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Introduction

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

Uses for Dimethyl Fumarate (Systemic)

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 (Systemic) 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.

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.

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.

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