What are the potential side effects of leflunomide ( Disease-Modifying Antirheumatic Drug - DMARD)?

Leflunomide Side Effects

Leflunomide's side effects predominantly involve gastrointestinal disturbances (especially diarrhea), hepatotoxicity requiring mandatory monitoring, bone marrow suppression, and teratogenicity, with rare but potentially fatal severe liver injury being the most serious concern. 1

Gastrointestinal Side Effects

• Diarrhea is the most common adverse effect, occurring in approximately 27% of patients in controlled trials 2
• Nausea affects approximately 13% of patients 2
• Other GI effects include dyspepsia (10%), abdominal pain, and loss of appetite 3, 4
• These symptoms typically occur early in treatment and may diminish with continued use 3

Hepatotoxicity (Most Critical)

• Rare cases of severe liver injury, including fatal outcomes, have been reported 1
• Most severe hepatotoxicity occurs within the first 6 months of therapy, particularly in patients with multiple risk factors for liver damage 1
• Elevated liver enzymes (ALT/AST) occur in approximately 10% of patients 1, 2
• In clinical practice studies, grade 2-3 hepatotoxicity occurred in 8.9% of patients, with the majority occurring within the first 6 months 5
• Monthly ALT monitoring is mandatory for the first 6 months, then every 6-8 weeks thereafter 1
• For ALT elevations 2-3 times upper limit of normal, dose reduction to 10 mg daily is recommended 1

Hematologic Toxicities

• Leukopenia occurs at higher frequency compared to placebo 3
• Rare but serious reports of pancytopenia, agranulocytosis, and thrombocytopenia have been documented 4, 6, 1
• The estimated incidence of pancytopenia ranges from 1 in 3,698 to 1 in 4,582 patients when taking leflunomide alone 6
• Complete blood count with differential must be monitored monthly for the first 6 months, then every 6-8 weeks thereafter 1
• Risk is highest in patients receiving concomitant immunosuppressive therapy (especially methotrexate) or those with prior hematologic abnormalities 1

Dermatologic Effects

• Alopecia (hair loss) occurs in approximately 9% of patients 1, 2
• Rash affects approximately 12% of patients 2
• Rare serious skin reactions including Stevens-Johnson syndrome and DRESS syndrome have been reported 3
• Patients should be instructed to report any new rash or mucous membrane lesions immediately 1

Infectious Complications

• Leflunomide causes immunosuppression, increasing susceptibility to serious and opportunistic infections 1
• Specific infections of concern include Pneumocystis jiroveci pneumonia, tuberculosis (including extrapulmonary), aspergillosis, and sepsis 1
• Respiratory infections occur in approximately 21% of patients 2
• Severe infections including sepsis, which may be fatal, have been reported 1

Other Notable Side Effects

• Hypertension occurs and requires blood pressure monitoring before starting treatment and periodically thereafter 1, 7
• Headache affects approximately 13% of patients 2
• Weight loss may occur, though the exact incidence is not yet definitively established 8
• Interstitial lung disease is a potential but not yet proven increased risk 8
• Peripheral neuropathy has been reported in postmarketing surveillance 8

Teratogenicity and Reproductive Concerns

• Leflunomide is Category X in pregnancy and absolutely contraindicated 4, 1
• The drug is teratogenic in animal studies and can cause fetal death or birth defects 1, 9
• Contraindicated in nursing mothers 4
• Both male and female patients of childbearing potential must use contraception 8, 9
• Drug elimination procedure with cholestyramine or activated charcoal is required before attempting pregnancy 1

Drug Interactions Increasing Toxicity

• Rifampin increases leflunomide levels by approximately 40% and should be used with extreme caution 4, 1
• Concomitant use with methotrexate resulted in 2-3 fold elevation in liver enzymes in 5 of 30 patients in one study 1
• Hepatotoxic drugs increase the risk of liver injury when used with leflunomide 1
• Warfarin may have increased INR when co-administered with leflunomide 1

Critical Monitoring Requirements

• Baseline assessment must include: complete history and physical examination, CBC with differential, liver function tests, blood pressure, and pregnancy test if indicated 4, 6
• First 6 months: Monthly CBC with differential and liver function tests 4, 6, 1
• After 6 months: Continue monitoring every 6-8 weeks if stable 4, 1
• If used concomitantly with methotrexate, monthly monitoring should continue indefinitely 1

When to Stop Leflunomide

• Discontinue immediately if: evidence of bone marrow suppression, ALT >3 times upper limit of normal, serious infection develops, or serious skin reactions occur 1
• Consider cholestyramine or activated charcoal washout procedure to rapidly eliminate the drug in these situations 1