FDA

Dimethyl Fumarate

Approved 24 Sept 2020OralCapsule, delayed release

The FDA lists this product in 36 strengths and forms.

Indications

Dimethyl fumarate delayed-release capsules are 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. Dimethyl fumarate delayed-release capsules are 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)

Contraindications

Dimethyl fumarate delayed-release capsule are contraindicated in patients with known hypersensitivity to dimethyl fumarate or to any of the excipients of dimethyl fumarate delayed-release capsule. Reactions have included anaphylaxis and angioedema [see Warnings and Precautions (5.1) ] . Known hypersensitivity to dimethyl fumarate or any of the excipients of dimethyl fumarate delayed-release capsule. (4)

Warnings and precautions

Anaphylaxis and Angioedema: Discontinue and do not restart dimethyl fumarate if these occur. (5.1) Progressive Multifocal Leukoencephalopathy (PML): Withhold dimethyl fumarate at the first sign or symptom suggestive of PML. (5.2) Herpes Zoster and Other Serious Opportunistic Infections: Consider withholding dimethyl fumarate in cases of serious infection until the infection has resolved. (5.3) Lymphopenia: Obtain a CBC including lymphocyte count before initiating dimethyl fumarate, after 6 months, and every 6 to 12 months thereafter.

Consider interruption of dimethyl fumarate if lymphocyte counts < 0.5 x 10 9 /L persist for more than 6 months. (5.4) Liver Injury: Obtain serum aminotransferase, alkaline phosphatase, and total bilirubin levels before initiating dimethyl fumarate and during treatment, as clinically indicated. Discontinue dimethyl fumarate if clinically significant liver injury induced by dimethyl fumarate is suspected. (5.5)

5.1Anaphylaxis and Angioedema

Dimethyl fumarate 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 dimethyl fumarate and seek immediate medical care should they experience signs and symptoms of anaphylaxis or angioedema.

At a glance

Brand name: Dimethyl Fumarate
Route: Oral
Dosage form: Capsule, delayed release
Applicant: Amneal
Status: Prescription
FDA approval: 24 Sept 2020
Application: ANDA210402-002

Indications

( 1)

Contraindications

Warnings and precautions

5.1Anaphylaxis and Angioedema

Pregnancy and breastfeeding

8.1Pregnancy Risk Summary

Available data from the dimethyl fumarate 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% to 4% and 15% to 20%, respectively. Data Human Data In a prospective observational dimethyl fumarate Pregnancy Registry (2013 to 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 to 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 mg/kg/day, 100 mg/kg/day, 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 mg/kg/day, 75 mg/kg/day, 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 mg/kg/day, 100 mg/kg/day, 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.

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) ] . Serious Gastrointestinal Reactions [see Warnings and Precautions (5.7) ] . Most common adverse reactions (incidence ≥ 10% and ≥ 2% placebo) were flushing, abdominal pain, diarrhea, and nausea. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Amneal Pharmaceuticals LLC at 1-877-835-5472 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. In placebo-controlled and uncontrolled clinical studies, a total of 2,513 patients have received dimethyl fumarate and been followed for periods up to 13 years with an overall exposure of 11,318 person-years.

Approximately 1,169 patients have received more than 5 years of treatment with dimethyl fumarate, and 426 patients have received at least 10 years of treatment with dimethyl fumarate. Adverse Reactions in Placebo-Controlled Trials In the two well-controlled studies demonstrating effectiveness, 1,529 patients received dimethyl fumarate with an overall exposure of 2,244 person-years [see Clinical Studies (14) ] . The adverse reactions presented in the table below are based on safety information from 769 patients treated with dimethyl fumarate delayed-release capsules 240 mg twice a day and 771 placebo-treated patients.

The most common adverse reactions (incidence ≥ 10% and ≥ 2% more than placebo) for dimethyl fumarate were flushing, abdominal pain, diarrhea, and nausea. Table 1: Adverse Reactions in Study 1 and 2 reported for Dimethyl Fumarate Delayed-Release Capsules 240 mg BID at ≥ 2% higher incidence than placebo Dimethyl Fumarate Delayed-Release Capsules N = 769 % Placebo N = 771 % Flushing 40 6 Abdominal pain 18 10 Diarrhea 14 11 Nausea 12 9 Vomiting 9 5 Pruritus 8 4 Rash 8 3 Albumin urine present 6 4 Erythema 5 1 Dyspepsia 5 3 Aspartate aminotransferase increased 4 2 Lymphopenia 2 < 1 Gastrointestinal Dimethyl fumarate 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 dimethyl fumarate compared with placebo. Four percent (4%) of patients treated with dimethyl fumarate 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 dimethyl fumarate; these events, none of which were fatal, included vomiting (0.3%) and abdominal pain (0.3%).

Hepatic Transaminases An increased incidence of elevations of hepatic transaminases in patients treated with dimethyl fumarate 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 dimethyl fumarate 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 dimethyl fumarate or placebo. Eosinophilia A transient increase in mean eosinophil counts was seen during the first 2 months of therapy.

6.2Post-marketing Experience

The following adverse reactions have been identified during post-approval use of dimethyl fumarate. 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) ].

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.

Dimethyl Fumarate

Indications

Contraindications

Warnings and precautions

5.1Anaphylaxis and Angioedema

At a glance

Two medicines in one question?

Dimethyl Fumarate

Indications

Contraindications

Warnings and precautions

5.1Anaphylaxis and Angioedema

At a glance

Two medicines in one question?

5.2Progressive Multifocal Leukoencephalopathy

5.3Herpes Zoster and Other Serious Opportunistic Infections

5.4Lymphopenia

Pregnancy and breastfeeding

8.1Pregnancy Risk Summary

Adverse reactions

6.1Clinical Trials Experience

6.2Post-marketing Experience

Composition

Strengths and forms

Official product information