Leflunomide (Arava)

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 hepatoxicity 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.

Breast-feeding is contraindicated on 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: leflonomide in rheumatoid arthritis – strengths and weaknesses.” Curr Opin Rheumatol 23:288.