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Amantadine Hydrochloride (Antiviral)

Pronunciation

Class: Adamantanes
VA Class: AM800
CAS Number: 665-66-7

Introduction

Antiviral;1 2 6 2 6 antiparkinsonian agent;1 2 6 adamantane derivative.1 2 6

Uses for Amantadine Hydrochloride (Antiviral)

Treatment of Seasonal Influenza A Virus Infections

Has been used for treatment of uncomplicated respiratory tract illness caused by susceptible influenza A virus in adults, adolescents, and children ≥1 year of age.1 2 6

Amantadine and rimantadine have little or no activity against influenza B; not used for treatment of influenza B infection.1 2 6 24 26 27 45

Beginning in the 2005–2006 influenza season, most strains of influenza A (H3N2) circulating in the US were resistant to adamantanes (amantadine, rimantadine),121 and resistance to these drugs among seasonal influenza A (H3N2) isolates has remained high during subsequent influenza seasons.105 112 117 144 162 551 552 In addition, the influenza A (H1N1)pdm09 virus circulating during recent influenza seasons is resistant to amantadine and rimantadine.52 105 112 117 144 151 162 551 552

CDC and other experts recommend 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.112 144 488

Slideshow: 2013 Drug News Round-Up - Top 20 Stories

Consider viral surveillance data available from local and state health departments and the CDC when selecting an antiviral for treatment of seasonal influenza.112 137 144 Strains of circulating influenza viruses and the antiviral susceptibility of these strains constantly evolve.144

CDC issues recommendations concerning use of antivirals for treatment of influenza, and these recommendations are updated as needed during each influenza season.137 144 Information regarding influenza surveillance and updated recommendations for treatment of seasonal influenza are available from CDC at .

Prevention of Seasonal Influenza A Virus Infections

Has been used for prophylaxis of signs and symptoms of influenza infection caused by susceptible influenza A in adults, adolescents, and children ≥1 year of age.1 2 6

Amantadine and rimantadine have little or no activity against influenza B; not used for prevention of influenza B infection.1 2 6 24 26 27 45

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 2 6 105 112 116 144 488 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 2 6 105 112 116 144 488

CDC and other experts recommend 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.112 144 488

Consider viral surveillance data available from local and state health departments and the CDC when selecting an antiviral for prophylaxis of influenza.112 137 144 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

CDC issues recommendations concerning use of antivirals for prophylaxis of influenza, and these recommendations are updated as needed during each influenza season.137 144 Information regarding influenza surveillance and updated recommendations for prevention of seasonal influenza are available from CDC at .

Avian Influenza A Virus Infections

Has been recommended as alternative for treatment or prophylaxis of avian influenza A virus infections in certain situations.94

CDC and WHO recommend use of a neuraminidase inhibitor (oseltamivir, zanamivir) for treatment or prophylaxis of avian influenza A infections.50 94 104

If neuraminidase inhibitors unavailable, use of amantadine or rimantadine might be considered an alternative if local surveillance data indicate the strain is known or likely to be susceptible.94 Avian influenza A (H5N1) and avian influenza A (H7N9) generally have been resistant to adamantanes.50 94 104

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 2 6 Less effective than levodopa.1 2 6

Symptomatic treatment of antipsychotic-induced extrapyramidal effects.1 2 6

Amantadine Hydrochloride (Antiviral) Dosage and Administration

Administration

Oral Administration

Administer orally.1 2 6

Adverse effects (e.g., CNS effects) may be minimized if daily dosage is given in 2 equally divided doses.1 2 6 If insomnia occurs, the last daily dose should be taken several hours before bedtime.1 2 6

Commercially available as tablets or liquid-filled capsules containing 100 mg of the drug1 2 and as an oral solution containing 50 mg/5 mL.6

Dosage

Available as amantadine hydrochloride; dosage expressed in terms of amantadine hydrochloride.1 2 6

Reduced dosage recommended in geriatric adults ≥65 years of age and in patients with renal impairment.1 2 6 Reduction of usual dosage also may be needed in patients with CHF, peripheral edema, or orthostatic hypotension.1 2 6

Pediatric Patients

Treatment of Seasonal Influenza A Virus Infections
Oral

Children 1–9 years of age: 4.4–8.8 mg/kg (up to 150 mg) daily recommended by manufacturer.1 2 6 AAP recommends 5 mg/kg (up to 150 mg) daily in 2 divided doses.105

Children 9–12 years of age: 100 mg twice daily recommended by manufacturer.1 2 6

Children ≥10 years of age: AAP recommends 5 mg/kg daily in 2 divided doses in those weighing <40 kg or 100 mg twice daily in those weighing ≥40 kg.105

Children and adolescents ≥12 years of age: 200 mg once daily or 100 mg twice daily recommended by manufacturer.1 2 6

Initiate as soon as possible, preferably within 24–48 hours after onset of symptoms, and continue for 24–48 hours after symptoms disappear.1 2 6

Prevention of Seasonal Influenza A Virus Infections
Oral

Children 1–9 years of age: 4.4–8.8 mg/kg (up to 150 mg) daily recommended by manufacturer.1 2 6 AAP recommends 5 mg/kg (up to 150 mg) daily in 2 divided doses.105

Children 9–12 years of age: 100 mg twice daily recommended by manufacturer.1 2 6

Children ≥10 years of age: AAP recommends 5 mg/kg daily in 2 divided doses in those weighing <40 kg or 100 mg twice daily in those weighing ≥40 kg.105

Children and adolescents ≥12 years of age: 200 mg once daily or 100 mg twice daily recommended by manufacturer.1 2 6

Alternatively, AAP states children weighing >20 kg can receive 100 mg daily.105

Continue prophylaxis for at least 10 days following a known exposure.1 2 6 If used as adjunct to influenza vaccination, continue for 2–4 weeks after vaccine is given to provide prophylaxis until protective antibody response develops.1 2 6 (See Interactions.)

Adults

Treatment of Seasonal Influenza A Virus Infections
Oral

Adults <65 years of age: 200 mg once daily or 100 mg twice daily.1 2 6

Dosage may be decreased to 100 mg daily in those who experience CNS or other toxicities with 200 mg daily;1 2 6 relative efficacy of lower dosage not elucidated.1 2 6

Initiate as soon as possible, preferably within 24–48 hours after onset of symptoms, and continue for 24–48 hours after symptoms disappear.1 2 6

Prevention of Seasonal Influenza A Virus Infections
Oral

Adults <65 years of age: 200 mg once daily or 100 mg twice daily.1 2 6

Dosage may be decreased to 100 mg daily in those who experience CNS or other toxicities with 200 mg daily;1 2 6 relative efficacy of lower dosage not elucidated.1 2 6

Continue prophylaxis for at least 10 days following a known exposure.1 2 6 If used as adjunct to influenza vaccination, continue for 2–4 weeks after vaccine is given to provide prophylaxis until protective antibody response develops.1 2 6 (See Interactions.)

Parkinsonian Syndrome and Drug-induced Extrapyramidal Effects
Oral

100 mg twice daily.1 2 6

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 2 6

Dosage can be increased to 400 mg daily in divided doses in patients with parkinsonian syndrome.1 2 6

Dosage can be increased to 300 mg daily in divided doses in patients with drug-induced extrapyramidal reactions.1 2 6

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 2 6

Special Populations

Renal Impairment

Dosage in Adults with Renal Impairment126

Clcr (mL/minute per 1.73m2)

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 once daily for treatment or prophylaxis of influenza A virus infection in those ≥65 years of age.1 2 6 11 20 Dosage may need to be further reduced in some patients.144

Cautions for Amantadine Hydrochloride (Antiviral)

Contraindications

  • Known hypersensitivity to amantadine or any ingredient in the formulation.1 2 6

Warnings/Precautions

Warnings

Fatalities, Acute Toxicity, and Suicide Risk

Fatalities reported following overdosage.1 2 6 Overdosage has resulted in cardiac (arrhythmia, tachycardia, hypertension), respiratory, renal, or CNS toxicity; may be related to anticholinergic effects of the drug.1 2 6

Deaths due to drug accumulation (overdosage) reported in patients with renal impairment who received amantadine dosage higher than recommended for their degree of renal impairment.1 2 6 (See Renal Impairment under Cautions.)

Suicide attempts (including some fatalities) reported rarely; many patients received short courses of the drug for influenza treatment or prophylaxis.1 2 6

Suicide ideation or attempts reported in patients with or without a prior history of psychiatric disorders.1 2 6 Amantadine can exacerbate mental status in patients with a history of psychiatric disorders or substance abuse.1 2 6 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 2 6

Use with caution in patients with uncontrolled psychosis or severe psychoneurosis.1 2 6

Lowest reported lethal dose is 1 g.1 2 6 Prescriptions should be written for smallest quantity consistent with good patient management.1 2 6

CNS Effects

Patients with a history of epilepsy or other seizure disorders should be observed closely for possible increased seizure activity.1 2 6

Cardiovascular Effects

CHF reported; monitor patients with a history of CHF or peripheral edema.1 2 6 Dosage adjustment may be needed.1 2 6

Use with caution and adjust dosage as needed in patients with CHF, peripheral edema, or orthostatic hypotension.1

Ocular Effects

May cause mydriasis; do not use in patients with untreated angle-closure glaucoma.1 2 6

Sensitivity Reactions

Allergic reactions, including anaphylactic reaction,1 2 6 rash,1 2 6 eczematoid dermatitis,1 2 6 photosensitization,86 pruritus,1 2 6 and diaphoresis,1 2 6 reported rarely.

Use with caution in patients with recurrent eczematoid dermatitis.1 2 6

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 2 6 Abrupt discontinuance also may precipitate delirium, agitation, delusions, hallucinations, paranoid reaction, stupor, anxiety, depression, and slurred speech.1 2 6

Neuroleptic Malignant Syndrome

Possible neuroleptic malignant syndrome (NMS) reported; associated with dosage reduction or withdrawal of amantadine.1 2 6 Observe patients closely when dosage is reduced or the drug discontinued; this precaution is especially important in patients receiving concomitant therapy with an antipsychotic agent.1 2 6

Impulse Control and Compulsive Behaviors

Intense urges (e.g., urge to gamble, increased sexual urges, intense urges to spend money uncontrollably, other intense urges) and inability to control these urges reported in some patients receiving drugs that increase central dopaminergic tone and are generally used for treatment of parkinsonian syndrome, including amantadine.1 2 6 These urges stopped in some cases when dosage was reduced or the drug discontinued.1 2 6

Because patients may not recognize these behaviors as abnormal, ask patients and/or their caregivers whether new or increased gambling urges, sexual urges, uncontrolled spending, or other urges have developed during amantadine treatment; advise them of the importance of reporting such urges.1 2 6 Consider reducing dosage or discontinuing amantadine if a patient develops such urges while receiving the drug.1 2 6

Melanoma

Epidemiologic studies indicate patients with parkinsonian syndrome have a twofold to sixfold higher risk of developing melanoma than the general population.1 2 6 Unclear whether increased risk is due to parkinsonian syndrome or other factors (e.g., drugs used to treat Parkinson’s disease).1 2 6

Monitor for melanomas frequently and on a regular basis when using amantadine for any indication.1 2 6 Ideally, periodic skin examinations should be performed by appropriately qualified individuals (e.g., dermatologists).1 2 6

Resistance

Seasonal influenza A (H3N2) and influenza A (H1N1)pdm09 viruses circulating during recent influenza seasons have been resistant to adamantanes (amantadine, rimantadine).105 112 144 488 551 552

CDC and other experts recommend that adamantanes (amantadine, rimantadine) not be used for treatment or prevention of influenza in the US until susceptibility to these antiviral agents has been reestablished in circulating influenza A viruses.112 144 488

Differential Diagnosis

Serious bacterial infections may present with influenza-like symptoms or may coexist with or occur as complications of influenza.1 2 6 No evidence that amantadine prevents such complications.1 2 6

Not effective for treatment or prophylaxis of viral respiratory tract illnesses other than those due to susceptible influenza A virus.1 2 6

Influenza Vaccination

Not a substitute for annual vaccination with a seasonal influenza vaccine (influenza virus vaccine inactivated, influenza vaccine recombinant, influenza vaccine live intranasal).1 2 6 144

Although antivirals used for treatment or prevention of influenza, including amantadine, may be used concomitantly with or at any time before or after influenza virus vaccine inactivated,100 these antivirals may inhibit the vaccine virus contained in influenza vaccine live intranasal.1 2 6 100 (See Influenza Virus Vaccines under Interactions.)

Specific Populations

Pregnancy

Category C.1 2 6

Lactation

Do not use in nursing women.1 2 6 Distributed into milk.1 2 6

Pediatric Use

Safety and efficacy not established in neonates or infants <1 year of age.1 2 6

Geriatric Use

Substantially eliminated by the kidneys.1 2 6 Consider age-related decreases in renal function and the potential for concomitant disease when selecting dosage.1 2 6 (See Geriatric Patients under Dosage and Administration.)

Hepatic Impairment

Use with caution in patients with liver disease.1 2 6 Increased concentrations of liver enzymes reported.1 2 6

Renal Impairment

Deaths due to drug accumulation (overdosage) reported in patients with renal impairment who received amantadine dosage higher than recommended for their degree of renal impairment.1 2 6 Use reduced dosage in those with Clcr ≤50 mL/minute.1 2 6 (See Renal Impairment under Dosage and Administration.)

Common Adverse Effects

Nausea, 1 2 6 dizziness (lightheadedness),1 2 6 49 insomnia.1 2 6 49

Interactions for Amantadine Hydrochloride (Antiviral)

Specific Drugs

Drug

Interaction

Comments

Alcohol

Potential for increased CNS effects (dizziness, confusion, lightheadedness, orthostatic hypotension)1 2 6

Avoid excessive usage of alcohol1 2 6

Anticholinergic agents

Potential for increased adverse anticholinergic and CNS effects1 2 6 90 91 92 93

Dosage adjustment of both drugs may be needed1 2 6 90 91 92 93

Antihistamines

Potential for increased CNS effects51 127

Antipsychotic agents

Possible increased risk of NMS1 2 6 (see Neuroleptic Malignant Syndrome under Cautions)

Observe closely if amantadine dosage is reduced or amantadine discontinued1 2 6

CNS agents

Potential for increased adverse effects1 2 6

Use with caution1 2 6

CNS stimulants

Possibility of additive CNS stimulant effects127

Use with caution1 2 6 127

Co-trimoxazole

Toxic delirium reported in an individual who received co-trimoxazole and amantadine concomitantly98

Hydrochlorothiazide

Fixed combination of triamterene and hydrochlorothiazide (co-triamterzide): Possible increased amantadine plasma concentrations 1 2 6 90 126

Influenza virus vaccines

Influenza virus vaccine inactivated: Amantadine does not interfere with the antibody response to the vaccine1 2 6

Influenza vaccine live intranasal: Potential interference with antibody response to the live vaccine; no specific studies1 2 6 100

Influenza virus vaccine inactivated: May be administered concomitantly with or at any interval before or after amantadine1 2 6 100

Influenza vaccine live intranasal: Do not administer the live vaccine until ≥48 hours after amantadine is discontinued; do not administer amantadine until ≥2 weeks after administration of the vaccine, unless medically indicated;1 2 6 100 if amantadine given within 2 weeks after the vaccine, repeat vaccine dose ≥48 hours after last antiviral dose;100 alternatively, if amantadine given 2 days before to 14 days after the vaccine, revaccinate using the parenteral inactivated vaccine or parenteral recombinant vaccine100

Quinidine or quinine

Reduction in renal clearance of amantadine1 2 6 97

Thioridazine

Worsened tremor in geriatric patients with parkinsonian syndrome reported;1 2 6 not known whether similar effect could occur with other phenothiazines1 2 6

Urine acidifying drugs

Possible increased elimination of amantadine1 2 6

Amantadine Hydrochloride (Antiviral) Pharmacokinetics

Absorption

Bioavailability

Well absorbed from GI tract; peak plasma concentrations achieved in 2–4 hours.1 2 6 12 27 45 56 63 67

Onset

When used for parkinsonian syndrome, onset of action usually within 48 hours.1 2 6

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 2 6 67

There appears to be a relationship between plasma concentrations of amantadine and toxicity.1 2 6 As concentrations increase, toxicity becomes more prevalent.1 2 6

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 2 6

Distribution

Extent

Not fully characterized.1 2 6 67 99

Distributed into nasal secretions, erythrocytes, CSF, and milk.1 2 6 12 65 67

Plasma Protein Binding

67%.1 2 6 67

Elimination

Metabolism

Undergoes N-acetylation.1 2 6 67

Elimination Route

Principally excreted unchanged in urine by glomerular filtration and tubular secretion; about 5–15% excreted in urine as acetylamantadine.1 2 6 67

Only minimally removed by hemodialysis.1 2 6 8 9 67

Half-life

16 hours (range 9–31 hours).1 2 6

Special Populations

Half-life prolonged in patients with renal impairment (Clcr<40 mL/minute).1 2 6 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 2 6 9

Half-life prolonged in healthy geriatric adults.1 2 6 5 12 Half-life of 29 hours (range: 20–41 hours) reported in geriatric men 60–76 years of age.1 2 6 5

Stability

Storage

Oral

Tablets, Liquid-filled Capsules, Solution

20–25°C (may be exposed to 15–30°C).1 2 6

Actions and Spectrum

  • Adamantane-derivative (a symmetric tricyclic amine);1 2 6 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 susceptible H1N1, H2N2, and H3N2.1 2 6 24 25 26 27 38 42 45 48 58 59

  • Has little or no activity against influenza B.1 2 6 24 26 27 45

  • Beginning in the 2005–2006 influenza season, most influenza A (H3N2) strains circulating in the US were resistant to amantadine and rimantadine.121 Resistance to amantadine and rimantadine among seasonal influenza A (H3N2) circulating during recent influenza seasons has remained high.105 112 117 144 162 551 552

  • 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,117 139 162 the influenza A (H1N1)pdm09 virus circulating during recent influenza seasons is resistant to amantadine and rimantadine.52 117 144 151 162 551 552

  • Although some strains of avian influenza A (H5N1) have been susceptible to amantadine,38 42 126 avian influenza A virus strains tested (including H5N1 and H7N9) generally are resistant to adamantanes.76 50 104

  • Inhibits viral replication by interfering with the influenza A virus M2 protein, an integral membrane protein.1 2 6 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 2 6 21 22 24 25 26 27 28 29 39 45

  • Amantadine-resistant influenza A viruses also are resistant to rimantadine and vice versa.21 22 27 43 45 46 47 54

  • Mechanism of action in treatment of parkinsonian syndrome and drug-induced extrapyramidal reactions unknown.1 2 6 May enhance extracellular concentrations of dopamine at dopaminergic neurons, directly stimulating the dopamine receptor, or increasing sensitivity at receptors.1 2 6

Advice to Patients

  • Risk of CNS effects and blurred vision; use caution when alertness and motor coordination is needed.1 2 6

  • Advise patients with parkinsonian syndrome to gradually increase physical activity as symptoms improve.1 2 6

  • Importance of avoiding excessive alcohol usage.1 2 6

  • Importance of not getting up suddenly from a sitting or lying position; notify clinician if dizziness or lightheadedness occurs.1 2 6

  • Importance of notifying clinician if mood/mental changes, swelling of extremities, difficulty urinating, and/or dyspnea occur.1 2 6

  • Importance of taking amantadine as prescribed; importance of not taking more drug than prescribed.1 2 6 Importance of consulting clinician if there is no improvement after a few days or if drug appears less effective after a few weeks.1 2 6

  • Importance of seeking immediate medical attention for suspected overdose.1 2 6

  • Importance of consulting clinician before discontinuing amantadine.1 2 6

  • Importance of informing clinician if new or increased gambling urges, sexual urges, or other urges occur while receiving amantadine.1 2 6

  • 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 2 6

  • Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.1 2 6

  • Importance of advising patients of other important precautionary information.1 2 6 (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, liquid-filled

100 mg*

Amantadine Hydrochloride Capsules

Solution

50 mg/5 mL*

Amantadine Hydrochloride Oral Solution

Tablets

100 mg*

Amantadine Hydrochloride Tablets

Comparative Pricing

This pricing information is subject to change at the sole discretion of DS Pharmacy. This pricing information was updated 05/2014. 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 (UPSHER-SMITH): 30/$57.99 or 60/$113.97

Amantadine HCl 100MG Tablets (UPSHER-SMITH): 30/$52.99 or 90/$148.47

Amantadine HCl 50MG/5ML Syrup (HI-TECH): 120/$15.99 or 360/$43.96

AHFS DI Essentials. © Copyright, 2004-2014, Selected Revisions April 25, 2014. 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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