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

ADULT DOSING

  • 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.

DOSE ADJUSTMENT

Hepatic Impairment

  • Use is contraindicated in liver disease, or if ALT > 2 X ULN.
  • Not recommended with hepatitis B or C infection.

Renal Impairment

  • Leflunomide is contraindicated in moderate to severe renal impairment.

MONITORING

  • 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.

CONTRAINDICATIONS

  • 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.