Class: Immunomodulatory Agents
Chemical Name: 4-O-[2-(2,5-dioxopyrrolidin-1-yl)ethyl] 1-O-methyl (E)-but-2-enedioate
Molecular Formula: C11H13NO6
CAS Number: 1577222-14-0
Diroximel fumarate is an immunomodulatory agent.
Uses for Diroximel Fumarate
Diroximel fumarate has the following uses:
Diroximel fumarate is indicated for the treatment of relapsing forms of multiple sclerosis (MS), to include clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease, in adults.
Diroximel Fumarate Dosage and Administration
Diroximel fumarate is available in the following dosage form(s) and strength(s):
Delayed-release capsules: 231 mg.
It is essential that the manufacturer's labeling be consulted for more detailed information on dosage and administration of this drug. Dosage summary:
Dosage and Administration
Blood tests are required prior to initiation of diroximel fumarate.
Starting dose: 231 mg twice a day, orally, for 7 days.
Maintenance dose after 7 days: 462 mg (administered as two 231-mg capsules) twice a day, orally.
Swallow diroximel fumarate capsules whole and intact. Do not crush, chew, or sprinkle capsule contents on food.
Avoid administration of diroximel fumarate with a high-fat, high-calorie meal/snack.
Avoid co-administration of diroximel fumarate with alcohol.
Cautions for Diroximel Fumarate
Known hypersensitivity to diroximel fumarate, dimethyl fumarate, or to any of the excipients of diroximel fumarate.
Co-administration with dimethyl fumarate.
Anaphylaxis and Angioedema
Diroximel fumarate can cause anaphylaxis and angioedema after the first dose or at any time during treatment. Signs and symptoms in patients taking dimethyl fumarate (which has the same active metabolite as diroximel fumarate) have included difficulty breathing, urticaria, and swelling of the throat and tongue. Patients should be instructed to discontinue diroximel fumarate and seek immediate medical care should they experience signs and symptoms of anaphylaxis or angioedema.
Progressive Multifocal Leukoencephalopathy
Progressive multifocal leukoencephalopathy (PML) has occurred in patients with MS treated with dimethyl fumarate (which has the same active metabolite as diroximel fumarate). PML is an opportunistic viral infection of the brain caused by the JC virus (JCV) that typically only occurs in patients who are immunocompromised, and that usually leads to death or severe disability. A fatal case of PML occurred in a patient who received dimethyl fumarate for 4 years while enrolled in a clinical trial. During the clinical trial, the patient experienced prolonged lymphopenia (lymphocyte counts predominantly <0.5 × 109/L for 3.5 years) while taking dimethyl fumarate. The patient had no other identified systemic medical conditions resulting in compromised immune system function and had not previously been treated with natalizumab, which has a known association with PML. The patient was also not taking any immunosuppressive or immunomodulatory medications concomitantly.
PML has occurred in patients taking dimethyl fumarate in the postmarketing setting in the presence of lymphopenia (<0.8 × 109/L) persisting for more than 6 months. While the role of lymphopenia in these cases is uncertain, the majority of cases occurred in patients with lymphocyte counts <0.5×109/L.
At the first sign or symptom suggestive of PML, withhold diroximel fumarate and perform an appropriate diagnostic evaluation. Typical symptoms associated with PML are diverse, progress over days to weeks, and include progressive weakness on one side of the body or clumsiness of limbs, disturbance of vision, and changes in thinking, memory, and orientation leading to confusion and personality changes.
Magnetic resonance imaging (MRI) findings may be apparent before clinical signs or symptoms. Cases of PML diagnosed based on MRI findings and the detection of JCV DNA in the cerebrospinal fluid in the absence of clinical signs or symptoms specific to PML, have been reported in patients treated with other MS medications associated with PML. Many of these patients subsequently became symptomatic with PML. Therefore, monitoring with MRI for signs that may be consistent with PML may be useful, and any suspicious findings should lead to further investigation to allow for an early diagnosis of PML, if present. Lower PML-related mortality and morbidity have been reported following discontinuation of another MS medication associated with PML in patients with PML who were initially asymptomatic compared to patients with PML who had characteristic clinical signs and symptoms at diagnosis. It is not known whether these differences are due to early detection and discontinuation of MS treatment or due to differences in disease in these patients.
Diroximel fumarate may decrease lymphocyte counts. In the MS placebo-controlled trials with dimethyl fumarate (which has the same active metabolite as diroximel fumarate), mean lymphocyte counts decreased by approximately 30% during the first year of treatment with dimethyl fumarate and then remained stable. Four weeks after stopping dimethyl fumarate, mean lymphocyte counts increased but did not return to baseline. Six percent (6%) of dimethyl fumarate patients and <1% of placebo patients experienced lymphocyte counts <0.5 × 109/L (lower limit of normal 0.91 × 109/L). The incidence of infections (60% vs 58%) and serious infections (2% vs 2%) was similar in patients treated with dimethyl fumarate or placebo, respectively. There was no increased incidence of serious infections observed in patients with lymphocyte counts <0.8 × 109/L or ≤0.5 × 109/L in controlled trials, although one patient in an extension study developed PML in the setting of prolonged lymphopenia (lymphocyte counts predominantly <0.5 × 109/L for 3.5 years).
In controlled and uncontrolled clinical trials with dimethyl fumarate, 2% of patients experienced lymphocyte counts <0.5 × 109/L for at least six months, and in this group the majority of lymphocyte counts remained <0.5 × 109/L with continued therapy. Neither diroximel fumarate nor dimethyl fumarate have been studied in patients with preexisting low lymphocyte counts.
Obtain a complete blood count (CBC), including lymphocyte count, before initiating treatment with diroximel fumarate, 6 months after starting treatment, and then every 6 to 12 months thereafter, and as clinically indicated. Consider interruption of diroximel fumarate in patients with lymphocyte counts less than 0.5 × 109/L persisting for more than six months. Given the potential for delayed recovery of lymphocyte counts, continue to obtain lymphocyte counts until their recovery if diroximel fumarate is discontinued or interrupted because of lymphopenia. Consider withholding treatment from patients with serious infections until resolution. Decisions about whether or not to restart diroximel fumarate should be individualized based on clinical circumstances.
Clinically significant cases of liver injury have been reported in patients treated with dimethyl fumarate (which has the same active metabolite as diroximel fumarate) in the postmarketing setting. The onset has ranged from a few days to several months after initiation of treatment with dimethyl fumarate. Signs and symptoms of liver injury, including elevation of serum aminotransferases to greater than 5-fold the upper limit of normal and elevation of total bilirubin to greater than 2-fold the upper limit of normal have been observed. These abnormalities resolved upon treatment discontinuation. Some cases required hospitalization. None of the reported cases resulted in liver failure, liver transplant, or death. However, the combination of new serum aminotransferase elevations with increased levels of bilirubin caused by drug-induced hepatocellular injury is an important predictor of serious liver injury that may lead to acute liver failure, liver transplant, or death in some patients.
Elevations of hepatic transaminases (most no greater than 3 times the upper limit of normal) were observed during controlled trials with dimethyl fumarate.
Obtain serum aminotransferase, alkaline phosphatase (ALP), and total bilirubin levels prior to treatment with diroximel fumarate and during treatment, as clinically indicated. Discontinue diroximel fumarate if clinically significant liver injury induced by diroximel fumarate is suspected.
Diroximel fumarate may cause flushing (e.g., warmth, redness, itching, and/or burning sensation). In clinical trials of dimethyl fumarate (which has the same active metabolite as diroximel fumarate), 40% of dimethyl fumarate-treated patients experienced flushing. Flushing symptoms generally began soon after initiating dimethyl fumarate and usually improved or resolved over time. In the majority of patients who experienced flushing, it was mild or moderate in severity. Three percent (3%) of patients discontinued dimethyl fumarate for flushing and <1% had serious flushing symptoms that were not life-threatening but led to hospitalization.
Administration of diroximel fumarate with food may reduce the incidence of flushing. Studies with dimethyl fumarate show that administration of non-enteric coated aspirin (up to a dose of 325 mg) 30 minutes prior to dosing may reduce the incidence or severity of flushing.
Risk Summary: There are no adequate data on the developmental risk associated with the use of diroximel fumarate or dimethyl fumarate (which has the same active metabolite as diroximel fumarate) in pregnant women. 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 exposures.
In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. The background risk of major birth defects and miscarriage for the indicated population is unknown.
Animal Data: Oral administration of diroximel fumarate (0, 40, 100, or 400 mg/kg/day) to pregnant rats throughout organogenesis resulted in a decrease in fetal body weight and an increase in fetal skeletal variations at the highest dose 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 (0, 50, 150, or 350 mg/kg/day) to pregnant rabbits throughout organogenesis resulted in an increase in fetal skeletal malformations at the mid and high doses and reduced fetal body weight and increases in embryofetal death and fetal skeletal variations at the highest dose tested. The high dose was associated with maternal toxicity. 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 (0, 40, 100, or 400 mg/kg/day) 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.
Risk Summary: There are no data on the presence of diroximel fumarate or metabolites (MMF, HES) in human milk. The effects on the breastfed infant and on milk production are unknown.
The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for diroximel fumarate and any potential adverse effects on the breastfed infant from the drug or from the underlying maternal condition.
Safety and effectiveness in pediatric patients have not been established.
Clinical studies of dimethyl fumarate and diroximel fumarate did not include sufficient numbers of patients aged 65 years and over to determine whether they respond differently from younger patients.
No dosage adjustment is necessary in patients with mild renal impairment. Because of an increase in the exposure of a major metabolite [2-hydroxyethyl succinimide (HES)], use of diroximel fumarate is not recommended in patients with moderate or severe renal impairment.
Common Adverse Effects
Most common adverse reactions (incidence for dimethyl fumarate [which has the same active metabolite as diroximel fumarate] ≥10% and ≥2% more than placebo) were flushing, abdominal pain, diarrhea, and nausea.
It is essential that the manufacturer's labeling be consulted for more detailed information on interactions with this drug, including possible dosage adjustments. Interaction highlights:
Please see product labeling for drug interaction information.
Mechanism of Action
The mechanism by which diroximel fumarate exerts 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.
Advice to Patients
Advise the patient to read the FDA-approved patient labeling (Patient Information).
Dosage and Administration
Inform patients that they will be provided a starter dose bottle: one capsule twice a day for the first 7 days and then two capsules twice a day thereafter. Advise patients to take diroximel fumarate as instructed. Inform patients to swallow diroximel fumarate capsules whole and intact. Inform patients to not crush, chew, or sprinkle capsule contents on food. Inform patients that they should avoid a high-fat, high-calorie meal/snack at the time they take diroximel fumarate. If taken with food, the meal/snack should contain no more than 700 calories and no more than 30 g fat. Advise patients to avoid co-administration of diroximel fumarate with alcohol.
Anaphylaxis and Angioedema
Advise patients to discontinue diroximel fumarate and seek medical care if they develop signs and symptoms of anaphylaxis or angioedema.
Progressive Multifocal Leukoencephalopathy
Inform patients that progressive multifocal leukoencephalopathy (PML) has occured in patients who received dimethyl fumarate, and therefore may occur with diroximel fumarate. Inform the patient that PML is characterized by a progression of deficits and usually leads to death or severe disability over weeks or months. Inform the patient of the importance of contacting their healthcare provider if they develop any symptoms suggestive of PML. Inform the patient that typical symptoms associated with PML are diverse, progress over days to weeks, and include progressive weakness on one side of the body or clumsiness of limbs, disturbance of vision, and changes in thinking, memory, and orientation leading to confusion and personality changes.
Inform patients that diroximel fumarate may decrease lymphocyte counts. A blood test should be obtained before they start therapy. Blood tests are also recommended after 6 months of treatment, every 6 to 12 months thereafter, and as clinically indicated.
Inform patients that diroximel fumarate may cause liver injury. Instruct patients treated with diroximel fumarate to report promptly to their healthcare provider any symptoms that may indicate liver injury, including fatigue, anorexia, right upper abdominal discomfort, dark urine, or jaundice. A blood test should be obtained before patients start therapy and during treatment, as clinically indicated.
Flushing and Gastrointestinal (GI) Reactions
Flushing and GI reactions (abdominal pain, diarrhea, and nausea) are the most common reactions, especially at the initiation of therapy, and may decrease over time. Advise patients to contact their healthcare provider if they experience persistent and/or severe flushing or GI reactions. Advise patients experiencing flushing that taking diroximel fumarate with food (avoid high-fat, high-calorie meal or snack) or taking a non-enteric coated aspirin prior to taking diroximel fumarate may help.
Instruct patients that if they are pregnant or plan to become pregnant while taking diroximel fumarate they should inform their healthcare provider.
AHFSfirstRelease™. For additional information until a more detailed monograph is developed and published, the manufacturer's labeling should be consulted. It is essential that the manufacturer's labeling be consulted for more detailed information on usual uses, dosage and administration, cautions, precautions, contraindications, potential drug interactions, laboratory test interferences, and acute toxicity.
Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.
Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.
AHFS Drug Information. © Copyright 2021, Selected Revisions December 16, 2019. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.
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