Leflunomide Prescribing and Monitoring

Leflunomide is a pyrimidine synthesis inhibitor used in rheumatoid arthritis and psoriatic arthritis when methotrexate fails or cannot be used. Its active metabolite has a half-life of about 2 weeks and enterohepatic recycling, so effects and toxicity persist for months after stopping unless a washout is given.

Mechanism. Inhibition of dihydroorotate dehydrogenase blocks lymphocyte proliferation.

Contraindications. Pregnancy and breastfeeding, severe liver disease or ALT over twice the upper limit, severe immunodeficiency, uncontrolled infection, and active marrow suppression.

Usual maintenance. Leflunomide 10 to 20 mg orally once daily with or without food.

• Start at 10 mg daily to reduce diarrhoea and liver enzyme rises, and increase to 20 mg daily if response is incomplete after 4 to 8 weeks and liver tests are normal.
• Loading dose: 100 mg daily for 3 days is available for rapid onset, but it is often omitted because of gastrointestinal and liver adverse effects.

Combination. With methotrexate in resistant disease, but at the cost of higher hepatotoxicity and marrow risk; check liver tests every 2 weeks initially.

Washout (accelerated elimination). Colestyramine 8 g orally 3 times daily for 11 days (or activated charcoal 50 g every 6 hours for 11 days) when toxicity occurs, pregnancy is planned or recognised, or before starting another disease-modifying drug after adverse effects. Confirm a plasma metabolite level under 0.02 mg/L on 2 tests at least 14 days apart.

Kidney impairment. No dose adjustment in mild to moderate impairment; limited data in eGFR under 30 mL/min.

Liver impairment. Contraindicated if significant; ALT over twice the upper limit means reduce to 10 mg daily or stop.

Older adults. No dose change; monitor for hypertension, neuropathy and weight loss.

Hypertension. Blood pressure rises in about 10% of patients; treat and monitor.

Interactions.

• Methotrexate, isoniazid, azathioprine and other hepatotoxic drugs: additive liver toxicity.
• Warfarin: higher INR.
• Rifampicin: raises leflunomide metabolite levels.
• Colestyramine: reduces levels (used deliberately).
• Live vaccines: avoid.

Pregnancy and men. Women: stop at least 2 years before conception, or give the washout and confirm levels under 0.02 mg/L. Exposure in pregnancy: stop and start the washout at once. Men: use effective contraception, and consider washout before conception.

Regional. Screen for hepatitis B and C and tuberculosis before treatment; avoid in active hepatitis.

Baseline. Full blood count, ALT or AST, albumin, creatinine, hepatitis B and C serology, blood pressure, weight, chest radiograph and a pregnancy test.

Ongoing. Full blood count and liver tests every 2 weeks for 6 months, then every 8 weeks. Blood pressure at each visit. Weight and symptoms of neuropathy.

Withhold or reduce. ALT or AST between 2 and 3 times the upper limit: halve the dose and repeat in 2 to 4 weeks. Persistent elevation or over 3 times the upper limit: stop and start the washout. White cell count under 3.5 x 10⁹/L or neutrophils under 1.5 x 10⁹/L: stop.

Stop and escalate. Interstitial lung disease (new cough or breathlessness), severe skin reaction, peripheral neuropathy, serious infection or any pregnancy: stop, start the washout, and refer.