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DIMETHYL FUMARATE

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Dimethyl fumarate is an in vitro nicotinic acid receptor agonist and an in vivo activator of the Nuclear factor (erythroid-derived 2)-like 2 (Nrf2) pathway that is involved in the cellular response to oxidative stress, and is indicated to treat relapsing forms of multiple sclerosis.

Specific Substances

    1) Dimethyl (E) butenedioate
    2) Fumaric acid, dimethyl ester
    3) DMF
    4) 624-49-7 (CAS)
    1.2.1) MOLECULAR FORMULA
    1) C6-H8-O4 (Prod Info TECFIDERA(R) delayed-release oral capsules, 2013)

Available Forms Sources

    A) FORMS
    1) Dimethyl fumarate is available as 120 mg and 240 mg delayed-release capsules (Prod Info TECFIDERA(R) delayed-release oral capsules, 2013).
    B) USES
    1) Dimethyl fumarate is used for treating patients with relapsing forms of multiple sclerosis (Prod Info TECFIDERA(R) delayed-release oral capsules, 2013).

Overview

Life Support

    A) This overview assumes that basic life support measures have been instituted.

Clinical Effects

    0.2.1) SUMMARY OF EXPOSURE
    A) USES: Dimethyl fumarate is indicated to treat relapsing forms of multiple sclerosis.
    B) PHARMACOLOGY: Although the exact mechanism of effect in multiple sclerosis is unknown, dimethyl fumarate is an in vitro nicotinic acid receptor agonist and an in vivo activator of the Nuclear factor (erythroid-derived 2)-like 2 (Nrf2) pathway that is involved in the cellular response to oxidative stress.
    C) EPIDEMIOLOGY: Overdose has not been reported.
    D) WITH THERAPEUTIC USE
    1) COMMON: The most common adverse effects reported in at least 10% of patients during clinical trials were flushing, nausea, diarrhea, and abdominal pain.
    2) INFREQUENT: Other adverse effects that occurred in less than 10% of patients, but at a higher rate than in patients receiving a placebo, include lymphocytopenia, vomiting, dyspepsia, rash, erythema, pruritus, albuminuria, and elevated aspartate aminotransferase concentration.
    3) RARE: Progressive multifocal leukoencephalopathy has been rarely reported with dimethyl fumarate therapy.
    E) WITH POISONING/EXPOSURE
    1) There have been no reports of overdose. Signs and symptoms of an acute overdose are anticipated to be similar to excessive pharmacologic adverse events.
    0.2.20) REPRODUCTIVE
    A) Dimethyl fumarate (DMF) is classified as FDA pregnancy category C. Although there are no adequate or well controlled studies of DMF during human pregnancy, embryofetal toxicity (reduced fetal body weight and delayed ossification) and maternal toxicity (reduced body weight) have been reported in animal studies.

Laboratory Monitoring

    A) Monitor CBC with differential.
    B) No other specific laboratory tests are necessary unless otherwise clinically indicated.
    C) Plasma concentrations of dimethyl fumarate or its active metabolite, monomethyl fumarate, are not readily available or clinically useful in the management of overdose.

Treatment Overview

    0.4.2) ORAL/PARENTERAL EXPOSURE
    A) MANAGEMENT OF MILD TO MODERATE TOXICITY
    1) Treatment is symptomatic and supportive. Correct any significant fluid and/or electrolyte abnormalities in patients with severe diarrhea and/or vomiting.
    B) MANAGEMENT OF SEVERE TOXICITY
    1) Treatment is symptomatic and supportive.
    C) DECONTAMINATION
    1) PREHOSPITAL: Prehospital gastrointestinal decontamination is generally not necessary.
    2) HOSPITAL: Consider activated charcoal if the overdose is large, recent, the patient is not vomiting, and is able to maintain airway.
    D) AIRWAY MANAGEMENT
    1) Airway management is very unlikely to be necessary unless other toxic agents have been administered concurrently.
    E) ANTIDOTE
    1) None
    F) ENHANCED ELIMINATION
    1) Hemodialysis would be expected to remove monomethyl fumarate given its small volume of distribution and low protein binding.
    G) PATIENT DISPOSITION
    1) HOME CRITERIA: A patient with a small inadvertent exposure, that remains asymptomatic, can be managed at home.
    2) OBSERVATION CRITERIA: Patients with a deliberate overdose, and those who are symptomatic, should be sent to a healthcare facility for evaluation.
    3) ADMISSION CRITERIA: Patients who remain symptomatic despite treatment should be admitted.
    4) CONSULT CRITERIA: Consult a poison center or medical toxicologist for assistance in managing patients with severe toxicity or in whom the diagnosis is not clear.
    H) PITFALLS
    1) When managing a suspected dimethyl fumarate overdose, the possibility of multidrug involvement should be considered. Symptoms of overdose may be similar to reported side effects of the medication.
    I) PHARMACOKINETICS
    1) Dimethyl fumarate is metabolized to an active metabolite, monomethyl fumarate (MMF), prior to reaching systemic circulation via esterases in the gastrointestinal tract, blood, and tissues. Following oral administration of dimethyl fumarate, there is no quantifiable level of parent drug found in plasma. Protein binding of MMF is 27% to 45%; volume of distribution is 53 to 73 L. Major route of elimination, at approximately 60% of the dimethyl fumarate dose, is via exhalation of carbon dioxide. The half-life of MMF is approximately 1 hour.

Range Of Toxicity

    A) TOXICITY: A toxic dose has not been established. Overdose has not been reported.
    B) THERAPEUTIC DOSE: ADULT: Initially, the recommended dose is 120 mg orally twice daily. After 7 days, the dose should be increased to 240 mg orally twice daily. PEDIATRIC: Safety and efficacy have not been established in pediatric patients

Clinical Effects

Summary Of Exposure

    A) USES: Dimethyl fumarate is indicated to treat relapsing forms of multiple sclerosis.
    B) PHARMACOLOGY: Although the exact mechanism of effect in multiple sclerosis is unknown, dimethyl fumarate is an in vitro nicotinic acid receptor agonist and an in vivo activator of the Nuclear factor (erythroid-derived 2)-like 2 (Nrf2) pathway that is involved in the cellular response to oxidative stress.
    C) EPIDEMIOLOGY: Overdose has not been reported.
    D) WITH THERAPEUTIC USE
    1) COMMON: The most common adverse effects reported in at least 10% of patients during clinical trials were flushing, nausea, diarrhea, and abdominal pain.
    2) INFREQUENT: Other adverse effects that occurred in less than 10% of patients, but at a higher rate than in patients receiving a placebo, include lymphocytopenia, vomiting, dyspepsia, rash, erythema, pruritus, albuminuria, and elevated aspartate aminotransferase concentration.
    3) RARE: Progressive multifocal leukoencephalopathy has been rarely reported with dimethyl fumarate therapy.
    E) WITH POISONING/EXPOSURE
    1) There have been no reports of overdose. Signs and symptoms of an acute overdose are anticipated to be similar to excessive pharmacologic adverse events.

Neurologic

    3.7.2) CLINICAL EFFECTS
    A) PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY
    1) WITH THERAPEUTIC USE
    a) A 54-year-old woman with multiple sclerosis (MS) who was treated for approximately 4.5 years with dimethyl fumarate died as a result of progressive multifocal leukoencephalopathy (PML). For 3.5 years prior to the development of PML, her lymphocyte count was consistently below 500 cells/mcL. The patient was hospitalized for a presumed MS relapse and treated with corticosteroids. Her condition worsened and dimethyl fumarate therapy was discontinued. John Cunningham viral DNA was found in her cerebrospinal fluid, confirming a suggested diagnosis of PML. Seven weeks after drug discontinuation, she developed aspiration pneumonia due to dysphagia and died (U.S. Food and Drug Administration (FDA), 2014).

Gastrointestinal

    3.8.2) CLINICAL EFFECTS
    A) NAUSEA AND VOMITING
    1) WITH THERAPEUTIC USE
    a) A pooled analysis of 2 placebo-controlled clinical studies revealed that nausea occurred in 12% of patients administered dimethyl fumarate 240 mg twice daily (n=769) compared with 9% of patients administered placebo (n=771). Gastrointestinal effects typically occurred within the first month of treatment and decreased over time. Of patients administered dimethyl fumarate, 4% discontinued treatment because of gastrointestinal side effects compared with less than 1% of patients administered placebo. Serious gastrointestinal side effects were reported in 1% of patients administered dimethyl fumarate (Prod Info TECFIDERA(R) delayed-release oral capsules, 2013).
    b) A pooled analysis of 2 placebo-controlled clinical studies revealed that vomiting occurred in 9% of patients administered dimethyl fumarate 240 mg twice daily (n=769) compared with 5% of patients administered placebo (n=771). Gastrointestinal effects typically occurred within the first month of treatment and decreased over time. Of patients administered dimethyl fumarate, 4% discontinued treatment because of gastrointestinal side effects compared with less than 1% of patients administered placebo. Serious gastrointestinal side effects were reported in 1% of patients administered dimethyl fumarate (Prod Info TECFIDERA(R) delayed-release oral capsules, 2013).
    B) DIARRHEA
    1) WITH THERAPEUTIC USE
    a) A pooled analysis of 2 placebo-controlled clinical studies revealed that diarrhea occurred in 14% of patients administered dimethyl fumarate 240 mg twice daily (n=769) compared with 11% of patients administered placebo (n=771). Gastrointestinal effects typically occurred within the first month of treatment and decreased over time. Of patients administered dimethyl fumarate, 4% discontinued treatment because of gastrointestinal side effects compared with less than 1% of patients administered placebo. Serious gastrointestinal side effects were reported in 1% of patients administered dimethyl fumarate (Prod Info TECFIDERA(R) delayed-release oral capsules, 2013).
    C) ABDOMINAL PAIN
    1) WITH THERAPEUTIC USE
    a) A pooled analysis of 2 placebo-controlled clinical studies revealed that abdominal pain occurred in 18% of patients administered dimethyl fumarate 240 mg twice daily (n=769) compared with 10% of patients administered placebo (n=771). Gastrointestinal effects typically occurred within the first month of treatment and decreased over time. Of patients administered dimethyl fumarate, 4% discontinued treatment because of gastrointestinal side effects compared with less than 1% of patients administered placebo. Serious gastrointestinal side effects were reported in 1% of patients administered dimethyl fumarate (Prod Info TECFIDERA(R) delayed-release oral capsules, 2013).
    D) INDIGESTION
    1) WITH THERAPEUTIC USE
    a) A pooled analysis of 2 placebo-controlled clinical studies revealed that dyspepsia occurred in 5% of patients administered dimethyl fumarate 240 mg twice daily (n=769) compared with 3% of patients administered placebo (n=771). Gastrointestinal effects typically occurred within the first month of treatment and decreased over time. Of patients administered dimethyl fumarate, 4% discontinued treatment because of gastrointestinal side effects compared with less than 1% of patients administered placebo. Serious gastrointestinal side effects were reported in 1% of patients administered dimethyl fumarate (Prod Info TECFIDERA(R) delayed-release oral capsules, 2013).

Hepatic

    3.9.2) CLINICAL EFFECTS
    A) AST/SGOT LEVEL RAISED
    1) WITH THERAPEUTIC USE
    a) A pooled analysis of 2 placebo-controlled clinical studies revealed that increased AST occurred in 4% of patients administered dimethyl fumarate 240 mg twice daily (n=769) compared with 2% of patients administered placebo (n=771). Increases in hepatic enzymes typically occurred within the first 6 months of therapy and were typically less than 3 times the ULN (Prod Info TECFIDERA(R) delayed-release oral capsules, 2013).

Genitourinary

    3.10.2) CLINICAL EFFECTS
    A) ALBUMINURIA
    1) WITH THERAPEUTIC USE
    a) A pooled analysis of 2 placebo-controlled clinical studies revealed that albuminuria occurred in 6% of patients administered dimethyl fumarate 240 mg twice daily (n=769) compared with 4% of patients administered placebo (n=771) (Prod Info TECFIDERA(R) delayed-release oral capsules, 2013).

Hematologic

    3.13.2) CLINICAL EFFECTS
    A) LYMPHOCYTOPENIA
    1) WITH THERAPEUTIC USE
    a) A pooled analysis of 2 placebo-controlled clinical studies revealed that lymphopenia occurred in 2% of patients administered dimethyl fumarate 240 mg twice daily (n=769) compared with less than 1% of patients administered placebo (n=771) (Prod Info TECFIDERA(R) delayed-release oral capsules, 2013).
    b) During placebo-controlled clinical trials, the mean lymphocyte count decreased by approximately 30% during the first year of dimethyl fumarate therapy. After discontinuation of dimethyl fumarate, lymphocyte counts increased within 4 weeks, although they did not reach baseline levels. Lymphocyte counts less than 0.5 x 10(9)/L were reported in 6% of patients administered dimethyl fumarate compared with less than 1% of patients administered placebo (Prod Info TECFIDERA(R) delayed-release oral capsules, 2013).

Dermatologic

    3.14.2) CLINICAL EFFECTS
    A) ERUPTION
    1) WITH THERAPEUTIC USE
    a) A pooled analysis of 2 placebo-controlled clinical studies revealed that rash occurred in 8% of patients administered dimethyl fumarate 240 mg twice daily (n=769) compared with 3% of patients administered placebo (n=771) (Prod Info TECFIDERA(R) delayed-release oral capsules, 2013).
    B) ERYTHEMA
    1) WITH THERAPEUTIC USE
    a) A pooled analysis of 2 placebo-controlled clinical studies revealed that erythema occurred in 5% of patients administered dimethyl fumarate 240 mg twice daily (n=769) compared with 1% of patients administered placebo (n=771) (Prod Info TECFIDERA(R) delayed-release oral capsules, 2013).
    C) ITCHING OF SKIN
    1) WITH THERAPEUTIC USE
    a) A pooled analysis of 2 placebo-controlled clinical studies revealed that pruritus occurred in 8% of patients administered dimethyl fumarate 240 mg twice daily (n=769) compared with 4% of patients administered placebo (n=771) (Prod Info TECFIDERA(R) delayed-release oral capsules, 2013).
    D) FLUSHING
    1) WITH THERAPEUTIC USE
    a) A pooled analysis of 2 placebo-controlled clinical studies revealed that flushing occurred in 40% of patients administered dimethyl fumarate 240 mg twice daily (n=769) compared with 6% of patients administered placebo (n=771). Cases were usually mild to moderate in severity and typically improved or resolved over time. Of the 40%, less than 1% of patients reported serious flushing symptoms, and 3% of patients discontinued treatment because of flushing (Prod Info TECFIDERA(R) delayed-release oral capsules, 2013).

Reproductive

    3.20.1) SUMMARY
    A) Dimethyl fumarate (DMF) is classified as FDA pregnancy category C. Although there are no adequate or well controlled studies of DMF during human pregnancy, embryofetal toxicity (reduced fetal body weight and delayed ossification) and maternal toxicity (reduced body weight) have been reported in animal studies.
    3.20.2) TERATOGENICITY
    A) ANIMAL STUDIES
    1) RATS: Delayed ossification has been reported in rats following oral administration of DMF at doses of 250 mg/kg/day (Prod Info TECFIDERA(R) delayed-release oral capsules, 2013).
    3.20.3) EFFECTS IN PREGNANCY
    A) PREGNANCY CATEGORY
    1) Dimethyl fumarate is classified as FDA pregnancy category C (Prod Info TECFIDERA(R) delayed-release oral capsules, 2013).
    B) PREGNANCY REGISTRY
    1) Encourage patients exposed to dimethyl fumarate during pregnancy to enroll in a registry monitoring pregnancy outcomes. Patients can call 1-866-810-1462 or visit www.tecfiderapregnancyregistry.com to enroll (Prod Info TECFIDERA(R) oral delayed-release capsules, 2014).
    C) ANIMAL STUDIES
    1) RATS: Oral administration of DMF at 25, 100, or 250 mg/kg/day in rats during and throughout organogenesis and lactation resulted in reduced fetal body weight, increased lethality, delayed sexual maturation, and reduced testicular weight at the highest dose tested. Maternal toxicity was also observed at the highest dose tested, and neurobehavioral impairment was observed at all doses. The plasma AUC for monomethyl fumarate, the major metabolite, was 3 times the recommended human dose of 480 mg/day at the no effect dose in rats (Prod Info TECFIDERA(R) delayed-release oral capsules, 2013).
    2) RABBITS: Administration of DMF 25, 75, or 150 mg/kg/day in pregnant rabbits during organogenesis resulted in embryolethality and decreased maternal body weight at the highest dose tested. The plasma AUC for monomethyl fumarate, the major metabolite, was 5 times the recommended human dose of 480 mg/day at the no effect dose in rabbits (Prod Info TECFIDERA(R) delayed-release oral capsules, 2013).
    3.20.4) EFFECTS DURING BREAST-FEEDING
    A) LACK OF INFORMATION
    1) It is unknown whether dimethyl fumarate is excreted in human milk (Prod Info TECFIDERA(R) delayed-release oral capsules, 2013).
    3.20.5) FERTILITY
    A) ANIMAL STUDIES
    1) In male rats, increases in non-motile sperm were noted following oral administration of DMF at doses of 250 and 375 mg/kg/day administered prior to and throughout the mating period (Prod Info TECFIDERA(R) delayed-release oral capsules, 2013).
    2) In female rats, disruption of the estrous cycle and increases in embryolethality occurred following oral administration of DMF at a dose of 250 mg/kg/day, administered prior to and during mating and continuing to gestation day 7 (Prod Info TECFIDERA(R) delayed-release oral capsules, 2013).
    3) During subchronic and chronic oral toxicity studies of DMF, involving mice, rats, and dogs, testicular toxicity, including germinal epithelial degeneration, atrophy, hypospermia, and/or hyperplasia, was reported (Prod Info TECFIDERA(R) delayed-release oral capsules, 2013).

Carcinogenicity

    3.21.4) ANIMAL STUDIES
    A) CARCINOMA
    1) MICE: In mice, nonglandular stomach (forestomach) and kidney tumors were reported following oral administration of dimethyl fumarate at doses of 25, 75, 200, and 400 mg/kg/day for up to 2 years. Other types of carcinomas that occurred included squamous cell carcinomas and forestomach papillomas in males and females at 200 and 400 mg/kg/day, forestomach leiomyosarcomas in males and females at 400 mg/kg/day, renal tubular adenomas and carcinomas in males at 200 and 400 mg/kg/day, and renal tubular adenomas in females at 400 mg/kg/day (Prod Info TECFIDERA(R) delayed-release oral capsules, 2013).
    2) RATS: In rats, squamous cell carcinomas and forestomach papillomas occurred in males and females following oral administration of dimethyl fumarate at doses of 25, 50, 100, and 150 mg/kg/day. Testicular interstitial (Leydig) cell adenomas were reported at doses of 100 and 150 mg/kg/day (Prod Info TECFIDERA(R) delayed-release oral capsules, 2013).

Genotoxicity

    A) Dimethyl fumarate and its active metabolite, monomethyl fumarate, were not mutagenic in the in vitro Ames (bacterial reverse mutation) assay. Dimethyl fumarate and monomethyl fumarate were clastogenic in the in vitro chromosomal aberration assay in human peripheral blood lymphocytes in the absence of metabolic activation; however, dimethyl fumarate was not clastogenic in the in vivo micronucleus assay in the rat (Prod Info TECFIDERA(R) delayed-release oral capsules, 2013).

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Monitor CBC with differential.
    B) No other specific laboratory tests are necessary unless otherwise clinically indicated.
    C) Plasma concentrations of dimethyl fumarate or its active metabolite, monomethyl fumarate, are not readily available or clinically useful in the management of overdose.

Treatment

Life Support

    A) Support respiratory and cardiovascular function.

Patient Disposition

    6.3.1) DISPOSITION/ORAL EXPOSURE
    6.3.1.1) ADMISSION CRITERIA/ORAL
    A) Patients who remain symptomatic despite treatment should be admitted.
    6.3.1.2) HOME CRITERIA/ORAL
    A) A patient with a small inadvertent exposure, that remains asymptomatic, can be managed at home.
    6.3.1.3) CONSULT CRITERIA/ORAL
    A) Consult a poison center or medical toxicologist for assistance in managing patients with severe toxicity or in whom the diagnosis is not clear.
    6.3.1.5) OBSERVATION CRITERIA/ORAL
    A) Patients with a deliberate overdose, and those who are symptomatic, should be sent to a healthcare facility for evaluation.

Monitoring

    A) Monitor CBC with differential.
    B) No other specific laboratory tests are necessary unless otherwise clinically indicated.
    C) Plasma concentrations of dimethyl fumarate or its active metabolite, monomethyl fumarate, are not readily available or clinically useful in the management of overdose.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) Prehospital gastrointestinal decontamination is generally not necessary.
    6.5.3) TREATMENT
    A) SUPPORT
    1) Treatment is symptomatic and supportive. There is no antidote available.
    B) MONITORING OF PATIENT
    1) Monitor CBC with differential.
    2) No other specific laboratory tests are necessary unless otherwise clinically indicated.
    3) Plasma concentrations of dimethyl fumarate or its active metabolite, monomethyl fumarate, are not readily available or clinically useful in the management of overdose.

Enhanced Elimination

    A) HEMODIALYSIS
    1) Hemodialysis would be expected to remove monomethyl fumarate given its small volume of distribution and low protein binding.

Range Of Toxicity

Summary

    A) TOXICITY: A toxic dose has not been established. Overdose has not been reported.
    B) THERAPEUTIC DOSE: ADULT: Initially, the recommended dose is 120 mg orally twice daily. After 7 days, the dose should be increased to 240 mg orally twice daily. PEDIATRIC: Safety and efficacy have not been established in pediatric patients

Therapeutic Dose

    7.2.1) ADULT
    A) Initially, the recommended dose is 120 mg orally twice daily. After 7 days, the dose should be increased to 240 mg orally twice daily (Prod Info TECFIDERA(R) delayed-release oral capsules, 2013).
    1) The capsules should be swallowed whole and intact, without being crushed or chewed, and without the contents of the capsule being sprinkled on food (Prod Info TECFIDERA(R) delayed-release oral capsules, 2013).
    7.2.2) PEDIATRIC
    A) Safety and efficacy have not been established in pediatric patients (Prod Info TECFIDERA(R) delayed-release oral capsules, 2013).

Maximum Tolerated Exposure

    A) A toxic dose has not been established. Overdose has not been reported.

Pharmacology Toxicology

Pharmacologic Mechanism

    A) Although the exact mechanism of effect in multiple sclerosis is unknown, dimethyl fumarate is an in vitro nicotinic acid receptor agonist and an in vivo activator of the Nuclear factor (erythroid-derived 2)-like 2 (Nrf2) pathway that is involved in the cellular response to oxidative stress (Prod Info TECFIDERA(R) delayed-release oral capsules, 2013).

Physicochemical

Physical Characteristics

    A) Dimethyl fumarate is a white to off-white powder, and is highly soluble in water (Prod Info TECFIDERA(R) delayed-release oral capsules, 2013).

Molecular Weight

    A) 144.13 (Prod Info TECFIDERA(R) delayed-release oral capsules, 2013)

References

General Bibliography

    1) Product Information: TECFIDERA(R) delayed-release oral capsules, dimethyl fumarate delayed-release oral capsules. Biogen Idec, Inc, Cambridge, MA, 2013.
    2) Product Information: TECFIDERA(R) oral delayed-release capsules, dimethyl fumarate oral delayed-release capsules. Biogen Idec Inc. (per manufacturer), Cambridge, MA, 2014.
    3) U.S. Food and Drug Administration (FDA): FDA Drug Safety Communication: FDA warns about case of rare brain infection PML with MS drug Tecfidera (dimethyl fumarate). U.S. Food and Drug Administration (FDA). Silver Spring, MD. 2014. Available from URL: http://www.fda.gov/downloads/Drugs/DrugSafety/UCM424634.pdf. As accessed 2014-11-25.