Last updated: October 17, 2014
Trade Names: Arava
Drug Class: Antimetabolite, DMARD
Preparations: 10-, 20-, 100-mg tablets
Dose: Leflunomide can be initiated with a loading dose of 100 mg daily for 3 days followed by 20 mg/day. Most rheumatologists omit the loading dose to minimize GI side effects. A maintenance dose of 10 mg/day (or 20 mg every 2 days) may be effective in patients who cannot tolerate 20 mg/day. When used in combination with MTX the usual starting dose of leflunomide is 10 mg/day (for 4–8 weeks) with careful clinical and laboratory monitoring.
Mechanism of Action: Inhibition of dihydroorotate dehydrogenase and pyrimidine synthesis
Contraindications: Hypersensitivity to leflunomide, liver disease, hepatitis B or C infection, alcoholism, pregnancy and breast feeding, avoid live virus vaccines and BCG, impaired bone marrow function, uncontrolled infection, unwilling to use reliable contraception
Precautions: The patient must understand the risks and benefits of treatment and the requirement for monitoring. Exclude pregnancy before starting. Pregnant women must not receive leflunomide. Counsel regarding risk, and ensure that contraceptive methods are in place in both men and women before starting therapy. Women of child-bearing age who discontinue therapy should take cholestyramine 8 g three times daily for 11 days to reduce plasma levels to <0.02 mg/L on two consecutive tests at least 14 days apart. Without this elimination procedure, it could take as long as 2 years to reach these plasma concentrations. Although drug levels are higher in patients with impaired renal function, it appears that leflunomide can be used cautiously in such patients. Leflunomide is not dialyzed. Screen for TB before therapy. Avoid in patients with interstitial lung disease.
Baseline: CBC, platelets, LFTs, creatinine. Check for hepatitis B and C infection. Maintenance: Initially or with dose increases, check CBC and LFTs every 4 weeks for 6 months; then if LFTs are stable, every 6–8 weeks. Co-therapy with MTX or other immunosuppressants requires more frequent monitoring (e.g., every 4 weeks). Dose reduction is indicated for minor increases in liver enzymes. For elevations more than 3x normal discontinue and treat with cholestyramine. Discontinue leflunomide in patients with persistent liver test abnormalities. Monitor blood pressure.
Pregnancy Risk: X (teratogen). Leflunomide is teratogenic in animals. Ensure that women are not pregnant before starting treatment and ensure reliable contraception during treatment. When women of childbearing age discontinue leflunomide treatment, use the cholestyramine protocol described under Precautions to speed elimination of the drug.
Common: Diarrhea, GI cramps
Less common: Hypertension, hair loss, rash, nausea, vomiting, weight loss, minor LFT abnormalities
Uncommon: Allergy, interstitial pneumonitis, leukopenia, peripheral neuropathy, increased risk of infection, reactivation of TB
Rare: Stevens-Johnson syndrome or toxic epidermal necrolysis, liver failure, agranulocytosis, pancytopenia
Rifampin: Increased concentrations of the active form of leflunomide
Warfarin: Case reports of increased warfarin effect
Activated charcoal and cholestyramine: Enhance elimination of the drug by interfering with enterohepatic recycling
Tofacitinib: Co-therapy contraindicated
Teriflunomide: Is the active metabolite of leflunomide; avoid co-therapy
Methotrexate and other hepatotoxic and hemotoxic drugs: Increased toxicity
Patient Instructions: Do not become pregnant. Do not drink alcohol.
Comments: Leflunomide is as effective as MTX for RA and can be useful for patients who cannot tolerate MTX. Its long half-life and teratogenicity make it less suitable for women of childbearing age. GI symptoms limit tolerability. The combination of leflunomide and MTX is more effective than monotherapy but carries a greater risk of liver toxicity and careful monitoring is needed. The loading dose is usually omitted in clinical practice to improve GI tolerability. Minor toxicities can be managed by holding or lowering the dose and brief use of cholestyramine 8 g three times daily for 1–2 days to lower plasma concentrations by nearly 50%. Serious toxicities require drug cessation and a full-dose drug elimination (see Precautions). Leflunomide reduces uric acid.
Clinical Pharmacology: Well absorbed and rapidly converted to the active metabolite (A77 1726, teriflunomide). Hepatic metabolism with enterohepatic recycling. Half-life 15 days.
Behrens F, Koehm M, Burkhardt H. Update 2011: leflunomide in rheumatoid arthritis - strengths and weaknesses. Curr Opin Rheumatol. 2011;23:282-7. PMID: 21427581.