Leflunomide Pharmacology

Leflunomide is an oral pyrimidine synthesis inhibitor used for rheumatoid arthritis and psoriatic arthritis, particularly when methotrexate is not tolerated or insufficient. It is as effective as methotrexate and sulfasalazine in rheumatoid arthritis. It is teratogenic and has a very long half-life, so planning for pregnancy and toxicity needs active drug removal.

Mechanism. The active metabolite teriflunomide inhibits dihydroorotate dehydrogenase, blocking de novo pyrimidine synthesis and proliferation of activated lymphocytes.

Pharmacokinetics. Rapidly converted to teriflunomide; bioavailability about 80%; extensively protein bound; half-life about 2 weeks; enterohepatic recirculation prolongs exposure, so effects persist for up to 2 years after stopping without washout.

Dosing.

• Loading: 100 mg daily for 3 days (often omitted to reduce adverse effects).
• Maintenance: 10 to 20 mg once daily; start 10 mg in older adults and in liver or kidney concerns.
• Onset of benefit takes 4 to 12 weeks.
• Take with or without food.

Washout (accelerated elimination).

• Colestyramine 8 g three times daily for 11 days, or activated charcoal 50 g four times daily for 11 days.
• Needed for serious adverse effects, before pregnancy, or when switching to another hepatotoxic or marrow-suppressing drug.
• Confirm plasma teriflunomide under 0.02 mg/L on two tests 14 days apart before conception.

Combinations. Leflunomide plus methotrexate is more effective than either alone but raises liver toxicity, so use with close monitoring. Leflunomide with TNF inhibitors is used in refractory disease.

• First-line. Rheumatoid arthritis when methotrexate is contraindicated or not tolerated.
• Alternative. Psoriatic arthritis; adjunct to methotrexate in refractory disease.
• Specialist. Polyoma BK virus nephropathy after transplantation; selected vasculitis and lupus nephritis (limited evidence).
• Emergency. None.

Selection. Choose leflunomide for women who are not planning pregnancy and who have normal liver tests and blood pressure. Avoid in active hepatitis B or C or in patients with heavy alcohol use.

Contraindications. Pregnancy and women of childbearing potential without reliable contraception; breastfeeding; significant hepatic impairment; hepatitis B or C with active disease; severe immunodeficiency; bone marrow suppression; severe infection; hypoproteinaemia.

Serious adverse effects.

• Diarrhoea, nausea, mouth ulcers, alopecia, rash.
• Hepatotoxicity, including fatal liver failure (rare).
• Hypertension, peripheral neuropathy, interstitial lung disease (rare), neutropenia and infection.
• Weight loss.

Major interactions. Methotrexate and other hepatotoxic drugs (liver injury); rifampicin (raised teriflunomide); warfarin (raised INR); live vaccines; colestyramine reduces absorption; drugs highly protein bound (increased free fraction).

Common prescribing errors.

• Failing to counsel on pregnancy and washout.
• Starting without liver tests or hepatitis serology.
• Omitting blood pressure checks.
• Forgetting the drug stays for years after stopping.
• Combining with methotrexate without monitoring.

Special groups.

• Pregnancy: contraindicated; stop and complete washout before conception (also men planning to father a child, in whom washout is advised).
• Breastfeeding: avoid.
• Children: not routinely used; specialist care.
• Older adults: start 10 mg; watch infection.
• Kidney: no adjustment; low albumin in nephrotic states raises free drug.
• Liver: avoid in impairment.
• East Africa: screen for hepatitis B and C and HIV before starting, because viral hepatitis is common; colestyramine washout may be hard to obtain, so plan contraception and pregnancy carefully; check blood pressure.

Monitoring. Liver tests and full blood count monthly for 6 months, then every 6 to 8 weeks; blood pressure at baseline and each visit; weight; neuropathy symptoms. Reduce the dose or stop and wash out for transaminases over twice the upper limit; stop for over three times.

Referral and escalation. Jaundice or transaminases persistently raised; new cough or breathlessness; severe infection; pregnancy (immediate washout and specialist advice).

Comparison with alternative classes. Leflunomide matches methotrexate for efficacy and suits patients who cannot take it, but has more diarrhoea, hypertension and a long half-life. Sulfasalazine and hydroxychloroquine are weaker but safer in pregnancy.