Note: Amantadine is available as an IR capsule, tablet, and syrup and an ER capsule and tablet. The IR formulations are interchangeable with one another, but they are not interchangeable with the ER formulations; the ER formulations are not interchangeable with one another.
Drug-induced parkinsonism (alternative agent): Note: Use if patient cannot tolerate preferred agents (APA [Keepers 2020]).
ER tablet: Oral: Initial: 129 mg once daily; may increase based on response and tolerability by increments of 129 to 193 mg in weekly intervals to a maximum dose of 322 mg/day.
Immediate release: Oral: Initial: 100 mg twice daily; after 1 week, may increase based on response and tolerability to 300 mg/day in 3 divided doses (DiMascio 1976; Stroup 2021; manufacturer's labeling).
Multiple sclerosis–related fatigue (alternative agent) (off-label use):
Note: Reserve for patients who fail nonpharmacologic interventions and remain symptomatic despite treatment of underlying conditions (Olek 2022).
Immediate release: Oral: 100 mg twice daily (Ledinek 2013; Shaygannejad 2012).
Neuroleptic malignant syndrome, moderate to severe (off-label use):
Note: Consider for use in combination with supportive care, benzodiazepines, and dantrolene in patients with moderate to severe symptoms at presentation (eg, hyperthermia, evidence of rhabdomyolysis) and for those not responding to initial withdrawal of medication and supportive care (Bienvenu 2012; Pileggi 2016; Strawn 2007).
Immediate release: Oral or via NG tube: Initial: 100 mg once daily; may titrate based on response and tolerability to a maximum of 400 mg/day in 2 or 3 divided doses. After the patient is stabilized and symptoms have resolved, consider taper over days to weeks rather than abrupt discontinuation (Bhanushali 2004; Bienvenu 2012; Gortney 2009; Ngo 2019; Pileggi 2016; Strawn 2007; van Rensburg 2019).
Parkinson disease, dyskinesias (adjunctive therapy) or mild motor symptoms (monotherapy) (alternative agent):
Extended release:
Capsule: Oral: Initial: 137 mg once daily; after 1 week, increase to usual dose of 274 mg once daily.
Tablet: Oral: Initial: 129 mg once daily; may be increased based on response and tolerability by increments of 129 to 193 mg in weekly intervals to a maximum dose of 322 mg/day.
Immediate release: Oral: Initial: 100 mg twice daily or once daily (see: Note); after 1 week, may increase based on response and tolerability to usual maximum dose of 300 mg/day; some patients with dyskinesias may require up to 400 mg/day in 2 to 4 divided doses (Liang 2022; Sawada 2010; Spindler 2021).
Note: In patients with a serious concomitant illness or those receiving high doses of other antiparkinson drugs, initiate at 100 mg once daily; may increase to 100 mg twice daily, if needed, after 1 to several weeks.
Tardive dyskinesia (alternative agent) (off-label use):
Note: Reserve for patients who fail first-line treatments for tardive dyskinesia (Ricciardi 2019).
Immediate release: Oral: Initial: 100 mg once daily; may increase over ≥4 days up to 400 mg/day, in 1 to 4 divided doses (Angus 1997; Pappa 2010).
Discontinuation of therapy: Abrupt discontinuation may lead to worsening of Parkinson disease symptoms, hyperpyrexia, or changes in mental status. Reduce the dose by one-half for 1 to 2 weeks before discontinuing.
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
The renal dosing recommendations are based upon the best available evidence and clinical expertise. Senior Editorial Team: Bruce Mueller, PharmD, FCCP, FASN, FNKF; Jason A. Roberts, PhD, BPharm (Hons), B App Sc, FSHP, FISAC; Michael Heung, MD, MS.
Note: For acute short-term use (ie, neuroleptic malignant syndrome) no specific dose adjustments can be provided (has not been studied). Dosing should be individualized, weighing risks and benefits of over- and underdosing, and titrated to effect (expert opinion).
Altered kidney function: Oral:
Immediate release (Horadam 1981; Wu 1982; manufacturer's labeling):
Note: Renally adjusted dose recommendations are based on a usual recommended dose of 100 mg twice daily.
CrCl >50 mL/minute: No dosage adjustment necessary.
CrCl 30 to 50 mL/minute: 200 mg on day 1, then 100 mg/day.
CrCl 15 to <30 mL/minute: 200 mg on day 1, then 100 mg every other day.
CrCl <15 mL/minute: 200 mg once every 7 days.
Extended release (manufacturer's labeling):
|
eGFRa |
ER tablet |
ER capsule |
|---|---|---|
|
a MDRD equation is recommended in the manufacturer’s labeling for determining eGFR. | ||
|
≥60 mL/minute/1.73 m2 |
No dosage adjustment necessary. |
No dosage adjustment necessary. |
|
30 to <60 mL/minute/1.73 m2 |
Initial: 129 mg every other day; increase no more frequently than every 3 weeks to a maximum dose of 322 mg every other day. |
Initial: 68.5 mg once daily; after 1 week, increase to 137 mg once daily if needed. |
|
15 to <30 mL/minute/1.73 m2 |
Initial: 129 mg every 96 hours; increase no more frequently than every 4 weeks to a maximum dose of 322 mg every 96 hours. |
68.5 mg once daily. |
|
<15 mL/minute/1.73 m2 |
Use is contraindicated. |
Use is contraindicated. |
Hemodialysis, intermittent (thrice weekly): Not dialyzable (<5% of the dose removed by a 4-hour hemodialysis session) (Horadam 1981):
Extended release: Use is contraindicated.
Immediate release: Dose for CrCl <15 mL/minute.
Peritoneal dialysis: Unlikely to be significantly dialyzed (large Vd) (expert opinion):
Extended release: Use is contraindicated.
Immediate release: There are no specific dosage adjustment recommendations (has not been studied); however, since amantadine is unlikely to be dialyzed, dosing for CrCl <15 mL/minute may be considered (expert opinion).
CRRT:
Note: Drug clearance is dependent on the effluent flow rate, filter type, and method of renal replacement. Recommendations are based on high-flux dialyzers and effluent flow rates of 20 to 25 mL/kg/hour (or ~1,500 to 3,000 mL/hour) and minimal residual kidney function unless otherwise noted. Close monitoring of response and adverse reactions (eg, neurotoxicity) due to drug accumulation is important.
Extended release: Use is not recommended (expert opinion).
Immediate release: There are no specific dosage adjustment recommendations (has not been studied); however, since amantadine is unlikely to be dialyzed, dosing for CrCl <15 mL/minute may be considered (expert opinion).
PIRRT (eg, sustained, low-efficiency diafiltration):
Note: Drug clearance is dependent on the effluent flow rate, filter type, and method of renal replacement. Close monitoring of response and adverse reactions (eg, neurotoxicity) due to drug accumulation is important.
Extended release: Use is not recommended (expert opinion).
Immediate release: There are no specific dosage adjustment recommendations (has not been studied); however, since amantadine is unlikely to be dialyzed, dosing for CrCl <15 mL/minute may be considered (expert opinion).
There are no dosage adjustments provided in the manufacturer's labeling; use with caution.
(For additional information see "Amantadine: Pediatric drug information")
Attention-deficit/hyperactivity disorder (ADHD): Limited data available: Oral: Immediate release: Children ≥5 years and Adolescents: Initial: 50 mg/day; titrate up at 4 to 7 day intervals in 50 mg increments to effect; reported range: 50 to 150 mg/day in divided doses 1 to 3 times daily (morning, noon, and 4 PM); maximum daily dose (weight-dependent): <30 kg: 100 mg/day; ≥30 kg: 150 mg/day (Donfrancecso 2007; Mohammadi 2010); dosing based on two small open-label trials (n=24, n=20; age range: 5 to 14 years) which suggested improvements in symptoms; the comparison trial with methylphenidate (n=40) showed both amantadine and methylphenidate yielded significant improvement in ADHD symptoms (50% reduction from baseline symptoms), with no significant differences in efficacy between the groups; more frequent side effects in the methylphenidate group (Mohammadi 2010).
Autism (hyperactivity, irritability): Very limited data available (Hosenbocus 2013): Oral: Immediate release: Children ≥5 years and Adolescents: Initial: 2.5 mg/kg/dose once daily for 1 week, then increase to 2.5 mg/kg/dose twice daily; maximum daily dose: 200 mg/day; dosing based on short-term (4-week) double-blind, placebo-controlled trial of 39 pediatric patients (treatment group, n=19) which showed improvement in clinician-rated behavioral and hyperactivity ratings (King 2001).
Influenza A prophylaxis/treatment: Note: Amantadine should NOT be used for prophylaxis or treatment of influenza A infection due to high resistance rates (AAP 2020; CDC 2021; IDSA [Uyeki 2019]).
Children <9 years: Immediate release: Oral: 4.4 to 8.8 mg/kg/day in 2 divided doses until symptom resolution for 24 to 48 hours; maximum daily dose: 150 mg/day.
Children ≥9 years: Immediate release: Oral: 100 mg twice daily until symptom resolution for 24 to 48 hours.
Adolescents: Immediate release: Oral: 200 mg once daily or 100 mg twice daily until symptom resolution for 24 to 48 hours.
Multiple-sclerosis associated lassitude (fatigue): Limited data available; available dosing based on data in traumatic brain injury trials (Beers 2005; Pohl 2007): Oral: Immediate release:
Children 6 to <10 years or ≥10 years and weighing <40 kg: Oral: 2.5 mg/kg/dose twice daily; maximum daily dose: 150 mg/day.
Children ≥10 years and Adolescents weighing ≥40 kg: Oral: 100 mg twice daily.
Traumatic brain injury (TBI): Limited data available: Oral: Immediate release:
Children ≥6 years and Adolescents <16 years: 4 to 6 mg/kg/day in 2 divided doses; maximum daily dose (age or weight dependent): If <10 years or <40 kg: 150 mg/day; if ≥10 years or ≥40 kg: 200 mg/day (Beers 2005; McMahon 2009). While total daily dose similar in trials, the reported dosing approaches and efficacy results are variable (eg, timing of therapy initiation, duration of study, outcome measures) (Williams 2007). In an open-label, case-controlled trial of 27 pediatric patients with TBI within the last 24 months prior to enrollment (n=17 amantadine treatment, n=10 controls), patients received 5 mg/kg/day for entire study period of 12 weeks; results showed improvement in behavior (parental report) and a subset analysis suggested therapy more effective on cognition for those with more recent injury (Beers 2005). In a double-blind, placebo-controlled crossover trial of seven pediatric patients (mean age: 12.7 years) with TBI within last 12 weeks prior to enrollment, therapy was initiated at 4 mg/kg/day up to 300 mg/day for 1 week, and increased to 6 mg/kg/day up to 400 mg/day for Weeks 2 and 3 of the study duration; improved consciousness observed during treatment period of study (McMahon 2009; Vargus-Adams 2010).
Adolescents ≥16 years: Initial: 100 mg twice daily for 14 days; on Week 3 increase to 150 mg twice daily; may further increase to 200 mg twice daily on Week 4 if needed; dosing based on a multicenter, double-blind, placebo-controlled trial of 184 patients (age range: 16 to 65 years; treatment group, n=87) which showed 4 weeks of amantadine therapy initiated at 4 to 16 weeks postinjury increased the rate of functional recovery (Giacino 2012).
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
There are no pediatric-specific recommendations; based on experience in adult patients, dosing adjustment should be considered.
There are no dosage adjustments provided in the manufacturer's labeling; use with caution.
Refer to adult dosing; some patients tolerate the IR formulations better when administered in 2 divided daily doses (to avoid adverse neurologic reactions).
Discontinuation of therapy: Refer to adult dosing.
Excipient information presented when available (limited, particularly for generics); consult specific product labeling. [DSC] = Discontinued product
Capsule, Oral, as hydrochloride:
Generic: 100 mg
Capsule Extended Release 24 Hour, Oral, as hydrochloride [strength expressed as base]:
Gocovri: 68.5 mg, 137 mg
Solution, Oral, as hydrochloride:
Generic: 50 mg/5 mL (10 mL, 473 mL)
Tablet, Oral, as hydrochloride:
Generic: 100 mg
Tablet ER 24 Hour Therapy Pack, Oral, as hydrochloride:
Osmolex ER: 129 & 193 MG (60 ea) [contains fd&c blue #2 (indigotine), fd&c red #40 (allura red ac dye), fd&c yellow #6 (sunset yellow), quinoline yellow (d&c yellow #10)]
Tablet Extended Release 24 Hour, Oral, as hydrochloride [strength expressed as base]:
Osmolex ER: 129 mg [contains fd&c yellow #6 (sunset yellow), quinoline yellow (d&c yellow #10)]
Osmolex ER: 193 mg [contains fd&c blue #2 (indigotine), fd&c red #40 (allura red ac dye), fd&c yellow #6 (sunset yellow), quinoline yellow (d&c yellow #10)]
Osmolex ER: 258 mg [DSC] [contains fd&c blue #1 (brilliant blue), fd&c red #40 (allura red ac dye), fd&c yellow #6 (sunset yellow), quinoline yellow (d&c yellow #10)]
May be product dependent
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Capsule, Oral, as hydrochloride:
Generic: 100 mg
Syrup, Oral, as hydrochloride:
Generic: 50 mg/5 mL (500 mL)
Oral:
ER capsule: Administer at bedtime with or without food. Swallow whole; do not crush, chew, or divide capsules. If needed, sprinkle entire contents on a small amount (teaspoonful) of soft food, such as applesauce, and administer immediately without chewing.
ER tablet: Administer in the morning without regard to food. Swallow whole; do not crush, chew, or divide tablets.
Bariatric surgery: Some institutions may have specific protocols that conflict with these recommendations; refer to institutional protocols as appropriate.
Capsule, extended release: Capsule may be opened and contents sprinkled onto soft food of choice. Patient should be instructed to swallow the mixture without biting down or chewing.
Tablet, extended release: Do not cut, crush, or chew. Switch to IR formulation or consider amantadine ER capsule since it can be opened.
Oral: Immediate release: May be taken without regard to food. For regimens with multiple daily dosing, timing of doses may vary based upon patient tolerance (eg, if insomnia develops, administer evening dose several hours before bedtime) and use (for ADHD, administer morning and noon; if thrice-daily dosing, last dose should be given around 4 PM [Mohammadi 2010]).
Drug-induced parkinsonism (IR and ER tablet only): Treatment of drug-induced parkinsonism.
Parkinson disease, dyskinesias (adjunctive therapy) or mild motor symptoms (monotherapy):
Extended release:
Capsule: Treatment of dyskinesias in patients with Parkinson disease receiving levodopa-based therapy, with or without concomitant dopaminergic medications; treatment of "off" episodes in patients with Parkinson disease receiving levodopa/carbidopa.
Tablet: Treatment of Parkinson disease.
Immediate release: Treatment of idiopathic Parkinson disease (paralysis agitans), postencephalitic parkinsonism, parkinsonism in association with cerebral arteriosclerosis, and symptomatic parkinsonism, which may follow injury to the nervous system by carbon monoxide intoxication.
Multiple sclerosis–related fatigue; Neuroleptic malignant syndrome, moderate to severe; Tardive dyskinesia
Amantadine may be confused with amiodarone, raNITIdine, riMANTAdine
Symmetrel may be confused with Synthroid
Epidemiologic studies have suggested an association between amantadine and impulse control disorders and related disorders, manifesting as pathological gambling, increased libido (hypersexuality), compulsive or binge buying/eating, and/or other intense urges in patients with Parkinson disease (Ref). However, some studies did not find an association (Ref). In addition, extremely limited data suggests amantadine may offer benefit for pathological gambling in patients with Parkinson disease (Ref). Overall, most studies evaluating impulse control disorders involve patients with Parkinson disease receiving direct dopamine agonists or multiple dopaminergic medications, therefore, further studies may be needed to fully elucidate amantadine’s role in impulse control disorders (Ref).
Mechanism: Exact mechanism of action of amantadine has not been fully elucidated, but it is thought to have both dopaminergic and antiglutaminergic properties (as a N-methyl-D-aspartate [NMDA] glutamate receptor antagonist). Dopaminergic effects are generally believed to increase the risk for impulse control disorders while antiglutaminergic effects are thought to reduce these compulsive behaviors. Therefore, amantadine’s dual properties suggest a complex role regarding impulse control disorders (Ref).
Onset: Difficult to determine. For dopamine replacement therapies in general (not specific for amantadine), there may be a significant lag time between initiation of treatment and development of impulse control disorders (Ref)
Risk factors: Note: Based primarily on data involving dopamine agonists:
• Males (for PD) (Ref)
• Younger age (Ref)
• History of psychiatric symptoms (eg, anxiety, depression) (Ref)
• Family history of impulse control disorders (Ref)
• Earlier onset of PD (Ref)
• Longer duration of PD (Ref)
• Alcohol use (Ref)
• Smoking, current and past (Ref). Note: Conflicting evidence exists (Ref)
Amantadine frequently causes livedo reticularis (LR), a dermatologic condition of the small vessels causing reddish-blue reticulated patches primarily affecting the trunk and lower limbs, in adults with Parkinson disease. LR is typically asymptomatic and usually does not warrant discontinuation. If therapy is discontinued, LR is reversible and lesions typically resolve 2 to 4 weeks following cessation (Ref). LR has also been reported in children receiving off label uses of amantadine (Ref). In addition, livedo racemosa has also been reported rarely with amantadine (Ref).
Mechanism: Exact mechanism of amantadine is unknown, but it has been postulated that amantadine causes an interruption of the peripheral blood re-distribution, primarily in the dermal arteries or depletion of catecholamine stores in peripheral nerves (Ref).
Onset: Varied; it may occur within a few months to years after amantadine initiation (Ref)
Risk factors (possible):
• Females (Ref)
Amantadine may cause or exacerbate neuropsychiatric symptoms in adults, ranging from mood disturbances, hypersomnia or insomnia, nightmares, confusion, memory disturbances, disorientation, and agitation to severe delirium and psychotic symptoms (eg, paranoid ideation, delusion, visual or auditory hallucination). Psychotic symptoms have been attributed to underlying Parkinson disease, antiparkinsonian agents (including amantadine), or a combination of both. There are limited data suggesting antiparkinsonian drug therapy does not increase the risk of neuropsychiatric events, but rather arises in susceptible patients due to certain risk factors (Ref). Of note, neuropsychiatric events have also been reported in older adult patients receiving amantadine for influenza prophylaxis (Ref).
Mechanism: May be dose- and duration-related or due to underlying illness; the exact mechanism is unknown, although it has been postulated that psychotic events associated with amantadine may be due to enhanced dopamine effects and N-methyl-D-aspartate (NMDA) receptor antagonism (Ref). Other neurotransmitters may also play a role in neuropsychiatric effects, including cholinergic pathways, as amantadine also has anticholinergic properties (Ref).
Onset: Confusion and hallucination: Peak incidence in some studies has been observed during the third and ninth month of amantadine therapy
Risk factors:
• Higher doses or an abrupt change in dose (antiparkinsonian drugs in general) (Ref)
• Longer duration of therapy (patients with Parkinson disease also receiving levodopa) (Ref)
• Comorbid cognitive impairment or dementia (Ref)
• Older patients (hallucinations) (Ref)
• Concomitant treatment with anticholinergic medications (hallucinations, confusion, and delirium) (Ref)
Amantadine may cause or exacerbate orthostatic hypotension. Orthostatic hypotension may be asymptomatic or symptomatic, leading to dizziness and falling. Of note, neurogenic orthostatic hypotension is a common feature in patients with Parkinson disease (PD) (regardless of medication use) and results in an impaired capacity to respond to postural changes due to autonomic dysfunction from neurodegenerative processes in the brain stem (Ref).
Mechanism: Unclear, although orthostatic hypotension has been attributed to amantadine’s dopaminergic effects. In addition, other properties of amantadine may also play a role, including its arrhythmogenic properties (negative inotropic and chronotropic activity) as well as potential dose-dependent effects on cardiac muscarinic receptors. Amantadine also affects NMDA receptors which may play a role in bradycardia from chemoreflex activation (Ref).
Risk factors:
• Higher doses (Ref)
• Autonomic dysfunction (as with PD) (Ref)
• Concurrent medications that may cause orthostatic hypotension (eg, antihypertensive or antiarrhythmic medications, diuretics, levodopa, monoamine oxidase inhibitors, tricyclic antidepressants) (Ref)
• Cardiovascular disease (eg, heart failure) (Ref)
• Hypovolemia (Ref)
• Younger patients with asthenic features (Ref)
Abrupt withdrawal or rapid dosage reduction of amantadine has been associated with an acute and potentially fatal withdrawal syndrome resembling neuroleptic malignant syndrome (NMS). The syndrome has been referred to as acute akinesia, parkinsonism-hyperpyrexia syndrome (PHS), or neuroleptic malignant-like syndrome. The syndrome is very similar to NMS but occurs in a setting of withdrawal following exposure to dopamine agonists, levodopa, or amantadine in patients not receiving neuroleptics. In the setting of dopamine agonist therapy, it has also been referred to as dopamine agonist withdrawal syndrome. Regardless of terminology used, symptoms may begin with confusion or delirium and progress to unresponsiveness, catatonia, muscle rigidity, diaphoresis, tachycardia, pyrexia, autonomic instability, and elevated creatine kinase. Case reports describe symptoms usually resolving, typically within days, following the re-initiation of antiparkinson medication; however, in up to one-third of patients, there may be permanent sequelae or patients may not recover to previous baseline state (Ref).
Mechanism: Exact mechanism unknown; may be dose- and duration-related. Symptoms are likely to due to central dopaminergic depletion (Ref).
Onset: Rapid; in several cases involving amantadine, onset of symptoms ranged from 1 to 3 days following abrupt withdrawal (Ref).
Risk factors:
• Abrupt withdrawal or dosage decrease (Ref)
• Prolonged use (Ref)
• Older age (Ref)
• Underlying dementia (Ref)
The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified.
>10%:
Cardiovascular: Orthostatic hypotension (13%; including orthostatic dizziness, syncope, presyncope, and hypotension) (table 1), peripheral edema (16%)
|
Drug (Amantadine) |
Placebo |
Population |
Dose |
Dosage Form |
Indication |
Number of Patients (Amantadine) |
Number of Patients (Placebo) |
|---|---|---|---|---|---|---|---|
|
13% |
1% |
Adults |
274 mg once daily |
Extended-release capsules |
Treatment of dyskinesia or “off” episodes in patients with Parkinson disease receiving concomitant levodopa-based therapy |
100 |
98 |
Gastrointestinal: Constipation (13%), xerostomia (16%; may be more common in females)
Nervous system: Dizziness (16%) (table 2), falling (13%; may be more common in adults ≥65 years of age) (table 3), hallucination (21%; including auditory hallucination and visual hallucination; may be more common in adults ≥65 years of age) (table 4)
|
Drug (Amantadine) |
Placebo |
Population |
Dose |
Dosage Form |
Indication |
Number of Patients (Amantadine) |
Number of Patients (Placebo) |
|---|---|---|---|---|---|---|---|
|
16% |
1% |
Adults |
274 mg once daily |
Extended-release capsules |
Treatment of dyskinesia or “off” episodes in patients with Parkinson disease receiving concomitant levodopa-based therapy |
100 |
98 |
|
Drug (Amantadine) |
Placebo |
Population |
Dose |
Dosage Form |
Indication |
Number of Patients (Amantadine) |
Number of Patients (Placebo) |
|---|---|---|---|---|---|---|---|
|
13% |
7% |
Adults |
274 mg once daily |
Extended-release capsules |
Treatment of dyskinesia or “off” episodes in patients with Parkinson disease receiving concomitant levodopa-based therapy |
100 |
98 |
|
Drug (Amantadine) |
Placebo |
Population |
Dose |
Dosage Form |
Indication |
Number of Patients (Amantadine) |
Number of Patients (Placebo) |
|---|---|---|---|---|---|---|---|
|
21% |
3% |
Adults |
274 mg once daily |
Extended-release capsules |
Treatment of dyskinesia or “off” episodes in patients with Parkinson disease receiving concomitant levodopa-based therapy |
100 |
98 |
1% to 10%:
Cardiovascular: Livedo reticularis (6%; may be more common in females)
|
Drug (Amantadine) |
Placebo |
Population |
Dose |
Dosage Form |
Indication |
Number of Patients (Amantadine) |
Number of Patients (Placebo) |
|---|---|---|---|---|---|---|---|
|
6% |
0% |
Adults |
274 mg once daily |
Extended-release capsules |
Treatment of dyskinesia or “off” episodes in patients with Parkinson disease receiving concomitant levodopa-based therapy |
100 |
98 |
Dermatologic: Dyschromia (3%)
Gastrointestinal: Anorexia (1% to 5%), decreased appetite (6%), diarrhea (1% to 5%), nausea (8%), vomiting (3%)
Genitourinary: Benign prostatic hypertrophy (6%), urinary tract infection (10%)
Hematologic & oncologic: Bruise (6%)
Nervous system: Abnormal dreams (4%; may be more common in females), agitation (1% to 5%), anxiety (7%), apathy (2%), ataxia (3%; may be more common in males), confusion (3%), delusion (<3%), depression (6%; including depressed mood), drowsiness (<3%), dystonia (3%), fatigue (<3%), headache (6%), illusion (<3%), insomnia (7%), irritability (1% to 5%), nervousness (1% to 5%), paranoid ideation (<3%), suicidal ideation (≤2%), suicidal tendencies (≤2%)
|
Drug (Amantadine) |
Placebo |
Population |
Dose |
Dosage Form |
Indication |
Number of Patients (Amantadine) |
Number of Patients (Placebo) |
|---|---|---|---|---|---|---|---|
|
3% |
2% |
Adults |
274 mg once daily |
Extended-release capsules |
Treatment of dyskinesia or “off” episodes in patients with Parkinson disease receiving concomitant levodopa-based therapy |
100 |
98 |
|
Drug (Amantadine) |
Placebo |
Population |
Dose |
Dosage Form |
Indication |
Number of Patients (Amantadine) |
Number of Patients (Placebo) |
|---|---|---|---|---|---|---|---|
|
7% |
2% |
Adults |
274 mg once daily |
Extended-release capsules |
Treatment of dyskinesia or “off” episodes in patients with Parkinson disease receiving concomitant levodopa-based therapy |
100 |
98 |
Neuromuscular & skeletal: Joint swelling (3%), muscle spasm (3%)
Ophthalmic: Blurred vision (4%), cataract (3%; may be more common in females), dry eye syndrome (3%)
Respiratory: Cough (3%), dry nose (1% to 5%)
<1%:
Cardiovascular: Heart failure, hypertension
Dermatologic: Eczema, skin rash
Endocrine & metabolic: Decreased libido
Genitourinary: Urinary retention
Hematologic & oncologic: Leukopenia, neutropenia
Nervous system: Abnormality in thinking, amnesia, asthenia, euphoria, psychosis, seizure, slurred speech
Neuromuscular & skeletal: Hyperkinetic muscle activity
Ophthalmic: Corneal edema, decreased visual acuity, oculogyric crisis, optic nerve palsy, photophobia, visual disturbance (including punctate subepithelial or other corneal opacity)
Respiratory: Dyspnea
Postmarketing:
Cardiovascular: Cardiac arrhythmia (including malignant arrhythmias) (Kocaş 2015), hypotension, tachycardia (Kocaş 2015)
Dermatologic: Diaphoresis, pruritus
Endocrine & metabolic: Increased gamma-glutamyl transferase, increased lactate dehydrogenase
Gastrointestinal: Dysphagia
Hematologic & oncologic: Agranulocytosis, leukocytosis
Hepatic: Increased serum alanine aminotransferase, increased serum alkaline phosphatase, increased serum aspartate aminotransferase, increased serum bilirubin
Hypersensitivity: Anaphylaxis, hypersensitivity reaction
Nervous system: Abnormal gait, aggressive behavior (Stewart 1987), coma (Macchio 1993), EEG pattern changes (Estraneo 2015), hypertonia, impulse control disorder (including excessive eating, excessive shopping, increased libido, pathological gambling) (Walsh 2012), mania (Neagoe 2013), neuroleptic malignant syndrome (associated with dosage reduction or abrupt withdrawal of amantadine) (Ito 2001), paresthesia, sudden onset of sleep, tremor (Strong 1991), withdrawal syndrome (including delirium, exacerbation of Parkinson disease, or stupor) (Marxreiter 2017, Murray 2021)
Neuromuscular & skeletal: Hypokinesia, increased creatine phosphokinase in blood specimen
Ophthalmic: Keratitis (Nogaki 1993), mydriasis
Renal: Increased blood urea nitrogen, increased serum creatinine
Respiratory: Acute respiratory failure (Cattoni 2014), pulmonary edema (Cattoni 2014), tachypnea
Hypersensitivity to amantadine or any component of the formulation; end-stage renal disease (CrCl <15 mL/minute/1.73 m2) (extended release only).
Canadian labeling: Additional contraindications (not in US labeling): Renal impairment (CrCl <15 mL/minute).
Concerns related to adverse effects:
• CNS depression: May cause CNS depression, which may impair physical or mental abilities; patients must be cautioned about performing tasks that require mental alertness (eg, operating machinery or driving). Patients taking amantadine for Parkinson disease have reported falling asleep while engaged in activities of daily living, sometimes without warning. Patients with a concomitant sleep disorder may be at a greater risk. There is insufficient information that dose reduction will eliminate episodes of falling asleep or daytime somnolence.
• Melanoma: Risk for melanoma development is increased in Parkinson disease patients; drug causation or factors contributing to risk have not been established. Patients should be monitored closely and periodic skin examinations should be performed.
• Suicidal ideation/depression: There have been reports of suicidal ideation/attempt and depression in patients with and without a history of psychiatric illness. May exacerbate mental problems in patients with a history of mental illness.
Disease-related concerns:
• Cardiovascular disease: Use with caution in patients with heart failure, peripheral edema, or orthostatic hypotension. Dosage reduction may be required.
• Eczema: Use with caution in patients with a history of recurrent and eczematoid dermatitis.
• Glaucoma: Avoid in untreated angle closure glaucoma.
• Hepatic impairment: Use with caution in patients with hepatic impairment; rarely, reversible elevations in transaminases have been reported.
• Psychotic disorders: Use is not recommended in patients with preexisting psychotic disorders.
• Renal impairment: Use with caution in patients with renal impairment; dosage reduction recommended. Use of the extended-release products is contraindicated in end-stage renal disease (CrCl <15 mL/minute/1.73 m2).
• Seizure disorder: Use with caution in patients with a history of seizure disorder.
Special populations:
• Older adult: Use with caution in the elderly; may be more susceptible to CNS effects (using 2 divided daily doses of immediate-release products may minimize this effect). These patients may require dosage reductions.
Dosage form specific issues:
• Propylene glycol: Some dosage forms may contain propylene glycol; large amounts are potentially toxic and have been associated hyperosmolality, lactic acidosis, seizures and respiratory depression; use caution (AAP 1997; Zar 2007).
Other warnings/precautions:
• Tolerance: Tolerance has also been reported with long-term use (Zubenko 1984).
Some dosage forms may contain propylene glycol; in neonates, large amounts of propylene glycol delivered orally, intravenously (eg, >3,000 mg/day), or topically have been associated with potentially fatal toxicities which can include metabolic acidosis, seizures, renal failure, and CNS depression; toxicities have also been reported in children and adults including hyperosmolality, lactic acidosis, seizures, and respiratory depression; use caution (AAP 1997; Shehab 2009).
Substrate of OCT1, OCT2
Note: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed). For a complete list of drug interactions by individual drug name and detailed management recommendations, use the Lexicomp drug interactions program by clicking on the “Launch drug interactions program” link above.
Alcohol (Ethyl): May enhance the CNS depressant effect of Amantadine. Alcohol may also cause dose-dumping for at least one extended-release amantadine product. Risk X: Avoid combination
Alizapride: May diminish the therapeutic effect of Anti-Parkinson Agents (Dopamine Agonist). Risk X: Avoid combination
Alkalinizing Agents: May increase the serum concentration of Amantadine. Risk C: Monitor therapy
Amisulpride (Injection): May diminish the therapeutic effect of Anti-Parkinson Agents (Dopamine Agonist). Risk X: Avoid combination
Amisulpride (Oral): Anti-Parkinson Agents (Dopamine Agonist) may diminish the therapeutic effect of Amisulpride (Oral). Amisulpride (Oral) may diminish the therapeutic effect of Anti-Parkinson Agents (Dopamine Agonist). Risk X: Avoid combination
Anticholinergic Agents: Amantadine may enhance the anticholinergic effect of Anticholinergic Agents. Risk C: Monitor therapy
Antipsychotic Agents (First Generation [Typical]): Anti-Parkinson Agents (Dopamine Agonist) may diminish the therapeutic effect of Antipsychotic Agents (First Generation [Typical]). Antipsychotic Agents (First Generation [Typical]) may diminish the therapeutic effect of Anti-Parkinson Agents (Dopamine Agonist). Management: Avoid concomitant therapy if possible. If antipsychotic use is necessary, consider using atypical antipsychotics such as clozapine, quetiapine, or ziprasidone at lower initial doses, or a non-dopamine antagonist (eg, pimavanserin). Risk D: Consider therapy modification
Antipsychotic Agents (Second Generation [Atypical]): May diminish the therapeutic effect of Anti-Parkinson Agents (Dopamine Agonist). Management: Consider avoiding atypical antipsychotic use in patients with Parkinson disease. If an atypical antipsychotic is necessary, consider using clozapine, quetiapine, or ziprasidone at lower initial doses, or a non-dopamine antagonist (eg, pimavanserin). Risk D: Consider therapy modification
Brivudine [INT]: May enhance the adverse/toxic effect of Anti-Parkinson Agents (Dopamine Agonist). Specifically, the risk of chorea may be increased. Risk C: Monitor therapy
Bromopride: May diminish the therapeutic effect of Anti-Parkinson Agents (Dopamine Agonist). Risk C: Monitor therapy
BuPROPion: Anti-Parkinson Agents (Dopamine Agonist) may enhance the adverse/toxic effect of BuPROPion. Risk C: Monitor therapy
Carbonic Anhydrase Inhibitors: May increase the serum concentration of Amantadine. Risk C: Monitor therapy
Glycopyrrolate (Systemic): Amantadine may enhance the anticholinergic effect of Glycopyrrolate (Systemic). Risk C: Monitor therapy
Influenza Virus Vaccine (Live/Attenuated): Antiviral Agents (Influenza A and B) may diminish the therapeutic effect of Influenza Virus Vaccine (Live/Attenuated). Management: Avoid administration of live influenza virus vaccine (LAIV) within 2 weeks before or 48 hours after administration of antiviral agents. Consider avoiding LAIV if peramivir was given within the last 5 days or baloxavir was given within the last 17 days. Risk D: Consider therapy modification
Kava Kava: May enhance the adverse/toxic effect of Anti-Parkinson Agents (Dopamine Agonist). Kava Kava may diminish the therapeutic effect of Anti-Parkinson Agents (Dopamine Agonist). Risk C: Monitor therapy
Memantine: NMDA Receptor Antagonists may enhance the adverse/toxic effect of Memantine. Risk C: Monitor therapy
Methotrimeprazine: May diminish the therapeutic effect of Anti-Parkinson Agents (Dopamine Agonist). Anti-Parkinson Agents (Dopamine Agonist) may diminish the therapeutic effect of Methotrimeprazine. Risk X: Avoid combination
Metoclopramide: May diminish the therapeutic effect of Anti-Parkinson Agents (Dopamine Agonist). Risk X: Avoid combination
Propiverine: May enhance the adverse/toxic effect of Amantadine. Risk C: Monitor therapy
QuiNIDine: Amantadine may enhance the anticholinergic effect of QuiNIDine. QuiNIDine may increase the serum concentration of Amantadine. Risk C: Monitor therapy
Solriamfetol: May enhance the adverse/toxic effect of Anti-Parkinson Agents (Dopamine Agonist). Risk C: Monitor therapy
Sulpiride: May diminish the therapeutic effect of Anti-Parkinson Agents (Dopamine Agonist). Risk X: Avoid combination
Trimethoprim: May enhance the adverse/toxic effect of Amantadine. Specifically, the risk of myoclonus or delirium may be increased. Trimethoprim may increase the serum concentration of Amantadine. Risk C: Monitor therapy
Urinary Acidifying Agents: May decrease the serum concentration of Amantadine. Risk C: Monitor therapy
Adverse events have been observed in animal reproduction studies, and teratogenic events have been observed in humans (case reports) (Seier 2017).
When treatment for Parkinson disease is needed, agents other than amantadine are recommended in pregnant women (Seier 2017).
Amantadine is present in breast milk. Amantadine may alter breast milk production or excretion. According to the manufacturer, the decision to breastfeed during therapy should consider the risk of infant exposure, the benefits of breastfeeding to the infant, and benefits of treatment to the mother.
Renal function (baseline and as clinically indicated), mental status (especially at initiation and after dose increases) including psychosis, hallucinations, depression and suicidality, dizziness, blood pressure, and orthostasis (as clinically indicated).
Neuroleptic malignant syndrome: Electrolytes, PT/INR, aPTT, creatine kinase level, urine output, vital signs (including temperature) (Strawn 2007).
Antiviral:
Amantadine is no longer recommended as an antiviral (CDC 2020; IDSA [Uyeki 2019]). The mechanism of amantadine’s antiviral activity has not been fully elucidated. It appears to primarily prevent the release of infectious viral nucleic acid into the host cell by interfering with the transmembrane domain of the viral M2 protein. Amantadine is also known to prevent viral assembly during replication. Amantadine inhibits the replication of influenza A virus isolates from each of the subtypes (ie, H1N1, H2N2, and H3N2), but has very little or no activity against influenza B virus isolates.
Parkinson disease:
The exact mechanism of amantadine in the treatment of Parkinson disease and drug-induced extrapyramidal symptoms is not known. Data from early animal studies suggest that amantadine may have direct and indirect effects on dopamine neurons; however, recent studies have demonstrated that amantadine is a weak, noncompetitive NMDA receptor antagonist. Although amantadine has not been shown to possess direct anticholinergic activity, clinically, it exhibits anticholinergic-like side effects (dry mouth, urinary retention, and constipation).
Onset of action: Antidyskinetic: Within 48 hours
Absorption: Well absorbed
Distribution: Vd: Normal: 3 to 8 L/kg; Renal failure: 5.1 ± 0.2 L/kg (Aoki 1988)
Protein binding: Normal renal function: ~67%; Hemodialysis: ~59% (Aoki 1988)
Metabolism: Not appreciable; small amounts of an acetyl metabolite identified
Bioavailability: Immediate release: 86% to 94% (Aoki 1988)
Half-life elimination: Normal renal function: 16 ± 6 hours (9 to 31 hours); Healthy, older (≥60 years) males: 29 hours (range: 20 to 41 hours) (Aoki 1988); End-stage renal disease: 8 days
Time to peak, plasma: Extended-release capsule: 12 hours (mean; range: 6 to 20 hours); extended-release tablet: 7.5 hours (median; range: 5.5 to 12 hours); immediate release: 2 to 4 hours
Excretion: Urine (80% to 90% unchanged) by glomerular filtration and tubular secretion
Altered kidney function: Elimination half-life is increased 2- to 3-fold or greater when CrCl is less than 40 mL/minute/1.73 m2.
Older adult: Clearance is reduced
Capsule ER 24 Hour Therapy Pack (Gocovri Oral)
68.5 mg (per each): $59.87
137 mg (per each): $59.87
Capsules (Amantadine HCl Oral)
100 mg (per each): $0.97 - $2.15
Solution (Amantadine HCl Oral)
50 mg/5 mL (per mL): $0.15
Tablet ER 24 Hour Therapy Pack (Osmolex ER Oral)
129 & 193 mg (per each): $9.00
Tablet, 24-hour (Osmolex ER Oral)
129 mg (per each): $19.78
193 mg (per each): $19.78
Tablets (Amantadine HCl Oral)
100 mg (per each): $1.73 - $2.74
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