WARNING: HEPATOTOXICITY AND RISK OF TERATOGENICITY
Hepatotoxicity - Severe liver injury including fatal liver failure has been reported in patients treated with leflunomide, which is indicated for rheumatoid arthritis. A similar risk would be expected for teriflunomide because recommended doses of teriflunomide and leflunomide result in a similar range of plasma concentrations of teriflunomide. Concomitant use of AUBAGIO with other potentially hepatotoxic drugs may increase the risk of severe liver injury. Obtain transaminase and bilirubin levels within 6 months before initiation of AUBAGIO therapy. Monitor ALT levels at least monthly for six months after starting AUBAGIO. If drug induced liver injury is suspected, discontinue AUBAGIO and start an accelerated elimination procedure with cholestyramine or charcoal. AUBAGIO is contraindicated in patients with severe hepatic impairment. Patients with pre-existing liver disease may be at increased risk of developing elevated serum transaminases when taking AUBAGIO.
Risk of Teratogenicity - Based on animal data, AUBAGIO may cause major birth defects if used during pregnancy. Pregnancy must be excluded before starting AUBAGIO. AUBAGIO is contraindicated in pregnant women or women of childbearing potential who are not using reliable contraception. Pregnancy must be avoided during AUBAGIO treatment or prior to the completion of an accelerated elimination procedure after AUBAGIO treatment.
AUBAGIO® (teriflunomide) is indicated for the treatment of patients with relapsing forms of multiple sclerosis.
IMPORTANT SAFETY INFORMATION
WARNING: HEPATOTOXICITY AND RISK OF TERATOGENICITY
Severe liver injury including fatal liver failure has been reported in patients treated with leflunomide, which is indicated for rheumatoid arthritis. A similar risk would be expected for teriflunomide because recommended doses of teriflunomide and leflunomide result in a similar range of plasma concentrations of teriflunomide. AUBAGIO is contraindicated in patients with severe hepatic impairment and in patients taking leflunomide. Concomitant use of AUBAGIO with other potentially hepatotoxic drugs may increase the risk of severe liver injury. Obtain transaminase and bilirubin levels within 6 months before initiation of AUBAGIO therapy. Monitor ALT levels at least monthly for 6 months after starting AUBAGIO. If drug-induced liver injury is suspected, discontinue AUBAGIO and start an accelerated elimination procedure with cholestyramine or charcoal. Patients with pre-existing liver disease may be at increased risk of developing elevated serum transaminases when taking AUBAGIO.
Based on animal data, AUBAGIO may cause major birth defects if used during pregnancy. Pregnancy must be excluded before starting AUBAGIO. AUBAGIO is contraindicated in pregnant women or women of childbearing potential who are not using reliable contraception. Pregnancy must be avoided during AUBAGIO treatment or prior to the completion of an accelerated elimination procedure after AUBAGIO treatment.
Warnings and Precautions
Patients with pre-existing acute or chronic liver disease, or those with serum ALT >2 times the upper limit of normal (ULN) before initiating treatment, should not normally be treated with AUBAGIO. In clinical trials, if ALT elevation was >3 times the ULN on 2 consecutive tests, patients discontinued AUBAGIO and underwent accelerated elimination. Consider additional monitoring if coadministering AUBAGIO with other potentially hepatotoxic drugs; monitor patients who develop symptoms suggestive of hepatic dysfunction (eg, unexplained nausea, vomiting, abdominal pain, fatigue, anorexia, or jaundice and/or dark urine). If drug-induced liver injury is suspected, discontinue use of AUBAGIO, start accelerated elimination, and monitor liver tests weekly until normalized.
Before starting therapy, use of reliable contraception must be confirmed, and the patient counseled on risks to the fetus. Patients with delayed onset of menses or other reason to suspect pregnancy should immediately see their physician for pregnancy testing. Patients who become pregnant or wish to become pregnant should discontinue treatment, followed by accelerated elimination until plasma concentrations of <0.02 mcg/mL are verified. Women who become pregnant while taking AUBAGIO may enroll in the AUBAGIO pregnancy registry by calling 1-800-745-4447, option 2.
Teriflunomide is eliminated slowly from the plasma—it takes an average of 8 months, or up to 2 years in some patients, to reach plasma concentrations <0.02 mcg/mL. Elimination may be accelerated by administration of cholestyramine or charcoal, but this may cause disease activity to return in patients who were responding to AUBAGIO.
Decreases in white blood cell counts, mainly of neutrophils and lymphocytes, and platelets have been reported with AUBAGIO. Obtain a complete blood cell count within 6 months before starting treatment, with further monitoring based on signs and symptoms of bone marrow suppression. AUBAGIO is not recommended for patients with severe immunodeficiency, bone marrow disease, or severe uncontrolled infections. Tuberculosis (TB) has been observed in clinical studies of AUBAGIO. Before starting treatment, screen patients for latent TB infection with a tuberculin skin test. Treatment in patients with acute or chronic infections should not be started until the infection(s) is resolved. Administration of live vaccines is not recommended. The risk of malignancy, particularly lymphoproliferative disorders, or infection may be increased with the use of some medications with immunosuppressive potential including teriflunomide.
Peripheral neuropathy, including polyneuropathy and mononeuropathy, has been reported with AUBAGIO. Age >60 years, concomitant neurotoxic medications, and diabetes may increase the risk. If peripheral neuropathy is suspected, consider discontinuing treatment and performing accelerated elimination.
Transient acute renal failure and treatment-emergent hyperkalemia, as well as increased renal uric acid clearance, have been reported with AUBAGIO. Monitor renal function and potassium if symptoms of acute renal failure or hyperkalemia appear.
Interstitial lung disease and rare cases of Stevens-Johnson syndrome and toxic epidermal necrolysis have been reported with leflunomide; a similar risk would be expected for teriflunomide. If a severe skin reaction develops with AUBAGIO, stop treatment and use accelerated elimination.
Blood pressure increases and hypertension have occurred with AUBAGIO. Measure blood pressure at treatment initiation and manage any elevations during treatment.
Adverse Reactions: The most frequent adverse reactions (≥10% and ≥2% greater than placebo) with AUBAGIO 7 mg and 14 mg and placebo, respectively, were ALT increased (12% and 14% vs 7%), alopecia (10% and 13% vs 3%), diarrhea (15% and 18% vs 9%), influenza (9% and 12% vs 10%), nausea (9% and 14% vs 7%), and paresthesia (9% and 10% vs 8%).
Drug Interactions: Monitor patients when teriflunomide is coadministered with warfarin or drugs metabolized by CYP1A2 or CYP2C8.
Use in Specific Populations: AUBAGIO is detected in human semen. To minimize any possible fetal risk, men not wishing to father a child and their female partners should use reliable contraception and men wishing to father a child should discontinue therapy and undergo accelerated elimination, with verification of plasma concentrations <0.02 mcg/mL. Nursing mothers should not use AUBAGIO.
Generic Name and Formulations:
Teriflunomide 7mg, 14mg; tablets.
Indications for AUBAGIO:
Relapsing forms of multiple sclerosis (MS).
Adult Dose for AUBAGIO:
7mg or 14mg once daily.
Children's Dose for AUBAGIO:
Pyrimidine synthesis inhibitor.
Severe hepatic impairment. Pregnancy (Cat.X), women of childbearing potential not using reliable contraception. Co-administration with leflunomide.
Perform accelerated elimination procedure (see literature) after drug discontinuance. Severe liver injury may be possible; obtain transaminase and bilirubin levels within 6 months before starting, monitor ALT at least monthly for 6 months after starting. Discontinue if drug-induced liver injury suspected; monitor liver tests weekly until normalized. Pre-existing liver disease: increased risk of developing elevated serum transaminases. Obtain CBCs within 6 months prior to starting. Severe immunodeficiency, bone marrow disease, or severe, uncontrolled infections: not recommended. Screen for latent TB; do not start therapy until infection resolved. Monitor BP before starting and periodically. Diabetes, >60 years: increased risk of peripheral neuropathy. Monitor for new onset or worsening pulmonary symptoms, discontinue if interstitial lung disease suspected. Male patients: undergo elimination procedure before fathering child. Nursing mothers: not recommended.
See Contraindications. Live vaccines: not recommended. Risk of liver injury with hepatotoxic drugs. Risk of peripheral neuropathy with neurotoxic drugs. Potentiates drugs metabolized by CYP2C8 (eg, repaglinide, paclitaxel, pioglitazone, rosiglitazone), oral contraceptives. Antagonizes drugs metabolized by CYP1A2 (eg, duloxetine, alosetron, theophylline, tizanidine). Monitor INR. Concomitant immunosuppressives, immunomodulators: not evaluated.
ALT increased, alopecia, diarrhea, influenza, nausea, paresthesia; bone marrow suppression, immunosuppression potential, infection (consider suspending therapy), peripheral neuropathy; hyperkalemia, acute renal failure (check K+ levels); possible severe skin reactions (eg, Stevens-Johnson syndrome, toxic epidermal necrolysis; discontinue if occurs), respiratory effects.
Hepatic; >99% protein bound.