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)].

5.1 Anaphylaxis and Angioedema

Dimethyl fumarate delayed-release capsules 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 delayed-release capsules 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 dimethyl fumarate delayed-release capsules. 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 dimethyl fumarate delayed-release capsules for 4 years while enrolled in a clinical trial. During the clinical trial, the patient experienced prolonged lymphopenia (lymphocyte counts predominantly <0.5×109/L for 3.5 years) while taking dimethyl fumarate delayed-release capsules [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 (<0.9×109/L). While the role of lymphopenia in these cases is uncertain, the PML cases have occurred predominantly in patients with lymphocyte counts <0.8×109/L persisting for more than 6 months.

At the first sign or symptom suggestive of PML, withhold dimethyl fumarate delayed-release capsules 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.

5.3 Herpes Zoster and Other Serious Opportunistic Infections

Serious cases of herpes zoster have occurred with dimethyl fumarate, 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 dimethyl fumarate 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 dimethyl fumarate, 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 dimethyl fumarate delayed-release capsules treatment in patients with herpes zoster or other serious infections until the infection has resolved [see Adverse Reactions (6.2)].

5.4 Lymphopenia

Dimethyl fumarate delayed-release capsules may decrease lymphocyte counts. In the MS placebo-controlled trials, mean lymphocyte counts decreased by approximately 30% during the first year of treatment with dimethyl fumarate delayed-release capsules and then remained stable. Four weeks after stopping dimethyl fumarate delayed-release capsules, mean lymphocyte counts increased but did not return to baseline. Six percent (6%) of dimethyl fumarate delayed-release capsules patients and <1% of placebo patients experienced lymphocyte counts <0.5×109/L (lower limit of normal 0.91×109/L). The incidence of infections (60% vs 58%) and serious infections (2% vs 2%) was similar in patients treated with dimethyl fumarate delayed-release capsules or placebo, respectively. There was no increased incidence of serious infections observed in patients with lymphocyte counts <0.8×109/L or <0.5×109/L in controlled trials, although one patient in an extension study developed PML in the setting of prolonged lymphopenia (lymphocyte counts predominantly <0.5×109/L for 3.5 years) [see Warnings and Precautions (5.2)].

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 dimethyl fumarate delayed-release capsules was 96 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 dimethyl fumarate delayed-release capsules were as follows:

•

4.3 weeks in patients with mild lymphopenia (lymphocyte count ≥0.8×109/L) at discontinuation,

•

10 weeks in patients with moderate lymphopenia (lymphocyte count 0.5 to <0.8×109/L) at discontinuation, and

•

16.7 weeks in patients with severe lymphopenia (lymphocyte count <0.5×109/L) at discontinuation.

Dimethyl fumarate delayed-release capsules has not been studied in patients with pre-existing low lymphocyte counts.

Obtain a CBC, including lymphocyte count, before initiating treatment with dimethyl fumarate delayed-release capsules, 6 months after starting treatment, and then every 6 to 12 months thereafter, and as clinically indicated. Consider interruption of dimethyl fumarate delayed-release capsules in patients with lymphocyte counts less than 0.5×109/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 dimethyl fumarate delayed-release capsules are discontinued or interrupted due to lymphopenia. Consider withholding treatment from patients with serious infections until resolution. Decisions about whether or not to restart dimethyl fumarate delayed-release capsules should be individualized based on clinical circumstances.

5.5 Liver Injury

Clinically significant cases of liver injury have been reported in patients treated with dimethyl fumarate delayed-release capsules in the postmarketing setting. The onset has ranged from a few days to several months after initiation of treatment with dimethyl fumarate delayed-release capsules. 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 dimethyl fumarate delayed-release capsules and during treatment, as clinically indicated. Discontinue dimethyl fumarate delayed-release capsules if clinically significant liver injury induced by dimethyl fumarate delayed-release capsules is suspected.

5.6 Flushing

Dimethyl fumarate delayed-release capsules may cause flushing (e.g., warmth, redness, itching, and/or burning sensation). In clinical trials, 40% of dimethyl fumarate treated patients experienced flushing. Flushing symptoms generally began soon after initiating dimethyl fumarate delayed-release capsules and usually improved or resolved over time. In the majority of patients who experienced flushing, it was mild or moderate in severity. Three percent (3%) of patients discontinued dimethyl fumarate delayed-release capsules for flushing and <1% had serious flushing symptoms that were not life-threatening but led to hospitalization. Administration of dimethyl fumarate delayed-release capsules 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 dimethyl fumarate delayed-release capsules dosing may reduce the incidence or severity of flushing [see Dosing and Administration (2.1) and Clinical Pharmacology (12.3)].

5.7 Serious Gastrointestinal Reactions

Seriousgastrointestinal 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 dimethyl fumarate delayed-release capsules, 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 dimethyl fumarate delayed-release capsules; 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 dimethyl fumarate delayed-release capsules for new or worsening severe gastrointestinal signs and symptoms.

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.

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. 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.

6.2 Postmarketing 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

8.1 Pregnancy

Risk Summary

There are no adequate data on the developmental risk associated with the use of dimethyl fumarate delayed-release capsules 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 to 4% and 15 to 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

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.

12.2 Pharmacodynamics

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.e., the upper bound of the 90% confidence interval for the largest placebo-adjusted, baseline-corrected QTc was below 10 ms).

12.3 Pharmacokinetics

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 were performed with plasma MMF concentrations. Pharmacokinetic data were obtained in subjects with multiple sclerosis and healthy volunteers.

Absorption

The median Tmax of MMF is 2 to 2.5 hours. The peak plasma concentration (Cmax) and overall exposure (AUC) increased approximately dose proportionally in the dose range studied (120 mg to 360 mg). Following administration of dimethyl fumarate 240 mg twice a day with food, the mean Cmax of MMF was 1.87 mg/L and AUC was 8.21 mg.hr/L in MS patients.

A high-fat, high-calorie meal did not affect the AUC of MMF but decreased its Cmax by 40%. The Tmax was delayed from 2 hours to 5.5 hours. In this study, the incidence of flushing was reduced by approximately 25% in the fed state.

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 CO2 is the primary route of elimination, accounting for approximately 60% of the dimethyl fumarate dose. Renal and fecal elimination are minor routes of elimination, accounting for 16% and 1% of the dose respectively. Trace amounts of unchanged MMF were present in urine.

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 CYP inhibition and induction studies, or in P-glycoprotein studies. Single doses of interferon beta-1a or glatiramer acetate did not alter the pharmacokinetics of MMF. Aspirin, when administered approximately 30 minutes before dimethyl fumarate delayed-release capsules, did not alter the pharmacokinetics of MMF.

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.

Vaccines

A randomized, open-label study examined the concomitant use of dimethyl fumarate delayed-release capsules and several non-live vaccines in adults 27 to 55 years of age with relapsing forms of MS (38 subjects undergoing treatment with dimethyl fumarate delayed-release capsules at the time of vaccination and 33 subjects undergoing treatment with non-pegylated interferon at the time of vaccination). Concomitant exposure to dimethyl fumarate delayed-release capsules did not attenuate antibody responses to tetanus toxoid-containing vaccine, pneumococcal polysaccharide, and meningococcal vaccines relative to antibody responses in interferon-treated patients. The impact of these findings on vaccine effectiveness in this patient population is unknown. The safety and effectiveness of live or live-attenuated vaccines administered concomitantly with dimethyl fumarate delayed-release capsules have not been assessed.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

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 bacterial reverse mutation (Ames) assay. DMF and MMF were clastogenic in the in vitro chromosomal aberration assay in human peripheral blood lymphocytes in the absence of metabolic activation. DMF was not clastogenic in the in vivo micronucleus assay in the rat.

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/m2) basis.

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/m2 basis.

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.

13.2 Animal Toxicology and/or Pharmacology

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.