`CENTER FOR DRUG EVALUATION AND RESEARCH
`
`Approval Package for:
`
`
`APPLICATION NUMBER:
`
`NDA 204063/S-10
`
`
` For the treatment of patients with relapsing forms of
`multiple sclerosis.
`
`
`
`
`Tecfidera
`Trade Name:
`
`
`Dimethyl fumarate
`Generic Name:
`
`Sponsor:
`
`Approval Date:
`
`Indications:
`
`Biogen IDEC Inc.
`
`December 03, 2014
`
`

`

`CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`APPLICATION NUMBER:
`NDA 204063/S-10
`
`
`CONTENTS
`
`
`Reviews / Information Included in this NDA Review.
`
`
`
`Approval Letter
`Approvable Letter
`Labeling
`Summary Review
`Officer/Employee List
`Office Director Memo
`Cross Discipline Team Leader Review
`Medical Review(s)
`Chemistry Review(s)
`Environmental Assessment
`Pharmacology Review(s)
`Statistical Review(s)
`Microbiology Review(s)
`Clinical Pharmacology/Biopharmaceutics Review(s)
`Risk Assessment and Risk Mitigation Review(s)
`Proprietary Name Review(s)
`Other Review(s)
`Administrative/Correspondence Document(s)
`
`
`
`X
`
`X
`X
`
`
`
`
`
`
`
`
`
`
`
`
`X
`X
`
`

`

`CENTER FOR DRUG EVALUATION AND
`
`CENTER FOR DRUG EVALUATION AND
`RESEARCH
`RESEARCH
`
`
`
`
`
`APPLICATION NUMBER:
`NDA 204063/S-10
`NDA 204063/8-10
`
`
`APPLICA TION NUMBER:
`
`APPROVAL LETTER
`
`APPROVAL LETTER
`
`
`
`
`
`

`

`e", “"0"”:-
`
`.e'
`
`in gDEPARTMENTOFHEALTHANDHUMANSERVICES
`
`h
`
`NDA 204063/S-003, 8-008, and S-010
`
`SUPPLEMENT APPROVAL
`
`Food and Drug Administration
`Silver Spring MD 20993
`
`Biogen Idec
`Attention: Nadine D. Cohen, Ph.D.
`
`Senior Vice President, Regulatory Affairs
`14 Cambridge Center
`Cambridge, MA 02142
`
`Dear Dr. Cohen:
`
`Please refer to yoru' Supplemental New Drug Applications (sNDA):
`
`Application
`
`Product Name
`
`Submitted on:
`
`NDA 204063/8-003
`
`Tecfidera (dimethyl fumarate)
`
`January 31, 2014
`
`February 3, 2014
`
`g ro‘v‘al sun _ lement,” _
`This sun '. lement, submitted as a “Prior ‘
`a” (4) temporary dose reduction to manage flushing and
`The
`gastrointestinal side effects associated with Tecfidera treatment.
`
`Application
`
`Product Name
`
`NDA 204063/8-008
`
`Tecfidera (dimethyl furnarate)
`
`July 28. 2014
`
`July 28, 2014
`
`This su : ement, submitted as 3 “Prior .
`
`1 rovais ”lenient,” 7
`
`Highlights and Section 4: Contraindication for patients with known hypersensitivity to
`dimethyl fumarate or to any of the excipients of Tecfidera
`Section 5.1: Hypersensitivity reactions (section added)
`Section 8.1: Pregnancy registry phone number updated and website added
`
`
`
`NDA 204063/S-010
`
`Tecfider‘a (dimethyl frunarate) November 6. 2014 November 6. 2014
`
`This sun . lenient, submitted as :1 “Prior .
`
`.
`
`_‘ mval sun leme'n’t,” . ro: ses chan . es‘to:
`
`Highlights: Warnings and Precautions
`Section 2.1 — Dosing and Administration
`Section 5.2 — Progressive Multifocal Leukoencephalopathy (section added)
`Section 5.3 — Lymphopenia
`Section 17 — Patient Cormseling Information
`Patient Information
`
`Reference ID: 3666921
`
`

`

`
`
`
`
` NDA 204063/S-003, 008, and 010
`
` Page 2
`
`
` We also acknowledge receipt of your amendments to NDA 204063/S-003 dated February 21,
`
`
`
`
`2014 and November 19, 2014; NDA 204063/S-008 dated August 25, 2014, October 17, 2014,
`October 23, 2014, and October 29, 2014; and NDA 204063/S-010 dated November 7, 2014,
`November 25, 2014, November 26, 2014, and December 3, 2014.
`
`
` APPROVAL & LABELING
`
` We have completed our review of these supplemental applications, as amended. They are
`
`
`
`
`
`approved, effective on the date of this letter, for use as recommended in the enclosed, agreed-
`upon labeling text.
`
`
` CONTENT OF LABELING
`
`As soon as possible, but no later than 14 days from the date of this letter, submit the content of
`
`labeling [21 CFR 314.50(l)] in structured product labeling (SPL) format using the FDA
`
`
`
`
`
`automated drug registration and listing system (eLIST), as described at
`
`
`http://www.fda.gov/ForIndustry/DataStandards/StructuredProductLabeling/default.htm. Content
`
`
`of labeling must be identical to the enclosed labeling (text for the package insert, text for the
`
`
`patient package insert), with the addition of any labeling changes in pending “Changes Being
`
`
`
`Effected” (CBE) supplements, as well as annual reportable changes not included in the enclosed
`
`
`labeling.
`
`
`Information on submitting SPL files using eList may be found in the guidance for industry titled
`
`
`
`“SPL Standard for Content of Labeling Technical Qs and As at
`
`
`
`http://www.fda.gov/downloads/DrugsGuidanceComplianceRegulatoryInformation/Guidances/U
`CM072392.pdf.
`
`
`The SPL will be accessible from publicly available labeling repositories.
`
`
`
`Also within 14 days, amend all pending supplemental applications that include labeling changes
`
`
`for this NDA, including CBE supplements for which FDA has not yet issued an action letter,
`
`
`
`with the content of labeling [21 CFR 314.50(l)(1)(i)] in MS Word format, that includes the
`
`
`
`
`
`changes approved in these supplemental applications, as well as annual reportable changes and
`
`
`annotate each change. To facilitate review of your submission, provide a highlighted or marked-
`
`
`up copy that shows all changes, as well as a clean Microsoft Word version. The marked-up copy
`
`should provide appropriate annotations, including supplement number(s) and annual report
`
`
`
`
`
`
`
`date(s).
`
`
`PROMOTIONAL MATERIALS
`
`
`
`
`
`
`
`You may request advisory comments on proposed introductory advertising and promotional
`
`
`labeling. To do so, submit the following, in triplicate, (1) a cover letter requesting advisory
`
`comments, (2) the proposed materials in draft or mock-up form with annotated references, and
`
`(3) the package insert(s) to:
`
`
`
`
`
`Reference ID: 3666921
`
`

`

`
`
`
`
`
`
` NDA 204063/S-003, 008, and 010
`
` Page 3
`
`
` Food and Drug Administration
`
` Center for Drug Evaluation and Research
`
` Office of Prescription Drug Promotion (OPDP)
`
`
` 5901-B Ammendale Road
` Beltsville, MD 20705-1266
`
`
`
`
`
`You must submit final promotional materials and package insert(s), accompanied by a Form
`
`
`
`FDA 2253, at the time of initial dissemination or publication [21 CFR 314.81(b)(3)(i)]. Form
`
`FDA 2253 is available at
`http://www.fda.gov/downloads/AboutFDA/ReportsManualsForms/Forms/UCM083570.pdf.
`
`
` Information and Instructions for completing the form can be found at
`
` http://www.fda.gov/downloads/AboutFDA/ReportsManualsForms/Forms/UCM375154.pdf. For
`
`
` more information about submission of promotional materials to the Office of Prescription Drug
` Promotion (OPDP), see http://www.fda.gov/AboutFDA/CentersOffices/CDER/ucm090142.htm.
`
`
`
` All promotional materials that include representations about your drug product must be promptly
` revised to be consistent with the labeling changes approved in these supplements, including any
`
`
`
`
` new safety information [21 CFR 314.70(a)(4)]. The revisions in your promotional materials
`
`
`
`
`
`
` should include prominent disclosure of the important new safety information that appears in the
`
` revised package labeling. Within 7 days of receipt of this letter, submit your statement of intent
`
`
` to comply with 21 CFR 314.70(a)(4) to the address above or by fax to 301-847-8444.
`
`
`
`
`
`
`
`
`REPORTING REQUIREMENTS
`
`
`We remind you that you must comply with reporting requirements for an approved NDA
`
`
`
`(21 CFR 314.80 and 314.81).
`
`
`
`If you have any questions, contact Laurie Kelley, PA-C, Regulatory Project Manager, via
`
`
`
`
`telephone at (301) 796-5068 or via email at Laurie.Kelley@fda.hhs.gov.
`
`
`
`
`
`Sincerely,
`
`
`{See appended electronic signature page}
`
`
`Billy Dunn, M.D.
`
`Acting Director
`
`Division of Neurology Products
`
`Office of Drug Evaluation I
`
`Center for Drug Evaluation and Research
`
`
`
`
`ENCLOSURE(S):
`
`
`Content of Labeling
`
`
`Reference ID: 3666921
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`WILLIAM H Dunn
`12/03/2014
`
`Reference ID: 3666921
`
`

`

`CENTER FOR DRUG EVALUATION AND
`
` CENTER FOR DRUG EVALUATION AND
`RESEARCH
`RESEARCH
`
`
`
`
`
`APPLICATION NUMBER:
`NDA 204063/S-10
`NDA 204063/8-10
`
`
`APPLICA TION NUMBER:
`
`LABELING
`
`LABELING
`
`
`
`
`
`

`

`
`
`
` 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
`
`
`
`
`
`
`
`12/2014
`Dosage and Administration, Dosing Information (2.1)
`
`
`12/2014
`Contraindications (4)
`
`
`
`
`
`12/2014
`Warnings and Precautions, Anaphylaxis and Angioedema (5.1)
`
`
`
`
`
`Warnings and Precautions, PML (5.2)
`12/2014
`
`
`
`
`Warnings and Precautions, Lymphopenia (5.3)
`12/2014
`
`
`
`
`
`
` _________________
` __________________
`
`
`
`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*
`
`
`
`
`
`
`1
`
`2
`
`
`INDICATIONS AND USAGE
`
`
`
`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
`
`
`
`
`
`Pregnancy
`8.1
`
`
`8.3 Nursing Mothers
`
`
`
`8.4
`Pediatric Use
`
`
`
`6
`
`
`8
`
`
` Tecfidera NDA 204063/S-003, S-008, S-010
`
` FDA Approved Labeling Text 12/3/14
`
`
` ___________________
` ___________________
`
`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 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: 12/2014
`
`
`
`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.
`
`
`
`
`
`Reference ID: 3666921
`
`1
`
`
`
`
`
`
`
`

`

`
` Tecfidera NDA 204063/S-003, S-008, S-010
`
` FDA Approved Labeling Text 12/3/14
`
`
`
` FULL PRESCRIBING INFORMATION
`
`
`
`
`
` 1
`
`
`
` INDICATIONS AND USAGE
`
`
`
` TECFIDERA is indicated for the treatment of patients with relapsing forms of multiple sclerosis.
`
`
`
`
`
` 2
`
`
`
` 2.1
`
`
`
` DOSAGE AND ADMINISTRATION
`
`
`
` 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.
`
`
`
`
`
` 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)].
`
`
`
`
`
` 2.2
`
`
`
` Blood Test 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)].
`
`
`
`
`
`
`
`
`
`
`
`
` 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)].
`
`
`
`
`
`
`Reference ID: 3666921
`
`
`
`
`
`
`

`

`
` Tecfidera NDA 204063/S-003, S-008, S-010
`
` FDA Approved Labeling Text 12/3/14
`
`
`
`
` WARNINGS AND PRECAUTIONS
`
`
`
`
`
` Anaphylaxis and Angioedema
`
`
`
`
` 5
`
`
`
`
`
` 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.
`
`
`
`
`
` 5.2
`
`
`
` Progressive Multifocal Leukoencephalopathy
`
`
`
` A fatal case of progressive multifocal leukoencephalopathy (PML) occurred in a patient with MS
` who received TECFIDERA for 4 years while enrolled in a clinical trial. 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. 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
`
`
`
`
`
`
`
`role of lymphopenia in this case is unknown. 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.
`
`
`
`
`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.
`
`
`
` 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.
`
`
` In these patients, 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.
`
`
`
`
`
`
`Before initiating treatment with TECFIDERA, a CBC including lymphocyte count should be
`
`
`
`
`
`obtained. A CBC including lymphocyte count should also be obtained after 6 months of
`
`treatment, every 6 to 12 months thereafter, and as clinically indicated. Consider interruption of
`
`
`
`
`Reference ID: 3666921
`
`
`
`
`
`
`

`

`
` Tecfidera NDA 204063/S-003, S-008, S-010
`
` FDA Approved Labeling Text 12/3/14
`
`
`
`TECFIDERA in patients with lymphocyte counts <0.5 x 109/L persisting for more than six
`
`
` months. Given the potential for delay in lymphocyte recovery after discontinuation of
`
`
`TECFIDERA, consider following lymphocyte counts until lymphopenia is resolved.
`
`Withholding treatment should be considered in patients with serious infections until the
`infection(s) is resolved. Decisions about whether or not to restart TECFIDERA should be
`
`
`
`individualized based on clinical circumstances.
`
`
`
`
` 5.4
`
`
`
` 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)].
`
`
`
`
`
`
`
`
`
`
`
` • Flushing [see Warnings and Precautions (5.4)].
`
`
`
`
`
` 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.
`
`
`
`
`Reference ID: 3666921
`
`
`
`
`
`
`

`

`
` Tecfidera NDA 204063/S-003, S-008, S-010
`
` FDA Approved Labeling Text 12/3/14
`
`
`Adverse Reactions in Study 1 and 2 reported for TECFIDERA 240 mg BID
`
`at ≥ 2% higher incidence than placebo
`
`
`
`
`Table 1:
`
`
`
`
`
` TECFIDERA
`
` N=769
`
` %
`
`
` 40
`
` 18
`
` 14
`
` 12
`
` 9
`
` 8
`
` 8
`
` 6
`
` 5
`
` 5
`
` 4
`
` 2
`
`
` Placebo
`
` 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
`
`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.
`
`
`
`
`Reference ID: 3666921
`
`
`
`
`
`
`

`

`
` Tecfidera NDA 204063/S-003, S-008, S-010
`
` FDA Approved Labeling Text 12/3/14
`
`
`
` 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 1-866-810-1462 or
`
`visiting www.tecfiderapregnancyregistry.com.
`
`
`
` 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.
`
`
`
` 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.
`
`
`
`
`Reference ID: 3666921
`
`
`
`
`
`
`

`

`
` Tecfidera NDA 204063/S-003, S-008, S-010
`
` FDA Approved Labeling Text 12/3/14
`
`
`
` 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
`
`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).
`
`
`
`
`
`
`Reference ID: 3666921
`
`
`
`
`
`
`O
`
`H
`
`O
`
`O
`
`H
`
`O
`
`

`

`
` Tecfidera NDA 204063/S-003, S-008, S-010
`
` FDA Approved Labeling Text 12/3/14
`
`
`
` 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: 3666921
`
`
`
`
`
`
`

`

`
` Tecfidera NDA 204063/S-003, S-008, S-010
`
` FDA Approved Labeling Text 12/3/14
`
`
`
`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 ca