What are the features of leflunomide (Disease-Modifying Antirheumatic Drug (DMARD)) toxicities?

Features of Leflunomide Toxicities

Leflunomide toxicities primarily affect the gastrointestinal system, liver, bone marrow, and skin, with potentially severe hepatotoxicity being the most concerning adverse effect requiring careful monitoring. 1

Common Gastrointestinal Toxicities

• Most common adverse effects include nausea, diarrhea, loss of appetite, weight loss, and dyspepsia 1
• Gastrointestinal irritation is predominant among leflunomide's toxicity profile and often occurs early in treatment 1, 2
• These symptoms may diminish with continued use but can lead to discontinuation in some patients 3

Hepatotoxicity

• Severe liver injury can occur and may be fatal in rare cases 2, 1
• Most cases of severe hepatotoxicity occur within the first 6 months of therapy and in patients with multiple risk factors for liver damage 1, 2
• Elevated liver enzymes (particularly ALT/AST) are common and require regular monitoring 2, 1
• Risk of hepatotoxicity increases when leflunomide is combined with other hepatotoxic drugs, especially methotrexate 2, 4

Hematologic Toxicities

• Rare but serious reports of pancytopenia, agranulocytosis, and thrombocytopenia have been documented 1, 2
• Higher risk in patients who have recently used methotrexate or other immunosuppressive agents 2, 1
• Leukopenia was reported at a higher frequency compared to placebo in clinical trials 1
• Regular complete blood count monitoring is essential, especially during the first 6 months of therapy 1, 2

Immunosuppression and Infection Risk

• Increased susceptibility to infections, including opportunistic infections 2
• Severe infections including sepsis (potentially fatal) have been reported 2
• Particular risk for Pneumocystis jiroveci pneumonia, tuberculosis (including extrapulmonary), and aspergillosis 2
• Patients with severe immunodeficiency should not receive leflunomide 2

Dermatologic Toxicities

• Reversible alopecia (hair loss) is commonly reported 3, 2
• Rare cases of alopecia areata have been documented 5
• Various skin rashes and dermatologic reactions may occur 3

Other Notable Toxicities

• Hypertension requiring blood pressure monitoring 2, 3
• Headache and dizziness 1
• Peripheral neuropathy (rare) 3
• Teratogenicity - contraindicated in pregnancy (Category X) 1, 2
• Should not be used in nursing mothers 1, 2

Monitoring Recommendations

• Baseline assessment: Complete history and physical examination, CBC with differential, liver function tests, and pregnancy test if indicated 1
• Monthly CBC with differential and liver function tests for the first 6 months 1
• After 6 months, continue monitoring every 6-8 weeks if stable 1
• Blood pressure should be checked before starting treatment and periodically thereafter 2
• More frequent monitoring required when combined with other immunosuppressants, especially methotrexate 2

Risk Management

• Dose reduction to 10 mg/day may allow continued administration if ALT elevations are between 2-3 times ULN 2
• For ALT elevations >3 times ULN, leflunomide should be discontinued 2
• Drug elimination procedure with cholestyramine or activated charcoal may be necessary in cases of toxicity or when planning pregnancy 2
• Patients should be advised to report symptoms such as unusual tiredness, abdominal pain, jaundice, easy bruising, recurrent infections, or fever 2

Special Considerations

• Not recommended in patients with significant hepatic impairment or evidence of hepatitis B or C infection 2
• Contraindicated in patients with hypersensitivity to leflunomide or its metabolites 1
• Rifampin increases leflunomide levels and should be used with caution 1
• Appropriate contraception is essential during treatment for both men and women of reproductive potential 2