Dimethyl Fumarate - A Comprehensive Overview

Overview

Dimethyl fumarate is used in the management of relapsing forms of multiple sclerosis (a disorder affecting the brain and spinal cord). It is also used in clinically isolated syndrome (nerve symptoms that last for at least 24 hours), relapsing-remitting forms (symptoms flare up intermittently), and secondary progressive forms (relapses occur more frequently) of multiple sclerosis. The United States Food and Drug Administration (FDA) approved this medicine on March 27th, 2013. A recent (within six months) complete blood cell count (CBC) examination is recommended to identify patients with low lymphocyte counts before starting treatment with Dimethyl fumarate.

What Is Dimethyl Fumarate?

Dimethyl fumarate belongs to a class of medications called nuclear factor erythroid-derived 2-related factor-like 2 (NRF2) activators. It is the first line of oral treatment and a new disease-modifying therapeutic agent for patients with relapsing forms of multiple sclerosis. It works by reducing inflammation and preventing nerve damage, thus improving the symptoms of multiple sclerosis. Dimethyl fumarate modulates the immune response and possesses antioxidant properties that are known to protect against brain and spinal cord damage. Clinical studies have revealed that the drug efficiently reduces the relapse rate, slows the development of brain lesions, and delays the progression of physical disability.

Dimethyl Fumarate Structure:

Chemical Formula for Dimethyl Fumarate Structure: Dimethyl fumarate, also known as DMF, contains the elements carbon, hydrogen, and oxygen, chemically represented by C₆H₈O₄. The structure of molecules:

• Core structure: DMF is a methyl ester of fumaric acid; the latter is an unsaturated dicarboxylic acid derivative. As is usually characteristic of fumarate compounds, it has a double bond between two carbon atoms.

Groups for Function:

• Groups of ester: The molecule depicted here has two ester functional groups joining its two terminals with fumarate at its core structure.

• Double bond: It depends on the amount of carbon-carbon double bond C=C between the two adjacent carbon bones forming the molecule's core.

Indications of Dimethyl Fumarate:

Dimethyl fumarate for multiple sclerosis is an approved treatment for adults with relapsing forms.

Contraindications of Dimethyl Fumarate:

Dimethyl fumarate is not recommended for pregnant women and lactating mothers. It is also not preferred by children or patients over 65 years old.

Available Doses and Dose Forms

Form: Dimethyl fumarate is available in hard gelatin delayed-release capsules.

Dose: It is available in doses of 120 mg (milligrams) and 240 mg.

Warnings and Precautions

• Dimethyl fumarate can cause mild to moderate flushing symptoms, including redness, warmth, itching, and a burning sensation. These symptoms typically begin soon after treatment initiation and resolve over time. Taking dimethyl fumarate capsules with food can reduce the incidence of flushing.

• Dimethyl fumarate can lower the lymphocyte count; therefore, a recent complete blood cell count report is recommended before starting the treatment. It is also monitored annually or as clinically indicated. Treatment must be discontinued for patients with severe infections until they are resolved. Studies have not been performed in patients with pre-existing low lymphocyte counts.

• Dimethyl fumarate may cause anaphylaxis (severe allergic reaction) or angioedema (swelling under the skin) following the first dose or anytime during the treatment. Therefore, patients must be instructed to discontinue the medicine and consult a doctor immediately if they experience symptoms such as difficulty breathing, itching, or swelling of the throat and tongue.

• Dimethyl fumarate may cause liver injury in some patients; therefore, liver enzymes and total bilirubin levels are estimated before and during the treatment. If drug-induced liver injury is suspected, the treatment may be discontinued.

• Studies have reported that Dimethyl fumarate can cause progressive multifocal leukoencephalopathy, an opportunistic viral infection of the brain, in some patients with multiple sclerosis. Therefore, the treatment may be discontinued, and an appropriate diagnostic evaluation should be considered if the patient experiences symptoms such as weakness on one side of the body, vision problems, confusion, memory or thinking problems, and personality changes.

For Patients

What Is the Use of Dimethyl Fumarate?

Dimethyl fumarate (DMF) is mainly used to treat autoimmune diseases. The symptoms of multiple sclerosis, which is a condition affecting the brain and spinal cord, can be different for each person, and they may come and go. Some individuals exhibit mild signs, while others may experience more severe or persistent symptoms.

1. Multiple Sclerosis (MS) indication: DMF is approved for relapsing forms of MS. It helps slow the progression of symptoms in patients with MS and reduces the frequency of relapses.

2. Psoriasis indication: DMF is also used for psoriasis therapy if first-line treatments do not give a positive outcome. It improves overall skin condition by removing plaques and lesions caused by psoriasis.

How Is Dimethyl Fumarate Taken?

Dimethyl fumarate is available in delayed-release capsules, which means the medication does not break down immediately but is released in the intestine to prevent its interaction with stomach acids. The treatment begins with 120 mg Dimethyl fumarate capsules to be taken orally twice daily, with or without food. However, when taken with food, it reduces the flushing experience during the treatment.

The dose starts low and is increased after seven days. These capsules must be taken at approximately the same time every day, or precisely as instructed by your doctor. Even if you feel well, you must continue the medication and not stop it unless your doctor tells you to.

What Are the Side Effects of Dimethyl Fumarate?

Some of the possible side effects of Dimethyl fumarate include:

• Nausea and vomiting.

• Stomach pain.

• Diarrhea.

• Fever.

• Sore throat.

• Cough.

• Runny nose.

• Itching and rash.

• Swelling of the face, eyes, hands, and legs.

• Burning or tingling sensation on one side of the body, followed by rash or blisters.

• Headache.

• Excessive tiredness.

• Loss of appetite.

• Yellowish discoloration of the skin.

• Weakness on one side of the body.

• Dark-colored urine.

What Must the Patient Inform the Doctor Before Taking Dimethyl Fumarate?

• Before starting treatment, inform your doctor if you are allergic to Dimethyl fumarate, its ingredients, or any other medications.

• Before taking Dimethyl fumarate, you must inform your doctor if you suffer from short-term or long-term infections, chicken pox (a highly contagious viral infection), or any other medical conditions.

• Also, inform your doctor if you are taking any antibiotics, herbal medicines, vitamins, nutritional supplements, over-the-counter (OTC) medications, or any other prescription or non-prescription medications.

• Women must tell the doctor if they are pregnant, planning pregnancy, breastfeeding, or if they become pregnant while getting Dimethyl fumarate.

• Dimethyl fumarate can reduce white blood cell count; thus, the doctor will recommend a blood test before and during therapy.

• Liver function tests are performed before starting the treatment with Dimethyl fumarate and, if required, during therapy. Contact your doctor if you experience severe fatigue, stomach pain, loss of appetite, dark-colored urine, or yellowish discoloration of the skin.

Dietary Considerations

No special dietary requirements are necessary, and a normal diet can be followed unless instructed otherwise by the prescribing doctor.

Missed Dose

Take the missed dose as soon as you remember.

If it is almost time for your next dose, skip the missed one and continue as usual.

Do not take two doses at once.

Overdose

In case of an overdose, serious adverse effects, or if you experience seizures or have difficulty breathing, contact your doctor immediately so proper care can be given.

Storage

Dimethyl fumarate must be stored in its original packaging at a temperature of 15 to 30 degrees Celsius (59 to 86 degrees Fahrenheit), away from excessive light and moisture.

For Doctors

Pharmacological Aspects of Dimethyl Fumarate Drug

• Mechanism of Action: Dimethyl fumarate's exact mechanism of action or therapeutic effect in treating multiple sclerosis is unknown. However, Dimethyl fumarate and its metabolite, monomethyl fumarate (MMF), are known to activate the nuclear factor erythroid-derived 2-like 2 (NRF2) pathway, leading to an anti-inflammatory immune response and neuroprotection. This pathway is also involved in the cellular response to oxidative stress. Dimethyl fumarate suppresses pro-inflammatory genes by inhibiting nuclear factor kappa B, and monomethyl fumarate is recognized as a nicotinic acid receptor agonist. The drug reduces central nervous system (CNS) infiltration and alters the composition of lymphocyte subpopulations, especially for cytotoxic and effector T cells. This results in a shift from a proinflammatory to an anti-inflammatory phenotype.

• Pharmacodynamics: Dimethyl fumarate is an oral therapeutic agent indicated for the treatment of relapsing multiple sclerosis. Preclinical and clinical studies have shown that Dimethyl fumarate possesses anti-inflammatory and immunomodulatory properties. Both the drug and the metabolite significantly reduced immune cell activation, followed by the release of proinflammatory cytokines. Recent data have revealed that the pharmacodynamic response of Dimethyl fumarate is due to the activation of the nuclear factor erythroid-derived 2-like 2 (NRF2) pathway. These findings help to understand the tissue-specific target of Dimethyl fumarate and its potential in treating neurodegenerative diseases.

• Pharmacokinetics: After oral administration, Dimethyl fumarate undergoes rapid hydrolysis by the esterases and converts it to its active metabolite, monomethyl fumarate. The drug was not quantifiable in plasma; therefore, all pharmacokinetic analyses have been performed with monomethyl fumarate concentrations in plasma.

• Absorption: After administration of Dimethyl fumarate in patients with multiple sclerosis at a dose of 240 mg twice a day with food, the mean plasma concentration (C max) was around 1.87 mg/L (milligrams per liter), and the area under the curve was 8.21 mg. hr/L (milligrams per hour per liter). The time taken to achieve maximum concentration was around 2 to 2.5 hours.

• Distribution: Around 27 to 45 percent of MMF is bound to plasma proteins, and the apparent volume of distribution of monomethyl fumarate varies from 53 to 73 L (liters) in healthy subjects.

• Metabolism: Dimethyl fumarate is extensively metabolized to major metabolites such as monomethyl fumarate, fumaric acid, and glucose by esterases in the blood and gastrointestinal tract tissues before it reaches systemic circulation.

• Elimination: Dimethyl fumarate is mainly eliminated through the exhalation of carbon dioxide (about 60 percent), and the terminal half-life of MMF is around one hour. Renal and fecal routes are minor routes of elimination at approximately 16 percent and 1 percent, respectively.

• Drug Interactions: No potential drug interactions were identified in the in vitro studies of dimethyl fumarate or monomethyl fumarate. Administration of Aspirin about 30 minutes before Dimethyl fumarate did not exhibit any changes in the pharmacokinetics of MMF. Administration of oral contraceptives with Dimethyl fumarate did not show any significant interactions.

Clinical Studies

The safety and efficacy of Dimethyl fumarate were evaluated in two types of clinical studies conducted in patients with relapsing-remitting multiple sclerosis (RRMS). The median age of the patients was 39 years, with a diagnosis of multiple sclerosis lasting four years. The initial dose was 120 mg of Dimethyl fumarate, which was taken twice or thrice a day for seven days. Later, the dose was increased to 240 mg twice or thrice daily. Neurological examinations and magnetic resonance imaging (MRI) were conducted at baseline, periodically, and at suspected relapse. Dimethyl fumarate exhibited a significant effect on the relapse and MRI endpoints and a relatively significant impact on disability progression in comparison to a placebo.

Nonclinical Toxicology

• Carcinogenicity: Carcinogenicity studies conducted in rats and mice with an oral administration of dimethyl fumarate at doses of 25, 75, 200, and 400 mg/kg/day (milligram per kilogram per day) for up to two years exhibited an increase in non-glandular stomach, kidney tumors, and other malignancies such as squamous cell carcinoma, papillomas of the forestomach, and renal tubular adenomas and carcinomas.

• Mutagenesis: Dimethyl fumarate and its metabolite MMF were not mutagenic in the bacterial reverse mutation or Ames assay.

• Impairment of fertility: Oral administration of Dimethyl fumarate at 75, 250, and 375 mg/kg/day before and during mating showed no effect on fertility in male rats. However, in female rats, it disrupted the estrous cycle and raised the risk of embryo lethality at the highest dose.

Specific Considerations

• Pregnancy: Adequate and well-controlled clinical studies of Dimethyl fumarate have not been performed in pregnant women. Therefore, this drug is not recommended for pregnant women.

• Lactating mothers: The excretion of Dimethyl fumarate in human milk has not been studied; therefore, caution must be exercised when recommending the drug to lactating mothers.

• Pediatric use: The safety and effectiveness of Dimethyl fumarate have not been determined in children.

• Geriatric use: The clinical studies of Dimethyl fumarate did not include a sufficient number of subjects above 65 years of age to determine their response compared to the younger subjects.