`------------------------------DRUG INTERACTIONS-------------------------------
`
` Drugs metabolized by CYP2C8: Monitor patients as teriflunomide may
`increase their exposure (7)
`
`
` Teriflunomide may increase exposure of ethinylestradiol and
`levonorgestrel. Choose an appropriate oral contraceptive (7)
`
`
` Drugs metabolized by CYP1A2: Monitor patients as teriflunomide may
`decrease their exposure (7)
`
`
` Warfarin: monitor INR as teriflunomide may decrease INR (7)
`
`-----------------------USE IN SPECIFIC POPULATIONS------------------------
`
` Contraindicated in pregnancy; pregnancy registry available (4.2, 8.1)
`
`
`
`See 17 for PATIENT COUNSELING INFORMATION and Medication
`Guide
`
`
`
`
`
`
`
`
`
`Revised: 09/2012
`
`
`
`
`_____________________________________________________________________________________________________________________________________
`
`
`
`
` NDA 202992 – FDA Approved Labeling Text dated September 12, 2012
`HIGHLIGHTS OF PRESCRIBING INFORMATION
`
`-----------------------WARNINGS AND PRECAUTIONS-----------------------­
`These highlights do not include all the information needed to use
`
` AUBAGIO® safely and effectively. See full prescribing information for
`
` Elimination of AUBAGIO can be accelerated by administration of
`
` AUBAGIO.
`cholestyramine or activated charcoal for 11 days (5.3)
`
`
` AUBAGIO may decrease WBC. A recent CBC should be available before
`
`AUBAGIO (teriflunomide) tablets for oral administration.
`
`
`starting AUBAGIO. Monitor for signs and symptoms of infection.
`Initial U.S. Approval: 2012
`Consider suspending treatment with AUBAGIO and using accelerated
`
`
`elimination procedure in case of serious infection. Do not start AUBAGIO
`
`in patients with active infections (5.4)
`
` Peripheral neuropathy: If patient develops symptoms consistent with
`peripheral neuropathy, evaluate patient and consider discontinuing
`
`AUBAGIO and using accelerated elimination procedure (5.5)
`
` Acute renal failure/hyperkalemia: Monitor renal function and potassium in
`
`patients with symptoms of renal failure or hyperkalemia (5.6, 5.7)
`
`
` Severe skin reaction: Stop AUBAGIO and use accelerated elimination
`procedure (5.8)
`
`
` Blood pressure: Measure at treatment initiation. Monitor and manage
`appropriately during treatment (5.9)
`
`
`
`
`
`------------------------------ADVERSE REACTIONS-------------------------------
`
`Most common adverse reactions (≥10% and ≥2% greater than placebo): ALT
`increased, alopecia, diarrhea, influenza, nausea, and paresthesia. (6)
`
`
`To report SUSPECTED ADVERSE REACTIONS, contact Genzyme
`
`Corporation at 1-800-745-4447 or FDA at 1-800-FDA-1088 or
`www.fda.gov/medwatch.
`
`
` WARNING: HEPATOTOXICITY and RISK OF TERATOGENICITY
`
`
`
`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 AUBAGIO and
`monitor ALT levels at least monthly for six months (5.1). If drug induced
`liver injury is suspected, discontinue AUBAGIO and start accelerated
`elimination procedure (5.3).
`
`
`Risk of Teratogenicity
`
`Based on animal data, AUBAGIO may cause major birth defects if used
`
`during pregnancy. AUBAGIO is contraindicated in pregnant women or
`women of childbearing potential who are not using reliable contraception.
`Pregnancy must be avoided during AUBAGIO treatment. (4.2, 5.2)
`
`
`
`
`----------------------------INDICATIONS AND USAGE---------------------------
`AUBAGIO is a pyrimidine synthesis inhibitor indicated for the treatment of
`
`patients with relapsing forms of multiple sclerosis (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 (4.1, 5.1)
`
`
` Pregnancy (4.2, 5.2, 8.1)
`
`
` Current leflunomide treatment (4.3)
`
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`WARNING: HEPATOTOXICITY and RISK OF TERATOGENICITY
`
`
`INDICATIONS AND USAGE
`1
`
`2 DOSAGE AND ADMINISTRATION
`
`
`3 DOSAGE FORMS AND STRENGTHS
`
`4 CONTRAINDICATIONS
`
`4.1 Severe Hepatic Impairment
`
`4.2 Patients Who Are Pregnant or Women of Childbearing Potential
`
`Not Using Reliable Contraception
`
`4.3 Current treatment with leflunomide
`
`5 WARNINGS AND PRECAUTIONS
`
`5.1 Hepatotoxicity
`
`5.2 Use in Women of Childbearing Potential
`
`5.3 Procedure for Accelerated Elimination of Teriflunomide
`
`5.4 Bone marrow effects/Immunosuppression potential/Infections
`
`5.5 Peripheral Neuropathy
`
`
`5.6 Acute Renal Failure
`
`5.7 Hyperkalemia
`
`5.8 Skin Reactions
`
`5.9 Blood Pressure Effects
`
`5.10 Respiratory Effects
`
`
`5.11 Concomitant Use with Immunosuppressive/modulating therapies
`
`6 ADVERSE REACTIONS
`
`6.1 Clinical Trial Experience
`
`7 DRUG INTERACTIONS
`
`
`8 USE IN SPECIFIC POPULATIONS
`
`
`8.1 Pregnancy
`*Sections or subsections omitted from the full prescribing information are not
`
`
`
`8.3 Nursing Mothers
`listed.
`_______________________________________________________________________________________________________________________________________
`
`
`8.4 Pediatric Use
`
`8.5 Geriatric Use
`
`8.6 Hepatic Impairment
`
`8.7 Renal Impairment
`10 OVERDOSAGE
`
`11 DESCRIPTION
`12 CLINICAL PHARMACOLOGY
`12.1 Mechanism of Action
`
`12.2 Pharmacodynamics
`12.3 Pharmacokinetics
`
`13 NONCLINICAL TOXICOLOGY
`13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
`
`
`14 CLINICAL STUDIES
`16 HOW SUPPLIED/STORAGE AND HANDLING
`17 PATIENT COUNSELING INFORMATION
`
`17.1 Benefits and Risks
`
`
`17.2 Hepatic Effects
`17.3 Fetal Risk
`17.4 Blood Pressure Effects
`
`17.5 Risk of Infections
`
`17.6 Hematologic Effects
`
`
`
`
`Reference ID: 3188314
`
`Page 1 of 27
`
`Coalition Exhibit 1068
`Coalition v. Biogen
`IPR2015-01993
`
`

`

`
`
` NDA 202992 – FDA Approved Labeling Text dated September 12, 2012
`
`FULL PRESCRIBING INFORMATION
`
`
`
`
`
`WARNING: HEPATOTOXICITY and RISK OF TERATOGENICITY
`
`
`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 AUBAGIO
`with other potentially hepatotoxic drugs may increase the risk of severe liver injury.
`Obtain transaminase and bilirubin levels within 6 months before initiation of AUBAGIO
`therapy. Monitor ALT levels at least monthly for six months after starting AUBAGIO [see
`Warnings and Precautions (5.1)]. If drug induced liver injury is suspected, discontinue
`AUBAGIO and start an accelerated elimination procedure with cholestyramine or charcoal
`[see Warnings and Precautions (5.3)]. AUBAGIO is contraindicated in patients with severe
`hepatic impairment [see Contraindications (4.1)]. Patients with pre-existing liver disease
`
`may be at increased risk of developing elevated serum transaminases when taking
`AUBAGIO.
`
`Risk of Teratogenicity
`Based on animal data, AUBAGIO may cause major birth defects if used during pregnancy.
`Pregnancy must be excluded before starting AUBAGIO. AUBAGIO is contraindicated in
`pregnant women or women of childbearing potential who are not using reliable
`contraception. Pregnancy must be avoided during AUBAGIO treatment or prior to the
`completion of an accelerated elimination procedure after AUBAGIO treatment [see
`Contraindications (4.2), Warnings and Precautions (5.2), and Use in Specific Populations
`(8.1)].
`
`
`
`1. INDICATIONS AND USAGE
`
`
`AUBAGIO® is indicated for the treatment of patients with relapsing forms of multiple sclerosis
`[see Clinical Studies (14)].
`
`
`2. DOSAGE AND ADMINISTRATION
`
`The recommended dose of AUBAGIO is 7 mg or 14 mg orally once daily. AUBAGIO can be
`taken with or without food.
`
`Monitoring to assess safety
`
` Obtain transaminase and bilirubin levels within 6 months before initiation of AUBAGIO
`therapy. Monitor ALT levels at least monthly for six months after starting AUBAGIO
`[see Warnings and Precautions (5.1)].
`
` Obtain a complete blood cell count (CBC) within 6 months before the initiation of
`treatment with AUBAGIO. Further monitoring should be based on signs and symptoms
`
`of infection [see Warnings and Precautions (5.4)].
`
`Reference ID: 3188314
`
`Page 2 of 27
`
`

`

`
`
` NDA 202992 – FDA Approved Labeling Text dated September 12, 2012
`
`
` Prior to initiating AUBAGIO, screen patients for latent tuberculosis infection with a
`tuberculin skin test [see Warnings and Precautions (5.4)].
`
` Check blood pressure before start of AUBAGIO treatment and periodically thereafter
`[see Warnings and Precautions (5.10)].
`
`
`
`3. DOSAGE FORMS AND STRENGTHS
`
`AUBAGIO is available as 7 mg and 14 mg tablets.
`
`The 14 mg tablet is a pale blue to pastel blue, pentagonal film-coated tablet with the dose
`strength, “14” imprinted on one side and engraved with the corporate logo on the other side.
`Each tablet contains 14 mg of teriflunomide.
`
`The 7 mg tablet is a very light greenish-bluish grey to pale greenish-blue, hexagonal film-coated
`tablet with dose strength “7” imprinted on one side and engraved with the corporate logo on
`other side. Each tablet contains 7 mg of teriflunomide.
`
`
`4. CONTRAINDICATIONS
`
`4.1. Severe Hepatic Impairment
`
`Patients with severe hepatic impairment [see Warnings and Precautions (5.1)].
`
`4.2 Patients Who are Pregnant or Women of Childbearing Potential Not Using Reliable
`Contraception
`
`
`AUBAGIO may cause fetal harm when administered to a pregnant woman.
`
`In animal studies, teriflunomide has been shown to be selectively teratogenic and embryolethal
`in multiple species when administered during pregnancy at doses less than those used clinically.
`Nonclinical studies indicate further that the intended pharmacologic action of the drug is
`involved in the mechanism of developmental toxicity [see Use in Specific Populations (8.1)].
`
`AUBAGIO is contraindicated in women who are pregnant or women of child bearing potential
`not using reliable contraception. If this drug is used during pregnancy, or if the patient becomes
`pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus.
`If pregnancy does occur during treatment, the drug should be immediately discontinued and an
`accelerated elimination procedure should be initiated [see Warnings and Precautions (5.3)].
`Under these conditions, the patient should be referred to an obstetrician/gynecologist, preferably
`experienced in reproductive toxicity, for further evaluation and counseling. [See Warnings and
`Precautions and Use in Specific Populations (5.2, 8.1)]
`
`4.3. Current treatment with leflunomide
`
`Co-administration of teriflunomide with leflunomide is contraindicated.
`
`
`Reference ID: 3188314
`
`Page 3 of 27
`
`

`

`
`
` NDA 202992 – FDA Approved Labeling Text dated September 12, 2012
`
`
`
`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 AUBAGIO. Patients with pre-existing acute or chronic liver disease, or those with
`serum alanine aminotransferase (ALT) greater than two times the upper limit of normal (ULN)
`before initiating treatment, should not normally be treated with AUBAGIO. AUBAGIO is
`contraindicated in patients with severe hepatic impairment [see Contraindications (4)].
`
`
`In placebo-controlled trials, ALT greater than three times the ULN occurred in 14/429 (3%) and
`21/415 (5%) of patients on teriflunomide 7 mg and 14 mg, respectively, and 17/421 (4%) of
`patients on 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,
`AUBAGIO 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 AUBAGIO 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 AUBAGIO
`therapy. Monitor ALT levels at least monthly for six months after starting AUBAGIO. Consider
`additional monitoring when AUBAGIO is given with other potentially hepatotoxic drugs.
`Consider discontinuing AUBAGIO if serum transaminase increase (greater than three times the
`ULN) is confirmed. Monitor serum transaminase and bilirubin on AUBAGIO 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 AUBAGIO-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 Use in Women of Childbearing Potential
`There are no adequate and well-controlled studies evaluating AUBAGIO in pregnant women.
`However, based on animal studies, teriflunomide may increase the risk of teratogenic effects or
`fetal death when administered to a pregnant woman [see Contraindications (4.2)].
`
`
`Reference ID: 3188314
`
`Page 4 of 27
`
`

`

`
`
` NDA 202992 – FDA Approved Labeling Text dated September 12, 2012
`
`Women of childbearing potential must not be started on AUBAGIO until pregnancy is excluded
`and it has been confirmed that they are using reliable contraception. Before starting treatment
`with AUBAGIO, patients must be fully counseled on the potential for serious risk to the fetus.
`The patient must be advised that if there is any delay in onset of menses or any other reason to
`suspect pregnancy, they must notify the physician immediately for pregnancy testing and, if
`positive, the physician and patient must discuss the risk to the fetus. It is possible that rapidly
`lowering the plasma concentration of teriflunomide by instituting an accelerated elimination
`procedure may decrease the risk to the fetus from AUBAGIO [see Warnings and Precautions
`
`(5.3)].
`
`Upon discontinuing AUBAGIO, it is recommended that all women of childbearing potential
`undergo an accelerated elimination procedure. Women receiving AUBAGIO treatment who wish
`to become pregnant must discontinue AUBAGIO and undergo an accelerated elimination
`procedure, which includes verification of teriflunomide plasma concentrations less than 0.02
`mg/L (0.02 mcg/mL). Human plasma concentrations of teriflunomide less than 0.02 mg/L (0.02
`
`mcg/mL) are expected to have minimal risk. [see Contraindications (4.2), 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. Without an accelerated elimination
`procedure, it takes on average 8 months to reach plasma concentrations less than 0.02 mg/L,
`although because of individual variations in drug clearance it may take as long as 2 years. An
`accelerated elimination procedure could be used at any time after discontinuation of AUBAGIO.
`
`Elimination can be accelerated by either of the following procedures:
`
`
` Administration of cholestyramine 8 g every 8 hours for 11 days. If cholestyramine 8 g
`three times a day is not well tolerated, cholestyramine 4 g three times a day can be used.
`
`
` Administration of 50 g oral activated charcoal powder every 12 hours for 11 days.
`
`
`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 AUBAGIO treatment.
`
`5.4 Bone Marrow Effects/Immunosuppression Potential/Infections
`White Blood Cell (WBC) count decrease
`A mean decrease 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 AUBAGIO. 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 < 1.5x109/L was observed in 10% and 15% of patients on AUBAGIO 7
`
`Reference ID: 3188314
`
`Page 5 of 27
`
`

`

`
`
` NDA 202992 – FDA Approved Labeling Text dated September 12, 2012
`
`mg and 14 mg, respectively, compared with 5% of patients on placebo; lymphocyte count
`<0.8x109/L was observed in 7% and 10% of patients on AUBAGIO 7 mg and 14 mg,
`respectively, compared with 5% of patients on placebo. No cases of serious pancytopenia were
`reported in premarketing clinical trials of AUBAGIO but rare cases of pancytopenia,
`agranulocytosis, and thrombocytopenia have been reported in the postmarketing setting with
`leflunomide. A similar risk would be expected for teriflunomide [see Clinical Pharmacology
`
`(12.3)]. Obtain a complete blood cell count (CBC) within 6 months before the initiation of
`treatment with AUBAGIO. Further monitoring should be based on signs and symptoms
`
`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 AUBAGIO
`and using an accelerated elimination procedure. Reassess the benefits and risks prior to
`resumption of therapy. Instruct patients receiving AUBAGIO to report symptoms of infections to
`a physician.
`
`AUBAGIO 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 AUBAGIO, no overall increase in the risk of serious infections
`
`was observed with teriflunomide 7 mg (1.4%) or 14 mg (2.2%) compared to placebo (2.1%).
`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 post-marketing 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 AUBAGIO, cytomegalovirus hepatitis reactivation has been observed.
`
`In clinical studies with AUBAGIO, cases of tuberculosis have been observed. Prior to initiating
`AUBAGIO, screen patients for latent tuberculosis infection with a tuberculin skin test.
`AUBAGIO has not been studied in patients with a positive tuberculosis screen, and the safety of
`AUBAGIO in individuals with latent tuberculosis infection is unknown. For patients testing
`positive in tuberculosis screening, treat by standard medical practice prior to therapy with
`AUBAGIO.
`
`
`Vaccination
`
`No clinical data are available on the efficacy and safety of vaccinations in patients taking
`AUBAGIO. Vaccination with live vaccines is, however, not recommended. The long half-life of
`AUBAGIO should be considered when contemplating administration of a live vaccine after
`stopping AUBAGIO.
`
`Malignancy
`
`
`Reference ID: 3188314
`
`Page 6 of 27
`
`

`

`
`
` NDA 202992 – FDA Approved Labeling Text dated September 12, 2012
`
`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 AUBAGIO 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 AUBAGIO.
`
`5.5 Peripheral Neuropathy
`In placebo-controlled studies, peripheral neuropathy, including both polyneuropathy and
`mononeuropathy (e.g., carpal tunnel syndrome), was reported more frequently in patients taking
`AUBAGIO than in patients taking placebo. In one 108-week placebo-controlled study in 1086
`patients with multiple sclerosis, the incidence of peripheral neuropathy confirmed by nerve
`conduction studies was 1.2% (4 patients) and 1.9% (6 patients) on 7 mg and 14 mg of
`AUBAGIO, respectively, compared with 0% on placebo. Treatment was discontinued in 2
`patients with polyneuropathy, one on each dose; one of them recovered following treatment
`discontinuation. The other cases of peripheral neuropathy did not resolve with continued
`treatment. There have also been reports of peripheral neuropathy 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 AUBAGIO develops symptoms consistent with
`peripheral neuropathy, such as bilateral numbness or tingling of hands or feet, consider
`discontinuing AUBAGIO therapy and performing an accelerated elimination procedure [see
`Warnings and Precautions (5.3)].
`
`5.6 Acute Renal Failure
`
`
`In placebo-controlled trials, 10 of 844 (1.2%) of AUBAGIO-treated subjects had transient acute
`renal failure with a creatinine measurement increased by 100% or more of their baseline serum
`
`creatinine value, compared to 0 of 421 placebo-treated subjects. Seven of the 10 subjects had a
`nadir creatinine clearance less than 30 cc/minute. In each of the 10 subjects, the serum creatinine
`level was normal on the next reported measurement (6-48 days from the increase in creatinine)
`with continued teriflunomide use. These increased creatinine measurements occurred between 12
`
`weeks and 2 years after first dose of teriflunomide. Of the 6 subjects with available serum
`
`potassium measurements, 3 (50%) had hyperkalemia (measurements of 6.7, >7.3, and >7.3
`mmol/L). No associated symptoms were documented.
`
`AUBAGIO causes increases in renal uric acid clearance with mean decreases in serum uric acid
`of 20-30%. Acute uric acid nephropathy is a likely explanation for the cases of transient acute
`renal failure seen with teriflunomide. Although symptoms associated with acute uric acid
`nephropathy, such as loin pain or flank pain, were not reported, this information was not
`systematically collected. No inciting factors, such as dehydration, exercise, or increase in
`physical activity in the 30 days prior to the adverse event were reported, but this information was
`not systematically collected.
`
`5.7 Hyperkalemia
`
`Reference ID: 3188314
`
`Page 7 of 27
`
`

`

`
`
` NDA 202992 – FDA Approved Labeling Text dated September 12, 2012
`
`In placebo-controlled trials, treatment-emergent hyperkalemia >7.0 mmol/L occurred in 8/829
`(1.0%) of teriflunomide-treated subjects, compared to 1/414 (0.2%) of placebo-treated subjects.
`Two teriflunomide-treated subjects had hyperkalemia >7.0 mmol/L with acute renal failure.
`Possible causes in other cases were not documented. Check serum potassium level in
`AUBAGIO-treated patients with symptoms of hyperkalemia or with acute renal failure.
`
`5.8 Skin Reactions
`Rare cases of Stevens-Johnson syndrome and toxic epidermal necrolysis have been reported in
`patients with rheumatoid arthritis receiving leflunomide. A similar risk would be expected for
`teriflunomide [see Clinical Pharmacology (12.3)]. If a patient taking AUBAGIO develops any of
`
`these conditions, stop AUBAGIO therapy and perform an accelerated elimination procedure [see
`Warnings and Precautions (5.3)].
`
`
`5.9 Blood Pressure Increase
`In placebo-controlled studies, mean change from baseline in systolic blood pressure was 2.9
`mmHg and 2.7 mmHg for AUBAGIO 7 mg and 14 mg, respectively, and -1.3 mmHg for
`placebo. The change from baseline in diastolic blood pressure was 1.4 mmHg and 1.3 mmHg for
`
`AUBAGIO 7 mg and 14 mg, respectively, and -0.9 mmHg for placebo. Hypertension was
`reported as an adverse reaction in 4% of patients treated with 7 mg or 14 mg of AUBAGIO,
`compared with 2% on placebo. Check blood pressure before start of AUBAGIO treatment and
`periodically thereafter. Elevated blood pressure should be appropriately managed during
`treatment with AUBAGIO.
`
`5.10 Respiratory Effects
`Interstitial lung disease and worsening of pre-existing interstitial lung disease have been reported
`during treatment with leflunomide. A similar risk would be expected for teriflunomide [see
`Clinical Pharmacology (12.3)]. Interstitial lung disease may be fatal. Interstitial lung disease
`may occur acutely at any time during therapy and has 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 the 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)].
`
`
`
`
`5.11 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 AUBAGIO 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
`
`Reference ID: 3188314
`
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` NDA 202992 – FDA Approved Labeling Text dated September 12, 2012
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`
`
` of disease activity if the patient had been responding to AUBAGIO 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 (4.1) and Warnings and Precautions (5.1)]
`
` Bone Marrow Effects/Immunosuppression Potential/Infections [see Warnings and
`Precautions (5.4)]
`
`
` Peripheral Neuropathy [see Warnings and Precautions (5.5)]
`
`
` Acute Renal Failure [see Warnings and Precautions (5.6)]
`
`
` Hyperkalemia [see Warnings and Precautions (5.7)]
`
`
` Serious Skin Reactions [see Warnings and Precautions (5.8)]
`
`
` Blood Pressure Effects [see Warnings and Precautions (5.9)]
`
`
` Respiratory Effects [see Warnings and Precautions (5.10)
`
`
`
`The most frequent adverse reactions for AUBAGIO (incidence ≥10% and ≥2% greater than
`placebo) in the placebo-controlled studies were ALT increased, alopecia, diarrhea, influenza,
`nausea, and paresthesia. Alopecia was the most common cause of discontinuation because of
`adverse events in controlled clinical studies as compared to placebo (0.5% and 1.4% of patients
`on AUBAGIO 7 mg and 14 mg, respectively, and 0% on placebo).
`
`If desired, teriflunomide can be rapidly cleared from the body by the use of an accelerated
`elimination procedure [see Warnings and Precautions (5.3)].
`
`
`
`6.1 Clinical Trial Experience
`
`A total of 844 patients on 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
`MS (RMS). Approximately 72% of patients were female and the mean age was 38 years.
`
`Study 1 was a 108-week placebo-controlled clinical study in 1086 RMS patients treated with
`teriflunomide 7 mg (n=368), teriflunomide 14 mg (n=358), or placebo (n=360).
`
`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.
`
`
`Table 1 Adverse Reactions in Study 1 (occurring in ≥ 2% of patients, and reported for
`teriflunomide 7 mg or 14 mg at ≥ 2% higher rate than for placebo)
`
`
`
`
`
`
`
`Teriflunomide
`
`
`
`
`
`
`Reference ID: 3188314
`
`Page 9 of 27
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` NDA 202992 – FDA Approved Labeling Text dated September 12, 2012
`
`PRIMARY SYSTEM ORGAN CLASS
`Preferred Term (%)
`
`INFECTIONS AND INFESTATIONS
`
`Influenza
`Upper respiratory tract infection
`Bronchitis
`Sinusitis
`Cystitis
`
`Gastroenteritis viral
`Oral herpes
`
`
`BLOOD AND LYMPHATIC SYSTEM
`
`DISORDERS
`
`
`Neutropenia
`Leukopenia
`
`
`IMMUNE SYSTEM DISORDERS
`Seasonal allergy
`
`
`PSYCHIATRIC DISORDERS
`Anxiety
`
`
`NERVOUS SYSTEM DISORDERS
`Headache
`Paraesthesia
`
`Sciatica
`Burning sensation
`Carpal tunnel syndrome
`
`
`
`
`EYE DISORDERS
`Vision blurred
`
`Conjunctivitis
`
`
`CARDIAC DISORDERS
`Palpitations
`
`
`VASCULAR DISORDERS
`Hypertension
`
`
`
`GASTROINTESTINAL DISORDERS
`Diarrhoea
`Nausea
`Abdominal pain upper
`
`
`Toothache
`Abdominal distension
`
`
`
`14 mg
`(N=358)
`
`
`12%
`
`9%
`
`8%
`
`6%
`
`4%
`
`4%
`
`4%
`
`
`
`4%
`
`1%
`
`
`
`3%
`
`
`
`4%
`
`
`
`19%
`
`10%
`
`3%
`
`3%
`
`3%
`
`
`
`3%
`
`1%
`
`
`
`2%
`
`
`
`4%
`
`
`
`18%
`
`14%
`
`6%
`
`4%
`
`1%
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`7 mg
`(N=368)
`
`
`9%
`
`9%
`
`5%
`
`4%
`
`2%
`
`2%
`
`2%
`
`
`
`2%
`
`2%
`
`
`
`2%
`
`
`
`3%
`
`
`
`22%
`
`9%
`
`1%
`
`2%
`
`1%
`
`
`
`3%
`
`3%
`
`
`
`3%
`
`
`
`4%
`
`
`
`15%
`
`9%
`
`5%
`
`4%
`
`2%
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Placebo
`(N=360)
`
`
`10%
`
`7%
`
`6%
`
`4%
`
`1%
`
`1%
`
`2%
`
`
`
`0.3%
`
`0.3%
`
`
`
`1%
`
`
`
`2%
`
`
`
`18%
`
`8%
`
`1%
`
`1%
`
`0.3%
`
`
`
`1%
`
`1%
`
`
`
`1%
`
`
`
`2%
`
`
`
`9%
`
`7%
`
`4%
`
`2%
`
`0.3%
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Reference ID: 3188314
`
`Page 10 of 27
`
`

`

`
`
` NDA 202992 – FDA Approved Labeling Text dated September 12, 2012
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Teriflunomide
`
`7 mg
`14 mg
`(N=358)
`(N=368)
`
`
`
`
`
`
`Placebo
`(N=360)
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` 13%
`
` 3%
`
` 3%
`
`
`
`4%
`
`3%
`
`
`
`14%
`
`3%
`
`3%
`
`2%
`
`2%
`
`1%
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` 3%
`
` 1%
`
` 2%
`
`
`
`3%
`
`2%
`
`
`
`7%
`
`1%
`
`1%
`
`1%
`