AHFS Class:

• Fumarates 90:04.08

Generic Name(s):

• Monomethyl Fumarate

Monomethyl fumarate, a fumaric acid derivative, has immunomodulatory and disease-modifying activity in multiple sclerosis.1

Multiple Sclerosis

Monomethyl fumarate is indicated for the treatment of relapsing forms of multiple sclerosis (MS), including clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease, in adults.1

Monomethyl fumarate is the active metabolite of dimethyl fumarate, another fumaric acid derivative used in the treatment of MS; therefore, use of monomethyl fumarate is based on established bioequivalence to dimethyl fumarate and previous findings of efficacy and safety for dimethyl fumarate.1,2,3 In 2 randomized, double-blind, placebo-controlled studies in adults with relapsing forms of MS, dimethyl fumarate substantially reduced relapse rates and the development of new or enlarging T2 lesions at 2 years compared with placebo.1,2,17,18,19

Clinical Perspective

Monomethyl fumarate is one of several disease-modifying therapies used in the management of relapsing forms of MS.10,76,77 Although not curative, these therapies have all been shown to modify several measures of disease activity, including relapse rates, new or enhancing magnetic resonance imaging (MRI) lesions, and disability progression.76,78 The American Academy of Neurology (AAN) recommends that disease-modifying therapy be offered to patients with relapsing forms of MS who have had recent relapses and/or MRI activity; these experts state that the benefits versus risks (e.g., adverse effects or burden of taking a long-term medication) of treatment in patients who have not had relapses in 2 or more years and do not have active MRI lesions are not known.76 Because CNS damage occurs early and continues throughout the course of MS, other clinicians recommend that disease-modifying therapy be initiated as soon as possible following diagnosis and continued indefinitely unless there is a clear lack of benefit, adverse effects are intolerable, the patient is unable to adhere to the recommended treatment regimen, or a more appropriate treatment becomes available.77 Clinicians should consider the adverse effects, tolerability, method of administration, safety, efficacy, and cost of the drugs in addition to patient preferences when selecting an appropriate disease-modifying therapy.76,77

General

Patient Monitoring

• Because of risk of lymphopenia, obtain CBC (including lymphocyte count) prior to initiating therapy, at 6 months, and then every 6-12 months thereafter as clinically indicated.1
• Because of possible hepatic injury, perform liver function tests (i.e., serum aminotransferase, alkaline phosphatase, and total bilirubin concentrations) prior to initiating therapy and then as clinically indicated.1
• Monitor for new or worsening severe GI signs and symptoms during therapy.1

Premedication and Prophylaxis

• Administration of non-enteric coated aspirin (up to a dose of 325 mg) 30 minutes prior to monomethyl fumarate may reduce the incidence or severity of flushing.1

Administration

Administer monomethyl fumarate delayed-release capsules orally twice daily with or without food.1

Swallow delayed-release capsules whole and intact; do not crush, chew, or open contents of capsules and sprinkle on food.1

Dosage

Relapsing Forms of Multiple Sclerosis

The recommended initial dosage of monomethyl fumarate in adults with relapsing forms of multiple sclerosis (MS) is 95 mg twice daily for 7 days.1 After 7 days, the dosage should be increased to a maintenance dosage of 190 mg (administered as two 95-mg capsules) twice daily.1

Consider a temporary reduction in the maintenance dosage of monomethyl fumarate from 190 mg twice daily to 95 mg twice daily in patients who do not tolerate the usual maintenance dosage.1 The recommended maintenance dosage of 190 mg twice daily should be resumed within 4 weeks.1 Consider discontinuance of the drug in patients unable to tolerate a return to the usual maintenance dosage.1

Special Populations

Dosage in Hepatic Impairment

Monomethyl fumarate has not been evaluated in patients with hepatic impairment; however, the manufacturer states exposure to the drug is unlikely to be affected in such patients.1 Therefore, no dosage adjustment is necessary.1

Dosage in Renal Impairment

Monomethyl fumarate has not been evaluated in patients with renal impairment; however, the manufacturer states that exposure to the drug is unlikely to be affected in such patients.1 Therefore, no dosage adjustment is necessary.1

Dosage in Geriatric Patients

The manufacturer states that no dosage adjustment is necessary based on age.1

Contraindications

• Known hypersensitivity to monomethyl fumarate, dimethyl fumarate, diroximel fumarate, or any excipients in the formulation.1
• Concomitant use of dimethyl fumarate or diroximel fumarate.1

Warnings/Precautions

Anaphylaxis and Angioedema

Monomethyl fumarate can cause anaphylaxis and angioedema after the first dose or at any time during treatment.1 Signs and symptoms in patients taking dimethyl fumarate (the prodrug of monomethyl fumarate) have included difficulty breathing, urticaria, and swelling of the throat and tongue.1 Patients should be instructed to discontinue monomethyl fumarate and seek immediate medical care if they experience signs and symptoms of anaphylaxis or angioedema.1

Progressive Multifocal Leukoencephalopathy

Progressive multifocal leukoencephalopathy (PML) has occurred in patients with multiple sclerosis (MS) treated with dimethyl fumarate (the prodrug of monomethyl fumarate).1 PML is an opportunistic viral infection of the brain caused by the JC virus (JCV) that typically only occurs in patients who are immunocompromised, and that usually leads to death or severe disability.1 A fatal case of PML occurred in a patient who received dimethyl fumarate for 4 years while enrolled in a clinical trial.1 During the clinical trial, the patient experienced prolonged lymphopenia (lymphocyte counts predominantly <500/mm³ for 3.5 years) while taking dimethyl fumarate.1 The patient had no other conditions associated with compromised immune system function and had not previously been treated with natalizumab, which has a known association with PML.1 The patient also was not taking any immunosuppressive or immunomodulatory medications concomitantly.1

PML has also occurred in patients taking dimethyl fumarate in the postmarketing setting in the presence of lymphopenia (<900/mm³).1 While the role of lymphopenia in these cases is uncertain, the cases have occurred predominantly in patients with lymphocyte counts (<800/mm³) persisting for more than 6 months.1

Withhold monomethyl fumarate therapy at the first sign or symptom suggestive of PML, and perform an appropriate diagnostic evaluation.1 Symptoms typically associated with PML are diverse, progress over days to weeks, and include progressive weakness on one side of the body or clumsiness of limbs, disturbance of vision, and changes in thinking, memory, and orientation leading to confusion and personality changes. 1 MRI signs of PML may be apparent before clinical manifestations develop; cases of PML in the absence of clinical manifestations have been diagnosed in patients with MS receiving other drugs associated with PML based on MRI findings and the detection of JCV DNA in the CSF.1 Many of these patients subsequently became symptomatic with PML.1 Lower PML-related mortality and morbidity have been reported following discontinuation of another drug associated with PML in patients who were initially asymptomatic compared with patients who had characteristic clinical signs and symptoms at diagnosis.1 It is not known whether these differences are due to early detection and discontinuation of MS treatment or due to differences in disease in these patients.1 Therefore, MRI monitoring may be useful and any suspicious findings on MRI should be followed with further investigation.1

Infectious Complications

Serious cases of herpes zoster have occurred with dimethyl fumarate (the prodrug of monomethyl fumarate), including disseminated herpes zoster, herpes zoster ophthalmicus, herpes zoster meningoencephalitis, and herpes zoster meningomyelitis.1 These events may occur at any time during treatment.1

Other serious opportunistic infections reported in patients receiving dimethyl fumarate include viral (herpes simplex, West Nile virus, cytomegalovirus), fungal (candidiasis, aspergillosis), and bacterial (nocardiosis, listeriosis, tuberculosis) infections affecting various parts of the body such as the brain, meninges, spinal cord, GI tract, lungs, skin, eyes, and ears.1 Such infections have been reported in patients with lymphopenia as well as in patients with normal absolute lymphocyte counts.1

Monitor patients for signs and symptoms of herpes zoster or other opportunistic infections and treat the patient appropriately if any such infections develop.1 Consider withholding monomethyl fumarate treatment in patients with serious infections until the infection has resolved.1

Lymphopenia

Monomethyl fumarate may decrease lymphocyte counts.1 In placebo-controlled trials with dimethyl fumarate (the prodrug of monomethyl fumarate) in patients with MS, mean lymphocyte counts decreased by approximately 30% during the first year of treatment and then remained stable.1 Mean lymphocyte counts improved 4 weeks following discontinuance of the drug, but did not return to baseline values.1 The incidence of infections (60 and 58%) and serious infections (2 and 2%) was similar in patients receiving dimethyl fumarate and placebo, respectively.1 Although an increased incidence of serious infections was not observed in patients with decreased lymphocyte counts in controlled trials, one dimethyl fumarate-treated patient in an extension study developed PML in the setting of prolonged lymphopenia (i.e., lymphocyte counts predominantly <500/mm³ for 3.5 years).1

In controlled and uncontrolled clinical trials, 2% of dimethyl fumarate-treated patients had lymphocyte counts <500/mm³ for at least 6 months; in these patients, the majority of lymphocyte counts remained <500/mm³ with continued therapy.1 In those with prolonged, severe lymphopenia, the median time for lymphocyte counts to return to normal after discontinuing dimethyl fumarate was 96.0 weeks.1 Among patients who did not experience prolonged, severe lymphopenia during treatment, the median times for lymphocyte counts to return to normal after discontinuing dimethyl fumarate were 4.3 weeks in patients with mild lymphopenia (lymphocyte count ≥800/mm³), 10 weeks in patients with moderate lymphopenia (lymphocyte count 500-800/mm³), and 16.7 weeks in patients with severe lymphopenia (lymphocyte count <500/mm³).1

Neither monomethyl fumarate nor dimethyl fumarate have been studied in patients with preexisting low lymphocyte counts.1

Obtain a complete blood count (CBC), including lymphocyte count, before initiating therapy and at 6 months; continue monitoring every 6-12 months thereafter, and as clinically indicated.1 Consider interruption of monomethyl fumarate therapy in patients with lymphocyte counts <500/mm³ persisting for more than 6 months.1 Because of the potential for a delay in lymphocyte recovery, consider monitoring of lymphocyte counts until lymphopenia is resolved after the drug is discontinued.1

In patients with serious infections, consider withholding monomethyl fumarate treatment until the infection has resolved.1 The decision to resume therapy should be individualized based on clinical circumstances.1

Liver Injury

Clinically important liver injury has been reported in patients treated with dimethyl fumarate (the prodrug of monomethyl fumarate) in the postmarketing setting.1 Liver function test abnormalities (e.g., elevations in serum aminotransferase concentrations to more than fivefold the upper limit of normal [ULN] and elevations in total bilirubin concentrations to more than twofold the ULN) have been observed.1 Such abnormalities occurred within a few days to several months after initiation of therapy, and resolved upon discontinuance of the drug.1 Although liver failure and death did not occur in any of the reported cases, marked increases in liver function tests may be indicative of serious liver injury.1

Perform liver function tests (i.e., serum aminotransferase, alkaline phosphatase, and total bilirubin concentrations) prior to initiating monomethyl fumarate and during therapy as clinically indicated.1 If there is any evidence of liver injury, discontinue the drug.1

Flushing

Monomethyl fumarate may cause flushing (e.g., warmth, redness, itching, and/or burning sensation).1 In clinical trials of dimethyl fumarate (the prodrug of monomethyl fumarate), 40% of patients who received the drug experienced flushing.1 Symptoms generally began soon after initiating dimethyl fumarate and improved or resolved over time.1 In most patients, flushing was mild or moderate in severity.1 Discontinuance of therapy for flushing was reported in 3% of patients receiving dimethyl fumarate; less than 1% of patients had serious flushing symptoms that were not life-threatening but resulted in hospitalization.1

Studies with dimethyl fumarate have demonstrated that administration of non-enteric coated aspirin (up to a dose of 325 mg) 30 minutes prior to dosing may reduce the incidence and severity of flushing.1 In the monomethyl fumarate studies, the presence of food did not impact the incidence of flushing. 1

Serious Gastrointestinal Reactions

In the postmarketing setting, serious GI reactions (e.g., perforation, ulceration, hemorrhage, and obstruction, some with fatal outcomes) have been reported with the use of fumaric acid esters, with or without concomitant aspirin use.1 Most of these events have occurred within 6 months of fumaric acid ester treatment initiation.1

In controlled clinical trials, the incidence of serious GI adverse events was 1% in patients treated with dimethyl fumarate; these events, none of which were fatal, included vomiting (0.3%) and abdominal pain (0.3%).1 Monitor patients, promptly evaluate, and discontinue monomethyl fumarate for new or worsening severe GI signs and symptoms.1

Specific Populations

Pregnancy

There are no adequate data on the developmental risks associated with the use of monomethyl fumarate or dimethyl fumarate (the prodrug of monomethyl fumarate) during pregnancy.1 However, data from a pregnancy registry, observational studies, and pharmacovigilance related to the use of dimethyl fumarate in pregnancy have not indicated an increased risk of major birth defects, miscarriage, or other adverse maternal or fetal outcomes with that agent.1 Most dimethyl fumarate exposures occurred during the first trimester of pregnancy and the rate of major birth defects was 3.6% among 362 live births and stillbirths.1

In animal studies, adverse effects on offspring survival, growth, sexual maturation, and neurobehavioral function were observed when dimethyl fumarate was administered during pregnancy at clinically relevant doses.1

There is a pregnancy exposure registry that monitors outcomes in women exposed to monomethyl fumarate during pregnancy.1 To enroll in the registry, contact Banner Life Sciences at 1-866-663-9564.1

Lactation

It is not known whether monomethyl fumarate or dimethyl fumarate is distributed into human milk.1 The effects of monomethyl fumarate on the nursing infant or on milk production also are not known.1 Consider the benefits of breast-feeding along with the woman's clinical need for monomethyl fumarate and any potential adverse effects on the breast-fed infant from the drug or underlying maternal condition.1

Pediatric Use

Safety and efficacy of monomethyl fumarate have not been established in pediatric patients. 1

Geriatric Use

Clinical studies of dimethyl fumarate (the prodrug of monomethyl fumarate) and of monomethyl fumarate did not include sufficient numbers of patients ≥65 years of age to determine whether they respond differently from younger patients.1

Hepatic Impairment

Monomethyl fumarate has not been studied in patients with hepatic impairment.1

Renal Impairment

Monomethyl fumarate has not been studied in patients with renal impairment.1

Common Adverse Effects

Adverse reactions reported in ≥10% of patients with MS receiving dimethyl fumarate (the prodrug of monomethyl fumarate) and ≥2% more frequently than with placebo include flushing, abdominal pain, diarrhea, and nausea.1

No potential drug interactions with dimethyl fumarate or monomethyl fumarate were identified in cytochrome P-450 inhibition and induction studies or in P-glycoprotein studies.1

Aspirin

Non-enteric-coated aspirin 325 mg administered approximately 30 minutes prior to dimethyl fumarate (the prodrug of monomethyl fumarate) over 4 days in healthy individuals did not alter the pharmacokinetic profile of dimethyl fumarate and its active monomethyl fumarate metabolite, but reduced the incidence and severity of flushing.1,14

Fumaric Acid Derivatives

Both dimethyl fumarate and diroximel fumarate are metabolized to monomethyl fumarate.1 Therefore, monomethyl fumarate is contraindicated in patients receiving dimethyl fumarate or diroximel fumarate.1

Glatiramer Acetate

Administration of a single IM dose of glatiramer acetate did not alter the pharmacokinetics of monomethyl fumarate.1

Interferon Beta

Administration of a single IM dose of interferon beta-1a did not alter the pharmacokinetics of monomethyl fumarate.1

Oral Contraceptives

Concomitant use of dimethyl fumarate (the prodrug of monomethyl fumarate) and an oral contraceptive containing ethinyl estradiol and norelgestromin had no clinically important effects on either component of the contraceptive.1 Drug interaction studies with dimethyl fumarate have not been conducted with oral contraceptives containing other progestogens.1

Description

Monomethyl fumarate (MMF) is a fumaric acid derivative; the drug is the active metabolite of dimethyl fumarate, another fumaric acid derivative used in the treatment of multiple sclerosis (MS).1,17 The mechanism by which monomethyl fumarate exerts its therapeutic effect in MS is not known; however, the immunomodulatory effect of the drug appears to be mediated by many cells of the immune system.1,7,9,11 Dimethyl fumarate and monomethyl fumarate have been shown to activate the nuclear factor (erythroid-derived 2)-like 2 (Nrf2) pathway in vitro and in vivo in animals and humans;1,7,11,23 the Nrf2 antioxidant response pathway is involved in the cellular response to oxidative stress.1,7,9,11,23 In vitro and animal studies suggest that Nrf2-dependent upregulation of antioxidant response genes by dimethyl fumarate and MMF may protect various cells and tissues, including some in the CNS, from experimental toxic oxidative stress.7,11,23

Activation of the Nrf2 pathway by dimethyl fumarate and monomethyl fumarate also may inhibit proliferation of lymphocytes and hematopoietic stem cells.16 While fumaric acid derivative therapy causes substantial, dose-dependent reductions in peripheral lymphocytes, subsets of lymphocytes appear to be affected differently.16,23 In particular, more pronounced reductions in CD8⁺ T-cell counts than in CD4⁺ T-cell counts have been observed;16,23 subpopulations of other lymphocytes (e.g., memory T-cells, B-cells, natural killer [NK] cells) also have been altered.23 Such alterations in the composition of peripheral lymphocytes are thought to shift the immune profile towards an anti-inflammatory state in patients with MS.23

In addition, monomethyl fumarate has been shown to be a nicotinic acid receptor agonist in vitro.1 Nicotinic acid and fumaric acid derivatives can cause skin flushing as an adverse reaction; it has been suggested that such flushing reactions may be mediated by the activation of hydroxy-carboxylic acid receptor 2 (HCA₂) and involve the formation of prostaglandins.12,14

Following oral administration of monomethyl fumarate delayed-release capsules, the median time to peak plasma concentrations is 4.03 hours.1 Peak plasma concentrations and systemic exposure of monomethyl fumarate 190 mg and dimethyl fumarate 240 mg are bioequivalent.1,3 Administration of monomethyl fumarate delayed-release capsules with a high-fat, high-calorie meal did not significantly affect systemic exposure to the drug but decreased peak plasma concentrations by 20%, with prolonged absorption.1 The high-fat meal increased time to peak plasma concentrations from 4 to 11 hours.1 Monomethyl fumarate distributes into the CNS.23 The drug is metabolized via the tricarboxylic acid (TCA) cycle, with no involvement of cytochrome P450 (CYP) pathways.1 Fumaric acid, citric acid, and glucose are the major metabolites of monomethyl fumarate in plasma.1 Monomethyl fumarate is primarily expired as carbon dioxide with trace amounts of unchanged drug recovered in urine.1 The terminal half-life of monomethyl fumarate is approximately 0.5 hours; no circulating drug is present at 24 hours following oral administration of a 190-mg dose in the majority of individuals.1

Advice to Patients

• Advise patients to read the manufacturer's patient information.1
• Risk of anaphylaxis and angioedema.1 Advise patients to discontinue monomethyl fumarate and seek immediate medical care if they develop signs and symptoms of anaphylaxis or angioedema (e.g., difficulty breathing, urticaria, swelling of the throat and tongue).1
• Inform patients that progressive multifocal leukoencephalopathy (PML) has occurred in a patient treated with dimethyl fumarate (the prodrug of monomethyl fumarate), and is characterized by a progression of deficits and usually leads to death or severe disability over weeks to months.1 Immediately inform a clinician of any new or worsening symptoms suggestive of PML (e.g., progressive weakness on one side of the body; clumsiness of limbs; disturbance of vision; changes in cognition, memory, and orientation leading to confusion and personality changes) that have progressed over days to weeks.1
• Inform patients that they will be provided one strength of monomethyl fumarate when starting treatment: take one capsule for the 7 day starter dose and two capsules for the maintenance dose, both to be taken twice daily.1
• Inform patients to swallow monomethyl fumarate delayed-release capsules whole and intact, and not to crush, chew, or sprinkle the capsule contents on food.1 The capsules may be taken with or without food.1
• Inform patients that flushing and adverse GI reactions (e.g., abdominal pain, diarrhea, nausea) are common, particularly at the initiation of treatment, and that they may decrease over time.1 Advise patients to contact their clinician if they experience persistent and/or severe flushing or GI reactions (e.g., GI bleeding).1 Advise patients that taking non-enteric-coated aspirin prior to taking monomethyl fumarate may be helpful in certain cases.1
• Risk of decreased lymphocyte counts.1 Stress importance of periodic monitoring of CBCs.1
• Risk of herpes zoster and other serious opportunistic infections.1 Advise patients to contact their clinician if they develop any signs or symptoms associated with herpes zoster or other infections.1
• Risk of liver injury.1 Advise patients to immediately report any possible manifestations, including fatigue, anorexia, right upper abdominal discomfort, dark urine, or jaundice; stress importance of patients receiving liver function tests prior to and during treatment as clinically indicated to monitor for such effects.1
• Stress importance of women informing their clinician if they are or plan to become pregnant or plan to breast-feed.1 A pregnancy exposure registry monitors outcomes in women exposed to monomethyl fumarate during pregnancy.1 To enroll in the registry, contact Banner Life Sciences at 1-866-663-9564.1
• Advise patients to inform clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and herbal supplements, as well as any concomitant illnesses (e.g., leukopenia, lymphopenia, infections).1
• Inform patients of other important precautionary information.1

Additional Information

The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer's labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.

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3. Lategan TW, Wang L, Sprague TN et al. Pharmacokinetics and Bioavailability of Monomethyl Fumarate Following a Single Oral Dose of Bafiertam™ (Monomethyl Fumarate) or Tecfidera^® (Dimethyl Fumarate). CNS Drugs . 2021; 35:567-574. [PubMed 33797063]

6. Banner. Bafiertam^® Patient Support. From the Bafiertam website. Accessed 2024 Mar 15. [Web]

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9. Lin SX, Lisi L, Dello Russo C et al. The anti-inflammatory effects of dimethyl fumarate in astrocytes involve glutathione and haem oxygenase-1. ASN Neuro . 2011; 3:. [PubMed 21382015]

10. National Multiple Sclerosis Society. Treating MS: Medications. From the NMSS website. Accessed Mar 15, 2024. [Web]

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12. Hanson J, Gille A, Offermanns S. Role of HCA₂ (GPR109A) in nicotinic acid and fumaric acid ester-induced effects on the skin. Pharmacol Ther . 2012; 136:1-7. [PubMed 22743741]

14. Sheikh SI, Nestorov I, Russell H et al. Tolerability and pharmacokinetics of delayed-release dimethyl fumarate administered with and without aspirin in healthy volunteers. Clin Ther . 2013; 35:1582-94. [PubMed 24139424]

16. Spencer CM, Crabtree-Hartman EC, Lehmann-Horn K et al. Reduction of CD8+ T lymphocytes in multiple sclerosis patients treated with dimethyl fumarate. Neurol Neuroimmunol Neuroinflamm . 2015; 2:e76. [PubMed 25738172]

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23. Mills EA, Ogrodnik MA, Plave A et al. Emerging Understanding of the Mechanism of Action for Dimethyl Fumarate in the Treatment of Multiple Sclerosis. Front Neurol . 2018; 9:5. [PubMed 29410647]

76. 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. Neurology . 2018; 90:777-788. [PubMed 29686116]

77. Multiple Sclerosis Coalition. The use of disease-modifying therapies in multiple sclerosis: principles and current evidence summary. Available from National MS Society website. [Web]

78. National MS Society. Disease-modifying therapies for MS (updated March 2022). Available from National MS Society website. [Web]