Some of the views expressed in the following notes on newly approved products should be regarded as preliminary, as there may have been limited published data at the time of publication, and little experience in Australia of their safety or efficacy. However, the Editorial Executive Committee believes that comments made in good faith at an early stage may still be of value. Before new drugs are prescribed, the Committee believes it is important that more detailed information is obtained from the manufacturer's approved product information, a drug information centre or some other appropriate source.

Arava (Hoechst Marion Roussel)

10 mg, 20 mg and 100 mg tablets

Approved indication: rheumatoid arthritis

Australian Medicines Handbook Section 14

Disease modifying antirheumatic drugs, such as gold and methotrexate, are increasingly prescribed for patients with rheumatoid arthritis. These drugs are toxic and may not slow the progression of the disease. Leflunomide is an attempt to produce an effective, well tolerated treatment. It is an immuno modulating drug which inhibits the pyrimidine synthesis that is associated with cell proliferation. Leflunomide also has a weak anti-inflammatory action.

Patients begin taking leflunomide with a loading dose for three days. This is because the drug has a long half-life (2-3 weeks). There is extensive first pass metabolism which converts leflunomide to its active form. The active metabolite is slowly excreted into the urine and faeces. Smoking increases clearance.

Leflunomide has been compared with placebo and sulfasalazine, a drug with the capability of retarding disease progression. A total of 359 patients were randomized to be treated for 24 weeks. Although many patients did not complete the study, the arthritic symptoms and signs responded to treatment in 20% of the patients in the placebo group compared with 55% of the leflunomide group and 56% of the sulfasalazine group. X-rays revealed that there was less disease progression in the active treatment groups. The study did not have enough power to show a difference between leflunomide and sulfasalazine.1 Other studies suggest the efficacy of leflunomide and methotrexate may be similar.

While 96 of the 133 patients taking leflunomide completed the trial, 19 (14%) had to withdraw because of adverse events.1 Common problems were diarrhoea, nausea, rashes and alopecia. Other adverse effects include headache, dizziness, leucopenia and altered liver function. Regular white blood counts and liver function tests are recommended.

In October 1999 the European Medicines Evaluation Agency issued a statement warning the public about serious adverse reactions to leflunomide. There was particular concern about reports of pancytopenia and serious skin reactions including Stevens-Johnson syndrome and toxic epidermal necrolysis.

Few significant drug interactions have emerged, but live vaccines are not recommended until six months after the conclusion of treatment. Leflunomide is contraindicated in pregnancy.

Until more information is available about leflunomide it will probably be reserved for patients with severe active rheumatoid arthritis who cannot tolerate or do not respond to other disease modifying drugs.


  1. Smolen JS, Kalden JR, Scott DL, Rozman B, Kvien TK, Larsen A, et al. Efficacy and safety of leflunomide compared with placebo and sulphasalazine in active rheumatoid arthritis: a double-blind, randomised, multi centre trial. Lancet 1999;353:259-66.