AMANTADINE HYDROCHLORIDE- amantadine hydrochloride solution
Pharmaceutical Associates, Inc.
Amantadine Hydrochloride Oral Solution USP is designated generically as amantadine hydrochloride and chemically as 1-adamantanamine hydrochloride.
Amantadine hydrochloride is a stable white or nearly white crystalline powder, freely soluble in water and soluble in alcohol and in chloroform.
Amantadine hydrochloride has pharmacological actions as both an anti-Parkinson and an antiviral drug.
Amantadine Hydrochloride Oral Solution USP contains 50 mg of amantadine hydrochloride per 5 mL and has the following inactive ingredients: artificial raspberry flavor, citric acid, methylparaben, propylene glycol, propylparaben, purified water, sorbitol solution. May contain sodium hydroxide to adjust pH to approximately 2.3.
The mechanism by which amantadine hydrochloride 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 hydrochloride 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 hydrochloride 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 hydrochloride and the clinical response to therapy has not been established in man. Sensitivity test results, expressed as the concentration of amantadine hydrochloride 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 hydrochloride up to a concentration of 100 µg/mL.
Influenza A variants with reduced in vitro sensitivity to amantadine hydrochloride 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 hydrochloride and the clinical response to therapy has not been established.
Mechanism of Action: Parkinson’s Disease
The mechanism of action of amantadine hydrochloride in the treatment of Parkinson’s disease and drug-induced extrapyramidal reactions is not known. Data from earlier animal studies suggest that amantadine hydrochloride may have direct and indirect effects on dopamine neurons. More recent studies have demonstrated that amantadine hydrochloride is a weak, non-competitive NMDA receptor antagonist (K i = 10µM). Although amantadine hydrochloride 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.
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 hydrochloride have been identified in human urine. One metabolite, an N-acetylated compound, was quantified in human urine and accounted for 5 to 15% of the administered dose. Plasma acetylamantadine accounted for up to 80% of the concurrent amantadine hydrochloride plasma concentration in 5 of 12 healthy volunteers following the ingestion of a 200 mg dose of amantadine hydrochloride. 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 hydrochloride concentrations and toxicity. As concentration increases, toxicity seems to be more prevalent; however, absolute values of amantadine hydrochloride concentrations associated with adverse effects have not been fully defined.
Amantadine hydrochloride 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 hydrochloride 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 hydrochloride oral solution to five healthy volunteers, the mean ± SD maximum plasma concentration C max was 0.24 ± 0.04 µg/mL and ranged from 0.18 to 0.28 µg/mL. After 15 days of amantadine hydrochloride 100 mg b.i.d., the C max was 0.47 ± 0.11 µg/mL in four of the five volunteers. The administration of amantadine hydrochloride 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 C max (T max ) averaged about 2 to 4 hours.
Plasma amantadine hydrochloride clearance ranged from 0.2 to 0.3 L/hr/kg after the administration of 5 mg to 25 mg intravenous doses of amantadine hydrochloride to 15 healthy volunteers.
In six healthy volunteers, the ratio of amantadine hydrochloride 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 hydrochloride to 15 healthy subjects was 3 to 8 L/kg, suggesting tissue binding. Amantadine hydrochloride, 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 hydrochloride concentrations. Amantadine hydrochloride is approximately 67% bound to plasma proteins over a concentration range of 0.1 to 2.0 µg/mL. Following the administration of amantadine hydrochloride 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 hydrochloride 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 hydrochloride 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 hydrochloride, 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 hydrochloride 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 m 2 and averages eight days in patients on chronic maintenance hemodialysis. Amantadine hydrochloride is removed in negligible amounts by hemodialysis.
The pH of the urine has been reported to influence the excretion rate of amantadine hydrochloride. Since the excretion rate of 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.
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