Public Statement on Leflunomide (Arava) - Pancytopenia and Serious Skin Reactions
News
The European Commission granted marketing authorisations for the European Union to Hoechst Marion Roussel Deutschland GmbH on 2 September 1999 for the medicinal product Arava, which contains the active substance leflunomide. Arava is not yet marketed in the European Union.
Arava is indicated for the treatment of adult patients with active rheumatoid arthritis as a diseasemodifying antirheumatic drug (DMARD). The European Medicines Evaluation Agency's (EMEA) scientific committee, the Committee for Proprietary Medicinal Products (CPMP ), has been evaluating new safety information as it emerges.
Since September 1998, when Arava was launched in the United States, an estimated 76,100 patients have been treated world-wide. 16 potential cases of pancytopenia (a serious haematological reaction) and 9 cases of serious skin reactions have been reported.
Leflunomide inhibits cellular proliferation. Once administered, it is rapidly converted to an active metabolite (A771726). The elimination of A771726 is slow (i.e. from 1 to 4 weeks are required by the body to eliminate half of this product). Nevertheless, the elimination of this metabolite can be accelerated by the administration of another medicinal product, either cholestyramine or active charcoal (a so-called washout procedure).
The haematological reactions reported with leflunomide may be due to a direct toxicity of the active metabolite of leflunomide while the serious skin reactions may be the consequence of a hypersensitivity reaction to the compound. Furthermore, most of the haematological reactions occurred when leflunomide was administered concomitantly or after treatment with another DMARD or when treatment with leflunomide had just been changed to another DMARD exhibiting an haematological toxicity (e.g. methotrexate).
Following a review of the above information, the EMEA wishes to draw attention to the following:
- Recent treatment with hepatotoxic or haematotoxic DMARDs may result in increased side-effects. Therefore, the balance of risks and benefits has to be carefully considered before treatment with leflunomide is initiated.
- Since the active metabolite of leflunomide is slowly eliminated from the organism, serious undesirable effects might occur (e.g. hepatotoxicity, hematotoxicity or allergic reactions) even if the treatment with leflunomide has been stopped. Therefore, when such toxicity occurs or when switching to another DMARD after treatment with leflunomide or in case of desired pregnancy, a washout procedure should be performed.
- Considering that the risk associated with combination therapy, in particular in long-term treatment, is unknown and since such therapy can lead to additive or even synergistic toxicity, combination of leflunomide with another DMARD (e.g. methotrexate) is not advisable.
- Patients who experience symptoms such as paleness, tiredness, increased proneness to infections, bruising, skin rash or mucous membrane lesions (esp. in the mouth) should contact their doctor immediately.
- In the case of a desired pregnancy, patients wishing to become pregnant or father children should inform their doctor beforehand.
As an urgent measure, the prescribing and patient information has been modified through a rapid procedure at the request of the marketing authorisation holder. Before the launch of Arava in the European Union, the EMEA thought it necessary to provide this new information to the public.
Relevant changes to the product information (available on the EMEA website since July 1999) are indicated below. For the complete scientific evaluation of Arava and the complete revised product information see the European Public Assessment Report (CPMP/1694/99), also available on the EMEA website.