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 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 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 tablets 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.

Impulse Control/Compulsive Behaviors

Postmarketing reports suggest that patients treated with anti-Parkinson medications can experience intense urges to gamble, increased sexual urges, intense urges to spend money uncontrollably, and other intense urges. Patients may be unable to control these urges while taking one or more of the medications that are generally used for the treatment of Parkinson's disease and that increase central dopaminergic tone, including amantadine hydrochloride. In some cases, although not all, these urges were reported to have stopped when the dose was reduced or the medication was discontinued. Because patients may not recognize these behaviors as abnormal it is important for prescribers to specifically ask patients or their caregivers about the development of new or increased gambling urges, sexual urges, uncontrolled spending or other urges while being treated with amantadine hydrochloride. Physicians should consider dose reduction or stopping the medication if a patient develops such urges while taking amantadine hydrochloride.

Melanoma

Epidemiological studies have shown that patients with Parkinson's disease have a higher risk (2- to approximately 6-fold higher) of developing melanoma than the general population. Whether the increased risk observed was due to Parkinson's disease or other factors, such as drugs used to treat Parkinson's disease, is unclear. 

For the reasons stated above, patients and providers are advised to monitor for melanomas frequently and on a regular basis when using amantadine hydrochloride tablets for any indication. Ideally, periodic skin examinations should be performed by appropriately qualified individuals (e.g., dermatologists).

Other

The dose of amantadine hydrochloride may need careful adjustment in patients with congestive heart failure, peripheral edema, or orthostatic hypotension. Care should be exercised when administering amantadine hydrochloride to patients with a history of recurrent eczematoid rash, or to patients with psychosis or severe psychoneurosis not controlled by chemotherapeutic agents.

Serious bacterial infections may begin with influenza-like symptoms or may coexist with or occur as complications during the course of influenza. Amantadine hydrochloride has not been shown to prevent such complications.

Information for Patients

Patients should be advised of the following information:

Blurry vision and/or impaired mental acuity may occur.

Gradually increase physical activity as the symptoms of Parkinson's disease improve.

Avoid excessive alcohol usage, since it may increase the potential for CNS effects such as dizziness, confusion, lightheadedness and orthostatic hypotension.

Avoid getting up suddenly from a sitting or lying position. If dizziness or lightheadedness occurs, notify physician.

Notify physician if mood/mental changes, swelling of extremities, difficulty urinating and/or shortness of breath occur.

Do not take more medication than prescribed because of the risk of overdose. If there is no improvement in a few days, or if medication appears less effective after a few weeks, discuss with a physician.

Consult physician before discontinuing medication.

Seek medical attention immediately if it is suspected that an overdose of medication has been taken.

Drug Interactions

Careful observation is required when amantadine hydrochloride is administered concurrently with central nervous system stimulants.

Agents with anticholinergic properties may potentiate the anticholinergic-like side effects of amantadine.

Coadministration of thioridazine has been reported to worsen the tremor in elderly patients with Parkinson's disease, however, it is not known if other phenothiazines produce a similar response. Coadministration of Dyazide (triamterene/hydrochlorothiazide) resulted in a higher plasma amantadine concentration in a 61-year-old man receiving amantadine hydrochloride 100 mg TID for Parkinson's disease.1 It is not known which of the components of Dyazide contributed to the observation or if related drugs produce a similar response.

Coadministration of quinine or quinidine with amantadine was shown to reduce the renal clearance of amantadine by about 30%.

The concurrent use of amantadine hydrochloride with live attenuated influenza vaccine (LAIV) intranasal has not been evaluated. However, because of the potential for interference between these products, LAIV should not be administered within 2 weeks before or 48 hours after administration of amantadine hydrochloride, unless medically indicated. The concern about possible interference arises from the potential for antiviral drugs to inhibit replication of live vaccine virus. Trivalent inactivated influenza vaccine can be administered at any time relative to use of amantadine hydrochloride.

Carcinogenesis and Mutagenesis

Long-term in vivo animal studies designed to evaluate the carcinogenic potential of amantadine hydrochloride have not been performed. In several in vitro assays for gene mutation, amantadine hydrochloride did not increase the number of spontaneously observed mutations in four strains of Salmonella typhimurium (Ames Test) or in a mammalian cell line (Chinese Hamster Ovary cells) when incubations were performed either with or without a liver metabolic activation extract. Further, there was no evidence of chromosome damage observed in an in vitro test using freshly derived and stimulated human peripheral blood lymphocytes (with and without metabolic activation) or in an in vivo mouse bone marrow micronucleus test (140–550 mg/kg; estimated human equivalent doses of 11.7–45.8 mg/kg based on body surface area conversion).

Impairment of Fertility

The effect of amantadine on fertility has not been adequately tested, that is, in a study conducted under Good Laboratory Practice (GLP) and according to current recommended methodology. In a three litter, non-GLP, reproduction study in rats, amantadine hydrochloride at a dose of 32 mg/kg/day (equal to the maximum recommended human dose on a mg/m2 basis) administered to both males and females slightly impaired fertility. There were no effects on fertility at a dose level of 10 mg/kg/day (or 0.3 times the maximum recommended human dose on a mg/m2 basis); intermediate doses were not tested.

Failed fertility has been reported during human in vitro fertilization (IVF) when the sperm donor ingested amantadine 2 weeks prior to, and during the IVF cycle.

Pregnancy

Teratogenic Effects

Pregnancy Category C

The effect of amantadine on embryofetal and peri-postnatal development has not been adequately tested, that is, in studies conducted under Good Laboratory Practice (GLP) and according to current recommended methodology. However, in two non-GLP studies in rats in which females were dosed from 5 days prior to mating to Day 6 of gestation or on Days 7 to 14 of gestation, amantadine hydrochloride produced increases in embryonic death at an oral dose of 100 mg/kg (or 3 times the maximum recommended human dose on a mg/m2 basis). In the non-GLP rat study in which females were dosed on Days 7 to 14 of gestation, there was a marked increase in severe visceral and skeletal malformations at oral doses of 50 and 100 mg/kg (or 1.5 and 3 times, respectively, the maximum recommended human dose on a mg/m2 basis). The no-effect dose for teratogenicity was 37 mg/kg (equal to the maximum recommended human dose on a mg/m2 basis). The safety margins reported may not accurately reflect the risk considering the questionable quality of the study on which they are based. There are no adequate and well-controlled studies in pregnant women. Human data regarding teratogenicity after maternal use of amantadine is scarce. Tetralogy of Fallot and tibial hemimelia (normal karyotype) occurred in an infant exposed to amantadine during the first trimester of pregnancy (100 mg P.O. for 7 days during the 6th and 7th week of gestation). Cardiovascular maldevelopment (single ventricle with pulmonary atresia) was associated with maternal exposure to amantadine (100 mg/d) administered during the first 2 weeks of pregnancy. Amantadine hydrochloride should be used during pregnancy only if the potential benefit justifies the potential risk to the embryo or fetus.

Nursing Mothers

Amantadine hydrochloride is excreted in human milk. Use is not recommended in nursing mothers.

Pediatric Use

The safety and efficacy of amantadine hydrochloride in newborn infants and infants below the age of 1 year have not been established.

Usage in the Elderly

Because amantadine hydrochloride is primarily 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. The dose of amantadine hydrochloride tablets may need reduction in patients with congestive heart failure, peripheral edema, or orthostatic hypotension (see DOSAGE AND ADMINISTRATION).

Dosage for Prophylaxis and Treatment of Uncomplicated Influenza A Virus Illness

Adult

The adult daily dosage of amantadine hydrochloride tablets is 200 mg; two 100 mg tablets as a single daily dose. The daily dosage may be split into one tablet of 100 mg twice a day. If central nervous system effects develop in once-a-day dosage, a split dosage schedule may reduce such complaints. In persons 65 years of age or older, the daily dosage of amantadine hydrochloride tablets is 100 mg.                              

A 100 mg daily dose has also been shown in experimental challenge studies to be effective as prophylaxis in healthy adults who are not at high risk for influenza-related complications. However, it has not been demonstrated that a 100 mg daily dose is as effective as a 200 mg daily dose for prophylaxis, nor has the 100 mg daily dose been studied in the treatment of acute influenza illness. In recent clinical trials, the incidence of central nervous system (CNS) side effects associated with the 100 mg daily dose was at or near the level of placebo. The 100 mg dose is recommended for persons who have demonstrated intolerance to 200 mg of amantadine hydrochloride tablets daily because of CNS or other toxicities. 

Pediatric Patients

1 yr. to 9 yrs. of age

The total daily dose should be calculated on the basis of 2 to 4 mg/lb/day (4.4 to 8.8 mg/kg/day), but not to exceed 150 mg per day. 

9 yrs. to 12 yrs. of age

The total daily dose is 200 mg given as one tablet of 100 mg twice a day. The 100 mg daily dose has not been studied in this pediatric population. Therefore, there are no data which demonstrate that this dose is as effective as or is safer than the 200 mg daily dose in this patient population. 

Prophylactic dosing should be started in anticipation of an influenza A outbreak and before or after contact with individuals with influenza A virus respiratory tract illness. 

Amantadine hydrochloride tablets should be continued daily for at least 10 days following a known exposure. If amantadine hydrochloride tablets are used chemoprophylactically in conjunction with inactivated influenza A virus vaccine until protective antibody responses develop, then it should be administered for 2 to 4 weeks after the vaccine has been given. When inactivated influenza A virus vaccine is unavailable or contraindicated, amantadine hydrochloride tablets should be administered for the duration of known influenza A in the community because of repeated and unknown exposure. 

Treatment of influenza A virus illness should be started as soon as possible, preferably within 24 to 48 hours after onset of signs and symptoms, and should be continued for 24 to 48 hours after the disappearance of signs and symptoms.

Dosage for Parkinsonism

Adult

The usual dose of amantadine hydrochloride tablets is 100 mg twice a day when used alone.

Amantadine hydrochloride tablets have an onset of action usually within 48 hours. 

The initial dose of amantadine hydrochloride tablets is 100 mg daily for patients with serious associated medical illnesses or who are receiving high doses of other antiparkinson drugs. After one to several weeks at 100 mg once daily, the dose may be increased to 100 mg twice daily, if necessary. Occasionally, patients whose responses are not optimal with amantadine hydrochloride tablets at 200 mg daily may benefit from an increase up to 400 mg daily in divided doses. However, such patients should be supervised closely by their physicians. 

Patients initially deriving benefit from amantadine hydrochloride tablets not uncommonly experience a fall-off of effectiveness after a few months. Benefit may be regained by increasing the dose to 300 mg daily. Alternatively, temporary discontinuation of amantadine hydrochloride tablets for several weeks, followed by reinitiation of the drug, may result in regaining benefit in some patients. A decision to use other antiparkinson drugs may be necessary.

Dosage for the Concomitant Therapy

Some patients who do not respond to anticholinergic antiparkinson drugs may respond to amantadine hydrochloride tablets. When amantadine hydrochloride tablets or anticholinergic antiparkinson drugs are each used with marginal benefit, concomitant use may produce additional benefit. 

When amantadine hydrochloride tablets and levodopa are initiated concurrently, the patient can exhibit rapid therapeutic benefits. Amantadine hydrochloride tablets should be held constant at 100 mg daily or twice daily while the daily dose of levodopa is gradually increased to optimal benefit. 

When amantadine hydrochloride tablets are added to optimal well-tolerated doses of levodopa, additional benefit may result, including smoothing out the fluctuations in improvement which sometimes occur in patients on levodopa alone. Patients who require a reduction in their usual dose of levodopa because of development of side effects may possibly regain lost benefit with the addition of amantadine hydrochloride tablets.

Dosage for Drug-Induced Extrapyramidal Reactions

Adult

The usual dose of amantadine hydrochloride tablets is 100 mg twice a day. Occasionally, patients whose responses are not optimal with amantadine hydrochloride tablets at 200 mg daily may benefit from an increase up to 300 mg daily in divided doses.

Dosage for Impaired Renal Function

Depending upon creatinine clearance, the following dosage adjustments are recommended:

The recommended dosage for patients on hemodialysis is 200 mg every 7 days.