___________________ CONTRAINDICATIONS ___________________
`Known hypersensitivity to dimethyl fumarate or any of the excipients of
`TECFIDERA. (4)
` _______________ WARNINGS AND PRECAUTIONS _______________
`• Anaphylaxis and angioedema: Discontinue and do not restart TECFIDERA
`if these occur. (5.1)
`• Progressive multifocal leukoencephalopathy (PML): Withhold
`TECFIDERA at the first sign or symptom suggestive of PML. (5.2)
`• Lymphopenia: Obtain a CBC including lymphocyte count before initiating
`TECFIDERA, after 6 months, and every 6 to 12 months thereafter.
`Consider interruption of TECFIDERA if lymphocyte counts <0.5 x 109/L
`persist for more than six months. (5.3)
` ___________________ ADVERSE REACTIONS ___________________
`Most common adverse reactions (incidence ≥10% and ≥2% placebo) were
`flushing, abdominal pain, diarrhea, and nausea. (6.1)
`
`To report SUSPECTED ADVERSE REACTIONS, contact Biogen at 1-
`800-456-2255 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
` ______________ USE IN SPECIFIC POPULATIONS _______________
`Pregnancy: based on animal data, may cause fetal harm. (8.1)
`
`See 17 for PATIENT COUNSELING INFORMATION and FDA-
`approved patient labeling
`
`Revised: 2/2016
`
`8.5 Geriatric Use
`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
`13.2 Animal Toxicology and/or Pharmacology
`14 CLINICAL STUDIES
`16 HOW SUPPLIED/STORAGE AND HANDLING
`17
`PATIENT COUNSELING INFORMATION
`
`*Sections or subsections omitted from the full prescribing information are not
`listed.
`
`HIGHLIGHTS OF PRESCRIBING INFORMATION
`These highlights do not include all the information needed to use
`TECFIDERA safely and effectively. See full prescribing information for
`TECFIDERA.
`
`TECFIDERA® (dimethyl fumarate) delayed-release capsules, for oral use
`Initial U.S. Approval: 2013
` _________________ RECENT MAJOR CHANGES _________________
`Warnings and Precautions, PML (5.2)
`2/2016
`
` __________________ INDICATIONS AND USAGE _________________
`TECFIDERA is indicated for the treatment of patients with relapsing forms of
`multiple sclerosis (1)
` _______________ DOSAGE AND ADMINISTRATION ______________
`• Starting dose: 120 mg twice a day, orally, for 7 days (2.1)
`• Maintenance dose after 7 days: 240 mg twice a day, orally (2.1)
`• Swallow TECFIDERA capsules whole and intact. Do not crush, chew, or
`sprinkle capsule contents on food (2.1)
`• Take TECFIDERA with or without food (2.1)
` ______________ DOSAGE FORMS AND STRENGTHS _____________
`Delayed-release capsules: 120 mg and 240 mg (3)
`
`
`
`
` 1
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`
`INDICATIONS AND USAGE
`2
`DOSAGE AND ADMINISTRATION
`2.1 Dosing Information
`2.2 Blood Test Prior to Initiation of Therapy
`DOSAGE FORMS AND STRENGTHS
`3
`CONTRAINDICATIONS
`4
`5 WARNINGS AND PRECAUTIONS
`5.1 Anaphylaxis and Angioedema
`5.2
`Progressive Multifocal Leukoencephalopathy
`5.3 Lymphopenia
`5.4
`Flushing
`ADVERSE REACTIONS
`6.1 Clinical Trials Experience
`USE IN SPECIFIC POPULATIONS
`8.1
`Pregnancy
`8.3 Nursing Mothers
`8.4
`Pediatric Use
`
`6
` 8
`
`
`
`Page 1 of 17
`
`Coalition Exhibit 1066
`Coalition v. Biogen
`IPR2015-01993
`
`

`

`FULL PRESCRIBING INFORMATION
`
`INDICATIONS AND USAGE
`1
`TECFIDERA is indicated for the treatment of patients with relapsing forms of multiple sclerosis.
`
`2
`
`DOSAGE AND ADMINISTRATION
`
`Dosing Information
`2.1
`The starting dose for TECFIDERA is 120 mg twice a day orally. After 7 days, the dose should
`be increased to the maintenance dose of 240 mg twice a day orally. Temporary dose reductions
`to 120 mg twice a day may be considered for individuals who do not tolerate the maintenance
`dose. Within 4 weeks, the recommended dose of 240 mg twice a day should be resumed.
`Discontinuation of TECFIDERA should be considered for patients unable to tolerate return to
`the maintenance dose. The incidence of flushing may be reduced by administration of
`TECFIDERA with food. Alternatively, administration of non-enteric coated aspirin (up to a dose
`of 325 mg) 30 minutes prior to TECFIDERA dosing may reduce the incidence or severity of
`flushing [see Clinical Pharmacology (12.3)].
`
`TECFIDERA should be swallowed whole and intact. TECFIDERA should not be crushed or
`chewed and the capsule contents should not be sprinkled on food. TECFIDERA can be taken
`with or without food.
`
`Blood Test Prior to Initiation of Therapy
`2.2
`Obtain a complete blood cell count (CBC) including lymphocyte count before initiation of
`therapy [see Warnings and Precautions (5.3)].
`
`DOSAGE FORMS AND STRENGTHS
`3
`TECFIDERA is available as hard gelatin delayed-release capsules containing 120 mg or 240 mg
`of dimethyl fumarate. The 120 mg capsules have a green cap and white body, printed with “BG-
`12 120 mg” in black ink on the body. The 240 mg capsules have a green cap and a green body,
`printed with “BG-12 240 mg” in black ink on the body.
`
`CONTRAINDICATIONS
`4
`TECFIDERA is contraindicated in patients with known hypersensitivity to dimethyl fumarate or
`to any of the excipients of TECFIDERA. Reactions have included anaphylaxis and angioedema
`[see Warnings and Precautions (5.1)].
`
`Page 2 of 17
`
`

`

`5
`
`WARNINGS AND PRECAUTIONS
`
`Anaphylaxis and Angioedema
`5.1
`TECFIDERA can cause anaphylaxis and angioedema after the first dose or at any time during
`treatment. Signs and symptoms have included difficulty breathing, urticaria, and swelling of the
`throat and tongue. Patients should be instructed to discontinue TECFIDERA and seek immediate
`medical care should they experience signs and symptoms of anaphylaxis or angioedema.
`
`Progressive Multifocal Leukoencephalopathy
`5.2
`Progressive multifocal leukoencephalopathy (PML) has occurred in patients with MS treated
`with TECFIDERA. PML is an opportunistic viral infection of the brain caused by the JC virus
`(JCV) that typically only occurs in patients who are immunocompromised, and that usually leads
`to death or severe disability. A fatal case of PML occurred in a patient who received
`TECFIDERA for 4 years while enrolled in a clinical trial. During the clinical trial, the patient
`experienced prolonged lymphopenia (lymphocyte counts predominantly <0.5x109/L for 3.5
`years) while taking TECFIDERA [see Warnings and Precautions (5.3)]. The patient had no
`other identified systemic medical conditions resulting in compromised immune system function
`and had not previously been treated with natalizumab, which has a known association with PML.
`The patient was also not taking any immunosuppressive or immunomodulatory medications
`concomitantly.
`
`PML has also occurred in the postmarketing setting in the presence of lymphopenia (<0.8x109/L)
`persisting for more than 6 months. While the role of lymphopenia in these cases is uncertain, the
`majority of cases occurred in patients with lymphocyte counts <0.5x 109/L.
`
`At the first sign or symptom suggestive of PML, withhold TECFIDERA and perform an
`appropriate diagnostic evaluation. MRI findings may be apparent before clinical signs or
`symptoms. Typical symptoms associated with PML are diverse, progress over days to weeks,
`and include progressive weakness on one side of the body or clumsiness of limbs, disturbance of
`vision, and changes in thinking, memory, and orientation leading to confusion and personality
`changes.
`
`Lymphopenia
`5.3
`TECFIDERA may decrease lymphocyte counts. In the MS placebo controlled trials, mean
`lymphocyte counts decreased by approximately 30% during the first year of treatment with
`TECFIDERA and then remained stable. Four weeks after stopping TECFIDERA, mean
`lymphocyte counts increased but did not return to baseline. Six percent (6%) of TECFIDERA
`patients and <1% of placebo patients experienced lymphocyte counts <0.5x109/L (lower limit of
`normal 0.91x109/L). The incidence of infections (60% vs 58%) and serious infections (2% vs
`2%) was similar in patients treated with TECFIDERA or placebo, respectively. There was no
`increased incidence of serious infections observed in patients with lymphocyte counts
`<0.8x109/L or <0.5x109/L in controlled trials, although one patient in an extension study
`developed PML in the setting of prolonged lymphopenia (lymphocyte counts predominantly
`<0.5x109/L for 3.5 years) [see Warnings and Precautions (5.2)].
`
`Page 3 of 17
`
`

`

`In controlled and uncontrolled clinical trials, 2% of patients experienced lymphocyte counts <0.5
`x 109/L for at least six months, and in this group the majority of lymphocyte counts remained
`<0.5x109/L with continued therapy. TECFIDERA has not been studied in patients with pre-
`existing low lymphocyte counts.
`Obtain a CBC, including lymphocyte count, before initiating treatment with TECFIDERA, 6
`months after starting treatment, and then every 6 to 12 months thereafter, and as clinically
`indicated. Consider interruption of TECFIDERA in patients with lymphocyte counts less than
`0.5 x 109/L persisting for more than six months. Given the potential for delayed recovery of
`lymphocyte counts, continue to obtain lymphocyte counts until their recovery if TECFIDERA is
`discontinued or interrupted due to lymphopenia. Consider withholding treatment from patients
`with serious infections until resolution. Decisions about whether or not to restart TECFIDERA
`should be individualized based on clinical circumstances.
`
`
`Flushing
`5.4
`TECFIDERA may cause flushing (e.g., warmth, redness, itching, and/or burning sensation). In
`clinical trials, 40% of TECFIDERA treated patients experienced flushing. Flushing symptoms
`generally began soon after initiating TECFIDERA and usually improved or resolved over time.
`In the majority of patients who experienced flushing, it was mild or moderate in severity. Three
`percent (3%) of patients discontinued TECFIDERA for flushing and <1% had serious flushing
`symptoms that were not life-threatening but led to hospitalization. Administration of
`TECFIDERA with food may reduce the incidence of flushing. Alternatively, administration of
`non-enteric coated aspirin (up to a dose of 325 mg) 30 minutes prior to TECFIDERA dosing may
`reduce the incidence or severity of flushing [see Dosing and Administration (2.1) and Clinical
`Pharmacology (12.3)].
`
`ADVERSE REACTIONS
`6
`The following important adverse reactions are described elsewhere in labeling:
`• Anaphylaxis and Angioedema [see Warnings and Precautions (5.1)].
`• Progressive multifocal leukoencephalopathy [see Warnings and Precautions (5.2)].
`• Lymphopenia [see Warnings and Precautions (5.3)].
`• Flushing [see Warnings and Precautions (5.4)].
`
`Clinical Trials Experience
`6.1
`Because clinical trials are conducted under widely varying conditions, adverse reaction rates
`observed in 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.
`The most common adverse reactions (incidence ≥10% and ≥2% more than placebo) for
`TECFIDERA were flushing, abdominal pain, diarrhea, and nausea.
`Adverse Reactions in Placebo-Controlled Trials
`
`Page 4 of 17
`
`

`

`
`
`
`
`40
`18
`14
`12
`9
`8
`8
`6
`5
`5
`4
`2
`
`In the two well-controlled studies demonstrating effectiveness, 1529 patients received
`TECFIDERA with an overall exposure of 2244 person-years [see Clinical Studies (14)].
`The adverse reactions presented in the table below are based on safety information from 769
`patients treated with TECFIDERA 240 mg twice a day and 771 placebo-treated patients.
`Table 1:
`Adverse Reactions in Study 1 and 2 reported for TECFIDERA 240 mg BID
`at ≥ 2% higher incidence than placebo
`TECFIDERA
`Placebo
`N=769
`N=771
`%
`%
`
`
`
`6
`10
`11
`9
`5
`4
`3
`4
`1
`3
`2
`<1
`
`
`Flushing
`Abdominal pain
`Diarrhea
`Nausea
`Vomiting
`Pruritus
`Rash
`Albumin urine present
`Erythema
`Dyspepsia
`Aspartate aminotransferase increased
`Lymphopenia
`Gastrointestinal
`TECFIDERA caused GI events (e.g., nausea, vomiting, diarrhea, abdominal pain, and
`dyspepsia). The incidence of GI events was higher early in the course of treatment (primarily in
`month 1) and usually decreased over time in patients treated with TECFIDERA compared with
`placebo. Four percent (4%) of patients treated with TECFIDERA and less than 1% of placebo
`patients discontinued due to gastrointestinal events. The incidence of serious GI events was 1%
`in patients treated with TECFIDERA.
`Hepatic Transaminases
`An increased incidence of elevations of hepatic transaminases in patients treated with
`TECFIDERA was seen primarily during the first six months of treatment, and most patients with
`elevations had levels < 3 times the upper limit of normal (ULN). Elevations of alanine
`aminotransferase and aspartate aminotransferase to ≥ 3 times the ULN occurred in a small
`number of patients treated with both TECFIDERA and placebo and were balanced between
`groups. There were no elevations in transaminases ≥ 3 times the ULN with concomitant
`elevations in total bilirubin > 2 times the ULN. Discontinuations due to elevated hepatic
`transaminases were < 1% and were similar in patients treated with TECFIDERA or placebo.
`
`Eosinophilia
`A transient increase in mean eosinophil counts was seen during the first 2 months of therapy.
`Adverse Reactions in Placebo-Controlled and Uncontrolled Studies
`
`Page 5 of 17
`
`

`

`In placebo-controlled and uncontrolled clinical studies, a total of 2513 patients have received
`TECFIDERA and been followed for periods up to 4 years with an overall exposure of 4603
`person-years. Approximately 1162 patients have received more than 2 years of treatment with
`TECFIDERA. The adverse reaction profile of TECFIDERA in the uncontrolled clinical studies
`was consistent with the experience in the placebo-controlled clinical trials.
`
`8
`
`USE IN SPECIFIC POPULATIONS
`
`Pregnancy
`8.1
`Pregnancy Category C
`There are no adequate and well-controlled studies in pregnant women. In animals, adverse
`effects on offspring survival, growth, sexual maturation, and neurobehavioral function were
`observed when dimethyl fumarate (DMF) was administered during pregnancy and lactation at
`clinically relevant doses. TECFIDERA should be used during pregnancy only if the potential
`benefit justifies the potential risk to the fetus.
`In rats administered DMF orally (25, 100, 250 mg/kg/day) throughout organogenesis,
`embryofetal toxicity (reduced fetal body weight and delayed ossification) were observed at the
`highest dose tested. This dose also produced evidence of maternal toxicity (reduced body
`weight). Plasma exposure (AUC) for monomethyl fumarate (MMF), the major circulating
`metabolite, at the no-effect dose is approximately three times that in humans at the recommended
`human dose (RHD) of 480 mg/day. In rabbits administered DMF orally (25, 75, and 150
`mg/kg/day) throughout organogenesis, embryolethality and decreased maternal body weight
`were observed at the highest dose tested. The plasma AUC for MMF at the no-effect dose is
`approximately 5 times that in humans at the RHD.
`Oral administration of DMF (25, 100, and 250 mg/kg/day) to rats throughout organogenesis and
`lactation resulted in increased lethality, persistent reductions in body weight, delayed sexual
`maturation (male and female pups), and reduced testicular weight at the highest dose tested.
`Neurobehavioral impairment was observed at all doses. A no-effect dose for developmental
`toxicity was not identified. The lowest dose tested was associated with plasma AUC for MMF
`lower than that in humans at the RHD.
`Pregnancy Registry
`There is a pregnancy registry that monitors pregnancy outcomes in women exposed to
`TECFIDERA during pregnancy. Encourage patients to enroll by calling 1-866-810-1462 or
`visiting www.tecfiderapregnancyregistry.com.
`
`Nursing Mothers
`8.3
`It is not known whether this drug is excreted in human milk. Because many drugs are excreted in
`human milk, caution should be exercised when TECFIDERA is administered to a nursing
`woman.
`
`Page 6 of 17
`
`

`

`Pediatric Use
`8.4
`Safety and effectiveness in pediatric patients have not been established.
`
`Geriatric Use
`8.5
`Clinical studies of TECFIDERA did not include sufficient numbers of patients aged 65 and over
`to determine whether they respond differently from younger patients.
`
`DESCRIPTION
`11
`TECFIDERA contains dimethyl fumarate which is also known by its chemical name, dimethyl
`(E) butenedioate, (C6H8O4). It has the following structure:
`
`
`O
`
`H
`
`O
`
`O
`
`H
`
`O
`
`
`
`
`Dimethyl fumarate is a white to off-white powder that is highly soluble in water with a molecular
`mass of 144.13.
`TECFIDERA is provided as hard gelatin delayed-release capsules for oral administration,
`containing 120 mg or 240 mg of dimethyl fumarate consisting of the following inactive
`ingredients: microcrystalline cellulose, silicified microcrystalline cellulose, croscarmellose
`sodium, talc, silica colloidal silicon dioxide, magnesium stearate, triethyl citrate, methacrylic
`acid copolymer - Type A, methacrylic acid copolymer dispersion, simethicone (30% emulsion),
`sodium lauryl sulphate, and polysorbate 80. The capsule shell, printed with black ink, contains
`the following inactive ingredients: gelatin, titanium dioxide, FD&C blue 1; brilliant blue FCF,
`yellow iron oxide and black iron oxide.
`
`12
`
`CLINICAL PHARMACOLOGY
`
`12.1 Mechanism of Action
`The mechanism by which dimethyl fumarate (DMF) exerts its therapeutic effect in multiple
`sclerosis is unknown. DMF and the metabolite, monomethyl fumarate (MMF), have been shown
`to activate the Nuclear factor (erythroid-derived 2)-like 2 (Nrf2) pathway in vitro and in vivo in
`animals and humans. The Nrf2 pathway is involved in the cellular response to oxidative stress.
`MMF has been identified as a nicotinic acid receptor agonist in vitro.
`
`Page 7 of 17
`
`

`

`Pharmacodynamics
`12.2
`Potential to prolong the QT interval
`In a placebo controlled thorough QT study performed in healthy subjects, there was no evidence
`that dimethyl fumarate 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).
`
`Pharmacokinetics
`12.3
`After oral administration of TECFIDERA, dimethyl fumarate undergoes rapid presystemic
`hydrolysis by esterases and is converted to its active metabolite, monomethyl fumarate (MMF).
`Dimethyl fumarate is not quantifiable in plasma following oral administration of TECFIDERA.
`Therefore all pharmacokinetic analyses related to TECFIDERA were performed with plasma
`MMF concentrations. Pharmacokinetic data were obtained in subjects with multiple sclerosis and
`healthy volunteers.
`Absorption
`The median Tmax of MMF is 2-2.5 hours. The peak plasma concentration (Cmax) and overall
`exposure (AUC) increased approximately dose proportionally in the dose range studied (120 mg
`to 360 mg). Following administration of TECFIDERA 240 mg twice a day with food, the mean
`Cmax of MMF was 1.87 mg/L and AUC was 8.21 mg.hr/L in MS patients.
`A high-fat, high-calorie meal did not affect the AUC of MMF but decreased its Cmax by 40%.
`The Tmax was delayed from 2.0 hours to 5.5 hours. In this study, the incidence of flushing was
`reduced by approximately 25% in the fed state.
`Distribution
`The apparent volume of distribution of MMF varies between 53 and 73 L in healthy subjects.
`Human plasma protein binding of MMF is 27-45% and independent of concentration.
`Metabolism
`In humans, dimethyl fumarate is extensively metabolized by esterases, which are ubiquitous in
`the gastrointestinal tract, blood, and tissues, before it reaches the systemic circulation. Further
`metabolism of MMF occurs through the tricarboxylic acid (TCA) cycle, with no involvement of
`the cytochrome P450 (CYP) system. MMF, fumaric and citric acid, and glucose are the major
`metabolites in plasma.
`Elimination
`Exhalation of CO2 is the primary route of elimination, accounting for approximately 60% of the
`TECFIDERA dose. Renal and fecal elimination are minor routes of elimination, accounting for
`16% and 1% of the dose respectively. Trace amounts of unchanged MMF were present in urine.
`The terminal half-life of MMF is approximately 1 hour and no circulating MMF is present at 24
`hours in the majority of individuals. Accumulation of MMF does not occur with multiple doses
`of TECFIDERA.
`Specific Populations
`
`Page 8 of 17
`
`

`

`Body weight, gender, and age do not require dosage adjustment.
`No studies have been conducted in subjects with hepatic or renal impairment. However, neither
`condition would be expected to affect exposure to MMF and therefore no dosage adjustment is
`necessary.
`Drug Interaction Studies
`No potential drug interactions with dimethyl fumarate or MMF were identified in in vitro CYP
`inhibition and induction studies, or in P-glycoprotein studies. Single doses of interferon beta-1a
`or glatiramer acetate did not alter the pharmacokinetics of MMF. Aspirin, when administered
`approximately 30 minutes before TECFIDERA, did not alter the pharmacokinetics of MMF.
`
`13
`
`NONCLINICAL TOXICOLOGY
`
`Carcinogenesis, Mutagenesis, Impairment of Fertility
`13.1
`Carcinogenesis
`Carcinogenicity studies of dimethyl fumarate (DMF) were conducted in mice and rats. In mice,
`oral administration of DMF (25, 75, 200, and 400 mg/kg/day) for up to two years resulted in an
`increase in nonglandular stomach (forestomach) and kidney tumors: squamous cell carcinomas
`and papillomas of the forestomach in males and females at 200 and 400 mg/kg/day;
`leiomyosarcomas of the forestomach at 400 mg/kg/day in males and females; renal tubular
`adenomas and carcinomas at 200 and 400 mg/kg/day in males; and renal tubule adenomas at 400
`mg/kg/day in females. Plasma MMF exposure (AUC) at the highest dose not associated with
`tumors in mice (75 mg/kg/day) was similar to that in humans at the recommended human dose
`(RHD) of 480 mg/day.
`In rats, oral administration of DMF (25, 50, 100, and 150 mg/kg/day) for up to two years resulted
`in increases in squamous cell carcinomas and papillomas of the forestomach at all doses tested in
`males and females, and in testicular interstitial (Leydig) cell adenomas at 100 and 150
`mg/kg/day. Plasma MMF AUC at the lowest dose tested was lower than that in humans at the
`RHD.
`
`
`Mutagenesis
`Dimethyl fumarate (DMF) and monomethyl fumarate (MMF) were not mutagenic in the in vitro
`bacterial reverse mutation (Ames) assay. DMF and MMF were clastogenic in the in vitro
`chromosomal aberration assay in human peripheral blood lymphocytes in the absence of
`metabolic activation. DMF was not clastogenic in the in vivo micronucleus assay in the rat.
`Impairment of Fertility
`In male rats, oral administration of DMF (75, 250, and 375 mg/kg/day) prior to and throughout
`the mating period had no effect on fertility; however, increases in non-motile sperm were
`observed at the mid and high doses. The no-effect dose for adverse effects on sperm is similar to
`the recommended human dose (RHD) of 480 mg/day on a body surface area (mg/m2) basis.
`
`Page 9 of 17
`
`

`

`In female rats, oral administration of DMF (20, 100, and 250 mg/kg/day) prior to and during
`mating and continuing to gestation day 7 caused disruption of the estrous cycle and increases in
`embryolethality at the highest dose tested. The highest dose not associated with adverse effects
`(100 mg/kg/day) is twice the RHD on a mg/m2 basis.
`Testicular toxicity (germinal epithelial degeneration, atrophy, hypospermia, and/or hyperplasia)
`was observed at clinically relevant doses in mice, rats, and dogs in subchronic and chronic oral
`toxicity studies of DMF, and in a chronic oral toxicity study evaluating a combination of four
`fumaric acid esters (including DMF) in rats.
`
`Animal Toxicology and/or Pharmacology
`13.2
`Kidney toxicity was observed after repeated oral administration of dimethyl fumarate (DMF) in
`mice, rats, dogs, and monkeys. Renal tubule epithelia regeneration, suggestive of tubule
`epithelial injury, was observed in all species. Renal tubular hyperplasia was observed in rats with
`dosing for up to two years. Cortical atrophy and interstitial fibrosis were observed in dogs and
`monkeys at doses above 5 mg/kg/day. In monkeys, the highest dose tested (75 mg/kg/day) was
`associated with single cell necrosis and multifocal and diffuse interstitial fibrosis, indicating
`irreversible loss of renal tissue and function. In dogs and monkeys, the 5 mg/kg/day dose was
`associated with plasma MMF exposures less than or similar to that in humans at the
`recommended human dose (RHD).
`A dose-related increase in incidence and severity of retinal degeneration was observed in mice
`following oral administration of DMF for up to two years at doses above 75 mg/kg/day, a dose
`associated with plasma MMF exposure (AUC) similar to that in humans at the RHD.
`
`CLINICAL STUDIES
`14
`The efficacy and safety of TECFIDERA were demonstrated in two studies (Studies 1 and 2) that
`evaluated TECFIDERA taken either twice or three times a day in patients with relapsing-
`remitting multiple sclerosis (RRMS). The starting dose for TECFIDERA was 120 mg twice or
`three times a day for the first 7 days, followed by an increase to 240 mg twice or three times a
`day. Both studies included patients who had experienced at least 1 relapse over the year
`preceding the trial or had a brain Magnetic Resonance Imaging (MRI) scan demonstrating at
`least one gadolinium-enhancing (Gd+) lesion within 6 weeks of randomization. The Expanded
`Disability Status Scale (EDSS) was also assessed and patients could have scores ranging from 0
`to 5. Neurological evaluations were performed at baseline, every 3 months, and at the time of
`suspected relapse. MRI evaluations were performed at baseline, month 6, and year 1 and 2 in a
`subset of patients (44% in Study 1 and 48% in Study 2).
`Study 1: Placebo-Controlled Trial in RRMS
`Study 1 was a 2-year randomized, double-blind, placebo-controlled study in 1234 patients with
`RRMS. The primary endpoint was the proportion of patients relapsed at 2 years. Additional
`endpoints at 2 years included the number of new or newly enlarging T2 hyperintense lesions,
`number of new T1 hypointense lesions, number of Gd+ lesions, annualized relapse rate (ARR),
`and time to confirmed disability progression. Confirmed disability progression was defined as at
`
`Page 10 of 17
`
`

`

`least a 1 point increase from baseline EDSS (1.5 point increase for patients with baseline EDSS
`of 0) sustained for 12 weeks.
`Patients were randomized to receive TECFIDERA 240 mg twice a day (n=410), TECFIDERA
`240 mg three times a day (n=416), or placebo (n=408) for up to 2 years. The median age was 39
`years, median time since diagnosis was 4 years, and median EDSS score at baseline was 2. The
`median time on study drug for all treatment arms was 96 weeks. The percentages of patients who
`completed 96 weeks on study drug per treatment group were 69% for patients assigned to
`TECFIDERA 240 mg twice a day, 69% for patients assigned to TECFIDERA 240 mg three
`times a day and 65% for patients assigned to placebo groups.
`TECFIDERA had a statistically significant effect on all of the endpoints described above and the
`240 mg three times daily dose showed no additional benefit over the TECFIDERA 240 mg twice
`daily dose. The results for this study (240 mg twice a day vs. placebo) are shown in Table 2 and
`Figure 1.
`
`Clinical and MRI Results of Study 1
`TECFIDERA
`
`240 mg BID
`Placebo
`
`Table 2:
`
`
`
`
`Clinical Endpoints
` Proportion relapsing (primary endpoint)
` Relative risk reduction
`
` Annualized relapse rate
` Relative reduction
`
` Proportion with disability progression
` Relative risk reduction
`
`MRI Endpoints
` Mean number of new or newly enlarging
` T2 lesions over 2 years
`
` Percentage of subjects with no new or newly
`enlarging lesions
`
`
` Number of Gd+ lesions at 2 years
` Mean (median)
`
` Percentage of subjects with
`
`0 lesions
`
`1 lesion
`
`2 lesions
`
`3 to 4 lesions
`
`5 or more lesions
`
` Relative odds reduction
` (percentage)
`
`
`
`
`
`
`
`
`
`
`
`
`
`N=410
`27%
`49%
`
`0.172
`53%
`
`16%
`38%
`
`N=152
`2.6
`
`
` 45%
`
`
`0.1 (0)
`
`
`
` 93%
` 5%
` <1%
` 0
` <1%
`
`90%
`
`
`N=408
`46%
`
`0.364
`
`
`27%
`
`
`N=165
`17
`
`
`27%
`
`
`
`1.8 (0)
`
`
`
` 62%
` 10%
` 8%
` 9%
` 11%
`
`
`
`
`
`
`
`
`
`
`
`P-value
`
`<0.0001
`
`<0.0001
`
`
`0.0050
`
`<0.0001
`
`
`
`
`
`
`
`
`
`
`
`<0.0001
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Page 11 of 17
`
`

`

`
`
` Mean number of new T1 hypointense
` lesions over 2 years
`
`
`TECFIDERA
`240 mg BID
`1.5
`
`
`
`
`
`
`Placebo
`5.6
`
`
`
`P-value
`<0.0001
`
`Figure 1:
`
`Time to 12-Week Confirmed Progression of Disability (Study 1)
`
`
`
`
`Study 2: Placebo-Controlled Trial in RRMS
`Study 2 was a 2-year multicenter, randomized, double-blind, placebo-controlled study that also
`included an open-label comparator arm in patients with RRMS. The primary endpoint was the
`annualized relapse rate at 2 years. Additional endpoints at 2 years included the number of new or
`newly enlarging T2 hyperintense lesions, number of T1 hypointense lesions, number of Gd+
`lesions, proportion of patients relapsed, and time to confirmed disability progression as defined
`in Study 1.
`Patients were randomized to receive TECFIDERA 240 mg twice a day (n=359), TECFIDERA
`240 mg three times a day (n=345), an open-label comparator (n=350), or placebo (n=363) for up
`to 2 years. The median age was 37 years, median time since diagnosis was 3 years, and median
`
`Page 12 of 17
`
`

`

`EDSS score at baseline was 2.5. The median time on study drug for all treatment arms was 96
`weeks. The percentages of patients who completed 96 weeks on study drug per treatment group
`were 70% for patients assigned to TECFIDERA 240 mg twice a day, 72% for patients assigned
`to TECFIDERA 240 mg three times a day and 64% for patients assigned to placebo groups.
`TECFIDERA had a statistically significant effect on the relapse and MRI endpoints described
`above. There was no statistically significant effect on disability progression. The TECFIDERA
`240 mg three times daily dose resulted in no additional benefit over the TECFIDERA 240 mg
`twice daily dose. The results for this study (240 mg twice a day vs. placebo) are shown in
`Table 3.
`
`Table 3:
`
`
`
`
`Clinical Endpoints
` Annualized relapse rate
` Relative reduction
`
` Proportion relapsing
` Relative risk reduction
`
` Proportion with disability progression
` Relative risk reduction
`
`MRI Endpoints
` Mean number of new or newly enlarging
` T2 lesions over 2 years
`
` Percentage of subjects with no new or
` newly enlarging lesions
`
`
` Number of Gd+ lesions at 2 years
` Mean (median)
`
` Percentage of subjects with
`
`0 lesions
`
`1 lesion
`
`2 lesions
`
`3 to 4 lesions
`
`5 or more lesions
`
` Relative odds reduction
` (percentage)
`
`
` Mean number of new T1 hypointense
` lesions over 2 years
`
`
`
`
`Clinical and MRI Results of Study 2
`TECFIDERA
`
`240 mg BID
`Placebo
`
`N=363
`0.401
`
`
`41%
`
`
`17%
`
`
`N=144
`17.4
`
`
`12%
`
`
`N=359
`0.224
`44%
`
`29%
`34%
`
`13%
`21%
`
`N=147
`5.1
`
`
`27%
`
`
`
`
`0.5 (0.0)
`
`
`80%
` 11%
` 3%
` 3%
` 3%
`
`74%
`
`
`
`3.0
`
`
`
`
`
`
`
`2.0 (0.0)
`
`
`61%
`17%
` 6%
` 2%
`14%
`
`
`7.0
`
`
`
`
`
`
`
`
`
`
`
`P-value
`
`<0.0001
`
`
`0.0020
`
`
`0.25
`
`
`
`<0.0001
`
`
`
`
`
`
`
`
`
`
`
`
`<0.0001
`
`
`
`<0.0001
`
`Page 13 of 17
`
`

`

`HOW SUPPLIED/STORAGE AND HANDLING
`16
`TECFIDERA is available as hard gelatin delayed-release capsules in two strengths containing
`either 120 mg or 240 mg of dimethyl fumarate. The green and white 120 mg capsules are printed
`with “BG-12 120 mg” in black ink. The green 240 mg capsules are printed with “BG-12 240
`mg” in black ink. TECFIDERA is available as follows:
`30-day Starter Pack, (NDC 64406-007-03):
`
`7-day bottle 120 mg capsules, quantity 14
`
`23-day bottle 240 mg capsules, quantity 46
`
`
`120 mg capsules:
`7-day bottle of 14 capsules (NDC 64406-005-01)
`
`
`240 mg capsules:
`
`30-day bottle of 60 capsules (NDC 64406-006-02)
`Store at 15°C to 30°C (59 to 86°F). Protect the capsules from light. Store in original container.
`
`PATIENT COUNSELING INFORMATION
`17
`Advise the patient to read the FDA-approved patient labeling (Patient Information)
`Dosage
`Inform patients that they will be provided two strengths of TECFIDERA when starting
`treatment: 120 mg capsules for the 7 day