pharmacopeia

Dimethyl Fumarate

Other immunosuppressantsUS-FDASourced from openFDA
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Mechanism of action

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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.

Indications

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  • 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.ICD-10: G35

Contraindications

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  • 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 [see Warnings and Precautions (5.1) ].contraindicated

Dosage & administration

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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 capsule with or without food ( 2.1 ) 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 [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.

Warnings & precautions

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Anaphylaxis and angioedema: Discontinue and do not restart dimethyl fumarate if these occur. ( 5.1 ) Progressive multifocal leukoencephalopathy (PML): Withhold dimethyl fumarate at the first sign or symptom suggestive of PML. ( 5.2 ) Herpes zoster and other serious opportunistic infections: Consider withholding dimethyl fumarate in cases of serious infection until the infection has resolved. ( 5.3 ) Lymphopenia: Obtain a CBC including lymphocyte count before initiating dimethyl fumarate, after 6 months, and every 6 to 12 months thereafter. Consider interruption of dimethyl fumarate if lymphocyte counts <0.5 x 10 9 /L persist for more than six months. ( 5.4 ) Liver injury: Obtain serum aminotransferase, alkaline phosphatase, and total bilirubin levels before initiating dimethyl fumarate and during treatment, as clinically indicated. Discontinue dimethyl fumarate if clinically significant liver injury induced by dimethyl fumarate is suspected. ( 5.5 ) 5.1 Anaphylaxis and Angioedema Dimethyl fumarate 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 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.

Adverse reactions

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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) ]. Most common adverse reactions (incidence ≥10% and ≥2% placebo) were flushing, abdominal pain, diarrhea, and nausea. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact MSN pharmaceuticals Inc. at 1-855-668-2369 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 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. The most common adverse reactions (incidence ≥10% and ≥2% more than placebo) for dimethyl fumarate were flushing, abdominal pain, diarrhea, and nausea. 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) ].

Use in specific populations

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Pregnancy: Based on animal data, may cause fetal harm. ( 8.1 ) 8.1 Pregnancy Risk Summary 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. [see Data] 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.

Pharmacokinetics

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Metabolism
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.

Overdosage

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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.

Approval history

Sourced from openFDA
  • Mar 27, 2013NDANDA204063Biogen
  • Sep 24, 2020ANDAANDA210305Cipla
  • Sep 24, 2020ANDAANDA210402Amneal
  • Sep 24, 2020ANDAANDA210440Alkem Labs Ltd
  • Sep 24, 2020ANDAANDA210460Msn
  • Sep 24, 2020ANDAANDA210500Hetero Labs Ltd Iii
  • Sep 24, 2020ANDAANDA210538Zydus Pharms
  • Oct 6, 2020ANDAANDA210309Glenmark Pharms Ltd

FAERS reports

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Reference statistics only. FAERS reports are voluntarily submitted and are not incidence rates, safety signals, or causal evidence. Counts reflect reporting volume — how often a reaction was reported, not how often it occurs. For decision-grade use, consult openFDA and the FAERS Public Dashboard directly.
122,025 total reports matchedLatest report Share = reports listing the reaction ÷ total matched reports. Rows can sum to >100% because a single report often lists multiple reactions.
  1. 1Flushing17,08414%
  2. 2Nausea8,9657.3%
  3. 3Diarrhoea8,2856.8%
  4. 4Multiple Sclerosis Relapse8,0976.6%
  5. 5Fatigue6,9525.7%
  6. 6Multiple Sclerosis5,7234.7%
  7. 7Vomiting5,6474.6%
  8. 8Memory Impairment5,5654.6%
  9. 9Gastric Disorder5,5514.5%
  10. 10Abdominal Pain Upper5,4074.4%
  11. 11Drug Ineffective5,2154.3%
  12. 12Pruritus5,0614.1%
  13. 13Headache5,0344.1%
  14. 14Fall5,0194.1%
  15. 15Gait Disturbance4,6203.8%

Literature

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Recent PubMed references pinned to Dimethyl Fumarate as a MeSH major topic. Citations link to pubmed.ncbi.nlm.nih.gov.

Clinical trials

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The 10 most recently updated of 147 ClinicalTrials.gov registrations naming Dimethyl Fumarate as an intervention. Registration is not evidence of efficacy or safety — reference crosswalk only.

Frequently asked questions

How does Dimethyl Fumarate work?
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.
What is Dimethyl Fumarate used for?
According to FDA labeling, Dimethyl Fumarate carries indications including: 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.. This is a reference summary of labeled uses, not medical advice or a treatment recommendation.
What class of drug is Dimethyl Fumarate?
Dimethyl Fumarate is classified as Other immunosuppressants.
What are the brand names for Dimethyl Fumarate?
Dimethyl Fumarate is marketed under brand names including Tecfidera.
What are the contraindications for Dimethyl Fumarate?
Dimethyl Fumarate labeling lists contraindications including: 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 [see Warnings and Precautions (5.1) ].. Always consult the full prescribing information and a clinician.
Note. Data for dimethyl-fumarate is illustrative MVP content compiled from public sources. pharmacopeia is for educational and informational use only and is not a substitute for professional medical advice.

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