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
`(cid:12)
`(cid:48)(cid:82)(cid:86)(cid:87)(cid:3)(cid:70)(cid:82)(cid:80)(cid:80)(cid:82)(cid:81)(cid:3)(cid:68)(cid:71)(cid:89)(cid:72)(cid:85)(cid:86)(cid:72)(cid:3)(cid:85)(cid:72)(cid:68)(cid:70)(cid:87)(cid:76)(cid:82)(cid:81)(cid:86)(cid:3)(cid:11) (cid:76)(cid:81)(cid:70)(cid:76)(cid:71)(cid:72)(cid:81)(cid:70)(cid:72)(cid:3)(cid:149)(cid:20)(cid:19)(cid:8)(cid:3)(cid:68)(cid:81)(cid:71)(cid:3)(cid:149)(cid:21)(cid:8)(cid:3)(cid:83)(cid:79)(cid:68)(cid:70)(cid:72)(cid:69)(cid:82) (cid:3)(cid:90)(cid:72)(cid:85)e
`
`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: 9/2022
`
`
`
`
`
`
`
`
`
`
`
`
`
`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
`
`
`
`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
`
`
`2.1
`Dosing Information
`
`
`
`
`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 Opportunistic Infections
`
`
`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: 5053326
`
`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.
`
` DOSAGE AND ADMINISTRATION
`2
`
`
`
`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: 5053326
`
`
`This label may not be the latest approved by FDA.
`For current labeling information, please visit https://www.fda.gov/drugsatfda
`
`

`

`
`
`
`
`
`
`
`
`
`
`
` WARNINGS AND PRECAUTIONS
`5
`
`
`
`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: 5053326
`
`
`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
`(cid:70)(cid:82)(cid:88)(cid:81)(cid:87)(cid:86)(cid:3)(cid:71)(cid:72)(cid:70)(cid:85)(cid:72)(cid:68)(cid:86)(cid:72)(cid:71)(cid:3)(cid:69)(cid:92)(cid:3)(cid:68)(cid:83)(cid:83)(cid:85)(cid:82)(cid:91)(cid:76)(cid:80)(cid:68)(cid:87)(cid:72)(cid:79)(cid:92)(cid:3)(cid:22)(cid:19)(cid:8)(cid:3)(cid:71)(cid:88)(cid:85)(cid:76)(cid:81)(cid:74)(cid:3)(cid:87)(cid:75)(cid:72)(cid:3)(cid:73)(cid:76)(cid:85)(cid:86)(cid:87)(cid:3)(cid:92)(cid:72)(cid:68)(cid:85)(cid:3)(cid:82)(cid:73)(cid:3)(cid:87)(cid:85)(cid:72)(cid:68)(cid:87)(cid:80)(cid:72)(cid:81)(cid:87)(cid:3)(cid:90)(cid:76)(cid:87)(cid:75)(cid:3)(cid:55)(cid:40)(cid:38)(cid:41)(cid:44)(cid:39)(cid:40)(cid:53)(cid:36)(cid:3)(cid:68)(cid:81)(cid:71)(cid:3)(cid:87)(cid:75)(cid:72)(cid:81)(cid:3)
`remained stable. Four weeks after stopping TECFIDERA, mean lymphocyte counts increased but did not
`(cid:12)
`(cid:85)(cid:72)(cid:87)(cid:88)(cid:85)(cid:81)(cid:3)(cid:87)(cid:82)(cid:3)(cid:69)(cid:68)(cid:86)(cid:72)(cid:79)(cid:76)(cid:81)(cid:72)(cid:17)(cid:3)(cid:54)(cid:76)(cid:91)(cid:3)(cid:83)(cid:72)(cid:85)(cid:70)(cid:72)(cid:81)(cid:87)(cid:3) (cid:11)(cid:25)(cid:8) (cid:3)(cid:82)(cid:73)(cid:3)(cid:55)(cid:40)(cid:38)(cid:41)(cid:44)(cid:39)(cid:40)(cid:53)(cid:36)(cid:3)(cid:83)(cid:68)(cid:87)(cid:76)(cid:72)(cid:81)(cid:87)(cid:86)(cid:3)(cid:68)(cid:81)(cid:71)(cid:3)(cid:31)(cid:20)(cid:8)(cid:3)(cid:82)(cid:73)(cid:3)(cid:83)(cid:79)(cid:68)(cid:70)(cid:72)(cid:69)(cid:82)(cid:3)(cid:83)(cid:68)(cid:87)(cid:76)(cid:72)(cid:81)(cid:87)(cid:86)(cid:3)(cid:72)(cid:91)(cid:83)(cid:72)(cid:85)(cid:76)(cid:72)(cid:81)(cid:70)(cid:72)(cid:71)(cid:3)
`lymphocyte counts <0.5x109/L (lower limit of normal 0.91x109(cid:18)(cid:47)(cid:12)(cid:17)(cid:3)(cid:55)(cid:75)(cid:72)(cid:3)(cid:76)(cid:81)(cid:70)(cid:76)(cid:71)(cid:72)(cid:81)(cid:70)(cid:72)(cid:3)(cid:82)(cid:73)(cid:3)(cid:76)(cid:81)(cid:73)(cid:72)(cid:70)(cid:87)(cid:76)(cid:82)(cid:81)(cid:86)(cid:3)(cid:11)(cid:25)(cid:19)(cid:8)(cid:3)(cid:89)(cid:86)(cid:3)
`(cid:24)(cid:27)(cid:8)(cid:12)(cid:3)(cid:68)(cid:81)(cid:71)(cid:3)(cid:86)(cid:72)(cid:85)(cid:76)(cid:82)(cid:88)(cid:86)(cid:3)(cid:76)(cid:81)(cid:73)(cid:72)(cid:70)(cid:87)(cid:76)(cid:82)(cid:81)(cid:86)(cid:3)(cid:11)(cid:21)(cid:8)(cid:3)(cid:89)(cid:86)(cid:3)(cid:21)(cid:8)(cid:12)(cid:3)(cid:90)(cid:68)(cid:86)(cid:3)(cid:86)(cid:76)(cid:80)(cid:76)(cid:79)(cid:68)(cid:85)(cid:3)(cid:76)(cid:81)(cid:3)(cid:83)(cid:68)(cid:87)(cid:76)(cid:72)(cid:81)(cid:87)(cid:86)(cid:3)(cid:87)(cid:85)(cid:72)(cid:68)(cid:87)(cid:72)(cid:71)(cid:3)(cid:90)(cid:76)(cid:87)(cid:75)(cid:3)(cid:55)(cid:40)(cid:38)(cid:41)(cid:44)(cid:39)(cid:40)(cid:53)(cid:36)(cid:3)(cid:82)(cid:85)(cid:3)(cid:83)(cid:79)acebo,
`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)].
`
`(cid:44)(cid:81)(cid:3)(cid:70)(cid:82)(cid:81)(cid:87)(cid:85)(cid:82)(cid:79)(cid:79)(cid:72)(cid:71)(cid:3)(cid:68)(cid:81)(cid:71)(cid:3)(cid:88)(cid:81)(cid:70)(cid:82)(cid:81)(cid:87)(cid:85)(cid:82)(cid:79)(cid:79)(cid:72)(cid:71)(cid:3)(cid:70)(cid:79)(cid:76)(cid:81)(cid:76)(cid:70)(cid:68)(cid:79)(cid:3)(cid:87)(cid:85)(cid:76)(cid:68)(cid:79)(cid:86)(cid:15)(cid:3)(cid:21)(cid:8)(cid:3)(cid:82)(cid:73)(cid:3)(cid:83)(cid:68)(cid:87)(cid:76)(cid:72)(cid:81)(cid:87)(cid:86)(cid:3)(cid:72)(cid:91)(cid:83)(cid:72)(cid:85)(cid:76)(cid:72)(cid:81)(cid:70)(cid:72)(cid:71)(cid:3)(cid:79)(cid:92)(cid:80)(cid:83)(cid:75)(cid:82)(cid:70)(cid:92)(cid:87)(cid:72)(cid:3)(cid:70)(cid:82)(cid:88)(cid:81)(cid:87)(cid:86)(cid:3)
`<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.
`
`
`Reference ID: 5053326
`
`
`This label may not be the latest approved by FDA.
`For current labeling information, please visit https://www.fda.gov/drugsatfda
`
`

`

`
`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
`
`(cid:70)(cid:79)(cid:76)(cid:81)(cid:76)(cid:70)(cid:68)(cid:79)(cid:3)(cid:87)(cid:85)(cid:76)(cid:68)(cid:79)(cid:86)(cid:15)(cid:3)(cid:23)(cid:19)(cid:8)(cid:3)(cid:82)(cid:73)(cid:3)(cid:55)(cid:40)(cid:38)(cid:41)(cid:44)(cid:39)(cid:40)(cid:53)(cid:36)(cid:3)(cid:87)(cid:85)(cid:72)(cid:68)(cid:87)(cid:72)(cid:71)(cid:3)(cid:83)(cid:68)(cid:87)(cid:76)(cid:72)(cid:81)(cid:87)(cid:86)(cid:3)(cid:72)(cid:91)(cid:83)(cid:72)(cid:85)(cid:76)(cid:72)(cid:81)(cid:70)(cid:72)(cid:71)(cid:3)(cid:73)(cid:79)(cid:88)(cid:86)(cid:75)(cid:76)(cid:81)(cid:74)(cid:17)(cid:3)(cid:41)(cid:79)(cid:88)(cid:86)(cid:75)(cid:76)(cid:81)(cid:74)(cid:3)(cid:86)(cid:92)(cid:80)(cid:83)(cid:87)(cid:82)(cid:80)(cid:86)(cid:3)
`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
`(cid:83)(cid:72)(cid:85)(cid:70)(cid:72)(cid:81)(cid:87)(cid:3) (cid:11)(cid:22)(cid:8)(cid:12)(cid:3)(cid:82)(cid:73)(cid:3)(cid:83)(cid:68)(cid:87)(cid:76)(cid:72)(cid:81)(cid:87)(cid:86)(cid:3)(cid:71)(cid:76)(cid:86)(cid:70)(cid:82)(cid:81)(cid:87)(cid:76)(cid:81)(cid:88)(cid:72)(cid:71)(cid:3)(cid:55)(cid:40)(cid:38)(cid:41)(cid:44)(cid:39)(cid:40)(cid:53)(cid:36)(cid:3)(cid:73)(cid:82)(cid:85)(cid:3)(cid:73)(cid:79)(cid:88)(cid:86)(cid:75)(cid:76)(cid:81)(cid:74)(cid:3)(cid:68)(cid:81)(cid:71)(cid:3)(cid:31)(cid:20)(cid:8)(cid:3)(cid:75)(cid:68)(cid:71)(cid:3)(cid:86)(cid:72)(cid:85)(cid:76)(cid:82)(cid:88)(cid:86)(cid:3)(cid:73)(cid:79)(cid:88)(cid:86)(cid:75)(cid:76)(cid:81)(cid:74)(cid:3)
`symptoms that were not life-threatening but led to hospitalization. Administration of
`
`TECFIDERA with food may reduce the incidence of flushing. Alternatively, administration of
`non-enteric coated aspirin (up to a dose of 325 mg) 30 minutes prior to TECFIDERA dosing may
`reduce the incidence or severity of flushing [see Dosing and Administration (2.1) and Clinical
`Pharmacology (12.3)].
`
`
` ADVERSE REACTIONS
`
`6
`The following important adverse reactions are described elsewhere in labeling:
`
` • Anaphylaxis and Angioedema [see Warnings and Precautions (5.1)]
`
`
`• Progressive multifocal leukoencephalopathy [see Warnings and Precautions (5.2)]
`
`• 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)]
`
`
`
`
`
`
`
`
`Reference ID: 5053326
`
`
`This label may not be the latest approved by FDA.
`For current labeling information, please visit https://www.fda.gov/drugsatfda
`
`

`

`
`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.
`(cid:55)(cid:75)(cid:72)(cid:3)(cid:80)(cid:82)(cid:86)(cid:87)(cid:3)(cid:70)(cid:82)(cid:80)(cid:80)(cid:82)(cid:81)(cid:3)(cid:68)(cid:71)(cid:89)(cid:72)(cid:85)(cid:86)(cid:72)(cid:3)(cid:85)(cid:72)(cid:68)(cid:70)(cid:87)(cid:76)(cid:82)(cid:81)(cid:86)(cid:3)(cid:11)(cid:76)(cid:81)(cid:70)(cid:76)(cid:71)(cid:72)(cid:81)(cid:70)(cid:72)(cid:3)(cid:149)(cid:20)(cid:19)(cid:8)(cid:3)(cid:68)(cid:81)(cid:71)(cid:3)(cid:149)(cid:21)(cid:8)(cid:3)(cid:80)(cid:82)(cid:85)(cid:72)(cid:3)(cid:87)(cid:75)(cid:68)(cid:81)(cid:3)(cid:83)(cid:79)(cid:68)(cid:70)(cid:72)(cid:69)(cid:82)(cid:12)(cid:3)(cid:73)(cid:82)(cid:85)(cid:3)
`TECFIDERA were flushing, abdominal pain, diarrhea, and nausea.
`
`
`
`Table 1:
`
`
`
`Adverse Reactions in Study 1 and 2 reported for TECFIDERA 240 mg BID
`
`(cid:68)(cid:87)(cid:3)(cid:149)(cid:3)(cid:21)(cid:8)(cid:3)(cid:75)(cid:76)(cid:74)(cid:75)(cid:72)(cid:85)(cid:3)(cid:76)(cid:81)(cid:70)(cid:76)(cid:71)(cid:72)(cid:81)(cid:70)(cid:72)(cid:3)(cid:87)(cid:75)(cid:68)(cid:81)(cid:3)(cid:83)(cid:79)(cid:68)(cid:70)(cid:72)(cid:69)(cid:82)
`
`TECFIDERA
`Placebo
`N=769
`N=771
`
`
` (cid:8)
` (cid:8)
`
`
`
`
`
`
` 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
`
`(cid:83)(cid:79)(cid:68)(cid:70)(cid:72)(cid:69)(cid:82)(cid:17)(cid:3)(cid:41)(cid:82)(cid:88)(cid:85)(cid:3)(cid:83)(cid:72)(cid:85)(cid:70)(cid:72)(cid:81)(cid:87)(cid:3)(cid:11)(cid:23)(cid:8)(cid:12)(cid:3)(cid:82)(cid:73)(cid:3)(cid:83)(cid:68)(cid:87)(cid:76)(cid:72)(cid:81)(cid:87)(cid:86)(cid:3)(cid:87)(cid:85)(cid:72)(cid:68)(cid:87)(cid:72)(cid:71)(cid:3)(cid:90)(cid:76)(cid:87)(cid:75)(cid:3)(cid:55)(cid:40)(cid:38)(cid:41)(cid:44)(cid:39)(cid:40)(cid:53)(cid:36)(cid:3)(cid:68)(cid:81)(cid:71)(cid:3)(cid:79)(cid:72)(cid:86)(cid:86)(cid:3)(cid:87)(cid:75)(cid:68)(cid:81)(cid:3)(cid:20)(cid:8)(cid:3)(cid:82)(cid:73)(cid:3)(cid:83)(cid:79)(cid:68)(cid:70)(cid:72)(cid:69)(cid:82)(cid:3)
`patients discontinued due to gastrointesti(cid:81)(cid:68)(cid:79)(cid:3)(cid:72)(cid:89)(cid:72)(cid:81)(cid:87)(cid:86)(cid:17)(cid:3)(cid:55)(cid:75)(cid:72)(cid:3)(cid:76)(cid:81)(cid:70)(cid:76)(cid:71)(cid:72)(cid:81)(cid:70)(cid:72)(cid:3)(cid:82)(cid:73)(cid:3)(cid:86)(cid:72)(cid:85)(cid:76)(cid:82)(cid:88)(cid:86)(cid:3)(cid:42)(cid:44)(cid:3)(cid:72)(cid:89)(cid:72)(cid:81)(cid:87)(cid:86)(cid:3)(cid:90)(cid:68)(cid:86)(cid:3)(cid:20)(cid:8)(cid:3)
`in patients treated with TECFIDERA.
`
`Hepatic Transaminases
`An increased incidence of elevations of hepatic transaminases in patients treated with
`
`
`Reference ID: 5053326
`
`
`This label may not be the latest approved by FDA.
`For current labeling information, please visit https://www.fda.gov/drugsatfda
`
`

`

`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.
`(cid:40)(cid:79)(cid:72)(cid:89)(cid:68)(cid:87)(cid:76)(cid:82)(cid:81)(cid:86)(cid:3)(cid:82)(cid:73)(cid:3)(cid:68)(cid:79)(cid:68)(cid:81)(cid:76)(cid:81)(cid:72)(cid:3)(cid:68)(cid:80)(cid:76)(cid:81)(cid:82)(cid:87)(cid:85)(cid:68)(cid:81)(cid:86)(cid:73)(cid:72)(cid:85)(cid:68)(cid:86)(cid:72)(cid:3)(cid:68)(cid:81)(cid:71)(cid:3)(cid:68)(cid:86)(cid:83)(cid:68)(cid:85)(cid:87)(cid:68)(cid:87)(cid:72)(cid:3)(cid:68)(cid:80)(cid:76)(cid:81)(cid:82)(cid:87)(cid:85)(cid:68)(cid:81)(cid:86)(cid:73)(cid:72)(cid:85)(cid:68)(cid:86)(cid:72)(cid:3)(cid:87)(cid:82)(cid:3)(cid:149)(cid:3)(cid:22)(cid:3)(cid:87)(cid:76)(cid:80)(cid:72)(cid:86)(cid:3)(cid:87)(cid:75)(cid:72)(cid:3)(cid:56)(cid:47)(cid:49)(cid:3)
`occurred in a small number of patients treated with both TECFIDERA and placebo and were
`
`(cid:69)(cid:68)(cid:79)(cid:68)(cid:81)(cid:70)(cid:72)(cid:71)(cid:3)(cid:69)(cid:72)(cid:87)(cid:90)(cid:72)(cid:72)(cid:81)(cid:3)(cid:74)(cid:85)(cid:82)(cid:88)(cid:83)(cid:86)(cid:17)(cid:3)(cid:55)(cid:75)(cid:72)(cid:85)(cid:72)(cid:3)(cid:90)(cid:72)(cid:85)(cid:72)(cid:3)(cid:81)(cid:82)(cid:3)(cid:72)(cid:79)(cid:72)(cid:89)(cid:68)(cid:87)(cid:76)(cid:82)(cid:81)(cid:86)(cid:3)(cid:76)(cid:81)(cid:3)(cid:87)(cid:85)(cid:68)(cid:81)(cid:86)(cid:68)(cid:80)(cid:76)(cid:81)(cid:68)(cid:86)(cid:72)(cid:86)(cid:3)(cid:149)(cid:3)(cid:22)(cid:3)(cid:87)(cid:76)(cid:80)(cid:72)(cid:86)(cid:3)(cid:87)(cid:75)(cid:72)(cid:3)(cid:56)(cid:47)(cid:49)(cid:3)(cid:90)(cid:76)(cid:87)(cid:75)(cid:3)
`concomitant elevations in total bilirubin > 2 times the ULN. Discontinuations due to elevated
`
`
`
`
`
`Reference ID: 5053326
`
`This label may not be the latest approved by FDA.
`For current labeling information, please visit https://www.fda.gov/drugsatfda
`
`

`

`he(cid:83)(cid:68)(cid:87)(cid:76)(cid:70)(cid:3)(cid:87)(cid:85)(cid:68)(cid:81)(cid:86)(cid:68)(cid:80)(cid:76)(cid:81)(cid:68)(cid:86)(cid:72)(cid:86)(cid:3)(cid:90)(cid:72)(cid:85)(cid:72)(cid:3)(cid:31)(cid:3)(cid:20)(cid:8)(cid:3)(cid:68)(cid:81)(cid:71)(cid:3)(cid:90)(cid:72)(cid:85)(cid:72)(cid:3)(cid:86)(cid:76)(cid:80)(cid:76)(cid:79)(cid:68)(cid:85)(cid:3)(cid:76)(cid:81)(cid:3)(cid:83)(cid:68)(cid:87)(cid:76)(cid:72)(cid:81)(cid:87)(cid:86)(cid:3)(cid:87)(cid:85)(cid:72)(cid:68)(cid:87)(cid:72)(cid:71)(cid:3)(cid:90)(cid:76)(cid:87)(cid:75)(cid:3)(cid:55)(cid:40)(cid:38)(cid:41)(cid:44)(cid:39)(cid:40)(cid:53)(cid:36)(cid:3)(cid:82)(cid:85)(cid:3)
`placebo.
`
`Eosinophilia
`
`A transient increase in mean eosinophil counts was seen during the first 2 months of therapy.
`
`
`
`
` Postmarketing Experience
`
`6.2
`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
`(cid:43)(cid:72)(cid:83)(cid:68)(cid:87)(cid:82)(cid:69)(cid:76)(cid:79)(cid:76)(cid:68)(cid:85)(cid:92)(cid:3)(cid:39)(cid:76)(cid:86)(cid:82)(cid:85)(cid:71)(cid:72)(cid:85)(cid:86)(cid:29)(cid:3)(cid:47)(cid:76)(cid:89)(cid:72)(cid:85)(cid:3)(cid:73)(cid:88)(cid:81)(cid:70)(cid:87)(cid:76)(cid:82)(cid:81)(cid:3)(cid:68)(cid:69)(cid:81)(cid:82)(cid:85)(cid:80)(cid:68)(cid:79)(cid:76)(cid:87)(cid:76)(cid:72)(cid:86)(cid:3)(cid:11)(cid:72)(cid:79)(cid:72)(cid:89)(cid:68)(cid:87)(cid:76)(cid:82)(cid:81)(cid:86)(cid:3)(cid:76)(cid:81)(cid:3)(cid:87)(cid:85)(cid:68)(cid:81)(cid:86)(cid:68)(cid:80)(cid:76)(cid:81)(cid:68)(cid:86)(cid:72)(cid:86)(cid:3)(cid:149)(cid:3)(cid:22)(cid: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-(cid:23)(cid:8)(cid:3)(cid:68)(cid:81)(cid:71)(cid:3)(cid:20)(cid:24)-(cid:21)(cid:19)(cid:8)(cid:15)(cid:3)(cid:85)(cid:72)(cid:86)(cid:83)(cid:72)(cid:70)(cid:87)(cid:76)(cid:89)(cid:72)(cid:79)(cid:92)(cid:17)(cid:3)(cid:55)(cid:75)(cid:72)(cid:3)
`background risk of major birth defects and miscarriage for the indicated population is unknown.
`
`
`
`
`Reference ID: 5053326
`
`
`This label may not be the latest approved by FDA.
`For current labeling information, please visit https://www.fda.gov/drugsatfda
`
`

`

` 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.
`
`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 determ