 | |
| Clinical data | |
|---|---|
| Trade names | Vumerity |
| Other names | ALKS-8700 |
| AHFS/Drugs.com | Monograph |
| MedlinePlus | a620002 |
| License data | |
| Pregnancy category | |
| Routes of administration | By mouth |
| ATC code | |
| Legal status | |
| Legal status | |
| Pharmacokinetic data | |
| Protein binding | Monomethyl fumarate (MMF): 27–45% |
| Metabolism | Esterases,citric acid cycle |
| Metabolites | MMF (active), hydroxyethyl succinimide (HES, inactive),CO2 (inactive) |
| Eliminationhalf-life | 1 hour |
| Excretion | MMF: 60% lung, 15.5% urine (?), 0.9% faeces HES: 58–63% urine |
| Identifiers | |
| |
| CAS Number | |
| PubChemCID | |
| DrugBank | |
| ChemSpider | |
| UNII | |
| KEGG | |
| ChEMBL | |
| CompTox Dashboard(EPA) | |
| Chemical and physical data | |
| Formula | C11H13NO6 |
| Molar mass | 255.226 g·mol−1 |
| 3D model (JSmol) | |
| |
| |
Diroximel fumarate, sold under the brand nameVumerity, is amedication used for the treatment of relapsing forms ofmultiple sclerosis (MS).[3][5][6] It acts as animmunosuppressant andanti-inflammatory drug. Its most common adverse effects areflushing andgastrointestinal problems.[7]
Diroximel fumarate was approved for medical use in the United States in October 2019,[8] and in the European Union in November 2021.[4]
Diroximel fumarate is used for the treatment ofrelapsing-remitting multiple sclerosis.[7] In the US, it is additionally approved for other relapsing forms of MS such asclinically isolated syndrome and active secondary progressive disease.[9]
The drug is available as a white delayed-releasecapsule that isresistant to gastric acid and only dissolves in the intestine.[7][10]
Under the European Union's label, the drug is contraindicated in people withprogressive multifocal leukoencephalopathy (PML),[7] a disease of the brain caused by a virus. In the US, combination with the closely related drugdimethyl fumarate is contraindicated.[9]
No systematic studies of adverse effects under diroximel fumarate are available. The most common side effects in studies withdimethyl fumarate wereflushing (in 34% of patients treated with the drug, versus 5% in theplacebo group) andgastrointestinal effects such asdiarrhoea (14% versus 10%),nausea (12% versus 9%), abdominal pain (9% versus 4%), vomiting (8% versus 5%), andindigestion (5% versus 3%). Three percent of patients stopped the treatment because of flushing, 4% because of gastrointestinal side effects. A rare but potentially fatal adverse effect may be PML, which has been observed under treatment with dimethyl fumarate.[7]
No specific antidote is known. Adverse effects caused by overdosing diroximel fumarate are treated symptomatically.[7]
Diroximel fumarate does not interact withcytochrome P450 enzymes orP-glycoprotein. Itsactive metabolite,monomethyl fumarate, has a relatively lowplasma protein binding of 27 to 45%. Therefore, its potential forpharmacokinetic interactions is considered to be low.[7][9]
Inactivated vaccines can be given under diroximel fumarate therapy, based on experience with other immunosuppressant drugs, such as studies withtetanus,pneumococcal andmeningococcal vaccines. No studies regarding the effectiveness of these vaccines under diroximel fumarate have been conducted. No data are available regarding combination withlive vaccines,chemotherapy or immunosuppressants.Nephrotoxicity could be increased when the drug is combined withaminoglycoside antibiotics,diuretics,NSAIDs orlithium.[7][9]
The drug's mechanism of action is not well understood. Inpreclinical studies it activatednuclear factor erythroid 2-related factor 2 (NRF2), atranscription factor that is up-regulated underoxidative stress.[9]
Thepharmacokinetics of diroximel fumarate has been found to be practically identical to that of dimethyl fumarate. Both areprodrugs of monomethyl fumarate.[7][9]
Taking the drug with a high-calorie, high-fat meal slows down absorption, but has no relevant effect on overall absorption. The US label recommends not taking the drug together with high-calorie and high-fat meals.[9]
After ingestion, the substance is cleaved byesterase enzymes before reaching the systemic circulation, resulting in monomethyl fumarate (MMF), the active metabolite, and hydroxyethyl succinimide (HES), which is inactive. Diroximel fumarate itself is not present in the bloodstream. MMF reaches highest concentrations in theblood plasma 2.5 to 3 hours after ingestion.[7] When in the bloodstream, 27 to 45% are bound to plasma proteins.[9]
MMF is furthermetabolized tofumarate,citrate andglucose, ultimately entering thecitric acid cycle and being broken down tocarbon dioxide (CO2). About 60% of the substance leave the body as CO2 via the lungs, 15.5% are eliminated with the urine (according to another source, less than 0.3%[9]), and 0.9% are eliminated with the faeces. Theterminal half-life is one hour.[7]
HES is eliminated mainly with the urine (58 to 63%).[9]
The substance is a white to off-white powder. It is slightly soluble in water; that is, itssolubility is between 1:100 and 1:1000.[10] The molecule isachiral. The double bond of thefumarate moiety hasE configuration.
This drug was formulated by Alkermes in collaboration with Biogen.[11]
Diroximel fumarate was approved for medical use in the United States in October 2019.[8]
In September 2021, theCommittee for Medicinal Products for Human Use (CHMP) of theEuropean Medicines Agency (EMA) adopted a positive opinion, recommending the granting of a marketing authorization for the medicinal product Vumerity, intended for the treatment of adults with relapsing remitting multiple sclerosis.[12] The applicant for this medicinal product is Biogen Netherlands B.V.[12] Diroximel fumarate was approved for medical use in the European Union in November 2021.[4][13]
