DIMETHYL FUMARATE
Clinical safety rating: avoid
Contraindicated (not allowed)
Dimethyl fumarate activates the nuclear factor (erythroid-derived 2)-like 2 (Nrf2) pathway, leading to upregulation of antioxidant response elements and reduction of oxidative stress and inflammation. The exact mechanism in multiple sclerosis is unknown but may involve anti-inflammatory and neuroprotective effects.
| Metabolism | Dimethyl fumarate is extensively metabolized by esterases in the gut, blood, and tissues to monomethyl fumarate, the active metabolite. Further metabolism occurs via the tricarboxylic acid cycle. No CYP450 enzyme involvement. |
| Excretion | Renal: 40-60% as metabolites (primarily monomethyl fumarate, MMF); fecal: 15-30% as metabolites; respiratory: <5% as CO2; <0.1% excreted unchanged. |
| Half-life | Terminal elimination half-life of MMF is approximately 1 hour (range 0.5-1.5 h) with no accumulation upon repeated dosing; clinical effects persist beyond half-life due to sustained pharmacodynamic activity. |
| Protein binding | MMF: 27-45% bound to albumin and plasma proteins; parent DMF undergoes rapid hydrolysis pre-systemically and is not measured in plasma. |
| Volume of Distribution | Apparent Vd of MMF: approximately 0.6-1.0 L/kg; indicates distribution into total body water and some tissue binding. |
| Bioavailability | Oral: absolute bioavailability not established due to rapid presystemic hydrolysis; relative bioavailability of MMF is about 70-80% based on AUC compared to intravenous MMF; extensive first-pass metabolism. |
| Onset of Action | Oral: clinical effects (e.g., reduction in relapse rate in multiple sclerosis) observed within 4-8 weeks; peak plasma MMF concentrations reached 2-2.5 hours post-dose. |
| Duration of Action | Oral: duration of clinical effect is 12-24 hours with twice-daily dosing; sustained efficacy over long-term treatment; no acute tolerance reported. |
240 mg orally twice daily, initiated at 120 mg twice daily for 7 days, then titrated to 240 mg twice daily.
| Dosage form | CAPSULE, DELAYED RELEASE |
| Renal impairment | No dose adjustment required for mild to moderate renal impairment. Use with caution in severe renal impairment (CrCl <30 mL/min) due to lack of data; monitor renal function. |
| Liver impairment | No dose adjustment required for mild (Child-Pugh A) or moderate (Child-Pugh B) hepatic impairment. Avoid use in severe (Child-Pugh C) hepatic impairment. |
| Pediatric use | Not approved for use in pediatric patients. Safety and efficacy not established. |
| Geriatric use | No specific dose adjustment recommended. Monitor renal function and tolerability due to potential age-related declines in renal function. |
| 1st trimester | Consult provider |
| 2nd trimester | Consult provider |
| 3rd trimester | Consult provider |
Clinical note
No significant drug interactions Can cause flushing and GI events (nausea diarrhea abdominal pain) usually at treatment initiation.
| Breastfeeding | No data on excretion in human milk. M/P ratio unknown. Risk to infant cannot be excluded. Consider benefits of breastfeeding and risk to infant; alternatives may be preferred. |
| Teratogenic Risk | Pregnancy Category C. No adequate studies in pregnant women. In animal studies, oral administration during organogenesis resulted in increased post-implantation loss, reduced fetal weight, and visceral/skeletal abnormalities. Trimester 1: Potential risk based on animal data; avoid unless benefit outweighs risk. Trimester 2 & 3: Limited data; use only if necessary. |
■ FDA Black Box Warning
No FDA boxed warning.
| Common Effects | Flushing |
| Serious Effects |
["Known hypersensitivity to dimethyl fumarate or any excipients"]
| Precautions | ["Anaphylaxis and angioedema","Progressive multifocal leukoencephalopathy (PML) with severe, prolonged lymphopenia","Lymphopenia (monitor lymphocyte counts before and during treatment)","Herpes zoster and other serious infections","Hepatic injury (elevated transaminases)","Flushing and gastrointestinal events (nausea, diarrhea, abdominal pain)"] |
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| Fetal Monitoring | Monitor complete blood count (CBC) including lymphocytes at baseline and periodically (e.g., every 3 months). Monitor renal function and hepatic enzymes. Monitor for signs of infection, progressive multifocal leukoencephalopathy (PML). In pregnancy, additional fetal monitoring via ultrasound may be considered. |
| Fertility Effects | Animal studies show no impairment of male or female fertility. No human data on fertility effects. Theoretical risk of sperm abnormalities due to impact on rapidly dividing cells; however, not established. |