Identification
- Summary
Dimethyl fumarate is a medication used to treat patients with the relapsing-remitting form of multiple sclerosis.
- Brand Names
- Tecfidera
- Generic Name
- Dimethyl fumarate
- DrugBank Accession Number
- DB08908
- Background
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.4 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.2 Prior to its FDA approval, dimethyl fumarate had been used in Germany for treatment of psoriasis.2
- Type
- Small Molecule
- Groups
- Approved, Investigational
- Structure
Structure for Dimethyl fumarate (DB08908)
- Weight
- Average: 144.1253
Monoisotopic: 144.042258744 - Chemical Formula
- C6H8O4
- Synonyms
- (E)-But-2-enedioic acid dimethyl ester
- 1,2-bis(methoxycarbonyl)-trans-ethylene
- Dimethyl fumarate
- Dimethyl trans-ethylenedicarboxylate
- Dimethylfumarat
- Fumaric acid, dimethyl ester
- trans-1,2-Ethylenedicarboxylic acid dimethyl ester
- trans-Butenedioic acid dimethyl ester
- External IDs
- AZL O 211089
- AZL-O-211089
- BG 00012
- BG 12
- BG-00012
- BG-12
- BG00012
- FAG-201
- FP-187
- FP187
Pharmacology
- Indication
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
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- Contraindications & Blackbox Warnings
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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.3 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.4
- Mechanism of action
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). Both dimethyl fumarate and MMF up-regulate the Nuclear factor (erythroid-derived 2)-like 2 (Nrf2) pathway that is activated in response to oxidative stress. Dimethyl fumarate also suppresses pro-inflammatory genes through nuclear factor kappa B inhibition. Additionally, MMF acts as an agonist at the nicotinic acid receptor, but the relevance of this is unknown.2,4
It has been suggested that dimethyl fumarate exerts its immunomodulatory effects through changes in the composition and phenotype of immune cells. It reduces CNS infiltration and alters the composition of all lymphocyte subpopulations, especially for cytotoxic and effector T cells. This causes a shift from a mainly pro-inflammatory phenotype to an anti-inflammatory one.3
Target Actions Organism AKelch-like ECH-associated protein 1 binderHumans UTranscription factor p65 inhibitorbinderHumans - Absorption
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.4 The time to maximum concentration (tmax) of MMF ranges between 2 and 2.5 hours. In patients with multiple sclerosis given 240 mg of dimethyl fumarate two times a day with food, the Cmax and AUC were 1.87 mg/L and 8.21 mg⋅hr/L, respectively. High-fat, high-calorie meals decrease the Cmax of MMF by 40% and cause a tmax delay from 2 hours to 5.5 hours; however, these changes are not considered clinically significant.4
- Volume of distribution
In healthy people, monomethyl fumarate (MMF) has a variable volume of distribution of 53 to 73 litres.5
- Protein binding
Monomethyl fumarate (MMF), the active metabolite of dimethyl fumarate, has a plasma protein binding range of 27 to 45%, and the binding process is concentration-independent.5
- Metabolism
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. Cytochrome P450 (CYP) enzymes do not participate in the metabolism of dimethyl fumarate.5
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- Route of elimination
The main route of elimination of dimethyl fumarate is by CO2 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.5
- Half-life
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.4
- Clearance
Monomethyl fumarate (MMF), the active metabolite of dimethyl fumarate, has a rapid clearance. Its apparent clearance (Cl/F) appears to be dose-independent.5
- Adverse Effects
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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.4 In vivo carcinogenicity studies found that at doses ranging between 200 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.4 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.4
- Pathways
- Not Available
- Pharmacogenomic Effects/ADRs
- Not Available
Interactions
- Drug Interactions
- This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.
Drug Interaction Integrate drug-drug
interactions in your softwareAbatacept The risk or severity of adverse effects can be increased when Abatacept is combined with Dimethyl fumarate. Adalimumab The risk or severity of adverse effects can be increased when Adalimumab is combined with Dimethyl fumarate. Adenovirus type 7 vaccine live The risk or severity of infection can be increased when Adenovirus type 7 vaccine live is combined with Dimethyl fumarate. Aldesleukin The risk or severity of adverse effects can be increased when Aldesleukin is combined with Dimethyl fumarate. Alefacept The risk or severity of adverse effects can be increased when Alefacept is combined with Dimethyl fumarate. Alemtuzumab The risk or severity of adverse effects can be increased when Alemtuzumab is combined with Dimethyl fumarate. Allogeneic processed thymus tissue The therapeutic efficacy of Allogeneic processed thymus tissue can be decreased when used in combination with Dimethyl fumarate. Altretamine The risk or severity of adverse effects can be increased when Altretamine is combined with Dimethyl fumarate. Amsacrine The risk or severity of adverse effects can be increased when Amsacrine is combined with Dimethyl fumarate. Anakinra The risk or severity of adverse effects can be increased when Anakinra is combined with Dimethyl fumarate. 
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- Take with or without food. The incidence of flushing may be reduced by the administration of dimethyl fumarate with food; however, the product label states that it may be taken with or without food.
Products
Drug product information from 10+ global regionsOur datasets provide approved product information including:dosage, form, labeller, route of administration, and marketing period.Access drug product information from over 10 global regions.- Active Moieties
Name Kind UNII CAS InChI Key Monomethyl fumarate unknown 45IUB1PX8R 2756-87-8 NKHAVTQWNUWKEO-NSCUHMNNSA-N - Brand Name Prescription Products
Name Dosage Strength Route Labeller Marketing Start Marketing End Region Image Dimethyl Fumarate Capsule 240 mg/1 Oral Teva Pharmaceuticals USA, Inc. 2020-09-28 2024-04-30 US 
Dimethyl Fumarate Capsule 120 mg/1 Oral Teva Pharmaceuticals USA, Inc. 2020-09-28 2023-03-31 US Dimethyl Fumarate Mylan Capsule, delayed release 120 mg Oral Mylan Ireland Limited 2022-05-31 Not applicable EU 
Dimethyl Fumarate Mylan Capsule, delayed release 240 mg Oral Mylan Ireland Limited 2022-05-31 Not applicable EU Dimethyl Fumarate Mylan Capsule, delayed release 240 mg Oral Mylan Ireland Limited 2022-05-31 Not applicable EU Dimethyl Fumarate Mylan Capsule, delayed release 120 mg Oral Mylan Ireland Limited 2022-05-31 Not applicable EU Dimethyl Fumarate Mylan Capsule, delayed release 240 mg Oral Mylan Ireland Limited 2022-05-31 Not applicable EU Dimethyl Fumarate Mylan Capsule, delayed release 240 mg Oral Mylan Ireland Limited 2022-05-31 Not applicable EU Dimethyl Fumarate Mylan Capsule, delayed release 120 mg Oral Mylan Ireland Limited 2022-05-31 Not applicable EU Dimethyl Fumarate Mylan Capsule, delayed release 120 mg Oral Mylan Ireland Limited 2022-05-31 Not applicable EU - Generic Prescription Products
Name Dosage Strength Route Labeller Marketing Start Marketing End Region Image Ach-dimethyl Fumarate Capsule, delayed release 240 mg Oral Accord Healthcare Inc 2021-10-06 Not applicable Canada 
Ach-dimethyl Fumarate Capsule, delayed release 120 mg Oral Accord Healthcare Inc 2021-10-06 Not applicable Canada Apo-dimethyl Fumarate Capsule, delayed release 120 mg Oral Apotex Corporation 2021-10-04 Not applicable Canada Apo-dimethyl Fumarate Capsule, delayed release 240 mg Oral Apotex Corporation 2021-10-04 Not applicable Canada Dimethyl Fumarate Capsule, delayed release 240 mg/1 Oral Lupin Pharmaceuticals, Inc. 2020-10-31 Not applicable US Dimethyl fumarate Capsule, delayed release 240 mg/1 Oral Ascend Laboratories, LLC 2020-09-26 Not applicable US Dimethyl fumarate Capsule 120 mg/1 Oral PHARMATHEN INTERNATIONAL S.A. 2021-08-01 Not applicable US Dimethyl Fumarate Capsule 240 mg/1 Oral Glenmark Pharmaceuticals Inc., USA 2020-10-06 Not applicable US Dimethyl Fumarate Capsule, delayed release 120 mg/1 Oral Zydus Lifesciences Limited 2020-09-28 Not applicable US Dimethyl Fumarate Capsule, delayed release 120 mg/1 Oral Zydus Pharmaceuticals (USA) Inc. 2020-09-28 Not applicable US - Mixture Products
Name Ingredients Dosage Route Labeller Marketing Start Marketing End Region Image Dimethyl Fumarate Dimethyl fumarate (120 mg/1) + Dimethyl fumarate (240 mg/1) Capsule; Kit Oral PHARMATHEN INTERNATIONAL S.A. 2021-08-01 Not applicable US Dimethyl Fumarate Dimethyl fumarate (120 mg/1) + Dimethyl fumarate (240 mg/1) Capsule, delayed release; Kit Oral Amneal Pharmaceuticals NY LLC 2020-09-28 Not applicable US Dimethyl Fumarate Dimethyl fumarate (120 mg/1) + Dimethyl fumarate (240 mg/1) Capsule; Kit Oral TWi Pharmaceuticals, Inc. 2020-12-01 Not applicable US Dimethyl Fumarate Dimethyl fumarate (120 mg/1) + Dimethyl fumarate (240 mg/1) Capsule, delayed release; Kit Oral Zydus Pharmaceuticals (USA) Inc. 2020-09-28 Not applicable US Dimethyl Fumarate Dimethyl fumarate (120 mg/1) + Dimethyl fumarate (240 mg/1) Capsule, delayed release; Kit Oral Ascend Laboratories, LLC 2020-09-26 Not applicable US Dimethyl Fumarate Dimethyl fumarate (120 mg/1) + Dimethyl fumarate (240 mg/1) Capsule, delayed release; Kit Oral Accord Healthcare Inc. 2022-09-26 Not applicable US Dimethyl Fumarate Dimethyl fumarate (120 mg/1) + Dimethyl fumarate (240 mg/1) Capsule, delayed release; Kit Oral Cipla USA Inc. 2020-09-24 Not applicable US Dimethyl Fumarate Dimethyl fumarate (120 mg/1) + Dimethyl fumarate (240 mg/1) Capsule, delayed release; Kit Oral Lupin Pharmaceuticals, Inc. 2020-10-31 Not applicable US Dimethyl Fumarate Dimethyl fumarate (120 mg/1) + Dimethyl fumarate (240 mg/1) Capsule, delayed release; Kit Oral Camber Pharmaceuticals, Inc. 2020-09-24 Not applicable US Dimethyl Fumarate Dimethyl fumarate (120 mg/1) + Dimethyl fumarate (240 mg/1) Capsule, delayed release; Kit Oral Msn Laboratories Private Limited 2021-05-20 Not applicable US
Categories
- ATC Codes
- L04AX07 — Dimethyl fumarate
- Drug Categories
- Chemical TaxonomyProvided by Classyfire
- Description
- This compound belongs to the class of organic compounds known as fatty acid esters. These are carboxylic ester derivatives of a fatty acid.
- Kingdom
- Organic compounds
- Super Class
- Lipids and lipid-like molecules
- Class
- Fatty Acyls
- Sub Class
- Fatty acid esters
- Direct Parent
- Fatty acid esters
- Alternative Parents
- Dicarboxylic acids and derivatives / Methyl esters / Enoate esters / Organic oxides / Hydrocarbon derivatives / Carbonyl compounds
- Substituents
- Aliphatic acyclic compound / Alpha,beta-unsaturated carboxylic ester / Carbonyl group / Carboxylic acid derivative / Carboxylic acid ester / Dicarboxylic acid or derivatives / Enoate ester / Fatty acid ester / Hydrocarbon derivative / Methyl ester
- Molecular Framework
- Aliphatic acyclic compounds
- External Descriptors
- diester, methyl ester, enoate ester (CHEBI:76004)
- Affected organisms
- Humans and other mammals
Chemical Identifiers
- UNII
- FO2303MNI2
- CAS number
- 624-49-7
- InChI Key
- LDCRTTXIJACKKU-ONEGZZNKSA-N
- InChI
- InChI=1S/C6H8O4/c1-9-5(7)3-4-6(8)10-2/h3-4H,1-2H3/b4-3+
- IUPAC Name
- 1,4-dimethyl (2E)-but-2-enedioate
- SMILES
- [H]\C(=C(\[H])C(=O)OC)C(=O)OC
References
- Synthesis Reference
Pullagurla, MR., et al. (2020). Process for the synthesis of dimethyl fumarate (U.S. Patent No. US 10,626,076 B2). U.S. Patent and Trademark Office. https://patentimages.storage.googleapis.com/37/67/f2/c406d1a9840dac/US10626076.pdf
- General References
- Papadopoulou A, D'Souza M, Kappos L, Yaldizli O: Dimethyl fumarate for multiple sclerosis. Expert Opin Investig Drugs. 2010 Dec;19(12):1603-12. doi: 10.1517/13543784.2010.534778. Epub 2010 Nov 11. [Article]
- Venci JV, Gandhi MA: Dimethyl fumarate (Tecfidera): a new oral agent for multiple sclerosis. Ann Pharmacother. 2013 Dec;47(12):1697-702. doi: 10.1177/1060028013509232. Epub 2013 Oct 23. [Article]
- Blair HA: Dimethyl Fumarate: A Review in Relapsing-Remitting MS. Drugs. 2019 Dec;79(18):1965-1976. doi: 10.1007/s40265-019-01229-3. [Article]
- FDA Approved Drug Products: TECFIDERA (dimethyl fumarate) delayed-release capsules for oral use [Link]
- EMA Assessment Report: Tecfidera (dimethyl fumarate) capsules for oral use [Link]
- Santa Cruz Biotechnology: Dimethyl fumarate SDS [Link]
- External Links
- Human Metabolome Database
- HMDB0031257
- KEGG Drug
- D03846
- PubChem Compound
- 637568
- PubChem Substance
- 347827812
- ChemSpider
- 553171
- BindingDB
- 50504654
- 1373478
- ChEBI
- 76004
- ChEMBL
- CHEMBL2107333
- ZINC
- ZINC000003843378
- PharmGKB
- PA166152838
- PDBe Ligand
- EOU
- RxList
- RxList Drug Page
- Drugs.com
- Drugs.com Drug Page
- Wikipedia
- Dimethyl_fumarate
- PDB Entries
- 6lrz
Clinical Trials
- Clinical Trials
Phase Status Purpose Conditions Count 4 Completed Basic Science Relapsing Remitting Multiple Sclerosis (RRMS) 1 4 Completed Other Relapsing Remitting Multiple Sclerosis (RRMS) 1 4 Completed Treatment Multiple Sclerosis 3 4 Completed Treatment Multiple Sclerosis, Relapsing Forms of Multiple Sclerosis 1 4 Completed Treatment Multiple Sclerosis / Relapsing Remitting Multiple Sclerosis (RRMS) 1 4 Completed Treatment Psoriasis Vulgaris (Plaque Psoriasis) 1 4 Completed Treatment Relapsing Remitting Multiple Sclerosis (RRMS) 2 4 Recruiting Treatment Relapsing Remitting Multiple Sclerosis (RRMS) 1 4 Terminated Health Services Research Multiple Sclerosis 1 4 Terminated Treatment Relapsing Remitting Multiple Sclerosis (RRMS) 2
Pharmacoeconomics
- Manufacturers
- Not Available
- Packagers
- Not Available
- Dosage Forms
Form Route Strength Capsule, delayed release Oral Capsule, delayed release Oral 120 mg/1 Capsule, delayed release Oral 240 mg/1 Capsule, delayed release; kit Oral Capsule Oral 120 mg Capsule Oral 240 mg Tablet Oral 120 MG Tablet Oral 30 MG Tablet, delayed release Oral 120 mg Tablet, delayed release Oral 30 mg Tablet, extended release Oral 30 MG Capsule, delayed release Oral 120 mg Capsule, delayed release Oral 240 mg Capsule Oral 120 mg/1 Capsule Oral 240 mg/1 Capsule; kit Oral Capsule Oral Solution Oral 120.0 mg Solution Oral 240.0 mg Capsule, coated Oral 120 mg Capsule, coated Oral 240 mg - Prices
- Not Available
- Patents
Patent Number Pediatric Extension Approved Expires (estimated) Region US7320999 No 2008-01-22 2020-05-18 US US7619001 No 2009-11-17 2018-04-01 US US7803840 No 2010-09-28 2018-04-01 US US8399514 No 2013-03-19 2028-02-07 US US8524773 No 2013-09-03 2018-04-01 US US6509376 No 2003-01-21 2019-10-29 US US8759393 No 2014-06-24 2019-10-29 US US10391160 No 2019-08-27 2035-03-13 US US10959972 No 2021-03-30 2035-11-16 US US10555993 No 2020-02-11 2035-03-13 US US10994003 No 2021-05-04 2035-03-13 US US11007166 No 2021-05-18 2035-11-16 US US11007167 No 2021-05-18 2035-11-16 US US11129806 No 2021-09-28 2035-11-16 US US11246850 No 2015-11-16 2035-11-16 US
Properties
- State
- Solid
- Experimental Properties
Property Value Source melting point (°C) 102 From Santa Cruz Biotechnology SDS boiling point (°C) 192 From Santa Cruz Biotechnology SDS water solubility Highly soluble in water From FDA label - Predicted Properties
Property Value Source Water Solubility 12.9 mg/mL ALOGPS logP 0.45 ALOGPS logP 0.72 Chemaxon logS -1 ALOGPS pKa (Strongest Basic) -6.5 Chemaxon Physiological Charge 0 Chemaxon Hydrogen Acceptor Count 2 Chemaxon Hydrogen Donor Count 0 Chemaxon Polar Surface Area 52.6 Å2 Chemaxon Rotatable Bond Count 4 Chemaxon Refractivity 34.15 m3·mol-1 Chemaxon Polarizability 13.76 Å3 Chemaxon Number of Rings 0 Chemaxon Bioavailability 1 Chemaxon Rule of Five Yes Chemaxon Ghose Filter No Chemaxon Veber's Rule No Chemaxon MDDR-like Rule No Chemaxon - Predicted ADMET Features
- Not Available
Spectra
- Mass Spec (NIST)
- Not Available
- Spectra
Targets
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Yes
- Actions
- Binder
- General Function
- Transcription factor binding
- Specific Function
- Acts as a substrate adapter protein for the E3 ubiquitin ligase complex formed by CUL3 and RBX1 and targets NFE2L2/NRF2 for ubiquitination and degradation by the proteasome, thus resulting in the s...
- Gene Name
- KEAP1
- Uniprot ID
- Q14145
- Uniprot Name
- Kelch-like ECH-associated protein 1
- Molecular Weight
- 69665.765 Da
References
- Oh CJ, Kim JY, Choi YK, Kim HJ, Jeong JY, Bae KH, Park KG, Lee IK: Dimethylfumarate attenuates renal fibrosis via NF-E2-related factor 2-mediated inhibition of transforming growth factor-beta/Smad signaling. PLoS One. 2012;7(10):e45870. doi: 10.1371/journal.pone.0045870. Epub 2012 Oct 8. [Article]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- InhibitorBinder
- Curator comments
- Target undergoes covalent modification involving the cysteine 38 residue. This prevents nuclear translocation of the protein.
- General Function
- Ubiquitin protein ligase binding
- Specific Function
- NF-kappa-B is a pleiotropic transcription factor present in almost all cell types and is the endpoint of a series of signal transduction events that are initiated by a vast array of stimuli related...
- Gene Name
- RELA
- Uniprot ID
- Q04206
- Uniprot Name
- Transcription factor p65
- Molecular Weight
- 60218.53 Da
References
- Kastrati I, Siklos MI, Calderon-Gierszal EL, El-Shennawy L, Georgieva G, Thayer EN, Thatcher GR, Frasor J: Dimethyl Fumarate Inhibits the Nuclear Factor kappaB Pathway in Breast Cancer Cells by Covalent Modification of p65 Protein. J Biol Chem. 2016 Feb 12;291(7):3639-47. doi: 10.1074/jbc.M115.679704. Epub 2015 Dec 18. [Article]
Drug created at June 20, 2013 01:12 / Updated at December 08, 2022 17:54