Drug Safety-related Labeling Changes (SrLC)

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TECFIDERA (NDA-204063)

(DIMETHYL FUMARATE)

Safety-related Labeling Changes Approved by FDA Center for Drug Evaluation and Research (CDER)

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03/12/2024 (SUPPL-31)

Approved Drug Label (PDF)

8 Use in Specific Populations

8.1 Pregnancy

Additions and/or revisions underlined:

Risk Summary

Available data from the TECFIDERA Pregnancy Registry, observational studies, and pharmacovigilance with dimethyl fumarate use in pregnant women have not indicated an increased risk of major birth defects, miscarriage, or other adverse maternal or fetal outcomes. Most of the reported exposures to dimethyl fumarate occurred during the first trimester of pregnancy (see Data). 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).

The background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. 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.

Data

Human Data

In a prospective observational TECFIDERA Pregnancy Registry (2013-2022), the rate of major birth defects among 362 live births and stillbirths from women who were exposed to dimethyl fumarate during pregnancy was 3.6% (95% CI: 1.9-6.1). No specific pattern of major birth defects was identified. Important potential study limitations include exposure misclassification, no adjustment for confounders, and lack of an internal comparator cohort.

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.

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

PATIENT INFORMATION

Additions and/or revisions underlined:

…

Before taking and while you take TECFIDERA, tell your doctor if you have or have had:

• low white blood cell counts or an infection

• any other medical conditions

  Tell your doctor if you are:

• pregnant or plan to become pregnant. It is not known if TECFIDERA will harm your unborn baby. You and your doctor will have to decide if you should take TECFIDERA while you are pregnant or if you plan to become pregnant.

• breastfeeding or plan to breastfeed. It is not known if TECFIDERA passes into your breast milk. You and your doctor should decide if you will take TECFIDERA or breastfeed.

• taking prescription or over-the-counter medicines, vitamins, or herbal supplements

…

12/13/2023 (SUPPL-32)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.7 Serious Gastrointestinal Reactions

(Newly added subsection)

Serious gastrointestinal reactions, including perforation, ulceration, hemorrhage, and obstruction, some with fatal outcomes, have been reported in the postmarketing setting with the use of fumaric acid esters, including TECFIDERA, with or without concomitant aspirin use. The majority of these events have occurred within 6 months of fumaric acid ester treatment initiation. In controlled clinical trials, the incidence of serious gastrointestinal adverse events was 1% in patients treated with TECFIDERA; these events, none of which were fatal, included vomiting (0.3%) and abdominal pain (0.3%) [see Adverse Reactions (6.1)].

Monitor patients, promptly evaluate, and discontinue TECFIDERA for new or worsening severe gastrointestinal signs and symptoms.

6 Adverse Reactions

(Additions and/or revisions underlined)

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)]

• Serious Gastrointestinal Reactions [see Warnings and Precautions (5.7)]

6.1 Clinical Trials Experience

(Additions and/or revisions underlined)

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 clinical trial patients treated with TECFIDERA; these events, none of which were fatal, included vomiting (0.3%) and abdominal pain (0.3%).

6.2 Postmarketing Experience
(Additions and/or revisions underlined)

The following adverse reactions have 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; Gastrointestinal perforation, ulceration, obstruction, and hemorrhage [see Warnings and Precautions (5.7)]

…

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

17 PATIENT COUNSELING INFORMATION

(Additions and/or revisions underlined)

Advise the patient to read the FDA-approved patient labeling (Patient Information).

…

Gastrointestinal (GI) Events

Inform patients that GI events (abdominal pain, diarrhea, and nausea) are some of the most common adverse reactions, especially at the initiation of therapy, and may decrease over time. Some patients may experience more severe GI events. Advise patients to immediately contact their healthcare provider and discontinue TECFIDERA if they experience gastrointestinal bleeding (e.g., rectal bleeding, bloody diarrhea, hematemesis) or other serious gastrointestinal adverse events (e.g., severe abdominal pain, severe vomiting and/or diarrhea) [see Warnings and Precautions (5.7)].

…

02/10/2023 (SUPPL-29)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.4 Lymphopenia

Additions and/or revisions underlined:

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.

…

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 greater than or equal to 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.

6 Adverse Reactions

6.1 Clinical Trials Experience

Additions and/or revision underlined:

…

The most common adverse reactions (incidence greater than or equal to 10% and greater than or equal to 2% more than placebo) for TECFIDERA were flushing, abdominal pain, diarrhea, and nausea.

Table 1: Adverse Reactions in Study 1 and 2 Reported for TECFIDERA 240mg BID at greater than or equal to 2% higher incidence than placebo

…

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 greater than or equal 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 greater than or equal to 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.

8 Use in Specific Populations

8.1 Pregnancy

Additions and/or revisions underlined:

…

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.

…

09/29/2022 (SUPPL-28)

Approved Drug Label (PDF)

6 Adverse Reactions

6.1 Clinical Trials Experience

Additions and/or revisions underlined

…

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.

…

The most common adverse reactions (incidence greater than or equal to I0% and greater than or equal to 2% more than placebo) for TECFIDERA were flushing, abdominal pain, diarrhea, and nausea.

…

09/29/2022 (SUPPL-30)

Approved Drug Label (PDF)

6 Adverse Reactions

6.2 Postmarketing Experience

Additions and/or revisions underlined

…

Gastrointestinal Disorders: Acute pancreatitis

…

02/10/2022 (SUPPL-27)

Approved Drug Label (PDF)

6 Adverse Reactions

6.2 Postmarketing Experience

Additions and/or revisions underlined:

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.

Hepatobiliary Disorders: Liver function abnormalities (elevations in transaminases greater than or equal to 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

01/29/2021 (SUPPL-26)

Approved Drug Label (PDF)

6 Adverse Reactions

6.2 Postmarketing Experience

(Newly added information)

Rhinorrhea has been reported with TECFIDERA administration in post marketing experience.

12/11/2019 (SUPPL-25)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.2 Progressive Multifocal Leukoencephalopathy

(additions and/or revisions underlined)

…

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

...

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5.3 Herpes Zoster and Other Serious Opportunistic Infections

(new subsection added)

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

6 Adverse Reactions

(addition of the following to the bulleted line listing):

• Herpes Zoster and Other Serious Opportunistic Infections

6.2 Postmarketing Experience

(additions underlined)

…

Herpes zoster infection and other serious opportunistic infections have has been reported with TECFIDERA administration in postmarketing experience.

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

PATIENT COUNSELING INFORMATION

(additions underlined)

…

Herpes Zoster and Other Serious Opportunistic Infections

Inform patients that herpes zoster and other serious opportunistic infections have occurred in patients who received TECFIDERA. Instruct the patient of the importance of contacting their doctor if they develop any signs or symptoms associated with herpes zoster or other serious opportunistic infections.

…

PATIENT INFORMATION

(additions underlined)

…

What are the possible side effects of TECFIDERA?

…

• herpes zoster infections (shingles), including central nervous system infections

• other serious infections

...

07/10/2019 (SUPPL-24)

Approved Drug Label (PDF)

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

MEDICATION GUIDE

MEDICATION GUIDE

What is TECFIDERA?

Additions and/or revisions underlined:

• TECFIDERA is a prescription medicine used to treat relapsing forms of multiple sclerosis (MS), to include clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease, in adults.

12/15/2017 (SUPPL-20)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.2 Progressive Multifocal Leukoencephalopathy

(additions underlined)

…

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.

8 Use in Specific Populations

8.1 Pregnancy

(PLLR conversion, additions underlined)

Pregnancy Exposure Registry

There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to TECFIDERA during pregnancy. Encourage patients to enroll by calling 1-866-810-1462 or visiting www.tecfiderapregnancyregistry.com.

Risk Summary

There are no adequate data on the developmental risk associated with the use of TECFIDERA in pregnant women. In animals, adverse effects on offspring survival, growth, sexual maturation, and neurobehavioral function were observed when dimethyl fumarate (DMF) was administered during pregnancy and lactation at clinically relevant doses [see Data].

In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. The background risk of major birth defects and miscarriage for the indicated population is unknown.

Data

Animal Data

In rats administered DMF orally (25, 100, 250 mg/kg/day) throughout organogenesis, embryofetal toxicity (reduced fetal body weight and delayed ossification) were observed at the highest dose tested. This dose also produced evidence of maternal toxicity (reduced body weight). Plasma exposure (AUC) for monomethyl fumarate (MMF), the major circulating metabolite, at the no-effect dose is approximately three times that in humans at the recommended human dose (RHD) of 480 mg/day. In rabbits administered DMF orally (25, 75, and 150 mg/kg/day) throughout organogenesis, embryolethality and decreased maternal body weight were observed at the highest dose tested. The plasma AUC for MMF at the no-effect dose is approximately 5 times that in humans at the RHD.

Oral administration of DMF (25, 100, and 250 mg/kg/day) to rats throughout organogenesis and lactation resulted in increased lethality, persistent reductions in body weight, delayed sexual maturation (male and female pups), and reduced testicular weight at the highest dose tested.

Neurobehavioral impairment was observed at all doses. A no-effect dose for developmental toxicity was not identified. The lowest dose tested was associated with plasma AUC for MMF lower than that in humans at the RHD.

8.2 Lactation

(PLLR conversion, additions underlined)

Risk Summary

There no data on the presence of DMF or MMF in human milk. 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.

01/19/2017 (SUPPL-17)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.4 Liver Injury

(Newly added subsection)

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.

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.

6 Adverse Reactions

(Additions and/or revisions are underlined)

The following important adverse reactions are described elsewhere in labeling:

•         Liver Injury

6.2 Post Marketing Experience

(Newly added subsection)

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.

Liver function abnormalities (elevations in transaminases greater than or equal to 3 times ULN with concomitant elevations in total bilirubin greater than 2 times ULN) have been reported following TECFIDERA administration in post marketing experience.

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

17 PATIENT COUNSELING INFORMATION

(Newly added section)

Liver Injury

Inform patients that TECFIDERA may cause liver injury.  Instruct patients treated with TECFIDERA to report promptly any symptoms that may indicate liver injury, including fatigue, anorexia, right upper abdominal discomfort, dark urine, or jaundice. A blood test should be obtained before patients start therapy and during treatment, as clinically indicated.

Patient Information TECFIDERA® (tek" fi de' rah) (dimethyl fumarate) delayed-release capsules

(Additions and/or revisions are underlined)

What are the possible side effects of TECFIDERA?

• liver problems. Your doctor should do blood tests to check your liver function before you start taking TECFIDERA and during treatment if needed.  Tell your doctor right way if you get any of these symptoms of a liver problem during treatment.

o severe tiredness

o loss of appetite o pain on the right side of your stomach

o have dark or brown (tea color) urine

o yellowing of your skin or the white part of your eyes

02/29/2016 (SUPPL-14)

Approved Drug Label (PDF)

5 Warnings and Precautions

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 (5.3)]. The patient had no other identified systemic medical conditions resulting in compromised immune system function and had not previously been treated with natalizumab, which has a known association with PML. The patient was also not taking any immunosuppressive or immunomodulatory medications concomitantly.
• PML has also occurred in the postmarketing setting in the presence of lymphopenia (<0.8x109/L) persisting for more than 6 months. While the role of lymphopenia in these cases is uncertain, the majority of cases occurred in patients with lymphocyte counts <0.5x 109/L. At the first sign or symptom suggestive of PML, withhold TECFIDERA and perform an appropriate diagnostic evaluation. MRI findings may be apparent before clinical signs or symptoms. 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.

Lymphopenia

• 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.