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)
`
`
`• Herpes zoster and other serious opportunistic infections: Consider
`
`
`withholding TECFIDERA in cases of serious infection until the
`infection has resolved. (5.3)
`
`
`• 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 × 109/L persist for more than 6 months. (5.4)
`
`
`
`
`
`
`
`• 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. (5.5)
`
`
`
`ADVERSE REACTIONS
`
`
`
`
`
`
`
`Most common adverse reactions (incidence ≥10% and ≥2% placebo) were
`
`
`flushing, abdominal pain, diarrhea, and nausea. (6.1)
`To report SUSPECTED ADVERSE REACTIONS, contact Biogen at 1-
`
`
`
`800-456-2255 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
`
`
`USE IN SPECIFIC POPULATIONS
`
`Pregnancy: Based on animal data, may cause fetal harm. (8.1)
`
`
`
`See 17 for PATIENT COUNSELING INFORMATION and FDA
`
`approved patient labeling.
`
`
`
`Revised: 2/2023
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Lactation
`8.2
`
`
`
`Pediatric Use
`8.4
`
`
`Geriatric Use
`8.5
`
`
`10 OVERDOSE
`
`
`11 DESCRIPTION
`
`
`12 CLINICAL PHARMACOLOGY
`
`
`
`12.1 Mechanism of Action
`
`
`12.2
`Pharmacodynamics
`
`
`12.3
`Pharmacokinetics
`
`
`13 NONCLINICAL TOXICOLOGY
`
`
`Carcinogenesis, Mutagenesis, Impairment of
`13.1
`
`Fertility
`
`
`
`13.2 Animal Toxicology and/or Pharmacology
`
`
`14 CLINICAL STUDIES
`
`
`
`16 HOW SUPPLIED/STORAGE AND HANDLING
`
`
`17 PATIENT COUNSELING INFORMATION
`
`*Sections or subsections omitted from the full prescribing information are not
`
`listed.
`
`
`
` HIGHLIGHTS OF PRESCRIBING INFORMATION
`
`
` These highlights do not include all the information needed to use
`TECFIDERA safely and effectively. See full prescribing information
`
`for TECFIDERA.
`
`
`
`TECFIDERA® (dimethyl fumarate) delayed-release capsules, for oral
`use
`
` Initial U.S. Approval: 2013
`
`
`
`RECENT MAJOR CHANGES _________________
`
` _______________
`Warnings and Precautions, Lymphopenia (5.4)
`
`
`02/2023
`
`
`
`
`INDICATIONS AND USAGE
`
`TECFIDERA is indicated for the treatment of relapsing forms of multiple
`
`sclerosis (MS), to include clinically isolated syndrome, relapsing-remitting
`
`
`disease, and active secondary progressive disease, in adults. (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)
`
`
`
`CONTRAINDICATIONS
`
`Known hypersensitivity to dimethyl fumarate or any of the excipients of
`
`TECFIDERA. (4)
`
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`
`
`
`1
`
`2
`
`
`
`INDICATIONS AND USAGE
`
`
`DOSAGE AND ADMINISTRATION
`
`
`
`Dosing Information
`2.1
`
`
`
`2.2
`Blood Tests Prior to Initiation of Therapy
`
`
`
`
`DOSAGE FORMS AND STRENGTHS
`3
`
`
`CONTRAINDICATIONS
`4
`
`
`
`5 WARNINGS AND PRECAUTIONS
`
`
`
`Anaphylaxis and Angioedema
`5.1
`
`
`
`5.2
`Progressive Multifocal Leukoencephalopathy
`
`
`
`
`5.3
`Herpes Zoster and Other Serious OpportunisticInfections
`
`
`5.4
`Lymphopenia
`
`
`
`5.5
`Liver Injury
`
`
`5.6
`Flushing
`
`ADVERSE REACTIONS
`
`
`
`Clinical Trials Experience
`6.1
`
`
`
`6.2
`Post Marketing Experience
`
`
`USE IN SPECIFIC POPULATIONS
`
`
`8.1
`Pregnancy
`
`
`6
`
`
`8
`
`1
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Reference ID: 5124770
`
`This label may not be the latest approved by FDA.
`For current labeling information, please visit https://www.fda.gov/drugsatfda
`
`

`

`
`
`
`
`
`
` FULL PRESCRIBING INFORMATION
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`INDICATIONS AND USAGE
`1
`
` TECFIDERA is indicated for the treatment of relapsing forms of multiple sclerosis (MS), to
`
` include clinically isolated syndrome, relapsing-remitting disease, and active secondary
`
`
` progressive disease, in adults.
`
`
` 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 (5.4)].
`
` Obtain serum aminotransferase, alkaline phosphatase, and total bilirubin levels prior to treatment
`
` with TECFIDERA [see Warnings and Precautions (5.5)].
`
` DOSAGE FORMS AND STRENGTHS
`
`
`
`
` 3
` TECFIDERA is available as hard gelatin delayed-release capsules containing 120 mg or 240 mg
`
`
` of dimethyl fumarate. The 120 mg capsules have a green cap and white body, printed with “BG-
`
`
`
` 12 120 mg” in black ink on the body. The 240 mg capsules have a green cap and a green body,
` printed with “BG-12 240 mg” in black ink on the body.
`
`
`
`
` 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: 5124770
`
`
`This label may not be the latest approved by FDA.
`For current labeling information, please visit https://www.fda.gov/drugsatfda
`
`

`

`
`
` 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.
`
`
`
`
` 5.2
` Progressive Multifocal Leukoencephalopathy
` 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 (5.4)]. 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
`
`
`
` (<0.9x109/L). While the role of lymphopenia in these cases is uncertain, the PML cases have
`
`
` occurred predominantly in patients with lymphocyte counts <0.8x109/L persisting for more than
`
`6 months.
`
`
`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.
`
`
`
`
`Reference ID: 5124770
`
`
`This label may not be the latest approved by FDA.
`For current labeling information, please visit https://www.fda.gov/drugsatfda
`
`

`

` Herpes Zoster and Other Serious Opportunistic Infections
` 5.3
`
`
`
`Serious cases of herpes zoster have occurred with TECFIDERA, including disseminated herpes
`
`
`zoster, herpes zoster ophthalmicus, herpes zoster meningoencephalitis, and herpes zoster
`
`
`
`
`
`meningomyelitis. These events may occur at any time during treatment. Monitor patients on
`
`
`
`TECFIDERA for signs and symptoms of herpes zoster. If herpes zoster occurs, appropriate
`
`
`treatment for herpes zoster should be administered.
`
`
`Other serious opportunistic infections have occurred with TECFIDERA, including cases of
`
`serious viral (herpes simplex virus, West Nile virus, cytomegalovirus), fungal (Candida and
`
`
`
`Aspergillus), and bacterial (Nocardia, Listeria monocytogenes, Mycobacterium tuberculosis)
`
`
`infections. These infections have been reported in patients with reduced absolute lymphocyte
`
`
`
`counts (ALC) as well as in patients with normal ALC. These infections have affected the brain,
`
`meninges, spinal cord, gastrointestinal tract, lungs, skin, eye, and ear. Patients with symptoms
`
`and signs consistent with any of these infections should undergo prompt diagnostic evaluation
`
`
`and receive appropriate treatment.
`
`
`Consider withholding TECFIDERA treatment in patients with herpes zoster or other serious
`
`
`
`infections until the infection has resolved [see Adverse Reactions (6.2)].
`
`
` 5.4
` 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 prolonged, severe
`
`
`
`
` lymphopenia, (defined as lymphocyte counts <0.5 x 109/L for at least six months); in this group
`
`
` of patients, the majority of lymphocyte counts remained <0.5x109/L with continued therapy. In
`
`
`
`
`
` these patients with prolonged, severe lymphopenia, the median time for lymphocyte counts to
`return to normal after discontinuing TECFIDERA was 96.0 weeks.
`
`In these controlled and uncontrolled clinical studies, among patients who did not experience
`
`
`
`
`prolonged, severe lymphopenia during treatment, the median times for lymphocyte counts to
`
`
`return to normal after discontinuing TECFIDERA were as follows:
`
`
`
`
` • 4.3 weeks in patients with mild lymphopenia (lymphocyte count ≥0.8x109/L) at
`
`
`discontinuation,
` • 10.0 weeks in patients with moderate lymphopenia (lymphocyte count 0.5 to
`<0.8x109/L) at discontinuation, and
`
` • 16.7 weeks in patients with severe lymphopenia (lymphocyte count <0.5x109/L) at
`
`discontinuation.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`TECFIDERA has not been studied in patients with pre-existing low lymphocyte counts.
`
`
`Reference ID: 5124770
`
`
`This label may not be the latest approved by FDA.
`For current labeling information, please visit https://www.fda.gov/drugsatfda
`
`

`

`
`
`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.
`
`
`
` Liver Injury
` 5.5
`
`
`
` 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.
`
`
`
`
`
` 5.6
` 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)].
`
`
`
`
`Reference ID: 5124770
`
`
`This label may not be the latest approved by FDA.
`For current labeling information, please visit https://www.fda.gov/drugsatfda
`
`

`

`
` 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)]
`
`
`
`
` • Herpes Zoster and Other Serious Opportunistic Infections [see Warnings and Precautions
`
`
`
` (5.3)]
` • Lymphopenia [see Warnings and Precautions (5.4)]
`
`
` • Liver Injury [see Warnings and Precautions (5.5)]
`
`
`
`
` • Flushing [see Warnings and Precautions (5.6)]
`
`
`
`
`
`
`
`
`
`
`
`
`
` Clinical Trials Experience
` 6.1
`
`
`
`
`
`
` Because clinical trials are conducted under widely varying conditions, adverse reaction rates
` observed in clinical trials of a drug cannot be directly compared to rates in the clinical trials of
`
`
`
`
` another drug and may not reflect the rates observed in clinical practice.
`
`In placebo-controlled and uncontrolled clinical studies, a total of 2513 patients have received
`
`
`TECFIDERA and been followed for periods up to 13 years with an overall exposure of 11,318
`
` person-years. Approximately 1169 patients have received more than 5 years of treatment with
`TECFIDERA, and 426 patients have received at least 10 years of treatment with
`TECFIDERA.
`
`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.
`
`
`
`The most common adverse reactions (incidence ≥10% and ≥2% more than placebo) for
`
`TECFIDERA were flushing, abdominal pain, diarrhea, and nausea.
`
`
`Reference ID: 5124770
`
`
`This label may not be the latest approved by FDA.
`For current labeling information, please visit https://www.fda.gov/drugsatfda
`
`

`

`
`
` Adverse Reactions in Study 1 and 2 reported for TECFIDERA 240 mg BID
`
` at ≥ 2% higher incidence than placebo
`
`
`
` Placebo
` TECFIDERA
`
`
` N=771
`
`
`
` N=769
`
`
`
`
`
` %
` %
`
`
`
`
`
`
` 40
`
` 18
`
` 14
`
` 12
`
` 9
`
` 8
`
` 8
`
` 6
`
` 5
`
` 5
`
` 4
`
` 2
`
`
`
` 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) 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.
`
`
`
`
`
` Table 1:
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Reference ID: 5124770
`
`
`This label may not be the latest approved by FDA.
`For current labeling information, please visit https://www.fda.gov/drugsatfda
`
`

`

`
`
` 6.2
`
`
`
` Postmarketing 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.
` Gastrointestinal Disorders: Acute Pancreatitis
`
`Hepatobiliary Disorders: Liver function abnormalities (elevations in transaminases ≥ 3
`times ULN with concomitant elevations in total bilirubin > 2 times ULN) [see Warnings
`
`
`and Precautions (5.5)]
`
`Infections and Infestations: Herpes zoster infection and other serious opportunistic infections
`
`
`
`
`[see Warnings and Precautions (5.3)]
`Respiratory, Thoracic, and Mediastinal Disorders: Rhinorrhea
`
`Skin and Subcutaneous: Alopecia
`
`
` USE IN SPECIFIC POPULATIONS
`
` 8
`
` 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.
`
`Reference ID: 5124770
`
`
`
`
`This label may not be the latest approved by FDA.
`For current labeling information, please visit https://www.fda.gov/drugsatfda
`
`

`

` 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.
`
`
`
`
` 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.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Reference ID: 5124770
`
`
`This label may not be the latest approved by FDA.
`For current labeling information, please visit https://www.fda.gov/drugsatfda
`
`

`

` DESCRIPTION
` 11
`
`
`
` 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.
`
`
`
`
`
` Pharmacodynamics
` 12.2
` Potential to prolong the QT interval
`
`
` In a placebo controlled thorough QT study performed in healthy subjects, there was no evidence
`
` that dimethyl fumarate caused QT interval prolongation of clinical significance (i.e., the upper
` bound of the 90% confidence interval for the largest placebo-adjusted, baseline-corrected QTc
`
`
` was below 10 ms).
`
`
`
`
`Reference ID: 5124770
`
`
`This label may not be the latest approved by FDA.
`For current labeling information, please visit https://www.fda.gov/drugsatfda
`
`

`

`
`
` 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
`
`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
`
`
`
`
`
`Reference ID: 5124770
`
`
`This label may not be the latest approved by FDA.
`For current labeling information, please visit https://www.fda.gov/drugsatfda
`
`

`

` 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.
`
`
`
` Vaccines
` A randomized, open-label study examined the concomitant use of TECFIDERA and several non-
`
`
` live vaccines in adults 27-55 years of age with relapsing forms of MS (38 subjects undergoing
` treatment with TECFIDERA at the time of vaccination and 33 subjects undergoing treatment
`
`
` with non-pegylated interferon at the time of vaccination). Concomitant exposure to
`TECFIDERA did not attenuate antibody responses to tetanus toxoid-containing vaccine,
`pneumococcal polysaccharide, and meningococcal vaccines relative to antibody responses in
`interferon-treated patients. The impact of these findings on vaccine effectiveness in this patient
`
`
`
`population is unknown. The safety and effectiveness of live or live-attenuated vaccines
`
`administered concomitantly with TECFIDERA have not been assessed.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` NONCLINICAL TOXICOLOGY
`
`
` 13
`
` Carcinogenesis, Mutagenesis, Impairment of Fertility
` 13.1
`
`
` Carcinogenesis
` Carcinogenicity studies