DIMETHYL FUMARATE- dimethyl fumarate_capsule, delayed release

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 in vivo in vitro 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. , the upper bound of the 90% confidence interval for the largest placebo-adjusted, baseline-corrected QTc was below 10 ms). After oral administration of dimethyl fumarate delayed-release capsules, 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 dimethyl fumarate delayed-release capsules. Therefore all pharmacokinetic analyses related to dimethyl fumarate delayed-release capsules were performed with plasma MMF concentrations. Pharmacokinetic data were obtained in subjects with multiple sclerosis and healthy volunteers. Absorption The median T max max max A high-fat, high-calorie meal did not affect the AUC of MMF but decreased its C max max 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 to 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 CO 2 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 dimethyl fumarate delayed-release capsules. 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 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.

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.

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 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 capsule 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. 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.

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. 1 To report SUSPECTED ADVERSE REACTIONS, contact Torrent Pharma Inc. at 1-800-912-9561 or FDA at 1-800-FDA-1088 or www. gov/medwatch. 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 delayed-release capsules 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 delayed-release capsules, and 426 patients have received at least 10 years of treatment with dimethyl fumarate delayed-release capsules. Adverse Reactions in Placebo-Controlled Trials In the two well-controlled studies demonstrating effectiveness, 1,529 patients received dimethyl fumarate delayed-release capsules 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 delayed-release capsules 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 delayed-release capsules caused GI events (e. , 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 delayed-release capsules compared with placebo. Four percent (4%) of patients treated with dimethyl fumarate delayed-release capsules 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 delayed-release capsules; these events, none of which were fatal, included vomiting (0. 3%) and abdominal pain (0. Hepatic Transaminases An increased incidence of elevations of hepatic transaminases in patients treated with dimethyl fumarate delayed-release capsules 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 delayed-release capsules 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 delayed-release capsules or placebo. Eosinophilia A transient increase in mean eosinophil counts was seen during the first 2 months of therapy. The following adverse reactions have been identified during post-approval use of dimethyl fumarate delayed-release capsules. 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 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.

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) 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. 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 (2013-2022), 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. 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. 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. Safety and effectiveness in pediatric patients have not been established. Clinical studies of dimethyl fumarate delayed-release capsules did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger patients.

Warnings and Precautions, Serious Gastrointestinal Reactions ( 5.7

NONCLINICAL TOXICOLOGY
Carcinogenesis Carcinogenicity studies of dimethyl fumarate (DMF) were conducted in mice and rats. In mice, oral administration of DMF (25, 75, 200, and 400 mg/kg/day) for up to two years resulted in an increase in nonglandular stomach (forestomach) and kidney tumors: squamous cell carcinomas and papillomas of the forestomach in males and females at 200 and 400 mg/kg/day; leiomyosarcomas of the forestomach at 400 mg/kg/day in males and females; renal tubular adenomas and carcinomas at 200 and 400 mg/kg/day in males; and renal tubule adenomas at 400 mg/kg/day in females. Plasma MMF exposure (AUC) at the highest dose not associated with tumors in mice (75 mg/kg/day) was similar to that in humans at the recommended human dose (RHD) of 480 mg/day. In rats, oral administration of DMF (25, 50, 100, and 150 mg/kg/day) for up to two years resulted in increases in squamous cell carcinomas and papillomas of the forestomach at all doses tested in males and females, and in testicular interstitial (Leydig) cell adenomas at 100 and 150 mg/kg/day. Plasma MMF AUC at the lowest dose tested was lower than that in humans at the RHD. Mutagenesis Dimethyl fumarate (DMF) and monomethyl fumarate (MMF) were not mutagenic in the in vitro in vitro in vivo Impairment of Fertility In male rats, oral administration of DMF (75, 250, and 375 mg/kg/day) prior to and throughout the mating period had no effect on fertility; however, increases in non-motile sperm were observed at the mid and high doses. The no-effect dose for adverse effects on sperm is similar to the recommended human dose (RHD) of 480 mg/day on a body surface area (mg/m 2 In female rats, oral administration of DMF (20, 100, and 250 mg/kg/day) prior to and during mating and continuing to gestation day 7 caused disruption of the estrous cycle and increases in embryolethality at the highest dose tested. The highest dose not associated with adverse effects (100 mg/kg/day) is twice the RHD on a mg/m 2 Testicular toxicity (germinal epithelial degeneration, atrophy, hypospermia, and/or hyperplasia) was observed at clinically relevant doses in mice, rats, and dogs in subchronic and chronic oral toxicity studies of DMF, and in a chronic oral toxicity study evaluating a combination of four fumaric acid esters (including DMF) in rats. Kidney toxicity was observed after repeated oral administration of dimethyl fumarate (DMF) in mice, rats, dogs, and monkeys. Renal tubule epithelia regeneration, suggestive of tubule epithelial injury, was observed in all species. Renal tubular hyperplasia was observed in rats with dosing for up to two years. Cortical atrophy and interstitial fibrosis were observed in dogs and monkeys at doses above 5 mg/kg/day. In monkeys, the highest dose tested (75 mg/kg/day) was associated with single cell necrosis and multifocal and diffuse interstitial fibrosis, indicating irreversible loss of renal tissue and function. In dogs and monkeys, the 5 mg/kg/day dose was associated with plasma MMF exposures less than or similar to that in humans at the recommended human dose (RHD). A dose-related increase in incidence and severity of retinal degeneration was observed in mice following oral administration of DMF for up to two years at doses above 75 mg/kg/day, a dose associated with plasma MMF exposure (AUC) similar to that in humans at the RHD.
CLINICAL STUDIES
The efficacy and safety of dimethyl fumarate delayed-release capsules were demonstrated in two studies (Studies 1 and 2) that evaluated dimethyl fumarate delayed-release capsules taken either twice or three times a day in patients with relapsing-remitting multiple sclerosis (RRMS). The starting dose for dimethyl fumarate delayed-release capsules was 120 mg twice or three times a day for the first 7 days, followed by an increase to 240 mg twice or three times a day. Both studies included patients who had experienced at least 1 relapse over the year preceding the trial or had a brain Magnetic Resonance Imaging (MRI) scan demonstrating at least one gadolinium-enhancing (Gd+) lesion within 6 weeks of randomization. The Expanded Disability Status Scale (EDSS) was also assessed and patients could have scores ranging from 0 to 5. Neurological evaluations were performed at baseline, every 3 months, and at the time of suspected relapse. MRI evaluations were performed at baseline, month 6, and year 1 and 2 in a subset of patients (44% in Study 1 and 48% in Study 2). Study 1: Placebo-Controlled Trial in RRMS Study 1 was a 2-year randomized, double-blind, placebo-controlled study in 1,234 patients with RRMS. The primary endpoint was the proportion of patients relapsed at 2 years. Additional endpoints at 2 years included the number of new or newly enlarging T2 hyperintense lesions, number of new T1 hypointense lesions, number of Gd+ lesions, annualized relapse rate (ARR), and time to confirmed disability progression. Confirmed disability progression was defined as at least a 1 point increase from baseline EDSS (1. 5 point increase for patients with baseline EDSS of 0) sustained for 12 weeks. Patients were randomized to receive dimethyl fumarate delayed-release capsules 240 mg twice a day (n=410), dimethyl fumarate delayed-release capsules 240 mg three times a day (n=416), or placebo (n=408) for up to 2 years. The median age was 39 years, median time since diagnosis was 4 years, and median EDSS score at baseline was 2. The median time on study drug for all treatment arms was 96 weeks. The percentages of patients who completed 96 weeks on study drug per treatment group were 69% for patients assigned to dimethyl fumarate delayed-release capsules 240 mg twice a day, 69% for patients assigned to dimethyl fumarate delayed-release capsules 240 mg three times a day and 65% for patients assigned to placebo groups. Dimethyl fumarate delayed-release capsules had a statistically significant effect on all of the endpoints described above and the 240 mg three times daily dose showed no additional benefit over the dimethyl fumarate delayed-release capsules 240 mg twice daily dose. The results for this study (240 mg twice a day vs. placebo) are shown in Table 2 and Figure 1. Table 2: Clinical and MRI Results of Study 1 Dimethyl Fumarate Delayed-Release Capsules 240 mg BID Placebo P-value Clinical Endpoints N=410 N=408 Proportion relapsing (primary endpoint) 27% 46% <0. 0001 Relative risk reduction 49% Annualized relapse rate 0. 0001 Relative reduction 53% Proportion with disability progression 16% 27% 0. 0050 Relative risk reduction 38% MRI Endpoints N=152 N=165 Mean number of new or newly enlarging T2 lesions over 2 years 2. 0001 Percentage of subjects with no new or newly enlarging lesions 45% 27% Number of Gd+ lesions at 2 years Mean (median) 0. 8 (0) Percentage of subjects with 0 lesions 93% 62% 1 lesion 5% 10% 2 lesions <1% 8% 3 to 4 lesions 0 9% 5 or more lesions <1% 11% Relative odds reduction (percentage) 90% <0. 0001 Mean number of new T1 hypointense lesions over 2 years 1. 0001 Figure 1: Time to 12-Week Confirmed Progression of Disability (Study 1) Study 2: Placebo-Controlled Trial in RRMS Study 2 was a 2-year multicenter, randomized, double-blind, placebo-controlled study that also included an open-label comparator arm in patients with RRMS. The primary endpoint was the annualized relapse rate at 2 years. Additional endpoints at 2 years included the number of new or newly enlarging T2 hyperintense lesions, number of T1 hypointense lesions, number of Gd+ lesions, proportion of patients relapsed, and time to confirmed disability progression as defined in Study 1. Patients were randomized to receive dimethyl fumarate delayed-release capsules 240 mg twice a day (n=359), dimethyl fumarate delayed-release capsules 240 mg three times a day (n=345), an open-label comparator (n=350), or placebo (n=363) for up to 2 years. The median age was 37 years, median time since diagnosis was 3 years, and median EDSS score at baseline was 2. The percentages of patients who completed 96 weeks on study drug per treatment group were 70% for patients assigned to dimethyl fumarate delayed-release capsules 240 mg twice a day, 72% for patients assigned to dimethyl fumarate delayed-release capsules 240 mg three times a day and 64% for patients assigned to placebo groups. Dimethyl fumarate delayed-release capsules had a statistically significant effect on the relapse and MRI endpoints described above. There was no statistically significant effect on disability progression. The dimethyl fumarate delayed-release capsules 240 mg three times daily dose resulted in no additional benefit over the dimethyl fumarate delayed-release capsules 240 mg twice daily dose. placebo) are shown in Table 3. Table 3: Clinical and MRI Results of Study 2 Dimethyl Fumarate Delayed-Release Capsules 240 mg BID Placebo P-value Clinical Endpoints N=359 N=363 Annualized relapse rate 0. 0001 Relative reduction 44% Proportion relapsing 29% 41% 0. 0020 Relative risk reduction 34% Proportion with disability progression 13% 17% 0. 25 Relative risk reduction 21% MRI Endpoints N=147 N=144 Mean number of new or newly enlarging T2 lesions over 2 years 5. 0001 Percentage of subjects with no new or newly enlarging lesions 27% 12% Number of Gd+ lesions at 2 years Mean (median) 0. 0) Percentage of subjects with 0 lesions 80% 61% 1 lesion 11% 17% 2 lesions 3% 6% 3 to 4 lesions 3% 2% 5 or more lesions 3% 14% Relative odds reduction (percentage) 74% <0. 0001 Mean number of new T1 hypointense lesions over 2 years 3.

Torrent Pharmaceuticals Limited

• Address:

  OFF ASHRAM ROAD, S/N TORRENT HOUSE, EXTERIOR - EX

• Email:

  Log in to view

DIMETHYL FUMARATE- dimethyl fumarate_capsule, delayed release Product manual source documgent