HIGHLIGHTS OF PRESCFIIBING INFORMATION
`
`T DOSAGE FORMS AND STRENGTHS T:
`
`These highlights do not Include all the information needed to use AUBAGlO°
`safely and effectively. See full prescribing Information for AUBAGIO.
`AUBAGIO“ (terifiunomide) tablets, for oral use
`
`WARNING: HEPATOTOXICITY and RISK OF TERATOGENICTTY
`
`
`
`See full prescribing Information for complete boxed wamlng
`Hepatotoxiclty
`Severe liver injury including tatal 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 terltlunomide. Obtain transamlnase and bllirubln 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 ma|or birth defects if used
`d“''“9 P'°9'“"'°V- AU3‘°'° '5 °°"''°'"‘‘'°a‘°°'
`"1 P'°9"°"' "°'“°" °'
`women of childbearing potential who are not using reliable contraception.
`Pregnancy must be avoided during AUBAGIO treatment. (4.2, 5.2)
`
`RECENT MAJOR CHANGES
`
`Warnings and Precautions (5)
`
`10/2014
`
`Te INDICATIONS AND USAGE Te
`AUBAGIO is a pyrimidine synthesis inhibitor indicated for the treatment of patients with
`relapsing forms of multiple sclerosis (1)
`
`7 mg and I4 m9 I“”“°°aI°d Iab'°I5 I3)
`CONTRAINDICATIONS
`° 3°V°'9 hepatic ‘Impairment (4-1: 5-1)
`:
`.3,
`T WARNINGS AND PRECAUTIONS T
`o Elimination of AUBAGIO can be accelerated by administration at cholestyramine
`or activated charcoal for 11 days (5.3)
`o AUBAGIO may decrease WBC. A recent CBC should be available before starting
`AUBAGIO. Monitor for signs and symptoms of infection. Consider suspending
`treatment with AUBAGIO in case of serious infection. Do not start AUBAGIO in
`patients with active infections (5.4)
`o if patient develops symptoms consistent with peripheral neuropathy, evaluate
`patient and consider discontinuing AUBAGIO (5.5)
`0 Stop AUBAGIO if patient develops Stevens-Johnson syndrome or toxic epidennai
`necroiysis (5.6)
`o AUBAGIO may increase blood pressure. Measure blood pressure at treatment
`initiation and monitor blood pressure during treatment (5.7)
`T ADVERSE REACTIONS T
`Most common adverse reactions (210% and 22% greater than placebo): headache,
`diarrhea, nausea, aiopecia, increase in ALT (6)
`
`To report SUSPECTED ADVERSE REACTIONS contact Genzyme Corporation at
`1_3m_745_4447 0, FDA at 1_8oo_FDA_1o88 or ,da_goV/medwmm
`_
`DRUG INTERACTIONS
`0 Drugs metabolized by CYP2C8 and 0AT3 transporters: Monitor patients because
`teriiiunomide may increase exposure of these drugs (7)
`o Teritlunomide may increase exposure of ethinyiestradioi and ievonorgestrel.
`Choose an appropriate oral contraceptive (7)
`0 Drugs metabolized by CYP1A2: Monitor patients because teriflunomide may
`decrease exposure of these dmgs (7)
`o Wariarin: Monitor INR as teriflunomide may decrease INR (7)
`0 Drugs metabolized by BCRP and OATP1B1/B3 transporters: Monitor patients
`because teritiunomide may increase exposure of these drugs (7)
`o Rosuvastatin: The dose of rosuvastatin should not exceed 10 mg once daily in
`patients taking AUBAGIO (7)
`
`See 17 for PATIENT COUNSELING INFORMATION and FDA-approved Medication
`jj DOSAGE AND ADMINISTRATION jj Guide
`7 mg or 14 mg orally once daily, with or without food. (2)
`
`Revised: 10/2014a
`
`FULL PRESCRIBING INFORMATION: CONTENTS‘
`
`1
`2
`3
`4
`
`WARNING: HEPATOTOXICITY and RISK OF TERATOGENICITY
`Hepatotoxicity
`Risk of Teratogengcny
`INDICATIONS AND USAGE
`DOSAGE AND ADMINISTRATION
`DOSAGE FORMS AND STRENGTHS
`CONTRAINDICATIONS
`4.1.
`Severe Hepatic Impainnent
`4.2
`Patients Who are Pregnant or Women of Chiidbearing Potential Not Using
`Reliable Contraception
`Current treatment with leflunomide
`4.3.
`5 WARNINGS AND PRECAUTIONS
`
`Hepatotoxioity
`Use in Women ot childbearing Potential
`Procedure for Accelerated Elimination oi Teritlunomide
`
`Bone Marrow Effects/lmmunosuppression Potentiavinfections
`Peripheral Neuropathy
`Skin Reactions
`Increased Blood Pressure
`
`5.1
`5.2
`5.3
`
`5.4
`5.5
`5.6
`5.7
`
`5.8
`5.9
`
`6
`
`ADVERSE REACTTONS
`
`7
`8
`
`Clinical Trials Experience
`6.1
`DRUG INTERACTIONS
`USE IN SPECIFIC POPULATIONS
`3-1
`PFGQMHCY
`5-3
`Nursing M°ih°'$
`5-4
`P°d‘a""° U39
`3-5
`G°"a‘"° U59
`3-5
`H°paf'° "“paI"“°"I
`8-7
`R°”aI I'"paI""9"I
`10 OVERDOSAGE
`11
`DESCRIPTION
`12
`CLINICAL PHARMACOLOGY
`
`12.1 Mechanism of Action
`12.2
`Pharrnacodynamics
`12.3
`Pharmacokinetics
`
`13 NONCLINICAL TOXICOLOGY
`13.1
`Carcinogenesis, Mutagenesis, impairment ct Fertility
`CLINICAL STUDIES
`14
`16 HOW SUPPLIED/STORAGE AND HANDLING
`
`Respiratory Effects
`Concomitant Use with
`Therapies
`
`immunosuppressive or
`
`immunomodulating
`
`17
`
`PATIENT COUNSELING INFORMATION
`‘Sections or subsections omitted from the full prescribing intonnation are not
`listed
`
`Page 1 0f 7
`
`‘
`
`Biogen Exhibit 2073
`Coalition V. Biogen
`IPR2015—01993
`
`

`

`FULL PRESCRIBING INFORMATION
`
`WARNING: HEPATOTOXICITY and RISK OF TERATOGENICITY
`
`Hepatotoxlclty
`Severe liver Injury including fatal liver failure has been reported In patients
`treated with letlunomide, which is Indicated for rheumatoid arthritis. A similar
`risk would be expected for teriflunomide because recommended doses of
`teriilunomide and letlunomide result In a similar range of plasma concentra-
`tions of teriflunomide. Concomitant use of AUBAGIO with other potentially
`hepatotoxic drugs may Increase the risk of severe liver injury. Obtain transami-
`nase and billrubln 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. )]. AUBAGIO is
`contraindicated in patients with severe hepatic Impairment [see Contraindi-
`cations (4.1)]. Patients with pre-existing liver dlsse may be at increased risk
`of developing elevated serum transamlnases when taking AUBAGIO.
`Risk of Teratogenlclty
`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 childbring 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 (52), and Use in Specific Populations (8.1)].
`
`1
`INDICATIONS AND USAGE
`AL|iBAG|0" is incficated for the treatment of patients with relapsing toms of multiple
`sc erosis.
`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 safeg
`0 Obtain transaminase and bilirubin levels within 6 months before initiation ofAUBAGlO
`therapy. Monitor ALT levels at least monthly for six months after starting AUBAGIO
`[see Wamrigs and Precautions (5.1)].
`0 Obtain a complete blood cell count (CBC) within 6 months before the initiation oi
`treatment with AUBAGIO. Further monitoring should be based on signs and symp-
`toms oi infection [see Warnings and Precautions (5.4)).
`o Prior to initiating AUBAGIO, screen patients for latent tuberculosis infection with a
`tuberculin skin test or blood test for myoobacterium tuberculosis infection [see
`Warnings and Precautions (5.4)).
`0 Check blood pressure before start of AUBAGIO treatment and periodically thereafter
`[see Wamrigs and Precautions (5.01.
`DOSAGE FORMS AND STRENGTHS
`3
`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 oi teriilunomide.
`The 7 mg tablet is a very Iigit 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 oi tenflunomide.
`4
`CONTRAINDICATIONS
`4.1. Severe Hepatic impairment
`Patients with severe hepatic impairment see Wamings and Precautions (5.1')1.
`4.2 Patients Who are Pregnant or
`omen of childbearing Potential
`ot Using
`Reliable Contraception
`AUBAGIO may cause ietal hann when administered to a pregnant woman.
`In animal studies,
`teriilunomide has been shown to be selectively teratogenic and
`embryolethal in multiple species when administered during pregnancy at doses less than
`those used clinicaly. 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 pre nant while taking this drug, the patient should be fioprised oi the
`potential hazard to a etus. If pregnancy does occur during treatment, the
`rug should be
`immediately discontinued and an accelerated enmination 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 toidcity, for
`further evaluation and counseling [see Warnings and Precautions and Use in Specific
`Popuiafions (5.2, 8.1)].
`4.3. Current treatment with letlunomide
`Co-administration of tenflunomide with Ieflunomide is contraindicated.
`5 WARNINGS AND PRECAUTIONS
`5.1 Hepatotoxlclty
`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 teriilunomide because recommended doses of teriflunomide and
`letlunomide result in a similar range of plasma concentrations of teriflunomide. Patients
`with preexisting liver disease may be at increased risk of developing elevated senim
`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
`
`Page 2 of 7
`
`upper limit oi nonnal (ULN) before initiating treatment, should not normally be treated with
`AUBAGIO. AUBAGIO is contraindicated in patients with severe hepatic impairment [see
`Contraindcations (4.1)].
`In placebocontrclled trials, ALT greater than three times the ULN occurred in 61/1045
`(5.8%) and 62/1002 (6.2%) oi patients receiving AUBAGIO 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 oi treatment Half oi the cases retumed to
`nonnal without drug discontinuation.
`In clinical trials, ii ALT elevation was greater than
`three times the ULN on two consecutive tests, AUBAGIO was discontinued and patients
`underwent an accelerated elimination procedure [see Wamrigs and Precautions (5.3)). Of
`the patients who underwent discontinuation and accelerated elimination in controlled trials,
`half returned to nonnal or near nonnal 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 piasmapheresis and cholestyramine accelerated elimination procedure.
`AUBAGIO-induced liver injury in this patient could not be ruled out.
`Obtain serum transaminase and bilirubin levels within 6 months before initiation oi
`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 confinned. Monitor serum transaminase and biiirubin
`on AUBAGIO therapy, particularly in patients who develop symptoms suggestive oi hepatic
`dysfunction, such as unexplained nausea, vomiting, abdominal pain, fatigue, anorexia, or
`jaundice andior dark urine. If liver injury is suspected to be AUBAGIO-induced, discontinue
`AUBAGIO and start an accelerated elimination procedure [see Warnings and Precautions
`(5.3)) and monitor liver tests weekly umil nonnaiized. If AUBAGIO-induced liver injury is
`unlikely because some other probable cause has been found, resumption of AUBAGIO
`therapy may be considered.
`5.2 Use In Women of childbearing Potential
`There are no adequate and welicontroiled studies evaluating AUBAGIO in pregnant
`women. However, based on animal studies,
`teriilunomide may increase the risk oi
`teratogenic effects or fetal death when administered to a pregnant woman [see Contrain-
`dications (4.2)).
`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 it 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, it positive, the physidan 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 AUBA IO, it is recommended that all women oi 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 teriilunomide plasma concentrations
`less than 0.02 mg/L (0.02 mcg/mL). Human plasma concentrations of teriilunomide less
`than 0.02 mg/I. (0.02 mcgimL) are expected to have minimal risk [see Contraindications
`(4.2), Wamhgs and Precautions (5.3) and Use in Specific Populations (8.1)).
`5.3 Procedure for Accelerated Elimination of Teriflunomlde
`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/I., 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 discon-
`ures:
`gnuation of AUBAGIO. Elimination can be accelerated by either of the folowing proce-
`0 Administration of cholestyramine 8 g every 8 hours for 11 days. If cholestyramine 8
`use .
`gethreedtimes a day is not well tolerated, cholestyramine 4 g three times a day can
`0 Administration of 50 g oral activated charcoal powder every 12 hours for 11 days.
`It either elimination procedure is poorly tolerated, treatment days do not need to be
`consecutive unless there is a need to lower teriilunomide plasma concentration rapidy.
`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 it the patient had been responding to AUBAGIO treatment
`5.4 Bone Marrow Ettectsllmmunosuppression Potential/Infections
`White Blood Cell
`BC count decrease
`(WBC) count of approximately 15% (mainly
`A mean decrease in white blood cell
`neutrophils and lymphocytes) and in platelet count of approximately 10% was observed
`in placebo-controlled trials with 7 mg and 14 mg of AUBAGIO compared to baseline. The
`decrease in mean WBC count occuned during the first 6 weeks and WBC count remained
`low during treatment.
`In placebo-controlled studies, neutrophil court < 1.5x10°/L was
`observed in 12% and 16% of patients receiving AUBAGIO 7 mg and 14 mg, respectively,
`compared with 7% of patients receiving placebo;
`lymphocyte count <0.8x10°/L was
`observed in 10% and 12% of patients receiving AUBAGIO 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 AUBAGIO but rare cases of pancytopenia,
`agranulocytosis, and thrombocytopenia have been reported in the postmarketing setting
`with lefluncmide. A similar risk would be expected for AUBAGIO [see Ciinii Pharma-
`ooiogy (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 lniection /Tuberculosis Screening
`the
`Patients with active acute or chronic infections should not start treatment until
`infeciion(s) is resolved.
`it a patient develops a serious infection consider suspending
`treatment with AUBAGIO and using an accelerated eimination 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, uncontroled infections. Medications like AUBAGIO that have immu-
`nosuppression 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 AUBAGIO 7 mg (2.2%) or 14 mg (2.7%) compared to
`placebo (2.2%). However, one fatal case of ldebsieila pneumonia sepsis occurred in a
`patient taking AUBAGIO 14 mg for 1.7 years. Fatal infections have been reported in the
`post-marketing setting in patients receiving leflunomide, espedally Pneumocysfis jimveci
`pneumonia and aspergillosis. Most of the reports were confounded by concomitant
`inmunosuppressant therapy and/or comorbid illness which,
`in addition to rheumatoid
`disease, may predispose patients to infection. In cfinical stucfies with AUBAGIO, cyto-
`megalovirus hepatitis reactivation has been observed.
`In cliriicai studies with AUBAGIO, cases of tuberculosis have been observed. Prior to
`initiating AUBAGIO, screen patients for latent tuberculosis infection with a tuberculin skin
`test or with a blood test for mycobacterium tuberculosis infection. AUBAGIO has not been
`studed in patients with a positive tuberculosis screen, and the safety of AUBAGIO in
`hdividuals with latent tubercilosis infection is unknown. For patients testing positive in
`tiberculosis screenhg, treat by standard medical practice prior to therapy with AUBAGIO.
`Vaccinatbn
`No cfinical data are available on the efficacy and safety of live vaccinations in patients
`taking AUBAGIO. Vaccination with live vaccines is not recommended. The long half-life of
`AUBAGIO should be considered when contemplatng administration of a live vaccine after
`stopping AUBAGIO.
`Mam!
`The risk of malignancy, paniculariy Iymphoproliferafive disorders, is ‘ncreased with the use
`of some immunosippressive medications. There is a potential for immunosuppression with
`AUBAGIO. 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), occurred more frequently ‘:1 patients
`taking AUBAGIO 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 AUBAGIO, respectively, compared with 0.4%
`receiving placebo (4 patients). Treatment was discontinued in 0.7% (8 patients) with
`confirmed peripheral neuropathy (3 patients receiving AUBAGIO 7 mg and 5 patients
`receiving AUBAGIO 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 receivhg lefluriomide.
`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 pertonning an accelerated elimination
`procedure [see Wairrlngs and Precautions (5.3)].
`5.6 Skin Reactions
`Rare cases of Stevens-Johnson syndrome and toxic epidermal necrolysis have been
`reported in patients with rheumatoid arthritis receivhg leflunomide. A similar risk would be
`expected for AUBAGIO [see Cliniml Pharmacology (12.3)). If a patient taking AUBAGIO
`develops any of these conditions, stop AUBAGIO therapy and perfonri an accelerated
`elimination procedure [see Warnings and Premutions (5.3)].
`5.7
`Increased Blood Pressure
`In placebo-controlled stucfies, the mean change from baseline to the end of study in
`systofic blood pressure was +2.8 mmHg and +2.7 mmHg for AUBAGIO 7 mg and 14 mg,
`respectively, and -0.6 mmHg for placebo. The change from baseline in dastolic blood
`pressure was +1.4 mmHg and +1.9 mmHg for AUBAGIO 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 AUBAGIO compared with 1.8% for placebo. Check
`blood pressure before start of AUBAGIO treatment and penocfically thereafter. Elevated
`blood pressure should be appropriately managed during treatment with AUBAGIO.
`5.8 Respiratory Effects
`Interstitial lung disease and worsening of pre-eidsting interstitial lung disease have been
`reported during treatment with leflmomide. A similar risk would be expected forAUBAG|O
`[see Clinical Pharmacology (12.3)). Interstitial lung iisease may be fatal. Interstitial lung
`disease may occur acutely at any time during therapy and has a variable clinical
`presentation. New onset or worseniig 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)].
`5.9 Concomitant Use with immunosuppressive or lmmunomodulatlng Therapies
`Co-admiriistration with antineoplastic, or immunosuppressive therapies used for treatment
`of miltiple sclerosis has not been evaluated. Safety studies in which AUBAGIO was
`concomitantly administered with other immune modilating therapies for up to one year
`(interferon beta, glatiramer acetate) did not reveal any specific safety concems. The long
`tenn safety of these combinations in the treatment of miltiple sclerosis has not been
`estabished.
`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 elinination procedure may decrease this risk, but may
`also potentialy result in return of disease activity if the patient had been responding to
`AUBAGIO treatment [see Wamrigs and Precautions (5.8)].
`
`Page 3 of 7
`
`ADVERSE REACTIONS
`6
`The following serious adverse reactions are described elsewhere in the prescribing
`inionnation:
`o Hepatotoxicity [see Conuaindbations (4.1) and Warnings and Precaufions (5.1)]
`o Bone Manow Efiectsllmmunosuppression Potentialllnfections [see Warnings and
`Precautions (5.4))
`0 Peripheral Neuropathy [see Warnings and Precautions (5.5))
`0 Skin Reactions [see Wamrrgs and Precautions (5.6))
`0 Increased Blood Pressure [see Wamhgs and Precautions (5.7)]
`o Respiratory Effects [see Wamrigs and Precautions (5.8)]
`6.1 Clinical Trials Experience
`Because clinical trials are conducted under widely varying conditions, adverse reaction
`rates observed in the ciinical trials of a drug cannot be directly compared to rates in the
`clinical trials of another drug and may not reflect the rates observed in clinical practice.
`A total of 2047 patients receiving AUBAGIO (7 m or 14
`once daily) constituted the
`safety population in the pooled analysis of pla
`contro
`studies in patients with
`relapsing tonne of multiple sclerosis; of these, 71% were female. The average age was
`37 years.
`Table 1 lists adverse reactions in placebo-controlled trials with rates that were at least 2%
`for AUBAGIO patients and also at least 2% above the rate in placebo patients. The most
`common were headache, an increase in ALT, diarrhea, alopeda, and nausea. The adverse
`reaction most commonly associated with discontiiuation was an increase in ALT (3.3%,
`2.6%, and 2.3% of all patients in the AUBAGIO 7 mg, AUBAGIO 14 mg, and placebo
`treatment arms, respectively).
`Table 1. Adverse Reactions In Pooled Placebo-controlled Studies In Patients
`with Relaging Forms of Multiple Sclerosis
`AUBAGIO
`AUBAGIO
`
`Adverse Reaction
`Headache
`Increase in Alanine
`amiriotransferase
`Diarrhea
`Alopecia
`Nausea
`Paresthesia
`Arthraigia
`Neutropenia
`Hypertension
`
`7 nag
`(N=1
`18%
`
`5)
`
`14 m&
`(N=10
`16%
`
`)
`
`Placebo
`(N=997)
`15%
`
`13%
`13%
`10%
`8%
`8%
`8%
`4%
`3%
`
`15%
`14%
`13%
`11%
`9%
`6%
`6%
`4%
`
`9%
`8%
`5%
`7%
`7%
`5%
`2%
`2%
`
`Cardiovascular deaths
`Four cardiovascular deaths, including three sudden deaths, and one myocardial infarction
`in a patient with a history of hyperlipidemia and hypertension were reported among
`approidmately 2600 patients exposed to AUBAGIO in the premarketing database. These
`cardiovascular deaths occurred during uncontrolled extension studies, one to nine years
`after initiation of treatment. A relationship between AUBAGIO and cardiovascular death
`has not been established.
`Acute Renal Failure
`In placebo-controlled studies, creathine values increased more than 100% over baseline
`in 8/1045 (0.8%) patients in the 7 mg AUBAGIO group and 6/1002 (0.6%) patients "n the
`14 mg AUBAGIO groip versus 4/997 (0.4%) patients in the placebo group. These
`elevations were transient. Some elevations were accompanied by hypeikalemia.
`AUBAGIO may cause acute uric acid nephropathy with transient acute renal faiure
`because AUBAGIO increases renal uric acid clearance.
`hatemia
`In clinical trials, 18% of AUBAGIO-treated patients had hypophosphatemia with serun
`phosphorus levels of at least 0.6 mmol/L, compared to 7% of placebo-treated patients; 4%
`of AUBAGIO-treated patients had hypophosphatemia with serum phosphorus levels at
`least 0.3 mmol/L but less than 0.6 mmol/L, compared to 0.8% of placebo-treated patients.
`No patient in any treatment group had a serum phosphorus below 0.3 mrnoVL.
`7
`DRUG INTERACTIONS
`Effect of AUBAGIO on CYP2C8 substrates
`Teriflunomide is an inhibitor of CYP2C8 ‘n vivo. In patients taking AUBAGIO, exposure of
`drugs metabolized by CYP2C8 (e.g., paclitaxel, piogitazone, repaglinide, rosiglitazone)
`may be increased. Monitor these patients and adjust the dose of the concomitant dnrg(s)
`metabolized by CYP2C8 as required [see Clinical Pharmacology (12.3)).
`Effect of AUBAGIO on warfarii
`Coadmhistration of AUBAGIO with warfarin requires close monitoring of the intemational
`nonnalized ratio (INR) because AUBAGIO may decrease peak INR by approximately 25%.
`Effect of AUBAGIO on oral contraceptives
`AUBAGIO may increase the systemic exposures of ethinylestradiol and levonorgestrel.
`Consideration should be given to the type or dose of contraceptives used in combiiation
`with AUBAGIO [see Clinil Pharmacology (12.3)).
`Effect of AUBAGIO on CYP1A2 substrates
`Teriflunomide may be a weak inducer of CYP1A2 in vivo. In patients taking AUBAGIO,
`exposure of drugs metabolized by CYP1A2 (e.g., alosetron, duloxetine,
`theophyiline,
`tizanidine) may be reduced. Monitor these patients and adjust the dose of the concomitant
`drug(s) metabolized by CYP1A2 as required [see Clinical Pharrmcobgy (12.3)).
`Effect of AUBAGIO on organic anion transgrter 3 (OAT3) substrates
`Teriflunomide inhibits the activity of OAT3 in vivo. In patients taking AUBAGIO, exposure
`of drugs which are OAT3 substrates (e.g., cefaclor, cimetidine, dprofloxacin, penicillin G,
`ketoprofen, furcsemide, methotrexate, zidovudine) may be increased. Monitor these
`patients and arjust the dose of the concomitant drug(s) which are OAT3 sibstrates as
`required [see Clinical Pharmacology ( 12.3)].
`
`

`

`Effect of AUBAGIO on BCRP and organic anion transporting polypeptide B1 and B3
`(OATP1B1/1B3) substrates
`Teriflunomide inhibits the activity of BCRP and OATP1B1/1B3 in vivo. For a patient taking
`AUBAGIO, the dose of rosuvastatin should not exceed 10 mg once daily. For other
`substrates of BCRP (e.g., mitoxantrone) and drugs in the OATP family (e.g., methotrexate,
`rifampin), especially HMG-Co reductase inhibitors (e.g., atorvastatin, nateglinide, pravas-
`tatin, repaglinide, and simvastatin), consider reducing the dose of these drugs and monitor
`patients closely for signs and symptoms of increased exposures to the drugs while patients
`are taking AUBAGIO [see Clinical Pharmacology (12.3)].
`8
`USE IN SPECIFIC POPULATIONS
`8.1 Pregnancy
`Pregnancy Category X [see Contraindications (4.2) and Warnings and Precautions (5.2)]
`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 embryofetal death
`were observed at doses not associated with maternal
`toxicity. Adverse effects on
`embryofetal development were observed following dosing at various stages throughout
`organogenesis. Maternal plasma exposure at
`the no-effect
`level (1.0 mg/kg/day) for
`embryofetal 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 embryofetal death at doses
`associated with minimal maternal toxicity. Maternal plasma exposure at the no-effect dose
`(1.0 mg/kg/day) for embryofetal 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 pre- 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 devel-
`opmental toxicity. At recommended doses in humans, teriflunomide and leflunomide result
`in a similar range of plasma concentrations of teriflunomide.
`Use in Males
`AUBAGIO is detected in human semen. Animal studies to specifically evaluate the risk of
`male-mediated fetal toxicity have not been conducted. To minimize any possible risk, men
`not wishing to father a child and their female partners should use reliable contraception.
`Men wishing to father a child should discontinue use of AUBAGIO and undergo an
`accelerated elimination procedure to decrease the plasma concentration of teriflunomide
`to less than 0.02 mg/L (0.02 mcg/mL) [see Warnings and Precautions (5.3)].
`Pregnancy Registry
`Although AUBAGIO is contraindicated in pregnancy, a pregnancy registry has been
`established to monitor
`fetal outcomes of pregnant women exposed to AUBAGIO.
`Physi