TECFIDERA
Clinical safety rating: caution
Comprehensive clinical and safety monograph for TECFIDERA (TECFIDERA).
Dimethyl fumarate (DMF) is a methyl ester of fumaric acid. The exact mechanism of action in multiple sclerosis is unknown. It is thought to activate the nuclear factor (erythroid-derived 2)-like 2 (Nrf2) pathway, which induces antioxidant response elements and upregulates cytoprotective genes, reducing oxidative stress and inflammation.
| Metabolism | DMF is rapidly hydrolyzed by esterases to monomethyl fumarate (MMF), the active metabolite. MMF is further metabolized via the tricarboxylic acid (TCA) cycle. No significant involvement of cytochrome P450 enzymes. |
| Excretion | Dimethyl fumarate is extensively metabolized; less than 1% is excreted unchanged in urine. The major metabolite, monomethyl fumarate, is further metabolized via the tricarboxylic acid cycle. Excretion occurs primarily as CO2 via exhalation, with about 60% of a dose recovered as CO2. Renal excretion accounts for approximately 16% of the dose as metabolites, and fecal excretion accounts for about 1%. |
| Half-life | The terminal elimination half-life of monomethyl fumarate (MMF) is approximately 1 hour. Due to rapid metabolism and elimination, MMF does not accumulate with multiple doses. No context of clinical significance is observed for accumulation. |
| Protein binding | Monomethyl fumarate is 27%–45% bound to plasma proteins, primarily albumin. |
| Volume of Distribution | The volume of distribution of monomethyl fumarate is approximately 60 L (0.86 L/kg for a 70 kg individual), suggesting distribution into total body water. |
| Bioavailability | Oral bioavailability of dimethyl fumarate (as monomethyl fumarate) is not determined due to extensive first-pass metabolism. However, systemic exposure to MMF is proportional to dose over the therapeutic range. Food increases MMF Cmax by 70% and AUC by 40% but does not alter clinical effect. |
| Onset of Action | Oral administration: Clinical reduction in relapse rate and MRI lesion activity is observed after several weeks of treatment. Onset of clinical benefit is typically seen within 2–3 months. |
| Duration of Action | Duration of action is related to continuous dosing. Pharmacodynamic effects (e.g., reduction in immune cell subsets) persist over the dosing interval of twice daily. Clinical benefit is maintained with regular dosing; no specific duration of action per dose is defined. |
| Action Class | Immunomodulator- Multiple sclerosis (oral) |
| Brand Substitutes | Dyfira 120mg Capsule, Sclerogem 120mg Capsule |
240 mg orally twice daily.
| Dosage form | CAPSULE, DELAYED RELEASE |
| Renal impairment | No dose adjustment required for GFR >=30 mL/min; not recommended for GFR <30 mL/min due to lack of data. |
| Liver impairment | No dose adjustment required for mild to moderate hepatic impairment (Child-Pugh A or B); contraindicated in severe hepatic impairment (Child-Pugh C). |
| Pediatric use | For patients aged 13 years and older: 120 mg orally twice daily for 7 days, then 240 mg orally twice daily. Not approved for children under 13 years. |
| Geriatric use | No specific dose adjustment required; use caution due to age-related decline in renal function. |
| 1st trimester | Consult provider |
| 2nd trimester | Consult provider |
| 3rd trimester | Consult provider |
Clinical note
Comprehensive clinical and safety monograph for TECFIDERA (TECFIDERA).
| Breastfeeding | It is not known whether dimethyl fumarate or its metabolites are excreted in human milk. No M/P ratio is available. Due to potential adverse effects in nursing infants, breastfeeding is not recommended during treatment and for 24 hours after the last dose. |
| Teratogenic Risk | Tecfidera (dimethyl fumarate) is not recommended for use during pregnancy due to potential fetal harm. In animal studies, administration during organogenesis resulted in increased incidence of malformations and embryofetal death at clinically relevant exposures. First trimester: Risk cannot be excluded; human data insufficient. Second and third trimesters: No specific data; theoretical risk based on animal findings. |
■ FDA Black Box Warning
None
| Serious Effects |
["Known hypersensitivity to dimethyl fumarate or any excipients.","History of anaphylaxis or angioedema to dimethyl fumarate."]
| Precautions | ["Anaphylaxis and angioedema: can occur after the first dose or at any time during treatment. Discontinue if occurs.","Progressive multifocal leukoencephalopathy (PML): has occurred in patients with prolonged lymphopenia. Monitor lymphocyte counts and suspend treatment if PML suspected.","Lymphopenia: monitor complete blood count before initiation and every 6-12 months thereafter. Consider interruption if lymphocyte counts <0.5 x 10^9/L for >6 months.","Hepatic injury: elevated transaminases and serious liver injury reported. Monitor liver function tests.","Flushing and gastrointestinal events: common, may decrease with administration with food or temporary dose reduction."] |
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| Fetal Monitoring | If used during pregnancy, monitor fetal growth and development through serial ultrasound assessments. Also monitor maternal complete blood count (CBC) with differential and liver function tests (LFTs) periodically due to potential lymphopenia and hepatic effects. |
| Fertility Effects | Reproductive toxicity studies in animals did not show adverse effects on male or female fertility. However, no human data are available. Tecfidera may cause lymphopenia, which theoretically could impact fertility, but no direct evidence is demonstrated. |