Leflunomide: long-acting DMARD with strict monitoring and pregnancy rules

The UK product information describes leflunomide as indicated for adults with active rheumatoid arthritis as a disease-modifying antirheumatic drug and for active psoriatic arthritis. It is a selective immunosuppressant with antiproliferative properties, which means it slows the activity of immune cells involved in joint inflammation.

It has to be started and supervised by specialists. The information warns that recent or concurrent treatment with liver-toxic or blood-toxic DMARDs such as methotrexate may increase the risk of serious reactions, so starting it is a careful decision.

In both rheumatoid and psoriatic arthritis, the product information describes a loading dose of 100mg once daily for 3 days, noting that omitting the loading dose may lower the risk of adverse events, followed by a lower daily maintenance dose set by the specialist.

Monitoring is part of the treatment, not an optional extra. ALT (a liver enzyme) and a complete blood count, including white cells and platelets, must be checked together before starting, every two weeks during the first six months, and every 8 weeks thereafter. Liver enzyme rises of 2 to 3 times the upper limit of normal may prompt a dose reduction and weekly checks, and larger rises call for stopping and washout.

The active metabolite, A771726, has a long half-life, usually 1 to 4 weeks, so serious effects such as liver toxicity, blood toxicity or allergic reactions might still occur after stopping. If a serious reaction occurs, or if switching to another DMARD, a washout procedure may be used to clear the metabolite faster. Cholestyramine or activated charcoal rapidly reduce the metabolite, which is why they are otherwise not recommended during treatment.

The information stresses that switching from leflunomide to another DMARD without following the washout may increase the risk of serious reactions even for a long time afterwards.

The most frequent common effects include a mild rise in blood pressure, reduced white blood cells, tingling or numbness, headache, dizziness, diarrhoea, nausea and rash. Rare but serious problems include severe liver injury (mostly in the first 6 months), serious infections, severe blood problems and severe skin reactions. Colitis, including microscopic colitis, has been reported, so unexplained chronic diarrhoea should be reported.

Seek medical advice promptly for yellow skin or eyes, fever or sore throat, persistent diarrhoea, unexplained bruising or bleeding, or breathlessness. Immunosuppressants may also increase susceptibility to infections and, with some agents, the risk of malignancy.

The contraindications include hypersensitivity (especially previous Stevens-Johnson syndrome or toxic epidermal necrolysis), impaired liver function, severe immunodeficiency states, significantly impaired bone marrow function or significant anaemia or low blood counts from other causes, serious infections, moderate to severe renal insufficiency, severe low protein levels such as in nephrotic syndrome, pregnancy, and breastfeeding.

The active metabolite is suspected to cause serious birth defects, so women who could become pregnant must use reliable contraception during treatment and afterwards until levels have fallen. After stopping, plasma levels can stay above the safe threshold for a prolonged period, and a waiting period of about 2 years is described unless an accelerated washout is used. Anyone who suspects pregnancy must tell the specialist immediately.

Methotrexate co-administration showed raised liver enzymes in some patients, and concurrent hepatotoxic or haematotoxic DMARDs are not advisable. Warfarin and other coumarin anticoagulants may show increased prothrombin time, so INR monitoring is needed. NSAIDs and corticosteroids can be continued after starting leflunomide. Live attenuated vaccines are not recommended.

Because of additive liver toxicity, it is recommended that alcohol be avoided during treatment. Tell your specialist or pharmacist about every medicine and supplement you take.