Usage
- Dimethyl fumarate is prescribed for the treatment of relapsing forms of multiple sclerosis (MS), including clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease. It is also sometimes used to treat plaque psoriasis.
- Pharmacological classification: Immunomodulator, Nrf2 activator.
- Mechanism of action: Dimethyl fumarate is rapidly metabolized to monomethyl fumarate, its primary active metabolite. The precise mechanism of action in MS is not fully understood, but it is thought to involve activation of the nuclear factor erythroid 2-related factor 2 (Nrf2) pathway, leading to antioxidant and anti-inflammatory effects. It also modulates immune cell function, reducing inflammatory responses that contribute to MS.
Alternate Names
- DMF
- Tecfidera (brand name)
How It Works
- Pharmacodynamics: Dimethyl fumarate exerts its effects through activation of the Nrf2 pathway, leading to increased expression of antioxidant and anti-inflammatory proteins. It also modulates lymphocyte function, shifting the balance from pro-inflammatory Th1 and Th17 cells towards Th2 cells, thereby reducing inflammatory responses in the central nervous system.
- Pharmacokinetics: Dimethyl fumarate is rapidly absorbed and hydrolyzed to monomethyl fumarate, its active metabolite. It does not accumulate with multiple doses. Monomethyl fumarate has a half-life of about 1 hour and is primarily eliminated through the tricarboxylic acid (TCA) cycle, with a small amount excreted in urine. Food intake can enhance its bioavailability. Body weight influences exposure to the drug. No dose adjustments are needed for patients with renal or hepatic impairment, although caution is advised in severe cases.
- Mode of action: Monomethyl fumarate activates the Nrf2 pathway by binding to Kelch-like ECH-associated protein 1 (Keap1), leading to the release and nuclear translocation of Nrf2. Nrf2 then binds to antioxidant response elements (AREs) in the promoter regions of genes encoding antioxidant and anti-inflammatory proteins, increasing their expression. Dimethyl fumarate also interacts with immune cells, including lymphocytes, reducing the production of pro-inflammatory cytokines.
- Elimination pathways: Primarily metabolized through the TCA cycle, with a small amount excreted in the urine.
Dosage
Standard Dosage
Adults:
- Initial dose: 120 mg orally twice daily for 7 days.
- Maintenance dose: 240 mg orally twice daily.
- The capsules should be swallowed whole and not crushed, chewed, or opened. They can be taken with or without food, although taking with food may improve tolerability in patients experiencing flushing or gastrointestinal adverse reactions. High-fat, high-protein meals have been shown to further reduce flushing.
Children:
- The safety and effectiveness in children under 10 have not been established.
- For adolescents aged 13 and older, the adult dosing applies.
- Limited data exist for children aged 10 to 12, and no official dosage recommendations can be made for this age group.
Special Cases:
- Elderly Patients: No dose adjustment is typically required based on age alone. However, it’s essential to consider concomitant diseases and other medications common in elderly patients, necessitating careful monitoring.
- Patients with Renal Impairment: No dose adjustment is needed, but caution is advised in patients with severe renal impairment.
- Patients with Hepatic Dysfunction: No dose adjustment is needed, but caution is advised in patients with severe hepatic impairment.
- Patients with Comorbid Conditions: Close monitoring is required for patients with severe gastrointestinal disorders or serious infections.
Clinical Use Cases
Dimethyl fumarate’s approved use is limited to the treatment of relapsing forms of MS. Its use in settings like intubation, surgical procedures, mechanical ventilation, ICU, or emergency situations is not established.
Dosage Adjustments
Temporary dose reduction to 120 mg twice daily can be considered for patients who experience intolerable side effects at the maintenance dose. The recommended maintenance dose of 240 mg twice daily should be resumed within 4 weeks, if tolerated. Discontinuation should be considered for patients unable to tolerate returning to the maintenance dose.
Side Effects
Common Side Effects
- Flushing (warmth, redness, itching, burning sensation)
- Gastrointestinal issues (abdominal pain, diarrhea, nausea, vomiting)
- Itching
- Rash
Rare but Serious Side Effects
- Anaphylaxis and angioedema
- Progressive multifocal leukoencephalopathy (PML)
- Lymphopenia
- Liver injury
- Severe infections
- Herpes virus reactivation
Long-Term Effects
- The long-term effects of dimethyl fumarate are still being studied, but PML is a significant concern with prolonged use. Regular monitoring of white blood cell counts and liver function is essential.
Adverse Drug Reactions (ADR)
- Anaphylaxis
- Angioedema
- PML
- Liver injury
Contraindications
- Hypersensitivity to dimethyl fumarate or any of its components.
- Suspected or confirmed PML.
Drug Interactions
- Dimethyl fumarate can interact with other immunomodulators, like natalizumab or rituximab, increasing the risk of infections.
- It is important to avoid concomitant use of medications containing diroximel fumarate or monomethyl fumarate.
- Live attenuated vaccines should not be administered to patients receiving dimethyl fumarate.
- Potential interactions exist with numerous other medications, and a thorough medication review is essential before initiating therapy.
- Alcohol consumption may worsen flushing.
Pregnancy and Breastfeeding
- Pregnancy Safety Category: Not recommended during pregnancy and in women of childbearing potential not using effective contraception. Animal studies indicate potential fetal harm. Use only if clearly needed and the potential benefit outweighs the potential risk to the fetus.
- Breastfeeding: It is unknown whether dimethyl fumarate enters breast milk. While small amounts may be present, a 4-5 hour delay between dosing and breastfeeding can help reduce infant exposure. The developmental and health benefits of breastfeeding should be weighed against the potential risks.
Drug Profile Summary
- Mechanism of Action: Activates Nrf2 pathway, leading to antioxidant and anti-inflammatory effects. Modulates lymphocyte function, shifting towards an anti-inflammatory profile.
- Side Effects: Flushing, gastrointestinal issues, itching, rash; rarely PML, anaphylaxis, liver injury.
- Contraindications: Hypersensitivity, PML.
- Drug Interactions: Other immunomodulators, live vaccines, multiple other drugs.
- Pregnancy & Breastfeeding: Not recommended during pregnancy; caution advised during breastfeeding.
- Dosage: Adults: 120 mg twice daily for 7 days, then 240 mg twice daily. Pediatrics: 13 years and older same as adults. Children under 10: not established.
- Monitoring Parameters: Complete blood count (CBC) including lymphocyte counts, liver function tests (LFTs), and neurological examinations.
Popular Combinations
Dimethyl fumarate is typically used as monotherapy in MS. Combination therapy is generally not recommended due to the potential for increased side effects and drug interactions.
Precautions
- Pre-screening for allergies, renal/hepatic function, and complete blood count is recommended.
- Monitor for signs and symptoms of PML.
- Avoid live vaccines.
- Counsel patients on the risk of flushing and gastrointestinal side effects and strategies to manage these.
FAQs (Frequently Asked Questions)
Q1: What is the recommended dosage for Dimethyl fumarate?
A: Adults: 120 mg twice daily for 7 days, then 240 mg twice daily. Adolescents (13 years and older): Same as adults. Children (under 10 years): Safety and efficacy not established.
Q2: What are the most common side effects of Dimethyl fumarate?
A: Flushing, gastrointestinal upset (diarrhea, nausea, vomiting, abdominal pain), itching, and rash.
Q3: What are the serious side effects of Dimethyl fumarate?
A: Progressive multifocal leukoencephalopathy (PML), anaphylaxis, angioedema, liver injury, and lymphopenia.
Q4: Can Dimethyl fumarate be taken during pregnancy?
A: Dimethyl fumarate is generally not recommended during pregnancy due to potential fetal harm. Consult with a physician regarding the risks and benefits if pregnancy occurs while taking the drug.
Q5: Can Dimethyl fumarate be taken while breastfeeding?
A: Limited data exists regarding the use of Dimethyl fumarate during breastfeeding. It may enter breast milk in small amounts. Discuss with a physician to assess potential risks and benefits and consider a 4–5 hour delay between the dose and breastfeeding.
Q6: How does Dimethyl fumarate work?
A: The exact mechanism is unclear, but it primarily acts by activating the Nrf2 pathway, resulting in antioxidant and anti-inflammatory effects. It also immunomodulates lymphocyte function, shifting the response away from inflammation.
Q7: Are there any contraindications for Dimethyl fumarate?
A: Yes. Known hypersensitivity to Dimethyl fumarate or any of its components. Also contraindicated in suspected or confirmed progressive multifocal leukoencephalopathy (PML).
Q8: What should patients be monitored for while taking Dimethyl fumarate?
A: Regular monitoring of complete blood count (CBC), including lymphocyte counts, liver function tests, and neurological examinations. Patients should also be closely observed for any signs and symptoms suggesting PML or other serious side effects.
Q9: What are the key drug interactions with Dimethyl fumarate?
A: Avoid concomitant use of other immunomodulators (e.g., natalizumab, rituximab) and live vaccines. Other drug interactions exist; consult a comprehensive drug interaction resource for further information.
