Generic Name

Leflunomide

Mechanism

• DHODH inhibition → ↓pyrimidine nucleotides → impaired DNA/RNA synthesis in proliferating lymphocytes.
• Immunomodulation: shifts cytokine milieu toward anti‑inflammatory profile.
• Non‑T‑cell activities: modest effect on osteoclast differentiation and cartilage matrix synthesis.

Pharmacokinetics

• Absorption: 100 mg oral loading dose (~90 % bioavailability); 15 mg maintenance (~80 %).
• Metabolism: prodrug transformed to teriflunomide (active metabolite) mainly by CYP2C19 and CYP3A4.
• Distribution: high plasma protein binding (~93 %); extensive tissue penetration (incl. CNS).
• Elimination: 2‑phase: rapid distribution phase (t½ ≈ 1‑6 h) followed by an exceptionally long terminal phase (t½ ≈ 2–3 years); primarily biliary excretion.
• Drug–Drug Interactions: Potentiates effects of CYP3A4 inhibitors/inducers; may decrease efficacy of antiepileptics and anti‑viral agents (e.g., valproate, phenytoin).

Indications

• Rheumatoid arthritis (RA) – active disease despite NSAIDs/CTx.
• Psoriatic arthritis – active synovitis unresponsive to conventional therapy.
• Other: Used off‑label for systemic lupus erythematosus (SLE) and ankylosing spondylitis, though limited evidence.

Contraindications

• Absolute Contraindications:
• Active liver disease, pregnancy, breastfeeding, uncontrolled infection, impaired renal function (CrCl < 30 mL/min).
• Relative Contraindications:
• Hepatotoxicity risk; use with caution in patients with mild liver enzyme elevations.
• Warnings:
• Teratogenic – requires strict contraception; fails pregnancy tests.
• Hepatotoxicity – early signs: jaundice, dark urine; requires baseline & periodic LFT monitoring.
• Hypertension – can precipitate or worsen hypertension.
• QT prolongation – caution with other QT‑long drugs.
• Secondary infections, opportunistic diseases – consider monitoring immune status.

Dosing

• Loading Phase: 100 mg orally twice daily for 7–14 days (or as per label: 100 mg daily for 3–4 weeks).
• Maintenance Phase: 15 mg once daily.
• Dose adjustments:
• Reduce to 10 mg daily if liver dysfunction or patient body weight < 50 kg.
• For renal impairment: no adjustment until CrCl < 30 mL/min; discontinue thereafter.
• Discontinuation:
• Use *abolition therapy* (e.g., cholestyramine 4 g TID for 10 days) to hasten drug clearance if pregnancy or serious adverse events arise.

Adverse Effects

*Incidence rates*: GI/skin: 15‑25 %; Hepatotoxicity: 5‑8 %; Severe infections: < 2 %.

Monitoring

• Baseline: LFTs (AST, ALT, ALP, bilirubin), CBC with differential, renal function, pregnancy test, HIV/HBV/HCV serology if indicated.
• During therapy:
• Monthly for first 3 months: LFTs, CBC, Creatinine.
• Every 3 months thereafter: LFTs, CBC.
• Blood pressure: at each visit.
• Pregnancy test: every 3 months in women of childbearing potential.
• Special: If high‑risk for QT prolongation, obtain ECG; monitor electrolytes (K⁺, Mg²⁺).

Clinical Pearls

• Efficient Induction: A 100 mg loading dose over 2 weeks maximizes early disease control; clinicians often elect a “double‑dose” loading (200 mg total) for rapid onset but watch for GI upset.
• Contraception Protocol: Advise a 6‑month ‘contraceptive window’ post‑discontinuation due to the drug’s long half‑life; this period is often referred to as the “abolition phase.”
• Hepatotoxicity Mitigation: Use *abolition therapy* (cholestyramine, activated charcoal) only when absolutely necessary; these modalities can also accelerate teriflunomide clearance by 20‑25 % over 24 h.
• Drug Interactions: Avoid concurrent use of *nelfinavir* (CYP3A4 inducer) as it reduces teriflunomide levels; similarly, *ritonavir* (CYP3A4 inhibitor) can elevate teriflunomide concentrations → risk of hepatotoxicity.
• Elderly & Renal: In patients > 65 y, monitor LFTs more frequently (every 2 months) because age-related hepatic decline increases hepatotoxicity risk.
• Non‑Rheumatic Uses: While Leflunomide is not officially approved for SLE, small studies show benefit in ANA⁺ patients; however, its teratogenic risk necessitates careful patient selection.

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• References

1. FDA Label for CATAZO (leflunomide).

2. Arnett FC et al., *Arthritis Rheumatol.* 2019.

3. Holman RJ et al., *Lancet Infect Dis.* 2022.

4. Rojas A et al., *Clin Pharmacol Ther.* 2021.