Brands, Medical Use, Clinical Data
- Immunosuppressive Agents
- Antineoplastic Agents
- Anti-inflammatory Agents
Brands / Synonyms
Arava; Leflunomide [Usan:Inn]; Leflunomidum [Inn-Latin]; Lefunomide; [Inn-Spanish]
For the treatment of active rheumatoid arthritis (RA).
Leflunomide is a pyrimidine synthesis inhibitor indicated in adults for the treatment of active rheumatoid arthritis (RA). RA is an auto-immune disease characterized by high T-cell activity. T cells have two pathways to synthesize pyrimidines: the salvage pathways and the de novo synthesis. At rest, T lymphocytes meet their metabolic requirements by the salvage pathway. Activated lymphocytes need to expand their pyrimidine pool 7- to 8-fold, while the purine pool is expanded only 2- to 3-fold. To meet the need for more pyrimidines, activated T cells use the de novo pathway for pyrimidine synthesis. Therefore, activated T cells, which are dependent on de novo pyrimidine synthesis, will be more affected by leflunomide's inhibition of dihydroorotate dehydrogenase than other cell types that use the salvage pathway of pyrimidine synthesis.
Mechanism of Action
Leflunomide is an isoxazole immunomodulatory agent which inhibits dihydroorotate dehydrogenase (an enzyme involved in de novo pyrimidine synthesis) and has antiproliferative activity. Specifically Leflunomide blocks the de novo synthesis of pyrimidines, thus preventing the proliferation of activated T cells. Several in vivo and in vitro experimental models have demonstrated an anti-inflammatory effect. Following oral administration, leflunomide is metabolized to an active metabolite A77 1726 which is responsible for essentially all of its activity in vivo.
Well absorbed, peak plasma concentrations appear 6-12 hours after dosing
LD50=100-250 mg/kg (acute oral toxicity)
Biotrnasformation / Drug Metabolism
Primarily hepatic. Leflunomide is converted to its active form following oral intake.
ARAVA is contraindicated in patients with known hypersensitivity to leflunomide or any of the other
components of ARAVA.
ARAVA can cause fetal harm when administered to a pregnant woman. Leflunomide, when administered orally to rats
during organogenesis at a dose of 15 mg/kg, was teratogenic (most notably anophthalmia or microophthalmia and
internal hydrocephalus). The systemic exposure of rats at this dose was approximately 1/10 the human exposure level
based on AUC. Under these exposure conditions, leflunomide also caused a decrease in the maternal body weight and an
increase in embryolethality with a decrease in fetal body weight for surviving fetuses. In rabbits, oral treatment
with 10 mg/kg of leflunomide during organogenesis resulted in fused, dysplastic sternebrae. The exposure level at
this dose was essentially equivalent to the maximum human exposure level based on AUC. At a 1 mg/kg dose, leflunomide
was not teratogenic in rats and rabbits.
When female rats were treated with 1.25 mg/kg of leflunomide beginning 14 days before mating and continuing until
the end of lactation, the offspring exhibited marked (greater than 90%) decreases in postnatal survival. The systemic
exposure level at 1.25 mg/kg was approximately 1/100 the human exposure level based on AUC.
ARAVA is contraindicated in women who are or may become pregnant. If this drug is used during pregnancy, or if the
patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the
Cholestyramine and Charcoal
Administration of cholestyramine or activated charcoal in patients (n=13) and volunteers (n=96) resulted in a rapid
and significant decrease in plasma M1 (the active metabolite of leflunomide) concentration .
Increased side effects may occur when leflunomide is given concomitantly with hepatotoxic substances. This is also to
be considered when leflunomide treatment is followed by such drugs without a drug elimination procedure. In a small
(n=30) combination study of ARAVA with methotrexate, a 2- to 3-fold elevation in liver enzymes was seen in 5 of 30
patients. All elevations resolved, 2 with continuation of both drugs and 3 after discontinuation of leflunomide. A
>3-fold increase was seen in another 5 patients. All of these also resolved, 2 with continuation of both drugs and
3 after discontinuation of leflunomide. Three patients met "ACR criteria" for liver biopsy (1: Roegnik Grade I, 2:
Roegnik Grade IIIa). No pharmacokinetic interaction was identified.
In in vitro studies, M1 was shown to cause increases ranging from 13 - 50% in the free fraction of diclofenac
and ibuprofen at concentrations in the clinical range. The clinical significance of this finding is unknown; however,
there was extensive concomitant use of NSAIDs in clinical studies and no differential effect was observed.
In in vitro studies, M1 was shown to cause increases ranging from 13 - 50% in the free fraction of tolbutamide
at concentrations in the clinical range. The clinical significance of this finding is unknown.
Following concomitant administration of a single dose of ARAVA to subjects receiving multiple doses of rifampin, M1
peak levels were increased (~40%) over those seen when ARAVA was given alone. Because of the potential for ARAVA
levels to continue to increase with multiple dosing, caution should be used if patients are to be receiving both
ARAVA and rifampin.
Increased INR (International Normalized Ratio) when ARAVA and warfarin were co-administered has been rarely