AUBAGIO (teriflunomide) tablets

AUBAGIO (teriflunomide) tablets

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AUBAGIO (teriflunomide) tablets

AUBAGIO (teriflunomide) is an oral de novo pyrimidine synthesis inhibitor of the DHO-DH enzyme, with the chemical name (Z)-2-Cyano-3-hydroxy-but-2-enoic acid-(4-trifluoromethylphenyl)-amide. Its molecular weight is 270.21, and the empirical formula is C12H9F3N2O2

Teriflunomide is a white to almost white powder that is sparingly soluble in acetone, slightly soluble in polyethylene glycol and ethanol, very slightly soluble in isopropanol and practically insoluble in water.

Teriflunomide is formulated as film-coated tablets for oral administration. AUBAGIO tablets contain 7 mg or 14 mg of teriflunomide and the following inactive ingredients: lactose monohydrate, corn starch, hydroxypropyl cellulose, microcrystalline cellulose, sodium starch glycolate, and magnesium stearate. The film coating for the 14 mg tablet is made of hypromellose, titanium dioxide, talc, polyethylene glycol and indigo carmine aluminum lake. In addition to these, the 7 mg tablet film coating includes iron oxide yellow.

Indications and usage

AUBAGIO is a pyrimidine synthesis inhibitor indicated for the treatment of relapsing forms of multiple sclerosis (MS), to include clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease, in adults.

Dosage and administration

The recommended dose of AUBAGIO is 7 mg or 14 mg orally once daily. AUBAGIO can be taken with or without food.

Mechanism of Action

Teriflunomide, an immunomodulatory agent with anti-inflammatory properties, inhibits dihydroorotate dehydrogenase, a mitochondrial enzyme involved in de novo pyrimidine synthesis. The exact mechanism by which teriflunomide exerts its therapeutic effect in multiple sclerosis is unknown but may involve a reduction in the number of activated lymphocytes in CNS.

Contraindications

  • Patients with severe hepatic impairment
  • Pregnant women and females of reproductive potential not using effective contraception. AUBAGIO may cause fetal harm
  • Patients with a history of a hypersensitivity reaction to teriflunomide, leflunomide, or to any of the inactive ingredients in AUBAGIO. Reactions have included anaphylaxis, angioedema, and serious skin reactions
  • Coadministration with leflunomide

Adverse reactions

Most common adverse reactions (≥10% and ≥2% greater than placebo): headache, diarrhea, nausea, alopecia, increase in ALT.

Warnings and precautions

Hepatotoxicity

Clinically significant and potentially life-threatening liver injury, including acute liver failure requiring transplant, has been reported in patients treated with AUBAGIO in the postmarketing setting. Patients with pre-existing liver disease and patients taking other hepatotoxic drugs may be at increased risk for developing liver injury when taking AUBAGIO. Clinically significant liver injury can occur at any time during treatment with AUBAGIO.

Patients with pre-existing acute or chronic liver disease, or those with serum alanine aminotransferase (ALT) greater than two times the upper limit of normal (ULN) before initiating treatment, should not normally be treated with AUBAGIO. AUBAGIO is contraindicated in patients with severe hepatic impairment

Embryofetal Toxicity

AUBAGIO may cause fetal harm when administered to a pregnant woman. Teratogenicity and embryofetal lethality occurred in animal reproduction studies in multiple animal species at plasma teriflunomide exposures similar to or lower than that in humans at the maximum recommended human dose (MRHD) of 14 mg/day

Procedure for Accelerated Elimination of Teriflunomide

Teriflunomide is eliminated slowly from the plasma. Without an accelerated elimination procedure, it takes on average 8 months to reach plasma concentrations less than 0.02 mg/L, although because of individual variations in drug clearance it may take as long as 2 years. An accelerated elimination procedure could be used at any time after discontinuation of AUBAGIO. Elimination can be accelerated by either of the following procedures:

  • Administration of cholestyramine 8 g every 8 hours for 11 days. If cholestyramine 8 g three times a day is not well tolerated, cholestyramine 4 g three times a day can be used.
  • Administration of 50 g oral activated charcoal powder every 12 hours for 11 days.

Hypersensitivity Reactions: AUBAGIO can cause anaphylaxis and severe allergic reactions. Signs and symptoms have included dyspnea, urticaria, and angioedema including lips, eyes, throat, and tongue

Malignancy: The risk of malignancy, particularly lymphoproliferative disorders, is increased with the use of some immunosuppressive medications. There is a potential for immunosuppression with AUBAGIO.

Serious Skin Reactions: Cases of serious skin reactions, sometimes fatal, including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and drug reaction with eosinophilia and systemic symptoms (DRESS), have been reported with AUBAGIO. Fatal outcomes were reported in one case of TEN and one case of DRESS.

Drug Reaction with Eosinophilia and Systemic Symptoms

Drug reaction with eosinophilia and systemic symptoms (DRESS), also known as multiorgan hypersensitivity, has occurred with AUBAGIO. One fatal case of DRESS that occurred in close temporal association (34 days) with the initiation of AUBAGIO treatment has been reported in the postmarketing setting. DRESS typically, although not exclusively, presents with fever, rash, lymphadenopathy and/or facial swelling, in association with other organ system involvement, such as hepatitis, nephritis, hematologic abnormalities, myocarditis, or myositis, sometimes resembling an acute viral infection. Eosinophilia is often present.

Peripheral Neuropathy: In placebo-controlled studies, peripheral neuropathy, including both polyneuropathy and mononeuropathy (e.g., carpal tunnel syndrome), occurred more frequently in patients taking AUBAGIO than in patients taking placebo.

Respiratory Effects: Interstitial lung disease, including acute interstitial pneumonitis, has been reported with AUBAGIO in the postmarketing setting.

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Drug interactions

Effect of AUBAGIO on CYP2C8 Substrates: Teriflunomide is an inhibitor of CYP2C8 in vivo. In patients taking AUBAGIO, exposure of drugs metabolized by CYP2C8 (e.g., paclitaxel, pioglitazone, repaglinide, rosiglitazone) may be increased. Monitor these patients and adjust the dose of the concomitant drug(s) metabolized by CYP2C8 as required.

Effect of AUBAGIO on Warfarin: Coadministration of AUBAGIO with warfarin requires close monitoring of the international normalized ratio (INR) because AUBAGIO may decrease peak INR by approximately 25%.

Effect of AUBAGIO on Oral Contraceptives: AUBAGIO may increase the systemic exposures of ethinylestradiol and levonorgestrel. Consideration should be given to the type or dose of contraceptives used in combination with AUBAGIO

Effect of AUBAGIO on CYP1A2 Substrates: Teriflunomide may be a weak inducer of CYP1A2 in vivo. In patients taking AUBAGIO, exposure of drugs metabolized by CYP1A2 (e.g., alosetron, duloxetine, theophylline, tizanidine) may be reduced. Monitor these patients and adjust the dose of the concomitant drug(s) metabolized by CYP1A2 as required.

Effect of AUBAGIO on Organic Anion Transporter 3 (OAT3) Substrates: Teriflunomide inhibits the activity of OAT3 in vivo. In patients taking AUBAGIO, exposure of drugs which are OAT3 substrates (e.g., cefaclor, cimetidine, ciprofloxacin, penicillin G, ketoprofen, furosemide, methotrexate, zidovudine) may be increased. Monitor these patients and adjust the dose of the concomitant drug(s) which are OAT3 substrates as required.

Effect of AUBAGIO on BCRP and Organic Anion Transporting Polypeptide B1 and B3 (OATP1B1/1B3) Substrates: Teriflunomide inhibits the activity of BCRP and OATP1B1/1B3 in vivo. For a patient taking AUBAGIO, the dose of rosuvastatin should not exceed 10 mg once daily. For other substrates of BCRP (e.g., mitoxantrone) and drugs in the OATP family (e.g., methotrexate, rifampin), especially HMG-Co reductase inhibitors (e.g., atorvastatin, nateglinide, pravastatin, repaglinide, and simvastatin), consider reducing the dose of these drugs and monitor patients closely for signs and symptoms of increased exposures to the drugs while patients are taking AUBAGIO

Use in specific populations

Pregnancy: AUBAGIO is contraindicated for use in pregnant women and females of reproductive potential not using effective contraception because of the potential for fetal harm based on animal data

Lowering the plasma concentration of teriflunomide by instituting an accelerated drug elimination procedure as soon as pregnancy is detected may decrease the risk to the fetus from AUBAGIO. The accelerated drug elimination procedure includes verification that the plasma teriflunomide concentration is less than 0.02 mg/L

Lactation: There are no data on the presence of AUBAGIO in human milk, the effects on the breastfed infant, or the effects on milk production. Teriflunomide was detected in rat milk following a single oral dose. Because of the potential for adverse reactions in a breastfed infant from AUBAGIO, women should not breastfeed during treatment with AUBAGIO.

Contraception: Females of reproductive potential should use effective contraception while taking AUBAGIO. If AUBAGIO is discontinued, use of contraception should be continued until it is verified that plasma concentrations of teriflunomide are less than 0.02 mg/L (0.02 mcg/mL, the level expected to have minimal fetal risk, based on animal data).

Females of reproductive potential who wish to become pregnant should discontinue AUBAGIO and undergo an accelerated elimination procedure. Effective contraception should be used until it is verified that plasma concentrations of teriflunomide are less than 0.02 mg/L (0.02 mcg/mL)

Males: AUBAGIO is detected in human semen. Animal studies to specifically evaluate the risk of male mediated fetal toxicity have not been conducted. To minimize any possible risk, men not wishing to father a child and their female partners should use effective contraception. Men wishing to father a child should discontinue use of AUBAGIO and either undergo an accelerated elimination procedure or wait until verification that the plasma teriflunomide concentration is less than 0.02 mg/L (0.02 mcg/mL)

Pediatric Use: Safety and effectiveness in pediatric patients have not been established.

Geriatric Use: Clinical studies of AUBAGIO did not include patients over 65 years old.

Hepatic Impairment: No dosage adjustment is necessary for patients with mild and moderate hepatic impairment. The pharmacokinetics of teriflunomide in severe hepatic impairment has not been evaluated. AUBAGIO is contraindicated in patients with severe hepatic impairment

Renal Impairment: No dosage adjustment is necessary for patients with mild, moderate, and severe renal impairment

Overdosage

There is no experience regarding teriflunomide overdose or intoxication in humans. Teriflunomide 70 mg daily up to 14 days was well tolerated by healthy subjects. In the event of clinically significant overdose or toxicity, cholestyramine or activated charcoal is recommended to accelerate elimination

Storage

Store at 68°F to 77°F (20°C to 25°C) with excursions permitted between 59°F and 86°F (15°C and 30°C).

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