention. As your body adjusts to the medicine during treatment these side effects may go away. Your health care professional may also be able to tell you about ways to reduce or prevent some of these side effects. If any of the following side effects continue, are bothersome or if you have any questions about them, check with your health care professional:

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


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]

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]


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]

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]


Common (1% to 10%): Hypertension, chest pain
Postmarketing reports: Angina pectoris, migraine, palpitation, tachycardia, vasculitis, vasodilation, varicose vein[Ref]


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]


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


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]


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


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]


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]


Frequency not reported: Hyperthyroidism[Ref]


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


Frequency not reported: Renal failure[Ref]


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]


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


Common (1% to 10%): Flu Syndrome
Postmarketing reports: Opportunistic infections, severe infections including sepsis that may be fatal[Ref]


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


1. Kaltwasser JP, Nash P, Gladman D, et al. "Efficacy and safety of leflunomide in the treatment of psoriatic arthritis and psoriasis: a multinational, double-blind, randomized, placebo-controlled clinical trial." Arthritis Rheum 50 (2004): 1939-50

2. Jenks KA, Stamp LK, O'donnell JL, Savage RL, Chapman PT "Leflunomide-associated infections in rheumatoid arthritis." J Rheumatol 34 (2007): 2201-3

3. Cerner Multum, Inc. "Australian Product Information." O 0

4. Cerner Multum, Inc. "UK Summary of Product Characteristics." O 0

5. "Product Information. Arava (leflunomide)." Hoechst Marion-Roussel Inc, Kansas City, MO.

6. Takeishi M, Akiyama Y, Akiba H, Adachi D, Hirano M, Mimura T "Leflunomide induced acute interstitial pneumonia." J Rheumatol 32 (2005): 1160-3

7. Hyeon Ju J, Kim SI, Lee JH, et al. "Risk of interstitial lung disease associated with leflunomide treatment in Korean patients with rheumatoid arthritis." Arthritis Rheum 56 (2007): 2094-2096

8. Siva C, Eisen SA, Shepherd R, et al. "Leflunomide use during the first 33 months after food and drug administration approval: Experience with a national cohort of 3,325 patients." Arthritis Rheum 49 (2003): 745-51

9. Gottenberg JE, Venancie PY, Mariette X "Alopecia areata in a patient with rheumatoid arthritis treated with leflunomide." J Rheumatol 29 (2002): 1806-7

10. McCoy CM "Leflunomide-associated skin ulceration." Ann Pharmacother 36 (2002): 1009-11

11. Bonnel RA, Graham DJ "Peripheral neuropathy in patients treated with leflunomide." Clin Pharmacol Ther 75 (2004): 580-5

12. Teraki Y, Hitomi K, Sato Y, Hamamatsu Y, Izaki S "Leflunomide-induced toxic epidermal necrolysis." Int J Dermatol 45 (2006): 1370-1

13. Hill RL, Topliss DJ, Purcell PM "Pancytopenia associated with leflunomide and methotrexate." Ann Pharmacother 37 (2003): 149

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