Brand name: Bafiertam
Drug class: Immunomodulatory Agents

Medically reviewed by Drugs.com on Apr 10, 2024. Written by ASHP.

[Web]

Introduction

Fumaric acid derivative with immunomodulatory and disease-modifying activity in multiple sclerosis. Active metabolite of dimethyl fumarate.

Uses for Monomethyl Fumarate

Multiple Sclerosis

Treatment of relapsing forms of MS, including clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease.

Monomethyl fumarate is the pharmacologically active metabolite of dimethyl fumarate; use of monomethyl fumarate is based on established bioequivalence to dimethyl fumarate and previous efficacy and safety findings with dimethyl fumarate. Dimethyl fumarate has been shown to substantially reduce relapse rates and new or enlarging T2 lesions.

Monomethyl fumarate is one of several disease-modifying therapies used in the management of relapsing forms of MS. Although not curative, these therapies have all been shown to modify several measures of disease activity, including relapse rates, new or enhancing MRI lesions, and disability progression.

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 lesion activity. Clinicians should consider adverse effects, tolerability, method of administration, safety, efficacy, and cost of the drugs in addition to patient preferences when selecting an appropriate therapy.

Monomethyl Fumarate Dosage and Administration

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.

• 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.

• Monitor for new or worsening severe GI signs and symptoms during therapy.

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.

Administration

Oral Administration

Administer orally twice daily with or without food.

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

Dosage

Adults

Relapsing Forms of MS

Oral

Initially, 95 mg twice daily for 7 days. After 7 days, increase to a maintenance dosage of 190 mg (administered as two 95-mg capsules) twice daily.

May consider a temporary reduction in maintenance dosage from 190 mg twice daily to 95 mg twice daily in patients who do not tolerate the usual maintenance dosage. Resume recommended maintenance dosage of 190 mg twice daily within 4 weeks. Consider discontinuance of therapy in patients unable to tolerate a return to the usual maintenance dosage.

Special Populations

Hepatic Impairment

Not evaluated in patients with hepatic impairment; however, exposure unlikely to be altered. No dosage adjustment is necessary.

Renal Impairment

Not evaluated in patients with renal impairment; however, exposure unlikely to be altered. No dosage adjustment is necessary.

Geriatric Patients

Manufacturer makes no special dosage recommendations.

Cautions for Monomethyl Fumarate

Contraindications

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

• Concomitant use of dimethyl fumarate or diroximel fumarate.

Warnings/Precautions

Anaphylaxis and Angioedema

May cause anaphylaxis or angioedema after the first dose or at any time during therapy. Hypersensitivity reactions, including difficulty breathing, urticaria, and swelling of the throat and tongue reported with dimethyl fumarate (the prodrug of monomethyl fumarate).

Discontinue therapy if any signs or symptoms of anaphylaxis or angioedema occur. (See Contraindications under Cautions.)

Progressive Multifocal Leukoencephalopathy (PML)

PML, an opportunistic infection of the brain caused by the JC virus, reported in patients receiving dimethyl fumarate (the prodrug of monomethyl fumarate). PML has been reported with dimethyl fumarate in the setting of prolonged lymphopenia, including a fatal case of PML in a patient with MS who had lymphocyte counts <500/mm³ for 3.5 years.

At the first sign or symptom suggestive of PML, immediately withhold therapy and perform appropriate diagnostic evaluation. MRI signs of PML may be apparent before clinical manifestations develop.

Infectious Complications

Serious cases of herpes zoster and other opportunistic infections (viral, fungal, and bacterial) reported with dimethyl fumarate (the prodrug of monomethyl fumarate); has occurred in patients with lymphopenia as well as in patients with normal lymphocyte counts. May occur at any time during therapy.

Monitor for signs and symptoms of herpes zoster or other opportunistic infections. If any manifestations of such infections occur, promptly evaluate and treat patient appropriately. Consider interruption of therapy in patients with serious infections until infection resolves.

Lymphopenia

May decrease lymphocyte counts. In clinical trials with dimethyl fumarate (the prodrug of monomethyl fumarate), mean lymphocyte counts decreased by approximately 30% during the first year of therapy. Lymphocyte counts improved 4 weeks following discontinuance of the drug, but did not return to baseline values.

Increased incidence of serious infections not observed in patients with decreased lymphocyte counts, but one case of PML developed in the setting of prolonged lymphopenia.

Not studied in patients with preexisting low lymphocyte counts.

Obtain CBC, including lymphocyte count, prior to initiation of therapy, at 6 months, then every 6–12 months during therapy as clinically indicated.

In patients with lymphocyte counts <500/mm³ persisting for >6 months, consider interruption of therapy. Consider monitoring lymphocyte counts until lymphopenia has resolved after the drug is discontinued since lymphocyte recovery may be delayed.

In patients with serious infections, consider withholding treatment until infection resolves. Consider patient's clinical circumstances when deciding whether to restart therapy.

Hepatic Injury

Liver injury, sometimes requiring hospitalization, reported with dimethyl fumarate (the prodrug of monomethyl fumarate). Liver function test abnormalities (e.g., elevations in serum aminotransferase concentrations to more than fivefold the ULN and elevations in total bilirubin concentrations to more than twofold the ULN) observed. Occurred within a few days to several months after initiation of therapy with dimethyl fumarate and resolved upon treatment discontinuance.

No cases resulted in liver failure, liver transplantation, or death; however, abnormal liver function tests may predict serious liver injury.

Perform liver function tests (i.e., serum aminotransferase, alkaline phosphatase, and total bilirubin concentrations) prior to and during therapy as clinically indicated. Discontinue drug if liver injury suspected.

Flushing

May cause flushing (e.g., warmth, redness, itching, burning sensation). In clinical trials of dimethyl fumarate (the prodrug of monomethyl fumarate), flushing was reported in 40% of patients who received the drug. Symptoms generally are mild to moderate, begin soon after initiating therapy, and improve or resolve over time.

Administration with non-enteric-coated aspirin (up to a dose of 325 mg) 30 minutes before monomethyl fumarate may reduce incidence and/or severity of flushing.

Serious Gastrointestinal Reactions

Serious GI reactions (e.g., perforation, ulceration, hemorrhage, and obstruction, some with fatal outcomes) reported with use of fumaric acid esters, with or without concomitant aspirin use. Most have occurred within 6 months of fumaric acid ester initiation. Monitor patients, promptly evaluate, and discontinue monomethyl fumarate for new or worsening severe GI signs and symptoms.

Specific Populations

Pregnancy

No adequate data on developmental risk associated with use during pregnancy. Based on animal data, may cause fetal harm.

There is a pregnancy exposure registry that monitors outcomes in women exposed to monomethyl fumarate during pregnancy. To enroll in the registry, contact Banner Life Sciences at 1-866-663-9564.

Lactation

Not known whether monomethyl fumarate is distributed into human milk.

Effects on nursing infant or on milk production also not known.

Consider 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.

Pediatric Use

Safety and efficacy not established in pediatric patients.

Geriatric Use

Insufficient experience in patients ≥65 years of age to determine whether they respond differently than younger adults.

Hepatic Impairment

Not studied in individuals with hepatic impairment; however, hepatic impairment not expected to affect systemic exposure. Dosage adjustment not necessary.

Renal Impairment

Not studied in individuals with renal impairment; however, renal impairment not expected to affect systemic exposure. Dosage adjustment not necessary.

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.

Drug Interactions

Not metabolized by CYP isoenzymes; therefore, clinically important interactions with CYP inhibitors or inducers not expected. Studies involving inhibition or induction of CYP isoenzymes and P-glycoprotein (P-gp) have not revealed any potential drug interactions.

Specific Drugs

Monomethyl Fumarate Pharmacokinetics

Absorption

Bioavailability

Peak plasma concentrations and systemic exposure of monomethyl fumarate 190 mg and dimethyl fumarate 240 mg are bioequivalent.

Food

Administration with a high-fat, high-calorie meal did not significantly affect systemic exposure but decreased peak plasma concentrations by 20%, with prolonged absorption; time to peak plasma concentrations was delayed from 4 to 11 hours.

Plasma Concentrations

Following oral administration, median time to peak plasma concentrations is 4.03 hours.

Distribution

Extent

Distributes into the CNS.

Plasma Protein Binding

27–45%.

Elimination

Metabolism

Metabolized via the tricarboxylic acid (TCA) cycle, with no involvement of CYP pathways. Fumaric acid, citric acid, and glucose are major metabolites of monomethyl fumarate in plasma.

Elimination Route

Primarily expired as carbon dioxide with trace amounts of unchanged drug recovered in urine.

Half-life

Approximately 0.5 hours.

Stability

Storage

Oral

Delayed-release Capsules

Store unopened bottles at 2–8°C; do not freeze.

Store opened bottles at 20–25°C (may expose to 15–30°C); store in original container and protect from light.

Actions

• Exact mechanism of action in MS is unknown; however, immunomodulatory effect appears to be mediated by many cells of the immune system.

• Monomethyl fumarate (MMF) and its prodrug, dimethyl fumarate, activate the nuclear factor (erythroid-derived 2)-like 2 (Nrf2) pathway in vitro and in vivo in animals and humans. The Nrf2 antioxidant response pathway is involved in the cellular response to oxidative stress.

• 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.

• Activation of the Nrf2 pathway by dimethyl fumarate and MMF also may inhibit proliferation of lymphocytes and hematopoietic stem cells. Dose-dependent reduction in peripheral lymphocytes occurs, with a more pronounced reduction in CD8⁺ T-cell counts than in CD4⁺ T-cell counts; subsets of other lymphocytes (e.g., memory T-cells, B-cells, natural killer [NK] cells) also altered. Alterations in composition of peripheral lymphocytes thought to shift the immune profile towards an anti-inflammatory state in patients with MS.

• Monomethyl fumarate is a nicotinic acid receptor agonist in vitro. Nicotinic acid and fumaric acid derivatives can cause skin flushing; flushing reactions may be mediated by activation of hydroxy-carboxylic acid receptor 2 (HCA₂) and involve formation of prostaglandins.

Advice to Patients

• Advise patients to read the manufacturer's patient information.

• Risk of anaphylaxis and angioedema. 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).

• Inform patients that 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. Imediately 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.

• 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.

• Inform patients to swallow monomethyl fumarate delayed-release capsules whole and intact, and not to crush, chew, or sprinkle the capsule contents on food. The capsules may be taken with or without food.

• 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. Advise patients to contact their clinician if they experience persistent and/or severe flushing or GI reactions (e.g., GI bleeding). Advise patients that taking non-enteric-coated aspirin prior to taking monomethyl fumarate may be helpful in certain cases.

• Risk of decreased lymphocyte counts. Importance of periodic monitoring of CBCs.

• Risk of herpes zoster and other serious opportunistic infections. Advise patients to contact their clinician if they develop any signs or symptoms associated with herpes zoster or other infections.

• Risk of liver injury. Advise patients to immediately report any possible manifestations, including fatigue, anorexia, right upper abdominal discomfort, dark urine, or jaundice; importance of patients receiving liver function tests prior to and during treatment as clinically indicated to monitor for such effects.

• Importance of women informing their clinician if they are or plan to become pregnant or plan to breast-feed. A pregnancy exposure registry monitors outcomes in womenexposed to monomethyl fumarate during pregnancy. To enroll in the registry, contact Banner Life Sciences at 1-866-663-9564.

• 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).

• Inform patients of other important precautionary information.

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.

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Monomethyl fumarate is available through a specialty pharmacy network. Clinicians may consult the Bafiertam website at [Web] or call 855-322-6637 for specific availability information.

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