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Amantadine Hydrochloride

Amantadine hydrochloride is a synthetic antiviral agent that is active against influenza A.

Amantadine HCl

Drug Interactions

Careful observation of the patient is advised if amantadine is administered concurrently with drugs that affect the CNS, including CNS stimulants, antihistamines, or anticholinergic agents.

Drugs with Anticholinergic Activity

Administration of amantadine in patients receiving drugs with anticholinergic activity may result in increased adverse anticholinergic and CNS effects. When amantadine is administered to patients already near the limit of tolerance for anticholinergic agents, atropinism with nocturnal confusion and hallucinations may gradually develop. It has been suggested that the dosage of the anticholinergic agent be reduced prior to the initiation of amantadine therapy or that the dose of either drug be reduced if atropine-like adverse effects appear.

While concomitant administration of amantadine and thioridazine has been reported to worsen tremor in geriatric patients with parkinsonian syndrome, it is not known whether a similar effect would occur with other phenothiazines.

Influenza Virus Vaccine

Amantadine hydrochloride does not interfere with the antibody response to influenza virus vaccine and the drug may be given concomitantly with the vaccine.

CNS Stimulants

To avoid the possibility of additive CNS stimulant effects, amantadine should be administered with caution to patients receiving CNS stimulants.

Co-trimoxazole

Concomitant administration of co-trimoxazole and amantadine may reduce the renal clearance of amantadine. Some evidence suggests that the interaction may be between amantadine and trimethoprim, a component of co-trimoxazole. Toxic delirium has occurred following initiation of co-trimoxazole in at least one patient who had been stabilized on amantadine; rapid resolution occurred following discontinuance of the drugs.

Other Drugs

Concomitant administration of amantadine hydrochloride (100 mg 3 times daily) and a combination preparation containing triamterene and hydrochlorothiazide (co-triamterzide) in a 61-year-old man with parkinsonian syndrome resulted in increased plasma concentrations of amantadine; however, it is not known which component of the combination preparation may have been responsible for the interaction or whether related drugs would produce a similar effect.

Concomitant administration of quinidine or quinine with amantadine may reduce the renal clearance of amantadine.

Concomitant use of amantadine and antihistamines that affect that CNS (e.g., those exhibiting anticholinergic activity) may increase the incidence of adverse CNS reactions.

Acute Toxcicity

Manifestations

Fatalities have been reported following overdosage of amantadine. The lowest reported acute lethal dose of the drug has been 2 g.

Acute overdosage of amantadine has resulted in cardiac dysfunction (e.g., arrhythmia, tachycardia, hypertension); pulmonary edema and respiratory distress (including adult respiratory distress syndrome [ARDS]); renal dysfunction (e.g., increased BUN, decreased creatinine clearance, renal insufficiency); or CNS toxicity (e.g., insomnia, anxiety, aggressive behavior, hypertonia, hyperkinesia, tremor, confusion, disorientation, depersonalization, fear, delirium, hallucinations, psychotic reactions, lethargy, somnolence, coma). Hyperthermia also has occurred with amantadine overdosage. In addition, seizures may be exacerbated in patients with a history of a seizure disorder.

In a patient who ingested 2.8 g of amantadine hydrochloride, manifestations of amantadine overdosage included slightly dilated pupils that contracted minimally to light; urinary retention; mild, mixed acid-base disturbances; and an acute toxic psychosis manifested as disorientation, visual hallucinations, and aggressive behavior. A patient who ingested 2.5 g became comatose and developed cardiopulmonary arrest several hours after the ingestion. Although the arrest was treated successfully, during the arrest and subsequent 48 hours, ventricular tachyarrhythmias manifested as atypical ventricular tachycardia (torsades de pointes) and ventricular fibrillation occurred; therapy with adrenergic agents, particularly dopamine, appeared to exacerbate the ventricular tachyarrhythmias. The patient subsequently died of aspiration pneumonia and respiratory distress.

Treatment

There is no specific antidote for amantadine overdosage. If overdosage of amantadine is recent, prompt gastric lavage or induction of emesis is indicated. General supportive measures (including establishment of adequate respiratory exchange by maintenance of an airway, control of respiration and oxygen administration) should be instituted and cardiovascular status, blood pressure, pulse, respiration, temperature, serum electrolytes, urinary output, and urine pH should be monitored.

Electrocardiographic monitoring may be necessary since malignant tachyarrhythmias can occur following amantadine overdosage.

Fluids should be forced and, if necessary, given IV. Acidifying agents may be administered to increase the rate of amantadine excretion; only minimal amounts of amantadine are removed by hemodialysis. If there is no record of recent voiding, catheterization should be done.

The patient should be observed for hyperactivity and seizures; if required, sedatives and anticonvulsant therapy should be administered. Slow IV administration of physostigmine 1- and 2-mg doses at 1- to 2-hour intervals in one adult and 0.5-mg doses at 5- to 10-minute intervals (to a maximum of 2 mg/hour) in a child has been effective in the management of CNS toxicity caused by amantadine.

However, the risk of physostigmine in the management of overdosage should be considered.Chlorpromazine was useful for the treatment of toxic psychosis in one patient. The patient also should be observed for the possible development of arrhythmias and hypotension; if required, appropriate antiarrhythmic and antihypotensive therapy should be administered. Caution should be employed when using adrenergic agents to maintain blood pressure and heart rate, since these agents may further predispose the patient to the development of serious ventricular tachyarrhythmias.

Mechanism of Action

The exact mechanism of the antiviral activity of amantadine has not been fully elucidated

Amantadine, like rimantadine, inhibits viral replication by interfering with the influenza A virus M2 protein, an integral membrane protein. The M2 protein of influenza A functions as a ion channel and is important in at least 2 aspects of virus replication, disassembly of the infecting virus particle and regulation of the ionic environment of the transport pathway. By interfering with the ion channel function of the M2 protein, amantadine inhibits 2 stages in the replicative cycle of influenza A. Early in the virus replicative cycle, amantadine inhibits uncoating of the virus particle, presumably by inhibiting the acid-mediated dissociation of the virion nucleic acid and proteins, which prevents nuclear transport of viral genome material.

Amantadine also prevents viral maturation in some strains of influenza A (e.g., H7 strains) by promoting pH-induced conformational changes in influenza A hemagglutinin during its intracellular transport late in the replicative cycle. Adsorption of the virus to and penetration into cells do not appear to be affected by amantadine. In addition, amantadine does not interfere with the synthesis of viral components (e.g., RNA-directed RNA polymerase activity).

Amantadine treatment of established influenza A infection does not appear to interfere with antibody response to the infection; however, some reduction in local immune responses has been observed in some patients. Because prophylactic use of amantadine can prevent influenza illness and to a lesser extent subclinical infection, some individuals who take amantadine can still develop immune responses that may protect them when they are exposed to the same or antigenically related viruses following discontinuance of amantadine prophylaxis. Amantadine does not interfere with the immunogenicity of influenza A virus vaccine.

Amantadine-mediated increases in lysosomal pH may inhibit virus-induced membrane fusion in enveloped RNA viruses that are susceptible to higher concentrations of amantadine than those required to inhibit influenza A.

Spectrum

Amantadine shares the antiviral spectrum of activity of rimantadine. Cell culture studies have shown that low concentrations of amantadine (i.e., less than 1 mcg/mL) produce an inhibitory action against most strains of influenza A, including H1N1, H2N2, and H3N2. The drug also has been shown to inhibit virtually all other naturally occurring human and animal strains of influenza A, including the avian H5N1 strain. In tissue culture systems, the 50% inhibitory concentration of amantadine for influenza A viruses ranges from 100 ng/mL to 25 mcg/mL depending on the assay protocol, size of the virus inoculum, influenza A strain, and the cell type used. By plaque inhibition, the 50% inhibitory concentration of rimantadine or amantadine for influenza A viruses ranges from 0.01 to less than 1 mcg/mL.

The precise relationship between in vitro susceptibility of influenza A virus to amantadine and clinical response to therapy with the drug has not been determined. Results of several in vitro studies indicate that amantadine is less active on a weight basis than rimantadine.

Genetic studies indicate that the amino acid sequence in the transmembrane portion of the M2 protein of influenza A virus influences susceptibility of the virus to amantadine and rimantadine. Single amino acid changes in a critical transmembrane region of the M2 protein are associated with antiviral resistance to the drugs, providing further evidence of the importance of this domain in the protein as a target site for antiviral activity.

There is some evidence that susceptibility of certain strains (e.g., H7) may be influenced by gene coding for the viral hemagglutinin.

Amantadine has little or no activity against influenza B at concentrations that inhibit influenza A. At very high concentrations (10-50 mcg/mL), the drug exhibits some in vitro activity against influenza B and other enveloped viruses (e.g., influenza C, parainfluenzae, respiratory syncytial virus), but this activity is considered clinically irrelevant because of the relatively high, potentially toxic doses that would be required.

Resistance

In vitro, resistance to amantadine can be produced at a relatively high frequency in strains of influenza A virus exposed to low concentrations of the drug. Influenza A virus strains with an in vitro EC50 (concentration of the drug required to produce a 50% reduction of antigenic material) exceeding 1 mcg/mL generally are considered resistant to amantadine. Naturally occurring amantadine-resistant strains of influenza A virus reportedly occur in vitro with a frequency of 1 in 104 to 1 in 103; however, such strains have been isolated in up to about 33% of individuals who have received amantadine or rimantadine therapy for influenza A infection, and resistant strains also have been isolated from individuals living at home or in an institution where other residents are taking or recently have taken one of these antivirals. Amantadine-resistant strains of influenza A can emerge within 2-3 days of initiating treatment with the drug.

Although the frequency with which resistant strains emerge and the extent of their transmission have not been elucidated fully, limited evidence suggests that following treatment with amantadine in immunocompetent patients infected with initially susceptible strains of influenza A, 10-30% will shed amantadine-resistant virus. Limited information is available on the emergence of drug-resistant influenza A virus in immunocompromised patients receiving amantadine or rimantadine; isolates recovered from immunocompromised patients (adult bone marrow transplant recipients, adults with leukemia) who shed virus for longer than 3 days have been screened for antiviral susceptibility. While initial viral isolates were susceptible to amantadine or rimantadine, subsequent isolates from almost all of the patients were resistant.

While amantadine-resistant strains appear to be pathogenic and transmissible, there is no evidence that amantadine-resistant strains are more virulent or more transmissible than strains that are susceptible to the drug. Resistance has rarely been detected during screening of naturally occurring epidemic strains of influenza A, and most clinical or population-based strains isolated to date are susceptible to amantadine and rimantadine. The mechanism(s) of resistance to amantadine has not been fully elucidated, but resistance to the drug appears to result from point mutations in the viral RNA segment 7 encoding the M2 protein that leads to amino acid alterations at residue 31 or nearby positions in the transmembrane portion of the M2 protein of the virus.

Amantadine-resistant strains of influenza A are completely cross-resistant to rimantadine. Influenza A virus strains resistant to amantadine and rimantadine may be susceptible to oseltamivir or zanamivir.

Pharmacokinetics

Absorption

Amantadine hydrochloride is well absorbed from the GI tract. Mean peak blood amantadine concentrations of 0.3 mcg/mL have been reported to occur 1-4 hours after an oral dose of amantadine hydrochloride 2.5 mg/kg. Following oral administration of a single 100-mg capsule of amantadine hydrochloride, mean peak plasma concentrations of 0.22 mcg/mL occurred within 3.3 hours.

Following oral administration of a single 100-mg dose of amantadine hydrochloride as the oral solution, peak plasma concentrations averaged 0.24 mcg/mL and were achieved within 2-4 hours.

Peak plasma concentrations averaged 0.47 mcg/mL in individuals receiving amantadine hydrochloride oral solution 100 mg twice daily for 15 days. Following oral administration of amantadine hydrochloride 200 mg as a tablet in fasting adults 19-27 years of age or fasting geriatric individuals 60-70 years of age, peak plasma concentrations averaged 0.51 or 0.8 mcg/mL, respectively.

While peak plasma concentrations are directly related to amantadine hydrochloride dose up to a dosage of 200 mg daily, dosages exceeding 200 mg daily may result in a greater than proportional increase in peak plasma concentration. In a small number of patients who received 300 mg of amantadine hydrochloride daily (200 mg in the morning and 100 mg in the afternoon), steady-state blood concentrations of 0.68-1.01 mcg/mL were reached after 4-5 days of therapy. In healthy young adults receiving 25, 100, or 150 mg twice daily, steady-state trough plasma concentrations averaged 0.11, 0.3, or 0.59 mcg/mL, respectively.

Plasma amantadine concentrations in geriatric patients receiving the drug in a dosage of 100 mg daily reportedly approximate those attained in younger adults receiving the drug in a dosage of 200 mg daily; it is not known whether this occurs because of normal decline in renal function or other age-related factors In one study, 3 patients with severe renal impairment showed symptoms of toxicity and elevated steady-state blood concentrations (2.5-4.4 mcg/mL) following 200 mg of amantadine hydrochloride daily.

One metabolite, acetylamantadine, has been detected in plasma in less than 50% of individuals receiving a single amantadine hydrochloride 200-mg dose. In those individuals with detectable plasma acetylamantadine, concentration of the metabolite represented up to 80% of the concurrent amantadine concentration.

Distribution

Distribution of amantadine hydrochloride into body tissues and fluids has not been fully characterized.

In animals, amantadine is distributed into heart, lung, liver, kidney, and spleen. In a study in mice, lung tissue concentrations of amantadine were much higher than blood concentrations.

Following oral administration, amantadine is distributed into nasal secretions in concentrations that are lower than plasma concentrations. Following oral administration of a single 200-mg dose of amantadine hydrochloride in healthy young and geriatric adults, amantadine concentrations in nasal secretions or plasma averaged 0.15 mcg/g or 0.58 mcg/mL at 1 hour, 0.28 mcg/g or 51 mcg/mL at 4 hours, and 0.39 mcg/g or 0.45 mcg/mL at 8 hours. A substantial proportion of amantadine appears to distribute into erythrocytes, with an erythrocyte to plasma ratio of 2.7 reported in men with normal renal function and 1.4 in men with substantial renal impairment. In one patient, the CSF concentration of amantadine was approximately one-half the blood concentration. Amantadine distributes into human breast milk.

The volume of distribution following IV administration of amantadine reportedly is 3-8 L/kg in healthy individuals. Amantadine is about 67% bound to plasma proteins over a concentration range of 0.1-2 mcg/mL.

Elimination

The elimination half-life of amantadine has been variously reported as 9-37 hours, with an average of 24 hours or less. Clearance of amantadine is reduced, plasma concentrations of the drug are increased, and elimination half-life may be prolonged in healthy geriatric adults compared with healthy young adults. A half-life of 29 hours (range: 20-41 hours) has been reported in geriatric men 60-76 years of age. In addition, the half-life of amantadine is prolonged at least twofold to threefold in patients with impaired renal function (i.e., creatinine clearance less than 40 mL/minute per 1.73 m). In one study, the half-life ranged from 18.5-81.3 hours in patients with creatinine clearances of 13.7-43.1 mL/minute per 1.73 m and averaged 8.3 days (range: 7-10.3 days) in patients undergoing chronic hemodialysis.

While amantadine principally is excreted unchanged in urine by glomerular filtration and tubular secretion, at least 8 metabolites have been identified in urine. Amantadine undergoes N-acetylation, and about 5-15% of an absorbed dose is excreted in urine as acetylamantadine. Whether this metabolic pathway is affected by acetylator phenotype remains to be determined. The clinical importance of amantadine metabolites is unknown. Acidification of urine increases the rate of amantadine excretion, and administration of urine-acidifying drugs may increase amantadine elimination from the body. Amantadine is only minimally removed by hemodialysis. In patients with renal failure who received a single 300-mg oral dose of amantadine hydrochloride, only 5% or less of the dose was removed into the dialysate following a 4-hour period of hemodialysis.

Chemistry and Stability

Chemistry

Amantadine hydrochloride is a synthetic adamantane-derivative (a symmetric tricyclic amine) antiviral agent. Amantadine is structurally related to rimantadine, differing only in the side chain of the 10 carbon ring. While the structure-activity relationship of the adamantanes remains to be determined, the octanol/water coefficient for amantadine is substantially lower than that for rimantadine.

Amantadine hydrochloride occurs as a white or practically white, crystalline powder which has a bitter taste and has solubilities of approximately 400 mg/mL in water and 200 mg/mL in alcohol at 25°C. Amantadine hydrochloride has a pKa of 9.56

Stability

Commercially available amantadine hydrochloride tablets and capsules should be stored in tight containers at a controlled room temperature of 25°C; limited exposure to temperatures of 15-30°C is permitted. Amantadine hydrochloride oral solution should be stored in tight containers at a controlled room temperature of 25°C; limited exposure to temperatures of 15-30°C is permitted and freezing should be avoided.

Preparations

Amantadine Hydrochloride

Oral Capsules, liquid- 100 mg filled

Tablets 100 mg Symmetrel®, Endo

Solution 50 mg/5 mL Symmetrel® Syrup, (with parabens) Endo

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Synonyms of Amantadine:

1-aminoadamantane, Adamantamine, Adamantanamine, Adamantylamine, Amantadine Base, Amantadine HCL, Amantadine Hydrochloride, Amantidine, Aminoadamantane

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