Dosing & Uses
Dosage Forms & Strengths
capsule, delayed-release
- 231mg
Multiple Sclerosis
Indicated for treatment of relapsing forms of multiple sclerosis (MS), to include clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease
Initial: 231 mg PO BID
Maintenance: After 7 days, increase to 462 mg (two 231-mg capsules) PO BID
Unable to tolerate maintenance dose
- Consider temporarily reducing dose to 231 mg PO BID if maintenance dose is not tolerated
- Within 4 weeks, resume dose at 462 mg PO BID
- Consider discontinuing treatment for patients unable to tolerate return to the maintenance dosage
Dosage Modifications
Renal impairment
- Mild: No dosage adjustment necessary
- Moderate-severe: Not recommended
Hepatic impairment
- No studies have been conducted in subjects with hepatic impairment
- Not expected to affect exposure to monomethyl fumarate (MMF) and therefore no dosage adjustment is necessary
Dosing Considerations
Monitoring parameters
Obtain CBC count (including lymphocyte count), AST/ALT, alkaline phosphatase, and total bilirubin levels before initiation
Monitor CBC count, including lymphocyte count, 6 months after initiation and then q6-12mo thereafter, as clinically indicated
Monitor AST/ALT, alkaline phosphatase, and total bilirubin levels during treatment, as clinically indicated
Safety and efficacy not established
Interactions
Interaction Checker
No Results
Contraindicated
Serious - Use Alternative
Significant - Monitor Closely
Minor
Contraindicated (1)
- dimethyl fumarate
diroximel fumarate, dimethyl fumarate. pharmacodynamic synergism. Contraindicated. Concomitant use of diroximel fumarate and dimethyl fumarate is contraindicated. Both are metabolized to monomethyl fumarate. Initiate diroximel fumarate the day following the discontinuation of dimethyl fumarate.
Serious - Use Alternative (7)
- axicabtagene ciloleucel
diroximel fumarate, axicabtagene ciloleucel. Either increases effects of the other by immunosuppressive effects; risk of infection. Avoid or Use Alternate Drug.
- brexucabtagene autoleucel
diroximel fumarate, brexucabtagene autoleucel. Either increases effects of the other by immunosuppressive effects; risk of infection. Avoid or Use Alternate Drug.
- ciltacabtagene autoleucel
diroximel fumarate, ciltacabtagene autoleucel. Either increases effects of the other by immunosuppressive effects; risk of infection. Avoid or Use Alternate Drug.
- ethanol
ethanol decreases levels of diroximel fumarate by unspecified interaction mechanism. Avoid or Use Alternate Drug. Mean peak plasma MMF concentration for diroximel fumarate was decreased by 9% and 21%, when coadministered with 240 mL of 5% v/v and 40% v/v of ethanol, respectively.
- idecabtagene vicleucel
diroximel fumarate, idecabtagene vicleucel. Either increases effects of the other by immunosuppressive effects; risk of infection. Avoid or Use Alternate Drug.
- lisocabtagene maraleucel
diroximel fumarate, lisocabtagene maraleucel. Either increases effects of the other by immunosuppressive effects; risk of infection. Avoid or Use Alternate Drug.
- tisagenlecleucel
diroximel fumarate, tisagenlecleucel. Either increases effects of the other by immunosuppressive effects; risk of infection. Avoid or Use Alternate Drug.
Monitor Closely (5)
- isavuconazonium sulfate
diroximel fumarate and isavuconazonium sulfate both decrease immunosuppressive effects; risk of infection. Use Caution/Monitor.
- ozanimod
ozanimod, diroximel fumarate. Either increases effects of the other by immunosuppressive effects; risk of infection. Use Caution/Monitor. Coadministration with immunosuppressive therapies may increase the risk of additive immune effects during therapy and in the weeks following administration. When switching from drugs with prolonged immune effects, consider the half-life and mode of action of these drugs in order to avoid unintended additive immunosuppressive effects.
- ponesimod
ponesimod and diroximel fumarate both increase immunosuppressive effects; risk of infection. Use Caution/Monitor. Caution if coadministered because of additive immunosuppressive effects during such therapy and in the weeks following administration. When switching from drugs with prolonged immune effects, consider the half-life and mode of action of these drugs to avoid unintended additive immunosuppressive effects.
- siponimod
siponimod and diroximel fumarate both increase immunosuppressive effects; risk of infection. Use Caution/Monitor. Caution if coadministered because of additive immunosuppressive effects during such therapy and in the weeks following administration. When switching from drugs with prolonged immune effects, consider the half-life and mode of action of these drugs to avoid unintended additive immunosuppressive effects.
- ublituximab
ublituximab and diroximel fumarate both increase immunosuppressive effects; risk of infection. Modify Therapy/Monitor Closely. Owing to potential additive immunosuppressive effects, consider duration of effect and mechanism of action of these therapies if coadministered
Minor (0)
Adverse Effects
>10%
Flushing (40%)
Abdominal pain (18%)
Diarrhea (14%)
Nausea (12%)
1-10%
Vomiting (9%)
Pruritus (8%)
Rash (8%)
Albumin urine present (6%)
Erythema (5%)
Dyspepsia (5%)
AST increased (4%)
Lymphopenia (2%)
Frequency Not Defined
Transient increase in mean eosinophil counts
Postmarketing Reports
Liver function abnormalities (elevations in ALT/AST ≥3x ULN with concomitant elevations in total bilirubin >2x ULN)
Herpes zoster infection and other serious opportunistic infections
Rhinorrhea
Alopecia
Acute pancreatitis
Warnings
Contraindications
Hypersensitivity to diroximel fumarate, dimethyl fumarate, or to any of the excipients
Taking dimethyl fumarate
Cautions
Anaphylaxis and angioedema may occur; discontinue and do not restart treatment if these occur
Progressive multifocal leukoencephalopathy (PML) has occurred; withhold dose at the first sign or symptom suggestive of PML
May decrease lymphocyte counts; consider interruption of treatment if lymphocyte counts <0.5 x109/L persist >6 mo
Clinically significant cases of liver injury have been reported; discontinue treatment if clinically significant liver injury induced by diroximel fumarate is suspected
May cause flushing (eg, warmth, redness, itching, burning sensation); administration of dose with food may reduce flushing incidence
PML cases have occurred predominantly in patients with lymphocyte counts
<0.8×109/L persisting for more than 6 months
Herpes zoster and opportunistic infections
- Serious cases of herpes zoster have occurred in patients treated with dimethyl fumarate (which has the same active metabolite diroximel fumarate) including disseminated herpes zoster, herpes zoster ophthalmicus, herpes zoster meningoencephalitis, and herpes zoster meningomyelitis
- Events may occur at any time during treatment; monitor patients for signs and symptoms of herpes zoster; if herpes zoster occurs, appropriate treatment for herpes zoster should be administered
- Other serious opportunistic infections have occurred with dimethyl fumarate, including cases of serious viral (herpes simplex virus, West Nile virus, cytomegalovirus), fungal (Candida and Aspergillus), and bacterial (Nocardia, Listeria monocytogenes, Mycobacterium tuberculosis) infections
- These infections have been reported in patients with reduced absolute lymphocyte counts (ALC) as well as in patients with normal ALC.
- Infections have affected the brain, meninges, spinal cord, gastrointestinal tract, lungs, skin, eye, and ear; patients with symptoms and signs consistent with these infections should undergo prompt diagnostic evaluation and receive appropriate treatment
- Consider withholding treatment in patients with herpes zoster or other serious infections until infection has resolved
Drug interaction overview
- Concomitant use of dimethyl fumarate and diroximel fumarate is contraindicated, as both are metabolized to monomethyl fumarate; initiate diroximel fumarate the day following the discontinuation of dimethyl fumarate
Pregnancy & Lactation
Pregnancy
No adequate data on the developmental risk associated with the use or dimethyl fumarate (which has the same active metabolite as diroximel fumarate) in pregnant women
Animal studies
- In animal studies, administration of diroximel fumarate during pregnancy or throughout pregnancy and lactation resulted in adverse effects on embryofetal and offspring development (increased incidences of skeletal abnormalities, increased mortality, decreased body weights, neurobehavioral impairment) at clinically relevant drug exposure
Lactation
There are no data on the presence of diroximel fumarate or metabolites (MMF, 2-hydroxyethyl succinimide [HES]) in human milk
Effects on the breastfed infant and on milk production are unknown
Pregnancy Categories
A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.
B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk. C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done. D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk. X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist. NA: Information not available.Pharmacology
Mechanism of Action
Mechanism of action by which diroximel fumarate elicits its therapeutic effect in multiple sclerosis is unknown
MMF, the active metabolite of diroximel fumarate, has been shown to activate the nuclear factor (erythroid-derived 2)-like 2 (Nrf2) pathway in vitro and in vivo in animals and humans
The Nrf2 pathway is involved in the cellular response to oxidative stress; MMF has been identified as a nicotinic acid receptor agonist in vitro
Absorption
Peak plasma time: 2.5-3 hr
Peak plasma concentration: 2.11 mg/L
Mean steady-state AUC: 8.32 mg⋅hr/mL
Effect of food
- Relative to fasted state, peak plasma time of MMF was delayed from 2.5 hr (fasted state) to 4.5 hr (low-fat, low-calorie meal or a medium-fat, medium-calorie meal) and 7 hr (high-fat, high-calorie meal) in the fed state
- No impact of low, medium, or high-fat meals on the AUC of MMF after administration
Distribution
Vd: 72-83 L
Protein bound: 27-45%
Metabolism
Extensively metabolized by esterases, which are ubiquitous in the gastrointestinal tract, blood, and tissues, to the major active metabolite, MMF, before it reaches the systemic circulation
Further metabolism of MMF occurs through the tricarboxylic acid (TCA) cycle, with no involvement of the CYP450 system
Fumaric and citric acid, and glucose are the major metabolites of MMF in plasma
Esterase metabolism of diroximel fumarate also produces HES, an inactive major metabolite
Elimination
Half-life: ~1 hr
Excretion
MMF: Mainly eliminated as carbon dioxide in the expired air with only trace amounts; urine (<0.3% of the total dose)
HES: Urine (58-63% of the dose)
Administration
Oral Administration
Swallow capsules whole and intact
Do not crush, chew, or sprinkle capsule contents on food
If taken with food, avoid a high-fat, high-calorie meal/snack; meal/snack should contain ≤700 calories and ≤30 g fat
Avoid coadministration with alcohol
Administration of nonenteric coated aspirin (up to a 325-mg dose) 30 min before diroximel fumarate dosing may reduce the incidence or severity of flushing
Storage
Store at 20-25ºC (68-77ºF); excursions permitted to 15-3ºC (59-86ºF)
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Formulary
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