Pharmacology.

Leflunomide’s active metabolite (M1) inhibits dihydro-oratate dehydrogenase, thereby inhibiting pyrimidine biosynthesis. M1 exhibits immunomodulating and anti-inflammatory effects.

Administration and Adult Dosage.

PO for rheumatoid arthritis 100 mg/day for 3 days, then 20 mg/day. Reduce dose to 10 mg if 20 mg is not tolerated.

Pediatric Dosage.

Safety and efficacy not established.

Geriatric Dosage.

Same as adult dosage.

Dosage Forms.

Tab 10, 20, 100 mg.

Patient Instructions.

Do not use if you are pregnant or planning to become pregnant. Men should use condoms because leflunomide can cause birth defects. Also, men planning on fathering children should discontinue leflunomide therapy and consult with their physicians. If you experience any major medical problems while on therapy, notify your physician. Avoid alcohol because this medication with alcohol can increase the risk of liver damage. Avoid immunizations unless approved by your physician.

Missed Doses. Take a missed dose as soon as you remember; if it is near the time for next dose, skip the dose; do not take a double dose.

Pharmacokinetics.

Fate. Leflunomide is 80% bioavailable, with peak plasma levels achieved in 6–12 hr. Because of its long half-life, an oral loading dosage is given over 3 days. Leflunomide is metabolized to a primary active metabolite (M1), with the parent drug rarely detectable in plasma. The specific site of metabolism is unknown; however, hepatic cytosolic and microsomal cellular fractions have been identified. Vdss of M1 is 0.13 L/kg; 99.3% is bound to albumin. M1 is eliminated by renal and biliary routes. Approximately 45% is eliminated as glucuronide and oxanilic acid metabolites in the urine and 48% as M1 in the feces.

t1⁄2. (M1) 18 ± 9 days.

Adverse Reactions.

Diarrhea, dyspepsia, hypertension, headache, rash, alopecia, and elevated liver function tests occur frequently.

Contraindications.

Immunocompromised patients; those positive for hepatitis B or C; pre-existing hepatic impairment; women planning to conceive.

Precautions.

Caution in patients with renal insufficiency. Do not give live vaccines to patients receiving leflunomide.

Drug Interactions.

Potentially hepatotoxic medications such as methotrexate can increase risk of hepatotoxicity. Rifampin increases peak plasma levels of M1. M1 inhibits CYP2C9. Plasma-free fraction of NSAIDs and tolbutamide levels might be increased. Co-administration with cholestyramine or activated charcoal decreases M1 levels.

Parameters to Monitor.

Monitor ALT at baseline and then monthly. If ALT levels are stable, monitor per clinical judgment.

Notes. If toxicity develops or if plasma levels must be decreased quickly, follow this drug elimination protocol: administer cholestyramine 8 g tid for 11 days. Verify that plasma levels are <0.02 mg/L by 2 separate tests at least 14 days apart. Without this procedure, drug elimination can take up to 2 yr. Leflunomide is equally or more effective than traditional antirheumatic agents such as methotrexate, sulfasalazine, injectable gold, and cyclosporine.