Amantadine Hydrochloride: Package Insert and Label Information

AMANTADINE HYDROCHLORIDE- amantadine hydrochloride tablet
AMANTADINE HYDROCHLORIDE- amantadine hydrochloride capsule, gelatin coated
Marlex Pharmaceuticals Inc

AMANTADINE HYDROCHLORIDE- amantadine hydrochloride tablet/ capsules
Marlex Pharmaceuticals, Inc.

Amantadine Hydrochloride Tablets , USP

Amantadine Hydrochloride Capsules, USP

Rx only

DESCRIPTION

Amantadine hydrochloride is designated generically as amantadine hydrochloride and chemically as 1-adamantanamine hydrochloride.

Chemical Structure

C10H17N•HCl

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.

Each tablet intended for oral administration contains 100 mg amantadine hydrochloride and has the following inactive ingredients: microcrystalline cellulose, povidone, sodium starch glycolate, magnesium stearate, and colloidal silicon dioxide.

Amantadine hydrochloride, USP is available as 100 mg capsules for oral administration. Inactive ingredients: magnesium stearate, microcrystalline cellulose, Povidone, Sodium Starch Glycolate, Colloidal Silicon Dioxide. The capsule shells and imprinting ink contain FD&C Blue #1, FD&C Red #40, gelatin, FD&C Yellow #6, sodium lauryl sulfate, and titanium dioxide.

CLINICAL PHARMACOLOGY

Pharmacodynamics

Mechanism of Action

Antiviral

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.

Antiviral Activity

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 mcg/mL to 25 mcg/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 mcg/mL.

Drug Resistance

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.

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 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

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 to 15% of the administered dose. Plasma acetyl amantadine 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. Acetyl amantadine 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 mcg/mL (range: 0.18 to 0.32 mcg/mL). The time to peak concentration was 3.3 ± 1.5 hours (range: 1.5 to 8 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 mcg/mL and ranged from 0.18 to 0.28 mcg/mL. After 15 days of amantadine 100 mg b.i.d., the Cmax was 0.47 ± 0.11 mcg/mL in four of the five volunteers. The administration of amantadine as a 200 mg single dose to 6 healthy subjects resulted in a Cmax of 0.51 ± 0.14 mcg/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 mcg/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 mcg/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/1.73m2 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 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.

Amantadine Hydrochloride Indications and Usage

Amantadine Hydrochloride are indicated for the prophylaxis and treatment of signs and symptoms of infection caused by various strains of influenza A virus. Amantadine Hydrochloride are also indicated in the treatment of Parkinsonism and drug-induced extrapyramidal reactions.

Influenza a Prophylaxis

Amantadine Hydrochloride are indicated for chemoprophylaxis against signs and symptoms of influenza a virus infection. Because Amantadine Hydrochloride do not completely prevent the host immune response to influenza A infection, individuals who take this drug may still develop immune responses to natural disease or vaccination and may be protected when later exposed to antigenically related viruses. Following vaccination during an influenza A outbreak, Amantadine Hydrochloride prophylaxis should be considered for the 2- to 4- week time period required to develop an antibody response.

Influenza A Treatment

Amantadine Hydrochloride are also indicated in the treatment of uncomplicated respiratory tract illness caused by influenza A virus strains especially when administered early in the course of illness. There are no well-controlled clinical studies demonstrating that treatment with Amantadine Hydrochloride will avoid the development of influenza A virus pneumonitis or other complications in high-risk patients. There is no clinical evidence indicating that Amantadine Hydrochloride are effective in the prophylaxis or treatment of viral respiratory tract illnesses other than those caused by influenza A virus strains.

The following points should be considered before initiating treatment or prophylaxis with Amantadine Hydrochloride:

  • Amantadine Hydrochloride are not a substitute for early vaccination on an annual basis as recommended by the Centers for Disease Control and Prevention Advisory Committee on Immunization Practices.
  • Influenza viruses change over time. Emergence of resistance mutations could decrease drug effectiveness. Other factors (for example, changes in viral virulence) might also diminish clinical benefit of antiviral drugs. Prescribers should consider available information on influenza drug susceptibility patterns and treatment effects when deciding whether to use Amantadine Hydrochloride.

Parkinson’s disease / Syndrome

Amantadine Hydrochloride are indicated in the treatment of idiopathic Parkinson’s disease (Paralysis Agitans), post-encephalitic Parkinsonism, and symptomatic Parkinsonism, which may follow injury to the nervous system, by carbon monoxide intoxication. It is indicated in those elderly patients believed to develop Parkinsonism in association with cerebral arteriosclerosis. In the treatment of Parkinson’s disease, Amantadine Hydrochloride are less effective than levodopa, (-)-3-(3, 4-dihydroxyphenyl)-L-alanine and its efficacy in comparison with the anticholinergic antiparkinson drugs has not yet been established.

Drug-Induced Extrapyramidal Reactions

Amantadine Hydrochloride are indicated in the treatment of drug-induced extrapyramidal reactions. Although anticholinergic-type side effects have been noted with Amantadine Hydrochloride when used in patients with drug-induced extrapyramidal reactions, there is a lower incidence of these side effects than that observed with the anticholinergic antiparkinson drugs.

CONTRAINDICATIONS

Amantadine Hydrochloride are contraindicated in patients with known hypersensitivity to amantadine hydrochloride or to any of the other ingredients in Amantadine Hydrochloride

WARNINGS

Deaths

Deaths have been reported from overdose with amantadine hydrochloride. The lowest reported acute lethal dose was 1 gram. Acute toxicity may be attributable to the anticholinergic effects of amantadine. Drug overdose has resulted in cardiac, respiratory, renal or central nervous system toxicity. Cardiac dysfunction includes arrhythmia; tachycardia and hypertension (see OVERDOSAGE).

Deaths due to drug accumulation (overdosage) have been reported in patients with renal impairment, who were prescribed higher than recommended doses of Amantadine Hydrochloride USP for their level of renal function (see DOSAGE AND ADMINISTRATION; Dosage of Impaired Renal Function and OVERDOSAGE).

Suicide Attempts

Suicide attempts, some of which have been fatal, have been reported in patients treated with amantadine hydrochloride, many of whom received short courses for influenza treatment or prophylaxis. The incidence of suicide attempts is not known and the pathophysiologic mechanism is not understood. Suicide attempts and suicidal ideation have been reported in patients with and without prior history of psychiatric illness. Amantadine hydrochloride can exacerbate mental problems in patients with a history of psychiatric disorders or substance abuse. Patients who attempt suicide may exhibit abnormal mental states, which include disorientation, confusion, depression, personality changes, agitation, aggressive behavior, hallucinations, paranoia, other psychotic reactions, and somnolence or insomnia. Because of the possibility of serious adverse effects, caution should be observed when prescribing Amantadine Hydrochloride to patients being treated with drugs having CNS effects, or for whom the potential risks outweigh the benefit of treatment.

CNS Effects

Patients with a history of epilepsy or other “seizures” should be observed closely for possible increased seizure activity.

Patients receiving Amantadine Hydrochloride who note central nervous system effects or blurring of vision should be cautioned against driving or working in situations where alertness and adequate motor coordination are important.

Other

Patients with a history of congestive heart failure or peripheral edema should be followed closely as there are patients who developed congestive heart failure while receiving Amantadine Hydrochloride.

Patients with Parkinson’s disease improving on Amantadine Hydrochloride should resume normal activities gradually and cautiously, consistent with other medical considerations, such as the presence of osteoporosis or phlebothrombosis.

Because Amantadine Hydrochloride have anticholinergic effects and may cause mydriasis, it should not be given to patients with untreated angle closure glaucoma.

PRECAUTIONS

Amantadine hydrochloride should not be discontinued abruptly in patients with Parkinson’s disease since a few patients have experienced a parkinsonian crisis, i.e., a sudden marked clinical deterioration, when this medication was suddenly stopped. The dose of anticholinergic drugs or of amantadine hydrochloride should be reduced if atropine-like effects appear when these drugs are used concurrently. Abrupt discontinuation may also precipitate delirium, agitation, delusions, hallucinations, paranoid reaction, stupor, anxiety, depression and slurred speech.

Neuroleptic Malignant Syndrome (NMS)

Sporadic cases of possible Neuroleptic Malignant Syndrome (NMS) have been reported in association with dose reduction or withdrawal of amantadine hydrochloride therapy. Therefore, patients should be observed carefully when the dosage of amantadine hydrochloride is reduced abruptly or discontinued, especially if the patient is receiving neuroleptics.

NMS is an uncommon but life-threatening syndrome characterized by fever or hyperthermia; neurologic findings including muscle rigidity, involuntary movements, altered consciousness; mental status changes; other disturbances such as autonomic dysfunction, tachycardia, tachypnea, hyper- or hypotension; laboratory findings such as creatine phosphokinase elevation, leukocytosis, myoglobinuria, and increased serum myoglobin.

The early diagnosis of this condition is important for the appropriate management of these patients. Considering NMS as a possible diagnosis and ruling out other acute illnesses (e.g., pneumonia, systemic infection, etc.) is essential. This may be especially complex if the clinical presentation includes both serious medical illness and untreated or inadequately treated extrapyramidal signs and symptoms (EPS). Other important considerations in the differential diagnosis include central anticholinergic toxicity, heat stroke, drug fever and primary central nervous system (CNS) pathology.

The management of NMS should include: 1) intensive symptomatic treatment and medical monitoring, and 2) treatment of any concomitant serious medical problems for which specific treatments are available. Dopamine agonists, such as bromocriptine, and muscle relaxants, such as dantrolene are often used in the treatment of NMS; however, their effectiveness has not been demonstrated in controlled studies.

Renal disease

Because amantadine hydrochloride is mainly excreted in the urine, it accumulates in the plasma and in the body when renal function declines. Thus, the dose of amantadine hydrochloride should be reduced in patients with renal impairment and in individuals who are 65 years of age or older (see DOSAGE AND ADMINISTRATION: Dosage for Impaired Renal Function).

Liver disease

Care should be exercised when administering amantadine hydrochloride to patients with liver disease. Rare instances of reversible elevation of liver enzymes have been reported in patients receiving amantadine hydrochloride, though a specific relationship between the drug and such changes has not been established.

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