AHFS Class:

• Adamantanes 28:36.04

Generic Name(s):

• Amantadine Hydrochloride

Amantadine hydrochloride is a synthetic adamantane derivative that has pharmacologic activity as an anti-Parkinson and antiviral agent.109

Parkinsonian Syndrome

Amantadine hydrochloride is used in the treatment of parkinsonism, including idiopathic parkinson disease (paralysis agitans) and parkinsonism resulting from encephalitis (postencephalitic parkinsonism), carbon monoxide intoxication, or cerebral arteriosclerosis.109,113,114,227 Various preparations of the drug are commercially available for this use, including immediate-release and extended-release formulations.109,113,114,227 Amantadine extended-release capsules are specifically indicated for the treatment of dyskinesia in patients with parkinson disease receiving levodopa-based therapy, with or without concomitant dopaminergic medications, and for adjunctive treatment to levodopa/carbidopa in patients with parkinson disease experiencing "off" episodes.227

Amantadine has been used as monotherapy in patients with early parkinson disease as well as adjunctive therapy in patients with later stages of the disease.3,7,8,10,15,29,31,34,41,61,157,223 The drug 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.3,7,8,10,15,29,34,41,56,61 Subjective responses such as a sense of well-being or elevation of mood have also been reported.3,7,8,10,15,29,34,41,56,61 While amantadine may be effective as initial monotherapy of parkinson disease, particularly in patients with resting tremors, symptomatic benefits may last only a few weeks.157,215,223 In some patients, benefits may be regained by increasing dosage or by discontinuing the drug for several weeks and then resuming therapy.10 As adjunctive therapy, amantadine is typically used for the treatment of levodopa-induced dyskinesia; while the drug has produced substantial reductions in dyskinesia in some patients, evidence of efficacy is mixed and based principally on small randomized, controlled studies.157,215,223,226,227

Levodopa (in combination with carbidopa) is currently the most effective drug for relieving the motor symptoms of parkinson disease.157,201,215,223 However, the effectiveness of levodopa decreases over time as the disease progresses and most patients develop motor complications (e.g., motor fluctuations, dyskinesias) with long-term use.157,201,215,223 Strategies for reducing the risk of motor complications include adjusting the dosage of levodopa or adding other antiparkinsonian agents such as amantadine.157,215,223,226 Alternatively, other antiparkinsonian agents may be initiated first to postpone the use of levodopa; this strategy is generally considered for younger patients who have mild and tolerable clinical manifestations.157,215,223

Drug-induced Extrapyramidal Effects

Amantadine is also used for the treatment of drug-induced extrapyramidal symptoms (EPS).109,113,114

Amantadine is generally used in patients with antipsychotic-induced pseudoparkinsonism and appears to be as effective as anticholinergic agents for this type of EPS.56,161 Amantadine may be especially useful when anticholinergic agents should be avoided (e.g., in patients with glaucoma or urinary retention).56,161 Evidence supporting the use of amantadine for antipsychotic-induced akathisia is limited; although the drug may be effective in some patients, tolerance to its therapeutic effects may develop.160,161

General

Patient Monitoring

• Patients with a history of seizures should be observed closely for possible increased seizure activity.109,113,114,227
• Monitor patients for impulse control/compulsive behaviors such as intense urges to gamble, increased sexual urges, uncontrolled spending, or other urges.109,113,114,227
• Monitor patients for depression, including suicidal ideation or behavior.109,113,114,227
• Monitor patients frequently and regularly for melanoma; periodic skin examinations should be performed by appropriately qualified individuals (e.g., dermatologists).109,113,114
• Monitor patients for dizziness and orthostatic hypotension, especially after starting therapy or increasing the dosage.109,113,114,227
• Monitor patients for hallucinations throughout treatment, particularly after initiation of therapy and after dosage changes.109,113,114,227

Other General Considerations

• Do not discontinue amantadine treatment abruptly in patients with parkinson disease.109,113,114,227
• When discontinuing therapy, gradually taper dosage.109,113,114,227

Administration

Amantadine hydrochloride is administered orally as conventional (i.e., immediate-release) tablets, conventional capsules, extended-release capsules, or a conventional oral solution.109,113,114,227

Conventional Preparations

Conventional preparations of amantadine are commercially available as tablets or liquid-filled capsules containing 100 mg of the drug or as an oral solution containing 50 mg/5 mL.109,113,114

Extended-release Capsules

Amantadine extended-release capsules are administered orally once daily at bedtime with or without food.227 The capsules should be swallowed whole and not crushed, chewed, or divided.227 If necessary, the capsules may be opened and the contents sprinkled on a small amount (e.g., teaspoonful) of soft food such as applesauce; the drug/food mixture should be swallowed immediately without chewing and not stored for later use.227

Dosage

Dosage of amantadine hydrochloride conventional tablets, capsules, and oral solution is expressed in terms of amantadine hydrochloride;109,113,114 dosage of amantadine hydrochloride extended-release capsules is expressed in terms of amantadine.227

Parkinsonism

Conventional (Immediate-release) Preparations

For the treatment of parkinsonism, the usual adult dosage of amantadine hydrochloride as conventional tablets, capsules, or oral solution is 100 mg twice daily.109,113,114 In patients receiving high dosages of other antiparkinsonian drugs or with other serious comorbid illnesses, the recommended initial dosage is 100 mg daily; after one to several weeks, dosage may be increased to 100 mg twice daily if necessary.109,113,114 Occasionally, patients with parkinsonian syndrome may benefit from a dosage increase up to 400 mg daily in divided doses.109,113,114 However, patients receiving a daily dosage of 400 mg should be supervised closely by their clinicians.109,113,114

Patients who initially benefit from amantadine may experience a decrease in effectiveness after a few months of therapy.109,113,114 If loss of effectiveness occurs, benefit may be regained by increasing the dosage to 300 mg daily.109,113,114 Alternatively, temporary discontinuation of the drug for several weeks, followed by reinstitution of amantadine therapy may result in regained benefit in some patients.109,113,114 The use of other antiparkinsonian agents may be necessary.109,113,114 If amantadine and levodopa therapy are initiated concurrently, the manufacturer recommends that the amantadine hydrochloride dosage be continued at 100 mg once or twice daily while the daily dosage of levodopa is gradually increased to optimal benefit.109,113,114

The usual dosage of amantadine may need to be reduced in patients with congestive heart failure, peripheral edema, orthostatic hypotension, or impaired renal function.109,113,114

Extended-release Capsules

For the treatment of dyskinesia or "off" episodes in patients with parkinson disease receiving levodopa-based therapy, the recommended initial adult dosage of amantadine extended-release capsules is 137 mg once daily at bedtime.227 Dosage should be increased after 1 week to the recommended dosage of 274 mg (given as two 137-mg capsules) once daily at bedtime.227

When discontinuing therapy in patients who have been receiving the drug for more than 4 weeks, the dose should be reduced by half, if possible, during the final week of dosing.227

If a dose is missed, the next dose should be taken at the regularly scheduled time.227

Drug-induced Extrapyramidal Effects

Conventional Preparations

For the treatment of drug-induced extrapyramidal effects, the usual adult dosage of conventional amantadine hydrochloride is 100 mg twice daily.109,113,114 Occasionally, patients with a suboptimal response at a dosage of 200 mg daily may benefit from a dosage increase to 300 mg daily in divided doses.109,113,114

The usual dosage of amantadine may need to be reduced in patients with congestive heart failure, peripheral edema, orthostatic hypotension, or impaired renal function.109,113,114

Special Populations

Hepatic Impairment

The manufacturer makes no specific dosage adjustment recommendations for patients with hepatic impairment.109,113,114,227

Renal Impairment

Conventional preparations: In patients with renal impairment receiving conventional preparations of amantadine hydrochloride, dosage should be adjusted as follows.109,113,114 Patients with creatinine clearance of 30-50 mL/minute per 1.73 m² should receive 200 mg of amantadine hydrochloride on the first day, followed by 100-mg maintenance doses given once daily; patients with creatinine clearance of 15-29 mL/minute per 1.73 m² should receive 200 mg of amantadine hydrochloride on the first day, followed by 100 mg on alternate days.109,113,114 Patients with creatinine clearance less than 15 mL/minute per 1.73 m² and hemodialysis patients should receive 200 mg every 7 days.109,113,114

Extended-release capsules:Dosage adjustment of amantadine extended-release capsules is not required in patients with mild renal impairment (creatinine clearance of 60-89 mL/minute per 1.73 m²).227 In patients with moderate renal impairment (creatinine clearance of 30-59 mL/minute per 1.73 m²), the initial dosage should be reduced to 68.5 mg once daily at bedtime; if needed, the dosage may be increased in 1 week to a maximum of 137 mg once daily.227 In patients with severe renal impairment (creatinine clearance of 15-29 mL/minute per 1.73 m²), the recommended dosage is 68.5 mg once daily at bedtime.227 Use of the extended-release capsules is contraindicated in patients with end-stage renal disease (creatinine clearance less than 15 mL/minute per 1.73 m²).227

Geriatric Patients

Dosage of amantadine conventional preparations should be reduced in geriatric patients 65 years of age or older.109,113,114 The manufacturer of the extended-release capsules states that no dosage adjustment is required based on a however, because elderly patients are more likely to have decreased renal function, care should be taken to select dosage with caution and it may be useful to monitor renal function.227

Contraindications

• Patients with known hypersensitivity to amantadine hydrochloride or any ingredients in the formulations.109,113,114

Warnings/Precautions

Deaths from Overdosage

Deaths from overdosage of amantadine have occurred; the lowest reported acute lethal dose was 1 g.109,113,114 Acute toxicity may be attributed to the anticholinergic effects of the drug.109,113,114 Overdosage also has been reported in patients with renal impairment who were prescribed higher than recommended doses of amantadine for their level of renal function.109,114

Suicidality and Depression

Suicide attempts (resulting in death in some patients) and suicidal ideation have been reported in patients receiving amantadine, many of whom received short courses of the drug for influenza prophylaxis or treatment.109,113,114,227

Patients receiving amantadine should be monitored for depression, including suicidal ideation and behavior.109,113,114,227 Clinicians should weigh the risks versus benefits of treatment in patients with a history of suicidality or depression.109,113,114,227

Hallucinations and Psychotic Behavior

Hallucinations and other psychiatric symptoms or behaviors (e.g., confusion, psychosis, personality changes, agitation, aggressive behavior, paranoia) have been reported with amantadine.109,113,114,227 Patients should be monitored for these effects, particularly after initiation of therapy and when dosage is increased or decreased.109,113,114,227 Use of amantadine is generally not advised in patients with major psychotic disorders because of the risk of exacerbating psychosis.109,113,114,227

CNS Effects

Patients with active seizure disorders appear to be at risk of an increased frequency of seizures during amantadine therapy.107 Seizures also have been reported in patients with renal impairment and in geriatric individuals.106 Patients with a history of seizures should be observed closely for possible increased seizure activity.109,113,114

Because of possible CNS effects or visual disturbances, patients receiving amantadine should be warned that the drug may impair their ability to perform hazardous activities requiring mental alertness or physical coordination such as operating machinery or driving a motor vehicle.109,113,114

Falling Asleep During Activities of Daily Living

Falling asleep while engaged in activities of daily living, including operating a motor vehicle, has been reported in patients with parkinson disease; such events have sometimes resulted in accidents.227 Some patients did not perceive warning signs, such as excessive drowsiness, and believed they were alert prior to sudden sleep onset.227

Prior to initiating amantadine therapy, advise patients of the potential to develop drowsiness and inquire about any factors that may increase the risk of somnolence (e.g., concomitant use of sedating drugs or alcohol, presence of sleep disorders).227 If a patient develops daytime sleepiness or episodes of falling asleep during activities that require active participation (e.g., conversations, eating), amantadine generally should be discontinued.227 If a decision is made to continue therapy, the patient should be advised not to drive and to avoid other potentially dangerous activities.227 There is insufficient information to establish whether dosage reduction will eliminate this adverse event.227

Dizziness and Orthostatic Hypotension

Dizziness and orthostatic hypotension have been reported in patients receiving amantadine.109,113,114,227 In clinical trials, 29% of patients receiving amantadine extended-release capsules experienced dizziness, syncope, orthostatic hypotension, presyncope, postural dizziness, or hypotension compared with 2% of placebo-treated patients.227

Patients receiving amantadine should be monitored for signs and symptoms of orthostatic hypotension, particularly after initiation of therapy and when dosage is increased.227 The manufacturer of the extended-release capsules states that concomitant use of alcohol is not recommended.227

Withdrawal-Emergent Hyperpyrexia and Confusion

A symptom complex resembling possible neuroleptic malignant syndrome (NMS; characterized by fever, muscular rigidity, altered consciousness, autonomic instability) has been reported in patients receiving drugs that increase central dopaminergic tone; such reactions have been associated with rapid dosage reduction or withdrawal of the drug.109,113,114,227 Observe patients carefully when dosage of amantadine is reduced abruptly or discontinued.109,113,114,227

Abrupt discontinuation of amantadine in patients with parkinson disease may cause an increase in symptoms of the disease or cause delirium, agitation, delusions, hallucinations, paranoid reaction, stupor, anxiety, depression, or slurred speech.109,113,114,227 Avoid sudden discontinuation of amantadine in such patients.109,113,114,227

Impulse Control and Compulsive Behaviors

Intense urges and compulsive behaviors (e.g., urge to gamble, increased sexual urges, binge eating, uncontrolled spending, other intense urges) and the inability to control these urges have been reported in patients receiving drugs that increase central dopaminergic tone, including amantadine.109,113,114,227 These urges stopped in some cases when dosage was reduced or the drug was discontinued.109,113,114,227

If a patient develops intense urges and compulsive behaviors (e.g., urge to gamble, increased sexual urges, binge eating, uncontrolled spending, other intense urges) while receiving amantadine, consider reducing the dosage or discontinuing therapy.109,113,114,227 In addition, because patients may not recognize such behaviors as abnormal, clinicians should specifically ask patients or caregivers whether any new or increased urges or behaviors have developed during treatment with amantadine.109,113,114,227

Melanoma

Data from epidemiologic studies indicate that patients with parkinson disease have an approximately 2- to 6-fold greater risk of developing melanoma than the general population.109,113,114 It is unclear whether this increased risk is due to the disease or other factors (e.g., drugs used to treat the disease).109,113,114 Because of these findings, some manufacturers recommend that patients and clinicians monitor for melanoma on a frequent and regular basis during amantadine therapy.109,113,114 Periodic skin examinations should ideally be performed by qualified clinicians (e.g., dermatologists).109,113,114

Specific Populations

Pregnancy

Amantadine 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/m² basis), but not when administered in a dosage of 37 mg/kg daily (the maximum recommended human dosage on a mg/m².109,113,114,227 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.124,125 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.109,113,114

Lactation

Because amantadine is distributed into human milk, some manufacturers state that the drug should not be used in nursing women.109,113,114,227

Pediatric Use

Safety and efficacy of amantadine for the treatment of parkinson disease have not been established in pediatric patients; the majority of individuals with parkinson disease are 65 years of age or older.227 When used in children, amantadine has caused CNS symptoms, which resolved when the drug was discontinued.110 An increased incidence of seizures has been reported in children with an underlying seizure disorder receiving amantadine.110

Geriatric Use

The majority of individuals with parkinson disease are 65 years of age or older.227 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.109,115

Reduced dosages may be needed in geriatric patients ≥65 years of age because of renal decline in such patients.109

Hepatic Impairment

Care should be exercised when administering amantadine to patients with liver disease.109,113,114 Rare cases of reversible elevation of liver enzymes have been reported in patients receiving the drug.109,113,114

Renal Impairment

Because amantadine is mainly excreted in the urine, drug accumulation may occur in patients with renal impairment.109,113,114 The half-life of amantadine is prolonged at least 2- to 3-fold in patients with impaired renal function (i.e., creatinine clearance less than 40 mL/minute per 1.73 m²).100,101,109,124 Reduced dosages of amantadine are recommended in patients with renal impairment.109,113,114,227

Amantadine is only minimally removed by hemodialysis.100,101,109 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.100

Common Adverse Effects

The most common adverse effects (5-10%) of amantadine administered as conventional (immediate-release) preparations include nausea, dizziness, and insomnia.109,113,114

The most common adverse effects (>10%) with extended-release amantadine capsules include hallucination, dizziness, dry mouth, peripheral edema, constipation, fall, and orthostatic hypotension.227

In vitro studies indicate that amantadine does not significantly inhibit the enzyme activity of drug metabolizing cytochrome P-450 (CYP) isoenzymes 1A2, 2B6, 2C19, 2C8, 2C9, 2D6, 2E1, 3A4, and 3A5.227

Amantadine has negligible or no inhibitory activity against cellular transporters (P-gp, BCRP, MATE2-K, OAT1, OAT3, OATP1B1, and OATP1B3) at clinically relevant plasma concentrations.227

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.109 However, administration of amantadine in patients receiving drugs with anticholinergic activity may result in increased adverse anticholinergic effects.109,113,114,227 Dosage of the anticholinergic agent or amantadine should be reduced if atropine-like effects occur when the drugs are administered concomitantly.227

Drugs Affecting Urinary pH

Since the excretion rate of amantadine increases rapidly when the urine is acidic, administration of urine acidifying drugs may increase the elimination of the drug.109,113,114,227 Alterations of urine pH towards the alkaline condition may lead to drug accumulation, possibly increasing adverse reactions.227 Monitor for efficacy or adverse reactions of amantadine in situations where urine pH may be altered to a more acidic or alkaline state, respectively.227

Alcohol

Concomitant use of alcohol and amantadine is not recommended because of the potential for increased risk of CNS effects.109,113,114,227

CNS Stimulants

To avoid the possibility of additive CNS stimulant effects, amantadine should be administered with caution to patients receiving other CNS stimulant drugs.109,113,114

Influenza Virus Vaccine

Because of its antiviral properties, amantadine may interfere with the efficacy of live attenuated influenza vaccines.109,113,114,227 Therefore, live vaccines are not recommended during treatment with amantadine.109,113,114,227 Inactivated influenza vaccines may be used, as appropriate.109,113,114,227

Other Drugs

Concomitant administration of amantadine hydrochloride (100 mg 3 times daily) and a combination preparation containing triamterene and hydrochlorothiazide in a 61-year-old man with parkinson 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.109,113,114

Concomitant administration of quinidine or quinine with amantadine may reduce the renal clearance of amantadine.109,113,114

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.126

Concomitant use of amantadine and thioridazine has been reported to worsen the tremor in geriatric patients with parkinson disease; however, it is not known if other phenothiazines produce a similar response.109,113,114

Description

The exact mechanism of action of amantadine hydrochloride in the treatment of parkinsonian syndrome and drug-induced extrapyramidal reactions is not known.109,113,114,227 Amantadine does not appear to have direct anticholinergic activity; however, the drug causes anticholinergic-like effects such as dry mouth, urinary retention, and constipation.109 Amantadine is a weak uncompetitive antagonist of the NMDA receptor and may have direct and indirect effects on the dopaminergic system.109,113,114,226,227

Amantadine hydrochloride is well absorbed from the GI tract.109,113,114 While peak plasma concentrations are directly related to amantadine hydrochloride dosages up to 200 mg daily, dosages exceeding 200 mg daily may result in a greater than proportional increase in peak plasma concentration.109,113,114 While amantadine principally is excreted unchanged in urine by glomerular filtration and tubular secretion, at least 8 metabolites have been identified in urine.109,113,114,116,227 The elimination half-life of amantadine has been variously reported as 9-37 hours, with an average of 24 hours or less.109,113,114,117,119 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.100,101,109,116

Following oral administration of amantadine as the extended-release capsules, dose-proportional pharmacokinetics were observed over the dose range of 68.5-274 mg.227 Time to peak plasma concentration after a single dose is approximately 12 hours and steady-state concentrations are achieved in 4 days.227 Food does not affect amantadine pharmacokinetics when given as the extended-release capsules; administration of capsule contents with applesauce also did not affect pharmacokinetics of the drug.227

Advice to Patients

• Advise the patient to read the FDA-approved patient labeling (Patient Information).227
• Instruct patients on proper administration of the specific dosage form of amantadine prescribed.109,113,114,227
• Advise patients that sleepiness and fatigue have been reported with amantadine and patients treated with parkinson disease drugs have reported falling asleep while engaged in activities of daily living.227 These adverse reactions may affect the ability to drive and operate machinery safely.227
• Advise patients that blurry vision and/or impaired mental acuity may occur.109,113,114,227
• Advise patients to gradually increase physical activity as the symptoms of parkinson disease improve.109
• Inform patients and caregivers that hallucinations and paranoia can occur while taking amantadine.109,113,114,227 Advise patients to report unreal visions, sounds, or sensations, or other psychotic behavior to their healthcare provider promptly should they develop.109,113,114,227
• Inform patients of the potential for experiencing intense urges to gamble, increased sexual urges, intense urges to spend money, binge eating, and other intense urges and the inability to control these urges while taking one or more drugs that increase central dopaminergic tone.109,113,114,227
• Advise patients to contact their healthcare provider before stopping amantadine.109,113,114,227 Advise patients to inform their healthcare provider if they develop withdrawal symptoms such as fever, confusion, or severe muscle stiffness.109,113,114,227
• Advise patients to avoid excessive alcohol usage, since it may increase the potential for CNS effects such as dizziness, confusion, lightheadedness, and orthostatic hypotension.109,113,114,227
• Advise patients to avoid getting up suddenly from a sitting or lying position.109,113,114,227 If dizziness or lightheadedness occurs, notify a physician.109,113,114,227
• Instruct patients, family members, and caregivers to notify their healthcare provider if depressed mood, depression, changes in behavior or thinking, and suicidal ideation or behavior develop during treatment.109,113,114,227
• Advise patients to not take more medication than prescribed because of the risk of overdose.109,113,114,227 If there is no improvement in a few days, or if the drug appears less effective after a few weeks, discuss with a physician.109,113,114,227 Advise patients to seek medical attention immediately if a suspected overdosage has occurred.109,113,114,227
• Advise patients to inform their clinician of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal supplements, as well as any concomitant illnesses.109,113,114,227
• Advise women to inform their clinician if they are or plan to become pregnant or plan to breast-feed.109,113,114,227
• Inform patients of other important precautionary information.109,113,114,227

Additional Information

The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer's labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.

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