Leflunomide Side Effects

Medically reviewed by Drugs.com. Last updated on Mar 13, 2025.

Applies to leflunomide: oral tablet.

Precautions

It is very important that your doctor check your progress at regular visits to make sure that this medicine is working properly. Blood tests may be needed to check for unwanted effects.

You will need to have your blood pressure measured before starting this medicine and while you are using it. If you notice any change to your recommended blood pressure, call your doctor right away. If you have questions about this, talk to your doctor.

Using this medicine while you are pregnant can harm your unborn baby. Use an effective form of birth control to keep from getting pregnant. If you think you have become pregnant while using the medicine, tell your doctor right away.

Leflunomide may also cause birth defects if the father is using it when his sexual partner becomes pregnant. Men taking leflunomide should use condoms as a form of birth control during sexual intercourse. A man intending to father a child should Stop taking leflunomide and check with his doctor right away.

Do not use this medicine if you are also using teriflunomide. Using these medicines together may cause unwanted serious side effects.

Check with your doctor right away if you have pain or tenderness in the upper stomach, pale stools, dark urine, loss of appetite, nausea, vomiting, or yellow eyes or skin. These could be symptoms of a serious liver problem.

Leflunomide can temporarily lower the number of white blood cells in your blood, increasing the chance of getting an infection. It can also lower the number of platelets, which are necessary for proper blood clotting. If this occurs, there are certain precautions you can take, especially when your blood count is low, to reduce the risk of infection or bleeding:

• If you can, avoid people with infections. Check with your doctor immediately if you think you are getting an infection or if you get a fever or chills, cough or hoarseness, lower back or side pain, or painful or difficult urination.
• Check with your doctor immediately if you notice any unusual bleeding or bruising, black, tarry stools, blood in the urine or stools, or pinpoint red spots on your skin.
• Be careful when using a regular toothbrush, dental floss, or toothpick. Your medical doctor, dentist, or nurse may recommend other ways to clean your teeth and gums. Check with your medical doctor before having any dental work done.
• Do not touch your eyes or the inside of your nose unless you have just washed your hands and have not touched anything else in the meantime.
• Be careful not to cut yourself when you are using sharp objects such as a safety razor or fingernail or toenail cutters.
• Avoid contact sports or other situations where bruising or injury could occur.

This medicine may cause drug reaction with eosinophilia and systemic reactions (DRESS), including serious skin reactions. Check with your doctor right away if you have any blistering, peeling, or loose skin, chills, itching, joint or muscle pain, red skin lesions, often with a purple center, sores, ulcers, or white spots in the mouth or on the lips, or unusual tiredness or weakness.

You will need to have a skin test for tuberculosis before you start using this medicine. Tell your doctor if you or anyone in your home has ever had a positive reaction to a tuberculosis test.

Using this medicine may increase your risk of getting serious infections or cancer. Talk to your doctor if you have concerns about this risk.

Check with your doctor right away if you are having burning, numbness, tingling, or painful sensations in the arms, hands, legs, or feet. These could be symptoms of a condition called peripheral neuropathy.

Check with your doctor right away if you have a cough with or without a fever, shortness of breath, or any difficulty with breathing.

While you are being treated with leflunomide, and after you stop using it, do not have any vaccinations without your doctor's approval. Live virus vaccines should not be given while receiving this medicine.

Do not take other medicines unless they have been discussed with your doctor. This includes prescription or nonprescription (over-the-counter [OTC]) medicines and herbal or vitamin supplements.

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:

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:

For healthcare professionals

Applies to leflunomide: oral tablet.

Gastrointestinal adverse events

• 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]

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

• 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]

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]

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

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

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

• 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]

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]

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]

See also:

Frequently asked questions

• What are the new drugs for rheumatoid arthritis (RA)?

Further information

Leflunomide side effects can vary depending on the individual. Always consult your healthcare provider to ensure the information displayed on this page applies to your personal circumstances.

Note: Medication side effects may be underreported. If you are experiencing side effects that are not listed, submit a report to the FDA by following this guide.

Medical Disclaimer