Amantadine

Special Alerts

CDC Health Advisory on Influenza Chemoprophylaxis and Treatment - October 19, 2004

The Centers for Disease Control and Prevention (CDC) has developed interim recommendations on the use of antiviral medications for the 2004-05 influenza season. In the United States, four antiviral medications (amantadine, rimantadine, oseltamivir, and zanamivir) are approved for treatment of influenza (only limited supplies of zanamivir are available). When used for treatment within the first 2 days of illness, all four antiviral medications are similarly effective, reducing the duration of illness by 1-2 days. Amantadine, rimantadine, and oseltamivir are approved for chemoprophylaxis of influenza.

In the 2004-05 Antiviral Medications Usage Guidelines, the CDC encourages the use of amantadine or rimantadine for chemoprophylaxis and use of oseltamivir or zanamivir for treatment (as supplies allow), in part to minimize the development of amantadine resistance among circulating influenza viruses. People who are at high risk of serious complications from influenza may benefit most from antiviral medications. Therefore, in general, people who fall into these high-risk groups should be given priority for use of influenza antiviral medications:

Treatment should be initiated in any person experiencing a potentially life-threatening influenza-related illness or any person at high risk for serious complications of influenza and who is within the first 2 days of illness onset should be treated with antiviral medications. Pregnant women should consult their primary provider regarding use of influenza antiviral medications.

Chemoprophylaxis is recommended for all persons who live or work in institutions caring for people at high risk of serious complications of influenza infection should be given antiviral medications in the event of an institutional outbreak. All persons at high risk of serious influenza complications should be given antiviral medications if they are likely to be exposed to others infected with influenza. Antiviral medications can be considered in other situations when the available supply of such medications is locally adequate. Where the supplies of both influenza vaccine and influenza antiviral medications may not be sufficient to meet demand, CDC does not recommend the use of influenza antiviral medications for chemoprophylaxis of non-high risk persons in the community.

The United States has a limited supply of influenza antiviral medications stored in the Strategic National Stockpile for emergency situations. Influenza antiviral medications in the SNS can be requested only by State or Territory Health Departments.

Complete guidelines may be viewed at: http://www.cdc.gov/flu/professionals/treatment/0405antiviralguide.htm

For further information on detection and control of influenza outbreaks in acute care facilities, see http://www.cdc.gov/ncidod/hip/INFECT/flu_acute.htm

Pronunciation

(a MAN ta deen)

U.S. Brand Names

Symmetrel®

Synonyms

Adamantanamine Hydrochloride; Amantadine Hydrochloride

Generic Available

Yes

Canadian Brand Names

Endantadine®; PMS-Amantadine; Symmetrel®

Use

Prophylaxis and treatment of influenza A viral infection; treatment of parkinsonism; treatment of drug-induced extrapyramidal symptoms

Use - Unlabeled/Investigational

Creutzfeldt-Jakob disease

Pregnancy Risk Factor

Pregnancy Implications

Teratogenic effects were observed in animal studies; limited data in humans. Impaired fertility has also been reported during animal studies and during human in vitro fertilization.

Lactation

Enters breast milk/not recommended

Contraindications

Hypersensitivity to amantadine or any component of the formulation

Warnings/Precautions

Use with caution in patients with liver disease, history of recurrent and eczematoid dermatitis, uncontrolled psychosis or severe psychoneurosis, seizures, and in those receiving CNS stimulant drugs; reduce dose in renal disease. When treating Parkinson's disease, do not discontinue abruptly. In many patients, the therapeutic benefits of amantadine are limited to a few months. Elderly patients may be more susceptible to CNS effects (using 2 divided daily doses may minimize this effect). Has been associated with neuroleptic malignant syndrome (associated with dose reduction or abrupt discontinuation). Has not been shown to prevent bacterial infection or complications when used as prophylaxis or treatment of influenza A. Use with caution in patients with CHF, peripheral edema, or orthostatic hypotension. Avoid in angle closure glaucoma.

Adverse Reactions

1% to 10%:

Cardiovascular: Orthostatic hypotension, peripheral edema

Central nervous system: Insomnia, depression, anxiety, irritability, dizziness, hallucinations, ataxia, headache, somnolence, nervousness, dream abnormality, agitation, fatigue, confusion

Dermatologic: Livedo reticularis

Gastrointestinal: Nausea, anorexia, constipation, diarrhea, xerostomia

Respiratory: Dry nose

<1%: Amnesia, CHF, decreased libido, dyspnea, eczematoid dermatitis, euphoria, hyperkinesis, hypertension, instances of convulsions, leukopenia, neutropenia, oculogyric episodes, photosensitivity, psychosis, rash, slurred speech, urinary retention, visual disturbances, vomiting, weakness; withdrawal reactions may include delirium, hallucinations and psychosis

Overdosage/Toxicology

Symptoms of overdose include nausea, vomiting, slurred speech, blurred vision, lethargy, hallucinations, seizures, and myoclonic jerking. Acute toxicity may be primarily due to anticholinergic effects. The minimum lethal dose may be as low as 1 g. Treatment should be directed at reducing CNS stimulation, controlling seizures, and maintaining cardiovascular function.

Drug Interactions

Anticholinergics may potentiate CNS side effects of amantadine; monitor for altered response. Includes benztropine and trihexyphenidyl, as well as agents with anticholinergic activity such as quinidine, tricyclics, and antihistamines.

Thiazide diuretics: Hydrochlorothiazide has been reported to increase the potential for toxicity with amantadine (limited documentation); monitor response

Triamterene: Has been reported to increase the potential for toxicity with amantadine (limited documentation); monitor response

Trimethoprim: Has been reported to increase the potential for toxicity with amantadine (limited documentation); monitor for acute confusion

Ethanol/Nutrition/Herb Interactions

Ethanol: Avoid ethanol (may increase CNS adverse effects).

Stability

Store at 15°C to 30°C (59°F to 86°F); protect from freezing

Mechanism of Action

As an antiviral, blocks the uncoating of influenza A virus preventing penetration of virus into host; antiparkinsonian activity may be due to its blocking the reuptake of dopamine into presynaptic neurons or by increasing dopamine release from presynaptic fibers

Pharmacodynamics/Kinetics

Onset of action: Antidyskinetic: Within 48 hours

Absorption: Well absorbed

Distribution: Vd: Normal: 1.5-6.1 L/kg; Renal failure: 5.1 ± 0.2 L/kg; in saliva, tear film, and nasal secretions; in animals, tissue (especially lung) concentrations higher than serum concentrations; crosses blood-brain barrier

Protein binding: Normal renal function: ~67%; Hemodialysis: ~59%

Metabolism: Not appreciable; small amounts of an acetyl metabolite identified

Bioavailability: 86% to 90%

Half-life elimination: Normal renal function: 16 ± 6 hours (9-31 hours); End-stage renal disease: 7-10 days

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

Total clearance: 2.5-10.5 L/hour

Dosage

Oral:

Children:

Influenza A treatment:

1-9 years: 5 mg/kg/day in 2 divided doses (manufacturers range: 4.4-8.8 mg/kg/day); maximum dose: 150 mg/day

10 years and <40 kg: 5 mg/kg/day; maximum dose: 150 mg/day

10-12 years and 40 kg: 100 mg twice daily.

13 years: Refer to Adults dosing

Note: Initiate within 24-48 hours after onset of symptoms; discontinue as soon as possible based on clinical response (generally within 3-5 days or within 24-48 hours after symptoms disappear)

Influenza A prophylaxis: Refer to "Influenza A treatment" dosing

Note: Continue treatment 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)

Adults:

Drug-induced extrapyramidal symptoms: 100 mg twice daily; may increase to 300-400 mg/day, if needed

Parkinson's disease or Creutzfeldt-Jakob disease (unlabeled use): 100 mg twice daily as sole therapy; may increase to 400 mg/day if needed with close monitoring; initial dose: 100 mg/day if with other serious illness or with high doses of other anti-Parkinson drugs

Influenza A viral infection: 100 mg twice daily; initiate within 24-48 hours after onset of symptoms; discontinue as soon as possible based on clinical response (generally within 3-5 days or within 24-48 hours after symptoms disappear)

Influenza A prophylaxis: 100 mg twice daily

Elderly: 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).

Dosing interval in renal impairment:

Clcr 30-50 mL/minute: Administer 200 mg on day 1, then 100 mg/day

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

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

Hemodialysis: Administer 200 mg every 7 days

Peritoneal dialysis: No supplemental dose is needed

Continuous arterio-venous or venous-venous hemofiltration: No supplemental dose is needed

Monitoring Parameters

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

Patient Education

Take as directed; do not increase dosage, take more often than prescribed, or discontinue without consulting prescriber. Maintain adequate hydration (2-3 L/day of fluids) unless instructed to restrict fluid intake, and void before taking medication. Take last dose of day in the afternoon to reduce incidence of insomnia. Avoid alcohol, sedatives, or hypnotics unless consulting prescriber. You may experience decreased mental alertness or coordination (use caution when driving, climbing stairs, or engaging in tasks requiring alertness until response to drug is known); or nausea or dry mouth (small, frequent meals, frequent mouth care, sucking lozenges, or chewing gum may help). Report unusual swelling of extremities, respiratory difficulty or shortness of breath, change in gait or increased tremors, or changes in mentation (eg, depression, anxiety, irritability, hallucination, slurred speech). Pregnancy/breast-feeding precautions: Inform prescriber if you are pregnant. Breast-feeding is not recommended.

Nursing Implications

If insomnia occurs, the last daily dose should be given several hours before retiring; assess parkinsonian symptoms prior to and throughout course of therapy

Additional Information

Patients with intolerable CNS side effects often do better with rimantadine.

Dental Health: Effects on Dental Treatment

Key adverse event(s) related to dental treatment: Xerostomia (prolonged use may cause significant xerostomia; normal salivary flow resumes upon discontinuation) and orthostatic hypotension.

Dental Health: Vasoconstrictor/Local Anesthetic Precautions

No information available to require special precautions

Dosage Forms

Capsule, as hydrochloride: 100 mg

Syrup, as hydrochloride (Symmetrel®): 50 mg/5 mL (480 mL) [raspberry flavor]

Tablet, as hydrochloride (Symmetrel®): 100 mg

References

Allen RM, "Palliative Treatment of Tardive Dyskinesia With Combination of Amantadine-Neuroleptic Administration," Biol Psychiatry , 1982, 17(6):719-27.

Alphs L and Davis JM, "Noncatecholaminergic Treatments of Tardive Dyskinesia," J Clin Psychopharmacol , 1982, 2(6):380-5.

Aoki FY and Sitar DS, "Amantadine Kinetics in Healthy Elderly Men: Implications for Influenza Prevention," Clin Pharmacol Ther , 1985, 37(2):137-44.

Aoki FY and Sitar DS, "Clinical Pharmacokinetics of Amantadine Hydrochloride," Clin Pharmacokinet , 1988, 14(1):35-51.

Arden NH, Patriarca PA, Fasano MB, et al, "The Roles of Vaccination and Amantadine Prophylaxis in Controlling an Outbreak of Influenza A (H3N2) in a Nursing Home," Arch Intern Med , 1988, 148(4):865-8.

Berkowitz CD, "Treatment of Acute Amantadine Toxicity With Physostigmine," J Pediatr , 1979, 95(1):144-5.

Borison RL, "Amantadine in the Management of Extrapyramidal Side Effects," Clin Neuropharmacol , 1983, 6(Suppl 1):57-63.

Centers for Disease Control, "Prevention and Control of Influenza. Recommendations of the Advisory Committee on Immunization Practices (ACIP)," MMWR Recomm Rep , 2003, 52(RR-8):16-22.

Douglas RG Jr, "Prophylaxis and Treatment of Influenza," N Engl J Med , 1990, 322(7):443-50.

"Drugs for Non-HIV Viral Infections," Med Lett Drugs Ther , 2002, 44(1123):9-16.

Farrell S, Lee DC, and McNamara B, "Amantadine Overdose: Considerations for the Treatment of Cardiac Toxicity," Clin Toxicol , 1995, 33(5):516-7.

Keating MR, "Antiviral Agents," Mayo Clin Proc , 1992, 67(2):160-78.

Koller WC, Silver DE, and Lieberman A, "An Algorithm for the Management of Parkinson's Disease," Neurology , 1994, 44(12 Suppl 10):1-52.

Miller KS and Miller JM, "Toxic Effects of Amantadine in Patients With Renal Failure," Chest , 1994, 105(5):1630.

Poldinger W, "Therapy of Extrapyramidal Side Effects, With Particular Reference to Persistent Dyskinesia and Lithium Tremor," International Pharmacopsychiatry , 1978, 13(4):230-3.

Sartori M, Pratt CM, and Young JB, "Torsade de Pointe: Malignant Cardiac Arrhythmias Induced by Amantadine Poisoning," Am J Med , 1984, 77(2):388-91.

Somani SK, Degelau J, Cooper SL, et al, "Comparison of Pharmacokinetic and Safety Profiles of Amantadine 50- and 100-mg Daily Doses in Elderly Nursing Home Residents," Pharmacotherapy , 1991, 11(6):460-6.

Stange KC, Little DW, and Blatnik B, "Adverse Reactions to Amantadine Prophylaxis of Influenza in a Retirement Home," J Am Geriatr Soc , 1991, 33(7):700-5.

Strong DK, Eisenstat DD, Bryson SM, et al, "Amantadine Neurotoxicity in a Pediatric Patient With Renal Insufficiency," DICP , 1991, 25(11):1175-7.

Yang CC and Deng JF, "Anticholinergic Syndrome With Severe Rhabdomyolysis in Amantadine Poisoning," Clin Toxicol , 1995, 33(5):518.

International Brand Names

Adekin® (DE); Aman® (DE); Amanta AbZ® (DE); Amantadin AL® (DE); Amantadina Level® (ES); Amantadina Llorente® (ES); Amantadina® (RO); Amantadin beta® (DE); Amantadin-HCl Sandoz® (DE); Amantadin Holsten® (DE); Amantadin Lindo® (DE); Amantadin-neuraxpharm® (DE); Amantadin-ratiopharm® (DE); Amantadin Stada® (DE); Amantadin-Sulfat Sandoz® (DE); Amantadin-TEVA® (DE); amantadin von ct® (DE); Amantagamma® (DE); Amanta-HCl-AZU® (DE); Amantan® (BE, LU); Amanta-Sulfat-AZU® (DE); Amantix® (CO, PL); Amantrel® (IN); Amazolon® (JP); Amixx® (DE); a.m.t.® (DE); A-Parkin® (IL, RO); Atarin® (CN, FI); Chemogen® (CZ); Endantadine® (CA); Hofcomant® (AT); InfectoFlu® (DE); Infex® (DE); Lysovir® (GB); Mantadan® (IT); Mantadix® (BE, FR, LU); Mantidan® (BR); Paritrel® (IL, RO); PK-Merz® (CH, CL, CR, CY, CZ, DE, DO, EG, GT, HN, HU, IL, JO, KW, LB, LU, MT, PA, RU, SV); PK-Merz-Schoeller® (AT); PMS-Amantadine (CA); Prayanol® (CL); Symmetrel® (AU, CA, CH, GB, IE, NL, NZ, SG, ZA); Tregor® (DE); Viregyt-K® (CZ, HU, PL, RO); Virosol® (AR); Virucid® (AT)

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