Leflunomide is a pyrimidine synthesis inhibitor indicated in adults for the treatment of active rheumatoid arthritis (RA). RA is an auto-immune disease characterized by high T-cell activity. T cells have two pathways to synthesize pyrimidines: the salvage pathways and the de novo synthesis. At rest, T lymphocytes meet their metabolic requirements by the salvage pathway. Activated lymphocytes need to expand their pyrimidine pool 7- to 8-fold, while the purine pool is expanded only 2- to 3-fold. To meet the need for more pyrimidines, activated T cells use the de novo pathway for pyrimidine synthesis. Therefore, activated T cells, which are dependent on de novo pyrimidine synthesis, will be more affected by leflunomide's inhibition of dihydroorotate dehydrogenase than other cell types that use the salvage pathway of pyrimidine synthesis.

Pharmacology

Leflunomide is an isoxazole immunomodulatory agent which inhibits de novo pyrimidine synthesis and has anti-proliferative activity. Following oral administration, it is rapidly metabolized to A771726, which is active in vitro and is presumed to be the active drug in vivo. Leflunomide has demonstrated prophylactic and therapeutic effects in animal models of autoimmune disease. In addition, leflunomide has exhibited anti-inflammatory and weak analgesic and antipyretic activity. In a model of experimental septicemia, leflunomide did not alter the resistance of mice to bacterial pathogens.

Leflunomide is indicated in adults for the treatment of active rheumatoid arthritis (RA) to reduce signs and symptoms and to retard structural damage as manifested by x-ray erosions and joint space narrowing.

Leflunomide once-daily oral dosing for rheumatoid arthritis patients. After a loading dose of 100 mg once daily for 3 days, the maintenance dose is 20 mg once daily. Leflunomide does not require step wise dose increment over time. The dose may be decreased to 10 mg daily if tolerability issues arise.

Leflunomide is contraindicated in patients with known hypersensitivity to leflunomide or any of the other components of leflunomide, hepatic impairment, severe uncontrolled infections and bone marrow dysplasia.

Adverse reactions associated with the use of leflunomide include diarrhea, nausea, vomiting, abdominal pain, headache, respiratory infection, bronchitis, elevated liver enzymes, aggravation of pre-existing hypertension, alopecia, and rash.

Overdose Effects

There is no human experience regarding leflunomide over dosage. In the event of a significant overdose or toxicity, cholestyramine or charcoal administration is recommended to accelerate elimination.

Caution should be taken for those female with child bearing potential who are not using reliable contraception and for the subject of renal insufficiency. Leflunomide should be stopped before becoming pregnant. Liver function should be monitored before starting treatment.

Pregnancy & Lactation

Leflunomide is not recommended for pregnant women. Pregnancy must be avoided during leflunomide treatment or prior to the completion of the drug elimination procedure after leflunomide treatment. Leflunomide should not be used by nursing mothers. It is not known whether leflunomide is excreted in human milk. Many drugs are excreted in human milk and there is a potential for serious adverse reactions in nursing infants from leflunomide. Therefore, a decision should be made whether to proceed with nursing or initiate treatment with leflunomide, taking into account the importance of the drug to the mother.