Amantadine

(a MAN ta deen)

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.

Hypersensitivity to amantadine or any component of the formulation; end-stage renal disease (CrCl <15 mL/minute/1.73 m²) (extended release only).

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.

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.

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.

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.

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.

Store at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F). Protect immediate-release capsules from moisture and exposure to light.

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

Syrup, 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, fd&c yellow #10 (quinoline yellow), fd&c yellow #6 (sunset yellow)]

Tablet Extended Release 24 Hour, Oral, as hydrochloride [strength expressed as base]:

Osmolex ER: 129 mg [contains fd&c yellow #10 (quinoline yellow), fd&c yellow #6 (sunset yellow)]

Osmolex ER: 193 mg [contains fd&c blue #2 (indigotine), fd&c red #40, fd&c yellow #10 (quinoline yellow), fd&c yellow #6 (sunset yellow)]

Osmolex ER: 258 mg [DSC] [contains brilliant blue fcf (fd&c blue #1), fd&c red #40, fd&c yellow #10 (quinoline yellow), fd&c yellow #6 (sunset yellow)]

Alcohol (Ethyl): May enhance the CNS depressant effect of Amantadine. Alcohol may also cause dose-dumping for at least one extended-release amantadine product. Avoid combination

Alizapride: May diminish the therapeutic effect of Anti-Parkinson Agents (Dopamine Agonist). Avoid combination

Alkalinizing Agents: May increase the serum concentration of Amantadine. Monitor therapy

Amisulpride (Injection): May diminish the therapeutic effect of Anti-Parkinson Agents (Dopamine Agonist). 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). Avoid combination

Anticholinergic Agents: Amantadine may enhance the anticholinergic effect of Anticholinergic Agents. 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). 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). 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. Monitor therapy

Bromopride: May diminish the therapeutic effect of Anti-Parkinson Agents (Dopamine Agonist). Monitor therapy

BuPROPion: Anti-Parkinson Agents (Dopamine Agonist) may enhance the adverse/toxic effect of BuPROPion. Monitor therapy

Carbonic Anhydrase Inhibitors: May increase the serum concentration of Amantadine. Monitor therapy

Glycopyrrolate (Systemic): Amantadine may enhance the anticholinergic effect of Glycopyrrolate (Systemic). 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. 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). Monitor therapy

Memantine: NMDA Receptor Antagonists may enhance the adverse/toxic effect of Memantine. 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. Avoid combination

Methylphenidate: May enhance the adverse/toxic effect of Anti-Parkinson Agents (Dopamine Agonist). Monitor therapy

Metoclopramide: May diminish the therapeutic effect of Anti-Parkinson Agents (Dopamine Agonist). Avoid combination

Propiverine: May enhance the adverse/toxic effect of Amantadine. Monitor therapy

QuiNIDine: Amantadine may enhance the anticholinergic effect of QuiNIDine. QuiNIDine may increase the serum concentration of Amantadine. Monitor therapy

Solriamfetol: May enhance the adverse/toxic effect of Anti-Parkinson Agents (Dopamine Agonist). Monitor therapy

Sulpiride: May diminish the therapeutic effect of Anti-Parkinson Agents (Dopamine Agonist). Avoid combination

Trimethoprim: May enhance the adverse/toxic effect of Amantadine. Specifically, the risk of myoclonus and/or delirium may be increased. Amantadine may increase the serum concentration of Trimethoprim. Trimethoprim may increase the serum concentration of Amantadine. Monitor therapy

Urinary Acidifying Agents: May decrease the serum concentration of Amantadine. Monitor therapy

Renal function (baseline and as clinically indicated), mental status including psychosis, hallucinations, depression and suicidality, dizziness, blood pressure, and orthostasis (as clinically indicated)

May interfere with urine detection of amphetamines/methamphetamines (false-positive).

The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified.

>10%:

Cardiovascular: Orthostatic hypotension (≤29%; may be more common in men), presyncope (≤29%), syncope (≤29%), peripheral edema (1% to 16%)

Central nervous system: Dizziness (≤29%), delusions (≤25%), hallucination (≤25%), illusion (≤25%), paranoia (≤25%), falling (13%)

Gastrointestinal: Xerostomia (1% to 16%; may be more common in women), constipation (1% to 13%)

1% to 10%:

Cardiovascular: Livedo reticularis (1% to 6%; may be more common in women)

Central nervous system: Insomnia (5% to 10%), anxiety (1% to 7%), depression (1% to 6%), headache (1% to 6%), abnormal dreams (1% to 5%; may be more common in women), agitation (1% to 5%), ataxia (1% to 5%; may be more common in men and adults ≥65 years old), confusion (1% to 5%), drowsiness (1% to 5%), fatigue (1% to 5%), irritability (1% to 5%), nervousness (1% to 5%), dyschromia (3%), dystonia (3%), apathy (2%), suicidal ideation (≤2%)

Gastrointestinal: Nausea (5% to 10%; may be more common in women), decreased appetite (6%), anorexia (1% to 5%), diarrhea (1% to 5%), vomiting (3%)

Genitourinary: Urinary tract infection (10%), benign prostatic hypertrophy (6%)

Hematologic & oncologic: Bruise (6%)

Neuromuscular & skeletal: Joint swelling (3%), muscle spasm (3%)

Ophthalmic: Blurred vision (4%), cataract (3%; may be more common in women), xerophthalmia (3%)

Respiratory: Dry nose (1% to 5%), cough (3%)

<1%, postmarketing, and/or case reports: Abnormal gait, abnormality in thinking, acute respiratory tract failure, aggressive behavior, agranulocytosis, amnesia, anaphylaxis, asthenia, cardiac arrhythmia (including malignant arrhythmias), cardiac failure, coma, corneal edema, decreased libido, decreased visual acuity, delirium, diaphoresis, dysphagia, dyspnea, eczema, edema, EEG pattern changes, euphoria, fever, hyperkinesia, hypersensitivity reaction, hypertension, hypertonia, hypokinesia, hypotension, impulse control disorder, increased blood urea nitrogen, increased creatine phosphokinase, increased gamma-glutamyl transferase, increased lactate dehydrogenase, increased libido, increased serum alkaline phosphatase, increased serum ALT, increased serum AST, increased serum bilirubin, increased serum creatinine, keratitis, leukocytosis, leukopenia, mania, mydriasis, neuroleptic malignant syndrome (associated with dosage reduction or abrupt withdrawal of amantadine), neutropenia, oculogyric crisis, optic nerve palsy, paresthesia, pathological gambling, pruritus, psychosis, pulmonary edema, seizure, skin photosensitivity, skin rash, slurred speech, stupor, tachycardia, tachypnea, tremor, urinary retention, visual disturbance (including punctate subepithelial or other corneal opacity)

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.

• Impulse control disorders: Dopamine agonists used for Parkinson disease or restless legs syndrome have been associated with compulsive behaviors and/or loss of impulse control, which has manifested as pathological gambling, libido increases (hypersexuality), urges to spend money, and/or binge eating. Causality has not been established, and controversy exists as to whether this phenomenon is related to the underlying disease, prior behaviors/addictions, and/or drug therapy. Dose reduction or discontinuation of therapy has been reported to reverse these behaviors in some, but not all cases.

• 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.

• Psychosis: Visual and auditory hallucinations, delusions, illusions, and paranoia were reported in clinical trials; monitor for the occurrence of these symptoms especially at initiation and after dose increases. Use is not recommended in patients with preexisting psychotic disorders.

• 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; dizziness, syncope, orthostatic hypotension, presyncope, postural dizziness, and hypotension have been reported in clinical trials. 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.

• 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:

• Elderly: 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).

• Withdrawal syndrome: A symptom complex resembling neuroleptic malignant syndrome (elevated temperature, muscular rigidity, altered consciousness, and autonomic instability) with no other obvious cause has been reported in association with rapid dose reduction, withdrawal of, or changes in drugs that increased central dopaminergic dose. Abrupt discontinuation of amantadine may cause agitation, anxiety, delirium, delusions, depression, hallucinations, paranoia, parkinsonian crisis, slurred speech, or stupor. Upon discontinuation of amantadine therapy, gradually taper dose.

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).

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).

Well absorbed

V_d: Normal: 3 to 8 L/kg; Renal failure: 5.1 ± 0.2 L/kg (Aoki 1988)

Not appreciable; small amounts of an acetyl metabolite identified

Urine (80% to 90% unchanged) by glomerular filtration and tubular secretion

Antidyskinetic: Within 48 hours

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

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

Normal renal function: ~67%; Hemodialysis: ~59% (Aoki 1988)

What is this drug used for?

• It is used to treat or prevent the flu.

• It is used to treat Parkinson's disease and side effects caused by some other drugs.

• It may be given for other reasons. Talk with the doctor.

All drugs may cause side effects. However, many people have no side effects or only have minor side effects. Call your doctor or get medical help if any of these side effects or any other side effects bother you or do not go away:

• Dry mouth

• Constipation

• Lack of appetite

• Abnormal dreams

• Dry nose

• Diarrhea

• Loss of strength and energy

• Tablet shell in stool

• Nausea

• Headache

• Anxiety

• Trouble sleeping

WARNING/CAUTION: Even though it may be rare, some people may have very bad and sometimes deadly side effects when taking a drug. Tell your doctor or get medical help right away if you have any of the following signs or symptoms that may be related to a very bad side effect:

• Confusion

• Severe dizziness

• Passing out

• Sensing things that seem real but are not

• Seizures

• Shortness of breath

• Excessive weight gain

• Swelling of arms or legs

• Difficult urination

• Blurred vision

• Uncontrollable urges

• Change in balance

• Falls

• Depression like thoughts of suicide, anxiety, emotional instability, agitation, irritability, panic attacks, mood changes, behavioral changes, or confusion

• Skin growths

• Mole changes

• Urinary tract infection like blood in the urine, burning or painful urination, passing a lot of urine, fever, lower abdominal pain, or pelvic pain.

• Narcolepsy

• Severe fatigue

• Neuroleptic malignant syndrome like fever, muscle cramps or stiffness, dizziness, severe headache, confusion, change in thinking, fast heartbeat, abnormal heartbeat, or sweating a lot.

• Signs of an allergic reaction, like rash; hives; itching; red, swollen, blistered, or peeling skin with or without fever; wheezing; tightness in the chest or throat; trouble breathing, swallowing, or talking; unusual hoarseness; or swelling of the mouth, face, lips, tongue, or throat.

Note: This is not a comprehensive list of all side effects. Talk to your doctor if you have questions.

Consumer Information Use and Disclaimer: This information should not be used to decide whether or not to take this medicine or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a limited summary of general information about the medicine’s uses from the patient education leaflet and is not intended to be comprehensive. This limited summary does NOT include all information available about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to this medicine. This information is not intended to provide medical advice, diagnosis or treatment and does not replace information you receive from the healthcare provider. For a more detailed summary of information about the risks and benefits of using this medicine, please speak with your healthcare provider and review the entire patient education leaflet.