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amantadine 100 mg capsule

Out of Stock Manufacturer VENSUN PHARMACE 42543049301
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Parkinsonian Syndrome and Drug-induced Extrapyramidal Effects

Amantadine hydrochloride is used in the symptomatic treatment of all forms of parkinsonian syndrome including the postencephalitic, idiopathic, and arteriosclerotic types and for the relief of parkinsonian signs and symptoms of carbon monoxide poisoning and antipsychotic agent-induced (e.g., phenothiazines) extrapyramidal effects. There is no evidence that the drug alters the course of parkinsonian syndrome. Amantadine is less effective than levodopa in the treatment of parkinsonian syndrome. Although amantadine's efficacy in comparison to anticholinergic antiparkinsonian agents has not been definitely established, results of several studies suggest that amantadine is at least as effective as the anticholinergic agents. Similarly, in studies in patients with phenothiazine-induced parkinsonian signs and symptoms, amantadine was at least as effective in decreasing extrapyramidal symptoms as benztropine mesylate or trihexyphenidyl hydrochloride. Amantadine may be especially useful in the treatment of drug-induced extrapyramidal symptoms when drugs with anticholinergic properties should be avoided (e.g., in patients with glaucoma or urinary retention).

Amantadine has been reported to produce objective or subjective improvement in extrapyramidal symptoms, including akinesia, rigidity, tremor, salivation, gait disturbances, and total functional disability, in approximately one-half of the patients treated. Subjective responses such as a sense of well-being or elevation of mood have also been reported. Improvement in extrapyramidal symptoms is apparent within 4-48 hours following initiation of amantadine therapy, and optimum results are achieved within 2 weeks to 3 months. A definite correlation between the degree of improvement and the age or sex of the patient and duration or severity of disease has not been determined. Sustained improvement may last up to 30 months; however, some patients experience a reduction in benefit after 1-3 months of amantadine therapy. In some patients, benefits may be regained by increasing dosage or by discontinuing the drug for several weeks and then resuming therapy.

Addition of amantadine to a therapeutic regimen of anticholinergic antiparkinsonian agents (e.g., benztropine mesylate, trihexyphenidyl hydrochloride, or procyclidine hydrochloride) has produced further improvement. Concomitant administration of amantadine and levodopa has resulted in a greater reduction in parkinsonian symptoms than occurred with amantadine alone. Combined therapy with amantadine and levodopa has been reported to be more effective than levodopa alone in patients who cannot tolerate large doses of levodopa; however, the addition of amantadine to levodopa therapy does not usually provide significant additional benefit when patients are already receiving full therapeutic doses of levodopa.

Other Uses

Amantadine has been used in the treatment of spastic pseudosclerosis (Jakob-Creutzfeldt disease) with some success, although exacerbations of the disease have occurred in some patients. There is no evidence that the drug is effective in the treatment of mental depression, Huntington's chorea, essential tremor, tardive dyskinesia, or other neurologic diseases.

For information on the use of amantadine in the prophylaxis and symptomatic treatment of influenza A virus infections, see Amantadine Hydrochloride 8:18.04.

Dosage and Administration


Amantadine hydrochloride is administered orally. It has been suggested that if insomnia occurs, the last daily dose should be taken several hours before retiring.


The usual dosage of amantadine may need to be reduced in patients with congestive heart failure, peripheral edema, orthostatic hypotension, or impaired renal function.

In the treatment of all forms of parkinsonian syndrome including the postencephalitic, idiopathic, and arteriosclerotic types and for the relief of parkinsonian signs and symptoms of carbon monoxide poisoning or antipsychotic agent-induced (e.g., phenothiazines) extrapyramidal effects, the usual dosage of amantadine in patients without recognized renal disease is 100 mg twice daily. When patients are receiving other antiparkinsonian drugs or have other serious illnesses, the initial dosage is 100 mg daily. The onset of action of amantadine usually occurs within 48 hours. After 1-2 weeks, dosage may be increased to 100 mg twice daily, if necessary. Occasionally, patients with drug-induced extrapyramidal reactions whose responses are not optimal with a dosage of 200 mg daily may benefit from a dosage increase to 300 mg daily in divided doses, and patients with parkinsonian syndrome may benefit from a dosage increase up to 400 mg daily in divided doses. However, patients receiving more than 200 mg daily should be supervised closely by their physicians. In one study, increasing the daily dose from 200 mg to 400 mg increased the severity of adverse effects without significantly increasing beneficial effects.

Since renal function normally declines with age and amantadine-induced adverse effects have been reported more frequently in geriatric patients, patients 65 years of age or older without recognized renal disease should receive a reduced dosage of 100 mg daily to minimize the risk of toxicity.

Patients with parkinsonian syndrome who derive benefit from amantadine occasionally experience a decrease in effectiveness after a few months of therapy. If loss of effectiveness occurs, benefit may be regained by increasing the dosage to 300 mg daily. Alternatively, temporary discontinuation of the drug for several weeks, followed by reinstitution of amantadine therapy may result in regained benefit in some patients. The use of other antiparkinson drugs may be necessary. If amantadine and levodopa therapy are initiated concurrently, the manufacturer of amantadine recommends that amantadine dosage be continued at 100 mg once or twice daily while the daily dosage of levodopa is gradually increased to optimal benefit.

Dosage in Renal Impairment

In patients with renal impairment, amantadine dosage should be carefully adjusted and some clinicians recommend that blood concentrations of the drug be monitored frequently. One manufacturer recommends that patients with creatinine clearances of 15-50 mL/minute per 1.73 m receive 200 mg of amantadine on the first day, followed by 100-mg maintenance doses given once daily in patients with creatinine clearances of 30-50 mL/minute per 1.73 m or once every other day in those with creatinine clearances of 15-29 mL/minute per 1.73 m. This manufacturer recommends that patients with creatinine clearances less than 15 mL/minute per 1.73 m and hemodialysis patients receive 200 mg of amantadine every 7 days.


Nervous System Effects

Many of the adverse effects of amantadine hydrochloride are manifested as CNS or psychic disturbances which are reversible, usually dose related, and may appear within a few hours or days after initiation of amantadine therapy or after an increase in drug dosage. Dizziness (lightheadedness), insomnia, nervousness, anxiety, and impaired concentration are among the most frequent adverse effects of amantadine and have been reported in 5-10% of healthy, young adults receiving usual dosage of the drug (200 mg daily). However, limited data suggest that the incidence of adverse CNS effects may be lower in adults receiving a lower dosage of the drug. These adverse effects are usually mild, but may be more disturbing for geriatric patients than for younger patients. Symptoms generally diminish or cease soon after amantadine is discontinued; in some patients, symptoms subside after the first week of continued therapy with the drug. Irritability, depression, ataxia, confusion, somnolence, abnormal dreams, agitation, fatigue, headache, and hallucinations have been reported in 1-5% and psychosis, abnormal thinking, amnesia, hyperkinesia, weakness, and slurred speech have been reported in 1% or less of patients receiving amantadine. In addition, euphoria, forgetfulness, a sense of drunkenness or detachment, drowsiness, coma, stupor, delirium, hypokinesia, delusions, aggressive behavior, paranoid reaction, manic reaction, involuntary muscle contractions, gait abnormalities, paresthesia, EEG changes, tremor, and, rarely, lingual facial dyskinesia or seizures have been reported. Patients with active seizure disorders appear to be at risk of an increased frequency of seizures during amantadine therapy. Seizures also have been reported in patients with renal impairment and in geriatric individuals.

Suicide attempts (resulting in death in some patients) have been reported rarely in patients receiving amantadine, many of whom received short courses of the drug for influenza prophylaxis or treatment. The manufacturer states that the incidence and pathophysiology of these suicide attempts are not known. Suicide ideation or attempts have been reported in patients both with or without a prior history of psychiatric disorders. Amantadine can exacerbate mental status in patients with a history of psychiatric disorders or substance abuse. Patients with suicidal tendencies may exhibit abnormal mental states including disorientation, confusion, depression, personality changes, agitation, aggressive behavior, hallucinations, paranoia, other psychotic reactions, somnolence, or insomnia. Because of the possibility of serious adverse effects, amantadine should be administered with caution to patients receiving drugs with CNS activity and in those in whom potential risks outweigh benefits of therapy with the drug. Since intentional overdosage with amantadine has been reported in some patients, the least amount of drug feasible should be prescribed.

Sporadic cases of possible neuroleptic malignant syndrome (NMS) have been reported in patients receiving amantadine and were associated with dosage reduction or withdrawal of the drug. NMS is potentially fatal and requires immediate initiation of intensive symptomatic and supportive care. For additional information on NMS, see .

Livedo Reticularis

Livedo reticularis is a frequent adverse effect in patients receiving amantadine for treatment of parkinsonian syndrome. Livedo reticularis occurs mainly in the legs and diminishes when the legs are elevated. Livedo reticularis has been reported in 1-5% of patients, generally appears within 1 month to 1 year following initiation of amantadine therapy, and subsides within a few weeks to several months after discontinuance of the drug. In one study, livedo reticularis tended to fade or change into brown spots with prolonged amantadine therapy. It has been suggested that, in many instances, this adverse effect is actually an accentuation of preexisting, minor livedo reticularis and is a result of abnormal capillary permeability associated with peripheral vasoconstriction with lowering of skin temperature and decreased peripheral blood flow, and/or amantadine's depletion of catecholamines in peripheral nerve endings. Peripheral edema may precede or accompany livedo reticularis and may require dosage reduction or discontinuance of amantadine. The edema does not appear to be associated with an increase in total body water or sodium retention; it also may result from increased vascular permeability in cutaneous tissues.

GI Effects

Nausea is one of the most frequent adverse effects of amantadine and has been reported in 5-10% of patients receiving the usual dosage of the drug. Anorexia, constipation, and dry mouth have been reported in 1-5% and vomiting has been reported in up to 1% of patients receiving amantadine. Abdominal discomfort or dysphagia has also been reported.

Other Adverse Effects

Orthostatic hypotension and peripheral edema have been reported in 1-5% and congestive heart failure, urinary retention, decreased libido, dyspnea, rash, and visual disturbances (e.g., punctate subepithelial or other corneal opacity, decreased visual acuity), corneal edema, light sensitivity, and optic nerve palsy have been reported in up to 1% of patients receiving amantadine. Other adverse effects that have been reported rarely include leukopenia, neutropenia, eczematoid dermatitis, photosensitization, oculogyric episodes, and increased frequency of urination. Cardiac arrest, arrhythmias (including malignant arrhythmias), hypotension, tachycardia, acute respiratory failure, pulmonary edema, tachypnea, keratitis, mydriasis, allergic reactions (including anaphylactic reactions), edema, and fever have occurred in patients receiving amantadine. Leukocytosis, pruritus, and diaphoresis also have occurred in patients receiving amantadine. Reversible elevations of serum liver enzyme concentrations have been reported in some patients receiving amantadine.

Precautions and Contraindications

Amantadine should be administered with caution in patients with liver disease or a history of recurrent eczematoid dermatitis, uncontrolled psychosis or severe psychoneurosis, epilepsy or other seizures, and in those receiving drugs with CNS activity. Patients with a history of seizures should be observed closely for possible increased seizure activity. Because of possible CNS effects or visual disturbances, patients receiving amantadine should be warned that the drug may impair ability to perform hazardous activities requiring mental alertness or physical coordination such as operating machinery or driving a motor vehicle. Because amantadine may cause mydriasis, the drug should not be used in patients with untreated angle-closure glaucoma. Amantadine should be used with caution and dosage of the drug may need careful adjustment in patients with renal impairment, congestive heart failure, peripheral edema, or orthostatic hypotension. Dosage of the drug should be reduced in patients with active seizure disorders and in geriatric patients 65 years of age or older. Geriatric patients with cerebrovascular disease and/or renal impairment should be observed particularly closely for signs of amantadine toxicity. Patients who respond to amantadine should resume normal activities gradually and with caution, especially if other underlying conditions such as osteoporosis or phlebothrombosis are present.

Amantadine should not be abruptly discontinued in patients with parkinsonian syndrome because some patients have experienced exacerbations of parkinsonian symptoms within 24 hours after discontinuance of the drug. A few patients have developed parkinsonian crises, manifested as confusion, marked increase in rigidity, urinary retention, and bulbar palsy, within 3 days after abrupt discontinuance of the drug, even in the absence of apparent clinical improvement with amantadine therapy. In patients receiving concomitant levodopa-amantadine therapy, continued levodopa administration may not compensate fully for the withdrawal of amantadine.

Because possible neuroleptic malignant syndrome was reported in patients receiving amantadine and was associated with a dosage reduction or withdrawal of the drug, patients, especially those receiving antipsychotic agents, should be observed closely when the dosage of amantadine is reduced or the drug is discontinued.

Amantadine is contraindicated in patients with known hypersensitivity to the drug.

Pediatric Precautions

Safety and efficacy of amantadine in children younger than 1 year of age have not been established. When used in children, amantadine has caused CNS symptoms which resolved when the drug was discontinued. An increased incidence of seizures has been reported in children with an underlying seizure disorder receiving amantadine.

Mutagenicity and Carcinogenicity

Amantadine was not mutagenic in the Ames microbial test using Salmonella typhimurium or a mammalian mutagen assay using Chinese hamster ovary cells when the tests were performed with or without metabolic activation. In addition, there was no evidence of chromosome damage in an in vitro test using freshly derived and stimulated human peripheral blood lymphocytes (with or without metabolic activation) or an in vivo mouse bone marrow micronucleus test (140-550 mg/kg; estimated human equivalent dosage of 11.7-45.8 mg/kg based on body surface area conversion).

Long-term animal studies have not been performed to evaluate the carcinogenic potential of amantadine.

Pregnancy, Fertility, and Lactation


Amantadine hydrochloride has been reported to be embryotoxic/teratogenic in rats when administered in dosages of 50 and 100 mg/kg daily (1.5 and 3 times, respectively, the maximum recommended human dosage on a mg/m basis), but not when administered in a dosage of 37 mg/kg daily (the maximum recommended human dosage on a mg/m basis). One woman with a movement disorder similar to parkinsonian syndrome who may have been treated with amantadine hydrochloride (100 mg daily) during the first trimester of pregnancy delivered a child with a complex cardiovascular lesion (single ventricle and pulmonary atresia) that may have been caused by the drug. Fallot and tibial hemimelia (normal karyotype) were reported in an infant exposed to oral amantadine hydrochloride during the first trimester of pregnancy (100 mg daily for 7 days during week 6 and 7 of gestation). There are no adequate and well-controlled studies using amantadine in pregnant women, and the drug should be used during pregnancy only when the potential benefits outweigh the possible risks to the fetus.


In a rat reproduction study involving 3 litters, fertility was slightly impaired when amantadine hydrochloride was administered to both males and females in a dosage of 32 mg/kg daily (the maximum recommended human dosage on a mg/m basis). Fertility was not affected when the drug was given in a dosage of 10 mg/kg daily (0.3 times the maximum recommended human dosage on a mg/m basis); intermediate doses were not tested.

In one instance, failure was reported during human in vitro fertilization (IVF) when the sperm donor ingested amantadine 2 weeks before and during the IVF cycle.


Because amantadine is distributed into milk, the drug should not be used in nursing women.

Drug Interactions

Drugs with Anticholinergic Activity

Concomitant use of amantadine and an anticholinergic antiparkinson agent may provide additional benefit in patients who experience only marginal benefit with either agent alone. However, administration of amantadine in patients receiving drugs with anticholinergic activity may result in increased adverse anticholinergic 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.

Although concomitant administration of amantadine and thioridazine has been reported to worsen tremor in geriatric patients with Parkinson's disease, it is not known whether a similar effect would occur with other phenothiazines.

Influenza Virus Vaccine

Amantandine hydrochloride does not interfere with the antibody response to influenza virus vaccine and 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 other CNS stimulant drugs.

Other Drugs

Concomitant administration of amantadine (100 mg 3 times daily) and a combination preparation containing triamterene and hydrochlorothiazide (co-triamterzide) in a 61-year-old man with Parkinson's disease 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.

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.



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 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. Amantadine is about 67% bound to plasma proteins over a concentration range of 0.1-2 mcg/mL.


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.

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