___________________
`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)
`• Liver injury: Obtain serum aminotransferase, alkaline phosphatase, and
`total bilirubin levels before initiating TECFIDERA and during treatment,
`as clinically indicated. Discontinue TECFIDERA if clinically significant
`liver injury induced by TECFIDERA is suspected. (5.4)
`
`
`
` ___________________
`
`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: 12/2017
`
`8.4
`
`8.5
`
`Pediatric Use
`
`Geriatric Use
`
`10 OVERDOSE
`
`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
`
`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
`Dosage and Administration, Blood Tests Prior to
`Initiation of Therapy (2.2)
`Warnings and Precautions, PML (5.2)
`Warnings and Precautions, Liver Injury (5.4)
`
`
`1/2017
`12/2017
`1/2017
`
`
`
` __________________
` _________________
`
`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)
`
`
`
`
`
`
`
`
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`
`INDICATIONS AND USAGE
`
`DOSAGE AND ADMINISTRATION
`
`2.1
`
`2.2
`
`Dosing Information
`
`Blood Tests Prior to Initiation of Therapy
`
`DOSAGE FORMS AND STRENGTHS
`
`CONTRAINDICATIONS
`
` 1
`
`
`
`2
`
`3
`
`4
`
`5 WARNINGS AND PRECAUTIONS
`
`5.1
`
`5.2
`
`5.3
`
`5.4
`
`5.5
`
`Anaphylaxis and Angioedema
`
`Progressive Multifocal Leukoencephalopathy
`
`Lymphopenia
`
`Liver Injury
`
`Flushing
`
`6
`
`ADVERSE REACTIONS
`
`14 CLINICAL STUDIES
`
`6.1
`
`6.2
`
`Clinical Trials Experience
`
`Post Marketing Experience
`
`8
`
`USE IN SPECIFIC POPULATIONS
`
`8.1
`
`8.2
`
`Pregnancy
`
`Lactation
`
`16 HOW SUPPLIED/STORAGE AND HANDLING
`
`17 PATIENT COUNSELING INFORMATION
`
`*Sections or subsections omitted from the full prescribing information are not
`listed.
`
`
`
`
`
`
`1
`
`
`
`
`
`Biogen Exhibit 2067
`Mylan v. Biogen
`IPR 2018-01403
`
`Page 1 of 19
`
`

`

`
`
`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. 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.
`
`2.2
`
`Blood Tests Prior to Initiation of Therapy
`
`Obtain a complete blood cell count (CBC) including lymphocyte count before initiation of
`therapy [see Warnings and Precautions (5.3)].
`
`Obtain serum aminotransferase, alkaline phosphatase, and total bilirubin levels prior to treatment
`with TECFIDERA [see Warnings and Precautions (5.4)].
`
`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
`
`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 19
`
`

`

`
`
`5
`
`WARNINGS AND PRECAUTIONS
`
`5.1
`
`Anaphylaxis and Angioedema
`
`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. 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.
`
`MRI findings may be apparent before clinical signs or symptoms. Cases of PML, diagnosed
`based on MRI findings and the detection of JCV DNA in the cerebrospinal fluid in the absence
`of clinical signs or symptoms specific to PML, have been reported in patients treated with other
`MS medications associated with PML. Many of these patients subsequently became
`symptomatic with PML. Therefore, monitoring with MRI for signs that may be consistent with
`PML may be useful, and any suspicious findings should lead to further investigation to allow for
`an early diagnosis of PML, if present. Lower PML-related mortality and morbidity have been
`reported following discontinuation of another MS medication associated with PML in patients
`with PML who were initially asymptomatic compared to patients with PML who had
`characteristic clinical signs and symptoms at diagnosis. It is not known whether these
`differences are due to early detection and discontinuation of MS treatment or due to differences
`in disease in these patients.
`
`
`
`
`
`
`
`
`
`Page 3 of 19
`
`

`

`
`
`5.3
`
`Lymphopenia
`
`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)].
`
`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.
`
`5.4
`
`Liver Injury
`
`Clinically significant cases of liver injury have been reported in patients treated with
`TECFIDERA in the postmarketing setting. The onset has ranged from a few days to several
`months after initiation of treatment with TECFIDERA. Signs and symptoms of liver injury,
`including elevation of serum aminotransferases to greater than 5-fold the upper limit of normal
`and elevation of total bilirubin to greater than 2-fold the upper limit of normal have been
`observed. These abnormalities resolved upon treatment discontinuation. Some cases required
`hospitalization. None of the reported cases resulted in liver failure, liver transplant, or death.
`However, the combination of new serum aminotransferase elevations with increased levels of
`bilirubin caused by drug-induced hepatocellular injury is an important predictor of serious liver
`injury that may lead to acute liver failure, liver transplant, or death in some patients.
`
`Elevations of hepatic transaminases (most no greater than 3 times the upper limit of normal)
`were observed during controlled trials [see Adverse Reactions (6.1)].
`
`Obtain serum aminotransferase, alkaline phosphatase (ALP), and total bilirubin levels prior to
`treatment with TECFIDERA and during treatment, as clinically indicated. Discontinue
`TECFIDERA if clinically significant liver injury induced by TECFIDERA is suspected.
`
`
`
`
`
`
`
`
`
`Page 4 of 19
`
`

`

`
`
`5.5
`
`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 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)].
`
`6
`
`ADVERSE REACTIONS
`
`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)].
`
`• Liver Injury [see Warnings and Precautions (5.4)].
`
`• Flushing [see Warnings and Precautions (5.5)].
`
`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
`
`
`
`
`Flushing
`Abdominal pain
`Diarrhea
`Nausea
`
`
`
`
`TECFIDERA
`N=769
`%
`
`Placebo
`N=771
`%
`
`
`
`
`
`6
`10
`11
`9
`
`40
`18
`14
`12
`
`
`
`
`
`
`Page 5 of 19
`
`

`

`Vomiting
`Pruritus
`Rash
`Albumin urine present
`Erythema
`Dyspepsia
`Aspartate aminotransferase increased
`Lymphopenia
`
`9
`8
`8
`6
`5
`5
`4
`2
`
`Gastrointestinal
`
`5
`4
`3
`4
`1
`3
`2
`<1
`
`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) during controlled trials.
`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.
`
`6.2
`
`Post Marketing Experience
`
`The following adverse reaction has been identified during post approval use of TECFIDERA.
`Because these reactions are reported voluntarily from a population of uncertain size, it is not
`always possible to reliably estimate their frequency or establish a causal relationship to drug
`exposure.
`
`
`
`
`
`
`
`
`
`
`
`Page 6 of 19
`
`

`

`
`
`Liver function abnormalities (elevations in transaminases ≥ 3 times ULN with concomitant
`elevations in total bilirubin > 2 times ULN) have been reported following TECFIDERA
`administration in post marketing experience [See Warnings and Precautions (5.4)].
`
`8
`
`USE IN SPECIFIC POPULATIONS
`
`8.1
`
`Pregnancy
`
`Pregnancy Exposure Registry
`
`There is a pregnancy exposure 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.
`
`Risk Summary
`
`There are no adequate data on the developmental risk associated with the use of TECFIDERA 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 [see Data].
`
`In the U.S. general population, the estimated background risk of major birth defects and
`miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. The
`background risk of major birth defects and miscarriage for the indicated population is unknown.
`
`Data
`
`Animal Data
`
`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.
`
`
`
`
`
`
`
`
`
`
`
`
`
`Page 7 of 19
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`

`

`
`
`8.2
`
`Lactation
`
`Risk Summary
`
`There are no data on the presence of DMF or MMF in human milk. The effects on the breastfed
`infant and on milk production are unknown.
`
`The developmental and health benefits of breastfeeding should be considered along with the
`mother’s clinical need for TECFIDERA and any potential adverse effects on the breastfed infant
`from the drug or from the underlying maternal condition.
`
`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.
`
`10
`
`OVERDOSE
`
`Cases of overdose with TECFIDERA have been reported. The symptoms described in these
`cases were consistent with the known adverse event profile of TECFIDERA.
`
`There are no known therapeutic interventions to enhance elimination of TECFIDERA nor is
`there a known antidote. In the event of overdose, initiate symptomatic supportive treatment as
`clinically indicated.
`
`11
`
`DESCRIPTION
`
`TECFIDERA contains dimethyl fumarate which is also known by its chemical name, dimethyl
`(E) butenedioate, (C6H8O4). It has the following structure:
`
`
`
`
`
`
`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
`
`
`
`
`
`
`
`
`
`O
`
`H
`
`O
`
`O
`
`H
`
`O
`
`Page 8 of 19
`
`

`

`
`
`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.
`
`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.
`
`
`
`
`
`
`
`
`
`Page 9 of 19
`
`

`

`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
`
`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.
`
`Oral Contraceptives
`
`The coadministration of dimethyl fumarate with a combined oral contraceptive (norelgestromin
`and ethinyl estradiol) did not elicit any relevant effects in oral contraceptives exposure. No
`interaction studies have been performed with oral contraceptives containing other progestogens.
`
`
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`13
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`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
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`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).
`
`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.
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`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 TECFIDER