NDC 69238-1304 Teriflunomide

Teriflunomide

NDC Product Code 69238-1304

NDC CODE: 69238-1304

Proprietary Name: Teriflunomide What is the Proprietary Name?
The proprietary name also known as the trade name is the name of the product chosen by the medication labeler for marketing purposes.

Non-Proprietary Name: Teriflunomide What is the Non-Proprietary Name?
The non-proprietary name is sometimes called the generic name. The generic name usually includes the active ingredient(s) of the product.

Drug Use Information

Drug Use Information
The drug use information is a summary and does NOT have all possible information about this product. This information does not assure that this product is safe, effective, or appropriate. This information is not individual medical advice and does not substitute for the advice of a health care professional. Always ask a health care professional for complete information about this product and your specific health needs.

  • This medication is used to treat multiple sclerosis-MS. It is not a cure for MS but is thought to work by decreasing certain immune system cells (lymphocytes) which can attack the nerves in your brain and spinal cord. This helps decrease the number of flare-ups (relapses) and may help slow down physical problems caused by MS.

Product Characteristics

Color(s):
GREEN (C48329 - PALE GREEN TO GREEN)
BLUE (C48333 - PALE BLUE TO BLUE)
Shape: ROUND (C48348)
Size(s):
6 MM
7 MM
Imprint(s):
AC;21
AC;22
Score: 1

NDC Code Structure

NDC 69238-1304-2

Package Description: 2 BLISTER PACK in 1 CARTON > 14 TABLET, FILM COATED in 1 BLISTER PACK

NDC 69238-1304-6

Package Description: 28 TABLET, FILM COATED in 1 BOTTLE

NDC Product Information

Teriflunomide with NDC 69238-1304 is a a human prescription drug product labeled by Amneal Pharmaceuticals Ny Llc. The generic name of Teriflunomide is teriflunomide. The product's dosage form is tablet, film coated and is administered via oral form. The RxNorm Crosswalk for this NDC code indicates multiple RxCUI concepts are associated to this product: 1310525 and 1310533.

Dosage Form: Tablet, Film Coated - A solid dosage form that contains medicinal substances with or without suitable diluents and is coated with a thin layer of a water-insoluble or water-soluble polymer.

Product Type: Human Prescription Drug What kind of product is this?
Indicates the type of product, such as Human Prescription Drug or Human Over the Counter Drug. This data element matches the “Document Type” field of the Structured Product Listing.

Teriflunomide Active Ingredient(s)

What is the Active Ingredient(s) List?
This is the active ingredient list. Each ingredient name is the preferred term of the UNII code submitted.


Inactive Ingredient(s)

About the Inactive Ingredient(s)
The inactive ingredients are all the component of a medicinal product OTHER than the active ingredient(s). The acronym "UNII" stands for “Unique Ingredient Identifier” and is used to identify each inactive ingredient present in a product.

  • 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)
  • 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)

Administration Route(s)

What are the Administration Route(s)?
The translation of the route code submitted by the firm, indicating route of administration.

  • Oral - Administration to or by way of the mouth.

Pharmacological Class(es)

What is a Pharmacological Class?
These are the reported pharmacological class categories corresponding to the SubstanceNames listed above.

  • Pyrimidine Synthesis Inhibitor - [EPC] (Established Pharmacologic Class)
  • Dihydroorotate Dehydrogenase Inhibitors - [MoA] (Mechanism of Action)

Product Labeler Information

What is the Labeler Name?
Name of Company corresponding to the labeler code segment of the Product NDC.

Labeler Name: Amneal Pharmaceuticals Ny Llc
Labeler Code: 69238
FDA Application Number: ANDA209613 What is the FDA Application Number?
This corresponds to the NDA, ANDA, or BLA number reported by the labeler for products which have the corresponding Marketing Category designated. If the designated Marketing Category is OTC Monograph Final or OTC Monograph Not Final, then the Application number will be the CFR citation corresponding to the appropriate Monograph (e.g. “part 341”). For unapproved drugs, this field will be null.

Marketing Category: ANDA - A product marketed under an approved Abbreviated New Drug Application. What is the Marketing Category?
Product types are broken down into several potential Marketing Categories, such as NDA/ANDA/BLA, OTC Monograph, or Unapproved Drug. One and only one Marketing Category may be chosen for a product, not all marketing categories are available to all product types. Currently, only final marketed product categories are included. The complete list of codes and translations can be found at www.fda.gov/edrls under Structured Product Labeling Resources.

Start Marketing Date: 10-01-2018 What is the Start Marketing Date?
This is the date that the labeler indicates was the start of its marketing of the drug product.

Listing Expiration Date: 12-31-2021 What is the Listing Expiration Date?
This is the date when the listing record will expire if not updated or certified by the product labeler.

Exclude Flag: N - NO What is the NDC Exclude Flag?
This field indicates whether the product has been removed/excluded from the NDC Directory for failure to respond to FDA"s requests for correction to deficient or non-compliant submissions ("Y"), or because the listing certification is expired ("E"), or because the listing data was inactivated by FDA ("I"). Values = "Y", "N", "E", or "I".

* Please review the disclaimer below.

Information for Patients

Teriflunomide

Teriflunomide is pronounced as (ter'' i floo' noe mide)

Why is teriflunomide medication prescribed?
Teriflunomide is used to prevent episodes of symptoms and slow the worsening of disability in patients with relapsing-remitting forms (course of disease where symptoms fl...
[Read More]

* Please review the disclaimer below.

Teriflunomide Product Labeling Information

The product labeling information includes all published material associated to a drug. Product labeling documents include information like generic names, active ingredients, ingredient strength dosage, routes of administration, appearance, usage, warnings, inactive ingredients, etc.

Product Labeling Index

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 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)].

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 SafetyObtain 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:Patients with severe hepatic impairment [see Warnings and Precautions (5.1)].Pregnant women and females of reproductive potential not using effective contraception. Teriflunomide may cause fetal harm [see Warnings and Precautions (5.2, 5.3) and Use in Specific Populations (8.1)].Patients with a history of a hypersensitivity reaction to teriflunomide, leflunomide, or to any of the inactive ingredients in teriflunomide tablets. Reactions have included anaphylaxis, angioedema, and serious skin reactions [see Warnings and Precautions (5.5)].Co-administration with leflunomide [see Clinical Pharmacology (12.3)].

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 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 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 ScreeningPatients 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.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 a live vaccine after stopping teriflunomide.MalignancyThe 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: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)]

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 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 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 FailureIn 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.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 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.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

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 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) 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 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)].

8.1 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 reactionsLowering 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)].DataHuman dataAvailable 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 SummaryThere 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)].ContraceptionFemales 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)].MalesTeriflunomide 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: 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.

12.1 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 IntervalIn 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.AbsorptionMedian 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. DistributionTeriflunomide 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.MetabolismTeriflunomide 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.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 a 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 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 substratesRepeated 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 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 3 (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 a 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 a low number of non-white patients in the clinical trials.

13.1 Carcinogenesis, Mutagenesis, Impairment Of Fertility

CarcinogenesisNo 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.MutagenesisTeriflunomide 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 FertilityOral 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 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)20.345(p = 0.0003)21.127Mean 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 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 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 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 69238-1303-6Carton 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 69238-1304-6Carton 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 ToxicityAdvise females of reproductive potentialOf the potential for fetal harm if teriflunomide is taken during pregnancyTo notify their healthcare provider immediately if a 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 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 ProcedureAdvise 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 InfectionsInform 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 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 UnitAhmedabad 382213, INDIADistributed by:Amneal Pharmaceuticals LLCBridgewater, NJ 08807Rev. 04-2020-03

Medication Guide

  • Teriflunomide (ter” i floo’ noe mide) TabletsRead 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 tablets1 time a month for 6 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 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 problemsare pregnant or are of childbearing age and not using effective birth controltake a medicine called leflunomideWhat should I tell my doctor before taking teriflunomide tablets? Before you take teriflunomide tablets, tell your doctor if you:have liver or kidney problemshave a 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 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:fevertirednessbody acheschillsnauseavomitingshould 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 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 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 UnitAhmedabad 382213, INDIADistributed by:Amneal Pharmaceuticals LLCBridgewater, NJ 08807 Rev. 09-2019-01

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