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

No Results

     activity indicator 
    No Interactions Found
    Interactions Found

    Contraindicated

      Serious - Use Alternative

        Significant - Monitor Closely

          Minor

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             activity indicator 

            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 (1)

            • 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.

            Monitor Closely (4)

            • 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.

            Minor (0)

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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)

              Herpes zoster infection and other serious opportunistic infections

              Rhinorrhea

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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

              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
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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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              Patient Handout

              A Patient Handout is not currently available for this monograph.
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              Formulary

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              The above information is provided for general informational and educational purposes only. Individual plans may vary and formulary information changes. Contact the applicable plan provider for the most current information.

              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.
              6 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
              NC NOT COVERED – Drugs that are not covered by the plan.
              Code Definition
              PA Prior Authorization
              Drugs that require prior authorization. This restriction requires that specific clinical criteria be met prior to the approval of the prescription.
              QL Quantity Limits
              Drugs that have quantity limits associated with each prescription. This restriction typically limits the quantity of the drug that will be covered.
              ST Step Therapy
              Drugs that have step therapy associated with each prescription. This restriction typically requires that certain criteria be met prior to approval for the prescription.
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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.