Dimethyl fumarate 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. Dimethyl fumarate appears to have neuroprotective and anti-inflammatory properties; these actions can help delay disability and disease progression. In the pivotal pre-approval trial, dimethyl fumarate 240 mg twice daily led to significant reductions in the annualized relapse rate over 2 years (0.17) as compared with placebo (0.36). The trial also showed a 38% decrease in risk of disability progression with treatment (p=0.005) and a significant improvement in quality of life scores as early as week 24. Similar results were found in another phase 3 trial: the annualized relapse rate over 2 years was significantly lower with dimethyl fumarate vs. placebo.
General Administration Information
For storage information, see the specific product information within the How Supplied section.
Route-Specific Administration
Oral Administration
Oral Solid Formulations
-Administer the capsules intact. Do not crush or sprinkle the capsule contents on food. Also, instruct the patient to not chew the capsule.
-The capsules may be taken with or without food, but administration with food may reduce the incidence of flushing.
Dimethyl fumarate has an active metabolite (MMF), and the possibility for serious infection exists with this 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) and other serious infections. 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 dimethyl 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 dimethyl 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. These events may occur at any time during treatment. Monitor patients on dimethyl fumarate 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 during treatment with dimethyl fumarate. 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 dimethyl fumarate treatment in patients with herpes zoster or other serious infections until the infection has resolved.
Among 769 dimethyl fumarate recipients, 40% had flushing in contrast to 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 (unspecified) (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 dimethyl fumarate 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 dosing may 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 dimethyl 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. 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 dimethyl fumarate for signs and symptoms of severe GI adverse reactions. Promptly evaluate and discontinue dimethyl fumarate if new or worsening symptoms of severe GI adverse reactions occur. Among 769 dimethyl fumarate recipients, 18% had abdominal pain in contrast to 10% of 771 placebo recipients. More dimethyl fumarate recipients also had diarrhea (14% vs. 11%), nausea (12% vs. 9%), vomiting (9% vs. 5%), and dyspepsia (5% vs. 3%). The incidence of gastrointestinal (GI) adverse events was higher 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 the effects as compared with less than 1% of placebo recipients. Diroximel fumarate, a related fumarate with the same active metabolite (MMF), may have a slight advantage for gastrointestinal (GI) tolerance over dimethyl fumarate. During a clinical study comparison, 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). Acute pancreatitis has been reported with dimethyl fumarate during postmarketing experience.
Dimethyl fumarate may cause eosinophilia, as a transient increase in mean eosinophil count was seen during the first 2 months of dimethyl fumarate receipt.
An increased incidence of elevated hepatic enzymes was seen primarily during the first 6 months of dimethyl fumarate treatment, and most patients with elevations had concentrations less than 3 times the upper limit of normal (ULN). Higher elevations of alanine aminotransferase and aspartate aminotransferase occurred in a small number of patents and were balanced between dimethyl fumarate recipients and placebo recipients. No hepatic transaminases at 3 times or more the ULN 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. None of the reported cases resulted in hepatic failure, liver transplant, or death. Obtain serum aminotransferase, alkaline phosphatase, and total bilirubin concentrations prior to and during treatment, as clinically indicated. Discontinue treatment if clinically significant liver injury induced by dimethyl fumarate is suspected.
Dimethyl fumarate can cause anaphylaxis and angioedema after the first dose or at any time during treatment. 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 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).
Rhinorrhea has been reported with dimethyl fumarate during postmarketing experience.
Alopecia has been reported with use of dimethyl fumarate during postmarketing experience.
Dimethyl fumarate is contraindicated in patients who have demonstrated hypersensitivity to dimethyl fumarate or any of its excipients. There have been reports of anaphylaxis and angioedema associated with dimethyl fumarate therapy which may occur after the first dose or any time during treatment.
Dimethyl fumarate use in patients with immunosuppression may be inadvisable. Obtain a complete blood count (CBC) including lymphocyte count before dimethyl 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 dimethyl fumarate until the infection is resolved. In placebo-controlled trials with dimethyl 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. Dimethyl fumarate has not been studied in patients with pre-existing low lymphocyte counts.
Progressive multifocal leukoencephalopathy (PML) has occurred with dimethyl 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. Similarly, suspect PML in any patient presenting with neurological symptoms; discontinue dimethyl fumarate at the first sign or symptom of PML and perform a diagnostic evaluation. As PML has occurred in the presence of prolonged lymphopenia, obtain a complete blood count (CBC) including lymphocyte count before dimethyl 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 dimethyl fumarate with caution in patients with hepatic disease. Postmarketing cases of clinically significant liver injury have been reported with dimethyl 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 prior to and during treatment, as clinically indicated. Discontinue treatment if clinically significant liver injury induced by dimethyl fumarate is suspected.
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 showed adverse effects on offspring survival, growth, sexual maturation, and neurobehavioral function when dimethyl fumarate was administered during pregnancy at clinically relevant doses. Animal reproductive studies are not always predictive of human response. Only use dimethyl fumarate during pregnancy if the potential benefit justifies the potential risk to the fetus.
There are no data on dimethyl fumarate and its 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 dimethyl fumarate and any potential adverse effects on the breast-fed infant from dimethyl 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. 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: 120 mg PO twice daily for 7 days, then 240 mg PO twice daily. Consider a temporary dose reduction to 120 mg PO twice daily for individuals who do not tolerate the maintenance dose. Resume the recommended dose of 240 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
480 mg/day PO.
-Geriatric
480 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
Specific guidelines for dosage adjustments in hepatic impairment are not available; it appears that no dosage adjustments are needed.
Patients with Renal Impairment Dosing
Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are needed.
*non-FDA-approved indication
Alemtuzumab: (Major) Concomitant use of dimethyl fumarate with alemtuzumab may increase the risk of immunosuppression. Avoid the use of these drugs together.
Diroximel 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.
Monomethyl Fumarate: (Contraindicated) Coadministration of monomethyl fumarate with dimethyl fumarate is contraindicated. Dimethyl fumarate is a prodrug of monomethyl fumarate. Monomethyl fumarate may be initiated the day following discontinuation of dimethyl 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 dimethyl fumarate. Concomitant use of ocrelizumab with dimethyl fumarate may increase the risk of immunosuppression. Avoid the use of these drugs together.
Ofatumumab: (Moderate) Concomitant use of ofatumumab with dimethyl 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 dimethyl 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 dimethyl 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. Dimethyl fumarate has beneficial effects on both factors. In regard to oxidative stress, dimethyl fumarate and its active metabolite monomethyl fumarate induce 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. Dimethyl fumarate may also improve mitochondrial function. In vitro, dimethyl fumarate 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 mice with experimental autoimmune encephalomyelitis, dimethyl fumarate reduced oxidative damage and consequential nerve fiber demyelination, which resulted in greater axonal preservation and improved motor function.
In regard to inflammation, dimethyl 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 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, dimethyl fumarate may modulate immune cell responses by suppressing pro-inflammatory-cytokine production or directly inhibiting pro-inflammatory pathways. For example, dimethyl fumarate prevents the nuclear entry of activated NF-kappaB, and activation of NF-kappaB by pro-inflammatory stimuli leads to the expression of genes inducing and maintaining inflammation.
Dimethyl fumarate is administered orally. After oral administration, dimethyl 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. Among healthy volunteers and patients with multiple sclerosis, plasma protein binding of MMF is 27-45% and is 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 CO2, which accounts for approximately 60% of a dimethyl fumerate dose. Renal elimination accounts for 16% of a dose, and fecal elimination accounts for 1% of the dose. Trace amounts of unchanged MMF are present in urine. The terminal half-life of MMF is approximately 1 hour, and no circulating MMF is present at 24 hours in most individuals. Accumulation of MMF does not occur with multiple dimethyl fumarate doses.
Affected cytochrome P450 (CYP450) isoenzymes and drug transporters: None
-Route-Specific Pharmacokinetics
Oral Route
After oral administration, dimethyl 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 Tmax of MMF is 2-2.5 hours. The Cmax and AUC increase approximately dose proportionally in the dose range of 120-360 mg. After oral receipt of 240 mg twice a day with food to patients with multiple sclerosis, the mean Cmax of MMF was 1.87 mg/L, and the AUC was 8.21 mg*hr/L. A high-fat, high-calorie meal did not affect the AUC of MMF but decreased its Cmax by 40% and delayed the Tmax from 2 hours to 5.5 hours. Dimethyl fumarate may be taken with or without food.
-Special Populations
Hepatic Impairment
Hepatic impairment is not expected to affect exposure to monomethyl fumarate and, therefore, no dosage adjustment of dimethyl fumarate is necessary. Dimethyl fumarate undergoes rapid pre-systemic hydrolysis to its active metabolite monomethyl fumarate.
Renal Impairment
Renal impairment is not expected to affect exposure to monomethyl fumarate and, therefore, no dosage adjustment of dimethyl fumarate is necessary. Dimethyl fumarate undergoes rapid pre-systemic hydrolysis to its active metabolite monomethyl fumarate.
Other
Vaccines
Concomitant exposure to dimethyl fumarate did not attenuate antibody responses to tetanus toxoid-containing vaccine, pneumococcal polysaccharide, and meningococcal vaccines relative to antibody responses in interferon-treated patients in adults 27 to 55 years with relapsing forms of MS (38 subjects undergoing treatment with dimethyl fumarate and 33 subjects undergoing treatment with non-pegylated interferon at the time of vaccination). The impact of these findings on vaccine efficacy is unknown. The safety and efficacy of live or live-attenuated vaccines administered concomitantly with dimethyl fumarate have not been assessed.