Saara Rawn MD/PhD, Raj Carmona MBBS FRCPC
INDICATIONS (including off-label uses)
- Rheumatoid arthritis
- Off-Label: Juvenile Idiopathic Arthritis, Psoriatic Arthritis, refractory Dermatomyositis, Systemic Lupus Erythematosus
- 20 mg PO once daily
- 10 mg once daily can be used as a starting dose if there are particular concerns for hepatotoxicity or myelosuppression (eg. prior adverse reactions with methotrexate), or if 20 mg is not tolerated.
- Use is contraindicated in liver disease, or if ALT > 2 X ULN.
- Not recommended with hepatitis B or C infection.
- Leflunomide is contraindicated in moderate to severe renal impairment.
- Baseline: CBC, serum creatinine, AST, ALT.
- Monthly for first 3-6 months: CBC, Cr, AST, ALT, Alb then every 2-3 months thereafter. Monitor more frequently if clinically indicated. If ALT 2-3 X ULN, reduce dose to 10 mg once daily and monitor ALT regularly. If persistently elevated > 2X ULN or 3X ULN, stop leflunomide and consider starting the drug elimination protocol.
- Drug elimination protocol: cholestyramine 8 g PO TID for 11 days or activated charcoal 50 g QID for 11 days.
- Severe hepatic impairment, pregnancy, moderate to severe renal impairment, immunodeficiency states, impaired bone marrow function.
COMMON SIDE EFFECTS AND ADVERSE REACTIONS
- GI side-effects are most common: Diarrhea (17-27%), nausea (9-13%), vomiting, oral mucosal ulcers
- Hepatic: Abnormal hepatic function tests (5% to 10%), increased serum ALT (>3 x ULN: 2% to 4%; reversible)
- Hematologic: can cause pancytopenia, thrombocytopenia, agranulocytosis
- Central nervous system: Headache (7-13%), dizziness (4-7%)
- Dermatologic: Alopecia (9-17%), skin rash (10-12%), Pruritus (4% to 6%)
- Cardiovascular: Hypertension (9-10%)
- Hypersensitivity: Hypersensitivity reaction (1% to 5%)
- Neuromuscular & skeletal: Back pain (5% to 8%), weakness (3% to 6%)
- Respiratory: Rarely, can be associated with ILD. Bronchitis (5% to 8%), rhinitis (2% to 5%)
PREGNANCY AND LACTATION
- Leflunomide is contraindicated in pregnancy as it is a teratogen. An accelerated drug elimination protocol is advised if a patient conceives on this medication.
- Breastfeeding is contraindicated with this medication.
MECHANISM OF ACTION
- Leflunomide inhibits the synthesis of the pyrimidine, ribonucleotide uridine monophosphate (rUMP). It achieves this by inhibiting the mitochondrial enzyme dihydroorotate dehydrogenase (DHODH) which prevents cells from advancing through G1 to S phase of the cell cycle by activating programmed cell death (via the p52 pathway).
SUMMARY OF EVIDENCE (in development)
- Smolen JS et al. 1999. “Efficacy and safety of leflunomide compared with placebo and sulphasalazine in active rheumatoid arthritis: a double-blind, randomized, multicenter trial. European Leflunomide Study Group.” Lancet 353:259.
- Behrens F et al. 2011. “Update 2011: leflunomide in rheumatoid arthritis – strengths and weaknesses.” Curr Opin Rheumatol 23:288.