Leflunomide

Leflunomide is a pyrimidine synthesis inhibitor used in rheumatoid arthritis and psoriatic arthritis, alone or combined with methotrexate. It is a prodrug whose active metabolite has a very long half-life, which dominates its safety planning, especially in pregnancy and after toxicity.

Class. Dihydroorotate dehydrogenase inhibitor, conventional synthetic disease-modifying anti-rheumatic drug.

Mechanism. The active metabolite teriflunomide blocks mitochondrial dihydroorotate dehydrogenase, depleting pyrimidines needed by rapidly proliferating activated T and B lymphocytes.

Pharmacokinetics. Rapid conversion to teriflunomide in gut wall and liver. Bioavailability is about 80 percent, protein binding over 99 percent, and enterohepatic recirculation gives a half-life of about 2 weeks. After stopping, plasma levels may stay detectable for up to 2 years without a washout.

Active rheumatoid arthritis (second line or in combination).

• Loading dose (optional): 100 mg once daily for 3 days. Many specialists omit it because it increases diarrhoea, hepatotoxicity and hypertension.

• Maintenance: 10 to 20 mg once daily, orally.

• Maximum dose: 20 mg once daily.

• Titration: start 10 mg and increase to 20 mg if response is inadequate and tolerated; reduce to 10 mg if adverse effects.

• Duration: long term.

Active psoriatic arthritis. Same loading and maintenance dose. Efficacy is less certain for skin disease.

Washout (accelerated elimination). Required before conception, after serious toxicity, or before urgent switching to another hepatotoxic or myelosuppressive drug. Colestyramine 8 g three times daily for 11 days (or activated charcoal 50 g four times daily for 11 days). Confirm teriflunomide plasma level under 0.02 mg/L on two tests 14 days apart.

Contraindications. Pregnancy and women of childbearing potential not using effective contraception, severe hepatic impairment, severe immunodeficiency, serious active infection, significant bone marrow depression, and concurrent teriflunomide.

Boxed-warning-level risks. Embryofoetal toxicity and severe, sometimes fatal, hepatotoxicity including acute liver failure.

Adverse effects. Common: diarrhoea, nausea, hair thinning, raised ALT, rash, hypertension, weight loss, headache. Serious: liver injury, interstitial lung disease (new or worsened, can be fatal), peripheral neuropathy, myelosuppression, severe skin reaction, serious infection including tuberculosis reactivation.

Major interactions. Methotrexate and other hepatotoxic drugs (additive liver injury), warfarin (raised INR), rifampicin (raised metabolite levels), colestyramine and charcoal (reduced levels), live vaccines (avoid), phenytoin and tolbutamide (raised levels), repaglinide, paclitaxel and other CYP2C8 substrates.

Common prescribing errors. Giving the full loading dose to patients on methotrexate or with liver disease; not planning washout before conception; continuing during respiratory symptoms.

Special groups.

• Pregnancy: contraindicated. Women planning conception must complete washout and confirm a level under 0.02 mg/L. If conception occurs on treatment, stop and start washout immediately.

• Men: counsel about washout before attempting conception.

• Breastfeeding: avoid.

• Children: not routinely used; specialist only.

• Older adults: no dose change but monitor liver enzymes and blood pressure closely.

• Kidney impairment: mild to moderate, no adjustment; severe or dialysis, avoid.

• Liver impairment: contraindicated in severe disease; avoid with ALT over twice the upper limit of normal.

• Region: screen for latent tuberculosis and hepatitis B and C before starting; both are common in East Africa and flare with immunomodulators.

Formulations. 10 mg and 20 mg tablets, once daily, with or without food.

Baseline. Full blood count, liver enzymes, albumin, creatinine, hepatitis B and C and HIV serology, latent tuberculosis assessment, blood pressure, weight and pregnancy test.

Monitoring. Liver enzymes and full blood count every 2 weeks for the first 6 months, then every 8 weeks. Blood pressure at each visit. Respiratory and neuropathy symptoms at each visit.

Stop thresholds.

• ALT over twice the upper limit of normal: reduce dose or hold and repeat in 2 weeks.

• ALT over three times the upper limit of normal despite dose reduction: stop and start washout.

• Neutrophils under 1.0 x 10^9/L, new interstitial lung disease, severe skin reaction, peripheral neuropathy, or uncontrolled hypertension: stop and start washout.

Referral and escalation. Refer to a rheumatologist for non-response at 3 to 6 months and to a hepatologist for persistent transaminase elevation. Stop and arrange washout before urgent switching.