dimethyl fumarate

Recent Major Changes Warnings and Precautions, Serious Gastrointestinal Reactions ( 5.7 ) 12/2023

1 INDICATIONS AND USAGE 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 )

2 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 dimethyl fumarate delayed-release capsules whole and intact. Do not crush, chew, or sprinkle capsule contents on food ( 2.1 ) • Take dimethyl fumarate delayed-release capsules with or without food ( 2.1 ) 2.1 Dosing Information The starting dose for dimethyl fumarate delayed-release capsules 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 dimethyl fumarate delayed-release capsules should be considered for patients unable to tolerate return to the maintenance dose. The incidence of flushing may be reduced by administration of dimethyl fumarate delayed-release capsules with food. Alternatively, administration of non-enteric coated aspirin (up to a dose of 325 mg) 30 minutes prior to dimethyl fumarate delayed-release capsules dosing may reduce the incidence or severity of flushing [see Clinical Pharmacology (12.3)] . Dimethyl fumarate delayed-release capsules should be swallowed whole and intact. Dimethyl fumarate delayed-release capsules should not be crushed or chewed, and the capsule contents should not be sprinkled on food. Dimethyl fumarate delayed-release capsules 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 dimethyl fumarate delayed-release capsules [see Warnings and Precautions ( 5.5 )].

3 DOSAGE FORMS AND STRENGTHS Dimethyl Fumarate Delayed-Release Capsules are available as hard gelatin delayed-release capsules containing 120 mg or 240 mg of dimethyl fumarate. The 120 mg capsules have a white opaque body imprinted with “307” in black ink and a blue cap imprinted with the Glenmark logo “G” in black ink. The 240 mg capsules have a blue body imprinted with “308” in black ink and a blue cap imprinted with the Glenmark logo “G” in black ink. Delayed-release capsules : 120 mg and 240 mg ( 3 )

4 CONTRAINDICATIONS Dimethyl fumarate delayed-release capsules are contraindicated in patients with known hypersensitivity to dimethyl fumarate or to any of the excipients of dimethyl fumarate delayed-release capsules. 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 capsules. ( 4 )

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 )] • 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 Glenmark Pharmaceuticals Inc., USA at 1 (888) 721-7115 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. In placebo-controlled and uncontrolled clinical studies, a total of 2513 patients have received dimethyl fumarate 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 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, 1529 patients received dimethyl fumarate 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 dimethyl fumarate 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 240 mg BID at ≥ 2% higher incidence than placebo Dimethyl Fumarate 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 2 times the ULN. Discontinuations due to elevated hepatic transaminases were 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

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary Available data from the Dimethyl Fumarate Delayed-Release Capsules 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 Delayed-Release Capsules 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: 1.9-6.1). 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. 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 dimethyl fumarate delayed-release capsules 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 dimethyl fumarate did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger patients.

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 .

11 DESCRIPTION Dimethyl Fumarate Delayed-Release Capsules contain dimethyl fumarate which is also known by its chemical name, dimethyl (E) butenedioate, (C 6 H 8 O 4 ). It has the following structure: Dimethyl fumarate is a white to off-white powder that is sparingly soluble in methanol; insoluble in water with a molecular mass of 144.13. Dimethyl Fumarate Delayed-Release Capsules are 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: croscarmellose sodium, hydrophobic colloidal silica, magnesium stearate, methacrylic acid and methyl methacrylate copolymer, methacrylic acid copolymer dispersion (Eudragit L30 D-55), microcrystalline cellulose, simethicone (30% emulsion), talc and triethyl citrate. Eudragit L30 D-55 has the following ingredients: copolymer of methacrylic acid and ethyl acrylate, sodium lauryl sulphate, polysorbate 80 and purified water. The capsule shell for Dimethyl Fumarate Delayed-Release Capsules, 120 mg and 240 mg contains gelatin, titanium dioxide, FD&C blue 1, iron oxide yellow and iron oxide black. The imprinting ink for Dimethyl Fumarate Delayed-Release Capsule, 120 mg and 240 mg has the following components: black iron oxide, potassium hydroxide, and shellac. structure

10 OVERDOSE Cases of overdose with dimethyl fumarate have been reported. The symptoms described in these cases were consistent with the known adverse event profile of dimethyl fumarate. There are no known therapeutic interventions to enhance elimination of dimethyl fumarate nor is there a known antidote. In the event of overdose, initiate symptomatic supportive treatment as clinically indicated.

16 HOW SUPPLIED/STORAGE AND HANDLING Dimethyl Fumarate Delayed-Release Capsules are available as hard gelatin delayed-release capsules in two strengths containing either 120 mg or 240 mg of dimethyl fumarate. The 120 mg capsules are size “1” hard gelatin capsules with a white opaque body imprinted with “307” in black ink and a blue cap imprinted with the Glenmark logo “G” in black ink, filled with white to off-white round shaped minitablets. The 240 mg capsules are size “0” hard gelatin capsules with a blue body imprinted with “308” in black ink and a blue cap imprinted with the Glenmark logo “G” in black ink, filled with white to off‐white round shaped minitablets. Dimethyl Fumarate Delayed-Release Capsules are available as follows: 30-day Starter Pack, (NDC 68462-570-78): 7-day bottle 120 mg capsules, quantity 14 - Store in original container. 23-day bottle 240 mg capsules, quantity 46 - Store in original container. 120 mg capsules: 7-day bottle of 14 capsules (NDC 68462-307-41) - Store in original container. Bottle of 500 count (NDC 68462-307-05) 240 mg capsules: 23-day bottle of 46 capsules (NDC 68462-308-68) - Store in original container. 30-day bottle of 60 capsules (NDC 68462-308-60) - Store in original container. Bottle of 500 count (NDC 68462-308-05) Store at 15°C to 30°C (59°F to 86°F). Protect the capsules from light.