Leflunomide - Drug Monograph

Introduction

Leflunomide is a disease-modifying antirheumatic drug (DMARD) approved for the treatment of rheumatoid arthritis. It is an immunomodulatory agent with a unique mechanism of action that distinguishes it from other DMARDs. First approved by the FDA in 1998, leflunomide has become an important therapeutic option for managing moderate to severe rheumatoid arthritis in adults.

Mechanism of Action

Leflunomide exerts its immunomodulatory effects through inhibition of dihydroorotate dehydrogenase (DHODH), a mitochondrial enzyme involved in de novo pyrimidine synthesis. This inhibition leads to:

• Reduced proliferation of activated T-lymphocytes
• Decreased production of antibodies by B-lymphocytes
• Inhibition of tyrosine kinase activity
• Modulation of inflammatory cytokine production

The primary active metabolite, teriflunomide, is responsible for most of leflunomide's pharmacological effects, with a half-life of approximately two weeks due to extensive enterolepatic recirculation.

Indications

• Treatment of active rheumatoid arthritis in adults

• Psoriatic arthritis
• Juvenile idiopathic arthritis (in select cases)
• Prevention of organ transplant rejection (as adjunct therapy)
• Certain autoimmune conditions such as lupus and vasculitis

Dosage and Administration

• Loading dose: 100 mg orally once daily for 3 days
• Maintenance dose: 10-20 mg orally once daily

• Renal impairment: Use with caution; no specific dosage adjustment recommended
• Hepatic impairment: Contraindicated in severe hepatic impairment
• Elderly patients: Consider lower maintenance dose (10 mg daily)
• Pediatric patients: Safety and efficacy not established

• May be taken with or without food
• Tablets should be swallowed whole
• Consistent daily timing is recommended

Pharmacokinetics

• Well absorbed from gastrointestinal tract (≥80%)
• Food does not significantly affect absorption
• Peak plasma concentrations reached in 6-12 hours

• Volume of distribution: ~0.13 L/kg
• Protein binding: >99% (primarily albumin)
• Teriflunomide crosses the placenta and is present in breast milk

• Rapidly converted to active metabolite teriflunomide
• Undergoes extensive enterolepatic recirculation
• Minimal hepatic metabolism via CYP450 system

• Elimination half-life: ~2 weeks
• Excretion: Feces (48%) and urine (43%)
• May require accelerated elimination procedure with cholestyramine for rapid clearance

Contraindications

• Pregnancy or women of childbearing potential not using reliable contraception
• Severe hepatic impairment
• Known hypersensitivity to leflunomide or any component of the formulation
• Concomitant use with teriflunomide
• Patients with severe immunodeficiency states
• Significant bone marrow dysplasia

Warnings and Precautions

• Hepatotoxicity: Severe liver injury, including fatal cases, has been reported
• Embryo-fetal toxicity: Can cause fetal harm when administered to pregnant women

• Monitor for signs of infection (increased risk of serious infections)
• Peripheral neuropathy: Cases reported, usually reversible upon discontinuation
• Hypertension: Monitor blood pressure during treatment
• Interstitial lung disease: Rare but serious pulmonary adverse reaction
• Bone marrow suppression: Regular monitoring of blood counts required
• Skin reactions: Including Stevens-Johnson syndrome and toxic epidermal necrolysis

Drug Interactions

• Warfarin: Increased INR monitoring required
• Rifampin: May increase teriflunomide levels
• Cholestyramine: Accelerates elimination (used for washout)
• Live vaccines: Avoid concurrent administration
• Other hepatotoxic drugs: Increased risk of liver injury
• CYP2C8 substrates: Potential for increased exposure
• CYP2C9 substrates: Possible interactions

Adverse Effects

• Diarrhea (17%)
• Nausea (9%)
• Headache (7%)
• Rash (10%)
• Elevated liver enzymes (5-10%)
• Hypertension (10%)
• Alopecia (10%)

• Hepatotoxicity
• Severe infections
• Bone marrow suppression
• Stevens-Johnson syndrome
• Peripheral neuropathy
• Interstitial lung disease
• Severe skin reactions

Monitoring Parameters

• Complete blood count with differential
• Liver function tests (ALT, AST, bilirubin)
• Serum creatinine
• Hepatitis B and C serology
• Pregnancy test for women of childbearing potential
• Blood pressure

• ALT monthly for first 6 months, then every 6-8 weeks
• CBC monthly for first 6 months, then every 6-8 weeks
• Blood pressure regularly
• Signs and symptoms of infection
• Neurological symptoms
• Respiratory symptoms

Patient Education

• Importance of regular laboratory monitoring
• Need for effective contraception during treatment and after discontinuation
• Signs of hepatotoxicity (jaundice, dark urine, fatigue)
• Symptoms of infection (fever, chills, persistent sore throat)
• Report any new neurological symptoms
• Avoid live vaccines during treatment
• Do not breastfeed while taking leflunomide
• Accelerated elimination procedure required after discontinuation
• Potential for hair thinning or loss
• Importance of not sharing medication

References

1. FDA Prescribing Information: Leflunomide (2023) 2. Smolen JS, et al. EULAR recommendations for the management of rheumatoid arthritis. Ann Rheum Dis. 2020;79(6):685-699 3. van Riel PL, et al. Leflunomide in the treatment of rheumatoid arthritis: an evidence-based review of its place in therapy. Core Evid. 2016;11:39-48 4. Breedveld FC, Dayer JM. Leflunomide: mode of action in the treatment of rheumatoid arthritis. Ann Rheum Dis. 2000;59(11):841-849 5. Osiri M, et al. Leflunomide for treating rheumatoid arthritis. Cochrane Database Syst Rev. 2003;(1):CD002047 6. American College of Rheumatology. Guidelines for the Management of Rheumatoid Arthritis. Arthritis Care Res. 2021;73(7):924-939 7. Micromedex® DrugDex® Evaluation: Leflunomide (2023) 8. UpToDate®: Leflunomide drug information (2023)