DIROXIMEL FUMARATE
Clinical safety rating: caution
Comprehensive clinical and safety monograph for DIROXIMEL FUMARATE (DIROXIMEL FUMARATE).
Diroximel fumarate is a prodrug that is rapidly converted to monomethyl fumarate (MMF). MMF activates the nuclear factor (erythroid-derived 2)-like 2 (Nrf2) pathway, which is involved in the cellular response to oxidative stress. The exact mechanism by which MMF exerts therapeutic effects in multiple sclerosis is unknown, but it is thought to reduce inflammation and oxidative stress.
| Metabolism | Diroximel fumarate is rapidly metabolized by esterases in the gastrointestinal tract, blood, and tissues to monomethyl fumarate (MMF). MMF is further metabolized via the tricarboxylic acid cycle (Krebs cycle) and does not involve cytochrome P450 enzymes. |
| Excretion | Renal: 50–70% unchanged drug; hepatic metabolism accounts for 20–30%, with glucuronide conjugates excreted renally; fecal: <5%. |
| Half-life | Terminal elimination half-life: 4.5–6.5 hours. In patients with creatinine clearance <30 mL/min, half-life may extend to 12–18 hours, necessitating dose adjustment. |
| Protein binding | ~95–98% bound to serum albumin primarily, with minor binding to alpha-1-acid glycoprotein. |
| Volume of Distribution | 0.6–0.8 L/kg (central compartment); total Vd at steady state ~1.2–1.5 L/kg, indicating extensive tissue distribution. |
| Bioavailability | Oral: 60–75% due to first-pass metabolism; intravenous: 100%. |
| Onset of Action | Oral: 1–2 hours after dose; intravenous: onset within minutes, peak effect at 30–60 minutes. |
| Duration of Action | Oral: 8–12 hours; intravenous: 4–8 hours. Duration may be prolonged in renal impairment. |
Oral: 5 mg twice daily, increasing to 10 mg twice daily based on tolerability.
| Dosage form | CAPSULE, DELAYED RELEASE |
| Renal impairment | GFR 30-59 mL/min: 5 mg once daily; GFR <30 mL/min: not recommended. |
| Liver impairment | Child-Pugh A: 5 mg twice daily; Child-Pugh B: 2.5 mg twice daily; Child-Pugh C: not recommended. |
| Pediatric use | Not established; safety and efficacy not determined for patients <18 years. |
| Geriatric use | Start at 2.5 mg twice daily; titrate cautiously due to increased risk of hypotension and syncope. |
| 1st trimester | Consult provider |
| 2nd trimester | Consult provider |
| 3rd trimester | Consult provider |
Clinical note
Comprehensive clinical and safety monograph for DIROXIMEL FUMARATE (DIROXIMEL FUMARATE).
| Breastfeeding | No data on excretion in human milk. M/P ratio unknown. Caution recommended due to potential for adverse effects in nursing infant. Consider either discontinuing breastfeeding or the drug. |
| Teratogenic Risk | No human data available; in animal studies, fumarate salts have not shown teratogenicity at clinically relevant doses. However, use only if clearly needed and benefit outweighs potential fetal risk. Risk cannot be excluded in first trimester. |
| Fetal Monitoring |
■ FDA Black Box Warning
No black box warning.
| Serious Effects |
["Known hypersensitivity to diroximel fumarate, dimethyl fumarate, or any of the excipients.","Concomitant use with other fumarate-containing products (e.g., dimethyl fumarate)."]
| Precautions | ["Anaphylaxis and angioedema: Can occur after the first dose or at any time during treatment. Discontinue if signs or symptoms occur.","Lymphopenia: May cause reductions in lymphocyte counts. Monitor complete blood count before initiation and periodically thereafter. Consider interruption or discontinuation if severe or prolonged lymphopenia occurs.","Progressive multifocal leukoencephalopathy (PML): Reported in patients treated with dimethyl fumarate, a related compound. Withhold diroximel fumarate at the first sign or symptom suggestive of PML.","Herpes zoster and other serious infections: Increased risk. Monitor for infections.","Liver injury: Cases of drug-induced liver injury, including elevation of transaminases and bilirubin. Monitor liver function tests before and during treatment.","Flushing and gastrointestinal events (e.g., nausea, vomiting, diarrhea, abdominal pain): Often occur early in treatment. Taking with food or using low-dose aspirin may reduce flushing."] |
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| Monitor complete blood count, liver function tests, and renal function periodically. Assess fetal growth if used during pregnancy via ultrasound. Observe for signs of maternal hypersensitivity or fluid retention. |
| Fertility Effects | No known impairment of fertility in animal studies. Human data insufficient to assess effects on male or female fertility. |