`NDA 204063 - FDA Approved Labeling Text dated March 27, 2013
`
`
`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
`
`
`
`-------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)
`
`
`
`
` Maintenance dose after 7 days: 240 mg twice a day, orally (2)
`
`
`
` Swallow TECFIDERA capsules whole and intact. Do not crush, chew, or
`
`
`sprinkle capsule contents on food (2)
`
`
`
` Take TECFIDERA with or without food (2)
`
`
`
`-------DOSAGE FORMS AND STRENGTHS-------
`Delayed-release capsules 120 mg and 240 mg (3)
`
`
`
`-------CONTRAINDICATIONS-------
`
`None (4)
`
`
`-------WARNINGS AND PRECAUTIONS-------
`
`TECFIDERA may cause lymphopenia. A recent CBC should be available
`before initiating treatment with TECFIDERA. A CBC is recommended
`annually, and as clinically indicated. Consider withholding treatment in
`
`patients with serious infections. (5.1, 6.1)
`
`
`-------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 Idec 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: 03/2013
`
`
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`
`
`1 INDICATIONS AND USAGE
`
`2 DOSAGE AND ADMINISTRATION
`
`2.1 Dosing Information
`2.2 Blood Test Prior to Initiation of Therapy
`
`3 DOSAGE FORMS AND STRENGTHS
`
`4 CONTRAINDICATIONS
`
`5 WARNINGS AND PRECAUTIONS
`
`5.1 Lymphopenia
`
`5.2 Flushing
`6 ADVERSE REACTIONS
`
`6.1 Clinical Trials Experience
`8 USE IN SPECIFIC POPULATIONS
`
`8.1 Pregnancy
`
`
`8.3 Nursing Mothers
`8.4 Pediatric Use
`
`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
`
`17.1 Dosage
`17.2 Flushing and Gastrointestinal (GI) Reactions
`17.3 Pregnancy and Pregnancy Registry
`
`17.4 Lymphocyte Counts
`
`
`
`* Sections or subsections omitted from the full prescribing information are not
`
`listed
`
`
`
`
`Reference ID: 3283381
`
`
`Biogen Exhibit 2133
`Mylan v. Biogen
`IPR2018-01403
`
`Page 1 of 15
`
`

`

`
`NDA 204063 - FDA Approved Labeling Text dated March 27, 2013
`
`
`
`
` FULL PRESCRIBING INFORMATION
`
`1 INDICATIONS AND USAGE
`
`TECFIDERA is indicated for the treatment of patients with relapsing forms of multiple sclerosis.
`
`
`
`
`2 DOSAGE AND ADMINISTRATION
`
`2.1 Dosing Information
`
`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. 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. Administration with food
`
`
`
`
`
`
`may reduce the incidence of flushing [see Clinical Pharmacology (12.3)].
`
`
`2.2 Blood Test Prior to Initiation of Therapy
`
`A recent complete blood cell count (CBC) (i.e., within 6 months) is recommended before initiation of therapy to identify patients with
`
`
`pre-existing low lymphocyte counts.
`
`3 DOSAGE FORMS AND STRENGTHS
`
`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.
`
`
`
`4 CONTRAINDICATIONS
`
`None.
`
`5 WARNINGS AND PRECAUTIONS
`
`5.1 Lymphopenia
`
`TECFIDERA may decrease lymphocyte counts [see Adverse Reactions (6.1)]. 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.
`
`
`
`
`
`
`Before initiating treatment with TECFIDERA, a recent CBC (i.e., within 6 months) should be available. A CBC is recommended
`
`annually, and as clinically indicated. Withholding treatment should be considered in patients with serious infections until the
`
`
`
`
`
`infection(s) is resolved. TECFIDERA has not been studied in patients with pre-existing low lymphocyte counts.
`
`5.2 Flushing
`
`
`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
`
`Reference ID: 3283381
`
`
`Page 2 of 15
`
`

`

`
`NDA 204063 - FDA Approved Labeling Text dated March 27, 2013
`
` 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.
`
`
`
`
`
` 6 ADVERSE REACTIONS
`
` The following important adverse reactions are described elsewhere in labeling: Lymphopenia, Flushing [see Warnings and
`
`Precautions (5.1, 5.2)].
`
`
`
`
`
`6.1 Clinical Trials Experience
`
` 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
`
`
`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
`
`
`
`
`Blood and Lymphatic System Disorders
` Lymphopenia
`
`Gastrointestinal Disorders
`
`
`Abdominal pain
`
`Diarrhea
`
`Nausea
`
`Vomiting
`
`Dyspepsia
`Vascular Disorders
`
`
` Flushing
`Skin and Subcutaneous Tissue Disorders
`
`
` Pruritus
`
` Rash
`
` Erythema
`Investigations
`
`
`
`Albumin urine present
`
`
`Aspartate aminotransferase increased
`
`Gastrointestinal
`
`
`
`TECFIDERA
`
`N=769
`%
`
`2
`
`18
`14
`12
`9
`5
`
`40
`
`8
`8
`5
`
`6
`4
`
`Placebo
`
`N=771
`%
`
`<1
`
`10
`11
`9
`5
`3
`
`6
`
`4
`3
`1
`
`4
`2
`
`
`
`
`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
`
`
`Reference ID: 3283381
`
`
`Page 3 of 15
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`

`

`
`NDA 204063 - FDA Approved Labeling Text dated March 27, 2013
`
` 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
`
`
`
` 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
`
`
`
` 8.1 Pregnancy
`
`
`
` 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 1-800-456-2255.
`
`
`8.3 Nursing Mothers
`
`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.
`
`Reference ID: 3283381
`
`
`Page 4 of 15
`
`

`

`
`NDA 204063 - FDA Approved Labeling Text dated March 27, 2013
`
`
`8.4 Pediatric Use
`
`Safety and effectiveness in pediatric patients have not been established.
`
`
`
`
`8.5 Geriatric Use
`
`Clinical studies of TECFIDERA did not include sufficient numbers of patients aged 65 and over to determine whether they respond
`
`
`
`
`differently from younger patients.
`
`
`
`11 DESCRIPTION
`
`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.
`
`
`
`Reference ID: 3283381
`
`
`Page 5 of 15
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`

`
`NDA 204063 - FDA Approved Labeling Text dated March 27, 2013
`
`
`12.2 Pharmacodynamics
`
`Potential to prolong the QT interval
`
`
`
`In a placebo controlled thorough QT study performed in healthy subjects, there was no evidence that 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).
`
`12.3 Pharmacokinetics
`
`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
`
`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
`
`Reference ID: 3283381
`
`
`Page 6 of 15
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`

`

`
`NDA 204063 - FDA Approved Labeling Text dated March 27, 2013
`
` 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
`
`13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
`
`
`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.
`
`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.
`
`
`13.2 Animal Toxicology and/or Pharmacology
`
`
`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).
`
`
`Reference ID: 3283381
`
`
`Page 7 of 15
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`

`
`NDA 204063 - FDA Approved Labeling Text dated March 27, 2013
`
` 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.
`
`
`
`14 CLINICAL STUDIES
`
`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 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.
`
`Table 2: Clinical and MRI Results of Study 1
`
`
`
`
`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
`
`Reference ID: 3283381
`
`
`TECFIDERA
`
`240 mg BID
`
`
`N=410
`
`27%
`49%
`
`
`
`0.172
`53%
`
`
`
`16%
`38%
`
`
`N=152
`2.6
`
`
` 45%
`
`
`
`Placebo
`
`
`N=408
`
`46%
`
`
`
`
`
`0.364
`
`
`27%
`
`
`
` N=165
`17
`
`
`27%
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`P-value
`
`<0.0001
`
`
`
`
`
`<0.0001
`
`
`0.0050
`
`
`
`
`<0.0001
`
`Page 8 of 15
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`

`

`
`NDA 204063 - FDA Approved Labeling Text dated March 27, 2013
`
`
` TECFIDERA
`240 mg BID
`
`
`Placebo
`
`1.8 (0)
`
`
`
`62%
`10%
`
`8%
`
`9%
`11%
`
`P-value
`
`
`
`
`
`
`
`
`
`
`
`<0.0001
`
`
`
`
`
`
`
`
`
`
`
`5.6
`
`< 0.0001
`
`
`
` 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
`
`
`
`
`
`
`
`
`
`
`0.1 (0)
`
`
`
` 93%
`
`5%
`<1%
`
`
`0
`<1%
`
`90%
`
`
`1.5
`
`
`
`
`
`
`
`
`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
`Reference ID: 3283381
`
`
`
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`Page 9 of 15
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`NDA 204063 - FDA Approved Labeling Text dated March 27, 2013
`
` 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 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 72% for patients assigned to TECFIDERA
` 240 mg twice a day, 70% 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 and MRI Results of Study 2
`
`
`
`TECFIDERA
`240 mg BID
`
`Placebo
`
`P-value
`
`
`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
`
`
`
`
`
`
`
`
`
`
`
`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
`
`
`
`
`
`
`
`
`N=363
`0.401
`
`
`41%
`
`
`17%
`
`
`N=144
`17.4
`
`
`12%
`
`
`
`
`
`
`2.0 (0.0)
`
`
`61%
`17%
`6%
`2%
`14%
`
`
`7.0
`
`
`
`
`
`Reference ID: 3283381
`
`
`
`
`
`
`<0.0001
`
`
`0.0020
`
`
`0.25
`
`
`
`
`
`
`<0.0001
`
`
`
`
`
`
`
`
`
`
`
`
`<0.0001
`
`
`
`
`
`
`<0.0001
`
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`NDA 204063 - FDA Approved Labeling Text dated March 27, 2013
`
`
`
`
`16 HOW SUPPLIED/STORAGE AND HANDLING
`
`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. Once opened, discard bottles of
`
`
`TECFIDERA after 90 days.
`
`
`
`17 PATIENT COUNSELING INFORMATION
`
`See FDA-approved patient labeling (Patient Information)
`
`
`17.1 Dosage
`
`
`Inform patients that they will be provided two strengths of TECFIDERA when starting treatment: 120 mg capsules for the 7 day
`starter dose and 240 mg capsules for the maintenance dose, both to be taken twice daily. Inform patients to swallow TECFIDERA
`
`
`capsules whole and intact. Inform patients to not crush, chew, or sprinkle capsule contents on food. Inform patients that TECFIDERA
`
`can be taken with or without food [see Dosage and Administration (2.1)].
`
`
`
`
`17.2 Flushing and Gastrointestinal (GI) Reactions
`
`
`Flushing and GI reactions (abdominal pain, diarrhea, and nausea) are the most common reactions, especially at the initiation of
`
`
`therapy, and may decrease over time. Advise patients to contact their healthcare provider if they experience persistent and/or severe
`
`
`
`
`flushing or GI reactions, as taking TECFIDERA with food may help [see Adverse Reactions (6.1)].
`
`
`
`
`
`17.3 Pregnancy and Pregnancy Registry
`
`
`Instruct patients that if they are pregnant or plan to become pregnant while taking TECFIDERA they should inform their physician.
`
`
`
`
`Encourage patients to enroll in the TECFIDERA Pregnancy Registry if they become pregnant while taking TECFIDERA. Advise
`
`patients to call 1-800-456-2255 for more information [see Use in Specific Populations (8.1)].
`
`
`
`17.4 Lymphocyte Counts
`
`
`Inform patients that TECFIDERA may decrease lymphocyte counts. A recent blood test (i.e., within 6 months) should be available
`
`
`
`before they start therapy to identify patients with pre-existing low lymphocyte counts. Blood tests are also recommended annually, and
`
`
`
`as clinically indicated [see Warnings and Precautions (5.1), Adverse Reactions (6.1)].
`
`Reference ID: 3283381
`
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`Page 11 of 15
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`
`NDA 204063 - FDA Approved Labeling Text dated March 27, 2013
`
`
`
`
` 41347-02
`
`Manufactured by:
`Biogen Idec Inc.
`Cambridge, MA 02142
`
`TECFIDERA is a trademark of Biogen Idec.
`© 2013 Biogen Idec
`
`
`Reference ID: 3283381
`
`
`Page 12 of 15
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`
`NDA 204063 - FDA Approved Labeling Text dated March 27, 2013
`
`
`Patient Information
`TECFIDERA™ (tek" fi de' rah)
`
`
`(dimethyl fumarate) delayed-release capsules
`
`What is TECFIDERA?
`
` TECFIDERA is a prescription medicine used to treat people with relapsing forms of multiple sclerosis
`(MS)
`
`
` It is not known if TECFIDERA is safe and effective in children under 18 years of age
`Before taking and while you take TECFIDERA, tell your doctor if you have or have had:
`
` low white blood cell counts or an infection
`
`
` any other medical con