Leflunomide (leflunomide)

Because of the possible role of the liver in the metabolism, elimination, and recirculation of leflunomide and because adverse hepatic effects have been reported with the drug, leflunomide is not recommended in patients with preexisting acute or chronic liver disease, including those who are seropositive for hepatitis B or C, or those with baseline serum ALT concentrations exceeding twice the upper limit of normal (ULN).

The manufacturer makes no specific recommendation for dosage adjustment in patients with renal impairment; however, caution is advised if leflunomide is used in such patients.

Leflunomide is administered orally as a single daily dose. The drug may be taken without regard to meals.

When leflunomide is used for the management of rheumatoid arthritis, the manufacturer recommends that therapy be initiated with a loading dosage given for 3 days followed by the usual daily dosage. Eliminating the loading dose regimen may decrease the risk of adverse effects; this could be important for patients at increased risk of hematologic or hepatic toxicity (e.g., those currently receiving or who have recently received methotrexate or other immunosuppressive agents). If this initial loading dosage is not used, steady-state plasma concentrations may not be attained for 2 months or longer.

Aspirin, nonsteroidal anti-inflammatory agents (NSAIAs), and low-dose corticosteroids may be continued in adults receiving leflunomide for the management of rheumatoid arthritis. Leflunomide has been used concomitantly with methotrexate in a limited number of patients with rheumatoid arthritis. The manufacturer states that concomitant administration of leflunomide with antimalarials, azathioprine, methotrexate, penicillamine, or oral or injectable gold has not been adequately studied.

No dosing information is available for this tab.

No dosing information is available for this tab.

Although specific drug interaction studies are not available, leflunomide has been administered concomitantly with aspirin, nonsteroidal anti-inflammatory agents (NSAIAs), or low dosages of oral corticosteroids (e.g., prednisone 10 mg daily) in clinical studies in patients with rheumatoid arthritis, and the manufacturer states that these drugs may be continued in patients receiving leflunomide. Leflunomide has been used concomitantly with methotrexate in a limited number of patients with rheumatoid arthritis, but the manufacturer states that concomitant administration of leflunomide with antimalarials, azathioprine, methotrexate, penicillamine, or oral or injectable gold has not been adequately studied. (See Drug Interactions: Methotrexate and also see Nonsteroidal Anti-inflammatory Agents.)

Because it can take up to 2 years for plasma concentrations of the active metabolite of leflunomide (A77 1726; commercially available as teriflunomide) to decrease to undetectable concentrations following discontinuance of the drug, the possibility exists that drug interactions could occur in patients who are no longer receiving leflunomide therapy. The risk of such drug interactions can be reduced by use of a drug elimination procedure to hasten elimination of A77 1726 after discontinuance of leflunomide therapy. (See Dosage and Administration: Drug Elimination Procedures.) A drug elimination procedure may be appropriate in patients who are discontinuing leflunomide therapy and will receive subsequent therapy with a drug having a known potential for hematologic suppression. However, it is possible that such a strategy may worsen rheumatoid arthritis symptoms in patients who had been responding to leflunomide.

There are no contraindication interactions for this drug.

There are no severe interactions for this drug.

There are no moderate interactions for this drug.

There is no enhanced messaging for this drug.

There are no contraindication contraindications for this drug.

There are no severe contraindications for this drug.

There are no moderate contraindications for this drug.

There is no enhanced messaging for this drug.

There are no severe adverse reactions for this drug.

There are no less severe adverse reactions for this drug.

No enhanced messaging available.

No enhanced messaging available.

Leflunomide can cause fetal toxicity when administered to pregnant women. Since the risks clearly outweigh any possible benefits in women who are or may become pregnant, leflunomide is contraindicated in such women. Leflunomide therapy should not be initiated in a woman of childbearing potential until pregnancy is excluded and it has been confirmed that the woman is using a reliable form of contraception.

Although there are no adequate and controlled studies to date in humans, leflunomide has been shown to increase the risk of fetal death or teratogenic effects in animals. Since the risks clearly outweigh any possible benefits in women who are or may become pregnant, leflunomide is contraindicated in such women. The potential for increased risk of birth defects should be discussed with female patients of childbearing potential, and clinicians should advise women that they may be at increased risk of having a child with birth defects if they are pregnant, become pregnant while receiving leflunomide, or do not wait to become pregnant until they have followed a drug elimination procedure following discontinuance of leflunomide.

If leflunomide is administered inadvertently during pregnancy or if the patient becomes pregnant while receiving the drug, leflunomide should be discontinued and the patient informed of the potential hazard to the fetus. Women of childbearing potential should be advised to notify their clinician immediately if they experience a delay in menses or believe they may be pregnant so that pregnancy testing can be done. Use of a drug elimination procedure to rapidly lower plasma concentrations of A77 1726 to undetectable concentrations early in a pregnancy (i.e., at the first delay in menses) may decrease the risk to the fetus. To monitor fetal outcomes of pregnant women exposed to leflunomide, clinicians are encouraged to register such patients by calling 877-311-8972.

The manufacturer recommends that all women of childbearing potential receive an 11-day cholestyramine drug elimination procedure to decrease plasma concentrations of A77 1726 to undetectable concentrations (less than 0.02 mcg/mL) following discontinuance of leflunomide therapy since these concentrations are presumed to be associated with minimal risk based on animal data. Following completion of the cholestyramine regimen, plasma concentrations of A77 1726 should be determined to verify that concentrations are undetectable. This is especially important in women who wish to become pregnant after discontinuing the drug.

Although available information does not indicate that leflunomide therapy is associated with an increased risk of male-mediated fetal toxicity, animal studies to evaluate this specific risk have not been conducted. To minimize risk, men wishing to father a child should consider discontinuing leflunomide therapy and undergoing an 11-day cholestyramine drug elimination procedure to decrease plasma concentrations of A77 1726 to undetectable levels.

Reproduction studies in rats and rabbits using leflunomide oral doses of 1 mg/kg have not revealed evidence of harm to the fetus. However, reproduction studies in rats using oral leflunomide dosages of 15 mg/kg daily during organogenesis (systemic exposure approximately 10% of the human exposure level to A77 1726 based on AUC) have shown teratogenic effects (most notably anophthalmia or microphthalmia and internal hydrocephalus). Under these exposure conditions, leflunomide also caused a decrease in maternal body weight, an increase in embryolethality, and a decrease in fetal body weight for surviving fetuses. Reproduction studies in rabbits using oral leflunomide dosages of 10 mg/kg daily during organogenesis (exposure equivalent to the maximum human exposure to A77 1726 based on AUC) resulted in fused, dysplastic sternebrae in offspring. In reproduction studies in female rats using leflunomide dosages of 1.25 mg/kg daily (systemic exposure approximately 1% of the human exposure level to A77 1726 based on AUC) beginning 14 days before mating and continuing until the end of lactation, the offspring exhibited marked (exceeding 90%) decreases in postnatal survival.

A77 1726 distributes into milk in rats. It is not known whether A77 1726 is distributed into human milk. Because of the potential for serious adverse reactions to leflunomide in nursing infants if it were distributed, a decision should be made whether to proceed with nursing or initiate therapy with leflunomide, taking into account the importance of the drug to the woman.

No enhanced messaging available.