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Tecfidera

Generic Name: Dimethyl Fumarate
Class: Immunomodulatory Agents
VA Class: IM900
Chemical Name: Dimethyl (2E)-but-2-enedioate
Molecular Formula: C6H8O4
CAS Number: 624-49-7

Introduction

Fumaric acid derivative with immunomodulatory and disease-modifying activity in multiple sclerosis.1 7 8 9 10 11

Uses for Tecfidera

Multiple Sclerosis (MS)

Used in management of relapsing forms of MS (e.g., relapsing-remitting MS [RRMS]).1 2 3

Direct comparative studies between dimethyl fumarate and other oral drugs used in relapsing forms of MS (e.g., fingolimod, teriflunomide) have not been 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

Slideshow: Multiple Sclerosis: What's New in Treatment Options?

Efficacy not established and not FDA-labeled for use in patients with primary-progressive MS.1 7 10

Tecfidera Dosage and Administration

General

  • Prior to initiating therapy, obtain a recent (i.e., within 6 months) CBC to identify patients with a preexisting low lymphocyte count.1 (See Lymphopenia under Cautions.)

Administration

Oral Administration

Administer orally twice daily without regard to meals.1 However, administration with food may reduce incidence of flushing and improve GI tolerability.1 10

Some evidence suggests that short-term administration (i.e., ≤4 days) of aspirin given 30 minutes prior to each dose of dimethyl fumarate may reduce the incidence and severity of flushing.10 (See Flushing under Cautions and also see Specific Drugs under Interactions.)

Swallow delayed-release capsules whole and intact.1 Do not crush or chew capsules; do not sprinkle the contents of the capsules on food.1

Dosage

Adults

Multiple Sclerosis
Oral

Initially, 120 mg twice daily.1 After 7 days, increase to maintenance dosage of 240 mg twice daily.1

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

Although the prescribing information does not provide specific dosage adjustment recommendations in patients experiencing flushing and/or adverse GI effects,1 a temporary reduction in maintenance dosage has been suggested in such cases (i.e., from 240 mg twice daily to 120 mg twice daily).10 (See Administration under Dosage and Administration.)

Special Populations

Hepatic Impairment

No dosage adjustment necessary.1 (See Elimination under Pharmacokinetics.)

Renal Impairment

No dosage adjustment necessary.1 (See Elimination under Pharmacokinetics.)

Geriatric Patients

No dosage adjustment necessary.1 (See Geriatric Use under Cautions.)

Cautions for Tecfidera

Contraindications

  • None known.1

Warnings/Precautions

Lymphopenia

May cause lymphopenia.1 2

Prior to therapy, obtain a recent (i.e., within 6 months) CBC to identify patients with preexisting low lymphocyte counts.1 Obtain CBC annually during therapy and as clinically indicated.1

Not studied in patients with preexisting low lymphocyte counts.1

In patients with serious infections, consider withholding treatment until the infection has resolved.1

Flushing

May cause flushing (e.g., warmth, redness, itching, burning sensation).1 2 3 14

Administration with food may reduce incidence of flushing.1 In addition, short-term administration of aspirin prior to each dose may reduce incidence and severity of flushing.10 14 (See Administration under Dosage and Administration, Specific Drugs under Interactions, and also see Actions.)

Specific Populations

Pregnancy

Category C.1

Tecfidera pregnancy registry (for patients) at 800-456-2255.1

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

Proteinuria, pruritus, reduced lymphocyte counts, increased aminotransferase concentrations (e.g., ALT, AST).1 2 3

Interactions for Tecfidera

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

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 10 14

Glatiramer

Single dose of glatiramer did not alter MMF pharmacokinetics1 10

Interferon beta

Single dose of interferon beta-1a did not alter MMF pharmacokinetics1 10

Oral contraceptives

Clinically important pharmacokinetic interactions unlikely10

Vaccines

Effectiveness of vaccines in patients receiving dimethyl fumarate not evaluated10

Tecfidera 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

  • 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

  • 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 Importance of advising patients to contact their clinician if they experience persistent and/or severe flushing or GI reactions; taking the drug with food may be helpful in such cases.1

  • Risk of decreased lymphocyte counts.1 Importance of informing patients that a CBC should be obtained within 6 months before starting therapy to identify patients with preexisting low lymphocyte counts and that monitoring the CBC is recommended annually and as clinically indicated during therapy.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 800-456-2255.1

  • Importance of informing clinician of existing or contemplated concomitant therapy, including prescription and OTC drugs and herbal supplements, as well as any concomitant illnesses.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.

Dimethyl Fumarate

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Capsules, delayed-release

120 mg

Tecfidera

Biogen Idec

240 mg

Tecfidera

Biogen Idec

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 Idec

AHFS DI Essentials. © Copyright, 2004-2014, Selected Revisions May 21, 2014. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

† Use is not currently included in the labeling approved by the US Food and Drug Administration.

References

1. Biogen Idec Inc. Tecfidera (dimethyl fumarate) delayed-release capsules prescribing information. Cambridge, MA; 2013 Mar 20.

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. [PubMed 23971970]

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.

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.

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.

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