What is the recommended dose of tetrabenazine for chorea associated with Huntington's disease?

Tetrabenazine Dosing for Huntington's Disease Chorea

Start tetrabenazine at 12.5 mg once daily in the first week, increase to 12.5 mg twice daily (25 mg/day) in the second week, then titrate upward by 12.5 mg weekly intervals until optimal chorea control is achieved or adverse effects occur, with careful attention to maximum dosing thresholds based on CYP2D6 metabolizer status. 1

Initial Titration Protocol

• Week 1: Begin with 12.5 mg once daily 1
• Week 2: Increase to 12.5 mg twice daily (total 25 mg/day) 1
• Week 3 onward: Increase by 12.5 mg increments weekly, guided by chorea response and tolerability 1

Dose Distribution Requirements

• Doses 37.5-50 mg/day: Must be divided into three times daily dosing, with maximum single dose of 25 mg 1
• Doses above 50 mg/day: Require CYP2D6 genotyping before further titration 1

Maximum Dosing Based on CYP2D6 Status

For Poor Metabolizers (PMs):

• Maximum daily dose: 50 mg/day 1
• Maximum single dose: 25 mg 1

For Extensive Metabolizers (EMs) and Intermediate Metabolizers (IMs):

• Maximum daily dose: 100 mg/day 1
• Maximum single dose: 37.5 mg 1

Real-World Dosing Patterns

• Most patients (66.5%) are maintained on doses ≤50 mg/day in clinical practice 2
• Mean effective dose in long-term studies ranges from 62.5-63.4 mg/day 3, 4
• Doses up to 300 mg/day have been used in specialized movement disorder clinics, though this exceeds FDA-approved maximums 3

Critical Dose Modifications

When using strong CYP2D6 inhibitors (fluoxetine, paroxetine):

• Do not exceed 50 mg/day total 1
• Maximum single dose: 25 mg 1

If serious adverse reactions occur:

• Stop titration immediately 1
• Reduce dose 1
• Consider withdrawal if adverse reactions persist 1

Efficacy Endpoints for Titration

• Target a 3.5-5.0 unit reduction in UHDRS chorea scores 5
• In long-term treatment, expect mean TMC score reduction of 4.6 units 4
• 75% of patients achieve marked or very good responses at optimal individualized doses 3

Common Reasons to Stop Upward Titration

• Optimal chorea control achieved (55.5% of cases) 2
• Intolerable adverse effects at higher doses (31.2% of cases) 2
• Maximum recommended dose reached despite suboptimal control (11.4% of cases) 2

Key Monitoring Parameters During Titration

• Depression and suicidality: Monitor at every visit, as tetrabenazine carries a boxed warning for increased risk 1
• Parkinsonism and akathisia: Common dose-limiting adverse effects requiring dose reduction 1, 4
• Sedation/somnolence: Occurs in 39% of patients and may necessitate slower titration 3
• Dysphagia: Monitor swallowing function, particularly at higher doses 4

Contraindications to Initiation

• Active suicidality or untreated/inadequately treated depression 1
• Hepatic impairment 1
• Concurrent use with MAOIs, reserpine, deutetrabenazine, or valbenazine 1

Clinical Context

Tetrabenazine remains a major treatment option for HD-related chorea alongside newer VMAT2 inhibitors (deutetrabenazine and valbenazine) 6. The careful weekly titration strategy balances efficacy against the significant risk of neuropsychiatric adverse effects, particularly depression, which led to the FDA boxed warning 1. The requirement for CYP2D6 genotyping above 50 mg/day reflects the drug's metabolism pathway and helps prevent excessive drug accumulation in poor metabolizers 1.