ADVERSE REACTIONS SECTION.

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 and Serious Skin Reactions [see Contraindications (4) and Warnings and Precautions (5.5)] Peripheral Neuropathy [see Warnings and Precautions (5.6)] Increased Blood Pressure [see Warnings and Precautions (5.7)] Respiratory Effects [see Warnings and Precautions (5.8)] Hepatotoxicity [see Contraindications (4) and Warnings and Precautions (5.1)] Bone Marrow Effects/Immunosuppression Potential/Infections [see Warnings and Precautions (5.4)] Hypersensitivity and Serious Skin Reactions [see Contraindications (4) and Warnings and Precautions (5.5)] Peripheral Neuropathy [see Warnings and Precautions (5.6)] Increased Blood Pressure [see Warnings and Precautions (5.7)] Respiratory Effects [see Warnings and Precautions (5.8)] Most common adverse reactions (>=10% and >=2% greater than placebo): headache, diarrhea, nausea, alopecia, increase in ALT. (6)To report SUSPECTED ADVERSE REACTIONS, contact Amneal Pharmaceuticals at 1-877-835-5472 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 ClinicalTrials Experience. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of 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 2,047 patients receiving teriflunomide (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 lists adverse reactions in placebo-controlled trials with rates that were at least 2% for teriflunomide 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 teriflunomide mg, teriflunomide 14 mg, and placebo treatment arms, respectively).Table 1: Adverse Reactions in Pooled Placebo-Controlled Studies in Patients with Relapsing Forms of Multiple SclerosisAdverse ReactionTeriflunomide7 mg(N=1045)Teriflunomide14 mg(N=1002)Placebo(N=997)Headache18%16%15%Increase in Alanine aminotransferase13%15%9%Diarrhea13%14%8%Alopecia10%13%5%Nausea8%11%7%Paresthesia8%9%7%Arthralgia8%6%5%Neutropenia4%6%2%Hypertension3%4%2%Cardiovascular DeathsFour cardiovascular deaths, including three sudden deaths, and one myocardial infarction in patient with history of hyperlipidemia and hypertension were reported among approximately 2,600 patients exposed to teriflunomide in the premarketing database. These cardiovascular deaths occurred during uncontrolled extension studies, one to nine years after initiation of treatment. relationship between teriflunomide and cardiovascular death has not been established.Acute Renal FailureIn placebo-controlled studies, creatinine values increased more than 100% over baseline in 8/1045 (0.8%) patients in the mg teriflunomide group and 6/1002 (0.6%) patients in the 14 mg teriflunomide group versus 4/997 (0.4%) patients in the placebo group. These elevations were transient. Some elevations were accompanied by hyperkalemia. Teriflunomide may cause acute uric acid nephropathy with transient acute renal failure because teriflunomide increases renal uric acid clearance.HypophosphatemiaIn clinical trials, 18% of teriflunomide-treated patients had hypophosphatemia with serum phosphorus levels of at least 0.6 mmol/L, compared to 7% of placebo-treated patients; 4% of teriflunomide-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 serum phosphorus below 0.3 mmol/L.. 6.2Postmarketing Experience. The following adverse reactions have been identified during postapproval use of teriflunomide. Because these reactions are reported voluntarily from population of uncertain size, it is not always possible to reliably estimate their frequency or establish causal relationship to drug exposure.Hypersensitivity reactions, some of which were severe, such as anaphylaxis and angioedema [see Warnings and Precautions (5.5)] Severe skin reactions, including toxic epidermal necrolysis and Stevens-Johnson syndrome [see Warnings and Precautions (5.5)] Psoriasis or worsening of psoriasis (including pustular psoriasis) Thrombocytopenia [see Warnings and Precautions (5.4)] Interstitial lung disease [see Warnings and Precautions (5.8)] Pancreatitis. Hypersensitivity reactions, some of which were severe, such as anaphylaxis and angioedema [see Warnings and Precautions (5.5)] Severe skin reactions, including toxic epidermal necrolysis and Stevens-Johnson syndrome [see Warnings and Precautions (5.5)] Psoriasis or worsening of psoriasis (including pustular psoriasis) Thrombocytopenia [see Warnings and Precautions (5.4)] Interstitial lung disease [see Warnings and Precautions (5.8)] Pancreatitis.

BOXED WARNING SECTION.

WARNING: HEPATOTOXICITY and EMBRYOFETAL TOXICITY. Hepatotoxicity Severe liver injury including fatal liver failure has been reported in patients treated with leflunomide, which is indicated for rheumatoid arthritis. similar risk would be expected for teriflunomide because recommended doses of teriflunomide and leflunomide result in similar range of plasma concentrations of teriflunomide. Concomitant use of teriflunomide with other potentially hepatotoxic drugs may increase the risk of severe liver injury.Obtain transaminase and bilirubin levels within months before initiation of teriflunomide therapy. Monitor ALT levels at least monthly for six months after starting teriflunomide [see Warnings and Precautions (5.1)]. If drug induced liver injury is suspected, discontinue teriflunomide and start an accelerated elimination procedure with cholestyramine or charcoal [see Warnings and Precautions (5.3)]. Teriflunomide 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 teriflunomide. Embryofetal ToxicityTeriflunomide 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 teriflunomide in females of reproductive potential. Advise females of reproductive potential to use effective contraception during teriflunomide treatment and during an accelerated drug elimination procedure after teriflunomide treatment. Stop teriflunomide 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)].. Hepatotoxicity Severe liver injury including fatal liver failure has been reported in patients treated with leflunomide, which is indicated for rheumatoid arthritis. similar risk would be expected for teriflunomide because recommended doses of teriflunomide and leflunomide result in similar range of plasma concentrations of teriflunomide. Concomitant use of teriflunomide with other potentially hepatotoxic drugs may increase the risk of severe liver injury.Obtain transaminase and bilirubin levels within months before initiation of teriflunomide therapy. Monitor ALT levels at least monthly for six months after starting teriflunomide [see Warnings and Precautions (5.1)]. If drug induced liver injury is suspected, discontinue teriflunomide and start an accelerated elimination procedure with cholestyramine or charcoal [see Warnings and Precautions (5.3)]. Teriflunomide 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 teriflunomide. Embryofetal ToxicityTeriflunomide 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 teriflunomide in females of reproductive potential. Advise females of reproductive potential to use effective contraception during teriflunomide treatment and during an accelerated drug elimination procedure after teriflunomide treatment. Stop teriflunomide 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 TOXICITYSee full prescribing information for complete boxed warning.HepatotoxicitySevere liver injury including fatal liver failure has been reported in patients treated with leflunomide, which is indicated for rheumatoid arthritis. similar risk would be expected for teriflunomide because recommended doses of teriflunomide and leflunomide result in similar range of plasma concentrations of teriflunomide. Obtain transaminase and bilirubin levels within months before initiation of teriflunomide and monitor ALT levels at least monthly for six months (5.1). If drug induced liver injury is suspected, discontinue teriflunomide and start accelerated elimination procedure (5.3). Embryofetal ToxicityTeratogenicity and embryolethality occurred in animals administered teriflunomide (5.2, 8.1). Exclude pregnancy prior to initiating teriflunomide 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 teriflunomide and use an accelerated drug elimination procedure if the patient becomes pregnant (5.2, 5.3, 8.1).. HepatotoxicitySevere liver injury including fatal liver failure has been reported in patients treated with leflunomide, which is indicated for rheumatoid arthritis. similar risk would be expected for teriflunomide because recommended doses of teriflunomide and leflunomide result in similar range of plasma concentrations of teriflunomide. Obtain transaminase and bilirubin levels within months before initiation of teriflunomide and monitor ALT levels at least monthly for six months (5.1). If drug induced liver injury is suspected, discontinue teriflunomide and start accelerated elimination procedure (5.3). Embryofetal ToxicityTeratogenicity and embryolethality occurred in animals administered teriflunomide (5.2, 8.1). Exclude pregnancy prior to initiating teriflunomide 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 teriflunomide and use an accelerated drug elimination procedure if the patient becomes pregnant (5.2, 5.3, 8.1).

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY. 12.1 Mechanism of Action. Teriflunomide, an immunomodulatory agent with anti-inflammatory properties, inhibits dihydroorotate dehydrogenase, 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 reduction in the number of activated lymphocytes in CNS.. 12.2 Pharmacodynamics. Potential to Prolong the QT IntervalIn placebo controlled thorough QT study performed in healthy 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 leflunomides activity in vivo. At recommended doses, teriflunomide and leflunomide result in similar range of plasma concentrations of teriflunomide.Based on population analysis of teriflunomide in healthy volunteers and MS patients, median t1/2 was approximately 18 and 19 days after repeated doses of mg and 14 mg respectively. It takes approximately months respectively to reach steady-state concentrations. The estimated AUC accumulation ratio is approximately 30 after repeated doses of or 14 mg.AbsorptionMedian time to reach maximum plasma concentrations is between to hours post dose following oral administration of teriflunomide.Food does not have clinically relevant effect on teriflunomide pharmacokinetics. DistributionTeriflunomide is extensively bound to plasma protein (>99%) and is mainly distributed in plasma. The volume of distribution is 11 after single intravenous (IV) administration.MetabolismTeriflunomide is the major circulating moiety detected in plasma. The primary biotransformation pathway to minor metabolites of teriflunomide is hydrolysis, with oxidation being minor pathway. Secondary pathways involve oxidation, N-acetylation and sulfate conjugation.EliminationTeriflunomide 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 single IV administration, the total body clearance of teriflunomide is 30.5 mL/h.Drug Interaction StudiesTeriflunomide is not metabolized by Cytochrome P450 or flavin monoamine oxidase enzymes. The potential effect of teriflunomide on other drugsCYP2C8 substratesThere was an increase in mean repaglinide Cmax and AUC (1.7- and 2.4-fold, respectively) following repeated doses of teriflunomide and 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 substratesRepeated doses of teriflunomide decreased mean Cmax and AUC of caffeine by 18% and 55%, respectively, suggesting that teriflunomide may be weak inducer of CYP1A2 in vivo [see Drug Interactions (7)].OAT3 substratesThere was an increase in mean cefaclor Cmax and AUC (1.43- and 1.54-fold, respectively), following repeated doses of teriflunomide, suggesting that teriflunomide is an inhibitor of organic anion transporter (OAT3) in vivo [see Drug Interactions (7)].BCRP and OATP1B1/1B3 substratesThere was an increase in mean rosuvastatin Cmax 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 contraceptivesThere was an increase in mean ethinylestradiol Cmax and AUC0-24 (1.58- and 1.54-fold, respectively) and levonorgestrel Cmax and AUC0-24 (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 teriflunomidePotent CYP and transporter inducers: Rifampin did not affect the pharmacokinetics of teriflunomide.Specific PopulationsHepatic impairmentMild 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 impairmentSevere renal impairment had no impact on the pharmacokinetics of teriflunomide [see Use in Specific Populations (8.7)].GenderIn population analysis, the clearance rate for teriflunomide is 23% less in females than in males.RaceEffect of race on the pharmacokinetics of teriflunomide cannot be adequately assessed due to low number of non-white patients in the clinical trials.

CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES. Four randomized, controlled, double-blind clinical trials established the efficacy of teriflunomide in patients with relapsing forms of multiple sclerosis.Study was double-blind, placebo-controlled clinical trial that evaluated once daily doses of teriflunomide mg and teriflunomide 14 mg for up to 26 months in patients with relapsing forms of multiple sclerosis. Patients were required to have diagnosis of multiple sclerosis exhibiting 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, 1,088 patients were randomized to receive teriflunomide mg (n=366), teriflunomide 14 mg (n=359), or placebo (n=363). At entry, patients had an Expanded Disability Status Scale (EDSS) score <=5.5. Patients had mean age of 38 years, mean disease duration of years, and mean EDSS at baseline of 2.7. total of 91% of patients had relapsing remitting multiple sclerosis, and 9% had progressive form of multiple sclerosis with relapses. The mean duration of treatment was 635, 627, and 631 days for teriflunomide mg, teriflunomide 14 mg, and placebo, respectively. The percentage of patients who completed the study treatment period was 75%, 73%, and 71% for teriflunomide mg, teriflunomide 14 mg, and placebo, respectively.There was statistically significant reduction in ARR for patients who received teriflunomide mg or teriflunomide 14 mg, compared to patients who received placebo (see Table 2). There was consistent reduction of the ARR noted in subgroups defined by sex, age group, prior multiple sclerosis therapy, and baseline disease activity.There was statistically significant reduction in the relative risk of disability progression at week 108 sustained for 12 weeks (as measured by at least 1-point increase from baseline EDSS <=5.5 or 0.5 point increase for those with baseline EDSS >5.5) in the teriflunomide 14 mg group compared to placebo (see Table and Figure 1).The effect of teriflunomide 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 teriflunomide mg and teriflunomide 14 mg groups than in the placebo group. Patients in both teriflunomide 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 Teriflunomide7 mgN=365Teriflunomide14 mgN=358PlaceboN=363Clinical EndpointsAnnualized relapse rate 0.370(p 0.0002)0.369(p 0.0005)0.539Relative risk reduction 31%31%Percent of patients remaining relapse-free at week 10853.7%56.5%45.6%Percent disability progression at week 108 21.7%(p 0.084)20.2%(p 0.028)27.3%Hazard ratio0.760.70MRI EndpointsMedian change from baseline in Total lesion volume1 (mL) at week 108 0.755(p= 0.0317)2 0.345(p 0.0003)2 1.127Mean number of Gd-enhancing T1-lesions per scan 0.570(p 0.0001)0.261(p 0.0001)1.3311Total lesion volume: sum of T2 and hypointense T1 lesion volume in mL2p-values based on cubic root transformed data for total lesion volumeFigure 1: Kaplan-Meier Plot of Time to Disability Progression Sustained for 12 Weeks (Study 1) Study was double-blind, placebo-controlled clinical trial that evaluated once daily doses of teriflunomide mg and teriflunomide 14 mg for up to 40 months in patients with relapsing forms of multiple sclerosis. Patients were required to have diagnosis of multiple sclerosis exhibiting 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 1,165 patients received teriflunomide mg (n=407), teriflunomide 14 mg (n=370), or placebo (n=388). Patients had mean age of 38 years, mean disease duration of years, and mean EDSS at baseline of 2.7. total of 98% of patients had relapsing remitting multiple sclerosis, and 2% had progressive form of multiple sclerosis with relapses. The mean duration of treatment was 552, 567, and 571 days for teriflunomide mg, teriflunomide 14 mg, and placebo, respectively. The percentage of patients who completed the study treatment period was 67%, 66%, and 68% for teriflunomide mg, teriflunomide 14 mg, and placebo, respectively.There was statistically significant reduction in the ARR for patients who received teriflunomide mg or teriflunomide 14 mg compared to patients who received placebo (see Table 3). There was consistent reduction of the ARR noted in subgroups defined by sex, age group, prior multiple sclerosis therapy, and baseline disease activity.There was statistically significant reduction in the relative risk of disability progression at week 108 sustained for 12 weeks (as measured by at least 1-point increase from baseline EDSS <=5.5 or 0.5 point increase for those with baseline EDSS >5.5) in the teriflunomide 14 mg group compared to placebo (See Table and Figure 2).Table 3: Clinical Results of Study Teriflunomide mgN=407Teriflunomide14 mgN=370PlaceboN=388Clinical EndpointsAnnualized relapse rate0.389(p 0.0183)0.319(p 0.0001)0.501Relative risk reduction22%36%Percent of patients remaining relapse-free at week 10858.2%57.1%46.8%Percent disability progression at week 10821.1%(p 0.762)15.8%(p 0.044)19.7%Hazard ratio0.960.69Figure 2: Kaplan-Meier Plot of Time to Disability Progression Sustained for 12 Weeks (Study 2) Study was double-blind, placebo-controlled clinical trial that evaluated once daily doses of teriflunomide mg and teriflunomide 14 mg for up to 108 weeks in patients with relapsing multiple sclerosis. Patients were required to have had first clinical event consistent with acute demyelination occurring within 90 days of randomization with or more T2 lesions at least mm in diameter that were characteristic of multiple sclerosis. total of 614 patients received teriflunomide mg (n=203), teriflunomide 14 mg (n=214), or placebo (n=197). Patients had 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 teriflunomide mg (70.5%, <0.05) and teriflunomide 14 mg (72.2%, <0.05) groups than in the placebo group (61.7%). The effect of teriflunomide on MRI activity was also demonstrated in Study 4, randomized, double-blind, placebo-controlled clinical trial of multiple sclerosis patients with relapse. In Study 4, MRI was to be performed at baseline, weeks, 12 weeks, 18 weeks, 24 weeks, 30 weeks, and 36 weeks after treatment initiation. total of 179 patients were randomized to teriflunomide mg (n=61), teriflunomide 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 teriflunomide mg (1.06) and teriflunomide 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).. Image1. 4.

DRUG INTERACTIONS SECTION.

7 DRUG INTERACTIONS. Effect of Teriflunomide on CYP2C8 SubstratesTeriflunomide is an inhibitor of CYP2C8 in vivo. In patients taking teriflunomide, 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 Teriflunomide on WarfarinCo-administration of teriflunomide with warfarin requires close monitoring of the international normalized ratio (INR) because teriflunomide may decrease peak INR by approximately 25%.Effect of Teriflunomide on Oral ContraceptivesTeriflunomide may increase the systemic exposures of ethinylestradiol and levonorgestrel. Consideration should be given to the type or dose of contraceptives used in combination with teriflunomide [see Clinical Pharmacology (12.3)].Effect of Teriflunomide on CYP1A2 SubstratesTeriflunomide may be weak inducer of CYP1A2 in vivo. In patients taking teriflunomide, 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 Teriflunomide on Organic Anion Transporter (OAT3) SubstratesTeriflunomide inhibits the activity of OAT3 in vivo. In patients taking teriflunomide, 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 Teriflunomide on BCRP and Organic Anion Transporting Polypeptide B1 and B3 (OATP1B1/1B3) SubstratesTeriflunomide inhibits the activity of BCRP and OATP1B1/1B3 in vivo. For patient taking teriflunomide, 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 teriflunomide [see Clinical Pharmacology (12.3)].. 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 teriflunomide. (7) 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 teriflunomide. (7).

INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING INFORMATION. Advise the patient to read the FDA-approved patient labeling (Medication Guide). Medication Guide is required for distribution with teriflunomide.Hepatotoxicity Inform patients that teriflunomide may increase liver enzymes and that their liver enzymes will be checked before starting teriflunomide and for at least months while they are taking teriflunomide. 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 ToxicityAdvise females of reproductive potentialOf the potential for fetal harm if teriflunomide is taken during pregnancyTo notify their healthcare provider immediately if pregnancy occurs or is suspectedTo use effective contraception during treatment with teriflunomide 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 teriflunomide and not wishing to father 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 child to discontinue use of teriflunomide and undergo an accelerated elimination procedure.Availability of an Accelerated Elimination ProcedureAdvise patients that teriflunomide may stay in the blood for up to years after the last dose and that an accelerated elimination procedure may be used if needed.Risk of InfectionsInform patients that they may develop lowering of their white blood cell counts and that their blood counts will be checked before starting teriflunomide.Inform patients that they may be more likely to get infections when taking teriflunomide and that they should contact their physician if they develop symptoms of infection, particularly in case of fever.Advise patients that the use of some vaccines should be avoided during treatment with teriflunomide and for at least months after discontinuation.Serious Allergic Reactions Advise patients to discontinue teriflunomide and seek immediate medical attention if any signs or symptoms of hypersensitivity reaction occur [see Contraindications (4) and Warnings and Precautions (5.5)]. Signs and symptoms include dyspnea, urticaria, and angioedema including lips, eyes, throat, and tongue or skin rash.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.Increased Blood PressureInform patients that teriflunomide may increase blood pressure.Lactation Advise females not to breastfeed during treatment with teriflunomide [see Use in Specific Populations (8.2)].Manufactured by:Amneal Pharmaceuticals Pvt. Ltd.Oral Solid Dosage Unit Ahmedabad 382213, INDIADistributed by: Amneal Pharmaceuticals LLC Bridgewater, NJ 08807Rev. 04-2020-03. Advise females of reproductive potential. Of the potential for fetal harm if teriflunomide is taken during pregnancy. To notify their healthcare provider immediately if pregnancy occurs or is suspected. To use effective contraception during treatment with teriflunomide 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 teriflunomide and not wishing to father 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 child to discontinue use of teriflunomide and undergo an accelerated elimination procedure.

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics. Teriflunomide is the principal active metabolite of leflunomide and is responsible for leflunomides activity in vivo. At recommended doses, teriflunomide and leflunomide result in similar range of plasma concentrations of teriflunomide.Based on population analysis of teriflunomide in healthy volunteers and MS patients, median t1/2 was approximately 18 and 19 days after repeated doses of mg and 14 mg respectively. It takes approximately months respectively to reach steady-state concentrations. The estimated AUC accumulation ratio is approximately 30 after repeated doses of or 14 mg.AbsorptionMedian time to reach maximum plasma concentrations is between to hours post dose following oral administration of teriflunomide.Food does not have clinically relevant effect on teriflunomide pharmacokinetics. DistributionTeriflunomide is extensively bound to plasma protein (>99%) and is mainly distributed in plasma. The volume of distribution is 11 after single intravenous (IV) administration.MetabolismTeriflunomide is the major circulating moiety detected in plasma. The primary biotransformation pathway to minor metabolites of teriflunomide is hydrolysis, with oxidation being minor pathway. Secondary pathways involve oxidation, N-acetylation and sulfate conjugation.EliminationTeriflunomide 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 single IV administration, the total body clearance of teriflunomide is 30.5 mL/h.Drug Interaction StudiesTeriflunomide is not metabolized by Cytochrome P450 or flavin monoamine oxidase enzymes. The potential effect of teriflunomide on other drugsCYP2C8 substratesThere was an increase in mean repaglinide Cmax and AUC (1.7- and 2.4-fold, respectively) following repeated doses of teriflunomide and 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 substratesRepeated doses of teriflunomide decreased mean Cmax and AUC of caffeine by 18% and 55%, respectively, suggesting that teriflunomide may be weak inducer of CYP1A2 in vivo [see Drug Interactions (7)].OAT3 substratesThere was an increase in mean cefaclor Cmax and AUC (1.43- and 1.54-fold, respectively), following repeated doses of teriflunomide, suggesting that teriflunomide is an inhibitor of organic anion transporter (OAT3) in vivo [see Drug Interactions (7)].BCRP and OATP1B1/1B3 substratesThere was an increase in mean rosuvastatin Cmax 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 contraceptivesThere was an increase in mean ethinylestradiol Cmax and AUC0-24 (1.58- and 1.54-fold, respectively) and levonorgestrel Cmax and AUC0-24 (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 teriflunomidePotent CYP and transporter inducers: Rifampin did not affect the pharmacokinetics of teriflunomide.Specific PopulationsHepatic impairmentMild 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 impairmentSevere renal impairment had no impact on the pharmacokinetics of teriflunomide [see Use in Specific Populations (8.7)].GenderIn population analysis, the clearance rate for teriflunomide is 23% less in females than in males.RaceEffect of race on the pharmacokinetics of teriflunomide cannot be adequately assessed due to low number of non-white patients in the clinical trials.

SPL MEDGUIDE SECTION.

Medication Guide. Teriflunomide (ter floo noe mide) TabletsRead this Medication Guide before you start using teriflunomide tablets and each time you get 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 should know about teriflunomide tablets Teriflunomide tablets may cause serious side effects, including:Liver problems: Teriflunomide tablets may cause serious liver problems that may lead to death. Your risk of liver problems may be higher if you take other medicines that also affect your liver. Your doctor should do blood tests to check your liver:within months before you start taking teriflunomide tablets1 time month for months after you start taking teriflunomide tabletsCall your doctor right away if you have any of the following symptoms of liver problems:nauseavomitingstomach painloss of appetitetirednessyour skin or the whites of your eyes turn yellowdark urineHarm to your unborn baby: Teriflunomide tablets may cause harm to your unborn baby. Do not take teriflunomide tablets if you are pregnant. Do not take teriflunomide tablets unless you are using effective birth control.If you are female, you should have pregnancy test before you start taking teriflunomide tablets. Use effective birth control during your treatment with teriflunomide tablets.After stopping teriflunomide tablets, continue using effective birth control until you have blood tests to make sure your blood levels of teriflunomide are low enough. If you become pregnant while taking teriflunomide tablets or within years after you stop taking it, tell your doctor right away.For men taking teriflunomide tablets:If your female partner plans to become pregnant, you should stop taking teriflunomide tablets and ask your doctor how to quickly lower the levels of teriflunomide tablets 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 teriflunomide tablets. Teriflunomide remains in your blood after you stop taking it, so continue using effective birth control until teriflunomide blood levels have been checked and they are low enough.Teriflunomide may stay in your blood for up to years after you stop taking it. Your doctor can prescribe medicine to help lower your blood levels of teriflunomide more quickly. Talk to your doctor if you want more information about this.What are teriflunomide tabletsTeriflunomide tablets are 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 teriflunomide tablets are safe and effective in children.Who should not take teriflunomide tablets Do not take teriflunomide if you:have had an allergic reaction to teriflunomide tablets or medicine called leflunomide have severe liver problemsare pregnant or are of childbearing age and not using effective birth controltake medicine called leflunomideWhat should tell my doctor before taking teriflunomide tablets Before you take teriflunomide tablets, tell your doctor if you:have liver or kidney problemshave fever or infection, or you are unable to fight infectionshave numbness or tingling in your hands or feet that is different from your MS symptomshave diabeteshave had serious skin problems when taking other medicineshave breathing problemshave high blood pressureare breastfeeding or plan to breastfeed. It is not known if teriflunomide passes into your breast milk. You and your doctor should decide if you will take teriflunomide tablets or breastfeed. You should not do both.Tell your doctor about all the medicines you take, including prescription and non-prescription medicines, vitamins, and herbal supplements.Using teriflunomide tablets and other medicines may affect each other causing serious side effects. Teriflunomide tablets may affect the way other medicines work, and other medicines may affect how teriflunomide tablets 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 list of these medicines if you are not sure.Know the medicines you take. Keep list of them to show your doctor or pharmacist when you get new medicine.How should take teriflunomide tabletsTake teriflunomide tablets exactly as your doctor tells you to take it.Take teriflunomide tablets time each day.Take teriflunomide tablets with or without food.What are possible side effects of teriflunomide tablets Teriflunomide tablets may cause serious side effects, including:See What is the most important information should know about teriflunomide tablets decreases in your white blood cell count. Your white blood cell counts should be checked before you start taking teriflunomide tablets. When you have low white blood cell count you:may have more frequent infections. You should have skin test for TB (tuberculosis) before you start taking teriflunomide tablets. Tell your doctor if you have any of these symptoms of an infection:fevertirednessbody acheschillsnauseavomitingshould not receive certain vaccinations during your treatment with teriflunomide tablets and for months after your treatment with teriflunomide tablets ends.numbness or tingling in your hands or feet that is different from your MS symptoms. You have greater chance of getting peripheral neuropathy if you:are over 60 years of agetake certain medicines that affect your nervous systemhave diabetesTell your doctor if you have numbness or tingling in your hands or feet that is different from your MS.Allergic reactions, including serious skin problems. Tell your doctor if you have difficulty breathing, itching, swelling on any part of your body including in your lips, eyes, throat or tongue, or any skin problems such as rash or redness and peeling.new or worsening breathing problems. Tell your doctor if you have shortness of breath or coughing with or without fever.high blood pressure. Your doctor should check your blood pressure before you start taking teriflunomide tablets and while you are taking teriflunomide tablets.The most common side effects of teriflunomide tablets include:headachediarrheanauseahair thinning or loss (alopecia)increases in the results of blood tests to check your liver functionTell your doctor if you have any side effect that bothers you or that does not go away.These are not all the possible side effects of teriflunomide tablets. 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 1-800-332-1088.How should store teriflunomide tabletsStore teriflunomide tablets at room temperature between 68 to 77F (20 to 25C).Keep teriflunomide tablets and all medicines out of reach of children.General information about the safe and effective use of teriflunomide tablets.Medicines are sometimes prescribed for purposes other than those listed in Medication Guide. Do not use teriflunomide tablets for condition for which it was not prescribed. Do not give teriflunomide tablets to other people, even if they have the same symptoms you have. It may harm them.This Medication Guide summarizes the most important information about teriflunomide tablets. If you would like more information, talk with your doctor. You can ask your doctor or pharmacist for information about teriflunomide tablets that is written for healthcare professionals.For more information, go to www.amneal.com or call Amneal Pharmaceuticals at 1-877-835-5472.What are the ingredients in teriflunomide tabletsActive ingredient: teriflunomide Inactive ingredients in mg and 14 mg tablets: corn starch, hydroxypropyl cellulose, lactose monohydrate, microcrystalline cellulose, magnesium stearate and sodium starch glycolate. The film coating for the mg and 14 mg tablet is made of colloidal anhydrous silica, FD C Blue 2/indigo carmine aluminum lake, hypromellose, polyethylene glycol, titanium dioxide and in addition to these, the mg tablet film coating includes iron oxide yellow.This Medication Guide has been approved by the U.S. Food and Drug Administration.Manufactured by:Amneal Pharmaceuticals Pvt. Ltd.Oral Solid Dosage Unit Ahmedabad 382213, INDIADistributed by: Amneal Pharmaceuticals LLC Bridgewater, NJ 08807 Rev. 09-2019-01. Liver problems: Teriflunomide tablets may cause serious liver problems that may lead to death. Your risk of liver problems may be higher if you take other medicines that also affect your liver. Your doctor should do blood tests to check your liver:within months before you start taking teriflunomide tablets1 time month for months after you start taking teriflunomide tabletsCall your doctor right away if you have any of the following symptoms of liver problems:nauseavomitingstomach painloss of appetitetirednessyour skin or the whites of your eyes turn yellowdark urine. within months before you start taking teriflunomide tablets. time month for months after you start taking teriflunomide tablets. 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: Teriflunomide tablets may cause harm to your unborn baby. Do not take teriflunomide tablets if you are pregnant. Do not take teriflunomide tablets unless you are using effective birth control.. If you are female, you should have pregnancy test before you start taking teriflunomide tablets. Use effective birth control during your treatment with teriflunomide tablets.. After stopping teriflunomide tablets, continue using effective birth control until you have blood tests to make sure your blood levels of teriflunomide are low enough. If you become pregnant while taking teriflunomide tablets or within years after you stop taking it, tell your doctor right away.. For men taking teriflunomide tablets:. If your female partner plans to become pregnant, you should stop taking teriflunomide tablets and ask your doctor how to quickly lower the levels of teriflunomide tablets 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 teriflunomide tablets. Teriflunomide remains in your blood after you stop taking it, so continue using effective birth control until teriflunomide blood levels have been checked and they are low enough.. have had an allergic reaction to teriflunomide tablets or medicine called leflunomide have severe liver problems. are pregnant or are of childbearing age and not using effective birth control. take medicine called leflunomide. have liver or kidney problems. have 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 teriflunomide passes into your breast milk. You and your doctor should decide if you will take teriflunomide tablets or breastfeed. You should not do both.. Take teriflunomide tablets exactly as your doctor tells you to take it.. Take teriflunomide tablets time each day.. Take teriflunomide tablets with or without food.. See What is the most important information should know about teriflunomide tablets decreases in your white blood cell count. Your white blood cell counts should be checked before you start taking teriflunomide tablets. When you have low white blood cell count you:. may have more frequent infections. You should have skin test for TB (tuberculosis) before you start taking teriflunomide tablets. Tell your doctor if you have any of these symptoms of an infection:fevertirednessbody acheschillsnauseavomiting. fever. tiredness. body aches. chills. nausea. vomiting. should not receive certain vaccinations during your treatment with teriflunomide tablets and for months after your treatment with teriflunomide tablets ends.. numbness or tingling in your hands or feet that is different from your MS symptoms. You have greater chance of getting peripheral neuropathy if you:are over 60 years of agetake certain medicines that affect your nervous systemhave diabetesTell your doctor if you have numbness or tingling in your hands or feet that is different from your MS.. are over 60 years of age. take certain medicines that affect your nervous system. have diabetes. Allergic reactions, including serious skin problems. Tell your doctor if you have difficulty breathing, itching, swelling on any part of your body including in your lips, eyes, throat or tongue, or any skin problems such as rash or redness and peeling.. new or worsening breathing problems. Tell your doctor if you have shortness of breath or coughing with or without fever.. high blood pressure. Your doctor should check your blood pressure before you start taking teriflunomide tablets and while you are taking teriflunomide tablets.. headache. diarrhea. nausea. hair thinning or loss (alopecia). increases in the results of blood tests to check your liver function. Store teriflunomide tablets at room temperature between 68 to 77F (20 to 25C).. Keep teriflunomide tablets and all medicines out of reach of children.

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS. Elimination of teriflunomide can be accelerated by administration of cholestyramine or activated charcoal for 11 days. (5.3) Teriflunomide may decrease WBC. recent CBC should be available before starting teriflunomide. Monitor for signs and symptoms of infection. Consider suspending treatment with teriflunomide in case of serious infection. Do not start teriflunomide in patients with active infections. (5.4) Stop teriflunomide if patient has anaphylaxis, angioedema, Stevens-Johnson syndrome, toxic epidermal necrolysis; initiate rapid elimination. (5.3, 5.5) If patient develops symptoms consistent with peripheral neuropathy, evaluate patient and consider discontinuing teriflunomide. (5.6) Teriflunomide may increase blood pressure. Measure blood pressure at treatment initiation and monitor blood pressure during treatment. (5.7) Elimination of teriflunomide can be accelerated by administration of cholestyramine or activated charcoal for 11 days. (5.3) Teriflunomide may decrease WBC. recent CBC should be available before starting teriflunomide. Monitor for signs and symptoms of infection. Consider suspending treatment with teriflunomide in case of serious infection. Do not start teriflunomide in patients with active infections. (5.4) Stop teriflunomide if patient has anaphylaxis, angioedema, Stevens-Johnson syndrome, toxic epidermal necrolysis; initiate rapid elimination. (5.3, 5.5) If patient develops symptoms consistent with peripheral neuropathy, evaluate patient and consider discontinuing teriflunomide. (5.6) Teriflunomide may increase blood pressure. Measure blood pressure at treatment initiation and monitor blood pressure during treatment. (5.7) 5.1 Hepatotoxicity. Severe liver injury including fatal liver failure and dysfunction has been reported in some patients treated with leflunomide, which is indicated for rheumatoid arthritis. similar risk would be expected for teriflunomide because recommended doses of teriflunomide and leflunomide result in similar range of plasma concentrations of teriflunomide. Patients with pre-existing liver disease may be at increased risk of developing elevated serum transaminases when taking teriflunomide. 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 teriflunomide. Teriflunomide is contraindicated in patients with severe hepatic impairment [see Contraindications (4)].In placebo-controlled trials, ALT greater than three times the ULN occurred in 61/1045 (5.8%) and 62/1002 (6.2%) of patients receiving teriflunomide mg and 14 mg, respectively, and 38/997 (3.8%) of patients receiving placebo, during the treatment period. These elevations occurred mostly within the first year of treatment. Half of the cases returned to normal without drug discontinuation. In clinical trials, if ALT elevation was greater than three times the ULN on two consecutive tests, teriflunomide was discontinued and patients underwent an accelerated elimination procedure [see Warnings and Precautions (5.3)]. Of the patients who underwent discontinuation and accelerated elimination in controlled trials, half returned to normal or near normal values within months.One patient in the controlled trials developed ALT 32 times the ULN and jaundice months after initiation of teriflunomide 14 mg treatment. The patient was hospitalized for weeks and recovered after plasmapheresis and cholestyramine accelerated elimination procedure. Teriflunomide-induced liver injury in this patient could not be ruled out.Obtain serum transaminase and bilirubin levels within months before initiation of teriflunomide therapy. Monitor ALT levels at least monthly for six months after starting teriflunomide. Consider additional monitoring when teriflunomide is given with other potentially hepatotoxic drugs. Consider discontinuing teriflunomide if serum transaminase increase (greater than three times the ULN) is confirmed. Monitor serum transaminase and bilirubin on teriflunomide therapy, particularly in patients who develop symptoms suggestive of hepatic dysfunction, such as unexplained nausea, vomiting, abdominal pain, fatigue, anorexia, or jaundice and/or dark urine. If liver injury is suspected to be teriflunomide-induced, discontinue teriflunomide and start an accelerated elimination procedure [see Warnings and Precautions (5.3)] and monitor liver tests weekly until normalized. If teriflunomide-induced liver injury is unlikely because some other probable cause has been found, resumption of teriflunomide therapy may be considered. 5.2 Embryofetal Toxicity. Teriflunomide may cause fetal harm when administered to pregnant woman. Teratogenicity and embryo-fetal 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 [see Use in Specific Populations (8.1)].Teriflunomide is contraindicated for use in pregnant women and in females of reproductive potential not using effective contraception [see Contraindications (4)]. Exclude pregnancy before starting treatment with teriflunomide in females of reproductive potential [see Dosage and Administration (2)]. Advise females of reproductive potential to use effective contraception during teriflunomide treatment and during an accelerated drug elimination procedure after teriflunomide treatment [see Use in Specific Populations (8.3)]. If woman becomes pregnant while taking teriflunomide, stop treatment with teriflunomide, apprise the patient of the potential risk to fetus, and perform an accelerated drug elimination procedure to achieve plasma teriflunomide concentration of less than 0.02 mg/L [see Warnings and Precautions (5.3)]. Upon discontinuing teriflunomide, it is recommended that all females of reproductive potential undergo an accelerated drug elimination procedure. Women receiving teriflunomide treatment who wish to become pregnant must discontinue teriflunomide and undergo an accelerated drug elimination procedure, which includes verification that plasma concentrations of teriflunomide are less than 0.02 mg/L (0.02 mcg/mL). Men wishing to father child should also discontinue use of teriflunomide 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 Use in Specific Population (8.3)]. Based on animal data, human plasma concentrations of teriflunomide of less than 0.02 mg/L (0.02 mcg/mL) are expected to have minimal embryofetal risk [see Contraindications (4), Warnings and Precautions (5.3) and Use in Specific Populations (8.1)]. 5.3Procedure for Accelerated Elimination of Teriflunomide. Teriflunomide is eliminated slowly from the plasma [see Clinical Pharmacology (12.3)]. Without an accelerated elimination procedure, it takes on average 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 years. An accelerated elimination procedure could be used at any time after discontinuation of teriflunomide. Elimination can be accelerated by either of the following procedures:Administration of cholestyramine g every hours for 11 days. If cholestyramine g three times day is not well tolerated, cholestyramine g three times day can be used.Administration of 50 oral activated charcoal powder every 12 hours for 11 days.If either elimination procedure is poorly tolerated, treatment days do not need to be consecutive unless there is need to lower teriflunomide plasma concentration rapidly.At the end of 11 days, both regimens successfully accelerated teriflunomide elimination, leading to more than 98% decrease in teriflunomide plasma concentrations.Use of the accelerated elimination procedure may potentially result in return of disease activity if the patient had been responding to teriflunomide treatment.. Administration of cholestyramine g every hours for 11 days. If cholestyramine g three times day is not well tolerated, cholestyramine g three times day can be used.. Administration of 50 oral activated charcoal powder every 12 hours for 11 days.. 5.4 Bone MarrowEffects/Immunosuppression Potential/Infections. Bone Marrow EffectsA mean decrease compared to baseline in white blood cell (WBC) count of approximately 15% (mainly neutrophils and lymphocytes) and in platelet count of approximately 10% was observed in placebo- controlled trials with mg and 14 mg of teriflunomide. The decrease in mean WBC count occurred during the first weeks and WBC count remained low during treatment. In placebo-controlled studies, neutrophil count <1.5 109/L was observed in 12% and 16% of patients receiving teriflunomide mg and 14 mg, respectively, compared with 7% of patients receiving placebo; lymphocyte count <0.8 109/L was observed in 10% and 12% of patients receiving teriflunomide mg and 14 mg, respectively, compared with 6% of patients receiving placebo. No cases of serious pancytopenia were reported in premarketing clinical trials of teriflunomide but rare cases of pancytopenia and agranulocytosis have been reported in the postmarketing setting with leflunomide. similar risk would be expected for teriflunomide [see Clinical Pharmacology (12.3)]. Cases of thrombocytopenia with teriflunomide, including rare cases with platelet counts less than 50,000/mm3, have been reported in the postmarketing setting. Obtain complete blood cell count (CBC) within months before the initiation of treatment with teriflunomide. Further monitoring should be based on signs and symptoms suggestive of bone marrow suppression.Risk of Infection/Tuberculosis ScreeningPatients with active acute or chronic infections should not start treatment until the infection(s) is resolved. If patient develops serious infection consider suspending treatment with teriflunomide and using an accelerated elimination procedure. Reassess the benefits and risks prior to resumption of therapy. Instruct patients receiving teriflunomide to report symptoms of infections to physician.Teriflunomide is not recommended for patients with severe immunodeficiency, bone marrow disease, or severe, uncontrolled infections. Medications like teriflunomide that have immunosuppression potential may cause patients to be more susceptible to infections, including opportunistic infections.In placebo-controlled studies of teriflunomide, no overall increase in the risk of serious infections was observed with teriflunomide mg (2.2%) or 14 mg (2.7%) compared to placebo (2.2%). However, one fatal case of klebsiella pneumonia sepsis occurred in patient taking teriflunomide 14 mg for 1.7 years. Fatal infections have been reported in the postmarketing setting in patients receiving leflunomide, especially Pneumocystis jiroveci pneumonia and aspergillosis. Most of the reports were confounded by concomitant immunosuppressant therapy and/or comorbid illness which, in addition to rheumatoid disease, may predispose patients to infection. In clinical studies with teriflunomide, cytomegalovirus hepatitis reactivation has been observed.In clinical studies with teriflunomide, cases of tuberculosis have been observed. Prior to initiating teriflunomide, screen patients for latent tuberculosis infection with tuberculin skin test or with blood test for mycobacterium tuberculosis infection. Teriflunomide has not been studied in patients with positive tuberculosis screen, and the safety of teriflunomide in individuals with latent tuberculosis infection is unknown. For patients testing positive in tuberculosis screening, treat by standard medical practice prior to therapy with teriflunomide.VaccinationNo clinical data are available on the efficacy and safety of live vaccinations in patients taking teriflunomdie. Vaccination with live vaccines is not recommended. The long half-life of teriflunomide should be considered when contemplating administration of live vaccine after stopping teriflunomide.MalignancyThe risk of malignancy, particularly lymphoproliferative disorders, is increased with the use of some immunosuppressive medications. There is potential for immunosuppression with teriflunomide. No apparent increase in the incidence of malignancies and lymphoproliferative disorders was reported in the teriflunomide clinical trials, but larger and longer-term studies would be needed to determine whether there is an increased risk of malignancy or lymphoproliferative disorders with teriflunomide.. 5.5 Hypersensitivityand Serious Skin Reactions. Teriflunomide can cause anaphylaxis and severe allergic reactions [see Contraindications (4)]. Signs and symptoms have included dyspnea, urticaria, and angioedema including lips, eyes, throat, and tongue.Cases of serious skin reactions, including cases of Stevens-Johnson syndrome (SJS) and fatal case of toxic epidermal necrolysis (TEN), have been reported with teriflunomide.In patients treated with leflunomide, the parent compound, very rare cases of Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) have also been reported. Inform patients of the signs and symptoms of anaphylaxis and angioedema and signs and symptoms that may signal serious skin reaction. Inform patients that fever associated with signs of other organ system involvement (e.g., rash, lymphadenopathy, or hepatic dysfunction) may be drug-related. Instruct patients to discontinue teriflunomide and seek immediate medical care should these signs and symptoms occur. Discontinue teriflunomide, unless the reactions are clearly not drug-related, and begin an accelerated elimination procedure immediately [see Warnings and Precautions (5.3)]. In such cases, patients should not be re-exposed to teriflunomide [see Contraindications (4)].. 5.6 PeripheralNeuropathy. In placebo-controlled studies, peripheral neuropathy, including both polyneuropathy and mononeuropathy (e.g., carpal tunnel syndrome), occurred more frequently in patients taking teriflunomide than in patients taking placebo. The incidence of peripheral neuropathy confirmed by nerve conduction studies was 1.4% (13 patients) and 1.9% (17 patients) of patients receiving mg and 14 mg of teriflunomide, respectively, compared with 0.4% receiving placebo (4 patients). Treatment was discontinued in 0.7% (8 patients) with confirmed peripheral neuropathy (3 patients receiving teriflunomide mg and patients receiving teriflunomide 14 mg). Five of them recovered following treatment discontinuation. Not all cases of peripheral neuropathy resolved with continued treatment. Peripheral neuropathy also occurred in patients receiving leflunomide.Age older than 60 years, concomitant neurotoxic medications, and diabetes may increase the risk for peripheral neuropathy. If patient taking teriflunomide develops symptoms consistent with peripheral neuropathy, such as bilateral numbness or tingling of hands or feet, consider discontinuing teriflunomide therapy and performing an accelerated elimination procedure [see Warnings and Precautions (5.3)].. 5.7 IncreasedBlood Pressure. In placebo-controlled studies, the mean change from baseline to the end of study in systolic blood pressure was +2.3 mmHg and +2.7 mmHg for teriflunomide mg and 14 mg, respectively, and -0.6 mmHg for placebo. The change from baseline in diastolic blood pressure was +1.4 mmHg and +1.9 mmHg for teriflunomide mg and 14 mg, respectively, and -0.3 mmHg for placebo. Hypertension was an adverse reaction in 3.1% and 4.3% of patients treated with mg or 14 mg of teriflunomide compared with 1.8% for placebo. Check blood pressure before start of teriflunomide treatment and periodically thereafter. Elevated blood pressure should be appropriately managed during treatment with teriflunomide.. 5.8 RespiratoryEffects. Interstitial lung disease, including acute interstitial pneumonitis, has been reported with teriflunomide in the postmarketing setting.Interstitial lung disease and worsening of pre-existing interstitial lung disease have been reported during treatment with leflunomide. Interstitial lung disease may be fatal and may occur acutely at any time during therapy with variable clinical presentation. New onset or worsening pulmonary symptoms, such as cough and dyspnea, with or without associated fever, may be reason for discontinuation of therapy and for further investigation as appropriate. If discontinuation of the drug is necessary, consider initiation of an accelerated elimination procedure [see Warnings and Precautions (5.3)].. 5.9 ConcomitantUse with Immunosuppressive or Immunomodulating Therapies. Co-administration with antineoplastic or immunosuppressive therapies used for treatment of multiple sclerosis has not been evaluated. Safety studies in which teriflunomide was concomitantly administered with other immune modulating therapies for up to one year (interferon beta, glatiramer acetate) did not reveal any specific safety concerns. The long term safety of these combinations in the treatment of multiple sclerosis has not been established.In any situation in which the decision is made to switch from teriflunomide to another agent with known potential for hematologic suppression, it would be prudent to monitor for hematologic toxicity, because there will be overlap of systemic exposure to both compounds. Use of an accelerated elimination procedure may decrease this risk, but may also potentially result in return of disease activity if the patient had been responding to teriflunomide treatment [see Warnings and Precautions (5.3)].