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Amantadine

Pronunciation

Pronunciation

(a MAN ta deen)

Index Terms

  • Adamantanamine Hydrochloride
  • Amantadine Hydrochloride
  • Symmetrel

Dosage Forms

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 (10 mL, 473 mL)

Tablet, Oral, as hydrochloride:

Generic: 100 mg

Pharmacologic Category

  • Anti-Parkinson Agent, Dopamine Agonist
  • Antiviral Agent
  • Antiviral Agent, Adamantane

Pharmacology

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 reactions 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).

Absorption

Well absorbed

Distribution

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

Metabolism

Not appreciable; small amounts of an acetyl metabolite identified

Excretion

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

Onset of Action

Antidyskinetic: Within 48 hours

Time to Peak

Plasma: 2-4 hours

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

Protein Binding

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

Special Populations: Renal Function Impairment

Elimination half-life is increased 2- to 3-fold or greater when CrCl is less than 40 mL/minute/1.73 m2.

Special Populations: Elderly

Clearance is reduced

Use: Labeled Indications

Drug-induced extrapyramidal reactions: Treatment of drug-induced extrapyramidal reactions.

Influenza A prophylaxis: 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: 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: 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.

Contraindications

Hypersensitivity to amantadine or any component of the formulation

Dosing: Adult

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

Parkinson's disease: 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 anti-parkinson drugs should be started at 100 mg once daily; may increase to 100 mg twice daily, if needed, after one to several weeks.

Dosing: Geriatric

Patients ≥65 years: Adjust dose based on renal function; some patients tolerate the drug better when it is given in 2 divided daily doses (to avoid adverse neurologic reactions).

Influenza A treatment/prophylaxis: 100 mg once daily

Dosing: Pediatric

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):

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: 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).

Dosing: Renal Impairment

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

CrCl 15 to 29 mL/minute: Administer 200 mg on day 1, then 100 mg on alternate days

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

Hemodialysis: Administer 200 mg every 7 days

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

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

Dosing: Hepatic Impairment

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

Storage

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 capsules from moisture.

Drug Interactions

Alcohol (Ethyl): May enhance the CNS depressant effect 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

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

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

BuPROPion: May increase the serum concentration of OCT2 Substrates. Monitor therapy

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

Highest Risk QTc-Prolonging Agents: QTc-Prolonging Agents (Indeterminate Risk and Risk Modifying) may enhance the QTc-prolonging effect of Highest Risk QTc-Prolonging Agents. Management: Avoid such combinations when possible. Use should be accompanied by close monitoring for evidence of QT prolongation or other alterations of cardiac rhythm. Consider therapy modification

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 vaccine administration. Persons receiving these agents within 2 weeks of the live intranasal spray vaccine should receive a repeat vaccine dose. 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

MiFEPRIStone: May enhance the QTc-prolonging effect of QTc-Prolonging Agents (Indeterminate Risk and Risk Modifying). Management: Though the drugs listed here have uncertain QT-prolonging effects, they all have some possible association with QT prolongation and should generally be avoided when possible. Consider therapy modification

Moderate Risk QTc-Prolonging Agents: QTc-Prolonging Agents (Indeterminate Risk and Risk Modifying) may enhance the QTc-prolonging effect of Moderate Risk QTc-Prolonging Agents. Monitor therapy

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

Test Interactions

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

Adverse Reactions

1% to 10%:

Cardiovascular: Livedo reticularis, orthostatic hypotension, peripheral edema

Central nervous system: Abnormal dreams, agitation, anxiety, ataxia, confusion, delirium, depression, dizziness, drowsiness, fatigue, hallucination, headache, insomnia, irritability, nervousness

Gastrointestinal: Anorexia, constipation, diarrhea, nausea, xerostomia

Respiratory: Dry nose

<1% (Limited to important or life-threatening): Abnormal gait, acute respiratory tract failure, aggressive behavior, agranulocytosis, amnesia, anaphylaxis, cardiac arrest, cardiac arrhythmia, cardiac failure, coma, decreased libido, delusions, diaphoresis, dysphagia, dyspnea, eczema, EEG pattern changes, euphoria, fever, hyperkinesia, hypersensitivity reaction, hypertension, hypertonia, hypokinesia, hypotension, increased blood urea nitrogen, increased creatine phosphokinase, increased gamma-glutamyl transferase, increased lactate dehydrogenase, increased serum alkaline phosphatase, increased serum ALT, increased serum AST, increased serum bilirubin, increased serum creatinine, keratitis, leukocytosis, leukopenia, mania, muscle spasm, mydriasis, neuroleptic malignant syndrome (associated with dosage reduction or abrupt withdrawal of amantadine), neutropenia, oculogyric crisis, paranoia, paresthesia, pruritus, psychosis, pulmonary edema, seizure, skin photosensitivity, skin rash, slurred speech, stupor, suicidal ideation, suicide, suicide attempt, tachycardia, tachypnea, tremor, urinary retention, visual disturbance, vomiting, weakness

Warnings/Precautions

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).

• 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), 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’s 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.

• Neuroleptic malignant syndrome: Has been associated with neuroleptic malignant syndrome (associated with dose reduction or abrupt discontinuation).

• Suicidal ideation: There have been reports of suicidal ideation/attempt 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.

• 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).

• Parkinson's disease: Appropriate use: When treating Parkinson disease, do not discontinue abruptly. In many patients, the therapeutic benefits of amantadine are limited to a few months.

• Psychosis: Use with caution in patients with uncontrolled psychosis or severe psychoneurosis.

• Renal impairment: Use with caution in patients with renal impairment; dosage reduction recommended.

• 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 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: May cause agitation, anxiety, delirium, delusions, depression, hallucinations, paranoia, parkinsonian crisis, slurred speech, or stupor. Upon discontinuation of amantadine therapy, gradually taper dose.

Monitoring Parameters

Renal function, Parkinson's symptoms, mental status, influenza symptoms, blood pressure

Pregnancy Risk Factor

C

Pregnancy Considerations

Adverse events have been observed in animal reproduction studies and teratogenic events have been observed in humans (case reports).

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).

Health care providers are encouraged to refer women exposed to influenza vaccine, or who have taken an antiviral medication during pregnancy to the Vaccines and Medications in Pregnancy Surveillance System (VAMPSS) by contacting The Organization of Teratology Information Specialists (OTIS) at (877) 311-8972

Patient Education

• 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 nausea 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, signs of depression (suicidal ideation, anxiety, emotional instability, or confusion), agitation, irritability, panic attacks, mood changes, skin growths, mole changes, 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 healthcare 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.

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