Class: Immunomodulatory Agents
- Fumaric Acid Derivatives
- Fumaric Acid Esters
VA Class: IM900
Chemical Name: Dimethyl (E)-but-2-enedioate
Molecular Formula: C6H8O4
CAS Number: 624-49-7
Medically reviewed by Drugs.com. Last updated on Nov 18, 2019.
Uses for Dimethyl Fumarate
Multiple Sclerosis (MS)
Dimethyl fumarate is one of several disease-modifying therapies used in the management of RRMS.76 77 Although not curative, these therapies have all been shown to modify several measures of disease activity, including relapse rates, new or enhancing magnetic resonance imaging (MRI) lesions, and disability progression.76 78
The American Academy of Neurology (AAN) recommends that disease-modifying therapy be offered to patients with RRMS who have had recent relapses and/or MRI lesion activity.76 Clinicians should consider adverse effects, tolerability, method of administration, safety, efficacy, and cost of the drugs in addition to patient preferences when selecting an appropriate therapy.76 77
Direct comparative studies between dimethyl fumarate and other oral drugs used in RRMS (e.g., fingolimod, teriflunomide) not performed to date; however, clinical experience suggests that dimethyl fumarate may be more effective than teriflunomide and better tolerated than fingolimod.1 2 3 13
Dimethyl Fumarate Dosage and Administration
Because of risk of lymphopenia, obtain a CBC, including lymphocyte count, prior to initiation of therapy, following 6 months of therapy, every 6–12 months thereafter, and as clinically indicated.1 (See Lymphopenia under Cautions.)
Because of possible hepatic injury, perform liver function tests (i.e., serum aminotransferase, alkaline phosphatase, and total bilirubin concentrations) prior to initiation of therapy and during therapy as clinically indicated.1 (See Hepatic Injury under Cautions.)
Administration of non-enteric-coated aspirin (≤325 mg) 30 minutes prior to dimethyl fumarate may reduce the incidence and severity of flushing.1 14 (See Flushing under Cautions and also see Specific Drugs under Interactions.)
The Tecfidera 30-day Starter Pack, which contains 120-mg capsules for the first 7 days of therapy and 240-mg capsules for the next 23 days of therapy, is designed to be used during the first month of therapy.1
In patients who do not tolerate the usual maintenance dosage, consider a temporary dosage reduction from 240 mg twice daily to 120 mg twice daily.1 Resume recommended maintenance dosage of 240 mg twice daily within 4 weeks.1 Consider drug discontinuance in patients unable to tolerate a return to the usual maintenance dosage.1
No dosage adjustment necessary.1 (See Special Populations under Pharmacokinetics.)
No dosage adjustment necessary.1 (See Special Populations under Pharmacokinetics.)
No dosage adjustment necessary.1 (See Geriatric Use under Cautions.)
Cautions for Dimethyl Fumarate
Known hypersensitivity to dimethyl fumarate or any excipients in the formulation.1 (See Anaphylaxis and Angioedema under Cautions.)
Anaphylaxis and Angioedema
May cause anaphylaxis or angioedema after the first dose or at any time during therapy.1 Signs and symptoms of hypersensitivity reactions have included difficulty breathing, urticaria, and swelling of the throat and tongue.1 (See Contraindications under Cautions and also see Advice to Patients.)
Progressive Multifocal Leukoencephalopathy (PML)
PML, an opportunistic infection of the brain caused by the JC virus, reported.1 An FDA alert in November 2014 described a fatal case of PML in a patient with MS treated with dimethyl fumarate for 4 years in a clinical trial.1 15 19 The patient had prolonged lymphopenia (i.e., lymphocyte counts predominantly <500/mm3 for 3.5 years) during dimethyl fumarate therapy;1 15 19 the causative role of lymphopenia in this case is not known.1 19 (See Lymphopenia under Cautions.) The patient had no other known medical conditions resulting in compromised immune system function, had not received natalizumab, and was not concurrently receiving any immunosuppressive or immunomodulatory drugs.1 15 19
At the first sign or symptom suggestive of PML (see Advice to Patients), immediately withhold dimethyl fumarate therapy and perform an appropriate diagnostic evaluation.1 15 MRI signs of PML may be apparent before clinical manifestations develop.1
May decrease lymphocyte counts.1 2 16 In placebo-controlled clinical trials, mean lymphocyte counts decreased by approximately 30% during the first year of therapy and remained stable thereafter.1 2 Mean lymphocyte counts improved 4 weeks following discontinuance of the drug, but did not return to baseline values.1 (See Actions.)
Although an increased incidence of serious infections was not observed in patients with decreased lymphocyte counts in controlled trials, one case of PML developed during an extension study in the setting of prolonged lymphopenia.1 (See Progressive Multifocal Leukoencephalopathy [PML] under Cautions.)
Not studied in patients with preexisting low lymphocyte counts.1
Obtain a CBC, including lymphocyte count, prior to initiation of dimethyl fumarate, following 6 months of therapy, every 6–12 months during therapy thereafter, and as clinically indicated.1
In patients with lymphocyte counts <500/mm3 persisting for >6 months, consider interruption of therapy.1 Consider monitoring lymphocyte counts until lymphopenia has resolved since lymphocyte recovery may be delayed following drug discontinuance.1
In patients with serious infections, consider withholding treatment until the infection has resolved.1 Consider patient's clinical circumstances when deciding whether to restart dimethyl fumarate therapy.1
Liver function test abnormalities (e.g., elevations in serum aminotransferase concentrations to more than fivefold the ULN and elevations in total bilirubin concentrations to more than twofold the ULN) reported during postmarketing experience.1 Occurred within a few days to several months after initiation of therapy and resolved upon treatment discontinuance.1 Although liver failure or death did not occur, marked elevations in liver function tests may be indicative of serious hepatic injury.1
Perform liver function tests (i.e., serum aminotransferase, alkaline phosphatase, and total bilirubin concentrations) prior to and during therapy as clinically indicated.1 Discontinue drug if liver injury suspected.1 (See Advice to Patients.)
May cause flushing (e.g., warmth, redness, itching, burning sensation).1 2 3 14 In clinical trials, 40% of dimethyl fumarate-treated patients experienced flushing.1 Symptoms generally are mild to moderate, begin soon after initiating therapy, and improve or resolve over time.1 3
Administration with food or pretreatment with non-enteric-coated aspirin may reduce incidence and/or severity of flushing.1 14 (See Administration under Dosage and Administration, see Specific Drugs under Interactions, and also see Actions.)
Effects of the drug on the nursing infant or on milk production not known.1
Consider benefits of breastfeeding along with the woman's clinical need for dimethyl fumarate and any potential adverse effects on the breastfed infant from the drug or underlying maternal condition.1
Safety and efficacy not established in pediatric patients <18 years of age.1
Insufficient experience in patients ≥65 years of age to determine whether they respond differently than younger adults.1 (See Geriatric Patients under Dosage and Administration.)
Common Adverse Effects
Flushing,1 2 3 14 abdominal pain,1 2 3 diarrhea,1 2 3 nausea.1 2 3 Incidence of flushing and adverse GI effects generally higher early in therapy (mainly in the first month) and decreases with continued therapy (see Administration under Dosage and Administration).1 2 10 21
Interactions for Dimethyl Fumarate
No potential drug interactions with dimethyl fumarate or its main active metabolite, MMF, identified in CYP inhibition and induction studies, P-glycoprotein studies, or studies of protein binding.1
Non-enteric-coated aspirin (325 mg given approximately 30 minutes before dimethyl fumarate over 4 days) did not alter MMF pharmacokinetics or incidence of adverse GI effects, but reduced incidence and severity of flushing1 14
Clinically important pharmacokinetic interactions unlikely10
Effectiveness of vaccines in patients receiving dimethyl fumarate not evaluated10
Dimethyl Fumarate Pharmacokinetics
Following oral administration, dimethyl fumarate undergoes rapid presystemic hydrolysis by esterases and is converted to its active metabolite, monomethyl fumarate (MMF).1
Dimethyl fumarate is not quantifiable in plasma after oral administration; pharmacokinetic analyses were performed with plasma MMF concentrations.1
Median time to peak plasma MMF concentrations is 2–2.5 hours.1
Accumulation of MMF does not occur with multiple oral doses.1
High-fat, high-calorie meal did not affect AUC of MMF, but decreased peak plasma concentrations of MMF by 40% and delayed time to reach peak concentrations from 2 to 5.5 hours; incidence of flushing was decreased by approximately 25% in the fed state.1
Plasma Protein Binding
MMF is 27–45% protein bound; protein binding is independent of concentration.1
Extensively metabolized by esterases (present in GI tract, blood, and tissues) to MMF before reaching systemic circulation.1 MMF is further metabolized by the tricarboxylic acid (TCA) cycle; the CYP system is not involved in its metabolism.1 The major metabolites in plasma are MMF, fumaric acid, citric acid, and glucose.1
Eliminated mainly (60%) by exhalation of carbon dioxide and to a minor extent by excretion in urine (16%) and feces (1%).1
MMF: Approximately 1 hour.1
Dimethyl fumarate and its active metabolite, MMF, activate the nuclear factor (erythroid-derived 2)-like 2 (Nrf2) pathway in vitro and in vivo in animals and humans.1 7 11 The Nrf2 antioxidant response pathway is involved in the cellular response to oxidative stress.1 7 9 11
Nrf2-dependent upregulation of antioxidant response genes by dimethyl fumarate and MMF may protect various cells and tissues, including some from the CNS, from experimental toxic oxidative stress.7 10 11
Activation of the Nrf2 pathway by dimethyl fumarate and MMF also may inhibit proliferation of lymphocytes and hematopoietic stem cells.16 Subsets of peripheral blood leucocytes and lymphocytes appear to be affected differently, with a more pronounced reduction in CD8+ T-cell counts than in CD4+ T-cell counts observed in dimethyl fumarate-treated patients.16
MMF is a nicotinic acid receptor agonist in vitro.1 Nicotinic acid and fumaric acid derivatives such as dimethyl fumarate can cause skin flushing; flushing reactions may be mediated by activation of hydroxy-carboxylic acid receptor 2 (HCA2) and involve formation of prostaglandins.12 14
Advice to Patients
Importance of reading the manufacturer's patient information prior to beginning dimethyl fumarate therapy and rereading it each time the prescription is refilled.1
Risk of anaphylaxis and angioedema.1 Importance of advising patients to discontinue dimethyl fumarate and seek immediate medical care if they develop signs and symptoms of anaphylaxis or angioedema (e.g., difficulty breathing, urticaria, swelling of the throat and tongue).1
Importance of informing patients that PML has occurred in a dimethyl fumarate-treated patient, and is characterized by a progression of deficits and usually leads to death or severe disability over weeks to months.1 15 Importance of immediately informing clinician of any new or worsening symptoms suggestive of PML (e.g., progressive weakness on one side of the body; clumsiness of limbs; disturbance of vision; changes in thinking, memory, and orientation leading to confusion and personality changes) that have progressed over days to weeks.1 15 Importance of advising patients not to stop taking dimethyl fumarate without first consulting with their clinician.15
Importance of informing patients that they will receive 2 capsule strengths when starting treatment: 120-mg capsules for the 7-day initial dosage and 240-mg capsules for the maintenance dosage.1 Both strengths should be taken twice daily.1
Importance of informing patients to swallow dimethyl fumarate delayed-release capsules whole and intact, and not to crush, chew, or sprinkle the capsule contents on food.1 Importance of informing patients that the capsules may be taken with or without food.1
Importance of informing patients that flushing and adverse GI effects (e.g., abdominal pain, diarrhea, nausea) are common, particularly at the initiation of treatment, and that they may decrease over time.1 21 Importance of advising patients to contact their clinician if they experience persistent and/or severe flushing or GI reactions.1 Importance of also advising patients that taking dimethyl fumarate with food or taking non-enteric-coated aspirin prior to taking dimethyl fumarate may be helpful in such cases.1 21
Risk of liver injury.1 Importance of advising patients to immediately report any possible manifestations, including fatigue, anorexia, right upper abdominal discomfort, dark urine, or jaundice; importance of patients receiving liver function tests prior to and during treatment as clinically indicated to monitor for such effects.1
Importance of women informing their clinician if they are or plan to become pregnant or plan to breast-feed.1 Importance of encouraging enrollment of pregnant women in the Tecfidera pregnancy registry at 866-810-1462 or on the website [Web].1
Importance of informing clinician of existing or contemplated concomitant therapy, including prescription and OTC drugs and herbal supplements, as well as any concomitant illnesses (e.g., leukopenia, lymphopenia, infections).1
Importance of informing patients of other important precautionary information.1 (See Cautions.)
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.
7-day bottle containing 14 delayed-release capsules of dimethyl fumarate 120 mg (Tecfidera)
23-day bottle containing 46 delayed-release capsules of dimethyl fumarate 240 mg (Tecfidera)
Tecfidera 30-Day Starter Pack
AHFS DI Essentials™. © Copyright 2021, Selected Revisions November 18, 2019. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.
1. Biogen Inc. Tecfidera (dimethyl fumarate) delayed-release capsules prescribing information. Cambridge, MA; 2018 June.
2. Gold R, Kappos L, Arnold DL et al. Placebo-controlled phase 3 study of oral BG-12 for relapsing multiple sclerosis. N Engl J Med. 2012; 367:1098-107. http://www.ncbi.nlm.nih.gov/pubmed/22992073?dopt=AbstractPlus
3. Fox RJ, Miller DH, Phillips JT et al. Placebo-controlled phase 3 study of oral BG-12 or glatiramer in multiple sclerosis. N Engl J Med. 2012; 367:1087-97. http://www.ncbi.nlm.nih.gov/pubmed/22992072?dopt=AbstractPlus
4. Bar-Or A, Gold R, Kappos L et al. Clinical efficacy of BG-12 (dimethyl fumarate) in patients with relapsing-remitting multiple sclerosis: subgroup analyses of the DEFINE study. J Neurol. 2013; 260:2297-305. http://www.ncbi.nlm.nih.gov/pubmed/23797999?dopt=AbstractPlus
5. Hutchinson M, Fox RJ, Miller DH et al. Clinical efficacy of BG-12 (dimethyl fumarate) in patients with relapsing-remitting multiple sclerosis: subgroup analyses of the CONFIRM study. J Neurol. 2013; 260:2286-96. http://www.ncbi.nlm.nih.gov/pubmed/23749293?dopt=AbstractPlus
6. Havrdova E, Hutchinson M, Kurukulasuriya NC et al. Oral BG-12 (dimethyl fumarate) for relapsing-remitting multiple sclerosis: a review of DEFINE and CONFIRM Evaluation of: Gold R, Kappos L, Arnold D, et al. Placebo-controlled phase 3 study of oral BG-12 for relapsing multiple sclerosis. N Engl J Med 2012;367:1098-107; and Fox RJ, Miller DH, Phillips JT, et al. Placebo-controlled phase 3 study of oral BG-12 or glatiramer in multiple sclerosis. N Engl J Med 2012;367:1087-97. Expert Opin Pharmacother. 2013; 14:145-56.
7. Stangel M, Linker RA. Dimethyl fumarate (BG-12) for the treatment of multiple sclerosis. Expert Rev Clin Pharmacol. 2013; 6:355-62. http://www.ncbi.nlm.nih.gov/pubmed/23927662?dopt=AbstractPlus
8. Albrecht P, Bouchachia I, Goebels N et al. Effects of dimethyl fumarate on neuroprotection and immunomodulation. J Neuroinflammation. 2012; 9:163. http://www.ncbi.nlm.nih.gov/pubmed/22769044?dopt=AbstractPlus http://www.pubmedcentral.nih.gov/picrender.fcgi?tool=pmcentrez&artid=3419128&blobtype=pdf
9. Lin SX, Lisi L, Dello Russo C et al. The anti-inflammatory effects of dimethyl fumarate in astrocytes involve glutathione and haem oxygenase-1. ASN Neuro. 2011; 3:. http://www.ncbi.nlm.nih.gov/pubmed/21382015?dopt=AbstractPlus http://www.pubmedcentral.nih.gov/picrender.fcgi?tool=pmcentrez&artid=3072764&blobtype=pdf
10. Biogen Idec Canada Inc. Tecfidera (dimethyl fumarate) delayed-release capsules 120 mg product monograph. Mississauga, Ontario; 2013 Mar 28.
11. Scannevin RH, Chollate S, Jung MY et al. Fumarates promote cytoprotection of central nervous system cells against oxidative stress via the nuclear factor (erythroid-derived 2)-like 2 pathway. J Pharmacol Exp Ther. 2012; 341:274-84. http://www.ncbi.nlm.nih.gov/pubmed/22267202?dopt=AbstractPlus
12. Hanson J, Gille A, Offermanns S. Role of HCA2 (GPR109A) in nicotinic acid and fumaric acid ester-induced effects on the skin. Pharmacol Ther. 2012; 136:1-7. http://www.ncbi.nlm.nih.gov/pubmed/22743741?dopt=AbstractPlus
13. Anon. Dimethyl fumarate (Tecfidera) for multiple sclerosis. Med Lett Drugs Ther. 2013; 55:45-7.
14. Sheikh SI, Nestorov I, Russell H et al. Tolerability and pharmacokinetics of delayed-release dimethyl fumarate administered with and without aspirin in healthy volunteers. Clin Ther. 2013; 35:1582-94. http://www.ncbi.nlm.nih.gov/pubmed/24139424?dopt=AbstractPlus
15. US Food and Drug Administration. FDA drug safety communication: FDA warns about case of rare brain infection PML with MS drug Tecfidera (dimethyl fumarate). Rockville, MD; 2014 Nov 25. From FDA website. Accessed 2015 Feb 23. http://www.fda.gov/downloads/Drugs/DrugSafety/UCM424634.pdf
16. Spencer CM, Crabtree-Hartman EC, Lehmann-Horn K et al. Reduction of CD8+ T lymphocytes in multiple sclerosis patients treated with dimethyl fumarate. Neurol Neuroimmunol Neuroinflamm. 2015; 2:e76. http://www.ncbi.nlm.nih.gov/pubmed/25738172?dopt=AbstractPlus http://www.pubmedcentral.nih.gov/picrender.fcgi?tool=pmcentrez&artid=4335821&blobtype=pdf
17. van Oosten BW, Killestein J, Barkhof F et al. PML in a patient treated with dimethyl fumarate from a compounding pharmacy. New Engl J Med. 2013: 368:1658-9.
18. Miller DH, Fox RJ, Phillips JT et al. Effects of delayed-release dimethyl fumarate on MRI measures in the phase 3 CONFIRM study. Neurology. 2015; 84:1145–52. http://www.ncbi.nlm.nih.gov/pubmed/25681448?dopt=AbstractPlus
19. Rosenkranz T, Novas M, Terborg C. PML in a patient with lymphocytopenia treated with dimethyl fumarate. New Engl J Med. 2015; 372:1476-8. http://www.ncbi.nlm.nih.gov/pubmed/25853765?dopt=AbstractPlus
20. Nieuwkamp DJ, Murk JL, van Oosten BW et al. PML in a patient without severe lymphocytopenia receiving dimethyl fumarate. New Engl J Med. 2015; 372:1474-6. http://www.ncbi.nlm.nih.gov/pubmed/25853764?dopt=AbstractPlus
21. Phillips JT, Hutchinson M, Fox R et al. Managing flushing and gastrointestinal events associated with delayed-release dimethyl fumarate: experiences of an international panel. Mult Scler Relat Disord. 2014; 3:513-9. http://www.ncbi.nlm.nih.gov/pubmed/25877064?dopt=AbstractPlus
76. Rae-Grant A, Day GS, Marrie RA et al. Practice guideline recommendations summary: Disease-modifying therapies for adults with multiple sclerosis: Report of the Guideline Development, Dissemination, and Implementation Subcommittee of the American Academy of Neurology. Neurology. 2018; 90:777-788. http://www.ncbi.nlm.nih.gov/pubmed/29686116?dopt=AbstractPlus
77. Multiple Sclerosis Coalition. The use of disease-modifying therapies in multiple sclerosis: principles and current evidence summary. Available from National MS Society website. http://www.nationalmssociety.org/getmedia/1e64b96c-9e55-400e-9a64-0cdf5e2d60fe/summaryDMTpaper_-final
78. National MS Society. Disease-modifying therapies for MS. Available from National MS Society website. http://stage.nationalmssociety.org/NationalMSSociety/media/MSNationalFiles/Brochures/Brochure-The-MS-Disease-Modifying-Medications.pdf
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