Version May 2024
Multiple sclerosis, relapsing: Note: 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).
Oral: Initial: 95 mg twice daily; after 7 days, increase to the maintenance dose: 190 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.
No dosage adjustment is necessary.
No dosage adjustment is necessary.
Side effects with maintenance dose: If the maintenance dose is not tolerated, consider temporary dose reduction to 95 mg twice daily; resume recommended maintenance dose of 190 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.
Hypersensitivity reaction (anaphylaxis or angioedema): Discontinue treatment.
Lymphocyte count <500/mm3 persisting for >6 months: Consider treatment interruption.
Progressive multifocal leukoencephalopathy: With the first sign/symptom suggestive of progressive multifocal leukoencephalopathy, withhold therapy and perform appropriate diagnostic evaluation.
Serious infection: Consider withholding treatment until infection resolves.
Refer to adult dosing.
The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified. All adverse reactions are reported with dimethyl fumarate, the prodrug of monomethyl fumarate.
>10%:
Cardiovascular: Flushing (40%)
Gastrointestinal: Abdominal pain (18%), diarrhea (14%), nausea (12%)
Infection: Infection (60%)
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
Hepatic: Increased liver enzymes, increased serum alanine aminotransferase
Hypersensitivity: Anaphylaxis, angioedema
Postmarketing:
Dermatologic: Alopecia
Gastrointestinal: Acute pancreatitis
Hepatic: Abnormal liver function, increased serum bilirubin, increased serum transaminases
Infection: Aspergillosis, cytomegalovirus disease, herpes simplex infection, herpes zoster infection (including disseminated, ophthalmicus, meningoencephalitis, and meningomyelitis), listeriosis, opportunistic infection
Respiratory: Rhinorrhea, tuberculosis
Hypersensitivity (eg, anaphylaxis, angioedema) to monomethyl fumarate, dimethyl fumarate, diroximel fumarate, or to any component of the formulation; concomitant use with dimethyl fumarate or diroximel fumarate.
Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
Concerns related to adverse effects:
• Flushing: May cause mild to moderate flushing (eg, warmth, redness, itching, burning sensation); flushing generally appears soon after initiation, and improves or resolves with subsequent dosing. Administration of aspirin (nonenteric coated ≤325 mg) 30 minutes prior to monomethyl fumarate or a temporary dose reduction may also reduce the incidence and severity of flushing.
• GI events: Severe GI reactions (eg, hemorrhage, obstruction, perforation, ulceration), including fatalities, 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 the prodrug dimethyl fumarate, with an onset ranging from a few days to several months after treatment initiation. Signs/symptoms of hepatic injury, including transaminase elevations >5 times the ULN and total bilirubin elevations >2 times ULN have been observed. 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 clinical trials with dimethyl fumarate; transaminase elevations ≥3 times ULN occurred rarely. Monitor LFTs prior to treatment initiation and during treatment. Discontinue treatment if monomethyl fumarate-induced hepatic injury is suspected.
• Hypersensitivity reactions: Anaphylaxis and angioedema may occur after the first dose or at any time during treatment.
• Infections: Serious cases of herpes zoster (eg, disseminated, ophthalmicus, meningoencephalitis, meningomyelitis) have been reported with the prodrug dimethyl fumarate; may develop any time during treatment. Other serious opportunistic infections have occurred, 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, the prodrug of monomethyl fumarate. A decline in absolute lymphocyte count (ALC) typically occurs in the first year of treatment and stabilizes. 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 monomethyl fumarate should be individualized based on clinical circumstances. Neither monomethyl fumarate nor dimethyl fumarate have been studied in patients with preexisting low lymphocyte counts.
• Progressive multifocal leukoencephalopathy: Cases of PML due to the John Cunningham (JC) virus, including fatality, have been reported with the prodrug dimethyl fumarate. Risk factors for development of PML include HIV, AIDS, cancer history, persistent leukocytopenia, sarcoidosis, and prior immunosuppressant use (Jamilloux 2014; Tan 2010). However, cases 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 <800/mm3 persisting for >6 months (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 mental status changes. Cases of PML have been diagnosed based on MRI findings and the detection of JC virus DNA in the cerebrospinal 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 monomethyl 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, as fumarate:
Bafiertam: 95 mg [contains peg-40 hydrog castor oil(cremophor rh40)]
No
Capsule, delayed release (Bafiertam Oral)
95 mg (per each): $66.39
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.
Oral: Swallow capsules whole and intact; do not crush, chew, or mix the contents with food. Administer with or without food. Administration of non–enteric-coated aspirin up to a dose of 325 mg 30 minutes prior to monomethyl fumarate may reduce the incidence of flushing.
Multiple sclerosis, relapsing: Treatment of relapsing forms of multiple sclerosis, including clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease, in adults.
Monomethyl fumarate may be confused with dimethyl fumarate.
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 Lexicomp drug interactions program by clicking on the “Launch drug interactions program” link above.
Dimethyl Fumarate: Monomethyl Fumarate may enhance the adverse/toxic effect of Dimethyl Fumarate. Risk X: Avoid combination
Diroximel Fumarate: Monomethyl Fumarate may enhance the adverse/toxic effect of Diroximel Fumarate. Risk X: Avoid combination
In general, disease-modifying therapies for multiple sclerosis (MS) are stopped prior to a planned pregnancy except in females at high risk of MS activity (AAN [Rae-Grant 2018]). Consider use of agents other than monomethylfumarate 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]).
In general, disease-modifying therapies for multiple sclerosis (MS) are not initiated during pregnancy, except in females at high risk of MS activity (AAN [Rae-Grant 2018]). When disease-modifying therapy is needed in these patients, other agents are preferred (ECTRIMS/ EAN [Montalban 2018]).
Patients exposed to monomethyl fumarate during pregnancy are encouraged to contact the manufacturer at 866-663-9564.
It is not known if monomethyl fumarate is 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 the benefits of treatment to the mother. Based on the low molecular weight and low protein binding, transfer of monomethyl fumarate into breast milk is expected. Until additional information is available, other sources do not recommend breastfeeding during therapy (Almas 2016; Dobson 2019).
CBC including lymphocyte counts (prior to initiation of therapy, 6 months after initiation, then every 6 to 12 months thereafter as clinically necessary); LFTs including transaminases, alkaline phosphatase, and total bilirubin (prior to treatment initiation and during treatment as clinically indicated); signs of infection in patients with lower lymphocyte counts at baseline and mild to moderate lymphopenia (Baharnoori 2018); MRI (baseline and as clinically indicated to monitor for early signs of progressive multifocal leukoencephalopathy); latent infection screening (eg, hepatitis, tuberculosis) in high-risk populations or in countries with high tuberculosis burden (baseline); signs and symptoms of severe GI reactions.
Monomethyl fumarate (MMF) and its prodrug, dimethyl fumarate, 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 monomethyl 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.
Absorption: High-fat, high-calorie meals prolong absorption and decrease Cmax by 20%.
Distribution: Vd (prodrug dimethyl fumarate): 53 to 73 L.
Protein binding: Prodrug dimethyl fumarate: 27% to 45%.
Metabolism: Through the tricarboxylic acid cycle, with no involvement of the CYP-450 system.
Half-life elimination: ~0.5 hour.
Time to peak: 4.03 hours; after high-fat meal: 11 hours.
Excretion: From studies with dimethyl fumarate: Exhalation of CO2: ~60% of dimethyl fumarate; urine (16% of dimethyl fumarate; trace amounts as unchanged monomethyl fumarate); feces (1% of dimethyl fumarate).
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