Introduction

Fumaric acid derivative with immunomodulatory and disease-modifying activity in multiple sclerosis (MS). Metabolized to the same active metabolite (monomethyl fumarate [MMF]) as dimethyl fumarate.

Uses for Diroximel Fumarate (Systemic)

Multiple Sclerosis

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

Diroximel fumarate is metabolized to the same pharmacologically active metabolite (monomethyl fumarate [MMF]) as dimethyl fumarate; therefore, efficacy is based on established bioequivalence to dimethyl fumarate. Efficacy and safety of diroximel fumarate expected to be similar to dimethyl fumarate, which has been shown to substantially reduce relapse rates and new or enlarging T2 lesions.

Compared with dimethyl fumarate, diroximel fumarate produces equivalent exposure to the active metabolite (MMF) but is associated with improved GI tolerability.

Diroximel 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.

Diroximel 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 diroximel fumarate may reduce the incidence or severity of flushing.

Administration

Oral Administration

Administer orally twice daily with or without food.

Administration with food may reduce incidence of flushing; however, avoid administration with a high-fat, high-calorie meal or snack. If taken with food, the meal or snack should contain no more than 700 calories and no more than 30 g fat.

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

Dosage

Adults

Relapsing Forms of Multiple Sclerosis

Oral

Initially, 231 mg twice daily. After 7 days, increase to maintenance dosage of 462 mg twice daily.

In patients not tolerating dosage of 462 mg twice daily, consider temporary reduction to 231 mg twice daily, and then resume recommended maintenance dosage of 462 mg twice daily within 4 weeks. If patient does not tolerate an increase back to recommended maintenance dosage, consider discontinuance of therapy.

Special Populations

Hepatic Impairment

No dosage adjustment necessary. Although no studies have been conducted, hepatic impairment not expected to affect exposure to active metabolite.

Renal Impairment

No dosage adjustment necessary in patients with mild renal impairment. Not recommended in patients with moderate or severe renal impairment because of possibility of increased exposure to a major metabolite.

Geriatric Patients

Manufacturer makes no specific dosage recommendations.

Contraindications

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

• Concomitant use of dimethyl fumarate.

Warnings/Precautions

Anaphylaxis and Angioedema

May cause anaphylaxis or angioedema after the first dose or at any time during therapy. Hypersensitivity reactions, including difficulty breathing, urticaria, and swelling of the throat and tongue reported with dimethyl fumarate (a drug with the same active metabolite as diroximel fumarate).

Discontinue diroximel fumarate if any signs or symptoms of anaphylaxis or angioedema occur.

Progressive Multifocal Leukoencephalopathy (PML)

PML, an opportunistic infection of the brain caused by the JC virus, reported in patients receiving dimethyl fumarate (a drug with the same active metabolite as diroximel fumarate). PML has been reported with dimethyl fumarate in the setting of prolonged lymphopenia, including a fatal case of PML in a patient with MS who had lymphocyte counts <500/mm³ for 3.5 years.

At the first sign or symptom suggestive of PML, immediately withhold therapy and perform 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 with dimethyl fumarate (a drug with the same active metabolite as diroximel fumarate); has occurred in patients with lymphopenia as well as in patients with normal lymphocyte counts. May occur at any time during therapy.

Monitor for signs and symptoms of herpes zoster or other opportunistic infections. If any manifestations of such infections occur, promptly evaluate and treat patient appropriately. Consider interruption of therapy in patients with serious infections until infection resolves.

Lymphopenia

May decrease lymphocyte counts. In clinical trials with dimethyl fumarate (a drug with the same active metabolite as diroximel fumarate), mean lymphocyte counts decreased by approximately 30% during the first year of therapy. Lymphocyte counts improved 4 weeks following discontinuance of the drug, but did not return to baseline values.

Increased incidence of serious infections not observed in patients with decreased lymphocyte counts, but one case of PML developed in the setting of prolonged lymphopenia.

Not studied in patients with preexisting low lymphocyte counts.

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

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

In patients with serious infections, consider withholding treatment until infection resolves. Consider patient's clinical circumstances when deciding whether to restart therapy.

Hepatic Injury

Liver injury, sometimes requiring hospitalization, reported with dimethyl fumarate (a drug with the same active metabolite as diroximel fumarate). 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) observed. Occurred within a few days to several months after initiation of therapy and resolved upon treatment discontinuance.

No cases resulted in liver failure, liver transplantation, or death; however, abnormal liver function tests may predict serious liver 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 of dimethyl fumarate (a drug with the same active metabolite as diroximel fumarate), flushing was reported in 40% of patients who received the drug. 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 (up to a dose of 325 mg) 30 minutes before diroximel fumarate may reduce incidence and/or severity of flushing.

Specific Populations

Pregnancy

No adequate data on developmental risk associated with use during pregnancy. Based on animal data, may cause fetal harm.

Lactation

Not known whether diroximel fumarate or its metabolites are distributed into human milk.

Effects on nursing infant or on milk production also not known.

Consider benefits of breast-feeding along with the woman's clinical need for diroximel 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.

Geriatric Use

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

Hepatic Impairment

Not studied in individuals with hepatic impairment; hepatic impairment not expected to affect systemic exposure to the active MMF metabolite.

Dosage adjustment not necessary in patients with hepatic impairment.

Renal Impairment

Dosage adjustment not necessary in patients with mild renal impairment.

Not recommended in patients with moderate or severe renal impairment because of increased systemic exposure to the inactive major metabolite HES; data on long-term use not available.

Common Adverse Effects

Adverse reactions reported with diroximel fumarate (≥10% and ≥2% more than placebo): Flushing, abdominal pain, diarrhea, and nausea.

Adverse reactions reported with diroximel fumarate are similar to those with dimethyl fumarate.

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 diroximel fumarate may reduce the incidence or severity of flushing.

Administration

Oral Administration

Administer orally twice daily with or without food.

Administration with food may reduce incidence of flushing; however, avoid administration with a high-fat, high-calorie meal or snack. If taken with food, the meal or snack should contain no more than 700 calories and no more than 30 g fat.

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

Dosage

Adults

Relapsing Forms of Multiple Sclerosis

Oral

Initially, 231 mg twice daily. After 7 days, increase to maintenance dosage of 462 mg twice daily.

In patients not tolerating dosage of 462 mg twice daily, consider temporary reduction to 231 mg twice daily, and then resume recommended maintenance dosage of 462 mg twice daily within 4 weeks. If patient does not tolerate an increase back to recommended maintenance dosage, consider discontinuance of therapy.

Special Populations

Hepatic Impairment

No dosage adjustment necessary. Although no studies have been conducted, hepatic impairment not expected to affect exposure to active metabolite.

Renal Impairment

No dosage adjustment necessary in patients with mild renal impairment. Not recommended in patients with moderate or severe renal impairment because of possibility of increased exposure to a major metabolite.

Geriatric Patients

Manufacturer makes no specific dosage recommendations.

No potential drug interactions with diroximel fumarate or its main active metabolite, MMF, identified in CYP, P-glycoprotein, or protein-binding studies.

Specific Drugs