Amantadine Hydrochloride

Pharmacodynamics

The mechanism by which amantadine exerts its antiviral activity is not clearly understood. It appears to mainly prevent the release of infectious viral nucleic acid into the host cell by interfering with the function of the transmembrane domain of the viral M2 protein. In certain cases, amantadine is also known to prevent virus assembly during virus replication. It does not appear to interfere with the immunogenicity of inactivated influenza A virus vaccine.

Amantadine inhibits the replication of influenza A virus isolates from each of the subtypes, i.e., H1N1, H2N2 and H3N2. It has very little or no activity against influenza B virus isolates. A quantitative relationship between the in vitro susceptibility of influenza A virus to amantadine and the clinical response to therapy has not been established in man. Sensitivity test results, expressed as the concentration of amantadine required to inhibit by 50% the growth of virus (ED50) in tissue culture vary greatly (from 0.1 µg/mL to 25.0 µg/mL) depending upon the assay protocol used, size of virus inoculum, isolates of influenza A virus strains tested, and the cell type used. Host cells in tissue culture readily tolerated amantadine up to a concentration of 100 µg/mL.

Influenza A variants with reduced in vitro sensitivity to amantadine have been isolated from epidemic strains in areas where adamantane derivatives are being used. Influenza viruses with reduced in vitro sensitivity have been shown to be transmissible and to cause typical influenza illness. The quantitative relationship between the in vitro sensitivity of influenza A variants to amantadine and the clinical response to therapy has not been established.

The mechanism of action of amantadine in the treatment of Parkinson's disease and drug-induced extrapyramidal reactions is not known. Data from earlier animal studies suggest that SYMMETREL (amantadine hydrochloride) may have direct and indirect effects on dopamine neurons. More recent studies have demonstrated that amantadine is a weak, non-competitive NMDA receptor antagonist (Ki = 10µM). Although amantadine has not been shown to possess direct anticholinergic activity in animal studies, clinically, it exhibits anticholinergic-like side effects such as dry mouth, urinary retention, and constipation.

Pharmacokinetics

SYMMETREL (amantadine hydrochloride) is well absorbed orally. Maximum plasma concentrations are directly related to dose for doses up to 200 mg/day. Doses above 200 mg/day may result in a greater than proportional increase in maximum plasma concentrations. It is primarily excreted unchanged in the urine by glomerular filtration and tubular secretion. Eight metabolites of amantadine have been identified in human urine. One metabolite, an N-acetylated compound, was quantified in human urine and accounted for 5-15% of the administered dose. Plasma acetylamantadine accounted for up to 80% of the concurrent amantadine plasma concentration in 5 of 12 healthy volunteers following the ingestion of a 200 mg dose of amantadine. Acetylamantadine was not detected in the plasma of the remaining seven volunteers. The contribution of this metabolite to efficacy or toxicity is not known.

There appears to be a relationship between plasma amantadine concentrations and toxicity. As concentration increases, toxicity seems to be more prevalent, however, absolute values of amantadine concentrations associated with adverse effects have not been fully defined.

Amantadine pharmacokinetics were determined in 24 normal adult male volunteers after the oral administration of a single amantadine hydrochloride 100 mg soft gel capsule. The mean ± SD maximum plasma concentration was 0.22 ± 0.03 µg/mL (range: 0.18 to 0.32 µg/mL). The time to peak concentration was 3.3 ± 1.5 hours (range: 1.5 to 8.0 hours). The apparent oral clearance was 0.28 ± 0.11 L/hr/kg (range: 0.14 to 0.62 L/hr/kg). The half-life was 17 ± 4 hours (range: 10 to 25 hours). Across other studies, amantadine plasma half-life has averaged 16 ± 6 hours (range: 9 to 31 hours) in 19 healthy volunteers.

After oral administration of a single dose of 100 mg amantadine syrup to five healthy volunteers, the mean ± SD maximum plasma concentration Cmax was 0.24 ± 0.04 µg/mL and ranged from 0.18 to 0.28 µg/mL. After 15 days of amantadine 100 mg b.i.d., the Cmax was 0.47 ± 0.11 µg/mL in four of the five volunteers. The administration of amantadine tablets as a 200 mg single dose to 6 healthy subjects resulted in a Cmax of 0.51 ± 0.14 µg/mL. Across studies, the time to Cmax (Tmax) averaged about 2 to 4 hours.

Plasma amantadine clearance ranged from 0.2 to 0.3 L/hr/kg after the administration of 5 mg to 25 mg intravenous doses of amantadine to 15 healthy volunteers.

In six healthy volunteers, the ratio of amantadine renal clearance to apparent oral plasma clearance was 0.79 ± 0.17 (mean ± SD).

The volume of distribution determined after the intravenous administration of amantadine to 15 healthy subjects was 3 to 8 L/kg, suggesting tissue binding. Amantadine, after single oral 200 mg doses to 6 healthy young subjects and to 6 healthy elderly subjects has been found in nasal mucus at mean ± SD concentrations of 0.15 ± 0.16, 0.28 ± 0.26, and 0.39 ± 0.34 µg/g at 1, 4, and 8 hours after dosing, respectively. These concentrations represented 31 ± 33%, 59 ± 61%, and 95 ± 86% of the corresponding plasma amantadine concentrations. Amantadine is approximately 67% bound to plasma proteins over a concentration range of 0.1 to 2.0 µg/mL. Following the administration of amantadine 100 mg as a single dose, the mean ± SD red blood cell to plasma ratio ranged from 2.7 ± 0.5 in 6 healthy subjects to 1.4 ± 0.2 in 8 patients with renal insufficiency.

The apparent oral plasma clearance of amantadine is reduced and the plasma half-life and plasma concentrations are increased in healthy elderly individuals age 60 and older. After single dose administration of 25 to 75 mg to 7 healthy, elderly male volunteers, the apparent plasma clearance of amantadine was 0.10 ± 0.04 L/hr/kg (range 0.06 to 0.17 L/hr/kg) and the half-life was 29 ± 7 hours (range 20 to 41 hours). Whether these changes are due to decline in renal function or other age related factors is not known.

In a study of young healthy subjects (n=20), mean renal clearance of amantadine, normalized for body mass index, was 1.5 fold higher in males compared to females (p < 0.032).

Compared with otherwise healthy adult individuals, the clearance of amantadine is significantly reduced in adult patients with renal insufficiency. The elimination half-life increases two to three fold or greater when creatinine clearance is less than 40 mL/min/1.73 m2 and averages eight days in patients on chronic maintenance hemodialysis. Amantadine is removed in negligible amounts by hemodialysis.

The pH of the urine has been reported to influence the excretion rate of SYMMETREL (amantadine hydrochloride) . Since the excretion rate of SYMMETREL (amantadine hydrochloride) increases rapidly when the urine is acidic, the administration of urine acidifying drugs may increase the elimination of the drug from the body.

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

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

Specific Drugs

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

Storage

Oral

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

• 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.)