Aubagio

6 ADVERSE REACTIONS The following serious adverse reactions are described elsewhere in the prescribing information: Hepatotoxicity [see Contraindications (4) and Warnings and Precautions (5.1) ] Bone Marrow Effects/Immunosuppression Potential/Infections [see Warnings and Precautions (5.4) ] Hypersensitivity Reactions [see Contraindications (4) and Warnings and Precautions (5.5) ] Serious Skin Reactions [see Warnings and Precautions (5.6) ] Drug Reaction with Eosinophilia and Systemic Symptoms [see Warnings and Precautions (5.7) ] Peripheral Neuropathy [see Warnings and Precautions (5.8) ] Increased Blood Pressure [see Warnings and Precautions (5.9) ] Respiratory Effects [see Warnings and Precautions (5.10) ] Pancreatitis in Pediatric Patients [see Warnings and Precautions (5.11) ] Most common adverse reactions (≥10% and ≥2% greater than placebo): headache, diarrhea, nausea, alopecia, increase in ALT. ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Genzyme Corporation at 1-800-745-4447 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. A total of 2047 patients receiving AUBAGIO (7 mg or 14 mg once daily) constituted the safety population in the pooled analysis of placebo-controlled studies in patients with relapsing forms of multiple sclerosis; of these, 71% were female. The average age was 37 years. Table 1 lists adverse reactions in placebo-controlled trials with rates that were at least 2% for AUBAGIO patients and also at least 2% above the rate in placebo patients. The most common were headache, an increase in ALT, diarrhea, alopecia, and nausea. The adverse reaction most commonly associated with discontinuation was an increase in ALT (3.3%, 2.6%, and 2.3% of all patients in the AUBAGIO 7 mg, AUBAGIO 14 mg, and placebo treatment arms, respectively). Table 1: Adverse Reactions in Pooled Placebo-Controlled Studies in Patients with Relapsing Forms of Multiple Sclerosis Adverse Reaction AUBAGIO 7 mg (N=1045) AUBAGIO 14 mg (N=1002) Placebo (N=997) Headache 18% 16% 15% Increase in Alanine aminotransferase 13% 15% 9% Diarrhea 13% 14% 8% Alopecia 10% 13% 5% Nausea 8% 11% 7% Paresthesia 8% 9% 7% Arthralgia 8% 6% 5% Neutropenia 4% 6% 2% Hypertension 3% 4% 2% Cardiovascular Deaths Four cardiovascular deaths, including three sudden deaths, and one myocardial infarction in a patient with a history of hyperlipidemia and hypertension were reported among approximately 2600 patients exposed to AUBAGIO in the premarketing database. These cardiovascular deaths occurred during uncontrolled extension studies, one to nine years after initiation of treatment. A relationship between AUBAGIO and cardiovascular death has not been established. Acute Renal Failure In placebo-controlled studies, creatinine values increased more than 100% over baseline in 8/1045 (0.8%) patients in the 7 mg AUBAGIO group and 6/1002 (0.6%) patients in the 14 mg AUBAGIO group versus 4/997 (0.4%) patients in the placebo group. These elevations were transient. Some elevations were accompanied by hyperkalemia. AUBAGIO may cause acute uric acid nephropathy with transient acute renal failure because AUBAGIO increases renal uric acid clearance. Hypophosphatemia In clinical trials, 18% of AUBAGIO-treated patients had hypophosphatemia with serum phosphorus levels of at least 0.6 mmol/L, compared to 7% of placebo-treated patients; 4% of AUBAGIO-treated patients had hypophosphatemia with serum phosphorus levels at least 0.3 mmol/L but less than 0.6 mmol/L, compared to 0.8% of placebo-treated patients. No patient in any treatment group had a serum phosphorus below 0.3 mmol/L. 6.2 Postmarketing Experience The following adverse reactions have been identified during postapproval use of AUBAGIO. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Blood and Lymphatic System Disorders: Thrombocytopenia [see Warnings and Precautions (5.4) ] Gastrointestinal Disorders: Pancreatitis, colitis Hepatobiliary Disorders: Drug-induced liver injury (DILI) [see Warnings and Precautions (5.1) ] Immune System Disorders: Hypersensitivity reactions, some of which were severe, such as anaphylaxis and angioedema [see Warnings and Precautions (5.5) ] Respiratory, Thoracic, and Mediastinal Disorders: Interstitial lung disease [see Warnings and Precautions (5.10) ] Skin and Subcutaneous Tissue Disorders: Severe skin reactions, including toxic epidermal necrolysis and Stevens-Johnson syndrome [see Warnings and Precautions (5.6) ] ; drug reaction with eosinophilia and systemic symptoms (DRESS) [see Warnings and Precautions (5.7) ] ; psoriasis or worsening of psoriasis (including pustular psoriasis and nail psoriasis); nail disorders

4 CONTRAINDICATIONS Severe hepatic impairment ( 4 , 5.1 ) Pregnancy ( 4 , 5.2 , 8.1 ) Hypersensitivity ( 4 , 5.5 ) Current leflunomide treatment ( 4 ) AUBAGIO is contraindicated in/with: Patients with severe hepatic impairment [see Warnings and Precautions (5.1) ] . Pregnant women and females of reproductive potential not using effective contraception. AUBAGIO may cause fetal harm [see Warnings and Precautions (5.2 , 5.3) and Use in Specific Populations (8.1) ] . 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 [see Warnings and Precautions (5.5) ]. Coadministration with leflunomide [see Clinical Pharmacology (12.3) ].

11 DESCRIPTION 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 C 12 H 9 F 3 N 2 O 2 with the following chemical structure: 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. Chemical Structure

2 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. 7 mg or 14 mg orally once daily, with or without food. ( 2 ) Monitoring to Assess Safety 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 [see Warnings and Precautions (5.1) ] . Obtain a complete blood cell count (CBC) within 6 months before the initiation of treatment with AUBAGIO. Further monitoring should be based on signs and symptoms of infection [see Warnings and Precautions (5.4) ] . Prior to initiating AUBAGIO, screen patients for latent tuberculosis infection with a tuberculin skin test or blood test for mycobacterium tuberculosis infection [see Warnings and Precautions (5.4) ] . Exclude pregnancy prior to initiation of treatment with AUBAGIO in females of reproductive potential [see Warnings and Precautions (5.2) ] . Check blood pressure before start of AUBAGIO treatment and periodically thereafter [see Warnings and Precautions (5.9) ] .

1 INDICATIONS AND USAGE AUBAGIO ® is 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. 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. ( 1 )

10 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 [see Warnings and Precautions (5.3) ] .

7 DRUG INTERACTIONS Drugs metabolized by CYP2C8 and OAT3 transporters: Monitor patients because teriflunomide may increase exposure of these drugs. ( 7 ) Teriflunomide may increase exposure of ethinylestradiol and levonorgestrel. Choose an appropriate oral contraceptive. ( 7 ) Drugs metabolized by CYP1A2: Monitor patients because teriflunomide may decrease exposure of these drugs. ( 7 ) Warfarin: Monitor INR as teriflunomide may decrease INR. ( 7 ) Drugs metabolized by BCRP and OATP1B1/B3 transporters: Monitor patients because teriflunomide may increase exposure of these drugs. ( 7 ) Rosuvastatin: The dose of rosuvastatin should not exceed 10 mg once daily in patients taking AUBAGIO. ( 7 ) 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 [see Clinical Pharmacology (12.3) ] . 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 [see Clinical Pharmacology (12.3) ] . 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 [see Clinical Pharmacology (12.3) ] . 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 [see Clinical Pharmacology (12.3) ] . 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 [see Clinical Pharmacology (12.3) ] .

12 CLINICAL PHARMACOLOGY 12.1 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. 12.2 Pharmacodynamics Potential to Prolong the QT Interval In a placebo-controlled thorough QT study performed in healthy adult subjects, there was no evidence that teriflunomide caused QT interval prolongation of clinical significance (i.e., the upper bound of the 90% confidence interval for the largest placebo-adjusted, baseline-corrected QTc was below 10 ms). 12.3 Pharmacokinetics Teriflunomide is the principal active metabolite of leflunomide and is responsible for leflunomide's activity in vivo . At recommended doses, teriflunomide and leflunomide result in a similar range of plasma concentrations of teriflunomide. Based on a population analysis of teriflunomide in healthy adult volunteers and adult MS patients, median t 1/2 was approximately 18 and 19 days after repeated doses of 7 mg and 14 mg respectively. It takes approximately 3 months respectively to reach steady-state concentrations. The estimated AUC accumulation ratio is approximately 30 after repeated doses of 7 or 14 mg. Absorption Median time to reach maximum plasma concentrations is between 1 to 4 hours post dose following oral administration of teriflunomide. Food does not have a clinically relevant effect on teriflunomide pharmacokinetics. Distribution Teriflunomide is extensively bound to plasma protein (>99%) and is mainly distributed in plasma. The volume of distribution is 11 L after a single intravenous (IV) administration. Metabolism Teriflunomide is the major circulating moiety detected in plasma. The primary biotransformation pathway to minor metabolites of teriflunomide is hydrolysis, with oxidation being a minor pathway. Secondary pathways involve oxidation, N-acetylation and sulfate conjugation. Elimination Teriflunomide is eliminated mainly through direct biliary excretion of unchanged drug as well as renal excretion of metabolites. Over 21 days, 60.1% of the administered dose is excreted via feces (37.5%) and urine (22.6%). After an accelerated elimination procedure with cholestyramine, an additional 23.1% was recovered (mostly in feces). After a single IV administration, the total body clearance of teriflunomide is 30.5 mL/h. Drug Interaction Studies Teriflunomide is not metabolized by Cytochrome P450 or flavin monoamine oxidase enzymes. The potential effect of AUBAGIO on other drugs CYP2C8 substrates There was an increase in mean repaglinide C max and AUC (1.7- and 2.4-fold, respectively) following repeated doses of teriflunomide and a single dose of 0.25 mg repaglinide, suggesting that teriflunomide is an inhibitor of CYP2C8 in vivo . The magnitude of interaction could be higher at the recommended repaglinide dose [see Drug Interactions (7) ] . CYP1A2 substrates Repeated doses of teriflunomide decreased mean C max and AUC of caffeine by 18% and 55%, respectively, suggesting that teriflunomide may be a weak inducer of CYP1A2 in vivo [see Drug Interactions (7) ]. OAT3 substrates There was an increase in mean cefaclor C max and AUC (1.43- and 1.54-fold, respectively), following repeated doses of teriflunomide, suggesting that teriflunomide is an inhibitor of organic anion transporter 3 (OAT3) in vivo [see Drug Interactions (7) ] . BCRP and OATP1B1/1B3 substrates There was an increase in mean rosuvastatin C max and AUC (2.65- and 2.51-fold, respectively) following repeated doses of teriflunomide, suggesting that teriflunomide is an inhibitor of BCRP transporter and organic anion transporting polypeptide 1B1 and 1B3 (OATP1B1/1B3) [see Drug Interactions (7) ] . Oral contraceptives There was an increase in mean ethinylestradiol C max and AUC 0-24 (1.58- and 1.54-fold, respectively) and levonorgestrel C max and AUC 0-24 (1.33- and 1.41-fold, respectively) following repeated doses of teriflunomide [see Drug Interactions (7) ] . Teriflunomide did not affect the pharmacokinetics of bupropion (a CYP2B6 substrate), midazolam (a CYP3A4 substrate), S-warfarin (a CYP2C9 substrate), omeprazole (a CYP2C19 substrate), and metoprolol (a CYP2D6 substrate). The potential effect of other drugs on AUBAGIO Potent CYP and transporter inducers: Rifampin did not affect the pharmacokinetics of teriflunomide. Specific Populations Hepatic impairment Mild and moderate hepatic impairment had no impact on the pharmacokinetics of teriflunomide. The pharmacokinetics of teriflunomide in severe hepatic impairment has not been evaluated [see Contraindications (4) , Warnings and Precautions (5.1) , and Use in Specific Populations (8.6) ] . Renal impairment Severe renal impairment had no impact on the pharmacokinetics of teriflunomide [see Use in Specific Populations (8.7) ] . Gender In a population analysis, the clearance rate for teriflunomide is 23% less in females than in males. Race Effect of race on the pharmacokinetics of teriflunomide cannot be adequately assessed due to a low number of non-white patients in the clinical trials.

12.1 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.

12.2 Pharmacodynamics Potential to Prolong the QT Interval In a placebo-controlled thorough QT study performed in healthy adult subjects, there was no evidence that teriflunomide caused QT interval prolongation of clinical significance (i.e., the upper bound of the 90% confidence interval for the largest placebo-adjusted, baseline-corrected QTc was below 10 ms).

12.3 Pharmacokinetics Teriflunomide is the principal active metabolite of leflunomide and is responsible for leflunomide's activity in vivo . At recommended doses, teriflunomide and leflunomide result in a similar range of plasma concentrations of teriflunomide. Based on a population analysis of teriflunomide in healthy adult volunteers and adult MS patients, median t 1/2 was approximately 18 and 19 days after repeated doses of 7 mg and 14 mg respectively. It takes approximately 3 months respectively to reach steady-state concentrations. The estimated AUC accumulation ratio is approximately 30 after repeated doses of 7 or 14 mg. Absorption Median time to reach maximum plasma concentrations is between 1 to 4 hours post dose following oral administration of teriflunomide. Food does not have a clinically relevant effect on teriflunomide pharmacokinetics. Distribution Teriflunomide is extensively bound to plasma protein (>99%) and is mainly distributed in plasma. The volume of distribution is 11 L after a single intravenous (IV) administration. Metabolism Teriflunomide is the major circulating moiety detected in plasma. The primary biotransformation pathway to minor metabolites of teriflunomide is hydrolysis, with oxidation being a minor pathway. Secondary pathways involve oxidation, N-acetylation and sulfate conjugation. Elimination Teriflunomide is eliminated mainly through direct biliary excretion of unchanged drug as well as renal excretion of metabolites. Over 21 days, 60.1% of the administered dose is excreted via feces (37.5%) and urine (22.6%). After an accelerated elimination procedure with cholestyramine, an additional 23.1% was recovered (mostly in feces). After a single IV administration, the total body clearance of teriflunomide is 30.5 mL/h. Drug Interaction Studies Teriflunomide is not metabolized by Cytochrome P450 or flavin monoamine oxidase enzymes. The potential effect of AUBAGIO on other drugs CYP2C8 substrates There was an increase in mean repaglinide C max and AUC (1.7- and 2.4-fold, respectively) following repeated doses of teriflunomide and a single dose of 0.25 mg repaglinide, suggesting that teriflunomide is an inhibitor of CYP2C8 in vivo . The magnitude of interaction could be higher at the recommended repaglinide dose [see Drug Interactions (7) ] . CYP1A2 substrates Repeated doses of teriflunomide decreased mean C max and AUC of caffeine by 18% and 55%, respectively, suggesting that teriflunomide may be a weak inducer of CYP1A2 in vivo [see Drug Interactions (7) ]. OAT3 substrates There was an increase in mean cefaclor C max and AUC (1.43- and 1.54-fold, respectively), following repeated doses of teriflunomide, suggesting that teriflunomide is an inhibitor of organic anion transporter 3 (OAT3) in vivo [see Drug Interactions (7) ] . BCRP and OATP1B1/1B3 substrates There was an increase in mean rosuvastatin C max and AUC (2.65- and 2.51-fold, respectively) following repeated doses of teriflunomide, suggesting that teriflunomide is an inhibitor of BCRP transporter and organic anion transporting polypeptide 1B1 and 1B3 (OATP1B1/1B3) [see Drug Interactions (7) ] . Oral contraceptives There was an increase in mean ethinylestradiol C max and AUC 0-24 (1.58- and 1.54-fold, respectively) and levonorgestrel C max and AUC 0-24 (1.33- and 1.41-fold, respectively) following repeated doses of teriflunomide [see Drug Interactions (7) ] . Teriflunomide did not affect the pharmacokinetics of bupropion (a CYP2B6 substrate), midazolam (a CYP3A4 substrate), S-warfarin (a CYP2C9 substrate), omeprazole (a CYP2C19 substrate), and metoprolol (a CYP2D6 substrate). The potential effect of other drugs on AUBAGIO Potent CYP and transporter inducers: Rifampin did not affect the pharmacokinetics of teriflunomide. Specific Populations Hepatic impairment Mild and moderate hepatic impairment had no impact on the pharmacokinetics of teriflunomide. The pharmacokinetics of teriflunomide in severe hepatic impairment has not been evaluated [see Contraindications (4) , Warnings and Precautions (5.1) , and Use in Specific Populations (8.6) ] . Renal impairment Severe renal impairment had no impact on the pharmacokinetics of teriflunomide [see Use in Specific Populations (8.7) ] . Gender In a population analysis, the clearance rate for teriflunomide is 23% less in females than in males. Race Effect of race on the pharmacokinetics of teriflunomide cannot be adequately assessed due to a low number of non-white patients in the clinical trials.

20230130

25

3 DOSAGE FORMS AND STRENGTHS AUBAGIO is available as 7 mg and 14 mg tablets. The 14 mg tablet is a pale blue to pastel blue, pentagonal film-coated tablet with the dose strength "14" imprinted on one side and engraved with the corporate logo on the other side. Each tablet contains 14 mg of teriflunomide. The 7 mg tablet is a very light greenish-bluish grey to pale greenish-blue, hexagonal film-coated tablet with the dose strength "7" imprinted on one side and engraved with the corporate logo on the other side. Each tablet contains 7 mg of teriflunomide. 7 mg and 14 mg film-coated tablets ( 3 )

Aubagio teriflunomide TERIFLUNOMIDE TERIFLUNOMIDE LACTOSE MONOHYDRATE STARCH, CORN HYDROXYPROPYL CELLULOSE, UNSPECIFIED MICROCRYSTALLINE CELLULOSE SODIUM STARCH GLYCOLATE TYPE A CORN MAGNESIUM STEARATE HYPROMELLOSE, UNSPECIFIED TITANIUM DIOXIDE TALC POLYETHYLENE GLYCOL, UNSPECIFIED FD&C BLUE NO. 2 FERRIC OXIDE YELLOW light greenish-bluish grey to pale greenish-blue 7 Aubagio teriflunomide TERIFLUNOMIDE TERIFLUNOMIDE LACTOSE MONOHYDRATE STARCH, CORN HYDROXYPROPYL CELLULOSE, UNSPECIFIED MICROCRYSTALLINE CELLULOSE SODIUM STARCH GLYCOLATE TYPE A CORN MAGNESIUM STEARATE HYPROMELLOSE, UNSPECIFIED TITANIUM DIOXIDE TALC POLYETHYLENE GLYCOL, UNSPECIFIED FD&C BLUE NO. 2 pale blue to pastel blue 14

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis No evidence of carcinogenicity was observed in lifetime carcinogenicity bioassays in mouse and rat. In mouse, teriflunomide was administered orally at doses up to 12 mg/kg/day for up to 95–104 weeks; plasma teriflunomide exposures (AUC) at the highest dose tested are approximately 3 times that in humans at the maximum recommended human dose (MRHD, 14 mg/day). In rat, teriflunomide was administered orally at doses up to 4 mg/kg/day for up to 97–104 weeks; plasma teriflunomide AUCs at the highest doses tested are less than that in humans at the MRHD. Mutagenesis Teriflunomide was negative in the in vitro bacterial reverse mutation (Ames) assay, the in vitro HPRT assay, and in in vivo micronucleus and chromosomal aberration assays. Teriflunomide was positive in an in vitro chromosomal aberration assay in human lymphocytes, with and without metabolic activation. Addition of uridine (to supplement the pyrimidine pool) reduced the magnitude of the clastogenic effect; however, teriflunomide was positive in the in vitro chromosomal aberration assay, even in the presence of uridine. 4-Trifluoromethylaniline (4-TFMA), a minor metabolite of teriflunomide, was positive in the in vitro bacterial reverse mutation (Ames) assay, the in vitro HPRT assay, and the in vitro chromosomal aberration assay in mammalian cells. 4-TFMA was negative in in vivo micronucleus and chromosomal aberration assays. Impairment of Fertility Oral administration of teriflunomide (0, 1, 3, 10 mg/kg/day) to male rats prior to and during mating (to untreated females) resulted in no adverse effects on fertility; however, reduced epididymal sperm count was observed at the mid and high doses tested. The no-effect dose for reproductive toxicity in male rats (1 mg/kg) is less than the MRHD on a mg/m 2 basis. Oral administration of teriflunomide (0, 0.84, 2.6, 8.6 mg/kg/day) to female rats, prior to and during mating (to untreated males) and continuing to gestation day 6, resulted in embryolethality, reduced fetal body weight, and/or malformations at all doses tested. Due to marked embryolethality at the highest dose tested, no fetuses were available for evaluation. The lowest dose tested is less than the MRHD on a mg/m 2 basis.

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis No evidence of carcinogenicity was observed in lifetime carcinogenicity bioassays in mouse and rat. In mouse, teriflunomide was administered orally at doses up to 12 mg/kg/day for up to 95–104 weeks; plasma teriflunomide exposures (AUC) at the highest dose tested are approximately 3 times that in humans at the maximum recommended human dose (MRHD, 14 mg/day). In rat, teriflunomide was administered orally at doses up to 4 mg/kg/day for up to 97–104 weeks; plasma teriflunomide AUCs at the highest doses tested are less than that in humans at the MRHD. Mutagenesis Teriflunomide was negative in the in vitro bacterial reverse mutation (Ames) assay, the in vitro HPRT assay, and in in vivo micronucleus and chromosomal aberration assays. Teriflunomide was positive in an in vitro chromosomal aberration assay in human lymphocytes, with and without metabolic activation. Addition of uridine (to supplement the pyrimidine pool) reduced the magnitude of the clastogenic effect; however, teriflunomide was positive in the in vitro chromosomal aberration assay, even in the presence of uridine. 4-Trifluoromethylaniline (4-TFMA), a minor metabolite of teriflunomide, was positive in the in vitro bacterial reverse mutation (Ames) assay, the in vitro HPRT assay, and the in vitro chromosomal aberration assay in mammalian cells. 4-TFMA was negative in in vivo micronucleus and chromosomal aberration assays. Impairment of Fertility Oral administration of teriflunomide (0, 1, 3, 10 mg/kg/day) to male rats prior to and during mating (to untreated females) resulted in no adverse effects on fertility; however, reduced epididymal sperm count was observed at the mid and high doses tested. The no-effect dose for reproductive toxicity in male rats (1 mg/kg) is less than the MRHD on a mg/m 2 basis. Oral administration of teriflunomide (0, 0.84, 2.6, 8.6 mg/kg/day) to female rats, prior to and during mating (to untreated males) and continuing to gestation day 6, resulted in embryolethality, reduced fetal body weight, and/or malformations at all doses tested. Due to marked embryolethality at the highest dose tested, no fetuses were available for evaluation. The lowest dose tested is less than the MRHD on a mg/m 2 basis.

NDA202992

Aubagio

teriflunomide

58468-0210

HUMAN PRESCRIPTION DRUG

ORAL

PRINCIPAL DISPLAY PANEL - 7 mg Tablet Bottle Carton NDC 58468-0211-4 Aubagio ® (teriflunomide) Tablets 7 mg Rx only Dispense with Medication Guide 30 Tablets sanofi PRINCIPAL DISPLAY PANEL - 7 mg Tablet Bottle Carton

Manufactured for: Genzyme Corporation Cambridge, MA 02141 A SANOFI COMPANY

17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Medication Guide). A Medication Guide is required for distribution with AUBAGIO. Hepatotoxicity Inform patients that AUBAGIO may cause liver injury, which can be life-threatening, and that their liver enzymes will be checked before starting AUBAGIO and at least monthly for 6 months after starting AUBAGIO [see Dosage and Administration (2) and Warnings and Precautions (5.1) ] . Advise patients that they should contact their physician if they have any unexplained nausea, vomiting, abdominal pain, fatigue, anorexia, or jaundice and/or dark urine. Embryofetal Toxicity Advise females of reproductive potential of the potential for fetal harm if AUBAGIO is taken during pregnancy to notify their healthcare provider immediately if a pregnancy occurs or is suspected to use effective contraception during treatment with AUBAGIO and until the teriflunomide plasma concentration is verified to be less than 0.02 mg/L [see Warnings and Precautions (5.2 , 5.3) , Use in Specific Populations (8.1 , 8.3) , Clinical Pharmacology (12.3) ] . Instruct men taking AUBAGIO and not wishing to father a child to use effective contraception to minimize any possible risk to the fetus; their female partners should also use effective contraception. Advise men wishing to father a child to discontinue use of AUBAGIO and undergo an accelerated elimination procedure. Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to AUBAGIO during pregnancy [see Use in Specific Populations (8.1) ] . Availability of an Accelerated Elimination Procedure Advise patients that AUBAGIO may stay in the blood for up to 2 years after the last dose and that an accelerated elimination procedure may be used if needed [see Warnings and Precautions (5.3) ] . Risk of Infections Inform patients that they may develop a lowering of their white blood cell counts and that their blood counts will be checked before starting AUBAGIO. Inform patients that they may be more likely to get infections when taking AUBAGIO and that they should contact their physician if they develop symptoms of infection, particularly in case of fever [see Warnings and Precautions (5.4) ] . Advise patients that the use of some vaccines should be avoided during treatment with AUBAGIO and for at least 6 months after discontinuation. Hypersensitivity Reactions Advise patients to discontinue AUBAGIO and seek immediate medical attention if any signs or symptoms of a hypersensitivity reaction occur [see Contraindications (4) and Warnings and Precautions (5.5) ] . Signs and symptoms can include dyspnea, urticaria, angioedema involving the lips, eyes, throat, or tongue, or skin rash. Serious Skin Reactions Advise patients to discontinue AUBAGIO and seek immediate medical attention if any signs of a serious skin reaction, such as SJS or TEN, occur [see Warnings and Precautions (5.6) ] . Signs and symptoms can include rash, mouth sores, blisters, or peeling skin. DRESS/Multi-organ Hypersensitivity Instruct patients and caregivers that a fever or rash associated with signs of other organ system involvement (e.g., lymphadenopathy, hepatic dysfunction) may be drug-related and should be reported to their healthcare provider immediately. AUBAGIO should be discontinued immediately if a serious hypersensitivity reaction is suspected [see Warnings and Precautions (5.7) ] . Peripheral Neuropathy Inform patients that they may develop peripheral neuropathy. Advise patients that they should contact their physician if they develop symptoms of peripheral neuropathy, such as numbness or tingling of hands or feet [see Warnings and Precautions (5.8) ] . Increased Blood Pressure Inform patients that AUBAGIO may increase blood pressure [see Warnings and Precautions (5.9) ] . Lactation Advise females not to breastfeed during treatment with AUBAGIO [see Use in Specific Populations (8.2) ] .

This Medication Guide has been approved by the U.S. Food and Drug Administration. Revised: April 2021 Medication Guide AUBAGIO ® (oh-BAH-gee-oh) (teriflunomide) tablets, for oral use Read this Medication Guide before you start using AUBAGIO and each time you get a refill. There may be new information. This information does not take the place of talking with your doctor about your medical condition or your treatment. What is the most important information I should know about AUBAGIO? AUBAGIO may cause serious side effects, including: Liver problems: AUBAGIO may cause serious liver problems, including liver failure that can be life-threatening and may require a liver transplant. Your risk of developing serious liver problems may be higher if you already have liver problems or take other medicines that also affect your liver. Your doctor should do blood tests to check your liver: within 6 months before you start taking AUBAGIO 1 time a month for 6 months after you start taking AUBAGIO Call your doctor right away if you have any of the following symptoms of liver problems: nausea vomiting stomach pain loss of appetite tiredness your skin or the whites of your eyes turn yellow dark urine Harm to your unborn baby: AUBAGIO may cause harm to your unborn baby. Do not take AUBAGIO if you are pregnant. Do not take AUBAGIO unless you are using effective birth control. If you are a female, you should have a pregnancy test before you start taking AUBAGIO. Use effective birth control during your treatment with AUBAGIO. After stopping AUBAGIO, continue using effective birth control until you have blood tests to make sure your blood levels of AUBAGIO are low enough. If you become pregnant while taking AUBAGIO or within 2 years after you stop taking it, tell your doctor right away. AUBAGIO Pregnancy Registry. If you become pregnant while taking AUBAGIO or during the 2 years after you stop taking AUBAGIO, talk to your doctor about enrolling in the AUBAGIO Pregnancy Registry at 1-800-745-4447, option 2. The purpose of this registry is to collect information about your health and your baby's health. For men taking AUBAGIO: If your female partner plans to become pregnant, you should stop taking AUBAGIO and ask your doctor how to quickly lower the levels of AUBAGIO in your blood. If your female partner does not plan to become pregnant, you and your female partner should use effective birth control during your treatment with AUBAGIO. AUBAGIO remains in your blood after you stop taking it, so continue using effective birth control until AUBAGIO blood levels have been checked and they are low enough. AUBAGIO may stay in your blood for up to 2 years after you stop taking it. Your doctor can prescribe a medicine to help lower your blood levels of AUBAGIO more quickly. Talk to your doctor if you want more information about this. What is AUBAGIO? AUBAGIO is a prescription medicine used to treat relapsing forms of multiple sclerosis (MS), to include clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease, in adults. It is not known if AUBAGIO is safe and effective in children. Who should not take AUBAGIO? Do not take AUBAGIO if you: have severe liver problems. are pregnant or are of childbearing age and not using effective birth control. have had an allergic reaction to leflunomide, teriflunomide, or any other ingredients in AUBAGIO. Please see the end of this Medication Guide for a complete list of ingredients in AUBAGIO. take a medicine called leflunomide. What should I tell my doctor before taking AUBAGIO? Before you take AUBAGIO, tell your doctor about all of your medical conditions, including if you: have liver or kidney problems. have a fever or infection, or you are unable to fight infections. have numbness or tingling in your hands or feet that is different from your MS symptoms. have diabetes. have had serious skin problems when taking other medicines. have breathing problems. have high blood pressure. are breastfeeding or plan to breastfeed. It is not known if AUBAGIO passes into your breast milk. You and your doctor should decide if you will take AUBAGIO or breastfeed. You should not do both. Tell your doctor about all the medicines you take , including prescription and over-the-counter medicines, vitamins, and herbal supplements. Using AUBAGIO and other medicines may affect each other causing serious side effects. AUBAGIO may affect the way other medicines work, and other medicines may affect how AUBAGIO works. Especially tell your doctor if you take medicines that could raise your chance of getting infections, including medicines used to treat cancer or to control your immune system. Ask your doctor or pharmacist for a list of these medicines if you are not sure. Know the medicines you take. Keep a list of them to show your doctor or pharmacist when you get a new medicine. How should I take AUBAGIO? Take AUBAGIO exactly as your doctor tells you to take it. Take AUBAGIO 1 time each day. Take AUBAGIO with or without food. What are possible side effects of AUBAGIO? AUBAGIO may cause serious side effects, including: see " What is the most important information I should know about AUBAGIO? " decreases in your white blood cell count. Your white blood cell counts should be checked before you start taking AUBAGIO. When you have a low white blood cell count you: may have more frequent infections. You should have a skin test for TB (tuberculosis) before you start taking AUBAGIO. Tell your doctor if you have any of these symptoms of an infection: fever tiredness body aches chills nausea vomiting should not receive certain vaccinations during your treatment with AUBAGIO and for 6 months after your treatment with AUBAGIO ends. allergic reactions. Stop taking AUBAGIO and call your doctor right away or get emergency medical help if you have difficulty breathing, itching, swelling on any part of your body including in your lips, eyes, throat, or tongue. serious skin reactions. AUBAGIO may cause serious skin reactions that may lead to death. Stop taking AUBAGIO and call your doctor right away or get emergency medical help if you have any of the following symptoms: rash or redness and peeling, mouth sores or blisters. other types of allergic reactions or serious problems that may affect different parts of the body such as your liver, kidneys, heart, or blood cells. You may or may not have a rash with these types of reactions. Other symptoms you may have are: severe muscle pain swollen lymph glands swelling of your face unusual bruising or bleeding weakness or tiredness yellowing of your skin or the white part of your eyes If you have a fever or rash with any of the above symptoms, stop taking AUBAGIO and call your doctor right away. numbness or tingling in your hands or feet that is different from your MS symptoms. You have a higher chance of getting these symptoms if you: are over 60 years of age take certain medicines that affect your nervous system have diabetes Tell your doctor if you have numbness or tingling in your hands or feet that is different from your MS. high blood pressure. Your doctor should check your blood pressure before you start taking AUBAGIO and while you are taking AUBAGIO. new or worsening breathing problems. These may be serious and lead to death. Call your doctor right away or get emergency medical help if you have shortness of breath or coughing with or without fever. The most common side effects of AUBAGIO include: headache diarrhea nausea hair thinning or loss (alopecia) increases in the results of blood tests to check your liver function These are not all the possible side effects of AUBAGIO. For more information, ask your doctor or pharmacist. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. How should I store AUBAGIO? Store AUBAGIO at room temperature between 68°F to 77°F (20°C to 25°C). Keep AUBAGIO and all medicines out of the reach of children. General information about the safe and effective use of AUBAGIO. Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use AUBAGIO for a condition for which it was not prescribed. Do not give AUBAGIO to other people, even if they have the same symptoms you have. It may harm them. You can ask your doctor or pharmacist for information about AUBAGIO that is written for health professionals. What are the ingredients in AUBAGIO? Active ingredient: teriflunomide Inactive ingredients in 7 mg and 14 mg tablets: lactose monohydrate, corn starch, hydroxypropyl cellulose, microcrystalline cellulose, sodium starch glycolate, magnesium stearate, hypromellose, titanium dioxide, talc, polyethylene glycol and indigo carmine aluminum lake. In addition, the 7 mg tablets also contain iron oxide yellow. For more information, go to www.aubagio.com or call Genzyme Medical Information Services at 1-800-745-4447, option 2. Manufactured for: Genzyme Corporation Cambridge, MA 02141 A SANOFI COMPANY

14 CLINICAL STUDIES Four randomized, controlled, double-blind clinical trials established the efficacy of AUBAGIO in patients with relapsing forms of multiple sclerosis. Study 1 was a double-blind, placebo-controlled clinical trial that evaluated once daily doses of AUBAGIO 7 mg and AUBAGIO 14 mg for up to 26 months in patients with relapsing forms of multiple sclerosis. Patients were required to have a diagnosis of multiple sclerosis exhibiting a relapsing clinical course, with or without progression, and to have experienced at least one relapse over the year preceding the trial or at least two relapses over the two years preceding the trial. Patients were required not to have received interferon-beta for at least four months, or any other multiple sclerosis medication for at least six months before entering the study, nor were these medications permitted during the study. Neurological evaluations were to be performed at screening, every 12 weeks until week 108, and after suspected relapses. MRI was to be performed at screening, and at week 24, 48, 72, and 108. The primary endpoint was the annualized relapse rate (ARR). In Study 1, 1088 patients were randomized to receive AUBAGIO 7 mg (n=366), AUBAGIO 14 mg (n=359), or placebo (n=363). At entry, patients had an Expanded Disability Status Scale (EDSS) score ≤5.5. Patients had a mean age of 38 years, mean disease duration of 5 years, and mean EDSS at baseline of 2.7. A total of 91% of patients had relapsing remitting multiple sclerosis, and 9% had a progressive form of multiple sclerosis with relapses. The mean duration of treatment was 635, 627, and 631 days for AUBAGIO 7 mg, AUBAGIO 14 mg, and placebo, respectively. The percentage of patients who completed the study treatment period was 75%, 73%, and 71% for AUBAGIO 7 mg, AUBAGIO 14 mg, and placebo, respectively. There was a statistically significant reduction in ARR for patients who received AUBAGIO 7 mg or AUBAGIO 14 mg, compared to patients who received placebo (see Table 2 ). There was a consistent reduction of the ARR noted in subgroups defined by sex, age group, prior multiple sclerosis therapy, and baseline disease activity. There was a statistically significant reduction in the relative risk of disability progression at week 108 sustained for 12 weeks (as measured by at least a 1-point increase from baseline EDSS ≤5.5 or a 0.5 point increase for those with a baseline EDSS >5.5) in the AUBAGIO 14 mg group compared to placebo (see Table 2 and Figure 1 ). The effect of AUBAGIO on several magnetic resonance imaging (MRI) variables, including the total lesion volume of T2 and hypointense T1 lesions, was assessed in Study 1. The change in total lesion volume from baseline was significantly lower in the AUBAGIO 7 mg and AUBAGIO 14 mg groups than in the placebo group. Patients in both AUBAGIO groups had significantly fewer gadolinium-enhancing lesions per T1-weighted scan than those in the placebo group (see Table 2 ). Table 2: Clinical and MRI Results of Study 1 AUBAGIO 7 mg N=365 AUBAGIO 14 mg N=358 Placebo N=363 Clinical Endpoints Annualized relapse rate 0.370 (p=0.0002) 0.369 (p=0.0005) 0.539 Relative risk reduction 31% 31% – Percent of patients remaining relapse-free at week 108 53.7% 56.5% 45.6% Percent disability progression at week 108 21.7% (p=0.084) 20.2% (p=0.028) 27.3% Hazard ratio 0.76 0.70 – MRI Endpoints Median change from baseline in Total lesion volume Total lesion volume: sum of T2 and hypointense T1 lesion volume in mL (mL) at week 108 0.755 (p=0.0317) p-values based on cubic root transformed data for total lesion volume 0.345 (p=0.0003) 1.127 Mean number of Gd-enhancing T1-lesions per scan 0.570 (p<0.0001) 0.261 (p<0.0001) 1.331 Figure 1: Kaplan-Meier Plot of Time to Disability Progression Sustained for 12 Weeks (Study 1) Study 2 was a double-blind, placebo-controlled clinical trial that evaluated once daily doses of AUBAGIO 7 mg and AUBAGIO 14 mg for up to 40 months in patients with relapsing forms of multiple sclerosis. Patients were required to have a diagnosis of multiple sclerosis exhibiting a relapsing clinical course and to have experienced at least one relapse over the year preceding the trial, or at least two relapses over the two years preceding the trial. Patients were required not to have received any multiple sclerosis medication for at least three months before entering the trial, nor were these medications permitted during the trial. Neurological evaluations were to be performed at screening, every 12 weeks until completion, and after every suspected relapse. The primary end point was the ARR. A total of 1165 patients received AUBAGIO 7 mg (n=407), AUBAGIO 14 mg (n=370), or placebo (n=388). Patients had a mean age of 38 years, a mean disease duration of 5 years, and a mean EDSS at baseline of 2.7. A total of 98% of patients had relapsing remitting multiple sclerosis, and 2% had a progressive form of multiple sclerosis with relapses. The mean duration of treatment was 552, 567, and 571 days for AUBAGIO 7 mg, AUBAGIO 14 mg, and placebo, respectively. The percentage of patients who completed the study treatment period was 67%, 66%, and 68% for AUBAGIO 7 mg, AUBAGIO 14 mg, and placebo, respectively. There was a statistically significant reduction in the ARR for patients who received AUBAGIO 7 mg or AUBAGIO 14 mg compared to patients who received placebo (see Table 3 ). There was a consistent reduction of the ARR noted in subgroups defined by sex, age group, prior multiple sclerosis therapy, and baseline disease activity. There was a statistically significant reduction in the relative risk of disability progression at week 108 sustained for 12 weeks (as measured by at least a 1-point increase from baseline EDSS ≤5.5 or a 0.5 point increase for those with a baseline EDSS >5.5) in the AUBAGIO 14 mg group compared to placebo (see Table 3 and Figure 2 ). Table 3: Clinical Results of Study 2 AUBAGIO 7 mg N=407 AUBAGIO 14 mg N=370 Placebo N=388 Clinical Endpoints Annualized relapse rate 0.389 (p=0.0183) 0.319 (p=0.0001) 0.501 Relative risk reduction 22% 36% – Percent of patients remaining relapse-free at week 108 58.2% 57.1% 46.8% Percent disability progression at week 108 21.1% (p=0.762) 15.8% (p=0.044) 19.7% Hazard ratio 0.96 0.69 – Figure 2: Kaplan-Meier Plot of Time to Disability Progression Sustained for 12 Weeks (Study 2) Study 3 was a double-blind, placebo-controlled clinical trial that evaluated once daily doses of AUBAGIO 7 mg and AUBAGIO 14 mg for up to 108 weeks in patients with relapsing multiple sclerosis. Patients were required to have had a first clinical event consistent with acute demyelination occurring within 90 days of randomization with 2 or more T2 lesions at least 3 mm in diameter that were characteristic of multiple sclerosis. A total of 614 patients received AUBAGIO 7 mg (n=203), AUBAGIO 14 mg (n=214), or placebo (n=197). Patients had a mean age of 32 years, EDSS at baseline of 1.7, and mean disease duration of two months. The proportion of patients free of relapse was greater in the AUBAGIO 7 mg (70.5%, p<0.05) and AUBAGIO 14 mg (72.2%, p<0.05) groups than in the placebo group (61.7%). The effect of AUBAGIO on MRI activity was also demonstrated in Study 4, a randomized, double-blind, placebo-controlled clinical trial of multiple sclerosis patients with relapse. In Study 4, MRI was to be performed at baseline, 6 weeks, 12 weeks, 18 weeks, 24 weeks, 30 weeks, and 36 weeks after treatment initiation. A total of 179 patients were randomized to AUBAGIO 7 mg (n=61), AUBAGIO 14 mg (n=57), or placebo (n=61). Baseline demographics were consistent across treatment groups. The primary endpoint was the average number of unique active lesions/MRI scan during treatment. The mean number of unique active lesions per brain MRI scan during the 36-week treatment period was lower in patients treated with AUBAGIO 7 mg (1.06) and AUBAGIO 14 mg (0.98) as compared to placebo (2.69), the difference being statistically significant for both (p=0.0234 and p=0.0052, respectively). Figure 1 Figure 2

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

8.4 Pediatric Use Safety and effectiveness in pediatric patients have not been established. Effectiveness of AUBAGIO for the treatment of relapsing form of multiple sclerosis in pediatric patients (10 to 17 years of age) was not established in an adequate and well-controlled clinical study in 166 patients (109 patients received once-daily doses of AUBAGIO and 57 patients received placebo) for up to 96 weeks. Pancreatitis has been reported in adults in the postmarketing setting, but appears to occur at higher frequency in the pediatric population. In this pediatric study, cases of pancreatitis were reported in 1.8% (2/109) of patients who received AUBAGIO compared to no patients in the placebo group. All patients in the pediatric trial recovered or were recovering after treatment discontinuation and accelerated elimination procedure [see Warnings and Precautions (5.11) ] . Additionally, elevated or abnormal blood creatine phosphokinase was reported in 6.4% of pediatric patients who received AUBAGIO compared to no patients in the placebo group. Juvenile Animal Toxicity Data Oral administration of teriflunomide (0, 0.3, 3, or 6 mg/kg/day) to young rats on postnatal days 21 to 70 resulted in suppression of immune function (T-cell dependent antibody response) at the mid and high doses, and adverse effects on male reproductive organs (reduced sperm count) and altered neurobehavioral function (increased locomotor activity) at the high dose. At the no-effect dose (0.3 mg/kg/day) for developmental toxicity in juvenile rats, plasma exposures were less than those in pediatric patients at the doses of AUBAGIO tested in the clinical study.

8.1 Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to AUBAGIO during pregnancy. Healthcare providers and patients are encouraged to report pregnancies by calling 1-800-745-4447, option 2. Risk Summary 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 [see Contraindications (4) and Warnings and Precautions (5.2) ] . In animal reproduction studies in rat and rabbit, oral administration of teriflunomide during organogenesis caused teratogenicity and embryolethality at plasma exposures (AUC) lower than that at the maximum recommended human dose (MRHD) of 14 mg/day [see Data ]. Available human data from pregnancy registries, clinical trials, pharmacovigilance cases, and published literature are too limited to draw any conclusions, but they do not clearly indicate increased birth defects or miscarriage associated with inadvertent teriflunomide exposure in the early first trimester when followed by an accelerated elimination procedure [see Clinical Considerations and Data ] . There are no human data pertaining to exposures later in the first trimester or beyond. In the US general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2%–4% and 15%–20%, respectively. The background risk of major birth defects and miscarriage in the indicated population is unknown. Clinical Considerations Fetal/Neonatal adverse reactions 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 [see Warnings and Precautions (5.3) and Clinical Pharmacology (12.3) ]. Data Human data Available human data are limited. Prospectively reported data (from clinical trials and postmarketing reports) from >150 pregnancies in patients treated with teriflunomide and >300 pregnancies in patients treated with leflunomide have not demonstrated an increased rate of congenital malformations or miscarriage following teriflunomide exposure in the early first trimester when followed by an accelerated elimination procedure. Specific patterns of major congenital malformations in humans have not been observed. Limitations of these data include an inadequate number of reported pregnancies from which to draw conclusions, the short duration of drug exposure in reported pregnancies, which precludes a full evaluation of the fetal risks, incomplete reporting, and the inability to control for confounders (such as underlying maternal disease and use of concomitant medications). Animal data When teriflunomide (oral doses of 1, 3, or 10 mg/kg/day) was administered to pregnant rats throughout the period of organogenesis, high incidences of fetal malformation (primarily craniofacial, and axial and appendicular skeletal defects) and fetal death were observed at doses not associated with maternal toxicity. Adverse effects on fetal development were observed following dosing at various stages throughout organogenesis. Maternal plasma exposure at the no-effect level (1.0 mg/kg/day) for fetal developmental toxicity in rats was less than that in humans at the maximum recommended human dose (MRHD, 14 mg/day). Administration of teriflunomide (oral doses of 1, 3.5, or 12 mg/kg/day) to pregnant rabbits throughout organogenesis resulted in high incidences of fetal malformation (primarily craniofacial, and axial and appendicular skeletal defects) and fetal death at doses associated with minimal maternal toxicity. Maternal plasma exposure at the no-effect dose (1.0 mg/kg/day) for fetal developmental toxicity in rabbits was less than that in humans at the MRHD. In studies in which teriflunomide (oral doses of 0.05, 0.1, 0.3, 0.6, or 1.0 mg/kg/day) was administered to rats during gestation and lactation, decreased growth, eye and skin abnormalities, and high incidences of malformation (limb defects) and postnatal death were observed in the offspring at doses not associated with maternal toxicity. Maternal plasma exposure at the no-effect dose for prenatal and postnatal developmental toxicity in rats (0.10 mg/kg/day) was less than that in humans at the MRHD. In animal reproduction studies of leflunomide, embryolethality and teratogenic effects were observed in pregnant rat and rabbit at or below clinically relevant plasma teriflunomide exposures (AUC). In published reproduction studies in pregnant mice, leflunomide was embryolethal and increased the incidence of malformations (craniofacial, axial skeletal, heart and great vessel). Supplementation with exogenous uridine reduced the teratogenic effects in pregnant mice, suggesting that the mode of action (inhibition of mitochondrial enzyme dihydroorotate dehydrogenase) is the same for therapeutic efficacy and developmental toxicity. At recommended doses in humans, teriflunomide and leflunomide result in a similar range of plasma concentrations of teriflunomide.

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to AUBAGIO during pregnancy. Healthcare providers and patients are encouraged to report pregnancies by calling 1-800-745-4447, option 2. Risk Summary 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 [see Contraindications (4) and Warnings and Precautions (5.2) ] . In animal reproduction studies in rat and rabbit, oral administration of teriflunomide during organogenesis caused teratogenicity and embryolethality at plasma exposures (AUC) lower than that at the maximum recommended human dose (MRHD) of 14 mg/day [see Data ]. Available human data from pregnancy registries, clinical trials, pharmacovigilance cases, and published literature are too limited to draw any conclusions, but they do not clearly indicate increased birth defects or miscarriage associated with inadvertent teriflunomide exposure in the early first trimester when followed by an accelerated elimination procedure [see Clinical Considerations and Data ] . There are no human data pertaining to exposures later in the first trimester or beyond. In the US general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2%–4% and 15%–20%, respectively. The background risk of major birth defects and miscarriage in the indicated population is unknown. Clinical Considerations Fetal/Neonatal adverse reactions 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 [see Warnings and Precautions (5.3) and Clinical Pharmacology (12.3) ]. Data Human data Available human data are limited. Prospectively reported data (from clinical trials and postmarketing reports) from >150 pregnancies in patients treated with teriflunomide and >300 pregnancies in patients treated with leflunomide have not demonstrated an increased rate of congenital malformations or miscarriage following teriflunomide exposure in the early first trimester when followed by an accelerated elimination procedure. Specific patterns of major congenital malformations in humans have not been observed. Limitations of these data include an inadequate number of reported pregnancies from which to draw conclusions, the short duration of drug exposure in reported pregnancies, which precludes a full evaluation of the fetal risks, incomplete reporting, and the inability to control for confounders (such as underlying maternal disease and use of concomitant medications). Animal data When teriflunomide (oral doses of 1, 3, or 10 mg/kg/day) was administered to pregnant rats throughout the period of organogenesis, high incidences of fetal malformation (primarily craniofacial, and axial and appendicular skeletal defects) and fetal death were observed at doses not associated with maternal toxicity. Adverse effects on fetal development were observed following dosing at various stages throughout organogenesis. Maternal plasma exposure at the no-effect level (1.0 mg/kg/day) for fetal developmental toxicity in rats was less than that in humans at the maximum recommended human dose (MRHD, 14 mg/day). Administration of teriflunomide (oral doses of 1, 3.5, or 12 mg/kg/day) to pregnant rabbits throughout organogenesis resulted in high incidences of fetal malformation (primarily craniofacial, and axial and appendicular skeletal defects) and fetal death at doses associated with minimal maternal toxicity. Maternal plasma exposure at the no-effect dose (1.0 mg/kg/day) for fetal developmental toxicity in rabbits was less than that in humans at the MRHD. In studies in which teriflunomide (oral doses of 0.05, 0.1, 0.3, 0.6, or 1.0 mg/kg/day) was administered to rats during gestation and lactation, decreased growth, eye and skin abnormalities, and high incidences of malformation (limb defects) and postnatal death were observed in the offspring at doses not associated with maternal toxicity. Maternal plasma exposure at the no-effect dose for prenatal and postnatal developmental toxicity in rats (0.10 mg/kg/day) was less than that in humans at the MRHD. In animal reproduction studies of leflunomide, embryolethality and teratogenic effects were observed in pregnant rat and rabbit at or below clinically relevant plasma teriflunomide exposures (AUC). In published reproduction studies in pregnant mice, leflunomide was embryolethal and increased the incidence of malformations (craniofacial, axial skeletal, heart and great vessel). Supplementation with exogenous uridine reduced the teratogenic effects in pregnant mice, suggesting that the mode of action (inhibition of mitochondrial enzyme dihydroorotate dehydrogenase) is the same for therapeutic efficacy and developmental toxicity. At recommended doses in humans, teriflunomide and leflunomide result in a similar range of plasma concentrations of teriflunomide. 8.2 Lactation Risk Summary 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. 8.3 Females and Males of Reproductive Potential Pregnancy Testing Exclude pregnancy prior to initiation of treatment with AUBAGIO in females of reproductive potential. Advise females to notify their healthcare provider immediately if pregnancy occurs or is suspected during treatment [see Warnings and Precautions (5.2 , 5.3) and Use in Specific Populations (8.1) ]. Contraception Females 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) [see Warnings and Precautions (5.2 , 5.3) and Use in Specific Populations (8.1) ] . 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) [see Warnings and Precautions (5.3) ]. 8.4 Pediatric Use Safety and effectiveness in pediatric patients have not been established. Effectiveness of AUBAGIO for the treatment of relapsing form of multiple sclerosis in pediatric patients (10 to 17 years of age) was not established in an adequate and well-controlled clinical study in 166 patients (109 patients received once-daily doses of AUBAGIO and 57 patients received placebo) for up to 96 weeks. Pancreatitis has been reported in adults in the postmarketing setting, but appears to occur at higher frequency in the pediatric population. In this pediatric study, cases of pancreatitis were reported in 1.8% (2/109) of patients who received AUBAGIO compared to no patients in the placebo group. All patients in the pediatric trial recovered or were recovering after treatment discontinuation and accelerated elimination procedure [see Warnings and Precautions (5.11) ] . Additionally, elevated or abnormal blood creatine phosphokinase was reported in 6.4% of pediatric patients who received AUBAGIO compared to no patients in the placebo group. Juvenile Animal Toxicity Data Oral administration of teriflunomide (0, 0.3, 3, or 6 mg/kg/day) to young rats on postnatal days 21 to 70 resulted in suppression of immune function (T-cell dependent antibody response) at the mid and high doses, and adverse effects on male reproductive organs (reduced sperm count) and altered neurobehavioral function (increased locomotor activity) at the high dose. At the no-effect dose (0.3 mg/kg/day) for developmental toxicity in juvenile rats, plasma exposures were less than those in pediatric patients at the doses of AUBAGIO tested in the clinical study. 8.5 Geriatric Use Clinical studies of AUBAGIO did not include patients over 65 years old. 8.6 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 [see Contraindications (4) , Warnings and Precautions (5.1) , and Clinical Pharmacology (12.3) ] . 8.7 Renal Impairment No dosage adjustment is necessary for patients with mild, moderate, and severe renal impairment [see Clinical Pharmacology (12.3) ] .

16 HOW SUPPLIED/STORAGE AND HANDLING AUBAGIO is available as 7 mg and 14 mg tablets. The 14 mg tablet is pale blue to pastel blue, pentagonal film-coated tablet with dose strength "14" imprinted on one side and engraved with corporate logo on the other side. Each tablet contains 14 mg of teriflunomide. The 7 mg tablet is very light greenish-bluish grey to pale greenish-blue, hexagonal film-coated tablet with dose strength "7" imprinted on one side and engraved with corporate logo on the other side. Each tablet contains 7 mg of teriflunomide. AUBAGIO 14 mg tablets are supplied as: NDC 58468-0210-4 Carton containing a bottle of 30 tablets NDC 58468-0210-1 Carton of 5 tablets with one blister card with five tablets AUBAGIO 7 mg tablets are supplied as: NDC 58468-0211-4 Carton containing a bottle of 30 tablets NDC 58468-0211-2 Carton of 5 tablets with one blister card with five tablets 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).

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).

WARNING: HEPATOTOXICITY and EMBRYOFETAL TOXICITY 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 [see Warnings and Precautions (5.1) ] . Concomitant use of AUBAGIO with other 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 [see Warnings and Precautions (5.1) ]. If drug induced liver injury is suspected, discontinue AUBAGIO and start an accelerated elimination procedure with cholestyramine or charcoal [see Warnings and Precautions (5.3) ] . AUBAGIO is contraindicated in patients with severe hepatic impairment [see Contraindications (4) ] . Patients with pre-existing liver disease may be at increased risk of developing elevated serum transaminases when taking AUBAGIO. Embryofetal Toxicity AUBAGIO is contraindicated for use in pregnant women and in females of reproductive potential who are not using effective contraception because of the potential for fetal harm. Teratogenicity and embryolethality occurred in animals at plasma teriflunomide exposures lower than that in humans. Exclude pregnancy before the start of treatment with AUBAGIO in females of reproductive potential. Advise females of reproductive potential to use effective contraception during AUBAGIO treatment and during an accelerated drug elimination procedure after AUBAGIO treatment. Stop AUBAGIO and use an accelerated drug elimination procedure if the patient becomes pregnant [see Contraindications (4) , Warnings and Precautions (5.2 , 5.3) , Use in Specific Populations (8.1 , 8.3) , and Clinical Pharmacology (12.3) ] . WARNING: HEPATOTOXICITY and EMBRYOFETAL TOXICITY See full prescribing information for complete boxed warning. 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 ( 5.1 ). Concomitant use of AUBAGIO with other hepatotoxic drugs may increase the risk of severe liver injury. Obtain transaminase and bilirubin levels within 6 months before initiation of AUBAGIO and monitor ALT levels at least monthly for six months ( 5.1 ). If drug induced liver injury is suspected, discontinue AUBAGIO and start accelerated elimination procedure ( 5.3 ). Embryofetal Toxicity Teratogenicity and embryolethality occurred in animals administered teriflunomide ( 5.2 , 8.1 ). Exclude pregnancy prior to initiating AUBAGIO therapy ( 4 , 5.2 , 8.1 , 8.3 ). Advise use of effective contraception in females of reproductive potential during treatment and during an accelerated drug elimination procedure ( 4 , 5.2 , 5.3 , 8.1 , 8.3 ). Stop AUBAGIO and use an accelerated drug elimination procedure if the patient becomes pregnant ( 5.2 , 5.3 , 8.1 ).