Amantadine

(a MAN ta deen)

Drug-induced extrapyramidal symptoms (immediate release and extended-release tablet only): Treatment of drug-induced extrapyramidal symptoms.

Influenza A prophylaxis (immediate release only): Chemoprophylaxis against signs and symptoms of influenza A virus infection; also refer to current Advisory Committee on Immunization Practices (ACIP) guidelines for recommendations during current influenza season.

Influenza A treatment (immediate release only): Treatment of uncomplicated respiratory tract illness caused by influenza A virus strains; also refer to current ACIP guidelines for recommendations during current influenza season.

Parkinson disease:

Extended release:

Capsule: Treatment of dyskinesia in patients with Parkinson disease receiving levodopa-based therapy, with or without concomitant dopaminergic medications.

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).

Influenza A treatment/prophylaxis:Note: Due to issues of resistance, amantadine is no longer recommended for the treatment or prophylaxis of influenza A (CDC 2011). Please refer to the current ACIP recommendations. The following is based on the manufacturer’s labeling:

Influenza A treatment: Immediate release: Oral: 200 mg once daily or 100 mg twice daily (may be preferred to reduce CNS effects); Note: Initiate within 24 to 48 hours after onset of symptoms; continue for 24 to 48 hours after symptom resolution (duration of therapy is generally 5 days [CDC 2011]).

Influenza A prophylaxis: Immediate release: Oral: 200 mg once daily or 100 mg twice daily (may be preferred to reduce CNS effects). Note: Continue prophylaxis throughout the peak influenza activity in the community or throughout the entire influenza season in patients who cannot be vaccinated. Development of immunity following vaccination takes ~2 weeks; amantadine therapy should be considered for high-risk patients from the time of vaccination until immunity has developed.

Drug-induced extrapyramidal symptoms:

Extended-release tablet: Oral: Initial: 129 mg once daily; may be increased in weekly intervals to a maximum dose of 322 mg/day.

Immediate release: Oral: 100 mg twice daily; may increase to 300 mg/day in divided doses, if needed

Parkinson disease:

Extended release:

Capsule (monotherapy or as an adjunct to dopaminergic medications): 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 in weekly intervals to a maximum dose of 322 mg/day.

Immediate release: Oral: Usual dose: 100 mg twice daily as monotherapy; may increase to 400 mg/day in divided doses, if needed, with close monitoring. Note: Patients with a serious concomitant illness or those receiving high doses of other antiparkinson drugs should be started at 100 mg once daily; may increase to 100 mg twice daily, if needed, after one to several weeks.

Chorea of Huntington disease (off-label use): Immediate release: Oral: 100 mg 3 to 4 times daily. Additional data may be necessary to further define the role of amantadine in this condition (Armstrong 2012; O'Suilleabhain 2003; Verhagen 2002).

Multiple sclerosis-related fatigue (off-label use): Immediate release: Oral: 100 mg twice daily. Additional data may be necessary to further define the role of amantadine in this condition (Ledinek 2013; Shaygannejad 2012).

Restless legs syndrome (off-label use): Immediate release: Oral: Initial: 100 mg daily; increase by 100 mg every 3 to 5 days based on response and tolerability up to 300 mg/day in 1 to 3 divided doses. Additional data may be necessary to further define the role of amantadine in this condition (Evidente 2000).

Traumatic brain injury (off-label use): Immediate release: Oral: Initial: 100 mg twice daily (morning and afternoon); may increase total daily dose by 100 mg every week based on response and tolerability up to 200 mg twice daily. Additional data may be necessary to further define the role of amantadine in this condition (Giacino 2012; Hammond 2014).

Discontinuation of therapy: Do not discontinue abruptly. For patients who have taken the extended-release capsule for more than 4 weeks, reduce dose by half for 1 week before discontinuing, if possible. Reduce the dose of the extended-release tablet gradually from higher doses to 129 mg/day for 1 to 2 weeks before discontinuing.

Drug-induced extrapyramidal symptoms/Parkinson disease: Refer to adult dosing; some patients tolerate the immediate-release formulations better when administered in 2 divided daily doses (to avoid adverse neurologic reactions).

Influenza A treatment/prophylaxis: Immediate release: Oral: 100 mg once daily. Note: Due to issues of resistance, amantadine is no longer recommended for the treatment or prophylaxis of influenza A (CDC 2011).

Discontinuation of therapy: Refer to adult dosing.

Influenza A treatment/prophylaxis: Children and Adolescents: Oral: Note: Due to issues of resistance, amantadine is no longer recommended for the treatment or prophylaxis of influenza A (CDC 2011). Please refer to the current ACIP recommendations.

Influenza A treatment (CDC 2011): Immediate release:

1 to 9 years: 5 mg/kg/day in 2 divided doses (manufacturer's range: 4.4 to 8.8 mg/kg/day); maximum dose: 150 mg/day

≥10 years and <40 kg: 5 mg/kg/day in 2 divided doses

≥10 years and ≥40 kg: 100 mg twice daily

Note: Initiate within 24 to 48 hours after onset of symptoms; continue for 24 to 48 hours after symptom resolution (duration of therapy is generally 5 days)

Influenza A prophylaxis: Immediate release: Refer to "Influenza A treatment" dosing. Note: Continue prophylaxis throughout the peak influenza activity in the community or throughout the entire influenza season in patients who cannot be vaccinated. Development of immunity following vaccination takes ~2 weeks; amantadine therapy should be considered for high-risk patients from the time of vaccination until immunity has developed. For children <9 years receiving influenza vaccine for the first time, amantadine prophylaxis should continue for 6 weeks (4 weeks after the first dose and 2 weeks after the second dose).

Discontinuation of therapy: Do not discontinue abruptly.

Extended-release capsule:

CrCl ≥60 mL/minute/1.73 m²: No dosage adjustment necessary.

CrCl 30 to 59 mL/minute/1.73 m²: Initial: 68.5 mg once daily; after 1 week increase to 137 mg once daily if needed

CrCl 15 to 29 mL/minute/1.73 m²: 68.5 mg once daily

CrCl <15 mL/minute/1.73 m² (ESRD): Use is contraindicated.

Hemodialysis: Inefficiently dialyzed; use is contraindicated.

Extended-release tablet:

CrCl ≥60 mL/minute/1.73 m²: No dosage adjustment necessary.

CrCl 30 to 59 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

CrCl 15 to 29 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

CrCl <15 mL/minute/1.73 m² (ESRD): Use is contraindicated.

Hemodialysis: Inefficiently dialyzed; use is contraindicated.

Immediate release:

CrCl 30 to 50 mL/minute: 200 mg on day 1, then 100 mg/day

CrCl 15 to 29 mL/minute: 200 mg on day 1, then 100 mg every other day

CrCl <15 mL/minute: 200 mg every 7 days

Hemodialysis: 200 mg every 7 days (inefficiently dialyzed)

Peritoneal dialysis: No supplemental dose is needed (Aronoff 2007)

Continuous renal replacement therapy: 100 mg once daily or every other day (Aronoff 2007)

There are no dosage adjustments provided in the manufacturer's labeling; use with caution.

Oral:

Extended-release 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.

Extended-release tablet: Administer in the morning without regard to food. Swallow whole; do not crush, chew, or divide tablets.

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.

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 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 [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: Anti-Parkinson Agents (Dopamine Agonist) may diminish the therapeutic effect of Amisulpride. Amisulpride 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 and monitor for decreased effects of both agents when these combinations cannot be avoided. Atypical antipsychotics such as clozapine and quetiapine may be less likely to reduce the effects of anti-Parkinson agents. Consider therapy modification

Antipsychotic Agents (Second Generation [Atypical]): May diminish the therapeutic effect of Anti-Parkinson Agents (Dopamine Agonist). Management: Consider using an alternative antipsychotic agent when possible in patients with Parkinson disease. If an atypical antipsychotic is necessary, consider using clozapine or quetiapine, which may convey the lowest interaction risk. Consider therapy modification

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 anti-influenza antivirals during the period beginning 48 hours prior to and ending 2 weeks after live influenza virus vaccine administration. Consider therapy modification

Memantine: NMDA Receptor Antagonists may enhance the adverse/toxic effect of Memantine. Monitor therapy

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). Monitor therapy

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

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

Tafenoquine: May increase the serum concentration of OCT2 Substrates. Management: Avoid use of OCT2 substrates with tafenoquine, and if the combination cannot be avoided, monitor closely for evidence of toxicity of the OCT2 substrate and consider a reduced dose of the OCT2 substrate according to that substrate's labeling. Consider therapy modification

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).

>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, 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), weakness

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.

• Influenza A: Appropriate use: Consult current guidelines. Due to increased resistance, the ACIP has recommended that rimantadine and amantadine no longer be used for the treatment or prophylaxis of influenza A in the United States until susceptibility has been re-established (CDC 2011).

• 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.

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

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 (Zubenko1984).

• 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 changed 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.

C

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).

Untreated influenza infection is associated with an increased risk of adverse events to the fetus and an increased risk of complications or death to the mother. Other agents are currently recommended for the treatment or prophylaxis influenza in pregnant women and women up to 2 weeks postpartum. Appropriate antiviral agents are currently recommended as an adjunct to vaccination and should not be used as a substitute for vaccination in pregnant women (CDC 2011; CDC 2014).

Antiviral:

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)

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience dry mouth, constipation, lack of appetite, fatigue, abnormal dreams, dry nose, diarrhea, loss of strength and energy, tablet shell in stool, nausea, headache, anxiety, or insomnia. Have patient report immediately to prescriber behavioral changes, confusion, severe dizziness, passing out, hallucinations, seizures, shortness of breath, excessive weight gain, swelling of arms or legs, difficult urination, blurred vision, uncontrollable urges, change in balance, falls, signs of depression (suicidal ideation, anxiety, emotional instability, or confusion), agitation, irritability, panic attacks, mood changes, skin growths, mole changes, signs of a urinary tract infection (hematuria, burning or painful urination, polyuria, fever, lower abdominal pain, or pelvic pain), narcolepsy, severe fatigue, or signs of neuroleptic malignant syndrome (fever, muscle cramps or stiffness, dizziness, severe headache, confusion, change in thinking, tachycardia, abnormal heartbeat, or sweating a lot) (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for health care professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience, and judgment in diagnosing, treating, and advising patients.