Introduction
Gocovri (amantadine) extended-release capsules are a novel therapeutic agent approved by the U.S. Food and Drug Administration (FDA) for the treatment of dyskinesia in patients with Parkinson's disease receiving levodopa-based therapy, with or without concomitant dopaminergic medications. It is also indicated for the treatment of OFF episodes in Parkinson's disease patients. Gocovri represents the first and only FDA-approved medication specifically indicated for dyskinesia in Parkinson's disease.
Mechanism of Action
Gocovri contains amantadine, which exerts its therapeutic effects through multiple mechanisms. Its primary action is non-competitive antagonism of N-methyl-D-aspartate (NMDA) glutamate receptors. This glutamate modulation is believed to reduce excessive glutamatergic stimulation that contributes to dyskinesia in Parkinson's disease. Additionally, amantadine has weak anticholinergic properties and may enhance dopamine release, inhibit dopamine reuptake, and stimulate dopamine receptors. The extended-release formulation provides sustained plasma concentrations that maintain therapeutic effects throughout the day with once-daily dosing.
Indications
- Treatment of dyskinesia in patients with Parkinson's disease receiving levodopa-based therapy, with or without concomitant dopaminergic medications
- Treatment of OFF episodes in patients with Parkinson's disease
Dosage and Administration
Initial Dose: 137 mg once daily at bedtime Maintenance Dose: May be increased to 274 mg once daily at bedtime after one week Administration: Should be taken at bedtime consistently. Capsules must be swallowed whole and not crushed, chewed, or divided. Special Populations:- Renal impairment: Dose adjustment required based on creatinine clearance
- CrCl 30-59 mL/min: Maximum 137 mg daily - CrCl 15-29 mL/min: Maximum 137 mg every other day - CrCl <15 mL/min: Not recommended
- Hepatic impairment: No specific dosage adjustment recommended
- Geriatric patients: Consider renal function when dosing
- Pediatric patients: Safety and effectiveness not established
Pharmacokinetics
Absorption: Peak plasma concentrations achieved approximately 8-12 hours after dosing Distribution: Volume of distribution is approximately 3-8 L/kg; protein binding is approximately 67% Metabolism: Primarily renal elimination with minimal hepatic metabolism (<10%) Elimination: Half-life is approximately 10-14 hours; primarily excreted unchanged in urine Special Considerations: The extended-release formulation provides sustained plasma concentrations with once-daily dosingContraindications
- Hypersensitivity to amantadine or any component of the formulation
- End-stage renal disease (CrCl <15 mL/min)
Warnings and Precautions
Suicidal Ideation and Behavior: Monitor for emergence or worsening of depression, suicidal thoughts or behavior Hallucinations/Psychotic Behavior: May occur, particularly in elderly patients Impulse Control/Compulsive Behaviors: Patients may experience intense urges to gamble, increased sexual urges, or other compulsive behaviors Falling Asleep During Activities of Daily Living: Somnolence may occur, including falling asleep during activities Orthostatic Hypotension: Monitor blood pressure, particularly when initiating therapy Congestive Heart Failure: Use with caution in patients with history of CHF or peripheral edema Neuroleptic Malignant Syndrome: Risk with abrupt reduction or discontinuation Renal Impairment: Requires dose adjustment based on creatinine clearance Pregnancy and Lactation: Use during pregnancy only if potential benefit justifies potential risk; amantadine is excreted in breast milkDrug Interactions
Alcohol: May increase CNS effects Anticholinergic agents: May potentiate anticholinergic effects CNS stimulants: May increase stimulant effects Drugs affecting renal secretion: Cimetidine, hydrochlorothiazide, triamterene may increase amantadine concentrations Dopamine agonists: May enhance dopaminergic effects Live attenuated influenza vaccine: Theoretical decreased effectivenessAdverse Effects
Most Common Adverse Reactions (≥5%):- Hallucinations (15%)
- Dizziness (13%)
- Dry mouth (11%)
- Peripheral edema (10%)
- Constipation (9%)
- Falls (7%)
- Nausea (6%)
- Orthostatic hypotension (5%)
- Suicidal ideation and behavior
- Neuropsychiatric symptoms
- Neuroleptic malignant syndrome
- Congestive heart failure
- Severe orthostatic hypotension
Monitoring Parameters
- Mental status and mood changes (particularly depression and suicidal ideation)
- Blood pressure (sitting and standing)
- Renal function (baseline and periodically)
- Signs of impulse control disorders
- Signs and symptoms of heart failure
- Dyskinesia improvement assessment
- OFF episode frequency and duration
- Fall risk assessment
Patient Education
- Take medication at bedtime consistently
- Swallow capsules whole; do not crush, chew, or divide
- Report any mood changes, depression, or suicidal thoughts immediately
- Be aware of potential for dizziness and orthostatic hypotension
- Avoid alcohol consumption during treatment
- Use caution when driving or operating machinery
- Report any unusual urges or compulsive behaviors
- Monitor for swelling in extremities and report to healthcare provider
- Do not discontinue abruptly without medical supervision
- Keep medication out of reach of children
References
1. FDA Prescribing Information: Gocovri (amantadine) extended-release capsules. 2021 2. Oertel W, Eggert K, Pahwa R, et al. Randomized, placebo-controlled trial of amantadine extended release for levodopa-induced dyskinesia in Parkinson's disease. Mov Disord. 2019;34(7):1010-1019 3. Pahwa R, Tanner CM, Hauser RA, et al. Amantadine extended release for levodopa-induced dyskinesia in Parkinson's disease (EASED Study). Mov Disord. 2015;30(6):788-795 4. Elmer LW, Juncos JL, Singer C, et al. Pooled analyses of phase III studies of ADS-5102 (amantadine) extended-release capsules for dyskinesia in Parkinson's disease. CNS Drugs. 2018;32(4):387-398 5. American Society of Health-System Pharmacists. AHFS Drug Information. 2023 6. Micromedex Solutions. Truven Health Analytics. 2023