Dimethyl Fumarate (Page 3 of 6)

6.2 Postmarketing Experience

The following adverse reaction has 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.
Liver function abnormalities (elevations in transaminases ≥ 3 times ULN with concomitant elevations in total bilirubin > 2 times ULN) have been reported following dimethyl fumarate delayed-release capsules administration in post marketing experience [See Warnings and Precautions (5.5)].

Herpes zoster infection and other serious opportunistic infections have has been reported with dimethyl fumarate delayed-release capsules administration in postmarketing experience [See Warnings and Precautions (5.3)].

8 USE IN SPECIFIC POPULATIONS

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 delayed-release capsules did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger patients.

10 OVERDOSE


Cases of overdose with dimethyl fumarate delayed-release capsules have been reported. The symptoms described in these cases were consistent with the known adverse event profile of dimethyl fumarate delayed-release capsules.
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.

11 DESCRIPTION

Dimethyl fumarate delayed-release capsules contain dimethyl fumarate which is also known by its chemical name, dimethyl (E) butenedioate, (C6 H8 O4 ). It has the following structure:

dimethylfumaratestructure

Dimethyl fumarate is a white to off white powder that is slightly soluble in dimethylformamide 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: calcium silicate, colloidal silicon dioxide, croscarmellose sodium, gelatin, magnesium stearate, methacrylic acid and ethyl acrylate copolymer, methacrylic acid and methyl methacrylate copolymer, poloxamer, polysorbate 80, silicified microcrystalline cellulose, sodium bicarbonate, sodium lauryl sulfate, talc, titanium dioxide and triethyl citrate. In addition, the 120 mg capsules also contain FD&C Blue 1, iron oxide black and iron oxide yellow. The imprinting ink contains the following inactive ingredients: black iron oxide, potassium hydroxide, propylene glycol, shellac and strong ammonia solution.

12 CLINICAL PHARMACOLOGY

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 delayed-release capsules 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 delayed-release capsules 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 2.0 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 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 delayed-release capsules 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.

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