Introduction
Tecfidera (dimethyl fumarate) is an oral disease-modifying therapy approved for the treatment of relapsing forms of multiple sclerosis (MS). It represents a significant advancement in MS management as an orally administered medication with both immunomodulatory and neuroprotective properties. Since its FDA approval in 2013, Tecfidera has become one of the most prescribed oral therapies for relapsing-remitting multiple sclerosis.
Mechanism of Action
Dimethyl fumarate's exact mechanism of action in multiple sclerosis is not fully elucidated but involves multiple pathways. The drug undergoes rapid hydrolysis to its active metabolite, monomethyl fumarate. It appears to activate the nuclear factor (erythroid-derived 2)-like 2 (Nrf2) pathway, which plays a crucial role in cellular defense against oxidative stress. Additionally, dimethyl fumarate demonstrates immunomodulatory effects through shifting the cytokine profile from pro-inflammatory Th1 to anti-inflammatory Th2 responses, reducing lymphocyte migration into the central nervous system, and promoting neuroprotective effects through enhanced mitochondrial function.
Indications
Tecfidera is indicated for the treatment of:
- Relapsing-remitting multiple sclerosis (RRMS)
- Clinically isolated syndrome (CIS)
- Active secondary progressive multiple sclerosis (in some regions)
Dosage and Administration
Initial dosage: 120 mg twice daily for 7 days Maintenance dosage: 240 mg twice daily beginning on day 8 Administration:- Administer with or without food
- Swallow capsules whole; do not crush, chew, or open capsules
- If gastrointestinal intolerance occurs, administration with food may improve tolerability
- Renal impairment: No dosage adjustment necessary
- Hepatic impairment: No dosage adjustment necessary
- Elderly: No specific dosage recommendations
- Pediatric: Safety and effectiveness not established
Pharmacokinetics
Absorption: Dimethyl fumarate is rapidly hydrolyzed by esterases to monomethyl fumarate (active metabolite). Peak plasma concentrations of monomethyl fumarate occur at 2-2.5 hours post-dose. Food does not significantly affect overall exposure but may delay Tmax. Distribution: Monomethyl fumarate is 27-40% protein bound. The volume of distribution is approximately 53-73 L. Metabolism: Extensive first-pass metabolism through ester hydrolysis. No significant cytochrome P450 metabolism. Elimination: Primarily exhaled as carbon dioxide (60%) with renal excretion of metabolites accounting for the remainder. Terminal half-life is approximately 1 hour. No accumulation observed with twice-daily dosing.Contraindications
- Hypersensitivity to dimethyl fumarate, monomethyl fumarate, or any excipients in the formulation
- History of anaphylactic reaction to dimethyl fumarate
Warnings and Precautions
Lymphopenia: Tecfidera may cause lymphopenia. Obtain CBC including lymphocyte count before initiating treatment, annually, and as clinically indicated. Consider interruption if lymphocyte counts remain <500/mm³ for more than six months. Progressive Multifocal Leukoencephalopathy (PML): Rare cases of PML have been reported in patients with MS treated with Tecfidera. Monitor for new neurological symptoms suggestive of PML. Liver Injury: Cases of clinically significant liver injury have been reported. Obtain serum aminotransferase, alkaline phosphatase, and total bilirubin levels before treatment initiation and during treatment as clinically indicated. Flushing and Gastrointestinal Events: Common adverse reactions that may improve over time. Administration with food may reduce flushing and gastrointestinal symptoms. Herpes Zoster and Other Serious Infections: Increased risk of serious infections, including herpes zoster.Drug Interactions
CYP Inducers: Strong CYP inducers (e.g., rifampin, carbamazepine, phenytoin) may decrease dimethyl fumarate exposure. Immunosuppressive or Immune-Modulating Therapies: Concurrent use may increase risk of additive immunosuppressive effects. Live Vaccines: Avoid administration of live vaccines during treatment.Adverse Effects
Very Common (≥10%):- Flushing (40%)
- Abdominal pain (18%)
- Diarrhea (14%)
- Nausea (12%)
- Pruritus (10%)
- Vomiting
- Dyspepsia
- Rash
- Erythema
- Albumin urine present
- Aspartate aminotransferase increased
- Lymphopenia
- Leukopenia
- Eosinophilia
- Progressive multifocal leukoencephalopathy (PML)
- Severe lymphopenia
- Liver injury
- Anaphylaxis and angioedema
Monitoring Parameters
Baseline:- Complete blood count with differential (especially lymphocyte count)
- Liver function tests
- Renal function tests
- Pregnancy test if applicable
- CBC with differential every 6 months or as clinically indicated
- Liver function tests periodically and as clinically indicated
- Monitoring for signs and symptoms of PML
- Monitoring for flushing and gastrointestinal symptoms
- Assessment of clinical response and disease activity
Patient Education
- Take medication exactly as prescribed; do not change dosage without medical supervision
- Flushing and gastrointestinal symptoms are common initially and often diminish over time
- Taking with food may reduce flushing and gastrointestinal side effects
- Report any new or worsening neurological symptoms immediately
- Report signs of infection (fever, chills, body aches)
- Use effective contraception during treatment
- Inform all healthcare providers about Tecfidera use before any vaccinations
- Store at room temperature (15-30°C/59-86°F)
- Do not crush, chew, or open capsules
References
1. Gold R, Kappos L, Arnold DL, et al. Placebo-controlled phase 3 study of oral BG-12 for relapsing multiple sclerosis. N Engl J Med. 2012;367(12):1098-1107. 2. Fox RJ, Miller DH, Phillips JT, et al. Placebo-controlled phase 3 study of oral BG-12 or glatiramer in multiple sclerosis. N Engl J Med. 2012;367(12):1087-1097. 3. Tecfidera® (dimethyl fumarate) Prescribing Information. Biogen Inc.; 2023. 4. Linker RA, Lee DH, Ryan S, et al. Fumaric acid esters exert neuroprotective effects in neuroinflammation via activation of the Nrf2 antioxidant pathway. Brain. 2011;134(Pt 3):678-692. 5. Rosenkranz T, Novas M, Terborg C. PML in a patient treated with dimethyl fumarate from a compounding pharmacy. N Engl J Med. 2013;368(17):1658-1659. 6. National Multiple Sclerosis Society. Disease Modifying Therapies for MS. 2023. 7. Rae-Grant A, Day GS, Marrie RA, et al. Comprehensive systematic review summary: Disease-modifying therapies for adults with multiple sclerosis. Neurology. 2018;90(17):789-800.