Diroximel fumarate



Diroximel fumarate is a drug used for the treatment of relapsing forms of Multiple Sclerosis (MS).

Brand Names
Generic Name
Diroximel fumarate
DrugBank Accession Number

Multiple Sclerosis (MS) is a chronic, debilitating neurological disease that can lead to profound cognitive and physical symptoms, severely affecting quality of life.3 It is the main cause of neurological disability not caused by trauma in the young adult population of both North America and Europe. Relapsing-remitting forms of MS lead to neurological symptoms that resolve and recur periodically. More than 80% of patients suffering from this disease have relapsing-remitting MS.4

Diroximel fumarate is a new drug from the fumarate class formulated to treat various relapsing forms of MS. This drug is bioequivalent to Dimethyl fumarate6,8(initially manufactured in 2013), but is less likely to cause gastrointestinal side effects, owing to its unique chemical structure. Diroximel fumarate was formulated by Alkermes in collaboration with Biogen, and was approved by the FDA in October 20198 and by the EMA in November 2021.12

Small Molecule
Approved, Investigational
Average: 255.226
Monoisotopic: 255.074287143
Chemical Formula
  • Diroximel fumarate
External IDs
  • ALKS 8700
  • ALKS-8700
  • ALKS8700
  • BIIB-098
  • BIIB098
  • RDC-5108
  • RDC5108



Diroximel fumarate is indicated for the treatment of relapsing forms of multiple sclerosis (MS) in adults; specifically active secondary progressive disease and clinically isolated syndrome, as well as relapsing-remitting MS.7,9,10,13

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Associated Conditions
Indication TypeIndicationCombined Product DetailsApproval LevelAge GroupPatient CharacteristicsDose Form
Treatment ofActive secondary progressive multiple sclerosis•••••••••••••••••
Treatment ofClinically isolated syndrome (cis)•••••••••••••••••
Treatment ofRelapsing remitting multiple sclerosis (rrms)•••••••••••••••••
Contraindications & Blackbox Warnings
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Diroximel fumarate relieves the neurological symptoms of relapsing MS with less gastrointestinal effects than its bioequivalent counterpart, dimethyl fumarate.2,7 It is important to note that diroximel fumarate can cause angioedema, anaphylaxis, hepatotoxicity, flushing, lymphopenia, and Progressive Multifocal Leukoencephalopathy (PML).7

Discontinue diroximel fumarate immediately if PML is suspected or if anaphylaxis or angioedema occur. Liver function and total bilirubin should be tested prior to initiating diroximel fumarate and during treatment. A complete blood count (CBC) should be obtained prior to starting diroximel fumarate, after the first 6 months of administration, and at subsequent intervals of 6 to 12 months following this period. Suspend treatment if lymphocyte counts are measured to be less than 0.5 × 109/L for more than 6 months.7

Mechanism of action

Currently, the mechanism of action of this drug in MS is not fully understood.7 Diroximel fumarate is hypothesized to regulate cell signaling pathways, causing beneficial immune and neuroprotective effects.2 Monomethyl fumarate (MMF) is the active metabolite of diroximel fumarate, and activates the nuclear factor (erythroid-derived 2)-like 2 (Nrf2) pathway in humans. This pathway occurs as a response to oxidative stress in cells.7

In addition to the above, MMF is a nicotinic acid receptor agonist in the laboratory setting. The relevance of this finding to the treatment of MS is unknown at this time.7 The mechanism by which this drug leads to less gastrointestinal effects is purported to be due to its lack of a methanol leaving group in its chemical structure, and substitution with inert 2-hydroxyethyl succinimide.2

UNeuronal acetylcholine receptor subunit alpha-10

Diroximel fumarate is rapidly absorbed in the gastrointestinal tract following administration, like its bioequivalent drug, dimethyl fumarate.6 The median Tmax of monomethyl fumarate (MMF) after oral administration ranges from 2.5-3 hours with a mean Cmax of 2.11 mg/L7. The bioequivalent drug, dimethyl fumarate, administered to healthy volunteers also shows a similar mean Tmax and Cmax.6

The average steady state concentration of this metabolite is estimated at 8.32 mg.hr/L after it is administered twice a day in patients with MS.7 The mean AUC0–∞ of the active metabolite is 88mg × min L−1. Food appears to significantly reduce the Cmax of diroximel fumarate's active metabolite, MMF, when compared to administration in the fasted state.6,7

Volume of distribution

The apparent volume of distribution ranges from 72L to 83L.7 Monomethyl fumarate (MMF), the active metabolite of diroximel fumarate, crosses the blood brain barrier.1

Protein binding

Plasma protein binding of MMF, the active metabolite of diroximel fumarate, ranges from 27-45%.7


Esterases heavily metabolize diroximel fumarate, as well as its bioequivalent drug, dimethyl fumarate, in the liver.6 These enzymes are present in high quantities in the gastrointestinal tract, tissues, and blood. Esterase metabolism of this drug produces the active metabolite, mono methyl fumarate (MMF), before it moves to the systemic circulation. In addition, the major inactive metabolite, 2-hydroxyethyl succinimide (HES) is produced along with small amounts of methanol, and another inactive metabolite, RDC-8439.2,7 Following esterase metabolism, the tricarboxylic acid (TCA)cycle further metabolizes MMF. The major metabolites of MMF in plasma include fumaric acid, citric acid, and glucose.6,7 It is important that methanol is a major metabolite of dimethyl fumarate metabolism, but a minor metabolite of diroximel fumarate metabolism, conferring its lower risk of gastrointestinal effects.2

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Route of elimination

Monomethyl fumarate is eliminated as carbon dioxide through expired breath. Negligible amounts, under 0.3% of the ingested dose, are measured in urine.7 The inactive metabolite, 2-hydroxyethyl succinimide (HES), representing 58-63% of the ingested dose, is excreted in urine.7


The terminal half-life of monomethyl fumarate (MMF), diroximel fumarate's active metabolite, is estimated to be 1 hour.6,7


No clearance information is available on the FDA label for diroximel fumarate7, however, clinical study results for its active metabolite, monomethyl fumarate show a mean apparent total clearance from the plasma after oral administration of 1.54 mgL−1.6

Adverse Effects
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Currently, an MSDS for diroximel fumarate is unavailable. The MSDS for its bioequivalent counterpart, dimethyl fumarate, indicates an oral LD50 of 2,240 mg/kg in rats.MSDS

There is no information regarding overdose on the FDA label for diroximel fumarate. Cases of overdose with its bioequivalent counterpart, dimethyl fumarate, have been reported in the literature, and symptoms reflect the adverse effects of this drug. These symptoms include nausea, vomiting, diarrhea, and flushing, among others.10,11 Currently there is no antidote to an overdose with diroximel fumarate or dimethyl fumarate. Symptomatic and supportive management are the only options up to this date if an overdose should occur.11

Not Available
Pharmacogenomic Effects/ADRs
Not Available


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.
AbataceptThe risk or severity of adverse effects can be increased when Abatacept is combined with Diroximel fumarate.
AdalimumabThe risk or severity of adverse effects can be increased when Adalimumab is combined with Diroximel fumarate.
Adenovirus type 7 vaccine liveThe risk or severity of infection can be increased when Adenovirus type 7 vaccine live is combined with Diroximel fumarate.
AldesleukinThe risk or severity of adverse effects can be increased when Aldesleukin is combined with Diroximel fumarate.
AlefaceptThe risk or severity of adverse effects can be increased when Alefacept is combined with Diroximel fumarate.
Food Interactions
  • Avoid alcohol.
  • Take with or without food. If taken with food, the meal/snack should contain no more than 700 calories and no more than 30 g fat. Taking diroximel fumarate with food may reduce the adverse effect of flushing.


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Brand Name Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
VumerityCapsule231 mg/1OralBiogen Inc.2019-10-29Not applicableUS flag
VumerityCapsule, delayed release231 mgOralBiogen Netherlands B.V.2022-01-17Not applicableEU flag
VumerityCapsule, delayed release231 mgOralBiogen Netherlands B.V.2022-01-17Not applicableEU flag


ATC Codes
L04AX09 — Diroximel fumarate
Drug Categories
Chemical TaxonomyProvided by Classyfire
This compound belongs to the class of organic compounds known as fatty acid esters. These are carboxylic ester derivatives of a fatty acid.
Organic compounds
Super Class
Lipids and lipid-like molecules
Fatty Acyls
Sub Class
Fatty acid esters
Direct Parent
Fatty acid esters
Alternative Parents
Pyrrolidine-2-ones / N-substituted carboxylic acid imides / N-alkylpyrrolidines / Dicarboxylic acids and derivatives / Methyl esters / Enoate esters / Dicarboximides / Lactams / Azacyclic compounds / Organonitrogen compounds
show 3 more
2-pyrrolidone / Aliphatic heteromonocyclic compound / Alpha,beta-unsaturated carboxylic ester / Azacycle / Carbonyl group / Carboxylic acid derivative / Carboxylic acid ester / Carboxylic acid imide / Carboxylic acid imide, n-substituted / Dicarboximide
show 15 more
Molecular Framework
Aliphatic heteromonocyclic compounds
External Descriptors
Not Available
Affected organisms
  • Humans

Chemical Identifiers

CAS number
InChI Key
1-[2-(2,5-dioxopyrrolidin-1-yl)ethyl] 4-methyl (2E)-but-2-enedioate


Synthesis Reference

Adv Ther (2019) 36:3154–3165 https://doi.org/10.1007/s12325-019-01085-3

General References
  1. Mills EA, Ogrodnik MA, Plave A, Mao-Draayer Y: Emerging Understanding of the Mechanism of Action for Dimethyl Fumarate in the Treatment of Multiple Sclerosis. Front Neurol. 2018 Jan 23;9:5. doi: 10.3389/fneur.2018.00005. eCollection 2018. [Article]
  2. Palte MJ, Wehr A, Tawa M, Perkin K, Leigh-Pemberton R, Hanna J, Miller C, Penner N: Improving the Gastrointestinal Tolerability of Fumaric Acid Esters: Early Findings on Gastrointestinal Events with Diroximel Fumarate in Patients with Relapsing-Remitting Multiple Sclerosis from the Phase 3, Open-Label EVOLVE-MS-1 Study. Adv Ther. 2019 Nov;36(11):3154-3165. doi: 10.1007/s12325-019-01085-3. Epub 2019 Sep 19. [Article]
  3. Ghasemi N, Razavi S, Nikzad E: Multiple Sclerosis: Pathogenesis, Symptoms, Diagnoses and Cell-Based Therapy. Cell J. 2017 Apr-Jun;19(1):1-10. Epub 2016 Dec 21. [Article]
  4. Dutta R, Trapp BD: Relapsing and progressive forms of multiple sclerosis: insights from pathology. Curr Opin Neurol. 2014 Jun;27(3):271-8. doi: 10.1097/WCO.0000000000000094. [Article]
  5. Sheikh SI, Nestorov I, Russell H, O'Gorman J, Huang R, Milne GL, Scannevin RH, Novas M, Dawson KT: Tolerability and pharmacokinetics of delayed-release dimethyl fumarate administered with and without aspirin in healthy volunteers. Clin Ther. 2013 Oct;35(10):1582-1594.e9. doi: 10.1016/j.clinthera.2013.08.009. [Article]
  6. Litjens NH, Burggraaf J, van Strijen E, van Gulpen C, Mattie H, Schoemaker RC, van Dissel JT, Thio HB, Nibbering PH: Pharmacokinetics of oral fumarates in healthy subjects. Br J Clin Pharmacol. 2004 Oct;58(4):429-32. doi: 10.1111/j.1365-2125.2004.02145.x. [Article]
  7. Vumerity FDA label [Link]
  8. Biogen and Alkermes Announce FDA Approval of VUMERITY™ (diroximel fumarate) for Multiple Sclerosis [Link]
  9. FDA Clears More Tolerable Diroximel Fumarate (Vumerity) for MS [Link]
  10. Drugs.com: FDA approves Vumerity [Link]
  11. FDA Approved Drug Products: TECFIDERA (dimethyl fumarate) delayed-release capsules, for oral use [Link]
  12. EMA Summary of Opinion: Vumerity (diroximel fumarate) [Link]
  13. FDA Approved Drug Products: VUMERITY (diroximel fumarate) delayed-release capsules, for oral use (February 2023) [Link]
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Clinical Trials

Clinical Trials
4Active Not RecruitingTreatmentRelapsing Remitting Multiple Sclerosis (RRMS)1
3CompletedTreatmentMultiple Sclerosis1
3CompletedTreatmentRelapsing Remitting Multiple Sclerosis (RRMS)1
3RecruitingTreatmentMultiple Sclerosis1
3RecruitingTreatmentRelapsing Multiple Sclerosis (RMS)1


Not Available
Not Available
Dosage Forms
CapsuleOral231 mg/1
CapsuleOral231.00 mg
Capsule, delayed releaseOral231 mg
Not Available
Patent NumberPediatric ExtensionApprovedExpires (estimated)Region
US9090558No2015-07-282033-09-20US flag
US10080733No2018-09-252033-09-20US flag
US8669281No2014-03-112033-09-20US flag


Experimental Properties
melting point (°C)102-106https://www.nwmissouri.edu/naturalsciences/sds/d/Dimethyl%20fumarate.pdf
boiling point (°C)192-193https://www.nwmissouri.edu/naturalsciences/sds/d/Dimethyl%20fumarate.pdf
Predicted Properties
Water Solubility5.5 mg/mLALOGPS
pKa (Strongest Basic)-6.3Chemaxon
Physiological Charge0Chemaxon
Hydrogen Acceptor Count4Chemaxon
Hydrogen Donor Count0Chemaxon
Polar Surface Area89.98 Å2Chemaxon
Rotatable Bond Count7Chemaxon
Refractivity59.35 m3·mol-1Chemaxon
Polarizability23.89 Å3Chemaxon
Number of Rings1Chemaxon
Rule of FiveYesChemaxon
Ghose FilterYesChemaxon
Veber's RuleNoChemaxon
MDDR-like RuleNoChemaxon
Predicted ADMET Features
Not Available


Mass Spec (NIST)
Not Available
SpectrumSpectrum TypeSplash Key
Predicted MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSsplash10-056r-2920000000-1c9e21a27d505eafe8c0
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSsplash10-0002-9610000000-d4f25cc48491aa3546aa
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSsplash10-0fg9-7930000000-ee534e25fb987b7c1c3f
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSsplash10-007a-9200000000-d849942f4c87bac08925
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSsplash10-006t-9000000000-100c0f671bbe0789a57b
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSsplash10-00ds-9200000000-2b00da307bd095dc29a9
Predicted 1H NMR Spectrum1D NMRNot Applicable
Predicted 13C NMR Spectrum1D NMRNot Applicable
Chromatographic Properties
Collision Cross Sections (CCS)
Not Available


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Pharmacological action
General Function
Receptor binding
Specific Function
Ionotropic receptor with a probable role in the modulation of auditory stimuli. Agonist binding may induce an extensive change in conformation that affects all subunits and leads to opening of an i...
Gene Name
Uniprot ID
Uniprot Name
Neuronal acetylcholine receptor subunit alpha-10
Molecular Weight
49704.295 Da
  1. Vumerity FDA label [Link]

Drug created at May 20, 2019 14:26 / Updated at May 25, 2024 00:54