Dimethyl fumarate

Relapsing Forms of Multiple Sclerosis

Dimethyl fumarate is used to manage relapsing forms of multiple sclerosis (MS) in adults. It is intended to help reduce the frequency of clinical relapses and may help slow the progression of physical disability caused by the disease.

This medication is specifically indicated for the following conditions:

• Clinically isolated syndrome: This refers to a single, first episode of neurologic symptoms that lasts at least 24 hours and may be the first sign of MS.
• Relapsing-remitting disease: This is the most common form of MS, characterized by clear attacks of symptoms (relapses) followed by periods of partial or complete recovery (remissions).
• Active secondary progressive disease: This is a stage of MS that follows an initial relapsing-remitting course, where the disease continues to worsen and patients still experience active relapses.

Dimethyl fumarate is not a cure for multiple sclerosis, but it is used as a long-term treatment to help manage the condition.

Mechanism of Action

The exact way dimethyl fumarate works to treat multiple sclerosis (MS) is not fully understood. However, medical experts believe it helps manage the condition by altering the immune system's response and protecting nerve cells from oxidative stress.

Reducing Inflammation

In multiple sclerosis, the immune system mistakenly attacks the protective covering of the nerves in the brain and spinal cord. Dimethyl fumarate is thought to change the behavior of the immune system to decrease the inflammation that causes these attacks. By reducing this inflammation, the medication may help decrease the frequency of relapses and slow the progression of physical disability.

Cellular Protection

Dimethyl fumarate and its active metabolite, monomethyl fumarate, have been shown to activate a specific pathway in the body known as the Nrf2 pathway. This pathway is involved in how cells respond to oxidative stress, which is a process that can damage or kill cells. By activating this pathway, the medication may help protect the brain and spinal cord cells from damage caused by the disease.

Common Side Effects

The most frequent side effects of dimethyl fumarate often involve the skin and digestive system. These may include:

• Flushing, which can cause redness, itching, burning, or a feeling of warmth
• Stomach pain or cramping
• Diarrhea
• Nausea or vomiting
• Indigestion

Flushing and stomach issues are most common when starting the medication and may decrease over time. Taking the medication with food may help reduce these effects.

Serious Side Effects

While less common, some side effects can be serious. Seek medical attention immediately if you experience:

• Signs of an allergic reaction, such as hives, swelling of the face or throat, or difficulty breathing
• Signs of liver problems, including yellowing of the skin or eyes (jaundice), dark urine, or pain on the right side of the stomach
• Signs of infection, such as fever, chills, or persistent cough
• Symptoms of shingles (herpes zoster), such as a painful skin rash or blisters
• Changes in mental status, confusion, or problems with vision, speech, or walking, which could indicate a rare but serious brain infection called progressive multifocal leukoencephalopathy (PML)

Serious Brain Infection (PML)

Progressive multifocal leukoencephalopathy (PML), a rare and potentially fatal viral infection of the brain, has been reported in patients taking dimethyl fumarate. This infection is caused by the John Cunningham (JC) virus. The risk may be higher in individuals with prolonged low white blood cell counts. Healthcare providers monitor for new or worsening neurological symptoms that may indicate PML.

Low White Blood Cell Counts

Dimethyl fumarate can decrease lymphocyte counts, which are white blood cells that help the body fight infections. Healthcare providers usually perform a complete blood count (CBC) before starting treatment and monitor levels regularly during therapy. Treatment may be interrupted if counts become significantly low to reduce the risk of serious infections.

Liver Injury

Clinically significant liver injury has occurred in patients using this medication. Monitoring of liver enzymes and bilirubin is recommended before starting treatment and as clinically indicated during use. Signs of potential liver problems include yellowing of the skin or eyes (jaundice), dark urine, and pain in the upper right stomach area.

Allergic Reactions

Serious hypersensitivity reactions, such as anaphylaxis and angioedema, have been reported. These reactions can occur after the first dose or at any time during treatment. Symptoms may include swelling of the face, lips, mouth, or tongue, and difficulty breathing.

Flushing and Gastrointestinal Effects

Flushing (warmth, redness, itching, or burning sensation) and gastrointestinal events (such as nausea, vomiting, and diarrhea) are common, particularly during the first few weeks of treatment. These symptoms often decrease in frequency over time. Taking the medication with food may help reduce the incidence of flushing.

Infections

Because the medication affects the immune system, there is an increased risk of serious infections, including shingles (herpes zoster) and other opportunistic infections. Treatment is generally not initiated in patients with active, serious infections.

Pregnancy

There is limited information regarding the safety of dimethyl fumarate in pregnant women. Animal studies have indicated that high doses of the medication may lead to fetal harm, including lower birth weight and delayed bone development. It is not yet known if these risks apply to humans.

If you are pregnant or planning to become pregnant, it is important to discuss the risks and benefits of continuing treatment with your healthcare provider. A pregnancy exposure registry may be available to collect information about the health of individuals and their babies who are exposed to the drug during pregnancy.

Breastfeeding

It is currently unknown if dimethyl fumarate passes into human breast milk or if it has any effect on a nursing infant or milk production. Because of the lack of data, patients should consult with a healthcare professional to determine the safest approach to infant feeding while taking this medication.

Dosage Forms

Dimethyl fumarate is available in the following form:

• Delayed-release oral capsules: These capsules are designed to be swallowed whole so that the medication is released in the intestines rather than the stomach.

FDA Approval Status

Dimethyl fumarate received its initial approval from the U.S. Food and Drug Administration (FDA) in 2013. It is indicated for the treatment of relapsing forms of multiple sclerosis (MS) in adults, which includes clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease.

Safety Communications

The FDA has issued safety communications regarding the risk of progressive multifocal leukoencephalopathy (PML), a rare and potentially fatal opportunistic viral infection of the brain. This risk is associated with a decrease in lymphocyte counts (lymphopenia) caused by the medication. The FDA required updates to the drug label to include information about these cases and to recommend monitoring of white blood cell counts before and during treatment.

Regulatory Warnings

While dimethyl fumarate does not currently require a Risk Evaluation and Mitigation Strategy (REMS) program, the FDA mandates specific warnings in the prescribing information regarding several serious risks:

• Anaphylaxis and Angioedema: Serious allergic reactions can occur at any time during treatment.
• Progressive Multifocal Leukoencephalopathy (PML): A rare brain infection that has occurred in patients with low lymphocyte counts.
• Lymphopenia: Dimethyl fumarate may decrease lymphocyte counts; blood tests are required before starting and every 6 to 12 months during treatment.
• Liver Injury: Reports of clinically significant liver injury have led to requirements for liver function testing before and during therapy.
• Flushing: A common side effect that is documented in the safety profile and may require clinical management.

Discontinuing Dimethyl Fumarate

There is currently no evidence that dimethyl fumarate causes physical dependence or a specific withdrawal syndrome when a person stops taking it. However, because this medication is used to manage a chronic condition, stopping it can have significant effects on your health.

Risk of Relapse

The primary concern when stopping dimethyl fumarate is the return of multiple sclerosis (MS) disease activity. If the medication is discontinued, you may experience:

• A return of previous MS symptoms.
• New or worsening relapses.
• Increased inflammation in the central nervous system.

Medical Supervision

You should not change your dose or stop taking this medication without talking to your healthcare provider first. If you are experiencing bothersome side effects, such as flushing or gastrointestinal issues, your doctor can help manage these symptoms or determine if a different treatment is necessary. If you must stop the medication, your doctor will monitor you for signs of MS progression.