Diroximel Fumarate is indicated for the treatment of relapsing forms of multiple sclerosis (MS) in adults, including: Clinically isolated syndrome (CIS), Relapsing-remitting disease (RRMS), Active secondary progressive disease (SPMS).

The exact mechanism by which diroximel fumarate exerts its therapeutic effect in multiple sclerosis is unknown. However, MMF (monomethyl fumarate), 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 also been identified as a nicotinic acid receptor agonist in vitro.

Blood Tests Prior to Initiation of Diroximel: Obtain the following prior to treatment with Diroximel:

• A complete blood cell count (CBC), including lymphocyte count
• Serum aminotransferase, alkaline phosphatase, and total bilirubin levels

Dosing Information: The starting dosage for Diroximel is 231 mg twice a day orally. After 7 days, the dosage should be increased to the maintenance dosage of 462 mg (administered as two 231 mg capsules) twice a day orally. Temporary dosage reductions to 231 mg twice a day may be considered for individuals who do not tolerate the maintenance dosage. Within 4 weeks, the recommended dosage of 462 mg twice a day should be resumed. Discontinuation of Diroximel should be considered for patients unable to tolerate return to the maintenance dosage. Administration of non-enteric coated aspirin (up to a dose of 325 mg) 30 minutes prior to Diroximel dosing may reduce the incidence or severity of flushing.

Administration Instructions: Swallow Diroximel capsules whole and intact. Do not crush or chew, or sprinkle the capsule contents on food. If taken with food, avoid a high-fat, high-calorie meal/snack; the meal/snack should contain no more than 700 calories and no more than 30 g fat.

Diroximel is contraindicated in patients:

• With known hypersensitivity to diroximel fumarate, dimethyl fumarate, or to any of the excipients of Diroximel. Reactions may include anaphylaxis and angioedema.
• Taking dimethyl fumarate (concomitant use).

The following important adverse reactions have been reported:

• Anaphylaxis and Angioedema
• Progressive Multifocal Leukoencephalopathy (PML)
• Herpes Zoster and other serious opportunistic infections
• Lymphopenia (low lymphocyte count)
• Liver Injury
• Flushing

Pregnancy: There are no adequate data on the developmental risk associated with the use of Diroximel or dimethyl fumarate (which has the same active metabolite as Diroximel) in pregnant women. Lactation: There are no data on the presence of diroximel fumarate or its metabolites (MMF, HES) in human milk. The effects on the breastfed infant and on milk production are unknown.

Anaphylaxis and Angioedema: Discontinue and do not restart diroximel if these occur.

Progressive Multifocal Leukoencephalopathy (PML): Withhold diroximel at the first sign or symptom suggestive of PML.

Herpes Zoster and other serious opportunistic infections: Consider withholding diroximel in cases of serious infection until the infection has resolved.

Lymphopenia: Obtain a CBC including lymphocyte count: Before initiating diroximel After 6 months Every 6 to 12 months thereafter. Consider interruption of diroximel if lymphocyte counts <0.5 × 10⁹/L persist for more than six months.

Liver Injury: Obtain serum aminotransferase, alkaline phosphatase, and total bilirubin levels: Before initiating diroximel, During treatment, as clinically indicated. Discontinue diroximel if clinically significant liver injury induced by diroximel is suspected.

Pediatric Use: Safety and effectiveness in pediatric patients have not been established.

Geriatric Use: Clinical studies of Dimethyl fumarate and Diroximel did not include sufficient numbers of patients aged 65 years and over to determine whether they respond differently from younger patients.

Renal Impairment: No dosage adjustment is necessary in patients with mild renal impairment.

Keep below 30°C. Protect from light and moisture. Keep out of the reach of children.