What is the recommended dosage of amantadine (Amantadine) for treating valproate-induced tremor?

Amantadine Dosing for Valproate-Induced Tremor

For valproate-induced tremor, amantadine 100 mg twice daily (200 mg/day total) is the recommended starting dose in adults under 65 years with normal renal function, though propranolol remains the superior first-line agent. 1

Evidence for Amantadine in Valproate-Induced Tremor

The only direct evidence for amantadine in valproate-induced tremor comes from a 1983 study that found amantadine "moderately effective" compared to propranolol (which was "clearly the most therapeutic") in treating tremor induced by chronic valproate therapy. 1 This study established the clinical rationale for using amantadine in this specific indication, though it remains a second-line option when propranolol is contraindicated or not tolerated. 1

Important caveat: A 2006 randomized controlled trial demonstrated that amantadine 100 mg twice daily was not effective for essential tremor, and 37.5% of patients actually experienced worsening postural tremor as an adverse effect. 2 This suggests amantadine's mechanism may be specific to drug-induced tremor rather than primary tremor disorders. 2

Standard Adult Dosing (Age <65 years, Normal Renal Function)

• Standard dose: 100 mg twice daily (200 mg/day total) 3
• This represents the FDA-approved adult dosage for amantadine indications 3
• The 1983 study used this dosing regimen when demonstrating moderate efficacy for valproate-induced tremor 1

Dose Adjustments for Elderly Patients (≥65 Years)

The maximum daily dose must be reduced to 100 mg/day (50 mg twice daily) in patients 65 years or older due to age-related decline in renal function. 3, 4

• This dose reduction is mandatory regardless of measured creatinine clearance, as renal function declines with age 3
• The lower dose minimizes central nervous system side effects while maintaining efficacy 4
• Some elderly patients may require further dose reduction based on tolerability 3

Renal Impairment Adjustments

Dose reduction is required for creatinine clearance <50 mL/min/1.73m². 3, 4

• Consult the package insert for specific dosing based on creatinine clearance 3, 4
• Patients should be monitored carefully for adverse reactions, as recommended doses provide only approximations 3
• Further dose reduction or discontinuation may be necessary if side effects develop 3, 4
• Hemodialysis contributes minimally to amantadine clearance 3

Critical Monitoring and Safety Considerations

Monitor closely for CNS side effects including nervousness, anxiety, insomnia, difficulty concentrating, and lightheadedness. 4

• Myoclonus and asterixis: A case report documented diffuse myoclonus and asterixis developing after 9 days on amantadine 100 mg twice daily in an 80-year-old patient, which resolved 3 days after discontinuation. 5 This emphasizes the importance of distinguishing between tremor improvement and new movement disorders.

• Worsening tremor: Given that 37.5% of patients experienced increased postural tremor with amantadine in the essential tremor trial, carefully assess whether tremor is actually improving or worsening. 2

• Sleep disturbances: If insomnia occurs, avoid taking the second dose too close to bedtime 4

Discontinuation Strategy

Amantadine must be tapered gradually rather than stopped abruptly to prevent withdrawal complications. 6

Standard Taper Schedule:

• Week 1: Reduce to 100 mg once daily (50% dose reduction) 6
• Week 2: Reduce to 50 mg once daily or 100 mg every other day 6
• Week 3: Discontinue completely, then observe for 3-5 days for delayed withdrawal reactions 6

Withdrawal Monitoring:

• Watch for fever, rigidity, altered mental status, confusion, autonomic instability (blood pressure changes, tachycardia) 6
• Elderly patients (≥65 years) require slower tapering over 3 weeks minimum 6
• Patients with renal impairment need even slower tapers (3-4 weeks) to allow adequate drug clearance 6

Clinical Decision Algorithm

1. First, attempt propranolol as it demonstrated superior efficacy in the only comparative study 1

2. If propranolol is contraindicated or not tolerated:

   • Age <65 years + CrCl ≥50: Start amantadine 100 mg twice daily 3, 1
   • Age ≥65 years: Start amantadine 50 mg twice daily (100 mg/day maximum) 3, 4
   • CrCl <50: Consult package insert for specific renal dosing 3, 4

3. Monitor at 1-2 weeks for efficacy and adverse effects, particularly myoclonus, worsening tremor, or CNS symptoms 4, 2, 5

4. If ineffective or poorly tolerated, taper gradually over 2-3 weeks and consider alternative agents 6