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Risk of Leflunomide-Associated Pancytopenia Appears Greater With Concomitant Methotrexate Treatment and Increased Patient Age

Leflunomide treatment is associated with severe pancytopaenia, the risk of which is increased when the drug is combined with methotrexate and when given to older patients, according to Australian researchers.

"Because of the long half-life of leflunomide, myelosuppression can persist after the drug is discontinued," said Jonathan Chan, MB, BS, MRCP, and colleagues of Princess Alexandra Hospital, Brisbane, Queensland. "Regular monitoring is essential for this serious adverse effect, even in patients who have been treated for years."

Previous clinical trials have demonstrated leflunomide to be superior to placebo and as effective as methotrexate or sulfasalazine. Additionally, the combination of leflunomide and methotrexate has been shown to be effective as add-on therapy in patients with active rheumatoid arthritis (RA) who have inadequate response to methotrexate alone.

However, the safety of leflunomide in combination with other disease-modifying antirheumatic drugs has not been fully evaluated.

In a recently published report, the researchers report 5 cases of severe pancytopaenia associated with concomitant leflunomide and methotrexate in patients admitted to the Princess Alexandra Hospital and review 13 additional cases of pancytopaenia with leflunomide, combined with methotrexate in 9 cases, reported since 2000.

Among the cases, 17 patients were being treated for RA, and 1 for systemic lupus erythematosus. Patient age ranged from 18 to 79 years, with all but 3 patients aged 60 years and over.

The time to onset of pancytopaenia was variable, ranging from 11 days to 4 years. Pancytopaenia was typically severe, requiring hospital admission for at least 14 patients. Sepsis was recorded in 6 cases.

Among the 5 recorded deaths, 4 of the patients had been treated with concomitant methotrexate during leflunomide therapy. In 1 case, the patient had been stable for 4 years during treatment with leflunomide, methotrexate, and hydroxychloroquine, prior to fatal pancytopaenia triggered by acute renal failure.

Information regarding routine blood cell count monitoring or measurement of leflunomide concentrations was not available.

Analysis showed an association between leflunomide treatment, with or without methotrexate, and severe pancytopaenia, with a probable causal association in 5 cases and possible association in the remainder suggested by the Naranjo probability scale.

The researchers note that the global updated leflunomide product information advises monitoring the complete blood cell count monthly for the first 6 months, and every 6?8 weeks thereafter.

"If leflunomide is used with concomitant methotrexate, monitoring should be performed monthly," they advised.

Ann Pharmacother 2004 Jul;38:7:1206-11. Epub 2004 Jun 08. "Leflunomide-Associated Pancytopenia With or Without Methotrexate"

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