Leflunomide

Isoxazole

Indications

Rheumatoid arthritis that cannot be managed with NSAIDs.
At least as effective as methotrexate, and more effective than sulfasalazine.

Mechanism

Inhibits dihydroorotate dehydrogenase (DHODH), and hence uridine synthesis.
Clinical response in 40–65% of patients. Slows the rate of bone erosion on X-ray.

Adverse effects

Diarrhoea, vomiting, alopecia. Raised AST, ALT. Anaemia, pancytopaenia esp. with methotrexate.

Contra-indications

Pregnancy

Pharmacokinetics

Quickly metabolised to A77 1726 (M1). Half life of M1 is approx. 2 weeks, hence loading dose is necessary. Renal impairment: A77 1726 (M1) levels higher, and M1 is not dialysable.

Discontinuation

Cholestyramine 8g tds for 11 days.