diroximel fumarate (Rx)

Brand and Other Names:Vumerity
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Dosing & Uses

AdultPediatric

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

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Interactions

Interaction Checker

and diroximel fumarate

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    Interactions Found

    Contraindicated

      Serious - Use Alternative

        Significant - Monitor Closely

          Minor

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            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)

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            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

            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

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            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.

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            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)

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            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

            FormularyPatient Discounts

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            Tier Description
            1 This drug is available at the lowest co-pay. Most commonly, these are generic drugs.
            2 This drug is available at a middle level co-pay. Most commonly, these are "preferred" (on formulary) brand drugs.
            3 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs.
            4 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
            5 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
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            Code Definition
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            Medscape prescription drug monographs are based on FDA-approved labeling information, unless otherwise noted, combined with additional data derived from primary medical literature.