CLEDERA

Dimethyl fumarate delayed-release capsule contains 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 freely soluble in dichloromethane and very slightly soluble in water with a molecular mass of 144.13.

Dimethyl fumarate is 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: colloidal silicon dioxide, croscarmellose sodium, magnesium stearate, methacrylic acid-ethyl acrylate copolymer, methacrylic acid methyl methacrylate copolymer, microcrystalline cellulose, polysorbate 80, sodium lauryl sulfate, talc and triethyl citrate.

The capsule shell contains the following inactive ingredients: gelatin and titanium dioxide and is imprinted with black ink, Black imprinting ink contains shellac, propylene glycol, black iron oxide and potassium hydroxide. structure.

is indicated for the treatment of adults and children aged 13 years and older with recurrent remitting multiple sclerosis (RPS-SR).

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.

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, 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.

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 T max of

MMF is 2-2.5 hours.

The peak plasma concentration (C max ) 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 C max 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 C max by 40%.

T max was delayed from 2.0 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 and 73 L in healthy subjects.

Human plasma protein binding of

MMF is to 45% and independent of concentration.

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 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.

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.

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, did not alter the pharmacokinetics of MMF.

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.

Pharmacotherapeutic group

Immunosuppressors, other immunosuppressors, ATC code: L04AX07.

The mechanism by which dimethyl fumarate exerts therapeutic effects in patients with PES ns is not fully known.

Preclinical studies indicate that pharmacodynamic responses to dimethyl fumarate appear to be mediated primarily by the activation of the transcriptional pathway of the nuclear factor NRF2 (erythroid-derived 2-like 2).

In patients, dimethyl fumarate increased the expression of the antioxidant genes NRF2-dependent (e.g. NAD(P)H dehydrogenase, quinone 1; . pharmacodynamic effects of the enzyme-reduced mitagonal cells, the enzyme-reduced mitagonal cells, the enzyme-reduced mitagonal cells, the enzyme-reduced mitagonal cells, the enzyme-reduced mitagonal cells, the enzyme-reduced mitagonal cells, the enzyme-reduced mitagonal cells, the enzyme-reparomicated mitagonal cells, the enzyme-

The most common adverse reactions (i.e., diarrhoea, nausea, abdominal pain, upper abdominal pain) are congestive puffs and gastrointestinal effects tend to occur at the beginning of treatment (mainly in the first month) and in patients with congestive puffs and gastrointestinal disorders, these disorders may continue intermittently during treatment with DIMETHYL FUMARATE BIOGARAN.

The most common adverse reactions reported and resulting in discontinuation of treatment (incidence >1%) in patients treated with dimethyl fumarate are the recombinant, recombinant, recombinant, recombinant, recombinant, recombinant, recombinant, recombinant, recombinant, recombinant, recombinant, recombinant, recombinant, recombinant, recombinant, recombinant, recombinant, recombinant, recombinant, recombinant, recombinant, recombinant, recombinant, recombinant, recombinant, recombinant, recombinant, recombinant, recombinant, recombinant, recombinant, recombinant, recombinant, recombinant, recombinant, recombinant, rec.

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.

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.