Dimethyl Fumarate (Monograph)

Brand name: Tecfidera
Drug class: Immunomodulatory Agents

Medically reviewed by Drugs.com on Sep 25, 2023. Written by ASHP.

[Web]

Introduction

Fumaric acid derivative with immunomodulatory and disease-modifying activity in multiple sclerosis (MS).

Uses for Dimethyl Fumarate

Multiple Sclerosis

Treatment of relapsing forms of MS, including clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease.

Dimethyl fumarate is one of several disease-modifying therapies used in the management of relapsing forms of MS. 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.

The American Academy of Neurology (AAN) recommends that disease-modifying therapy be offered to patients with relapsing forms of MS who have had recent relapses and/or MRI lesion activity. 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.

Direct comparative studies between dimethyl fumarate and other oral drugs used in relapsing forms of MS (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.

Efficacy not established in patients with primary-progressive MS^{† [off-label]}.

Dimethyl Fumarate Dosage and Administration

General

Patient Monitoring

• Because of risk of lymphopenia, obtain CBC (including lymphocyte count) prior to initiating therapy, at 6 months, and then every 6–12 months thereafter as clinically indicated.

• Because of possible hepatic injury, perform liver function tests (i.e., serum aminotransferase, alkaline phosphatase, and total bilirubin concentrations) prior to initiating therapy and then as clinically indicated.

Premedication and Prophylaxis

• Administration of non-enteric coated aspirin (up to a dose of 325 mg) 30 minutes prior to dimethyl fumarate may reduce the incidence or severity of drug-induced flushing.

Administration

Oral Administration

Administer orally twice daily with or without food. Administration with food may reduce incidence of flushing and improve GI tolerability.

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

Dosage

Adults

Relapsing Forms of Multiple Sclerosis

Oral

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

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. Resume recommended maintenance dosage of 240 mg twice daily within 4 weeks. Consider drug discontinuance in patients unable to tolerate a return to the usual maintenance dosage.

Special Populations

Hepatic Impairment

No dosage adjustment necessary.

Renal Impairment

No dosage adjustment necessary.

Geriatric Patients

No dosage adjustment necessary.

Cautions for Dimethyl Fumarate

Contraindications

• Known hypersensitivity to dimethyl fumarate or any excipients in the formulation.

• Concomitant use of diroximel fumarate.

Warnings/Precautions

Anaphylaxis and Angioedema

May cause anaphylaxis or angioedema after the first dose or at any time during therapy. Signs and symptoms of hypersensitivity reactions have included difficulty breathing, urticaria, and swelling of the throat and tongue.

Progressive Multifocal Leukoencephalopathy (PML)

PML, an opportunistic infection of the brain caused by the JC virus, reported. A fatal case of PML occurred in a patient with MS treated with dimethyl fumarate for 4 years in a clinical trial. The patient had prolonged lymphopenia (i.e., lymphocyte counts predominantly <500/mm³ for 3.5 years) but no other known conditions associated with compromised immune function.

PML also reported during postmarketing experience in the presence of lymphopenia persisting for >6 months. In addition, several cases of PML have been reported in Europe in patients receiving other preparations containing dimethyl fumarate.

At the first sign or symptom suggestive of PML, immediately withhold dimethyl fumarate therapy and perform an appropriate diagnostic evaluation. MRI signs of PML may be apparent before clinical manifestations develop.

Infectious Complications

Serious cases of herpes zoster and other opportunistic infections (viral, fungal, and bacterial) reported in patients with lymphopenia as well as in patients with normal absolute lymphocyte counts. May occur at any time during therapy.

Monitor for signs and symptoms of herpes zoster or other opportunistic infections. If manifestations of such infections occur, promptly evaluate and treat patient appropriately. Consider interruption of dimethyl fumarate therapy until the infection resolves.

Lymphopenia

May decrease lymphocyte counts. In placebo-controlled clinical trials, mean lymphocyte counts decreased by approximately 30% during the first year of therapy and remained stable thereafter. Lymphocyte counts improved 4 weeks following discontinuance of the drug, but did not return to baseline values.

Although increased incidence of serious infections was not observed in patients with decreased lymphocyte counts in controlled trials, one case of PML developed in the setting of prolonged lymphopenia.

Not studied in patients with preexisting low lymphocyte counts.

Obtain a CBC, including lymphocyte count, prior to initiation of dimethyl fumarate, at 6 months, and then every 6–12 months during therapy thereafter, and as clinically indicated.

In patients with lymphocyte counts <500/mm³ persisting for >6 months, consider interruption of therapy. Consider monitoring lymphocyte counts until lymphopenia has resolved since lymphocyte recovery may be delayed following drug discontinuance.

In patients with serious infections, consider interruption of dimethyl fumarate therapy until the infection resolves. Consider patient's clinical circumstances when deciding whether to restart dimethyl fumarate therapy.

Hepatic Injury

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. Occurred within a few days to several months after initiation of therapy and resolved upon treatment discontinuance. Although liver failure or death did not occur, marked elevations in liver function tests may be indicative of serious hepatic injury.

Perform liver function tests (i.e., serum aminotransferase, alkaline phosphatase, and total bilirubin concentrations) prior to and during therapy as clinically indicated. Discontinue drug if liver injury suspected.

Flushing

May cause flushing (e.g., warmth, redness, itching, burning sensation). In clinical trials, 40% of dimethyl fumarate-treated patients experienced flushing. Symptoms generally are mild to moderate, begin soon after initiating therapy, and improve or resolve over time.

Administration with food or pretreatment with non-enteric-coated aspirin may reduce incidence and/or severity of flushing.

Specific Populations

Pregnancy

No adequate data on developmental risks associated with use during pregnancy. Embryotoxic effects observed in animal studies.

A pregnancy registry has been established for Tecfidera. Encourage patients to enroll by calling 866-810-1462 or visiting [Web].

Lactation

Not known whether dimethyl fumarate or its metabolites distribute into human milk.

Effects of the drug on the nursing infant or on milk production not known.

Consider benefits of breast-feeding along with the woman's clinical need for dimethyl fumarate and any potential adverse effects on the breast-fed infant from the drug or underlying maternal condition.

Pediatric Use

Safety and efficacy not established in pediatric patients <18 years of age.

Geriatric Use

Insufficient experience in patients ≥65 years of age to determine whether they respond differently than younger adults.

Hepatic Impairment

Pharmacokinetics not studied in patients with hepatic impairment.

Renal Impairment

Pharmacokinetics not studied in patients with renal impairment.

Common Adverse Effects

Flushing, abdominal pain, diarrhea, nausea.

Drug Interactions

Not metabolized by CYP isoenzymes; therefore, clinically important interactions with CYP inhibitors or inducers not expected. No potential interactions with dimethyl fumarate or its active MMF metabolite identified in CYP, P-glycoprotein (P-gp), or protein-binding studies.

Specific Drugs

Dimethyl Fumarate Pharmacokinetics

Following oral administration, undergoes rapid and extensive metabolism by esterases to its active metabolite, monomethyl fumarate (MMF).

Absorption

Bioavailability

Median time to peak plasma MMF concentrations is 2–2.5 hours.

Accumulation of MMF does not occur with multiple oral doses.

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.

Distribution

Extent

Not known whether dimethyl fumarate or its metabolites distribute into human milk.

MMF distributes into the CNS.

Plasma Protein Binding

MMF is 27–45% protein bound; protein binding is independent of concentration.

Elimination

Metabolism

Extensively metabolized by esterases (present in GI tract, blood, and tissues) to MMF before reaching systemic circulation. MMF is further metabolized by the tricarboxylic acid (TCA) cycle; the CYP system is not involved in its metabolism. The major metabolites in plasma are MMF, fumaric acid, citric acid, and glucose.

Elimination Route

Eliminated mainly (60%) by exhalation of carbon dioxide and to a minor extent by excretion in urine (16%) and feces (1%).

Half-life

MMF: Approximately 1 hour.

Special Populations

Hepatic impairment: Pharmacokinetics not evaluated. However, hepatic impairment unlikely to affect exposure to MMF.

Renal impairment: Pharmacokinetics not evaluated. However, renal impairment unlikely to affect exposure to MMF.

Stability

Storage

Oral

Delayed-release Capsules

15–30°C; store in original container and protect from light.

Actions

• Exact mechanism of action in MS is unknown; however, immunomodulatory effect appears to be mediated by many cells of the immune system.

• 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. The Nrf2 antioxidant response pathway is involved in the cellular response to oxidative stress.

• Nrf2-dependent upregulation of antioxidant response genes by dimethyl fumarate and MMF may protect various cells and tissues, including some in the CNS, from experimental toxic oxidative stress.

• Activation of the Nrf2 pathway by dimethyl fumarate and MMF also may inhibit proliferation of lymphocytes and hematopoietic stem cells. Dose-dependent reduction in peripheral lymphocytes occurs, with a more pronounced reduction in CD8⁺ T-cell counts than in CD4⁺ T-cell counts; subsets of other lymphocytes (e.g., memory T-cells, B-cells, natural killer [NK] cells) also altered. Alterations in composition of peripheral lymphocytes thought to shift the immune profile towards an anti-inflammatory state in patients with MS.

• MMF is a nicotinic acid receptor agonist in vitro. 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.

Advice to Patients

• Importance of reading the manufacturer's patient information.

• Risk of anaphylaxis and angioedema. 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).

• 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. 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 cognition, memory, and orientation leading to confusion and personality changes) that have progressed over days to weeks. Importance of advising patients not to stop taking dimethyl fumarate without first consulting with their clinician.

• 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. Both strengths should be taken twice daily.

• 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. Importance of informing patients that the capsules may be taken with or without food.

• Importance of informing patients that flushing and adverse GI reactions (e.g., abdominal pain, diarrhea, nausea) are common, particularly at the initiation of treatment, and that they may decrease over time. Importance of advising patients to contact their clinician if they experience persistent and/or severe flushing or GI reactions. 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.

• Risk of decreased lymphocyte counts. Importance of periodic monitoring of CBCs.

• Risk of herpes zoster and other serious opportunistic infections. Importance of advising patients to contact clinician if they develop any signs or symptoms associated with herpes zoster or other infections.

• Risk of liver injury. 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.

• Importance of women informing their clinician if they are or plan to become pregnant or plan to breast-feed. Importance of encouraging enrollment of pregnant women in the Tecfidera pregnancy registry at 866-810-1462 or on the website [Web].

• 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).

• Importance of informing patients of other important precautionary information.

Additional Information

The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer’s labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.

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 is available through a specialty pharmacy network. Clinicians may consult the Tecfidera website at [Web] or call 800-456-2255 for specific availability information.

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

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Frequently asked questions

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