Dimethyl Fumarate

Dimethyl fumarate is an oral disease-modifying therapy for relapsing-remitting multiple sclerosis, with moderate efficacy and a mainly gastrointestinal and flushing tolerability profile. Its serious risks are lymphopenia, progressive multifocal leukoencephalopathy and liver injury.

Mechanism. Converted to monomethyl fumarate, which activates the Nrf2 antioxidant response and has immunomodulatory effects on lymphocytes.

Pharmacokinetics. Dimethyl fumarate is rapidly hydrolysed by esterases to monomethyl fumarate, with half-life about 1 hour. About 60% is exhaled as carbon dioxide, and the rest is excreted in urine and faeces. Food reduces peak levels and flushing.

First-line use. Relapsing-remitting multiple sclerosis in adults, and in some regions adolescents.

• Oral dimethyl fumarate: 120 mg twice daily for 7 days, then 240 mg twice daily. Maximum 480 mg daily.

• If flushing or gastrointestinal effects are troublesome, reduce temporarily to 120 mg twice daily for up to 4 weeks, then return to 240 mg twice daily.

• Treatment is long term while benefit continues.

Kidney, liver, weight and age.

• Kidney: no adjustment in mild to moderate impairment; use caution in severe impairment.

• Liver: no adjustment in mild to moderate impairment; use caution in severe impairment.

• Older adults: limited data over age 65.

Contraindications. Hypersensitivity, and suspected or confirmed progressive multifocal leukoencephalopathy.

Serious adverse effects. Prolonged lymphopenia, progressive multifocal leukoencephalopathy, serious infections including herpes zoster, liver enzyme elevation and liver injury, anaphylaxis and angioedema.

Common adverse effects. Flushing, abdominal pain, diarrhoea, nausea, vomiting, pruritus and rash.

Interactions. Avoid other fumarates. Use caution with immunosuppressants, nephrotoxic drugs and live vaccines. Taking a non-enteric aspirin dose 30 minutes before can reduce flushing.

Common prescribing errors. Starting without a baseline blood count and liver tests. Missing persistent lymphopenia. Giving live vaccines during treatment.

Special groups.

• Pregnancy: avoid unless clearly needed; stop if pregnancy occurs and the benefit does not outweigh the risk.

• Breastfeeding: avoid.

• Regional: before starting, check hepatitis B, hepatitis C, HIV, tuberculosis and varicella immunity, and complete needed vaccines before treatment.

Formulations. Delayed-release capsules 120 and 240 mg. Swallow whole with food, without crushing or chewing.

Monitoring.

• Baseline full blood count with lymphocyte count, liver function, creatinine and urinalysis, and a baseline brain scan.

• Full blood count about every 6 months, liver function periodically, and a brain scan if new neurological symptoms appear. Consider stopping if lymphocytes stay under 0.5 x 10^9/L for more than 6 months.

Stopping. No taper is needed.

Referral and escalation. Refer to a multiple sclerosis specialist for initiation, and urgently for new neurological deficits or serious infection.