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Symmetrel

Pronunciation

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

Slideshow: Block the Flu: Top 11 Reasons Why You Should Get Your Flu Vaccine Now

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

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

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

Actions 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 02/2014. 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 December 1, 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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