What is the recommended dosage and administration of dimethyl fumarate for multiple sclerosis treatment?

Dimethyl Fumarate Dosing and Administration for Multiple Sclerosis

Dimethyl fumarate should be initiated at 120 mg orally twice daily for 7 days, then increased to the maintenance dose of 240 mg orally twice daily, with capsules swallowed whole and intact (not crushed, chewed, or sprinkled), and may be taken with or without food. 1

Dosing Regimen

Initial Titration

• Starting dose: 120 mg orally twice daily for exactly 7 days 1
• Maintenance dose: 240 mg orally twice daily after the initial 7-day period 1

Administration Instructions

• Swallow delayed-release capsules whole and intact 1
• Do NOT crush, chew, or sprinkle capsule contents on food 1
• May be taken with or without food 1
• The twice-daily dosing regimen (240 mg BID) has equivalent efficacy to three-times-daily dosing with a similar safety profile, supporting the lower frequency option 2, 3

Clinical Efficacy Evidence

Dimethyl fumarate 240 mg twice daily reduces relapse rates by 44-53% and new MRI lesions by 71-90% compared to placebo in relapsing-remitting MS. 4

Relapse Reduction

• Reduces the proportion of patients experiencing relapses with a risk ratio of 0.64 (95% CI: 0.54-0.77) over 2 years compared to placebo 2
• Decreases annualized relapse rate significantly in phase III trials (DEFINE and CONFIRM) 3, 4

Disability Progression

• Reduces disability worsening with a risk ratio of 0.65 (95% CI: 0.53-0.81) in one pivotal trial, though evidence quality is considered low 2
• Slowed disability accumulation in DEFINE but not in CONFIRM trial 4

MRI Activity

• Significant reduction in gadolinium-enhancing lesions (MD: -1.53,95% CI: -1.91 to -1.41) 5
• Reduces T2 hyperintense lesion incidence significantly, including in pediatric patients aged 10-17 years 6

Baseline and Ongoing Monitoring Requirements

Pre-Treatment Assessment

• Complete blood count (CBC) including lymphocyte count 1
• Serum aminotransferase, alkaline phosphatase, and total bilirubin levels 1

During Treatment Monitoring

• CBC with lymphocyte count: After 6 months of treatment, then every 6-12 months thereafter 1
• Liver function tests: During treatment as clinically indicated 1
• Annual CBC is the minimum recommended frequency 4

MRI Surveillance

• For standard monitoring: At least once yearly 7
• For patients at risk of serious adverse events: Every 3-4 months 7
• MRI protocol should include T2 FLAIR, T2-weighted sequences, and gadolinium-enhanced T1-weighted sequences 7

Safety Profile and Adverse Events

Common Adverse Events (≥10% incidence)

The most frequent adverse events include 1, 2:

• Flushing (most common, peaks at treatment initiation) 4
• Gastrointestinal events: Abdominal pain, nausea, diarrhea, vomiting 1, 2, 4
• These are typically mild-to-moderate and manageable 2, 3

Serious but Uncommon Adverse Events

Lymphopenia and leukopenia occur significantly more with dimethyl fumarate than placebo (RR: 5.25-6.53), requiring vigilant monitoring. 2

• Lymphopenia: Risk ratio 5.25-5.69 compared to placebo 2
• Leukopenia: Risk ratio 5.23-6.53 compared to placebo 2
• Management: Consider interrupting treatment if lymphocyte counts <0.5 × 10⁹/L persist for more than 6 months 1

Critical Safety Warnings

Progressive Multifocal Leukoencephalopathy (PML)

• Withhold dimethyl fumarate immediately at the first sign or symptom suggestive of PML 1
• Enhanced surveillance with brain MRI every 3-4 months may be warranted in high-risk scenarios 8, 7

Anaphylaxis and Angioedema

• Discontinue permanently if these occur; do not restart 1

Hepatotoxicity

• Discontinue dimethyl fumarate if clinically significant liver injury induced by the drug is suspected 1

Herpes Zoster and Opportunistic Infections

• Consider withholding treatment in cases of serious infection until resolved 1
• No increased risk of opportunistic infections was observed in phase III trials 4

Special Populations

Pediatric Use (Ages 10-17)

• Same dosing regimen as adults: 120 mg BID for 7 days, then 240 mg BID 6
• Pharmacokinetic and safety profiles consistent with adult findings 6
• Demonstrated significant reduction in MRI activity in pediatric relapsing-remitting MS 6

Contraindications

• Known hypersensitivity to dimethyl fumarate or any excipients 1

Long-Term Treatment Considerations

• Minimum 5 years of treatment in extension studies (ENDORSE) showed continued benefit with no new or worsening safety signals 3
• Most patients require at least 3 months of treatment before assessing for breakthrough disease activity 7
• Early relapses may represent disease course before therapeutic effect takes hold 7

Clinical Positioning

Dimethyl fumarate is an effective first-line oral therapy for relapsing forms of MS with potent efficacy, convenient twice-daily dosing, and an acceptable long-term safety profile. 3, 4

• Appropriate for first-line treatment, breakthrough disease activity, and intolerance to other therapies 4
• May be considered for natalizumab-treated patients with positive JC virus serology seeking to reduce PML risk 4