Leflunomide

ARAVA is indicated for the treatment of adults with active rheumatoid arthritis (RA). ARAVA is a pyrimidine synthesis inhibitor indicated for the treatment of adults with active rheumatoid arthritis.

Leflunomide is an isoxazole immunomodulatory agent that inhibits dihydroorotate dehydrogenase (a mitochondrial enzyme involved in de novo pyrimidine synthesis) and has antiproliferative activity. Several in vivo and in vitro experimental models have demonstrated an anti-inflammatory effect.

Loading dosage for patients at low risk for ARAVA-associated hepatotoxicity and ARAVA-associated myelosuppression: 100 mg daily for 3 days. Maintenance dosage: 20 mg daily. Maximum recommended daily dosage: 20 mg once daily. If 20 mg once daily is not tolerated, may decrease dosage to 10 mg once daily. Screen patients for active and latent tuberculosis, pregnancy test (females), blood pressure, and laboratory tests before starting ARAVA.

ARAVA is contraindicated in: Pregnant women. ARAVA may cause fetal harm. If a woman becomes pregnant while taking this drug, stop ARAVA, apprise the patient of the potential hazard to the fetus, and begin a drug elimination procedure. Patients with severe hepatic impairment. Patients with known hypersensitivity to leflunomide or any of the other components of ARAVA. Known reactions include anaphylaxis. Patients being treated with teriflunomide. Pregnancy. Severe hepatic impairment. Hypersensitivity to ARAVA or any of its inactive components. Current teriflunomide treatment.

Boxed warning (embryo-fetal toxicity and hepatotoxicity warning: embryo-fetal toxicity and hepatotoxicity): Embryo-Fetal Toxicity Teratogenicity and embryo-lethality occurred in animals administered leflunomide. Exclude pregnancy prior to initiating ARAVA therapy. Advise use of effective contraception in females of reproductive potential during treatment and during a drug elimination procedure. After stopping ARAVA, it is recommended that an accelerated drug elimination procedure be used to reduce the plasma concentrations of the active metabolite, teriflunomide. Severe infections (including sepsis), pancytopenia, agranulocytosis, and thrombocytopenia: Stop ARAVA and use accelerated elimination procedure. Do not start ARAVA in patients with active infection. Monitor CBCs during treatment with ARAVA.

The following serious adverse reactions are described elsewhere in the labeling: Hepatotoxicity Immunosuppression Bone marrow suppression Serious infections Stevens-Johnson syndrome, toxic epidermal necrolysis, and drug reactions with eosinophilia and systemic symptoms Skin ulcers Peripheral neuropathy Interstitial lung disease The most commonly reported adverse reactions (≥10%) regardless of relation to ARAVA treatment were diarrhea, respiratory infection, nausea, headache, rash, abnormal liver enzymes, and dyspepsia.

Following oral administration, leflunomide is metabolized to an active metabolite, teriflunomide, which is responsible for essentially all of leflunomide's in vivo activity. Drug interaction studies have been conducted with both ARAVA (leflunomide) and with its active metabolite, teriflunomide, where the metabolite was directly administered to the test subjects. Drugs metabolized by CYP2C8 and OAT3 transporters: Monitor patients because teriflunomide may increase exposure of these drugs. Teriflunomide may increase exposure of ethinylestradiol and levonorgestrel. Choose an appropriate oral contraceptive. Drugs metabolized by CYP1A2: Monitor patients because teriflunomide may decrease exposure of these drugs. Warfarin: Monitor INR as teriflunomide may decrease INR.

Store at 25°C (77°F), excursions permitted to 15°C to 30°C (59°F to 86°F). Protect from light.