Version May 2024
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).
Multiple sclerosis, relapsing: Oral: Initial: 120 mg twice daily; after 7 days, increase to the maintenance dose: 240 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 necessary.
Hepatic impairment prior to treatment initiation:
No dosage adjustment necessary.
Hepatotoxicity during treatment:
Hepatic injury (suspected drug-induced), clinically significant: Discontinue treatment.
Side effects with maintenance dose: If maintenance dose is not tolerated (GI side effects, flushing), consider temporary dose reduction to 120 mg twice daily (resume recommended maintenance dose of 240 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. Adverse reactions reported in adults.
>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
Known hypersensitivity (eg, anaphylaxis, angioedema) to dimethyl fumarate or any component of the formulation
Concerns related to adverse effects:
• Dermatitis/irritation: May cause rash, pruritus, or erythema. There are case reports of contact dermatitis resulting from dimethyl fumarate exposure after use as a fungicide and desiccant in the shipping of furniture (Bruze 2011; Giménez-Arnau 2011; Ropper 2012).
• Flushing: 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.
• GI events: GI events (eg, nausea, vomiting, diarrhea, abdominal pain, dyspepsia) commonly occur with use; 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 an onset ranging from a few days to several months after treatment initiation. Signs/symptoms of hepatic injury, including transaminase elevations >5 times the upper 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. Liver function test 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, generally occurring in the first 6 months of treatment. Transaminase elevations ≥3 times ULN occurred rarely.
• 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; 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. A decline in absolute lymphocyte count (ALC) typically occurs in the first year of treatment and stabilizes, though an early ALC drop has been associated with later development of severe, prolonged lymphopenia. With a decline in ALC, an accompanying proportional decline occurs in lymphocyte subsets (eg, CD4+ and CD8+ central memory T-cells, memory B-cells) but is offset by a proportional increase in activated CD4+ and CD8+ T-cells, naive B-cells, and NK cells. Likely due to the shift in lymphocyte immunophenotypes, no increased risk of serious infections is seen in patients with a low T-cell subset count rendering monitoring of lymphocyte subsets of no clinical use (Mehta 2019). Monitor CBC and signs of infection (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 dimethyl fumarate should be individualized based on clinical circumstances. Dimethyl fumarate has not been studied in patients with preexisting low lymphocyte counts.
• Proteinuria: In clinical trials, proteinuria was reported at a slightly higher incidence than that observed with placebo; significance of these findings is unknown.
• Progressive multifocal leukoencephalopathy: Cases of progressive multifocal leukoencephalopathy (PML) due to the John Cunningham (JC) virus, including fatality, have been reported. Reported risk factors include persistent lymphopenia, prior immunosuppressant use, increased age, sarcoidosis, and cancer history (Jamilloux 2014; Jordan 2022; Lehmann-Horn 2016; Tan 2010). However, cases have been reported in patients who were not immunocompromised and had no prior exposure to immunosuppressive drugs, including natalizumab. Severe, long-standing lymphopenia is a primary risk factor for PML, and the majority of PML cases occur in patients with lymphocyte counts <800/mm3 (Jordan 2022; manufacturer’s labeling). 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 CSF 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).
Dosage form specific issues:
• Polysorbate 80: Some dosage forms may contain polysorbate 80 (also known as Tweens). Hypersensitivity reactions, usually a delayed reaction, have been reported following exposure to pharmaceutical products containing polysorbate 80 in certain individuals (Isaksson 2002; Lucente 2000; Shelley 1995). Thrombocytopenia, ascites, pulmonary deterioration, and renal and hepatic failure have been reported in premature neonates after receiving parenteral products containing polysorbate 80 (Alade 1986; CDC 1984). See manufacturer's labeling.
Other warnings/precautions:
• Immunizations: Avoid live-attenuated vaccines in patients who currently receive or have recently discontinued dimethyl fumarate; consider using live-attenuated vaccines only if risk of infection is high and inactivated vaccines are unavailable (AAN [Farez 2019]).
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Capsule Delayed Release, Oral:
Tecfidera: 120 mg, 240 mg [contains fd&c blue #1 (brilliant blue)]
Generic: 120 mg, 240 mg
Capsule Delayed Release Therapy Pack, Oral:
Tecfidera: Capsule, delayed release: 120 mg (14s) and Capsule, delayed release: 240 mg (46s) (60 ea) [contains fd&c blue #1 (brilliant blue)]
Generic: Capsule, delayed release: 120 mg (14s) and Capsule, delayed release: 240 mg (46s) (60 ea)
Yes
Capsule Delayed Release Therapy Pack (Tecfidera Oral)
120 & 240 mg (per each): $188.90
Capsule, delayed release (Dimethyl Fumarate Oral)
120 mg (per each): $146.23 - $148.95
240 mg (per each): $147.31 - $148.95
Capsule, delayed release (Tecfidera Oral)
120 mg (per each): $188.90
240 mg (per each): $188.90
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.
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Capsule Delayed Release, Oral:
Tecfidera: 120 mg, 240 mg [contains fd&c blue #1 (brilliant blue)]
Generic: 120 mg, 240 mg
Oral: Swallow capsules whole and intact; do not crush, chew, or sprinkle contents on food. Administer with or without food; administering with food, especially high-fat, high-protein food (eg, yogurt or peanut butter) may decrease the incidence of flushing and GI effects (Ref). Alternatively, the administration of aspirin (nonenteric coated up to a dose of 325 mg) 30 minutes prior to dimethyl fumarate may also reduce the incidence of flushing.
Bariatric surgery: Capsule, delayed release: Some institutions may have specific protocols that conflict with these recommendations; refer to institutional protocols as appropriate. Delayed-release capsule should not be opened. No IR formulation exists.
Multiple sclerosis, relapsing: Treatment of patients with relapsing forms of multiple sclerosis, including clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease.
Dimethyl fumarate may be confused with dimethyl sulfoxide, diroximel 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.
Diroximel Fumarate: Dimethyl Fumarate may enhance the adverse/toxic effect of Diroximel Fumarate. Risk X: Avoid combination
Monomethyl Fumarate: May enhance the adverse/toxic effect of Dimethyl Fumarate. Risk X: Avoid combination
Vaccines (Live): Dimethyl Fumarate may enhance the adverse/toxic effect of Vaccines (Live). Specifically, Dimethyl Fumarate may increase the risk of vaccinal infection. Dimethyl Fumarate may diminish the therapeutic effect of Vaccines (Live). Management: Non-US labeling for dimethyl fumarate states that live attenuated vaccine administration is not recommended during treatment. US labeling states that safety and effectiveness of live vaccines administered with dimethyl fumarate has not been assessed. Risk C: Monitor therapy
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 dimethyl 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]).
Information related to the use of dimethyl fumarate in pregnancy is limited (Gold 2015; MacDonald 2019; Nguyen 2019).
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]).
Females exposed to dimethyl fumarate during pregnancy are encouraged to enroll in the Pregnancy Registry by calling 866-810-1462 or visiting www.tecfiderapregnancyregistry.com.
It is not known if dimethyl 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 benefits of treatment to the mother. Until additional information is available, other sources do not recommend breastfeeding during therapy (Almas 2016; Dobson 2019).
CBC including lymphocyte counts (obtained prior to initiation of therapy, then every 3 months thereafter and as clinically necessary; for patients with lymphopenia; monitor until resolution; grade 3 lymphopenia should be monitored more frequently at intervals <3 months) (AAN [Rae-Grant 2018]); signs of infection (especially in patients with lower lymphocyte counts at baseline and mild to moderate lymphopenia [Baharnoori 2018]); LFTs (transaminases, alkaline phosphatase, total bilirubin; prior to treatment initiation and during treatment as clinically indicated); urinalysis (if proteinuria suspected and/or 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 and symptoms of severe GI reactions.
DMF 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 dimethyl fumarate (DMF) exerts a therapeutic effect in MS 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).
Distribution: Vd: MMF: 53 to 73 L
Protein binding: MMF: 27% to 45%
Metabolism: Undergoes rapid and extensive presystemic hydrolysis by esterases to its active metabolite, monomethyl fumarate (MMF); MMF is further metabolized via the tricarboxylic acid (TCA) cycle. Major serum metabolites include: MMF, fumaric acid, citric acid, and glucose.
Half-life elimination: MMF: ~1 hour
Time to peak: 2 to 2.5 hours; delayed to 5.5 hours with food
Excretion: CO2 via exhalation (~60%); urine (16%; trace amounts as unchanged MMF), feces (1%)
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