Monomethyl fumarate (MMF) is indicated for the treatment of adults with relapsing forms of multiple sclerosis, including clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease. Like dimethyl fumarate, MMF exhibits neuroprotective and anti-inflammatory properties; these actions can help delay disability and disease progression. Monomethyl fumarate is expected to have better gastrointestinal tolerability when compared to dimethyl fumarate. Monomethyl fumarate received FDA approval in April 2020.
General Administration Information
For storage information, see the specific product information within the How Supplied section.
Route-Specific Administration
Oral Administration
Oral Solid Formulations
-Administer with or without food.
-Have the patient swallow the capsules intact. Do not crush or sprinkle the capsule contents on food. Instruct the patient not to chew the capsule.
-Administration of a non-enteric coated aspirin (up to a dose of 325 mg) 30 minutes prior to dosing may reduce the incidence or severity of flushing.
Monomethyl fumarate (MMF) can cause anaphylaxis and angioedema after the first dose or at any time during treatment. Instruct patients to discontinue the drug and seek immediate medical treatment if they experience signs and symptoms of anaphylactoid reactions including difficulty breathing, urticaria, and swelling of the throat and tongue. In clinical studies, a total of 178 healthy subjects have received single doses of MMF and the adverse reaction profile of MMF was consistent with the experience in the placebo-controlled clinical trials with dimethyl fumarate (a prodrug of MMF). Flushing was the most common adverse event. Among dimethyl fumarate recipients (n= 769), 40% had flushing; most patients had mild or moderate flushing but 3% discontinued the drug because of flushing. Less than 1% had serious flushing symptoms that led to hospitalization but were not life-threatening. Flushing symptoms such as warmth, redness, itching, and/or a burning sensation generally began soon after dimethyl fumarate initiation and usually improved or resolved over time. Pruritus (8%), rash (unspecified) (8%), and erythema (5%) were also reported in patients receiving dimethyl fumarate at rates higher than with placebo. In the MMF studies, the presence of food did not impact the incidence of flushing; however, based on studies with dimethyl fumarate, the administration of non-enteric coated aspirin (up to a dose of 325 mg) 30 minutes prior to dosing may reduce the incidence or severity of flushing.
n clinical studies, a total of 178 healthy subjects have received single doses of monomethyl fumarate (MMF). The adverse reaction profile of MMF was consistent with the experience in the placebo-controlled clinical trials with dimethyl fumarate, a prodrug of MMF. In 2 placebo-controlled trials, dimethyl fumarate caused leukopenia and lymphopenia, but mean concentrations remained above the lower limit of normal. Severe lymphopenia increases the risk for development of progressive multifocal leukoencephalopathy (PML) and other serious infections. During a clinical trial, a fatal case of PML occurred in a patient with prolonged lymphopenia (lymphocyte counts predominantly less than 500 cells/mcL for 3.5 years) who received dimethyl fumarate for 4 years. The patient was not receiving other immunosuppressants and had no other medical conditions that compromised immune function. No prior exposure to natalizumab, which is associated with PML, was noted. PML has also occurred in the postmarketing setting in the presence of lymphopenia (less than 900 cells/mcL). While the role of lymphopenia in these cases is uncertain, the PML cases have predominantly occurred in patients with lymphocyte counts of less than 800 cells/mcL that persisted for at least 6 months. PML has been reported in 4 patients in Europe who were treated for psoriasis with a fixed combination product containing dimethyl fumarate and 3 monoethyl hydrogen fumarates (calcium, magnesium, and zinc salts) or a compounded version of fumaric acid esters. In 2 of the case reports, the patients had prolonged (2 and 5 years) severe lymphopenia prior to the diagnosis of PML. The other 2 patients had significant confounding factors for PML. Symptoms of PML may include progressive weakness on 1 side of the body, clumsiness of limbs, vision disturbance, confusion, and personality changes. At the first sign or symptom of PML, discontinue dimethyl fumarate and perform a diagnostic evaluation. To reduce the risk of PML, periodic monitoring of lymphocytes is recommended. MRI findings and detection of JC virus (JCV) DNA in the CSF in the absence of clinical signs and symptoms of PML have been reported in patients taking other multiple sclerosis medications associated with PML; many cases progressed to symptomatic PML. Consider MRI monitoring for signs consistent with PML, and promptly investigate any suspicious findings. White cell counts of less than 3,000 cells/mcL (National Cancer Institute Common Toxicity Criteria grade 2 or higher leukopenia) were noted in 10% of dimethyl fumarate recipients as compared with 1% of placebo recipients. The mean white cell counts decreased by approximately 10% to 12% during the first year and then stabilized. In regard to lymphopenia, 2% of 769 dimethyl fumarate recipients had lymphopenia in contrast to less than 1% of 771 placebo recipients. Lymphocyte counts of less than 500 cells/mcL (grade 3 or higher lymphopenia) were seen in 6% of dimethyl fumarate recipients as compared with less than 1% of placebo recipients. The mean lymphocyte counts decreased by approximately 30% during the first year of dimethyl fumarate treatment and then remained stable. The mean lymphocyte counts increased 4 weeks after dimethyl fumarate cessation but did not return to baseline concentrations. No differences in the incidences between the groups were noted for either infection (60% for dimethyl fumarate vs. 58% for placebo) or serious infection (2% in each group). Also, no increased incidence of serious infections was noted in patients with lymphocyte counts of less than 800 cells/mcL or 500 cells/mcL. However, dimethyl fumarate was not studied in patients with pre-existing low lymphocyte counts. Obtain a complete blood count (CBC) including lymphocyte count before monomethyl fumarate (MMF) initiation. A CBC including lymphocyte count should also be obtained after 6 months of treatment, every 6 to 12 months thereafter, and as clinically indicated. Consider interruption of therapy if lymphocyte counts less than 500 cells/mcL persist for more than 6 months. Because lymphocyte recovery may be delayed, following lymphocyte counts until lymphopenia is resolved is recommended. If a serious infection develops, consider withholding MMF until the infection is resolved. Serious cases of herpes zoster infection, including disseminated herpes zoster, herpes zoster ophthalmicus, herpes zoster meningoencephalitis, and herpes zoster meningomyelitis have occurred during treatment with dimethyl fumarate. These events may occur at any time during treatment. Monitor patients taking MMF for signs and symptoms of herpes zoster and treat as clinically appropriate. Other serious opportunistic infections, including cases of serious viral (herpes simplex virus, West Nile virus, cytomegalovirus), fungal (Candida and Aspergillus), and bacterial (Nocardia, Listeria monocytogenes, Mycobacterium tuberculosis) infections have occurred during treatment with dimethyl fumarate. These infections have been reported in patients with reduced and normal absolute lymphocyte counts, and have affected the brain, meninges, spinal cord, gastrointestinal tract, lungs, skin, eye, and ear. Patients with symptoms and signs consistent with any of these infections should undergo prompt diagnostic evaluation and receive appropriate treatment. Consider withholding MMF treatment in patients with herpes zoster or other serious infections until the infection has resolved.
In clinical studies, a total of 178 healthy subjects have received single doses of monomethyl fumarate (MMF). The adverse reaction profile of MMF was consistent with the experience in the placebo-controlled clinical trials with dimethyl fumarate, a prodrug of MMF. Among 769 dimethyl fumarate recipients, 18% had abdominal pain in contrast to 10% of 771 placebo recipients. More dimethyl fumarate recipients also had diarrhea (14% vs. 11%), nausea (12% vs. 9%), vomiting (9% vs. 5%), and dyspepsia (5% vs. 3%). The incidence of gastrointestinal (GI) adverse events was higher early in the course of treatment (primarily in month 1) and usually decreased over time. Most side effects were mild: 1% of dimethyl fumarate recipients had a serious GI adverse event, and 4% discontinued the drug because of the effects as compared with less than 1% of placebo recipients. Taking MMF with food may reduce the incidence of GI adverse event. Diroximel fumarate, a related fumarate with the same active metabolite (MMF), may have a slight advantage for gastrointestinal (GI) tolerance over dimethyl fumarate. During a clinical study comparison, less patients discontinued treatment because of GI adverse effects with diroximel fumarate (0.8%) than dimethyl fumarate (4.8%). The most common side effects reported in the study for both treatment groups were diarrhea (15.4% for diroximel fumarate; 22.3% for dimethyl fumarate) and nausea (14.6% for diroximel fumarate and 20.7% for dimethyl fumarate). Acute pancreatitis has been reported with use of dimethyl fumarate during postmarketing experience.
In clinical studies, a total of 178 healthy subjects have received single doses of monomethyl fumarate (MMF). The adverse reaction profile of MMF was consistent with the experience in the placebo-controlled clinical trials with dimethyl fumarate, a prodrug of MMF. An increased incidence of elevated hepatic enzymes was seen primarily during the first 6 months of dimethyl fumarate treatment, and most patients with elevations had concentrations less than 3 times the upper limit of normal (ULN). Higher elevations of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) occurred in a small number of patents and were balanced between dimethyl fumarate and placebo recipients. No hepatic transaminases at 3 times or more the ULN with concomitant elevations in total bilirubin more than 2 times the ULN were noted. Less than 1% of patients discontinued dimethyl fumarate due to elevated hepatic transaminases during clinical trials. Postmarketing cases of clinically significant liver injury have been reported with dimethyl fumarate. The onset has ranged from a few days to several months after initiation of treatment. Signs and symptoms of liver injury, including elevation of serum aminotransferases to greater than 5-fold the upper limit of normal and elevation of total bilirubin to more than 2-fold the ULN have been observed. Although the abnormalities resolved upon treatment discontinuation, some cases required hospitalization. None of the reported cases resulted in hepatic failure, liver transplant, or death. Obtain serum aminotransferase, alkaline phosphatase, and total bilirubin concentrations prior to and during MMF treatment, as clinically indicated. Discontinue treatment if clinically significant liver injury induced by MMF is suspected.
In clinical studies, a total of 178 healthy subjects have received single doses of monomethyl fumarate (MMF). The adverse reaction profile of MMF was consistent with the experience in the placebo-controlled clinical trials with dimethyl fumarate, a prodrug of MMF. Dimethyl fumarate may cause eosinophilia; a transient increase in mean eosinophil count was seen during the first 2 months of dimethyl fumarate receipt.
In clinical studies, a total of 178 healthy subjects have received single doses of monomethyl fumarate (MMF). The adverse reaction profile of MMF was consistent with the experience in the placebo-controlled clinical trials with dimethyl fumarate, a prodrug of MMF. In 2 placebo-controlled trials, albuminuria (proteinuria) occurred in 6% of patients who received dimethyl fumarate (n = 769) compared to 4% of patients who received placebo (n = 771).
Rhinorrhea has been reported during postmarketing experience with dimethyl fumarate, a prodrug of monomethyl fumarate.
Alopecia has been reported during postmarketing experience with dimethyl fumarate, a prodrug of monomethyl fumarate.
Monomethyl fumarate (MMF) is contraindicated in patients who have demonstrated hypersensitivity to MMF, dimethyl fumarate, diroximel fumarate, or any of its excipients. Anaphylaxis and angioedema associated with MMF therapy which may occur after the first dose or any time during treatment. MMF is also contraindicated in patients taking dimethyl fumarate or diroximel fumarate, as MMF is the active metabolite of these drugs.
Suspect progressive multifocal leukoencephalopathy (PML) in any patient presenting with neurological symptoms while taking monomethyl fumarate (MMF); discontinue the drug at the first sign or symptom of PML and perform a diagnostic evaluation. PML has occurred in patients with MS treated with dimethyl fumarate (the prodrug of MMF). As PML can be fatal, instruct patients to notify their healthcare provider immediately if they notice new or worsening neurological signs or symptoms such as ataxia, visual changes, or confusion. PML has occurred in the presence of prolonged lymphopenia, and practitioners should obtain a complete blood count (CBC) with differential including lymphocyte count before MMF initiation. A CBC including lymphocyte count should also be obtained 6 months after treatment initiation, every 6 to 12 months thereafter, and as clinically indicated. Consider MRI monitoring for signs that may be consistent with PML. MRI findings suggestive of PML and detection of JC virus (JCV) DNA in the CSF in the absence of clinical signs and symptoms of PML have been reported in patients treated with other multiple sclerosis medications; many cases progressed to symptomatic PML. Promptly investigate any suspicious findings to allow for early diagnosis.
Monomethyl fumarate (MMF) use in patients with immunosuppression may be inadvisable, as the drug may decrease lymphocyte counts and cause lymphopenia. The drug has not been studied in patients with pre-existing low lymphocyte counts. In the MS placebo-controlled trials with dimethyl fumarate (the prodrug of MMF), mean lymphocyte counts decreased by approximately 30% during the first year of treatment and then remained stable. Four weeks after stopping treatment, mean lymphocyte counts increased but did not return to baseline. Obtain a complete blood count (CBC), including lymphocyte count, before MMF initiation. A CBC including lymphocyte count should also be obtained 6 months after treatment initiation, every 6 to 12 months thereafter, and as clinically indicated. Consider treatment interruption in patients with lymphocyte counts less than 0.5 x 109/L persisting for more than 6 months. Obtain lymphocyte counts until their recovery if MMF is discontinued or interrupted because of lymphopenia. Consider withholding treatment from patients with serious infections until resolution. Consider individual clinical circumstances when deciding if therapy should be restarted.
Use monomethyl fumarate (MMF) with caution in patients with hepatic disease. Postmarketing cases of clinically significant liver injury have been reported with dimethyl fumarate (a prodrug of MMF). The onset of hepatotoxicity has ranged from a few days to several months after initiation of treatment. Signs and symptoms of liver injury, including elevation of serum aminotransferases to greater than 5-fold the upper limit of normal (ULN) and elevation of total bilirubin to greater than 2-fold the ULN have been observed. These abnormalities resolved upon treatment discontinuation. Some cases required hospitalization. None of the reported cases resulted in liver failure, liver transplant, or death. However, the combination of new serum aminotransferase elevations with increased concentrations of bilirubin caused by drug-induced hepatocellular injury is an important predictor of serious liver injury that may lead to acute liver failure, liver transplant, or death in some patients. Obtain liver function tests (LFTs) such as serum aminotransferase, alkaline phosphatase, and total bilirubin concentrations before initiating treatment and during treatment as clinically indicated. Discontinue treatment and promptly evaluate if clinically significant liver injury induced by MMF is suspected.
Only use monomethyl fumarate (MMF) during pregnancy if the potential benefit justifies the potential risk to the fetus. No adequate and well-controlled studies of the use of MMF in pregnant women exist, but animal studies showed adverse effects on offspring survival, growth, sexual maturation, and neurobehavioral function when dimethyl fumarate (a prodrug of MMF) was administered during pregnancy or throughout pregnancy and lactation at clinically relevant doses.
There are no data on monomethyl fumarate (MMF) and its presence in human milk, effects on the breast-fed infant, or effects on milk production. Consider the developmental and health benefits of breast-feeding along with the mother's clinical need for MMF and any potential adverse effects on the breast-fed infant from MMF or the underlying maternal condition. In animals, adverse effects on offspring survival, growth, sexual maturation, and neurobehavioral function were observed when dimethyl fumarate (prodrug of MMF) was administered during gestation and lactation at clinically relevant doses. Although data are limited, interferon beta-1a is considered an alternative therapy. A small number of nursing mothers receiving interferon beta-1a reported no adverse effects in their partially breast-fed infants, and the amount of interferon beta-1a excreted into breast milk appears to be insignificant. Based upon breast milk samples obtained during the study, the authors estimated that the maximum weight-adjusted dosage that an infant would receive was 0.006% of the maternal dose.
For the treatment of relapsing forms of multiple sclerosis, including clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease:
Oral dosage:
Adults: 95 mg PO twice daily for 7 days, then 190 mg PO twice daily. Consider a temporary dose reduction to 95 mg PO twice daily for individuals who do not tolerate the maintenance dose. Resume the recommended dose of 190 mg PO twice daily within 4 weeks. Consider discontinuation of therapy in persons unable to tolerate return to the maintenance dose.
Maximum Dosage Limits:
-Adults
380 mg/day PO.
-Geriatric
380 mg/day PO.
-Adolescents
Safety and efficacy have not been established.
-Children
Safety and efficacy have not been established.
-Infants
Safety and efficacy have not been established.
-Neonates
Safety and efficacy have not been established.
Patients with Hepatic Impairment Dosing
Specific guidelines for dosage adjustments in hepatic impairment are not available; it appears that no dosage adjustments are needed.
Patients with Renal Impairment Dosing
Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are needed.
*non-FDA-approved indication
Dimethyl Fumarate: (Contraindicated) Coadministration of monomethyl fumarate with dimethyl fumarate is contraindicated. Dimethyl fumarate is a prodrug of monomethyl fumarate. Monomethyl fumarate may be initiated the day following discontinuation of dimethyl fumarate. Use of these drugs together may lead to severe GI intolerance, immunosuppression, or hepatotoxicity.
Diroximel Fumarate: (Contraindicated) Coadministration of monomethyl fumarate with diroximel fumarate is contraindicated. Diroximel fumarate is a prodrug of monomethyl fumarate. Monomethyl fumarate may be initiated the day following discontinuation of diroximel fumarate. Use of these drugs together may lead to severe GI intolerance, immunosuppression, or hepatotoxicity.
Ocrelizumab: (Moderate) Ocrelizumab has not been studied in combination with other immunosuppressive or immune modulating therapies used for the treatment of multiple sclerosis, such as dimethyl fumarate. Concomitant use of ocrelizumab with dimethyl fumarate may increase the risk of immunosuppression. Avoid the use of these drugs together.
Ofatumumab: (Moderate) Concomitant use of ofatumumab with monomethyl fumarate may increase the risk of immunosuppression. Ofatumumab has not been studied in combination with other immunosuppressive or immune modulating therapies used for the treatment of multiple sclerosis, such as monomethyl fumarate. Consider the duration and mechanism of action of drugs with immunosuppressive effects when switching therapies for multiple sclerosis patients.
Ozanimod: (Moderate) Concomitant use of ozanimod with monomethyl fumarate may increase the risk of immunosuppression. Ozanimod has not been studied in combination with other immunosuppressive or immune modulating therapies used for the treatment of multiple sclerosis.
Inflammation and oxidative stress are central pathologic factors in multiple sclerosis. Monomethyl fumarate (MMF) has beneficial effects on both factors. MMF induces the nuclear 1 factor (erythroid-derived 2)-like 2 (Nrf2) antioxidant response pathway, which is the primary cellular defense against the cytotoxic effects of oxidative stress such as oxidative-stress-related neuronal death and damage to myelin in the CNS. Expression of antioxidant proteins is induced. MMF has been identified as a nicotinic acid receptor agonist in vitro.
Dimethyl fumarate (the prodrug of MMF), increased cellular redox potential, glutathione, ATP concentrations, and mitochondrial membrane potential in a concentration-dependent manner in vitro. Also, significantly improved astrocyte and neuron cell viability after toxic oxidative challenge was noted in a concentration-dependent manner. These drugs may modulate immune cell responses by shifting dendritic-cell differentiation. Immune deviation based on the active induction of autoreactive Th2 cells is a valid approach for the treatment of inflammatory autoimmune diseases mediated by autoreactive Th1 and Th17 cells such as multiple sclerosis. Intracellular concentrations of glutathione (GSH), the main intracellular reactive oxygen species scavenger, determine whether immune responses differentiate into either a Th1/Th17 or a Th2 phenotype. MMF depletes GSH, and GSH depletion induces type II dendritic cells by affecting two distinct signaling cascades: induction of HO-1 impairs production of IL-23, whereas silencing of STAT1 phosphorylation impairs IL-12 production. Induction of type II dendritic cells leads to the induction of Th2 cells and the inhibition of Th1/Th17 cells. In addition to shifting dendritic-cell differentiation, these drugs may modulate immune cell responses by suppressing pro-inflammatory-cytokine production or directly inhibiting pro-inflammatory pathways.
Monomethyl fumarate (MMF) is administered orally. The apparent volume of distribution of MMF is between 53 L and 73 L. Plasma protein binding is 27% to 45% and independent of concentration. Metabolism of MMF occurs through the tricarboxylic acid cycle; the cytochrome P450 system is not involved. MMF, fumaric acid, citric acid, and glucose are the major metabolites in plasma. From studies with dimethyl fumarate (the prodrug of MMF), the primary route of elimination is exhalation of CO2, accounting for 60% of the dimethyl fumarate dose. Renal and fecal elimination account for 16% and 1% of the dimethyl fumarate dose, respectively. Trace amounts of MMF were present in urine. The half-life of MMF is approximately 0.5 hour. No circulating MMF is present at 24 hours following oral administration of MMF under fasting conditions. Accumulation of MMF does not occur with multiple doses.
Affected cytochrome P450 (CYP450) isoenzymes and drug transporters: None
-Route-Specific Pharmacokinetics
Oral Route
The Cmax and exposure (AUC) of monomethyl fumarate (MMF) following oral administration of 190 mg under fasting conditions are bioequivalent to those after oral administration of 240 mg dimethyl fumarate delayed-release capsule. The median time to maximum concentration (Tmax) of monomethyl fumarate (MMF) is 4.03 hours. The AUC of MMF was not significantly affected by administration with a high-fat, high-calorie meal; however, Cmax decreased by 20% with prolonged absorption. The median Tmax of MMF was delayed from approximately 4 hours to 11 hours by a high-fat meal. MMF may be administered with or without food.
-Special Populations
Hepatic Impairment
While no studies have been conducted, hepatic impairment is not expected to affect exposure to monomethyl fumarate.
Renal Impairment
While no studies have been conducted, renal impairment is not expected to affect exposure to monomethyl fumarate.
Geriatric
Age did not affect the pharmacokinetics of monomethyl fumarate.
Gender Differences
Gender did not affect the pharmacokinetics of monomethyl fumarate.
Obesity
Body weight did not affect the pharmacokinetics of monomethyl fumarate.