Diroximel fumarate is an oral fumarate. Like dimethyl fumarate, the drug is indicated for the treatment of adults with relapsing forms of multiple sclerosis, including clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease. Oral fumarates appear to have neuroprotective and anti-inflammatory properties; these actions can help delay disability and disease progression. Diroximel fumarate has the same active metabolite (MMF) as dimethyl fumarate. In clinical studies assessing safety in adult patients with relapsing-remitting multiple sclerosis (RRMS), approximately 700 patients were treated with diroximel fumarate and approximately 490 patients received more than 1 year of treatment with the drug. The adverse reaction profile of diroximel fumarate was consistent with the experience in the placebo-controlled clinical trials with dimethyl fumarate. Diroximel fumarate's main advantage over dimethyl fumarate is better GI tolerability. Less patients discontinued treatment becuase of GI adverse effects with diroximel fumarate (0.8%) than dimethyl fumarate (4.8%). Diroximel fumarate was FDA approved in October 2019.
General Administration Information
For storage information, see the specific product information within the How Supplied section.
Route-Specific Administration
Oral Administration
-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.
Oral Solid Formulations
-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.
Diroximel fumarate has the same active metabolite (MMF) as dimethyl fumarate. In clinical studies assessing safety in adult patients with relapsing-remitting multiple sclerosis (RRMS), approximately 700 patients were treated with diroximel fumarate and approximately 490 patients received more than 1 year of treatment with the drug. The adverse reaction profile of diroximel fumarate was consistent with the experience in the placebo-controlled clinical trials with dimethyl fumarate.
Diroximel fumarate may decrease lymphocyte counts. Diroximel fumarate and dimethyl fumarate have the same active metabolite (MMF), and the possibility for serious infection exists with either medication. In two placebo-controlled trials, dimethyl fumarate caused leukopenia and lymphopenia, but mean concentrations remained above the lower limit of normal. Severe lymphopenia increases the risk for development of progressive multifocal leukoencephalopathy (PML). During a clinical trial, a fatal case of PML occurred in a patient with prolonged lymphopenia (lymphocyte counts predominantly less than 500 cells/mcL for 3.5 years) who received dimethyl fumarate for 4 years. The patient was not receiving other immunosuppressants and had no other medical conditions that compromised immune function. No prior exposure to natalizumab, which is associated with PML, was noted. PML has also occurred in the postmarketing setting in the presence of lymphopenia (less than 900 cells/mcL). While the role of lymphopenia in these cases is uncertain, the PML cases have predominantly occurred in patients with lymphocyte counts less than 800 cells/mcL that persisted for at least 6 months. PML has been reported in 4 patients in Europe who were treated for psoriasis with a fixed combination product containing dimethyl fumarate and 3 monoethyl hydrogen fumarates (calcium, magnesium, and zinc salts) or a compounded version of fumaric acid esters. In 2 of the case reports, the patients had prolonged (2 and 5 years) severe lymphopenia prior to the diagnosis of PML. The other 2 patients had significant confounding factors for PML. Symptoms of PML may include progressive weakness on 1 side of the body, clumsiness of limbs, vision disturbance, confusion, and personality changes. At the first sign or symptom of PML, discontinue dimethyl fumarate and perform a diagnostic evaluation. To reduce the risk of PML, periodic monitoring of lymphocytes is recommended. MRI findings and detection of JC virus (JCV) DNA in the CSF in the absence of clinical signs and symptoms of PML have been reported in patients taking other multiple sclerosis medications associated with PML; many cases progressed to symptomatic PML. Consider MRI monitoring for signs consistent with PML, and promptly investigate any suspicious findings. White cell counts of less than 3,000 cells/mcL (National Cancer Institute Common Toxicity Criteria grade 2 or higher leukopenia) were noted in 10% of dimethyl fumarate recipients as compared with 1% of placebo recipients. The mean white cell counts decreased by approximately 10% to 12% during the first year and then stabilized. During controlled trials, 2% of 769 dimethyl fumarate recipients had lymphopenia in contrast to less than 1% of 771 placebo recipients. Mean lymphocyte counts decreased by approximately 30% during the first year of dimethyl fumarate treatment and then remained stable. The mean lymphocyte counts increased 4 weeks after dimethyl fumarate cessation but did not return to baseline concentrations. Lymphocyte counts of less than 500 cells/mcL (grade 3 or higher lymphopenia) were seen in 6% of dimethyl fumarate recipients as compared with less than 1% of placebo recipients. Among patients who did not experience prolonged, severe lymphopenia in controlled and uncontrolled clinical trials, median times for lymphocyte normalization after treatment discontinuation were 4.3 weeks in patients with mild lymphopenia (lymphocyte count more than 800 cells/mcL), 10 weeks in patients with moderate lymphopenia (lymphocyte counts of 500 to 800 cells/mcL), and 16.7 weeks in patients with severe lymphopenia (lymphocyte counts less than 500 cells/mcL). Severe lymphopenia, defined as lymphocyte counts less than 500 cells/mcL for a minimum of 6 months, occurred in 2% of patients who received dimethyl fumarate. The median time for normalization of lymphocyte counts in patients with severe lymphopenia after treatment discontinuation was 96 weeks. In controlled trials, no differences in the incidences between the groups were noted for either infections (60% for dimethyl fumarate vs. 58% for placebo) or serious infections (2% in each group). Also, no increased incidence of serious infections was noted in patients with lymphocyte counts less than 800 cells/mcL or 500 cells/mcL. However, dimethyl fumarate was not studied in patients with pre-existing low lymphocyte counts. Obtain a complete blood count (CBC) including lymphocyte count before diroximel fumarate initiation. A CBC including lymphocyte count should also be obtained after 6 months of treatment, every 6 to 12 months thereafter, and as clinically indicated. Consider interruption of therapy if lymphocyte counts less than 500 cells/mcL persist for more than 6 months. Because lymphocyte recovery may be delayed, following lymphocyte counts until lymphopenia is resolved is recommended. If a serious infection develops, consider withholding diroximel fumarate until the infection is resolved. Serious cases of herpes zoster infection, including disseminated herpes zoster, herpes zoster ophthalmicus, herpes zoster meningoencephalitis, and herpes zoster meningomyelitis have occurred during treatment with dimethyl fumarate, and may also occur with diroximel fumarate. These events may occur at any time during treatment. Monitor patients for signs and symptoms of herpes zoster and treat as clinically appropriate. Other serious opportunistic infections, including cases of serious viral (herpes simplex virus, West Nile virus, cytomegalovirus), fungal (Candida and Aspergillus), and bacterial (Nocardia, Listeria monocytogenes, Mycobacterium tuberculosis) infections have occurred. These infections have been reported in patients with reduced and normal absolute lymphocyte counts, and have affected the brain, meninges, spinal cord, gastrointestinal tract, lungs, skin, eye, and ear. Patients with symptoms and signs consistent with any of these infections should undergo prompt diagnostic evaluation and receive appropriate treatment. Consider withholding the drug treatment in patients with herpes zoster or other serious infections until the infection has resolved.
Diroximel fumarate and dimethyl fumarate have the same active metabolite (MMF). Among 769 dimethyl fumarate recipients, 40% had flushing vs. 6% of 771 placebo recipients. Most patients had mild or moderate flushing, but 3% discontinued the drug because of flushing, and less than 1% had serious flushing symptoms that were not life-threatening but led to hospitalization. As compared with placebo recipients, more dimethyl fumarate recipients had pruritus (8% vs. 4%), rash (8% vs. 3%), and erythema (5% vs. 1%). Flushing symptoms such as warmth, redness, itching, and/or a burning sensation generally began soon after dimethyl fumarate initiation and usually improved or resolved over time. Administration of these drugs with food may reduce the incidence of flushing. For example, the incidence of flushing was reduced by approximately 25% in the fed state in 1 study. Alternatively, administration of non-enteric coated aspirin (up to a dose of 325 mg) 30 minutes prior to a dose may also reduce the incidence or severity of flushing.
Serious gastrointestinal (GI) reactions including GI perforation, GI bleeding, GI ulceration or peptic ulcer, and GI obstruction, some with fatal outcomes, have been reported during postmarketing experience with fumaric acid esters, including diroximel fumarate. Serious GI adverse reactions have been reported with and without concomitant use of aspirin, and most reactions occurred within 6 months of treatment initiation. Diroximel fumarate and dimethyl fumarate have the same active metabolite (MMF), and the incidence of serious GI adverse reactions in controlled clinical trials was 1% in patients treated with dimethyl fumarate. None of these reactions were fatal, and they included vomiting (0.3%) and abdominal pain (0.3%). Closely monitor patients treated with diroximel fumarate for signs and symptoms of severe GI adverse reactions. Promptly evaluate and discontinue diroximel fumarate if new or worsening symptoms of severe GI adverse reactions occur. The main advantage diroximel fumarate may have over dimethyl fumarate in terms of side effects may be an improvement in gastrointestinal (GI) tolerance. Patients treated with diroximel fumarate self-reported significantly fewer days of key GI symptoms as compared to dimethyl fumarate (p = 0.0003) during clinical study. Fewer patients discontinued treatment because of GI adverse effects with diroximel fumarate (0.8%) than dimethyl fumarate (4.8%). The most common side effects reported in the study for both treatment groups were diarrhea (15.4% for diroximel fumarate; 22.3% for dimethyl fumarate) and nausea (14.6% for diroximel fumarate and 20.7% for dimethyl fumarate). The side effects reported with diroximel fumarate were similar to those reported in dimethyl fumarate in placebo-controlled studies. Among dimethyl fumarate recipients during placebo-controlled clinical trials, abdominal pain (18%), diarrhea (14%), nausea (12%), vomiting (9%), and dyspepsia (5%) were reported as higher incidences vs. placebo. Gastrointestinal (GI) adverse events were more common early in the course of dimethyl fumarate treatment (primarily in month 1) and usually decreased over time. Most side effects were mild: 1% of dimethyl fumarate recipients had a serious GI adverse event, and 4% discontinued the drug because of GI effects vs. less than 1% of placebo recipients. Acute pancreatitis has been reported with dimethyl fumarate during postmarketing experience.
Diroximel fumarate and dimethyl fumarate have the same active metabolite (MMF). Dimethyl fumarate may cause eosinophilia, as a transient increase in mean eosinophil count was seen during the first 2 months of dimethyl fumarate receipt.
Obtain liver function tests (LFTs) and total bilirubin concentrations before and during diroximel fumarate treatment as clinically indicated and discontinue treatment if clinically significant liver injury induced by diroximel fumarate is suspected. Diroximel fumarate and dimethyl fumarate have the same active metabolite (MMF). An increased incidence of elevated hepatic enzymes was seen primarily during the first 6 months of dimethyl fumarate treatment; most elevations were less than 3 times the upper limit of normal (ULN). Higher elevations of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) occurred in a small number of patents and were balanced between dimethyl fumarate recipients and placebo recipients. No hepatic transaminases at 3 times the ULN or more with concomitant elevations in total bilirubin more than 2 times the ULN were noted. Less than 1% of patients discontinued dimethyl fumarate due to elevated hepatic transaminases during clinical trials. Postmarketing cases of clinically significant liver injury have been reported with dimethyl fumarate. The onset has ranged from a few days to several months after initiation of treatment. 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 more than 2-fold the ULN have been observed. Although the abnormalities resolved upon treatment discontinuation, some cases required hospitalization. In 2 placebo-controlled trials, AST elevations occurred in 4% of patients who received dimethyl fumarate (n = 769) compared to 2% of patients who received placebo (n = 771). None of the reported cases resulted in hepatic failure, liver transplant, or death.
Diroximel fumarate can cause anaphylaxis and angioedema after the first dose or at any time during treatment. Such reactions have occured with dimethyl fumarate (which has the same active metabolite, MMF). Instruct patients to discontinue the drug and seek immediate medical treatment if they experience signs and symptoms of anaphylactoid reactions including difficulty breathing, urticaria, and/or swelling of the throat and tongue.
Diroximel fumarate and dimethyl fumarate have the same active metabolite (MMF). In 2 placebo-controlled trials, albuminuria (proteinuria) occurred in 6% of patients who received dimethyl fumarate (n = 769) compared to 4% of patients who received placebo (n = 771). Similar incidences may occur with diroximel fumarate.
Diroximel fumarate and dimethyl fumarate have the same active metabolite (MMF). Rhinorrhea has been reported with dimethyl fumarate during postmarketing experience.
Diroximel fumarate and dimethyl fumarate have the same active metabolite (MMF). Alopecia has been reported with dimethyl fumarate during postmarketing experience.
Diroximel fumarate is contraindicated in patients who have demonstrated hypersensitivity to diroximel fumarate, dimethyl fumarate, or any of the product excipients. Anaphylaxis or angioedema may occur after the first dose or 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 hypersensitivity, such as anaphylaxis or angioedema.
Diroximel fumarate use in patients with immunosuppression may be inadvisable. Obtain a complete blood count (CBC) including lymphocyte count before diroximel fumarate initiation. A CBC including lymphocyte count should also be obtained after 6 months of treatment, every 6 to 12 months thereafter, and as clinically indicated. Consider interruption of therapy if lymphocyte counts less than 500 cells/mcL persist for more than 6 months. Because lymphocyte recovery may be delayed, following lymphocyte counts until lymphopenia is resolved is recommended. If a serious infection develops, consider withholding diroximel fumarate until the infection is resolved. 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 and then remained stable. Four weeks after stopping treatment, mean lymphocyte counts increased but did not return to baseline. Diroximel fumarate has not been studied in patients with pre-existing low lymphocyte counts.
Suspect progressive multifocal leukoencephalopathy (PML) in any patient presenting with neurological symptoms while taking diroximel fumarate; discontinue the drug at the first sign or symptom of PML and perform a diagnostic evaluation. PML has occurred in patients taking dimethyl fumarate, which has the same active metabolite as diroximel fumarate. As PML can be fatal, instruct patients to notify their healthcare provider immediately if they notice new or worsening neurological signs or symptoms such as ataxia, visual changes, or confusion. PML has occurred in the presence of prolonged lymphopenia, and practitioners should obtain a complete blood count (CBC) with differential including lymphocyte count before diroximel fumarate initiation. A CBC including lymphocyte count should also be obtained 6 months after treatment initiation, every 6 to 12 months thereafter, and as clinically indicated. Consider MRI monitoring for signs that may be consistent with PML. MRI findings suggestive of PML and detection of JC virus (JCV) DNA in the CSF in the absence of clinical signs and symptoms of PML have been reported in patients treated with other multiple sclerosis medications; many cases progressed to symptomatic PML. Promptly investigate any suspicious findings to allow for early diagnosis.
Use diroximel fumarate with caution in patients with hepatic disease. Postmarketing cases of clinically significant liver injury have been reported with dimethyl fumarate (which has the same active metabolite as diroximel fumarate). The onset of hepatotoxicity has ranged from a few days to several months after initiation of treatment. Signs and symptoms of liver injury, including elevation of serum aminotransferases to greater than 5-fold the upper limit of normal (ULN) and elevation of total bilirubin to greater than 2-fold the ULN 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. Obtain liver function tests (LFTs) such as serum aminotransferase, alkaline phosphatase, and total bilirubin concentrations before initiating treatment and during treatment as clinically indicated. Discontinue treatment and promptly evaluate if clinically significant liver injury induced by diroximel fumarate is suspected.
Diroximel fumarate is not recommended in patients with moderate or severe renal impairment, including renal failure, due to increased exposure to an inactive major metabolite (2-hydroxyethyl succinimide or HES).
Only use diroximel fumarate during pregnancy if the potential benefit justifies the potential risk to the fetus. Diroximel fumarate has the same active metabolite (MMF) as dimethyl fumarate. Data from the dimethyl fumarate pregnancy registry, pharmacovigilance, and other observational studies in pregnant women did not suggest an increased risk of major birth defects, miscarriage, or other adverse maternal or fetal outcomes. The majority of dimethyl fumarate exposure occurred during the first trimester. The risk of major birth defects was 3.6% (95% CI 1.9 to 6.1) in a prospective observational study of pregnancy registry data of 362 live births and stillbirths from women exposed to dimethyl fumarate. No specific pattern of major birth defects was identified. Study limitations included the inability to control for potential confounders, exposure misclassification, and a lack of an internal comparator cohort. Animal studies of diroximel fumarate showed adverse effects on offspring survival, growth, sexual maturation, and neurobehavioral function when 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. There is a pregnancy exposure registry that monitors outcomes in pregnant patients exposed to diroximel fumarate. Information about the registry can be obtained at www.vumeritypregnancyregistry.com or by calling 1-833-569-2635.
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.
For the treatment of relapsing forms of multiple sclerosis, including clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease:
Oral dosage:
Adults: 231 mg PO twice daily for 7 days, then 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 persons unable to tolerate return to the maintenance dose.
Maximum Dosage Limits:
-Adults
924 mg/day PO.
-Geriatric
924 mg/day PO.
-Adolescents
Safety and efficacy have not been established.
-Children
Safety and efficacy have not been established.
-Infants
Safety and efficacy have not been established.
-Neonates
Safety and efficacy have not been established.
Patients with Hepatic Impairment Dosing
No dosage adjustment is needed.
Patients with Renal Impairment Dosing
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.
*non-FDA-approved indication
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.
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
-Route-Specific Pharmacokinetics
Oral Route
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.
-Special Populations
Hepatic Impairment
Hepatic impairment is not expected to affect exposure to the active metabolite, MMF. No studies have been conducted in patients with hepatic impairment.
Renal Impairment
No clinically relevant pharmacokinetic changes in MMF (active metabolite) exposure occurred in subjects with mild, moderate, and severe renal impairment compared to healthy controls following a single dose of diroximel fumarate (8 subjects per cohort). The exposure to HES (inactive major metabolite) increased by 1.3, 1.8, and 2.7-fold with mild, moderate, and severe renal impairment. No data are available regarding the long-term use of diroximel fumarate in patients with moderate or severe renal impairment.
Geriatric
Age did not affect the pharmacokinetics of MMF, the active metabolite of diroximel fumarate.
Gender Differences
Gender did not affect the pharmacokinetics of MMF, the active metabolite of diroximel fumarate.
Ethnic Differences
Race did not affect the pharmacokinetics of MMF, the active metabolite of diroximel fumarate.
Other
Ethanol Ingestion
Administration of diroximel fumarate with 5% v/v and 40% v/v ethanol did not change total MMF exposure relative to administration with water. The mean peak plasma MMF concentration for diroximel fumarate decreased by 9% and 21%, however, when coadministered with 240 mL of 5% v/v and 40% v/v of ethanol, respectively. Avoid alcohol ingestion at the time of a diroximel fumarate dose.