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Diroximel fumarate: Drug information

Diroximel fumarate: Drug information
(For additional information see "Diroximel fumarate: Patient drug information")

For abbreviations, symbols, and age group definitions used in Lexicomp (show table)
Brand Names: US
  • Vumerity
Pharmacologic Category
  • Fumaric Acid Derivative
Dosing: Adult

Note: Safety: In high-risk populations or in countries with high tuberculosis burden, screen for latent infections (eg, hepatitis, tuberculosis) prior to initiating therapy. For patients who screen positive for latent infections, consult infectious disease or other appropriate specialists (eg, liver specialists) regarding treatment options before initiating therapy (AAN [Farez 2019]). Premedication: May administer aspirin (nonenteric coated ≤325 mg) 30 minutes prior to diroximel fumarate to reduce the incidence or severity of flushing.

Multiple sclerosis, relapsing

Multiple sclerosis, relapsing:

Oral: Initial: 231 mg twice daily; after 7 days, increase to the maintenance dose of 462 mg twice daily.

Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.

Dosing: Kidney Impairment: Adult

Mild impairment: No dosage adjustment necessary.

Moderate or severe impairment: Use not recommended due to increase in 2-hydroxyethyl succinimide exposure.

Dosing: Hepatic Impairment: Adult

Hepatic impairment prior to treatment initiation: No dosage adjustment necessary.

Hepatoxicity during treatment: Discontinue treatment if diroximel fumarate–induced hepatic injury is suspected.

Dosing: Adjustment for Toxicity: Adult

Side effects with maintenance dose: If maintenance dose is not tolerated, consider temporary dose reduction to 231 mg twice daily; resume recommended maintenance dose of 462 mg twice daily within 4 weeks. Consider discontinuation in patients who cannot tolerate return to the maintenance dose.

GI reactions, severe (hemorrhage, obstruction, perforation, ulceration): Discontinue treatment.

Lymphopenia:

Lymphocytes <500/mm3 persisting >6 months: Consider therapy interruption; once resolved, base the decision to restart therapy on individual clinical circumstances.

Infection, serious: Consider therapy interruption; once resolved, base the decision to restart therapy on individual clinical circumstances.

Progressive multifocal leukoencephalopathy: If progressive multifocal leukoencephalopathy (PML) is suspected, withhold therapy immediately and perform a diagnostic evaluation; permanently discontinue if PML is confirmed.

Dosing: Older Adult

Refer to adult dosing.

Adverse Reactions

The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified. All adverse reactions were reported in adults with dimethyl fumarate delayed-release capsules, which have the same active metabolite as diroximel fumarate.

>10%:

Cardiovascular: Flushing (40%)

Gastrointestinal: Abdominal pain (18%), diarrhea (14%), nausea (12%)

Infection: Infection (60%; similar to placebo; including aspergillosis, candidiasis, cytomegalovirus disease, herpes meningoencephalitis, herpes simplex infection, herpes zoster infection [including disseminated, meningomyelitis, or ophthalmicus], listeriosis, nocardiosis, opportunistic infection [including West Nile], tuberculosis)

1% to 10%:

Dermatologic: Erythema of skin (5%), pruritus (8%), skin rash (8%)

Endocrine & metabolic: Albuminuria (6%)

Gastrointestinal: Dyspepsia (5%), vomiting (9%)

Hematologic & oncologic: Lymphocytopenia (2% to 6%)

Hepatic: Increased serum aspartate aminotransferase (4%)

<1%: Nervous system: Progressive multifocal leukoencephalopathy

Frequency not defined: Hematologic & oncologic: Eosinophilia

Postmarketing:

Dermatologic: Alopecia

Gastrointestinal: Acute pancreatitis

Hepatic: Hepatic injury, increased serum bilirubin (>2 x ULN), increased serum transaminases (≥3 x ULN)

Respiratory: Rhinorrhea

Contraindications

Hypersensitivity (eg, anaphylaxis, angioedema) to diroximel fumarate, dimethyl fumarate, or to any component of the formulation; concomitant use of dimethyl fumarate.

Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.

Warnings/Precautions

Concerns related to adverse effects:

• Flushing: Dimethyl fumarate, which has the same active metabolite as diroximel fumarate, commonly causes mild to moderate flushing (eg, warmth, redness, itching, burning sensation); flushing generally appears soon after initiation, and improves or resolves with subsequent dosing. Administration with food may decrease flushing incidence. Administration of aspirin (nonenteric coated ≤325 mg) 30 minutes prior to diroximel fumarate may also reduce the incidence or severity of flushing.

• GI events: GI events (eg, diarrhea, nausea, upper abdominal pain, vomiting, constipation) commonly occur with dimethyl fumarate, which has the same active metabolite as diroximel fumarate. GI events generally occur in the first month of use and decrease thereafter. Severe GI reactions (eg, hemorrhage, obstruction, perforation, ulceration) occurring within 6 months (majority) of treatment initiation and with or without concomitant aspirin use have also been reported.

• Hepatotoxicity: Clinically significant postmarketing cases of hepatic injury have been reported with dimethyl fumarate, which has the same active metabolite as diroximel fumarate. Onset has ranged from a few days to several months after treatment initiation. Signs/symptoms of hepatic injury, including transaminase elevations >5 times ULN and total bilirubin elevations >2 times ULN have been observed with dimethyl fumarate. Some cases have required hospitalization; however, none of the cases were fatal or resulted in liver failure or transplant. LFT abnormalities resolved upon discontinuation. Drug-induced hepatocellular injury resulting in new-onset transaminase elevations combined with increased bilirubin levels is an important predictor of serious hepatic injury that may lead to acute hepatic failure, liver transplant, or death in some patients. Transaminase elevations (usually <3 times ULN) were observed in dimethyl fumarate clinical trials, generally occurring in the first 6 months of treatment. Transaminase elevations ≥3 times ULN occurred rarely. Monitor LFTs; discontinue treatment if diroximel fumarate–induced hepatic injury is suspected.

• Hypersensitivity reactions: Anaphylaxis and angioedema may occur after the first dose or at any time during treatment. Discontinue therapy if signs and symptoms of anaphylaxis or angioedema occur.

• Infections: Serious cases of herpes zoster (eg, disseminated, ophthalmicus, meningoencephalitis, meningomyelitis) have been reported with dimethyl fumarate, which has the same active metabolite as diroximel fumarate; may develop any time during treatment. Other serious opportunistic infections have occurred with dimethyl fumarate, including viral (eg, Cytomegalovirus, herpes simplex, West Nile), fungal (eg, Aspergillus, Candida), and bacterial (eg, Listeria monocytogenes, Mycobacterium tuberculosis, Nocardia), in patients with and without lymphopenia. Consider temporary interruption of therapy until infection has resolved. In high-risk populations or in countries with high tuberculosis burden, screen for latent infections (eg, hepatitis, tuberculosis) prior to initiating therapy. For patients who screen positive for latent infections, consult infectious disease or other specialists (eg, liver specialists) regarding treatment options before initiating therapy (AAN [Farez 2019]).

• Lymphopenia: Decreased lymphocyte counts may occur. The risk for lymphopenia is not reduced over time with dimethyl fumarate, which has the same active metabolite as diroximel fumarate. In patients receiving dimethyl fumarate with prolonged, severe lymphopenia (eg, lymphocytes <500 cells/mm3 for ≥6 months), the median time for lymphocyte counts to return to normal after discontinuation of therapy was 96 weeks; in patients with nonprolonged, mild to severe lymphopenia, the median time to return to normal after discontinuation of therapy ranged from 4 to 16.7 weeks, based on lymphopenia severity during treatment. Obtain a CBC, including lymphocyte count, prior to initiation of therapy, then every 3 to 6 months thereafter, and as clinically indicated (AAN [Rae-Grant 2018]; EMA 2015). Monitor for signs of infection in patients with lower lymphocyte counts at baseline and mild to moderate lymphopenia (Baharnoori 2018). Consider therapy interruption in patients with lymphocyte counts <500/mm3 persisting >6 months and in patients with serious infections. Progressive multifocal leukoencephalopathy (PML) may occur in patients with a lymphocyte count <500/mm3 for <6 months (Lehmann-Horn 2016). Due to a potential for delayed lymphocyte recovery following treatment interruption or discontinuation, monitor lymphocyte counts until lymphopenia is resolved. The decision to restart diroximel fumarate should be individualized based on clinical circumstances. Neither diroximel fumarate nor dimethyl fumarate have been studied in patients with preexisting low lymphocyte counts.

• Progressive multifocal leukoencephalopathy: Cases of progressive multifocal leukoencephalopathy (PML) due to the John Cunningham (JC) virus, including fatality, have occurred with dimethyl fumarate, which has the same active metabolite as diroximel fumarate. Risk factors for development of PML include HIV, AIDS, cancer history, rheumatologic disease history, persistent lymphocytopenia, sarcoidosis, and prior immunosuppressant use (Jamilloux 2014; Tan 2010). However, cases of PML have been reported with dimethyl fumarate use in patients who were not immunocompromised and had no prior exposure to immunosuppressive drugs, including natalizumab. Severe, long-standing lymphopenia was identified as a primary risk for PML, and the majority of PML cases occurred in patients with lymphocyte counts <500/mm3 (although the exact role of lymphopenia in PML is unknown). At the first sign or symptom suggestive of PML, withhold therapy immediately and perform a diagnostic evaluation; symptoms progress over days to weeks and may include progressive weakness on one side of the body or clumsiness of limbs, vision disturbances, and changes in mental status. Cases of PML have been diagnosed based on MRI findings and the detection of JC virus DNA in the cerebral spinal fluid without specific PML signs/symptoms. Monitoring with brain MRI for signs that may be consistent with PML may be beneficial and allow for an early diagnosis of PML (EMA 2015).

Other warnings/precautions:

• Immunizations: Avoid live-attenuated vaccines in patients who currently receive or have recently discontinued diroximel fumarate; consider using live-attenuated vaccines only if risk of infection is high and killed vaccines are unavailable (AAN [Farez 2019]).

Dosage Forms: US

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Capsule Delayed Release, Oral:

Vumerity: 231 mg [contains carrageenan]

Generic Equivalent Available: US

No

Pricing: US

Capsule, delayed release (Vumerity Oral)

231 mg (per each): $86.33

Disclaimer: A representative AWP (Average Wholesale Price) price or price range is provided as reference price only. A range is provided when more than one manufacturer's AWP price is available and uses the low and high price reported by the manufacturers to determine the range. The pricing data should be used for benchmarking purposes only, and as such should not be used alone to set or adjudicate any prices for reimbursement or purchasing functions or considered to be an exact price for a single product and/or manufacturer. Medi-Span expressly disclaims all warranties of any kind or nature, whether express or implied, and assumes no liability with respect to accuracy of price or price range data published in its solutions. In no event shall Medi-Span be liable for special, indirect, incidental, or consequential damages arising from use of price or price range data. Pricing data is updated monthly.

Administration: Adult

Oral: Administer with or without food. If administered with food, limit fat and calories to ≤30 g and ≤700 calories, respectively. Swallow capsule whole; do not crush, chew, or open.

Use: Labeled Indications

Multiple sclerosis, relapsing: Treatment of relapsing forms of multiple sclerosis, including clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease, in adults.

Metabolism/Transport Effects

None known.

Drug Interactions

Note: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed). For a complete list of drug interactions by individual drug name and detailed management recommendations, use the Lexicomp drug interactions program by clicking on the “Launch drug interactions program” link above.

Alcohol (Ethyl): May decrease serum concentrations of the active metabolite(s) of Diroximel Fumarate. Risk X: Avoid combination

Dimethyl Fumarate: May enhance the adverse/toxic effect of Diroximel Fumarate. Risk X: Avoid combination

Monomethyl Fumarate: May enhance the adverse/toxic effect of Diroximel Fumarate. Risk X: Avoid combination

Food Interactions

A high-fat (>30 g), high-calorie (>700 calories) meal may significantly decrease the maximum concentration of the major active metabolite, monomethyl fumarate (MMF). Alcohol decreases peak MMF plasma concentration when coadministered with diroximel fumarate. Management: Take diroximel fumarate with or without food. If taken with food, limit fat and calories to ≤30 g and ≤700 calories, respectively. Avoid alcohol at the same time a dose of diroximel fumarate is taken.

Reproductive Considerations

In general, disease-modifying therapies for multiple sclerosis are stopped prior to a planned pregnancy, except in females at high risk of multiple sclerosis activity (AAN [Rae-Grant 2018]). Consider use of agents other than diroximel fumarate for females at high risk of disease reactivation who are planning a pregnancy. Delaying pregnancy is recommended for females with persistent high disease activity; when disease-modifying therapy is needed in these patients, other agents are preferred (ECTRIMS/EAN [Montalban 2018]).

Pregnancy Considerations

Adverse events were observed in some animal reproduction studies.

In general, disease-modifying therapies for multiple sclerosis are not initiated during pregnancy, except in females at high risk of multiple sclerosis activity (AAN [Rae-Grant 2018]). When disease-modifying therapy is needed in these patients, other agents are preferred (ECTRIMS/ EAN [Montalban 2018]).

Breastfeeding Considerations

It is not known if diroximel fumarate or its active metabolite monomethyl fumarate are present in breast milk.

According to the manufacturer, the decision to breastfeed during therapy should consider the risk of infant exposure, the benefits of breastfeeding to the infant, and benefits of treatment to the mother.

Dietary Considerations

May administer with or without food. If taken with food, limit fat and calories to ≤30 g and ≤700 calories, respectively. Avoid alcohol at the same time a dose of diroximel fumarate is taken.

Monitoring Parameters

CBC, including lymphocytes (prior to initiation of therapy, then every 3 to 6 months thereafter, or as clinically indicated) (AAN [Rae-Grant 2018]; EMA 2015); LFT, including transaminases, alkaline phosphatase, total bilirubin (baseline and during treatment as clinically indicated); MRI (baseline and as clinically indicated to monitor for early signs of progressive multifocal leukoencephalopathy [PML]); latent infection screening (eg, hepatitis, tuberculosis) in high-risk populations or in countries with high tuberculosis burden (baseline); signs/symptoms of severe GI reactions, hypersensitivity, infections, and/or PML.

Mechanism of Action

Diroximel fumarate and its active metabolite, monomethyl fumarate (MMF), have been shown to activate the nuclear factor (erythroid-derived 2)-like 2 (Nrf2) pathway, which is involved in cellular response to oxidative stress. The mechanism by which diroximel fumarate exerts a therapeutic effect in multiple sclerosis is unknown, although it is believed to result from its anti-inflammatory and cytoprotective properties via activation of the Nrf2 pathway (Fox 2012; Gold 2012). MMF has also been identified as a nicotinic acid receptor agonist in vitro.

Pharmacokinetics (Adult Data Unless Noted)

Note: Diroximel fumarate is not quantifiable in plasma following oral administration due to extensive presystemic metabolism. All pharmacokinetic data are based on monomethyl fumarate (MMF) (major active metabolite), unless otherwise indicated.

Distribution: Vd: 72 to 83 L.

Protein binding: 27% to 45%.

Metabolism: Diroximel fumarate undergoes rapid and extensive presystemic hydrolysis by esterases to MMF (major active metabolite) and 2-hydroxyethyl succinimide (inactive major metabolite). MMF is further metabolized via the tricarboxylic acid cycle, with no involvement of the cytochrome P450 (CYP-450) system.

Half-life elimination: Terminal: 1 hour.

Time to peak: 2.5 to 3 hours (fasting), 4.5 hours (with a 350 to 700 calorie and 10 to 30 g fat meal); 7 hours (with a >700 calorie and >30 g fat meal).

Excretion: Urine (<0.3%); expired air (as carbon dioxide).

Pharmacokinetics: Additional Considerations (Adult Data Unless Noted)

Altered kidney function: 2-hydroxyethyl succinimide exposure increased by 1.3-, 1.8-, and 2.7-fold in patients with mild, moderate, and severe renal impairment, respectively, compared to healthy patients.

Brand Names: International
International Brand Names by Country
For country code abbreviations (show table)

  • (AR) Argentina: Vumerity;
  • (AT) Austria: Vumerity;
  • (AU) Australia: Vumerity;
  • (CH) Switzerland: Vumerity;
  • (EE) Estonia: Vumerity;
  • (ES) Spain: Vumerity;
  • (FI) Finland: Vumerity;
  • (FR) France: Vumerity;
  • (GB) United Kingdom: Vumerity;
  • (IE) Ireland: Vumerity;
  • (LU) Luxembourg: Vumerity;
  • (LV) Latvia: Vumerity;
  • (MX) Mexico: Vumerity;
  • (NL) Netherlands: Vumerity;
  • (NO) Norway: Vumerity;
  • (PL) Poland: Vumerity;
  • (PR) Puerto Rico: Vumerity;
  • (SE) Sweden: Vumerity
  1. Baharnoori M, Gonzalez CT, Chua A, et al. Predictors of hematological abnormalities in multiple sclerosis patients treated with fingolimod and dimethyl fumarate and impact of treatment switch on lymphocyte and leukocyte count. Mult Scler Relat Disord. 2018;20:51-57. doi: 10.1016/j.msard.2017.12.003 [PubMed 29304497]
  2. European Medicines Agency (EMA). Updated recommendations to minimise the risk of the rare brain infection PML with Tecfidera. Published October 23, 2015. Accessed November 11, 2019. https://www.ema.europa.eu/en/documents/press-release/updated-recommendations-minimise-risk-rare-brain-infection-pml-tecfidera_en.pdf
  3. Farez MF, Correale J, Armstrong MJ, et al. Practice guideline update summary: vaccine-preventable infections and immunization in multiple sclerosis: report of the Guideline Development, Dissemination, and Implementation Subcommittee of the American Academy of Neurology. Neurology. 2019;93(13):584-594. doi:10.1212/WNL.0000000000008157 [PubMed 31462584]
  4. Fox RJ, Miller DH, Phillips JT, et al; CONFIRM Study Investigators. Placebo-controlled phase 3 Study of oral BG-12 or glatiramer in multiple sclerosis [published correction appears in N Engl J Med. 2012;367(17):1673]. N Engl J Med. 2012;367(12):1087-1097. doi: 10.1056/NEJMoa1206328 [PubMed 22992072]
  5. Gold R, Kappos L, Arnold DL, et al; DEFINE Study Investigators. Placebo-controlled phase 3 study of oral BG-12 for relapsing multiple sclerosis [published correction appears in N Engl J Med. 2012;367(24):2362]. N Engl J Med. 2012;367(12):1098-1107. doi: 10.1056/NEJMoa1114287 [PubMed 22992073]
  6. Jamilloux Y, Néel A, Lecouffe-Desprets M, et al. Progressive multifocal leukoencephalopathy in patients with sarcoidosis. Neurology. 2014;82(15):1307-1313. doi: 10.1212/WNL.0000000000000318 [PubMed 24610328]
  7. Lehmann-Horn K, Penkert H, Grein P, et al. PML during dimethyl fumarate treatment of multiple sclerosis: How does lymphopenia matter? Neurology. 2016;87(4):440-441. doi: 10.1212/WNL.0000000000002900 [PubMed 27343070]
  8. Montalban X, Gold R, Thompson AJ, et al. ECTRIMS/EAN guideline on the pharmacological treatment of people with multiple sclerosis [published correction appears in Eur J Neurol. 2018;25(3):605]. Eur J Neurol. 2018;25(2):215-237. doi: 10.1111/ene.13536 [PubMed 29352526]
  9. Rae-Grant A, Day GS, Marrie RA, et al. Practice guideline recommendations summary: Disease-modifying therapies for adults with multiple sclerosis: Report of the Guideline Development, Dissemination, and Implementation Subcommittee of the American Academy of Neurology [published correction appears in Neurology. 2019;92(2):112]. Neurology. 2018;90(17):777-788. doi: 10.1212/WNL.0000000000005347 [PubMed 29686116]
  10. Tan CS, Koralnik IJ. Progressive multifocal leukoencephalopathy and other disorders caused by JC virus: clinical features and pathogenesis. Lancet Neurol. 2010;9(4):425-437. doi: 10.1016/S1474-4422(10)70040-5 [PubMed 20298966]
  11. Vumerity (diroximel fumarate) [prescribing information]. Cambridge, MA: Biogen Inc; December 2023.
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