monomethyl fumarate

Action and Spectrum

Actions and spectrum: 

monomethyl fumarate is a fumaric acid ester and an immunomodulatory agent that is used for the treatment of relapsing forms of multiple sclerosis. It is thought to have anti-inflammatory and neuroprotective effects by modulating the immune system and reducing oxidative stress. 

Drug Interaction

Adverse Reaction

Frequency defined 

>10% 

Nausea (12%) 

Diarrhea (14%) 

Abdominal pain (18%) 

Flushing (40%) 

1-10% 

Lymphopenia (2%) 

AST increased (4%) 

Erythema (5%) 

Dyspepsia (5%) 

Albumin urine present (6%) 

Pruritus (8%) 

Rash (8%) 

Vomiting (9%)  

Frequency not defined 

mean eosinophil levels briefly rising over the first two months of therapy 

Post marketing Reports 

Skin and subcutaneous: Alopecia 

Gastrointestinal disorders: Acute pancreatitis 

Liver function abnormalities: total bilirubin >2x ULN together with concomitant increase in AST/ALT 3x ULN 

Rhinorrhea: Respiratory, mediastinal, and thoracic disorders 

Infections: opportunistic infections, Herpes zoster infection 

Black Box Warning

Black Box Warning: 

monomethyl fumarate does not have a black box warning. 

Contraindication / Caution

Contraindication/Caution: 

Contraindication: 

monomethyl Fumarate is contraindicated in patients with severe allergic reactions (such as anaphylaxis) to dimethyl fumarate, diroximel fumarate, or any of its components. It is contraindicated in patients with progressive multifocal leukoencephalopathy (PML).  

Caution: 

• Liver function impairment: monomethyl Fumarate may cause a rise in liver enzymes. Patients with liver problems or those taking medications that could affect liver function should be monitored closely. 
• Decreased lymphocyte counts: Treatment with monomethyl Fumarate may decrease lymphocyte counts in some patients. Therefore, healthcare providers should monitor the complete blood count periodically. 
• Progressive multifocal leukoencephalopathy: It is a rare, life-threatening viral infection of the brain that can occur in patients with weakened immune systems. There have been reports of PML in patients receiving monomethyl Fumarate. 
• Allergic reactions: monomethyl Fumarate may cause an allergic reaction, including flushing, itching, and rash. If these symptoms occur, patients should seek medical attention. 
• Pregnancy and breast-feeding: There are limited information on the use of monomethyl Fumarate in pregnancy and breastfeeding.  
• Immunocompromised patients: monomethyl Fumarate in patients with weakened immune systems may increase the risk of infections.

Comorbidities: 

• Liver disease: monomethyl Fumarate may cause liver damage, so it must be used with caution in patients having the liver disease or a history of liver problems. 
• Kidney disease: monomethyl Fumarate may cause kidney damage, so it must be used with caution in patients having kidney disease or a history of kidney problems. 
• Infections: monomethyl Fumarate may increase the risk of infections, so it should be used with caution in patients with a history of recurrent infections. 
• Cardiovascular disease: monomethyl Fumarate may increase the risk of cardiovascular events, so it must be used with caution in patients suffering from cardiovascular disease. 
• Immunodeficiency: monomethyl Fumarate may impair the immune system, so it must be used with caution in patients with immunodeficiency or a history of recurrent infections. 

Pregnancy / Lactation

Pregnancy consideration: pregnancy category C 

Lactation: safety and efficacy not established  

Pregnancy category: 

• Category A: Satisfactory and well-controlled studies show no risk to the fetus in the first or later trimester. 
• Category B: There is no evidence of risk to the fetus found in animal reproduction studies and there are not enough studies on pregnant women. 
• Category C: Adverse effects on the fetus found with evidence in animal reproduction studies and no adequate evidence for an effect in humans, care must be taken for potential risks in pregnant women. 
• Category D: There is adequate data available with sufficient evidence of human fetal risk from various platforms, but despite potential risks may be used only in emergency cases for potential benefits. 
• Category X: Drugs listed in this category outweigh risks over benefits These category drugs should be prohibited for pregnant women. 
• Category N: There is no data available for the drug under this category. 

Pharmacology

Pharmacology: 

monomethyl fumarate (MMF) is an orally administered ester prodrug of fumaric acid, a natural intermediate in the citric acid cycle. MMF undergoes hydrolysis to its active metabolite, monomethyl fumarate (MMF) and dimethyl fumarate (DMF). The mechanism of action of MMF is not fully understood, but it is believed to have immunomodulatory and neuroprotective properties.

monomethyl fumarate (MMF)activates the nuclear factor erythroid 2-related factor 2 (Nrf2) pathway that leads to increased expression of antioxidant and anti-inflammatory genes and reduces the production of pro-inflammatory cytokines such as tumor necrosis factor-alpha (TNF-α) and interleukin-17 (IL-17). 

MMF also reduces the number of circulating lymphocytes by inducing apoptosis (programmed cell death) and inhibiting their migration into the central nervous system (CNS), which is thought to contribute to its therapeutic effects in multiple sclerosis (MS). MMF has been shown to reduce the number of active lesions and relapses in MS patients and to improve disability scores. It is also being investigated for the treatment of other autoimmune and inflammatory disorders.  

Pharmacodynamics: 

monomethyl fumarate (MMF) is an immunomodulatory drug used to treat relapsing-remitting multiple sclerosis (MS). It is the active metabolite of dimethyl fumarate (DMF). 

MMF activates the nuclear factor erythroid 2-related factor 2 (Nrf2) pathway. Nrf2 is the transcription factor that regulates the expression of antioxidant and cytoprotective genes, such as NAD(P)H and heme oxygenase-1 (HO-1): quinone oxidoreductase 1 (NQO1), which help protect cells from oxidative stress and inflammation. 

In addition to its effect on Nrf2, MMF also has immunomodulatory properties. It can reduce the activation and proliferation of T cells, inhibit the differentiation of Th1 and Th17 cells, and promote the differentiation of regulatory T cells (Tregs). These effects may contribute to the drug’s therapeutic efficacy in MS. 

MMF is rapidly hydrolyzed to DMF in vivo, which is then further metabolized to several downstream metabolites, including MMF, fumaric acid, and carbon dioxide.  

Pharmacokinetics: 

Absorption 

MMF is rapidly and completely absorbed from the gastrointestinal tract after oral administration. The oral bioavailability of MMF is approximately 60%. 

Distribution 

MMF is highly bound to plasma proteins (≥ 99%). The volume of distribution of MMF is about 0.1 to 0.2 L/kg. 

Metabolism 

MMF is rapidly metabolized in the body to its active metabolite, monomethyl fumarate (MMF), through presystemic hydrolysis by esterases in the gut wall and in the blood 

Elimination and excretion 

MMF is rapidly eliminated from the body. The elimination half-life of MMF is approximately 1 hour. MMF is primarily eliminated by the kidneys, and only a small amount is eliminated in the feces. About 60% of the administered dose is excreted in the urine, and about 1% is excreted in the feces. 

Adminstartion

Administration: 

monomethyl fumarate is available as an oral capsule and is administered orally. It is recommended to take monomethyl fumarate with food to reduce the incidence of flushing and gastrointestinal adverse effects.

The recommended starting dose is 120 mg twice daily for seven days, followed by an increase in the maintenance dose of 240 mg twice daily. The dose may be further increased to 360 mg twice daily if needed, based on tolerability and response. The maximum recommended dose is 720 mg twice daily. 

Patient Information Leaflet

Patient information leaflet 

Generic Name: monomethyl Fumarate 

Pronounced: [ MON-oh-METH-il-FUE-ma-rate]  

Why do we use monomethyl Fumarate? 

monomethyl fumarate is an oral medication used for the treatment of multiple sclerosis (MS). It is also used in treating psoriasis. It is believed to work by reducing inflammation and preventing damage to the myelin sheath, the protective covering that surrounds nerve fibers.