MYODURA

Dimethyl fumarate is an agent indicated for the treatment of relapsing forms of multiple sclerosis. 3, 4 The mechanism of action of dimethyl fumarate in multiple sclerosis is not well understood.

It is thought to involve dimethyl fumarate degradation to its active metabolite monomethyl fumarate (MMF) then MMF up-regulates the Nuclear factor (erythroid-derived 2)-like 2 (Nrf2) pathway that is activated in response to oxidative stress.

Dimethyl fumarate is marketed under the brand name Tecfidera, and it was the third oral disease-modifying agent for multiple sclerosis approved by the FDA, following fingolimod and teriflunomide.

Prior to its

FDA approval, dimethyl fumarate had been used in Germany for treatment of psoriasis.

Dimethyl fumarate is indicated for the treatment of relapsing forms of multiple sclerosis (MS), including clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease, in adults. 4, 7,

The physiological effects of dimethyl fumarate on the body are not well understood.

It has anti-inflammatory and cytoprotective effects, likely involved in its actions in multiple sclerosis (MS) patients.

Dimethyl fumarate does not cause clinically significant QT interval prolongation.

However, cases of progressive multifocal leukoencephalopathy, serious opportunistic infections, lymphopenia and liver injury have been reported in MS patients treated with this drug.

Dimethyl fumarate may also cause anaphylaxis and angioedema.

Once ingested, dimethyl fumarate is rapidly hydrolyzed by esterases to form monomethyl fumarate (MMF).

Therefore, there is a negligible amount of dimethyl fumarate in the body, and all pharmacokinetic information is quantified with MMF.

The time to maximum concentration (t max ) of MMF ranges between and 2.5 hours.

In patients with multiple sclerosis given 240 mg of dimethyl fumarate two times a day with food, the C max and AUC were 1.87 mg/L and 8.21 mg⋅hr/L, respectively.

High-fat, high-calorie meals decrease the C max of MMF by 40% and cause a t max delay from 2 hours to 5.5 hours; however, these changes are not considered clinically significant.

In healthy people, monomethyl fumarate (MMF) has a variable volume of distribution of 53-73 litres.

Dimethyl fumarate is quickly hydrolyzed by esterases in the gastrointestinal tract, tissues, and blood to form monomethyl fumarate (MMF), its active metabolite.

MMF then undergoes subsequent metabolism through the tricarboxylic acid (TCA) cycle.

The main metabolites of dimethyl fumarate are MMF, glucose, citric, and fumaric acid.

P450 (CYP) enzymes do not participate in the metabolism of dimethyl fumarate.

Hover over products below to view reaction partners Dimethyl fumarate Monomethyl fumarate.

The main route of elimination of dimethyl fumarate is by CO 2 exhalation, which accounts for 60% of the dose.

The other minor routes of elimination are through the kidney (16% of the dose) and feces (1% of the dose).

Trace amounts of unchanged monomethyl fumarate (the active metabolite of dimethyl fumarate) are present in urine.

The dimethyl fumarate metabolite monomethyl fumarate (MMF) has a short half-life of about 1 hour.

MMF does not accumulate after repeated doses of dimethyl fumarate.

Monomethyl fumarate (MMF), the active metabolite of dimethyl fumarate, has a rapid clearance.

Its apparent clearance (Cl/F) appears to be dose-independent.

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Cases of overdose with dimethyl fumarate have been reported, and symptoms were consistent with its adverse event profile.

There are no known therapeutic interventions to enhance dimethyl fumarate elimination nor an antidote.

The product label of dimethyl fumarate recommends initiating symptomatic supportive treatment as clinically indicated in case of overdose.

In vivo carcinogenicity studies found that at doses ranging between and 400 mg/kg/day, mice had a higher incidence of non-glandular stomach and kidney tumors.

The highest dose not associated with tumors in mice (75 mg/kg/day) is equivalent to the recommended human dose (RHD) of 480 mg/day.

Dimethyl fumarate did not show evidence of mutagenicity in the in vitro bacterial reverse mutation (Ames) assay.

Dimethyl fumarate was clastogenic in the in vitro chromosomal aberration assay in human peripheral blood lymphocytes in the absence of metabolic activation, but not clastogenic in the in vivo micronucleus assay in the rat.

Dimethyl fumarate is contraindicated in patients with known hypersensitivity to dimethyl fumarate or to any of the excipients of dimethyl fumarate.

Reactions have included anaphylaxis and angioedema.

Known hypersensitivity to dimethyl fumarate or any of the excipients of dimethyl fumarate.

Starting dose: 120 mg twice a day, orally, for 7 days Maintenance dose after 7 days: 240 mg twice a day, orally Swallow dimethyl fumarate delayed-release capsules whole and intact.

Do not crush, chew, or sprinkle capsule contents on food Take dimethyl fumarate delayed-release capsule with or without food 2.1 Dosing Information The starting dose for dimethyl fumarate delayed-release capsules are 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.

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.

Obtain serum aminotransferase, alkaline phosphatase, and total bilirubin levels prior to treatment with dimethyl fumarate delayed-release capsules.

Dimethyl fumarate is 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 white to off white colored enteric coated mini tablets filled in size "0" empty hard gelatin capsule shell with white opaque cap and white opaque body imprinted with "120 mg" with black ink.

The 240 mg capsules are white to off white colored enteric coated mini tablets filled in size "0" empty hard gelatin capsule shell with white opaque cap and white opaque body imprinted with "240 mg" with black ink.

Dimethyl fumarate delayed-release capsules are available as follows: 30-day Starter Pack, (NDC 69539-240-18): 120 mg (7-day bottle): bottle of 14 capsules (NDC 69539-042-55) 240 mg (23-day bottle): bottle of 46 capsules (NDC 69539-043-46) 120 mg capsules: bottle of 14 capsules (NDC 69539-042-61)Store in original container bottle of 500 capsules (NDC 69539-042-05) 240 mg capsules: bottle of 60 capsules (NDC 69539-043-60)Store in original container bottle of 500 capsules (NDC 69539-043-05) Store at 15°C to 30°C (59 to 86°F).

Protect the capsules from light.

There are no adequate data on the developmental risk associated with the use of dimethyl fumarate 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.

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.

Safety and effectiveness in pediatric patients have not been established.

Clinical studies of dimethyl fumarate did not include sufficient numbers of patients aged and over to determine whether they respond differently from younger patients.