LEFLUNOMIDE

Clinical safety rating: avoid

Contraindicated (not allowed)

How it works

Inhibits dihydroorotate dehydrogenase (DHODH), blocking de novo pyrimidine synthesis, thereby reducing lymphocyte proliferation.

What the body does with it

Metabolism	Metabolized primarily by the liver via hydrolysis and further metabolized to teriflunomide; CYP450 enzymes play a minor role.
Excretion	Primarily fecal (~48%) and renal (~43%) as metabolites. Teriflunomide, the active metabolite, undergoes enterohepatic recirculation and is eliminated via bile and feces. Less than 1% excreted as unchanged drug.
Half-life	Terminal half-life of teriflunomide is approximately 18-19 days (range 14-58 days) due to enterohepatic recirculation; clinical significance: prolonged washout required before switching to other disease-modifying antirheumatic drugs (DMARDs) or in case of toxicity.
Protein binding	>99% bound primarily to albumin; minor binding to other plasma proteins.
Volume of Distribution	0.13 L/kg in healthy volunteers; low Vd indicates limited tissue distribution, consistent with extensive plasma protein binding.
Bioavailability	Oral: approximately 80% (absolute bioavailability of teriflunomide from leflunomide prodrug); food does not significantly affect absorption.
Onset of Action	Oral: 4-8 weeks for clinical response in rheumatoid arthritis; may take up to 12 weeks for maximal effect.
Duration of Action	Prolonged; clinical effects persist for weeks to months after discontinuation due to long half-life and enterohepatic recycling. Recovery of immune function occurs slowly.

Classification & Brands

Action Class	Disease Modifying Anti-Rheumatoid Drugs (DMARDs)- Non biologics
Brand Substitutes	Rumalef 20 Tablet, Lefron 20mg Tablet, Arava 20mg Tablet, Lefmaa 20 Tablet, Immulef 20 Tablet

Dosing & administration

100 mg PO once daily for 3 days (loading dose), then 20 mg PO once daily (maintenance); may reduce to 10 mg PO once daily if not tolerated.

Dosage form	TABLET
Renal impairment	No dose adjustment required for mild-to-moderate renal impairment (CrCl >30 mL/min). Contraindicated in severe renal impairment (CrCl <30 mL/min) due to lack of data.
Liver impairment	Contraindicated in patients with significant hepatic impairment (Child-Pugh class B or C). Use with caution in mild hepatic impairment (Child-Pugh class A) with dose monitoring.
Pediatric use	Weight-based dosing for children ≥18 kg: Loading dose 100 mg PO once daily for 3 days; maintenance 20 mg PO once daily for weight ≥40 kg, 10 mg PO once daily for weight <40 kg. Not recommended for children <18 kg.
Geriatric use	No specific dose adjustment, but monitor renal function closely (CrCl should be >30 mL/min). Higher risk of hepatotoxicity and infections; consider 10 mg maintenance dose if tolerability concerns.

Use during pregnancy

1st trimester	Consult provider
2nd trimester	Consult provider
3rd trimester	Consult provider

Clinical note

Activated charcoal or cholestyramine can accelerate elimination Can cause hepatotoxicity and teratogenicity.

Breastfeeding	Contraindicated. Leflunomide is excreted in human milk; M/P ratio not established. Potential for serious adverse effects in nursing infant (immunosuppression, hepatotoxicity). Use alternative agents.
Teratogenic Risk	Category X: Contraindicated in pregnancy. First trimester: High risk of major congenital malformations (e.g., craniofacial, cardiac, skeletal defects) and spontaneous abortion. Second and third trimesters: Increased risk of fetal growth restriction, preterm birth, and teratogenic effects. Contraception required during treatment and for up to 2 years after discontinuation.

Warnings & precautions

■ FDA Black Box Warning

Can cause hepatotoxicity and severe liver injury; avoid use in patients with pre-existing liver disease or elevated liver enzymes.

Side Effect Profile

Serious Effects

Absolute Contraindications

Pregnancy, breastfeeding, severe hepatic impairment, severe immunodeficiency states, and hypersensitivity to leflunomide.

Clinical Precautions

Precautions

Hepatotoxicity, bone marrow suppression, immunosuppression leading to infections, peripheral neuropathy, severe skin reactions, and interstitial lung disease.

Clinical Tips & Counseling

Drug interactions

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