How should amantadine be dosed for Parkinson’s disease, including initial dose, titration, maximum dose, adjustments for patients ≥65 years or with moderate renal impairment, and what adverse effects and contraindications should be monitored?

Amantadine Dosing in Parkinson's Disease

Standard Adult Dosing (Ages 13-64 Years)

For Parkinson's disease in adults under 65 years with normal renal function, initiate amantadine immediate-release at 100 mg twice daily (total 200 mg/day), or consider amantadine extended-release 274 mg once daily at bedtime for levodopa-induced dyskinesia. 1, 2

Immediate-Release Formulation

• Start at 100 mg twice daily for standard Parkinson's disease symptoms 3
• This represents the FDA-approved dosing for adults in this age range 3

Extended-Release Formulation (GOCOVRI™)

• For levodopa-induced dyskinesia specifically, amantadine ER 274 mg once daily at bedtime is the only FDA-approved formulation and provides superior dyskinesia control compared to immediate-release 4, 5
• This formulation delivers higher amantadine concentrations during waking hours when dyskinesia is most problematic, with 1.4- to 2.0-fold higher plasma levels during the day versus immediate-release 6
• Demonstrated 27% reduction in dyskinesia scores and significantly increased ON time without troublesome dyskinesia 7

Critical Dose Reductions for Patients ≥65 Years

Reduce the maximum daily dose to 100 mg total (not 100 mg twice daily) in all patients 65 years and older, regardless of indication, due to age-related decline in renal function. 3, 1, 2, 8

• This means either 100 mg once daily or 50 mg twice daily 1
• Elderly women face higher risk of side effects than elderly men at equivalent doses due to smaller average body size 2, 8
• Failure to reduce dosing in elderly patients leads to drug accumulation and CNS toxicity, as amantadine is 90% excreted unchanged in urine 2, 9

Renal Impairment Adjustments

For creatinine clearance <50 mL/min/1.73m², mandatory dose reduction is required with extended dosing intervals based on specific creatinine clearance values. 3, 1, 2, 8

Specific Adjustments

• Creatinine clearance <50 mL/min/1.73m²: Consult package insert for specific interval recommendations based on exact clearance value 3, 1, 2
• Creatinine clearance ≤10 mL/min: Reduce to 100 mg once daily or less frequently 2
• Hemodialysis does not significantly clear amantadine, so dosing intervals cannot be shortened based on dialysis schedules 2, 9
• Patients with any degree of renal insufficiency require intensive monitoring for adverse reactions 3, 1, 2

Monitoring Requirements

• Observe carefully for adverse reactions, as recommended dosages provide only approximations of optimal dosing 3, 1
• Further dose reduction or discontinuation may be necessary if side effects develop 3, 1

Adverse Effects to Monitor

Common CNS Effects (5-14% at 200 mg/day)

• Nervousness, anxiety, insomnia, difficulty concentrating, and lightheadedness 3, 2, 8
• If sleep disturbances occur, avoid taking the second dose too close to bedtime 1, 8
• These effects are usually mild and resolve shortly after discontinuation 3

Severe CNS Effects (Associated with High Plasma Concentrations)

• Marked behavioral changes, delirium, hallucinations, agitation, and seizures 2
• These severe effects occur particularly in patients with renal insufficiency taking 200 mg/day 2
• Patients with seizure disorders require close observation for increased seizure activity 8

Extended-Release Specific Adverse Events

• Most common (>15% incidence): hallucinations, dizziness, dry mouth, and peripheral edema 4
• Constipation also frequently reported 7
• Most adverse events are transient and mild to moderate in severity 4

Contraindications and Precautions

High-Risk Populations Requiring Closer Monitoring

• Patients with seizure disorders or psychiatric conditions are at highest risk for severe withdrawal complications 1
• Elderly patients, particularly those ≥65 years, require close monitoring due to risk of drug accumulation 2
• Patients with creatinine clearance ≤50 mL/min require intensive monitoring 2

Drug Accumulation Risk

• Amantadine accumulates significantly with creatinine clearance ≤50 mL/min/1.73m², and plasma concentrations increase logarithmically with dose 8, 9
• The apparent volume of distribution is inversely related to dose, contributing to nonlinear pharmacokinetics 9

Common Prescribing Pitfalls to Avoid

1. Failing to reduce dose in elderly patients (≥65 years) to maximum 100 mg/day total leads to adverse effects 8
2. Not adjusting for renal impairment when CrCl <50 mL/min/1.73m² results in amantadine accumulation and severe toxicity 2, 8
3. Not consulting the package insert for specific renal dosing adjustments results in severe adverse effects from accumulation 2
4. Prescribing 100 mg twice daily (200 mg total) to elderly patients instead of 100 mg total daily is a critical error 3