VUMERITY

MS Agents

Administration of non-enteric coated aspirin (up to a dose of 325 mg) 30 minutes before a diroximel fumarate dose may reduce the incidence or severity of flushing.

Swallow the capsules whole and intact. Do not cut, crush or chew. Do not sprinkle the capsule contents on food.
Take with or without food. Administration with food may reduce the risk or severity of flushing. If taken with food, avoid giving with a high-fat, high-calorie meal or snack. The meal or snack should contain no more than 700 calories and 30 grams of fat.
Avoid administration of a diroximel fumarate dose with alcohol.

pancreatitis / Delayed / Incidence not known
angioedema / Rapid / Incidence not known
anaphylactoid reactions / Rapid / Incidence not known

proteinuria / Delayed / 6.0-6.0
erythema / Early / 5.0-5.0
eosinophilia / Delayed / Incidence not known
elevated hepatic enzymes / Delayed / Incidence not known

abdominal pain / Early / 18.0-18.0
diarrhea / Early / 14.0-15.4
nausea / Early / 12.0-14.6
vomiting / Early / 9.0-9.0
rash / Early / 8.0-8.0
pruritus / Rapid / 8.0-8.0
dyspepsia / Early / 5.0-5.0
urticaria / Rapid / Incidence not known
rhinorrhea / Early / Incidence not known
alopecia / Delayed / Incidence not known

VUMERITY

Rx

Oral fumarate
Indicated in adults with relapsing forms of multiple sclerosis, including clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease
Main advantage over dimethyl fumarate is better GI tolerability

231 mg PO twice daily for 7 days, then increase to the target dose of 462 mg PO twice daily. Consider a temporary dose reduction to 231 mg PO twice daily for individuals who do not tolerate the maintenance dose. Resume the recommended dose of 462 mg PO twice daily within 4 weeks. Consider discontinuation of therapy in patients unable to tolerate return to the maintenance dose. Max: 924 mg/day.

No dosage adjustment is needed.

CrCl 50 mL/minute or more: No dosage adjustment needed.
CrCl less than 50 mL/minute: Use is not recommended in patients with moderate or severe renal impairment.

Alemtuzumab: (Major) Concomitant use of diroximel fumarate with alemtuzumab may increase the risk of immunosuppression. Avoid the use of these drugs together.
Dimethyl Fumarate: (Contraindicated) Coadministration of diroximel fumarate with dimethyl fumarate is contraindicated. These agents are closely related. Use together may lead to severe GI intolerance, immunosuppression, or hepatotoxicity.
Ethanol: (Major) Alcohol should not be taken at the time of a diroximel fumarate delayed-release capsule dose. The active metabolite of diroximel fumarate is monomethyl fumarate, or MMF. The mean peak plasma MMF concentration decreased by 9% and 21%, when the dose was coadministered with 240 mL of 5% v/v and 40% v/v of alcohol, respectively. Total MMF exposure is not altered; coingestion of ethanol does not induce "dose dumping". (Moderate) Alcohol should not be taken at the time of a diroximel fumarate delayed-release capsule dose. The active metabolite of diroximel fumarate is monomethyl fumarate, or MMF. The mean peak plasma MMF concentration decreased by 9% and 21%, when the dose was coadministered with 240 mL of 5% v/v and 40% v/v of alcohol, respectively. Total MMF exposure is not altered; coingestion of ethanol does not induce "dose dumping".
Monomethyl Fumarate: (Contraindicated) Coadministration of monomethyl fumarate with diroximel fumarate is contraindicated. Diroximel fumarate is a prodrug of monomethyl fumarate. Monomethyl fumarate may be initiated the day following discontinuation of diroximel fumarate. Use of these drugs together may lead to severe GI intolerance, immunosuppression, or hepatotoxicity.
Ocrelizumab: (Moderate) Ocrelizumab has not been studied in combination with other immunosuppressive or immune modulating therapies used for the treatment of multiple sclerosis, such as diroximel fumarate. Concomitant use of ocrelizumab with diroximel fumarate may increase the risk of immunosuppression. Avoid the use of these drugs together.
Ofatumumab: (Moderate) Concomitant use of ofatumumab with diroximel fumarate may increase the risk of immunosuppression. Ofatumumab has not been studied in combination with other immunosuppressive or immune modulating therapies used for the treatment of multiple sclerosis, such as diroximel fumarate. Consider the duration and mechanism of action of drugs with immunosuppressive effects when switching therapies for multiple sclerosis patients.
Ozanimod: (Moderate) Concomitant use of ozanimod with diroximel fumarate may increase the risk of immunosuppression. Ozanimod has not been studied in combination with other immunosuppressive or immune modulating therapies used for the treatment of multiple sclerosis.

VUMERITY Oral Cap: 231mg

924 mg/day PO.

924 mg/day PO.

Safety and efficacy have not been established.

Safety and efficacy have not been established.

Safety and efficacy have not been established.

Safety and efficacy have not been established.

Inflammation and oxidative stress are central pathologic factors in multiple sclerosis. The active metabolite of diroximel fumarate, monomethyl fumarate (MMF), has beneficial effects on both factors. MMF induces the nuclear 1 factor (erythroid-derived 2)-like 2 (Nrf2) antioxidant response pathway, which is the primary cellular defense against the cytotoxic effects of oxidative stress such as oxidative-stress-related neuronal death and damage to myelin in the CNS. Expression of antioxidant proteins is induced. Diroximel fumarate may also improve mitochondrial function. In vitro, dimethyl fumarate, which is also metabolized to MMF, increased cellular redox potential, glutathione, ATP concentrations, and mitochondrial membrane potential in a concentration-dependent manner. Also, significantly improved astrocyte and neuron cell viability after toxic oxidative challenge was noted with dimethyl fumarate in a concentration-dependent manner.
In regard to inflammation, diroximel fumarate may modulate immune cell responses by shifting dendritic-cell differentiation. Immune deviation based on the active induction of auto reactive Th2 cells is a valid approach for the treatment of inflammatory autoimmune diseases mediated by auto reactive Th1 and Th17 cells such as multiple sclerosis. Intracellular concentrations of glutathione (GSH), the main intracellular reactive oxygen species scavenger, determine whether immune responses differentiate into either a Th1/Th17 or a Th2 phenotype. Dimethyl fumarate, which is also metabolized to MMF, depletes GSH, and GSH depletion induces type II dendritic cells by affecting two distinct signaling cascades: induction of HO-1 impairs production of IL-23, whereas silencing of STAT1 phosphorylation impairs IL-12 production. Induction of type II dendritic cells leads to the induction of Th2 cells and the inhibition of Th1/Th17 cells. In addition to shifting dendritic-cell differentiation, diroximel fumarate may modulate immune cell responses by suppressing pro-inflammatory-cytokine production or directly inhibiting pro-inflammatory pathways.

Diroximel fumarate is administered orally. After oral administration, diroximel fumarate is not quantifiable in plasma because it undergoes rapid pre-systemic hydrolysis by esterases that are ubiquitous in the gastrointestinal tract, blood, and tissues and is converted to its active metabolite monomethyl fumarate (MMF). Thus, all pharmacokinetic analyses were performed with plasma MMF concentrations. The apparent volume of distribution of MMF is between 72 L and 83 L. Plasma protein binding is 27% to 45% and independent of concentration. Metabolism of MMF occurs through the tricarboxylic acid cycle; the cytochrome P450 system is not involved. MMF, fumaric acid, citric acid, and glucose are the major metabolites in plasma. The primary route of elimination is exhalation of carbon dioxide with only trace amounts (less than 0.3% of the total dose recovered in urine). Accumulation of MMF does not occur with multiple diroximel fumarate doses. Esterase metabolism of diroximel fumarate also produces 2-hydroxyethyl succinimide (HES), an inactive major metabolite; HES is mainly eliminated in urine (58% to 63% of the dose).
 
Affected cytochrome P450 isoenzymes and drug transporters: None

After oral administration, diroximel fumarate is not quantifiable in plasma because it undergoes rapid pre-systemic hydrolysis and is converted to its active metabolite monomethyl fumarate (MMF) by esterases that are ubiquitous in the gastrointestinal tract, blood, and tissues. Thus, all pharmacokinetic analyses were performed with plasma MMF concentrations. The median time to maximum concentration (Tmax) of MMF is 2.5 to 3 hours. The maximum concentrations (Cmax) and exposure (AUC) increase approximately dose proportionally in the dose range of 462 to 924 mg. After oral receipt of 462 mg to patients with multiple sclerosis, the mean Cmax of MMF was 2.11 mg/L. The mean steady-state AUC was 8.32 mg x hour/L following twice daily dosing in patients with multiple sclerosis. Coadministration of diroximel fumarate with a high fat, high-calorie meal (900 to 1,000 calories, 50% of calories from fat) did not affect the AUC of MMF, but reduced the Cmax by approximately 44% compared to the fasted state. The Cmax of MMF with low-fat, low-calorie (350 to 400 calories, 10 to 15 grams fat) and medium-fat, medium-calorie (650 to 700 calories, 25 to 30 grams fat) was reduced by approximately 12% and 25%, respectively. The Tmax of MMF was delayed from 2.5 hours (fasted state) to 4.5 hours (low-fat, low-calorie meal or a medium-fat, medium-calorie meal) and 7 hours (high-fat, high-calorie meal) in the fed state. The total exposure (AUC) of MMF was not impacted by low, medium, or high-fat food content. Diroximel fumarate may be taken with or without food; however, if it is taken with food, the meal/snack should contain no more than 700 calories and 30 grams of fat.

Only use diroximel fumarate during pregnancy if the potential benefit justifies the potential risk to the fetus. No adequate and well-controlled studies of the use of diroximel fumarate in pregnant women exist, but animal studies showed adverse effects on offspring survival, growth, sexual maturation, and neurobehavioral function when dimethyl fumarate (which has the same active metabolite as diroximel fumarate) or diroximel fumarate was administered during pregnancy or throughout pregnancy and lactation at clinically relevant doses. Oral administration of diroximel fumarate to pregnant rats throughout organogenesis resulted in a decrease in fetal body weight and an increase in fetal skeletal variations at the highest dose (400 mg/kg/day) tested, which was associated with maternal toxicity. Plasma exposures (AUC) for MMF and HES (the major circulating drug-related compound in humans) at the no-effect dose (100 mg/kg/day) for adverse effects on embryofetal development were approximately 2 times those in humans at the recommended human dose (RHD) of 924 mg/day. Oral administration of diroximel fumarate to pregnant rabbits throughout organogenesis resulted in an increase in fetal skeletal malformations at the mid- and highest doses (150 and 350 mg/kg/day) and reduced fetal body weight and increases in embryofetal death and fetal skeletal variations at the highest dose tested. Plasma exposures (AUC) for MMF and HES at the no-effect dose (50 mg/kg/day) for adverse effects on embryofetal development were similar to (MMF) or less than (HES) those in humans at the RHD. Oral administration of diroximel fumarate to rats throughout gestation and lactation resulted in reduced weight, which persisted into adulthood, and adverse effects on neurobehavioral function in offspring at the highest dose tested. Plasma exposures (AUC) for MMF and HES at the no-effect dose for adverse effects on postnatal development (100 mg/kg/day) were approximately 3 times (MMF) or similar to (HES) those in humans at the RHD.

Use diroximel fumarate with caution during breast-feeding. There are no data on diroximel fumarate's presence in human milk, effects on the breast-fed infant, or effects on milk production. Consider the developmental and health benefits of breast-feeding along with the mother's clinical need for diroximel fumarate and any potential adverse effects on the breast-fed infant from diroximel fumarate or the underlying maternal condition. In animals, adverse effects on offspring survival, growth, sexual maturation, and neurobehavioral function were observed when dimethyl fumarate was administered during gestation and lactation at clinically relevant doses. Dimethyl fumarate has the same active metabolite, MMF, as diroximel fumarate. Although data are limited, interferon beta-1a is considered an alternative therapy. A small number of nursing mothers receiving interferon beta-1a reported no adverse effects in their partially breast-fed infants, and the amount of interferon beta-1a excreted into breast milk appears to be insignificant. Based upon breast milk samples obtained during the study, the authors estimated that the maximum weight-adjusted dosage that an infant would receive was 0.006% of the maternal dose.