Label: TERIFLUNOMIDE tablet, film coated

  • NDC Code(s): 69238-1303-2, 69238-1303-6, 69238-1304-2, 69238-1304-6
  • Packager: Amneal Pharmaceuticals NY LLC
  • Category: HUMAN PRESCRIPTION DRUG LABEL
  • DEA Schedule: None
  • Marketing Status: Abbreviated New Drug Application

Drug Label Information

Updated September 19, 2019

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  • HIGHLIGHTS OF PRESCRIBING INFORMATION
    These highlights do not include all the information needed to use TERIFLUNOMIDE TABLETS safely and effectively. See full prescribing information for TERIFLUNOMIDE TABLETS. 

    TERIFLUNOMIDE tablets, for oral use
    Initial U.S. Approval: 2012

    WARNING: HEPATOTOXICITY and EMBRYOFETAL TOXICITY

    See full prescribing information for complete boxed warning.

    • Hepatotoxicity
      Severe liver injury including fatal liver failure has been reported in patients treated with leflunomide, which is indicated for rheumatoid arthritis. A similar risk would be expected for teriflunomide because recommended doses of teriflunomide and leflunomide result in a similar range of plasma concentrations of teriflunomide. Obtain transaminase and bilirubin levels within 6 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 Toxicity
      Teratogenicity 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).

    RECENT MAJOR CHANGES

    Indication and Usage (1)                                                   09/2019
    Warnings and Precautions (5.2)                                        07/2019

    INDICATIONS AND USAGE

    Teriflunomide 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)

    DOSAGE AND ADMINISTRATION

    7 mg or 14 mg orally once daily, with or without food. (2)

    DOSAGE FORMS AND STRENGTHS

    7 mg and 14 mg film-coated tablets (3)

    CONTRAINDICATIONS

    • Severe hepatic impairment (4, 5.1)
    • Pregnancy (4, 5.2, 8.1)
    • Hypersensitivity (4, 5.5)
    • Current leflunomide treatment (4)

    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. A 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)

    ADVERSE REACTIONS

    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.

    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 teriflunomide. (7)

    See 17 for PATIENT COUNSELING INFORMATION and Medication Guide.

    Revised: 9/2019

  • Table of Contents
  • BOXED WARNING (What is this?)

    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. A similar risk would be expected for teriflunomide because recommended doses of teriflunomide and leflunomide result in a similar range of plasma concentrations of teriflunomide. Concomitant use of teriflunomide with other potentially hepatotoxic drugs may increase the risk of severe liver injury.
      Obtain transaminase and bilirubin levels within 6 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 Toxicity
      Teriflunomide 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)].
  • 1 INDICATIONS AND USAGE

    Teriflunomide tablets are 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.

  • 2 DOSAGE AND ADMINISTRATION

    The recommended dose of teriflunomide tablets are 7 mg or 14 mg orally once daily. Teriflunomide tablets can be taken with or without food.

    Monitoring to Assess Safety

    • Obtain transaminase and bilirubin levels within 6 months before initiation of teriflunomide tablets therapy. Monitor ALT levels at least monthly for six months after starting teriflunomide tablets [see Warnings and Precautions (5.1)].
    • Obtain a complete blood cell count (CBC) within 6 months before the initiation of treatment with teriflunomide tablets. Further monitoring should be based on signs and symptoms of infection [see Warnings and Precautions (5.4)].
    • Prior to initiating teriflunomide tablets, 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 teriflunomide tablets in females of reproductive potential [see Warnings and Precautions (5.2)].
    • Check blood pressure before start of teriflunomide tablets treatment and periodically thereafter [see Warnings and Precautions (5.7)].
  • 3 DOSAGE FORMS AND STRENGTHS

    Teriflunomide tablets are available as 7 mg and 14 mg tablets.

    Teriflunomide tablets, 7 mg are pale green to green colored, round, biconvex coated tablet debossed with “AC” and “21” on one side and plain on other side. Each tablet contains 7 mg of teriflunomide.

    Teriflunomide tablets, 14 mg are a pale blue to blue colored, round, biconvex coated tablet debossed with “AC” and “22” on one side and plain on other side. Each tablet contains 14 mg of teriflunomide.

  • 4 CONTRAINDICATIONS

    Teriflunomide is contraindicated in/with:

  • 5 WARNINGS AND PRECAUTIONS

    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. A similar risk would be expected for teriflunomide because recommended doses of teriflunomide and leflunomide result in a similar range of plasma concentrations of teriflunomide. 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 7 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 2 months.

    One patient in the controlled trials developed ALT 32 times the ULN and jaundice 5 months after initiation of teriflunomide 14 mg treatment. The patient was hospitalized for 5 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 6 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 a 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 a woman becomes pregnant while taking teriflunomide, stop treatment with teriflunomide, apprise the patient of the potential risk to a fetus, and perform an accelerated drug elimination procedure to achieve a 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 a 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)].

    5.3 Procedure 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 8 months to reach plasma concentrations less than 0.02 mg/L, although because of individual variations in drug clearance it may take as long as 2 years. An accelerated elimination procedure could be used at any time after discontinuation of teriflunomide. Elimination can be accelerated by either of the following procedures:

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

    If either elimination procedure is poorly tolerated, treatment days do not need to be consecutive unless there is a 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.

    5.4 Bone Marrow Effects/Immunosuppression Potential/Infections

    Bone Marrow Effects

    A 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 7 mg and 14 mg of teriflunomide. The decrease in mean WBC count occurred during the first 6 weeks and WBC count remained low during treatment. In placebo-controlled studies, neutrophil count <1.5 x 109/L was observed in 12% and 16% of patients receiving teriflunomide 7 mg and 14 mg, respectively, compared with 7% of patients receiving placebo; lymphocyte count <0.8 x 109/L was observed in 10% and 12% of patients receiving teriflunomide 7 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. A 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 a complete blood cell count (CBC) within 6 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 Screening

    Patients with active acute or chronic infections should not start treatment until the infection(s) is resolved. If a patient develops a 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 a 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 7 mg (2.2%) or 14 mg (2.7%) compared to placebo (2.2%).

    However, one fatal case of klebsiella pneumonia sepsis occurred in a 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 a tuberculin skin test or with a blood test for mycobacterium tuberculosis infection. Teriflunomide has not been studied in patients with a 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.

    Vaccination

    No 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 a live vaccine after stopping teriflunomide.

    Malignancy

    The risk of malignancy, particularly lymphoproliferative disorders, is increased with the use of some immunosuppressive medications. There is a 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 Hypersensitivity and 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 a 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 a serious skin reaction. Inform patients that a 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 Peripheral Neuropathy

    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 7 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 7 mg and 5 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 a 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 Increased Blood 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 7 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 7 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 7 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 Respiratory Effects

    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 a variable clinical presentation. New onset or worsening pulmonary symptoms, such as cough and dyspnea, with or without associated fever, may be a 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 Concomitant Use 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 a 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)].

  • 6 ADVERSE REACTIONS

    The following serious adverse reactions are described elsewhere in the prescribing information:

    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 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 1 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 7 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 Sclerosis

    Adverse Reaction

    Teriflunomide

    7 mg

    (N=1045)

    Teriflunomide

    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 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. A relationship between teriflunomide 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 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.

    Hypophosphatemia

    In 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 a serum phosphorus below 0.3 mmol/L.

    6.2 Postmarketing Experience

    The following adverse reactions have been identified during postapproval use of teriflunomide. 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.

  • 7 DRUG INTERACTIONS

    Effect of Teriflunomide on CYP2C8 Substrates

    Teriflunomide 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 Warfarin

    Co-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 Contraceptives

    Teriflunomide 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 Substrates

    Teriflunomide may be a 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 3 (OAT3) Substrates

    Teriflunomide 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) Substrates

    Teriflunomide inhibits the activity of BCRP and OATP1B1/1B3 in vivo. For a 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)].

  • 8 USE IN SPECIFIC POPULATIONS

    8.1 Pregnancy

    Risk Summary

    Teriflunomide 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% to 4% and 15% to 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 teriflunomide. 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 teriflunomide 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 teriflunomide, women should not breastfeed during treatment with teriflunomide.

    8.3 Females and Males of Reproductive Potential

    Pregnancy Testing

    Exclude pregnancy prior to initiation of treatment with teriflunomide 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 teriflunomide. If teriflunomide 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 teriflunomide 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

    Teriflunomide 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 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 Warnings and Precautions (5.3)].

    8.4 Pediatric Use

    Safety and effectiveness in pediatric patients have not been established.

    8.5 Geriatric Use

    Clinical studies of teriflunomide 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.

    Teriflunomide 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)].

  • 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)].

  • 11 DESCRIPTION

    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 C12 H9 F3 N2 O2 with the following chemical structure:

    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. Teriflunomide tablets contain 7 mg or 14 mg of teriflunomide and the following inactive ingredients: corn starch, hydroxypropyl cellulose, lactose monohydrate, microcrystalline cellulose, magnesium stearate and sodium starch glycolate. The film coating for the 7 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 7 mg tablet film coating includes iron oxide yellow.

  • 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 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 volunteers and MS patients, median t1/2 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 teriflunomide on other drugs

    CYP2C8 substrates
    There was an increase in mean repaglinide Cmax 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 Cmax 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 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 3 (OAT3) in vivo [see Drug Interactions (7)].

    BCRP and OATP1B1/1B3 substrates
    There 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 contraceptives
    There 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 teriflunomide

    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.

  • 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 to 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 to 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/m2 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/m2 basis.

  • 14 CLINICAL STUDIES

    Four randomized, controlled, double-blind clinical trials established the efficacy of teriflunomide in patients with relapsing forms of multiple sclerosis.

    Study 1 was a double-blind, placebo-controlled clinical trial that evaluated once daily doses of teriflunomide 7 mg and teriflunomide 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, 1,088 patients were randomized to receive teriflunomide 7 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 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 teriflunomide 7 mg, teriflunomide 14 mg, and placebo, respectively. The percentage of patients who completed the study treatment period was 75%, 73%, and 71% for teriflunomide 7 mg, teriflunomide 14 mg, and placebo, respectively.

    There was a statistically significant reduction in ARR for patients who received teriflunomide 7 mg or teriflunomide 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 teriflunomide 14 mg group compared to placebo (see Table 2 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 7 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 1

     

    Teriflunomide

    7 mg

    N=365

    Teriflunomide

    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 volume1 (mL) at week 108

    0.755

    (p= 0.0317)2

    0.345

    (p = 0.0003)2

    1.127

    Mean number of Gd-enhancing T1-lesions per scan

    0.570

    (p < 0.0001)

    0.261

    (p < 0.0001)

    1.331

    1Total lesion volume: sum of T2 and hypointense T1 lesion volume in mL

    2p-values based on cubic root transformed data for total lesion volume

    Figure 1: Kaplan-Meier Plot of Time to Disability Progression Sustained for 12 Weeks (Study 1)

    Image_1    

    Study 2 was a double-blind, placebo-controlled clinical trial that evaluated once daily doses of teriflunomide 7 mg and teriflunomide 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 1,165 patients received teriflunomide 7 mg (n=407), teriflunomide 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 teriflunomide 7 mg, teriflunomide 14 mg, and placebo, respectively. The percentage of patients who completed the study treatment period was 67%, 66%, and 68% for teriflunomide 7 mg, teriflunomide 14 mg, and placebo, respectively.

    There was a statistically significant reduction in the ARR for patients who received teriflunomide 7 mg or teriflunomide 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 teriflunomide 14 mg group compared to placebo (See Table 3 and Figure 2).

    Table 3: Clinical Results of Study 2

     

     

    Teriflunomide
    7 mg
    N=407

    Teriflunomide
    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)

     4  

    Study 3 was a double-blind, placebo-controlled clinical trial that evaluated once daily doses of teriflunomide 7 mg and teriflunomide 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 teriflunomide 7 mg (n=203), teriflunomide 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 teriflunomide 7 mg (70.5%, p <0.05) and teriflunomide 14 mg (72.2%, p <0.05) groups than in the placebo group (61.7%).

    The effect of teriflunomide 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 teriflunomide 7 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 7 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).

  • 16 HOW SUPPLIED/STORAGE AND HANDLING

    Teriflunomide Tablets, 7 mg are pale green to green colored, round, biconvex coated tablet debossed with “AC” and “21” on one side and plain on other side.
    They are available as follows:

    Bottle of 28 Tablets:                            NDC 69238-1303-6
    Carton of 28 Tablets:                          NDC 69238-1303-2
    (1 wallet composed of 2 folded blister cards of 14 tablets per blister card)

    Teriflunomide Tablets, 14 mg are pale blue to blue colored, round, biconvex coated tablet debossed with “AC” and “22” on one side and plain on other side.
    They are available as follows:

    Bottle of 28 Tablets:                            NDC 69238-1304-6
    Carton of 28 Tablets:                          NDC 69238-1304-2
    (1 wallet composed of 2 folded blister cards of 14 tablets per blister card)

    Store at 20° to 25°C (68° to 77°F); excursions permitted between 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature].

  • 17 PATIENT COUNSELING INFORMATION

    Advise the patient to read the FDA-approved patient labeling (Medication Guide).

    A 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 6 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 Toxicity

    • Advise females of reproductive potential
    • Instruct men taking teriflunomide 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 teriflunomide and undergo an accelerated elimination procedure.

    Availability of an Accelerated Elimination Procedure

    Advise patients that teriflunomide 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.

    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 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 6 months after discontinuation.

    Serious Allergic Reactions

    Advise patients to discontinue teriflunomide 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 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 Pressure

    Inform 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, INDIA

    Distributed by:
    Amneal Pharmaceuticals LLC
    Bridgewater, NJ 08807

    Rev. 09-2019-01

  • Medication Guide

    Teriflunomide (ter” i floo’ noe mide) Tablets

    Read this Medication Guide before you start using teriflunomide tablets 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 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 6 months before you start taking teriflunomide tablets
      • 1 time a month for 6 months after you start taking teriflunomide tablets

      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: 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 a female, you should have a 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 2 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 2 years after you stop taking it. Your doctor can prescribe a 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 tablets?

    Teriflunomide tablets are 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 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 a medicine called leflunomide
    • have severe liver problems
    • are pregnant or are of childbearing age and not using effective birth control
    • take a medicine called leflunomide

    What should I tell my doctor before taking teriflunomide tablets?

    Before you take teriflunomide tablets, tell your doctor 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 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 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 teriflunomide tablets?

    • Take teriflunomide tablets exactly as your doctor tells you to take it.
    • Take teriflunomide tablets 1 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 I 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 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 teriflunomide tablets. 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 teriflunomide tablets and for 6 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 a greater chance of getting peripheral neuropathy 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.

    • 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:

    • headache
    • diarrhea
    • nausea
    • hair thinning or loss (alopecia)
    • increases in the results of blood tests to check your liver function

    Tell 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 I store teriflunomide tablets?

    • Store teriflunomide tablets at room temperature between 68° to 77°F (20° to 25°C).
    • 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 a Medication Guide. Do not use teriflunomide tablets for a 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 tablets?

    Active ingredient: teriflunomide

    Inactive ingredients in 7 mg and 14 mg tablets: corn starch, hydroxypropyl cellulose, lactose monohydrate, microcrystalline cellulose, magnesium stearate and sodium starch glycolate. The film coating for the 7 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 7 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, INDIA

    Distributed by:
    Amneal Pharmaceuticals LLC
    Bridgewater, NJ 08807

    Rev. 09-2019-01

  • PRINCIPAL DISPLAY PANEL

    Teriflunomide Tablets, 7 mg
    Rx Only
    Amneal Pharmaceuticals LLC

    10

    10

    10

    10


    Teriflunomide Tablets, 14 mg
    Rx Only
    Amneal Pharmaceuticals LLC

    10

    10

    10

    10

  • INGREDIENTS AND APPEARANCE
    TERIFLUNOMIDE 
    teriflunomide tablet, film coated
    Product Information
    Product TypeHUMAN PRESCRIPTION DRUGItem Code (Source)NDC:69238-1303
    Route of AdministrationORAL
    Active Ingredient/Active Moiety
    Ingredient NameBasis of StrengthStrength
    TERIFLUNOMIDE (UNII: 1C058IKG3B) (TERIFLUNOMIDE - UNII:1C058IKG3B) TERIFLUNOMIDE7 mg
    Inactive Ingredients
    Ingredient NameStrength
    FD&C BLUE NO. 2 (UNII: L06K8R7DQK)  
    FERRIC OXIDE YELLOW (UNII: EX438O2MRT)  
    HYDROXYPROPYL CELLULOSE, UNSPECIFIED (UNII: 9XZ8H6N6OH)  
    HYPROMELLOSE, UNSPECIFIED (UNII: 3NXW29V3WO)  
    LACTOSE MONOHYDRATE (UNII: EWQ57Q8I5X)  
    MAGNESIUM STEARATE (UNII: 70097M6I30)  
    MICROCRYSTALLINE CELLULOSE (UNII: OP1R32D61U)  
    POLYETHYLENE GLYCOL, UNSPECIFIED (UNII: 3WJQ0SDW1A)  
    SILICON DIOXIDE (UNII: ETJ7Z6XBU4)  
    SODIUM STARCH GLYCOLATE TYPE A CORN (UNII: AG9B65PV6B)  
    STARCH, CORN (UNII: O8232NY3SJ)  
    TITANIUM DIOXIDE (UNII: 15FIX9V2JP)  
    Product Characteristics
    ColorGREEN (pale green to green) Scoreno score
    ShapeROUND (Biconvex) Size6mm
    FlavorImprint Code AC;21
    Contains    
    Packaging
    #Item CodePackage DescriptionMarketing Start DateMarketing End Date
    1NDC:69238-1303-22 in 1 CARTON10/01/2018
    114 in 1 BLISTER PACK; Type 0: Not a Combination Product
    2NDC:69238-1303-628 in 1 BOTTLE; Type 0: Not a Combination Product10/01/2018
    Marketing Information
    Marketing CategoryApplication Number or Monograph CitationMarketing Start DateMarketing End Date
    ANDAANDA20961310/01/2018
    TERIFLUNOMIDE 
    teriflunomide tablet, film coated
    Product Information
    Product TypeHUMAN PRESCRIPTION DRUGItem Code (Source)NDC:69238-1304
    Route of AdministrationORAL
    Active Ingredient/Active Moiety
    Ingredient NameBasis of StrengthStrength
    TERIFLUNOMIDE (UNII: 1C058IKG3B) (TERIFLUNOMIDE - UNII:1C058IKG3B) TERIFLUNOMIDE14 mg
    Inactive Ingredients
    Ingredient NameStrength
    FD&C BLUE NO. 2 (UNII: L06K8R7DQK)  
    HYDROXYPROPYL CELLULOSE, UNSPECIFIED (UNII: 9XZ8H6N6OH)  
    HYPROMELLOSE, UNSPECIFIED (UNII: 3NXW29V3WO)  
    LACTOSE MONOHYDRATE (UNII: EWQ57Q8I5X)  
    MAGNESIUM STEARATE (UNII: 70097M6I30)  
    MICROCRYSTALLINE CELLULOSE (UNII: OP1R32D61U)  
    POLYETHYLENE GLYCOL, UNSPECIFIED (UNII: 3WJQ0SDW1A)  
    SILICON DIOXIDE (UNII: ETJ7Z6XBU4)  
    SODIUM STARCH GLYCOLATE TYPE A CORN (UNII: AG9B65PV6B)  
    STARCH, CORN (UNII: O8232NY3SJ)  
    TITANIUM DIOXIDE (UNII: 15FIX9V2JP)  
    Product Characteristics
    ColorBLUE (Pale blue to blue) Scoreno score
    ShapeROUND (Biconvex) Size7mm
    FlavorImprint Code AC;22
    Contains    
    Packaging
    #Item CodePackage DescriptionMarketing Start DateMarketing End Date
    1NDC:69238-1304-22 in 1 CARTON10/01/2018
    114 in 1 BLISTER PACK; Type 0: Not a Combination Product
    2NDC:69238-1304-628 in 1 BOTTLE; Type 0: Not a Combination Product10/01/2018
    Marketing Information
    Marketing CategoryApplication Number or Monograph CitationMarketing Start DateMarketing End Date
    ANDAANDA20961310/01/2018
    Labeler - Amneal Pharmaceuticals NY LLC (123797875)