Amantadine
amantadine hydrochloride — Symmetrel, Gocovri, Osmolex ER
Indications
| Indication | Approved Population | Therapy Type | Status |
|---|---|---|---|
| Parkinson disease | Adults | Monotherapy or adjunctive with levodopa | FDA Approved |
| Drug-induced extrapyramidal reactions | Adults | Monotherapy | FDA Approved |
| Levodopa-induced dyskinesia in Parkinson disease (Gocovri ER) | Adults on levodopa-based therapy | Adjunctive to levodopa | FDA Approved |
| OFF episodes in Parkinson disease (Gocovri ER) | Adults on levodopa/carbidopa | Adjunctive to levodopa/carbidopa | FDA Approved |
| Influenza A virus prophylaxis and treatment | ≥1 year | Monotherapy | FDA Approved (no longer recommended by CDC due to resistance) |
Amantadine was initially approved for influenza A prophylaxis in 1966 and for Parkinson disease in 1973. Its antiviral use has been abandoned following the emergence of widespread resistance among circulating influenza A strains; the CDC has not recommended amantadine for influenza since 2011. Today, amantadine is primarily valued for its antiparkinsonian and antidyskinetic properties. The extended-release formulation Gocovri became the first drug specifically approved for levodopa-induced dyskinesia in 2017.
Traumatic brain injury (disorders of consciousness) — 100–200 mg twice daily to accelerate functional recovery in vegetative or minimally conscious states 4–16 weeks post-injury. Supported by an RCT in the NEJM (Giacino et al., 2012). Evidence quality: Moderate.
Multiple sclerosis–related fatigue — 100 mg twice daily, considered a first-line pharmacological option. Evidence quality: Moderate.
Huntington disease chorea — 100 mg two to four times daily. The AAN guideline (2012) considers amantadine likely effective for reducing chorea, though the magnitude of benefit is uncertain. Evidence quality: Low.
Dosing
Immediate-Release Amantadine — Adults
| Clinical Scenario | Starting Dose | Maintenance Dose | Maximum Dose | Notes |
|---|---|---|---|---|
| Parkinson disease — monotherapy, early-stage | 100 mg once daily | 100 mg twice daily | 400 mg/day | Can increase to 200 mg BID if needed; benefit may wane after several months Allow several weeks before assessing full response |
| Parkinson disease — adjunctive to levodopa | 100 mg once daily | 100 mg BID–TID | 300 mg/day | Begin at 100 mg/day when adding to existing antiparkinson regimen May reduce levodopa-induced dyskinesia |
| Drug-induced extrapyramidal symptoms | 100 mg twice daily | 100 mg BID | 300 mg/day | May begin at 100 mg/day and increase within one week |
| TBI — disorders of consciousness (off-label) | 100 mg BID | 150–200 mg BID | 400 mg/day | Titrate up every 3–4 days; based on NEJM trial protocol (Giacino 2012) Taper gradually to discontinue |
| MS-related fatigue (off-label) | 100 mg once daily | 100 mg BID | 200 mg/day | Give second dose early afternoon to reduce insomnia risk |
| Huntington chorea (off-label) | 100 mg BID | 100 mg TID–QID | 400 mg/day | AAN guideline considers likely effective; magnitude uncertain |
Extended-Release Formulations — Adults
| Clinical Scenario | Starting Dose | Maintenance Dose | Maximum Dose | Notes |
|---|---|---|---|---|
| Levodopa-induced dyskinesia (Gocovri ER) | 137 mg at bedtime | 274 mg at bedtime | 274 mg/day | Increase after 1 week; administer at bedtime for peak morning levels Swallow whole or sprinkle on applesauce; do not interchange with IR or Osmolex ER |
| Parkinson disease & drug-induced EPS (Osmolex ER) | 129 mg each morning | 129–322 mg each morning | 322 mg/day | Increase in weekly intervals; administer in the morning Not interchangeable with Gocovri or IR amantadine |
Renal Dose Adjustment (Immediate-Release)
| Creatinine Clearance | Recommended Dose | Maximum Dose | Frequency | Notes |
|---|---|---|---|---|
| 30–50 mL/min | 200 mg day 1, then 100 mg/day | 100 mg/day | Once daily | Half-life significantly prolonged |
| 15–29 mL/min | 200 mg day 1, then 100 mg | 100 mg every other day | Every other day | Monitor closely for toxicity |
| <15 mL/min / ESRD | Contraindicated — Poorly removed by hemodialysis (<5% per session) | |||
Gocovri, Osmolex ER, and immediate-release amantadine are not interchangeable. They differ in release kinetics, timing of administration (bedtime vs. morning), and approved indications. Gocovri is specifically designed for bedtime dosing so that peak plasma concentrations occur in the morning to address dyskinesia throughout waking hours. Deaths have been reported in patients with renal impairment who received doses that were too high for their kidney function.
Pharmacology
Mechanism of Action
Amantadine exerts its clinical effects through several complementary mechanisms. It functions as a weak, uncompetitive antagonist of the NMDA-type glutamate receptor, which is believed to underlie its antidyskinetic properties by modulating corticostriatal glutamatergic transmission. Amantadine also augments dopaminergic neurotransmission by enhancing dopamine release from presynaptic terminals, inhibiting dopamine reuptake, and possibly increasing dopamine receptor sensitivity. Although not a direct anticholinergic agent in preclinical studies, amantadine produces anticholinergic-like effects in humans, including dry mouth and urinary retention. Its original antiviral activity against influenza A stems from blockade of the viral M2 ion channel protein, preventing viral uncoating; this mechanism is now clinically irrelevant owing to near-universal resistance among circulating strains.
ADME Profile
| Parameter | Value | Clinical Implication |
|---|---|---|
| Absorption | Well absorbed orally; Tmax 2–4 h (IR), ~9 h (Osmolex ER), ~12 h (Gocovri); Cmax ~0.5 µg/mL after 200 mg IR | Food does not affect absorption; ER formulations designed for delayed peak to align with waking hours (Gocovri) or sustained daytime levels (Osmolex ER) |
| Distribution | Vd 3–8 L/kg; 67% protein-bound; crosses blood-brain barrier; found in nasal mucus | Large Vd with extensive tissue binding; CNS penetration underlies both therapeutic and neuropsychiatric effects |
| Metabolism | Only 5–15% metabolized; primary metabolite is N-acetylamantadine; does not significantly inhibit CYP450 isoforms | Minimal hepatic metabolism means few pharmacokinetic drug interactions via CYP enzymes; no dose adjustment for hepatic impairment formally defined |
| Elimination | ~90% renally excreted unchanged via glomerular filtration and tubular secretion; t½ 10–25 h (IR, healthy adults); markedly prolonged in renal impairment (up to 7–10 days in ESRD) | Renal dose adjustment is critical; acidic urine accelerates elimination while alkaline urine promotes accumulation; poorly dialyzable |
Side Effects
Adverse effect data below are drawn primarily from the Gocovri (ER) phase 3 clinical trials (EASE LID and EASE LID 3, pooled safety analysis, n=100 amantadine vs. n=100 placebo at 274 mg/day) and the immediate-release amantadine prescribing information. Incidence with IR formulations at standard doses (200–300 mg/day) is generally lower for most effects.
| Adverse Effect | Incidence | Clinical Note |
|---|---|---|
| Hallucinations (visual/auditory) | 21% vs 3% placebo | More common in patients ≥65 years (31%); predominantly visual; mostly mild-moderate; 86% resolved with dose adjustment or discontinuation |
| Dizziness | 16% vs 1% placebo | Often positional; more frequent in men (20%) than women (11%) |
| Dry mouth | 16% vs 1% placebo | Anticholinergic-like effect; more common in women (22%) than men (11%) |
| Peripheral edema | 16% vs 1% placebo | Monitor for heart failure exacerbation; may necessitate diuretic review |
| Constipation | 13% vs 3% placebo | Anticholinergic mechanism; encourage fluid and fibre intake |
| Falls | 13% vs 7% placebo | Increased risk in patients ≥65 (17% vs 8% in <65); multifactorial in PD population |
| Orthostatic hypotension | 13% vs 1% placebo | Advise slow positional changes; more frequent in patients ≥65 (8% vs 2% in <65) |
| Adverse Effect | Incidence | Clinical Note |
|---|---|---|
| Nausea | 8% (ER); ≥5% (IR) | Usually dose-related; taking with food may help |
| Insomnia | 7% (ER); ≥5% (IR) | Avoid late-afternoon dosing with IR; Gocovri given at bedtime by design |
| Anxiety | 7% (ER) | More common in men (11%) than women (2%) |
| Depression / depressed mood | 6% vs 1% placebo | Monitor for suicidality; may occur with or without prior psychiatric history |
| Livedo reticularis | 5% (ER); ~1% (IR) | Mottled, net-like skin discoloration, usually on lower extremities; reversible on discontinuation |
| Blurred vision | 4% (ER) | Distinguish from corneal edema (see Serious tier); inquire about eye pain |
| Confusional state | 3% vs 2% placebo | More common in elderly; evaluate for dose reduction |
| Urinary retention | ~1–3% | Anticholinergic mechanism; caution in patients with prostatic hyperplasia |
| Adverse Effect | Estimated Frequency | Typical Onset | Required Action |
|---|---|---|---|
| Neuroleptic malignant syndrome (NMS)-like reaction on abrupt withdrawal | Rare | 24–72 h after abrupt discontinuation | Never stop abruptly; taper over 1–2 weeks; supportive care including IV hydration and cooling if NMS develops |
| Suicidal ideation / attempt | <3% | Any time during treatment | Screen at initiation and follow-up; discontinue if severe depression or suicidality emerges |
| Corneal edema | Rare | Weeks to years after initiation | Ophthalmologic examination; taper and discontinue amantadine; corneal grafts may be required if unrecognized |
| Impulse control disorders (gambling, hypersexuality, compulsive spending) | Uncommon | Variable | Proactively ask patients about new urges; consider dose reduction or discontinuation |
| Seizures | Rare | Any time; risk increases with accumulation in renal impairment | Use with caution in seizure disorders; lower doses for renal impairment |
| Psychosis (delusions, paranoia) | <3% | Days to weeks after initiation or dose increase | Reduce dose or discontinue; avoid in patients with major psychotic disorders |
| Cardiac toxicity (QT effects, arrhythmia in overdose) | Rare (primarily overdose) | Acute overdose setting | Lowest reported lethal dose is 1 g amantadine HCl (~0.8 g base); supportive care, cardiac monitoring |
| Reason for Discontinuation (Gocovri ER) | Incidence | Context |
|---|---|---|
| Hallucinations | 8% vs 0% placebo | Leading cause; predominantly visual; more common in ≥65 years |
| Dry mouth | 3% vs 0% placebo | Anticholinergic mechanism |
| Peripheral edema | 3% vs 0% placebo | May require diuretic adjustment |
| Blurred vision | 3% vs 0% placebo | Distinguish from corneal edema |
| Postural dizziness / syncope | 2% vs 0% placebo | Positional mechanism; more common in early treatment |
| Abnormal dreams | 2% vs 1% placebo | Often vivid; may precede hallucinations |
| Dysphagia | 2% vs 0% placebo | Evaluate for PD-related vs. drug-related cause |
Hallucinations affect up to 21% of patients on Gocovri ER (274 mg) and are more common in older adults. In the pivotal trials, most hallucinations were mild to moderate. If hallucinations develop, first consider dose reduction before discontinuation. If the patient is ≥65 and taking other dopaminergic medications, review the overall dopaminergic load. Pimavanserin (an atypical antipsychotic approved for PD psychosis) may be considered if hallucinations persist despite amantadine dose reduction. Notably, none of the patients in the Gocovri trials required antipsychotic medications for hallucination management.
Drug Interactions
Amantadine has minimal hepatic metabolism and does not significantly inhibit CYP450 isoforms, so pharmacokinetic drug interactions are uncommon. The clinically relevant interactions are primarily pharmacodynamic (additive anticholinergic or CNS-depressant effects) and involve renal elimination pathways.
Monitoring
-
Renal Function
Baseline, then every 6–12 months
Routine Serum creatinine and estimated CrCl before initiation and periodically thereafter. Amantadine is almost entirely renally eliminated and accumulates rapidly when GFR declines. More frequent monitoring in elderly patients or those with fluctuating renal function. -
Mental Status
Each visit
Routine Assess for depression, suicidal ideation, hallucinations, psychotic symptoms, confusion, and impulse control disorders. Proactively ask about new urges (gambling, sexual, spending). Especially important at initiation and dose increases. -
Blood Pressure
Baseline, then periodically
Routine Including orthostatic measurements at initiation and after dose increases. Amantadine can cause orthostatic hypotension, particularly in elderly patients and those on other antihypertensives. -
Vision
If visual symptoms emerge
Trigger-based Corneal edema can develop weeks to years after starting amantadine. Ask about blurred vision or eye pain at each visit. Ophthalmologic examination if vision changes occur. If corneal edema is confirmed, taper and discontinue amantadine. -
Skin Examination
Annually
Routine Patients with Parkinson disease have an elevated baseline risk of melanoma. While a direct causal link with amantadine has not been established, periodic dermatological assessment is recommended by the Parkinson Foundation. -
Seizure Activity
Ongoing if seizure history
Trigger-based Amantadine may lower the seizure threshold; monitor patients with pre-existing seizure disorders or those at risk of drug accumulation due to renal impairment. -
Lower Extremity Edema
Each visit
Routine Peripheral edema occurs in up to 16% of patients on ER formulations. Patients with congestive heart failure require vigilance for fluid retention and worsening symptoms.
Contraindications & Cautions
Absolute Contraindications
- End-stage renal disease (CrCl <15 mL/min/1.73 m²) — amantadine accumulates to toxic levels with negligible clearance; deaths have occurred in this population (FDA PI).
- Known hypersensitivity to amantadine or any formulation component.
Relative Contraindications (Specialist Input Recommended)
- Major psychotic disorder — amantadine may worsen hallucinations and psychosis; generally not recommended unless under specialist supervision.
- Moderate to severe renal impairment (CrCl 15–59 mL/min) — requires significant dose reduction and close monitoring; risk of accumulation and CNS toxicity.
- Pregnancy — teratogenic in animal studies (embryolethality, skeletal malformations in rats and mice); use only if benefit clearly outweighs risk.
Use with Caution
- Seizure disorders — may exacerbate seizures, particularly at higher doses or with drug accumulation.
- Congestive heart failure — peripheral edema and water retention may worsen cardiac decompensation.
- Closed-angle glaucoma / prostatic hyperplasia — anticholinergic-like effects may worsen these conditions.
- Elderly patients — increased susceptibility to hallucinations, falls, confusion, and renal accumulation; start at lower doses.
- Hepatic impairment — limited data; use with caution although hepatic metabolism accounts for only 5–15% of clearance.
- Concomitant high anticholinergic burden — additive risk of confusion, ileus, urinary retention, and hyperthermia.
- Lactation — amantadine is excreted in breast milk and may alter milk production; weigh benefits vs. risks.
Abrupt discontinuation of amantadine can precipitate a syndrome resembling neuroleptic malignant syndrome, featuring high fever, muscle rigidity, altered consciousness, and autonomic instability. This risk applies to all formulations. The FDA prescribing information for Gocovri and Osmolex ER mandates gradual taper over 1–2 weeks before discontinuation. Clinicians should not abruptly stop amantadine even when switching between formulations.
Suicide, suicide attempts, and suicidal ideation have been reported in patients with and without prior psychiatric history during amantadine therapy. The prescribing information advises monitoring all patients for depression and emergent suicidality, and weighing benefits against risks in patients with a history of depression or suicidal behaviour.
Patient Counselling
Purpose of Therapy
Amantadine helps manage the symptoms of Parkinson disease — including tremor, stiffness, and slowness of movement — by boosting dopamine activity in the brain. In patients taking levodopa, the extended-release formulation (Gocovri) specifically targets involuntary movements (dyskinesia) that develop as a side effect of levodopa over time. It is not a cure for Parkinson disease, but it can meaningfully improve day-to-day function.
How to Take
Immediate-release amantadine is typically taken once or twice daily, ideally earlier in the day to reduce the risk of insomnia. Gocovri extended-release capsules are taken once daily at bedtime so that the medication reaches its highest levels in the blood by morning. Osmolex ER tablets are taken once daily in the morning. All extended-release products must be swallowed whole; they should not be crushed or chewed. Gocovri capsules can be opened and sprinkled on applesauce if the patient cannot swallow them whole.
Sources
- Amantadine hydrochloride capsules, USP — Prescribing Information. DailyMed / FDA. DailyMed Primary source for IR amantadine dosing, pharmacokinetics, adverse reactions, and contraindications.
- GOCOVRI (amantadine) extended-release capsules — Prescribing Information. Adamas Pharma, LLC / FDA. FDA Label Source for Gocovri ER dosing, dyskinesia indication, renal adjustments, and pooled adverse event data from EASE LID trials.
- OSMOLEX ER (amantadine) extended-release tablets — Prescribing Information. Vertical Pharmaceuticals / FDA. FDA Label Source for Osmolex ER dosing, pharmacokinetic parameters (protein binding, Vd, metabolism), and renal adjustment guidance.
- Pahwa R, Tanner CM, Hauser RA, et al. ADS-5102 (amantadine) extended-release capsules for levodopa-induced dyskinesia in Parkinson disease (EASE LID Study): a randomized clinical trial. JAMA Neurol. 2017;74(8):941–949. doi:10.1001/jamaneurol.2017.0943 Pivotal RCT demonstrating significant reduction in UDysRS total score with Gocovri 274 mg vs placebo over 12 weeks.
- Oertel W, Eggert K, Pahwa R, et al. Randomized, placebo-controlled trial of ADS-5102 (amantadine) extended-release capsules for levodopa-induced dyskinesia in Parkinson’s disease (EASE LID 3). Mov Disord. 2017;32(12):1701–1709. doi:10.1002/mds.27131 Second pivotal trial confirming antidyskinetic efficacy; source of pooled safety data with EASE LID.
- Giacino JT, Whyte J, Bagiella E, et al. Placebo-controlled trial of amantadine for severe traumatic brain injury. N Engl J Med. 2012;366(9):819–826. doi:10.1056/NEJMoa1102609 Landmark NEJM RCT (n=184) showing amantadine 200–400 mg/day accelerated functional recovery in post-traumatic disorders of consciousness.
- Armstrong MJ, Miyasaki JM; American Academy of Neurology. Evidence-based guideline: pharmacologic treatment of chorea in Huntington disease. Neurology. 2012;79(6):597–603. doi:10.1212/WNL.0b013e318263c443 AAN guideline rating amantadine as “likely effective” for chorea reduction, supporting off-label use.
- Fox SH, Katzenschlager R, Lim SY, et al. International Parkinson and Movement Disorder Society evidence-based medicine review: update on treatments for the motor symptoms of Parkinson’s disease. Mov Disord. 2018;33(8):1248–1266. doi:10.1002/mds.27372 MDS review classifying amantadine as “efficacious” for levodopa-induced dyskinesia based on accumulated trial evidence.
- Dekundy A, Pichler G, El Badry R, Scheschonka A, Danysz W. Amantadine for traumatic brain injury — supporting evidence and mode of action. Biomedicines. 2024;12(7):1558. doi:10.3390/biomedicines12071558 Comprehensive review of amantadine’s NMDA antagonism, dopaminergic effects, and neuroprotective properties in TBI.
- Chang C, Ramphul K. Amantadine. In: StatPearls. Treasure Island (FL): StatPearls Publishing; 2023. NCBI Bookshelf Concise clinical pharmacology overview covering mechanism, indications, adverse effects, and monitoring.
- Aoki FY, Sitar DS. Clinical pharmacokinetics of amantadine hydrochloride. Clin Pharmacokinet. 1988;14(1):35–51. doi:10.2165/00003088-198814010-00003 Definitive PK review establishing half-life ranges, volume of distribution, and renal clearance parameters in healthy subjects.
- Soung LS, Ing TS, Daugirdas JT, et al. Amantadine hydrochloride pharmacokinetics in hemodialysis patients. Ann Intern Med. 1980;93(1):46–49. doi:10.7326/0003-4819-93-1-46 Key study demonstrating that hemodialysis removes <5% of amantadine per session, informing the ESRD contraindication.
- Modi NB, Lindemulder B, Gocovri PK team. Bioavailability and pharmacokinetics of once-daily amantadine extended-release tablets in healthy volunteers. Clin Pharmacol Drug Dev. 2020;9(2):260–268. doi:10.1002/cpdd.696 Three phase 1 studies characterising Osmolex ER PK including Tmax (~9 h), half-life (~13 h), and dose proportionality.
- Hauser RA, Wargin W, Souza-Prien C, et al. Pharmacokinetics of ADS-5102 (amantadine) extended release capsules administered once daily at bedtime for the treatment of dyskinesia. Clin Pharmacokinet. 2019;58(1):77–88. doi:10.1007/s40262-018-0663-4 Characterised Gocovri delayed-release PK profile: Tmax ~12 h, bedtime dosing yielding peak morning concentrations.