ARAVA
Clinical safety rating: caution
Comprehensive clinical and safety monograph for ARAVA (ARAVA).
Leflunomide inhibits dihydroorotate dehydrogenase (DHODH), a key enzyme in de novo pyrimidine synthesis, thereby reducing T cell proliferation.
| Metabolism | Metabolized primarily in the liver via CYP1A2 and CYP2C19 to A771726 (active metabolite); undergoes further metabolism and enterohepatic recirculation. |
| Excretion | Following oral administration, ~90% of a dose is excreted in feces (primarily as parent drug and M1 metabolite) and ~10% in urine (M1 metabolite). Biliary excretion is a major route for the active metabolite teriflunomide. |
| Half-life | The terminal elimination half-life of teriflunomide is approximately 18–19 days due to enterohepatic recirculation. This long half-life necessitates a loading dose and may prolong time to steady state (>3 months). |
| Protein binding | Teriflunomide is extensively protein-bound (>99%), primarily to albumin. This high binding may lead to displacement interactions with other highly bound drugs. |
| Volume of Distribution | Apparent Vd of teriflunomide is approximately 0.15 L/kg, indicating distribution primarily in the plasma and extracellular fluid. The small Vd reflects high protein binding and limited tissue penetration. |
| Bioavailability | Oral bioavailability is approximately 80–85%; absorption is not significantly affected by food. |
| Onset of Action | Oral: Clinical effects (reduction in rheumatoid arthritis symptoms) typically observed within 4–6 weeks; maximum benefit may require 2–3 months. |
| Duration of Action | Dosing interval is once daily. The pharmacodynamic effect persists for several months after discontinuation due to the long half-life; an accelerated elimination procedure (cholestyramine or activated charcoal) is recommended when rapid clearance is needed. |
| Action Class | Disease Modifying Anti-Rheumatoid Drugs (DMARDs)- Non biologics |
| Brand Substitutes | Rumalef 10 Tablet, Lefrhum 10mg Tablet, Lefmaa 10 Tablet, Leftab 10mg Tablet, Leflunova 10mg Tablet, Rumalef 20 Tablet, Lefron 20mg Tablet, Lefmaa 20 Tablet, Immulef 20 Tablet, Lefumib 20mg Tablet |
100 mg orally once daily for 3 days (loading dose), then 20 mg orally once daily (maintenance); if not tolerated, may reduce to 10 mg orally once daily.
| Dosage form | TABLET |
| Renal impairment | No dose adjustment recommended for mild to moderate renal impairment; not studied in severe renal impairment (CrCl <30 mL/min) or dialysis. |
| Liver impairment | Contraindicated in patients with significant hepatic impairment (Child-Pugh class B or C); no adjustment needed for mild hepatic impairment (Child-Pugh class A). |
| Pediatric use | Not FDA-approved for pediatric use; safety and efficacy not established in patients <18 years. |
| Geriatric use | No specific dose adjustment required, but monitor renal function and liver function more frequently due to age-related decline; consider lower maintenance dose (10 mg/day) if tolerability issues arise. |
| 1st trimester | Consult provider |
| 2nd trimester | Consult provider |
| 3rd trimester | Consult provider |
Clinical note
Comprehensive clinical and safety monograph for ARAVA (ARAVA).
| Breastfeeding | Leflunomide is contraindicated in breastfeeding. M/P ratio not reported. The active metabolite teriflunomide is excreted in human milk in animal studies. Potential for serious adverse reactions in nursing infants, including immunosuppression and growth delay. |
| Teratogenic Risk | Leflunomide is contraindicated in pregnancy due to teratogenicity observed in animal studies. First-trimester exposure is associated with increased risk of major congenital malformations, including craniofacial, cardiovascular, and skeletal defects. Second and third-trimester risks are not well-studied but potential for fetal harm exists. Pregnancy must be excluded before initiating therapy. A drug elimination procedure (cholestyramine) is recommended to reduce plasma levels prior to conception. |
■ FDA Black Box Warning
Hepatotoxicity: severe liver injury including fatal outcomes reported; contraindicated in patients with impaired hepatic function. Also associated with immunosuppression leading to infections.
| Serious Effects |
Pregnancy or women of childbearing potential not using reliable contraception; severe hepatic impairment; hypersensitivity to leflunomide; patients with severe immunodeficiency or bone marrow dysplasia.
| Precautions | Hepatotoxicity, liver function monitoring required; immunosuppression/infections; bone marrow suppression; neuropathy; interstitial lung disease; skin reactions; vaccination considerations; pregnancy category X. |
| Food/Dietary | No specific food interactions. However, concurrent use of cholestyramine (if needed for washout) should be taken with food to minimize gastrointestinal side effects. |
Loading safety data…
| Fetal Monitoring | Perform pregnancy test before starting therapy and monthly thereafter in women of childbearing potential. Monitor liver function tests (AST, ALT) monthly for first 6 months, then every 6-8 weeks. Monitor complete blood count (CBC) monthly for first 6 months, then every 6-8 weeks. Monitor blood pressure regularly. |
| Fertility Effects | Leflunomide may impair fertility in both males and females. In male patients, leflunomide exposure may lead to oligospermia and reduced sperm motility. In females, it may cause menstrual irregularities and ovulatory dysfunction. Effects are potentially reversible upon discontinuation and washout with cholestyramine. |
| Clinical Pearls | Monitor liver function tests (ALT) monthly for first 6 months, then every 6-8 weeks thereafter. Leflunomide is contraindicated in pregnancy due to teratogenicity; use with reliable contraception. Washout with cholestyramine 8g TID for 11 days if planning pregnancy or severe adverse effects. Active metabolite has a half-life of 1-4 weeks. Can cause peripheral neuropathy; monitor for symptoms. |
| Patient Advice | Do not take if pregnant or planning pregnancy; use effective birth control during treatment and for 2 years after stopping (or until cholestyramine washout). · Avoid alcohol to reduce risk of liver damage. · Report any new numbness, tingling, or burning sensations to your doctor. · Take exactly as prescribed; do not stop without consulting your doctor. · May take up to 4 weeks to see benefit; full effect may take months. |