and painted by hand [500/mm:<500/mm 3 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 Flushing 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.) Specific Populations Pregnancy Category C. 1 Tecfidera pregnancy registry (for patients) at 866-810-1462 or . 1 Lactation Not known whether dimethyl fumarate or its metabolites distribute into human milk. 1 10 Use with caution in nursing women. 1 Pediatric Use Safety and efficacy not established in pediatric patients <18 years of age. 1 Geriatric Use 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 Proteinuria, pruritus, reduced lymphocyte counts, increased aminotransferase concentrations (e.g., ALT, AST), transient eosinophilia (during the first 2 months of therapy). 1 2 3 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 Specific Drugs Drug Interaction Comments Aspirin 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 flushing 1 14 Glatiramer acetate Single dose of glatiramer acetate did not alter MMF pharmacokinetics 1 10 Interferon beta Single dose of interferon beta-1a did not alter MMF pharmacokinetics 1 10 Oral contraceptives Clinically important pharmacokinetic interactions unlikely 10 Vaccines Effectiveness of vaccines in patients receiving dimethyl fumarate not evaluated 10 Dimethyl Fumarate Pharmacokinetics Absorption 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 Bioavailability Median time to peak plasma MMF concentrations is 2 2.5 hours. 1 Accumulation of MMF does not occur with multiple oral doses. 1 Food 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 Distribution Extent Not known whether dimethyl fumarate or its metabolites distribute into human milk. 1 10 Plasma Protein Binding MMF is 27 45% protein bound; protein binding is independent of concentration. 1 Elimination Metabolism 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 Elimination Route Eliminated mainly (60%) by exhalation of carbon dioxide and to a minor extent by excretion in urine (16%) and feces (1%). 1 Half-life MMF: Approximately 1 hour. 1 Special Populations Hepatic impairment: Pharmacokinetics not evaluated. 1 However, hepatic impairment unlikely to affect exposure to MMF. 1 Renal impairment: Pharmacokinetics not evaluated. 1 However, renal impairment unlikely to affect exposure to MMF. 1 Stability Storage Oral Delayed-release Capsules 15 30 C; store in original container and protect from light. 1 Once opened, discard bottles after 90 days. 1 Actions Exact mechanism of action in MS is unknown; however, immunomodulatory effect appears to be mediated by many cells of the immune system. 1 7 9 11 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 (HCA 2 ) 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 decreased lymphocyte counts. 1 Importance of periodic monitoring of CBCs. 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 . 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.) Preparations 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. Dimethyl Fumarate Routes Dosage Forms Strengths Brand Names Manufacturer Oral Capsules, delayed-release 120 mg Tecfidera Biogen 240 mg Tecfidera Biogen Kit 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 Biogen AHFS DI Essentials. Copyright 2017, Selected Revisions September 4, 2015. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814. Use is not currently included in the labeling approved by the US Food and Drug Administration. References 1. Biogen Inc. Tecfidera (dimethyl fumarate) delayed-release capsules prescribing information. Cambridge, MA; 2015 Apr. 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. [PubMed 22992073] 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. [PubMed 22992072] 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. [PubMed 23797999] 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. [PubMed 23749293] 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. [PubMed 23927662] 8. Albrecht P, Bouchachia I, Goebels N et al. Effects of dimethyl fumarate on neuroprotection and immunomodulation. J Neuroinflammation . 2012; 9:163. [PubMed 22769044] 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:. [PubMed 21382015] 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. [PubMed 22267202] 12. Hanson J, Gille A, Offermanns S. Role of HCA 2 (GPR109A) in nicotinic acid and fumaric acid ester-induced effects on the skin. Pharmacol Ther . 2012; 136:1-7. [PubMed 22743741] 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. [PubMed 24139424] 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. 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. [PubMed 25738172] 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. 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. [PubMed 25853765] 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. [PubMed 25853764] 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. [PubMed 25877064] Next Interactions Print this page Add to My Med List More about dimethyl fumarate Side Effects During Pregnancy Dosage Information Drug Interactions Support Group En Español 36 Reviews Add your own review/rating Drug class: selective immunosuppressants Consumer resources Dimethyl fumarate Dimethyl fumarate (Advanced Reading) Professional resources Dimethyl Fumarate (Wolters Kluwer) Other brands: Tecfidera Related treatment guides Multiple Sclerosis> ]} FEATURED: CAR-T Cell Therapy Overview Mechanism of Action KTE-C19 Studies KTE-C19 Cancer Targets Adverse Events Manufacturing Drug Status Rx Availability Prescription only C Pregnancy Category Risk cannot be ruled out N/A CSA Schedule Not a controlled drug Approval History Drug history at FDA Drug Class Selective immunosuppressants Related Drugs Multiple Sclerosis Copaxone , Tecfidera , Avonex , Ampyra , Aubagio , Gilenya , Tysabri , Rebif , glatiramer , Betaseron , natalizumab , teriflunomide , fingolimod , dalfampridine , interferon beta-1a , mitoxantrone , Glatopa , Extavia , Rebif Rebidose , Avonex Pen , Novantrone , prednisone , prednisolone , More... 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