Generic Name: Amantadine Hydrochloride (Antiviral)
Class: Adamantanes
VA Class: AM800
CAS Number: 665-66-7
Introduction
Antiviral;1 antiparkinsonian agent;1 adamantane derivative.1
Uses for Symmetrel
Treatment of Seasonal Influenza A Virus Infections
Symptomatic treatment of uncomplicated respiratory tract illness caused by susceptible influenza A virus in adults, adolescents, and children ≥1 year of age.1
Consider viral surveillance data available from local and state health departments and the CDC when selecting an antiviral for treatment of seasonal influenza.116 137 149 Strains of circulating influenza viruses and the antiviral susceptibility of these strains constantly evolve,116 144 and emergence of amantadine-resistant influenza virus may decrease effectiveness of the drug.1
Beginning in the 2005–2006 influenza season, most strains of influenza A (H3N2) circulating in the US were resistant to adamantanes (amantadine, rimantadine),10 77 116 121 and resistance to these drugs among seasonal influenza A (H3N2) isolates has remained high during subsequent influenza seasons.10 117 129 162 In addition, the 2009 pandemic influenza A (H1N1) virus was resistant to amantadine and rimantadine,52 117 151 162 and this strain is expected to continue to circulate during the 2010–2011 influenza season.144 162
Amantadine and rimantadine have little or no activity against influenza B.1 24 26 27 45
CDC recommends that adamantanes (amantadine, rimantadine) not be used for treatment of seasonal influenza in the US until susceptibility to these antiviral agents has been reestablished in circulating influenza A viruses.77
CDC issues recommendations concerning the use of antiviral agents for the treatment of influenza, and these recommendations are updated as needed during each influenza season.144 Information regarding influenza surveillance and updated recommendations for treatment of seasonal influenza are available from CDC at .
Prevention of Seasonal Influenza A Virus Infections
Prophylaxis of signs and symptoms of influenza infection caused by susceptible influenza A in adults, adolescents, and children ≥1 year of age.1
Annual vaccination with seasonal influenza virus vaccine, as recommended by the US Public Health Service Advisory Committee on Immunization Practices (ACIP), is the primary means of preventing seasonal influenza and its severe complications.1 10 116 144 149 161 Prophylaxis with an appropriate antiviral active against circulating influenza strains is considered an adjunct to vaccination for control and prevention of influenza in certain individuals.1 10 116 144 149 161
Conisder viral surveillance data available from local and state health departments and the CDC when selecting an antiviral for the prophylaxis of influenza.116 137 149 The most appropriate antiviral for prevention of influenza is selected based on information regarding the likelihood that the influenza strain is susceptible and the known adverse effects of the drug.137 144 Strains of circulating influenza viruses and the antiviral susceptibility of these strains constantly evolve;137 144 consider the possibility that emergence of amantadine-resistant influenza virus may decrease effectiveness of the drug.1
CDC recommends that adamantanes (amantadine, rimantadine) not be used for prevention of influenza in the US until susceptibility to these antiviral agents has been reestablished in circulating influenza A viruses.77
CDC issues recommendations concerning the use of antiviral agents for prophylaxis of influenza, and these recommendations are updated as needed during each influenza season.144 Information regarding influenza surveillance and updated recommendations for prevention of seasonal influenza are available from CDC at .
Avian Influenza A Virus Infections
May be used for treatment of avian influenza A virus infections† in certain situations.94 104
The WHO recommends use of a neuraminidase inhibitor (i.e., oseltamivir) for the treatment of avian influenza A infections.94 104
Concomitant use of a neuraminidase inhibitor (i.e., oseltamivir) and an adamantane (amantadine, rimantadine) can be considered in a patient with pneumonic disease or clinical progression if local surveillance data indicate the H5N1 virus is known or likely to be susceptible to an adamantane.104
Should not be used alone for treatment of avian influenza A if a neuraminidase inhibitor is available.94 104 126
Parkinsonian Syndrome and Drug-induced Extrapyramidal Effects
Symptomatic treatment of parkinsonian syndrome including postencephalitic, idiopathic, arteriosclerotic types and for the relief of parkinsonian signs and symptoms of carbon monoxide poisoning.1 Less effective than levodopa.1
Symptomatic treatment of antipsychotic-induced extrapyramidal effects.1
Symmetrel Dosage and Administration
Administration
Oral Administration
Administer orally.1
Treatment or prophylaxis of influenza: Given as a single daily dose or in 2 equally divided doses (may minimize adverse CNS effects).1
Parkinsonian syndrome and drug-induced extrapyramidal effects: Usually administered twice daily.1
If insomnia occurs, the last dose should be taken several hours before bedtime.1
Dosage
Available as amantadine hydrochloride; dosage expressed in terms of amantadine hydrochloride.1
Usual dosage may need to be reduced in patients with congestive heart failure, peripheral edema, orthostatic hypotension, or impaired renal function.1
Pediatric Patients
Treatment of Seasonal Influenza A Virus Infections
Oral
Children 1–9 years of age: 4.4–8.8 mg/kg (maximum 150 mg) daily recommended by manufacturer.1 AAP recommends 5 mg/kg (up to 150 mg) daily in 2 divided doses.10
Children 9–12 years of age: 100 mg twice daily recommended by manufacturer.1
Children ≥10 years of age: AAP recommends 5 mg/kg daily in 2 divided doses in those weighing <40 kg or 200 mg daily in 2 divided doses in those weighing ≥40 kg.10
Children and adolescents ≥12 years of age: 200 mg once daily or 100 mg twice daily recommended by manufacturer.1
Initiate amantadine treatment as soon as possible, preferably within 24–48 hours after onset of symptoms, and continue for up to 5 days or 24–48 hours after symptoms disappear.1
Prevention of Seasonal Influenza A Virus Infections
Oral
Children 1–9 years of age: 4.4–8.8 mg/kg (maximum 150 mg) daily recommended by manufacturer.1 AAP recommends 5 mg/kg (up to 150 mg) daily in 2 divided doses.10
Children 9–12 years of age: 100 mg twice daily recommended by manufacturer.1
Children ≥10 years of age: AAP recommends 5 mg/kg daily in 2 divided doses in those weighing <40 kg or 200 mg daily in 2 divided doses in those weighing ≥40 kg.10
Children and adolescents ≥12 years of age: 200 mg once daily or 100 mg twice daily recommended by manufacturer.1
Alternatively, AAP states children weighing >20 kg can receive 100 mg daily.10
Adults
Treatment of Seasonal Influenza A Virus Infections
Oral
200 mg once daily or 100 mg twice daily.1
Dosage may be decreased to 100 mg daily in those who experience CNS or other toxicities with 200 mg daily;1 relative efficacy of lower dosage not elucidated.1
Initiate amantadine treatment as soon as possible, preferably within 24–48 hours after onset of symptoms, and continue for up to 5 days or 24–48 hours after symptoms disappear.1
Prevention of Seasonal Influenza A Virus Infections
Oral
200 mg once daily or 100 mg twice daily.1
Dosage may be decreased to 100 mg daily in those who experience CNS or other toxicities with 200 mg daily;1 relative efficacy of lower dosage not elucidated.1
Parkinsonian Syndrome and Drug-induced Extrapyramidal Effects
Oral
100 mg twice daily.1
Patients with serious illness or receiving other antiparkinsonian drugs: 100 mg once daily for ≥1 week, then increase to 100 mg twice daily if necessary.1
Dosage can be increased to 400 mg daily in divided doses in patients with parkinsonian syndrome.1
Dosage can be increased to 300 mg daily in divided doses in patients with drug-induced extrapyramidal reactions.1
Prescribing Limits
Pediatric Patients
Treatment or Prevention of Seasonal Influenza A Virus Infections
Oral
Children 1–9 years of age: Maximum 150 mg daily.1
Special Populations
Renal Impairment
Dosage in Adults with Renal Impairment1
Clcr (mL/minute)
|
Dosage
|
|---|
30–50
|
200 mg on first day, then 100 mg daily
|
15–29
|
200 mg on first day, then 100 mg every other day
|
<15
|
200 mg every 7 days
|
Hemodialysis patients
|
200 mg every 7 days
|
Geriatric Patients
100 mg daily for treatment or prophylaxis of influenza A virus infection in those ≥65 years of age.1 11 20 23 101 Dosage may need to be further reduced in some patients.35
Cautions for Symmetrel
Contraindications
Warnings/Precautions
Warnings
Acute Toxicity and Suicide Risk
Fatalities reported following overdosage.1 Overdosage has resulted in cardiac (arrhythmia, tachycardia, hypertension), respiratory, renal, or CNS toxicity; may be related to anticholinergic effects of the drug.1
Suicide attempts (including some fatalities) reported rarely; many patients received short courses of the drug for influenza prophylaxis or treatment.1
Suicide ideation or attempts reported in patients with or without a prior history of psychiatric disorders.1 Amantadine can exacerbate mental status in patients with a history of psychiatric disorders or substance abuse.1 Patients with suicidal tendencies may exhibit abnormal mental states including disorientation, confusion, depression, personality changes, agitation, aggressive behavior, hallucinations, paranoia, other psychotic reactions, somnolence, or insomnia.1
Use with caution in patients with uncontrolled psychosis or severe psychoneurosis.1
Lowest reported lethal dose is 1 g.1 Prescriptions should be written for smallest quantity consistent with good patient management.1
CNS Effects
Patients with a history of seizure disorders should be observed closely for possible increased seizure activity.1 (See Pediatric Use under Cautions.)
Cardiovascular Effects
CHF reported; monitor patients with a history of CHF or peripheral edema.1 Dosage adjustment may be needed.1
Ocular Effects
Amantadine may cause mydriasis; the drug should not be used in patients with untreated angle-closure glaucoma.1
Sensitivity Reactions
Allergic reactions, including anaphylactic reaction,1 rash,1 eczematoid dermatitis,1 photosensitization,86 pruritus,1 and diaphoresis,1 reported rarely.
Use with caution in patients with recurrent eczematoid dermatitis.1
General Precautions
Abrupt Withdrawal of Amantadine
Do not abruptly discontinue amantadine in patients with parkinsonian syndrome; some patients have developed parkinsonian crises after abrupt discontinuance of the drug.1 Abrupt discontinuance also may precipitate delirium, agitation, delusions, hallucinations, paranoid reaction, stupor, anxiety, depression, and slurred speech.1
Neuroleptic Malignant Syndrome
Possible neuroleptic malignant syndrome (NMS) reported; associated with dosage reduction or withdrawal of amantadine.1 Patients should be observed closely when dosage is reduced or the drug discontinued; this precaution is especially important in patients receiving concomitant therapy with an antipsychotic agent.1
Melanoma
Epidemiologic studies indicate patients with parkinsonian syndrome have a twofold to sixfold higher risk of developing melanoma than the general population.1 Unclear whether increased risk is due to parkinsonian syndrome or other factors (e.g., drugs used to treat Parkinson’s disease).1
Monitor for melanomas frequently and on a regular basis when using amantadine for any indication.1 Ideally, periodic skin examinations should be performed by appropriately qualified individuals (e.g., dermatologists).1
Intense Urges
Intense urges (e.g., urge to gamble, increased sexual urges, other intense urges) and inability to control these urges reported in some patients receiving drugs that increase central dopaminergic tone and generally are used for treatment of parkinsonian syndrome, including amantadine.1 Although causal relationship not established, these urges stopped in some cases when dosage was reduced or the drug discontinued.1
Ask patients whether they have developed new or increased gambling urges, sexual urges, or other urges while receiving amantadine; advise them of the importance of reporting such urges.1 Consider reducing dosage or discontinuing amantadine if a patient develops such urges while receiving the drug.1
Other Viral or Bacterial Infections
Not effective for treatment or prophylaxis of viral respiratory tract illnesses other than those due to influenza A virus.1 (See Uses.)
Serious bacterial infections may present with influenza-like symptoms, coexist with influenza, or occur during influenza.1 Amantadine does not prevent such complications.1
Specific Populations
Pregnancy
Category C.1
Lactation
Distributed into milk.1 Use not recommended.1
Pediatric Use
Safety and efficacy not established in neonates or infants <1 year of age.1
Increased incidence of seizures reported in children with epilepsy.10
Geriatric Use
Substantially eliminated by the kidneys.1 Consider age-related decreases in renal function and the potential for concomitant disease when selecting dosage.1 (See Geriatric Patients under Dosage and Administration.)
Hepatic Impairment
Caution in patients with liver disease.1 Increased concentrations of liver enzymes reported.1
Renal Impairment
Dosage adjustment needed based on degree of renal impairment.1 (See Renal Impairment under Dosage and Administration.)
Common Adverse Effects
Nausea, 1 35 dizziness (lightheadedness),1 23 32 35 49 insomnia.1 23 32 35 49
Interactions for Symmetrel
Specific Drugs
Drug
|
Interaction
|
Comments
|
|---|
Alcohol
|
Potential for increased CNS effects (dizziness, confusion, lightheadedness, orthostatic hypotension)1
|
Avoid excessive usage of alcohol1
|
Anticholinergic agents
|
Potential for increased adverse anticholinergic and CNS effects1 90 91 92 93
|
Dosage adjustment of both drugs may be needed1 90 91 92 93
|
Antihistamines
|
Potential for increased CNS effects51 127
|
|
Antipsychotic agents
|
Possible increased risk of NMS1 (see Neuroleptic Malignant Syndrome under Cautions)
|
Observe closely if amantadine dosage is reduced or amantadine discontinued1
|
CNS agents
|
Potential for increased adverse effects1
|
Use with caution1
|
CNS stimulants
|
Possibility of additive CNS stimulant effects127
|
Caution1 127
|
Co-triamterzide (triamterene and hydrochlorothiazide)
|
Possible increased amantadine plasma concentrations 1 90 126
|
|
Co-trimoxazole
|
Toxic delirium reported in an individual who received co-trimoxazole and amantadine concomitantly98
|
|
Influenza virus vaccines
|
Influenza virus vaccine inactivated: Amantadine does not interfere with the antibody response to the vaccine1 24
Influenza virus vaccine live intranasal: Potential interference with antibody response to the live vaccine; no specific studies1 144
|
Influenza virus vaccine inactivated: May be administered concomitantly with or at any interval before or after amantadine1 24 144
Influenza virus vaccine live intranasal: Do not administer the live intranasal vaccine until at least 48 hours after amantadine is discontinued; do not administer amantadine until at least 2 weeks after administration of the live intranasal vaccine;1 144 repeat vaccination if influenza antiviral is given 2 days before to 14 days after the vaccine144
|
Quinidine or quinine
|
Potential for a reduction in renal clearance of amantadine1 97
|
|
Thioridazine
|
Worsened tremor in geriatric patients with parkinsonian syndrome reported1
|
Not known whether a similar effect could occur with other phenothiazines1
|
Urine acidifying drugs
|
Possible increased elimination of amantadine1
|
|
Symmetrel Pharmacokinetics
Absorption
Bioavailability
Well absorbed from GI tract; peak plasma concentrations achieved in 2–4 hours.1 12 27 45 56 63 67
Onset
When used for parkinsonian syndrome, onset of action usually within 48 hours.1
Plasma Concentrations
Peak plasma concentrations are directly related to amantadine hydrochloride dose up to 200 mg daily; dosages >200 mg daily may result in a greater than proportional increase in peak plasma concentration.1 67
There appears to be a relationship between plasma concentrations of amantadine and toxicity.1 As concentrations increase, toxicity becomes more prevalent.1
Special Populations
Plasma concentrations increased in patients with renal impairment.64
Plasma concentrations in geriatric patients receiving a dosage of 100 mg daily approximate those attained in younger adults receiving a dosage of 200 mg daily.1
Distribution
Extent
Not fully characterized.1 67 99
Distributed into nasal secretions, erythrocytes, CSF, and milk.1 12 65 67
Plasma Protein Binding
67%.1 67
Elimination
Metabolism
Undergoes N-acetylation.1 67
Elimination Route
Principally excreted unchanged in urine by glomerular filtration and tubular secretion; about 5–15% excreted in urine as acetylamantadine.1 67
Only minimally removed by hemodialysis.1 8 9 67
Half-life
16 hours (range 9–31 hours).1
Special Populations
Half-life prolonged in patients with renal impairment (Clcr<40 mL/minute).1 8 9 Half-life of 18.5–81.3 hours reported in patients with Clcr 13.7–43.1 mL/minute; half-life averages 8.3 days (range: 7–10.3 days) in patients undergoing chronic hemodialysis.1 9
Half-life prolonged in healthy geriatric adults.1 5 12 Half-life of 29 hours (range: 20–41 hours) reported in geriatric men 60–76 years of age.1 5
Stability
Storage
Oral
Tablets
25°C (may be exposed to 15–30°C).1
Solution
25°C (may be exposed to 15–30°C).1
ActionsActions and Spectrum
Adamantane-derivative (a symmetric tricyclic amine);1 26 27 44 45 structurally related to rimantadine.22 26 27 29 44 45 49
Has antiviral activity against some strains of influenza A, including some strains of H1N1, H2N2, and H3N2.1 24 25 26 27 41 42 45 48 58 59
Has little or no activity against influenza B.1 24 26 27 45
Worldwide incidence of influenza A viruses resistant to adamantanes (amantadine, rimantadine) has increased over the last several years.119 128
Beginning in the 2005–2006 influenza season, most influenza A (H3N2) strains circulating in the US were resistant to amantadine and rimantadine.77 121 Resistance to amantadine and rimantadine among seasonal influenza A (H3N2) isolates has remained high during subsequent influenza seasons.10 117 129 162
Although amantadine and rimantadine were active against most seasonal influenza A (H1N1) viruses circulating in the US during the 2008–2009 and 2009–2010 influenza seasons,117 133 139 162 the 2009 pandemic influenza A (H1N1) virus is resistant to amantadine and rimantadine.52 117 151 162
Some strains of avian influenza A (H5N1) have been susceptible to amantadine;41 42 126 other strains, including influenza A (H5N1) isolated from patients in Asia during 2004 and 2005, have been resistant.112 126
Inhibits viral replication by interfering with the influenza A virus M2 protein, an integral membrane protein.1 24 26 27 45 46 47 48
Strains of influenza A virus with reduced susceptibility to amantadine have been produced in vitro and have emerged during therapy with the drug.1 21 22 24 25 26 27 28 29 39 45
Amantadine-resistant influenza A viruses also are resistant to rimantadine,21 22 23 27 43 45 46 47 54 but may be susceptible to oseltamivir or zanamivir.23
Mechanism of action in treatment of parkinsonian syndrome and drug-induced extrapyramidal reactions unknown.1 May enhance extracellular concentrations of dopamine at dopaminergic neurons, directly stimulating the dopamine receptor, or increasing sensitivity at receptors.1
Advice to Patients
Risk of CNS effects and blurred vision; use caution when alertness and motor coordination is needed.1
Advise patients with parkinsonian syndrome to gradually increase physical activity as symptoms improve.1
Importance of avoiding excessive alcohol usage.1
Importance of not getting up suddenly from a sitting or lying position; notify clinician if dizziness or lightheadedness occurs.1
Importance of notifying clinician if mood/mental changes, swelling of extremities, difficulty urinating, and/or dyspnea occur.1
Importance of taking amantadine as prescribed; importance of not taking more drug than prescribed.1 Importance of consulting clinician if there is no improvement after a few days or if drug appears less effective after a few weeks.1
Importance of seeking immediate medical attention for suspected overdose.1
Importance of consulting clinician before discontinuing amantadine.1
Importance of informing clinician if new or increased gambling urges, sexual urges, or other urges occur while receiving amantadine.1
Importance of informing clinician of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal products, as well as any concomitant illnesses.1
Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.1
Importance of advising patients of other important precautionary information.1 (See Cautions.)
Preparations
Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.
* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name
Amantadine Hydrochloride
Routes
|
Dosage Forms
|
Strengths
|
Brand Names
|
Manufacturer
|
|---|
Oral
|
Capsules
|
100 mg*
|
Amantadine Hydrochloride Capsules
|
|
|
Solution
|
50 mg/5 mL*
|
Amantadine Hydrochloride Oral Solution
|
|
|
Tablets
|
100 mg*
|
Amantadine Hydrochloride Tablets
|
|
|
|
|
Symmetrel
|
Endo
|
Comparative Pricing
This pricing information is subject to change at the sole discretion of DS Pharmacy. This pricing information was updated 03/2011. Actual costs to patients will vary depending on the use of specific retail or mail-order locations and health insurance copays.
Amantadine HCl 100MG Capsules (SANDOZ): 30/$21.99 or 60/$43.17
Amantadine HCl 100MG Tablets (UPSHER-SMITH): 30/$39.99 or 90/$109.97
Amantadine HCl 50MG/5ML Syrup (HI-TECH): 120/$15.99 or 360/$43.96
Disclaimer
This report on medications is for your information only, and is not considered individual patient advice. Because of the changing nature of drug information, please consult your physician or pharmacist about specific clinical use.
The American Society of Health-System Pharmacists, Inc. and Drugs.com represent that the information provided hereunder was formulated with a reasonable standard of care, and in conformity with professional standards in the field. The American Society of Health-System Pharmacists, Inc. and Drugs.com make no representations or warranties, express or implied, including, but not limited to, any implied warranty of merchantability and/or fitness for a particular purpose, with respect to such information and specifically disclaims all such warranties. Users are advised that decisions regarding drug therapy are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and the information is provided for informational purposes only. The entire monograph for a drug should be reviewed for a thorough understanding of the drug's actions, uses and side effects. The American Society of Health-System Pharmacists, Inc. and Drugs.com do not endorse or recommend the use of any drug. The information is not a substitute for medical care.
AHFS Drug Information. © Copyright, 1959-2011, Selected Revisions December 2010. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.
† Use is not currently included in the labeling approved by the US Food and Drug Administration.
References
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42. Hayden FG. Antivirals for pandemic influenza. J Infect Dis. 1997; 176(Suppl 1):S56-61.
43. Belshe RB, Hay AJ. Drug resistance and mechanisms of action on influenza A viruses. J Respir Dis. 1989; 10(Suppl):S52-61.
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45. Anon. Amantadine and rimantadine. In: Kucers A, Crowe SM, Grayson ML et al, eds. The use of antibiotics: a clinical review of antibacterial, antifungal and antiviral drugs. 5th ed. Boston, MA: Butterworth-Heinemann; 1997:1834-54.
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