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 (Ref). 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:
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.
Mild impairment: No dosage adjustment necessary.
Moderate or severe impairment: Use not recommended due to increase in 2-hydroxyethyl succinimide exposure.
Hepatic impairment prior to treatment initiation: No dosage adjustment necessary.
Hepatoxicity during treatment: Discontinue treatment if diroximel fumarate–induced hepatic injury is suspected.
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.
Refer to adult dosing.
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
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.
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]).
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Capsule Delayed Release, Oral:
Vumerity: 231 mg [contains carrageenan]
No
Capsule, delayed release (Vumerity Oral)
231 mg (per each): $86.33
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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.
Multiple sclerosis, relapsing: Treatment of relapsing forms of multiple sclerosis, including clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease, in adults.
None known.
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 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
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.
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 patients at high risk of disease reactivation who are planning to become pregnant. 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]).
Adverse events were observed in some animal reproduction studies.
In general, disease-modifying therapies for multiple sclerosis are not initiated during pregnancy, except in patients 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]).
Data collection to monitor pregnancy and infant outcomes following exposure to diroximel fumarate is ongoing. Patients exposed to diroximel fumarate during pregnancy are encouraged to enroll in the pregnancy registry (1-833-569-2635 or https://www.blossomspregnancyregistry.com/).
It is not known if diroximel fumarate or its metabolites 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.
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.
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.
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.
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).
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.
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