Drug class: Adamantanes

Medically reviewed by Drugs.com on Sep 10, 2024. Written by ASHP.

Introduction

Synthetic adamantane derivative that has pharmacologic activity as an antiparkinson and antiviral agent.¹⁰⁹

Uses for Amantadine Hydrochloride (Antiparkinson)

Parkinsonian Syndrome

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 are commercially available for this use, including immediate-release and extended-release formulations.^{109 113 114 227}

Levodopa (in combination with carbidopa) is currently the most effective drug for relieving the motor symptoms of parkinson disease; however, effectiveness 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}

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 as adjunctive treatment to levodopa/carbidopa in patients with parkinson disease experiencing "off" episodes.²²⁷

Drug-induced Extrapyramidal Effects

Treatment of drug-induced extrapyramidal symptoms (EPS).^{109 113 114}

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}

Amantadine Hydrochloride (Antiparkinson) Dosage and Administration

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, taper dosage gradually.^{109 113 114 227}

Administration

Administer orally as conventional (i.e., immediate-release) tablets, conventional capsules, extended-release capsules, or conventional oral solution.^{109 113 114 227}

Conventional preparations: 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: administer orally once daily at bedtime with or without food.²²⁷ Swallow capsules whole; do not crush, chew, or divide.²²⁷ If necessary, capsules may be opened and contents sprinkled on a small amount (e.g., teaspoonful) of soft food such as applesauce; swallow the drug/food mixture immediately without chewing and do not store 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

Adults

Parkinsonism

Conventional (Immediate-release) Preparations

Oral

Usual dosage of 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, recommended initial dosage is 100 mg daily; after one to several weeks, may increase dosage to 100 mg twice daily if necessary.^{109 113 114}

Some patients may benefit from a dosage increase up to 400 mg daily in divided doses.^{109 113 114} Closely monitor patients receiving a daily dosage of 400 mg.^{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 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}

Usual dosage may need to be reduced in patients with CHF, peripheral edema, orthostatic hypotension, or impaired renal function.^{109 113 114}

Extended-release Capsules

Oral

For treatment of dyskinesia or "off" episodes in patients with parkinson disease receiving levodopa-based therapy, recommended initial dosage is 137 mg once daily at bedtime.²²⁷ Increase dosage after 1 week to 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, reduce dose 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 Reactions

Conventional (Immediate-release) Preparations

Oral

Usual dosage 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}

Usual dosage may need to be reduced in patients with CHF, peripheral edema, orthostatic hypotension, or impaired renal function.^{109 113 114}

Special Populations

Hepatic Impairment

Manufacturers make no dosage adjustment recommendations for patients with hepatic impairment.^{109 113 114 227}

Renal Impairment

Conventional preparations:Patients with Cl_cr 30–50 mL/minute per 1.73 m² should receive 200 mg on the first day, followed by 100 mg daily; patients with Cl_cr 15–29 mL/minute per 1.73 m² should receive 200 mg on the first day, followed by 100 mg on alternate days.^{109 113 114} Patients with Cl_cr <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 not required in patients with mild renal impairment (Cl_cr 60–89 mL/minute per 1.73 m²).²²⁷ In patients with moderate renal impairment (Cl_cr 30–59 mL/minute per 1.73 m²), reduce initial dosage to 68.5 mg once daily at bedtime; if needed, may increase dosage in 1 week to maximum of 137 mg once daily.²²⁷ In patients with severe renal impairment (Cl_cr 15–29 mL/minute per 1.73 m²), recommended dosage is 68.5 mg once daily at bedtime.²²⁷ Contraindicated in patients with end-stage renal disease (Cl_cr <15 mL/minute per 1.73 m²).²²⁷

Closely monitor patients with any degree of renal impairment for adverse reactions; further dosage reductions may be necessary.²²⁷

Geriatric Patients

Reduce dosage of amantadine conventional preparations in geriatric patients ≥65 years of age.^{109 113 114}

Manufacturer of extended-release capsule states no dosage adjustment required based on age; however, select dosage with caution and monitor renal function in elderly patients.²²⁷

Cautions for Amantadine Hydrochloride (Antiparkinson)

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 have occurred.^{109 113 114 227} Acute toxicity may be attributed to the anticholinergic effects of the drug.^{109 113 114 227}

Overdosage also reported in patients with renal impairment who were prescribed higher than recommended doses.^{109 114}

Suicidality and Depression

Suicide attempts (sometimes resulting in death) and suicidal ideation reported; in many cases, patients received short courses of the drug for influenza prophylaxis or treatment.^{109 113 114 227}

Monitor patients for depression, including suicidal ideation and behavior.^{109 113 114 227}

Weigh 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 (e.g., confusion, psychosis, personality changes, agitation, aggressive behavior, paranoia) reported.^{109 113 114 227}

Monitor patients for these effects, particularly after initiation of therapy and when dosage is increased or decreased.^{109 113 114 227}

Use of amantadine generally not advised in patients with major psychotic disorders because of risk of exacerbating psychosis.^{109 113 114 227}

CNS Effects

Possible increased seizure frequency in patients with active seizure disorders.^{109 113 114 227} Seizures also reported in patients with renal impairment and in geriatric individuals.^{109 113 114 227}

Observe patients with a history of seizures closely for possible increased seizure activity.^{109 113 114 227}

May impair ability to perform hazardous activities requiring mental alertness or physical coordination such as operating machinery or driving a motor vehicle.^{109 113 114 227}

Falling Asleep During Activities of Daily Living

Episodes of falling asleep while engaged in activities of daily living (e.g., driving) reported; sometimes resulting in accidents.²²⁷

Some patients perceived no warning signs (e.g., excessive drowsiness) and believed they were alert immediately prior to the event.²²⁷

Patients may not acknowledge drowsiness or sleepiness until directly questioned about such adverse effects during specific activities.²²⁷ Ask patients about any factors that may increase the risk of somnolence (e.g., concomitant sedating drugs or alcohol, presence of sleep disorders).²²⁷

In general, discontinue therapy if a patient develops daytime sleepiness or episodes of falling asleep during activities that require active participation (e.g., conversations, eating).²²⁷ If the drug is continued, advise patient not to drive and to avoid other potentially dangerous activities.²²⁷ Insufficient information to establish whether dosage reduction will eliminate this adverse event.²²⁷

Dizziness and Orthostatic Hypotension

Dizziness and orthostatic hypotension reported.^{109 113 114 227}

Monitor patients for signs and symptoms of orthostatic hypotension, particularly after initiation of therapy and when dosage is increased.²²⁷

Withdrawal-Emergent Hyperpyrexia and Confusion

A symptom complex resembling possible neuroleptic malignant syndrome (NMS; characterized by fever, muscular rigidity, altered consciousness, autonomic instability) reported with drugs that increase central dopaminergic tone; observed with rapid dosage reduction or withdrawal of drug.^{109 113 114 227}

Observe patients carefully when dosage is reduced abruptly or treatment is discontinued.^{109 113 114 227}

Impulse Control and Compulsive Behaviors

Intense urges (e.g., urge to gamble, increased sexual urges, binge eating, uncontrolled spending, other intense urges) and inability to control these urges reported with drugs that increase central dopaminergic tone.^{109 113 114 227}

Consider reducing dosage or discontinuing therapy if a patient develops such urges.^{109 113 114 227}

Melanoma

Melanoma observed more frequently in patients with parkinson disease than in the general population.^{109 113 114}

Monitor for melanoma on a frequent and regular basis.^{109 113 114} Periodic dermatologic screening is recommended by some manufacturers.^{109 113 114}

Specific Populations

Pregnancy

Embryotoxic/teratogenic effects observed in animal studies.^{109 113 114 227} No adequate and well-controlled studies in pregnant women.^{109 113 114 227} Use during pregnancy only when potential benefits outweigh possible risks to fetus.^{109 113 114 227}

Lactation

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 not established in pediatric patients; the majority of individuals with parkinson disease are ≥65 years of age.²²⁷

When used in children, amantadine has caused CNS symptoms, which resolved when the drug was discontinued.¹¹⁰

Increased incidence of seizures reported in children with an underlying seizure disorder receiving amantadine.¹¹⁰

Geriatric Use

Majority of individuals with parkinson disease are ≥65 years of age.²²⁷ Geriatric patients may have renal decline; reduced dosages may therefore be needed.¹⁰⁹

Hepatic Impairment

Use care when administering amantadine to patients with liver disease.^{109 113 114} Rare cases of reversible elevation of liver enzymes reported.^{109 113 114}

Renal Impairment

Mainly excreted in the urine; drug accumulation may occur when renal function declines.^{109 113 114} Reduced dosages recommended in patients with renal impairment.^{109 113 114 227}

Common Adverse Effects

Most common adverse effects (5–10%) with conventional (immediate-release) preparations: nausea, dizziness, insomnia.^{109 113 114}

Most common adverse effects (>10%) with extended-release capsules: hallucination, dizziness, dry mouth, peripheral edema, constipation, fall, orthostatic hypotension.²²⁷

Drug Interactions

Does not significantly inhibit CYP isoenzymes 1A2, 2B6, 2C19, 2C8, 2C9, 2D6, 2E1, 3A4, and 3A5.²²⁷

Negligible or no inhibitory activity against transporters (P-gp, BCRP, MATE2-K, OAT1, OAT3, OATP1B1, and OATP1B3).²²⁷

Drugs with Anticholinergic Activity

Concomitant use with other drugs with anticholinergic activity may result in increased adverse anticholinergic effects; reduce dosage of the anticholinergic agent or amantadine if atropine-like effects occur when these drugs are used concomitantly.^{109 113 114 227}

Drugs Affecting Urinary pH

Excretion rate of amantadine increases rapidly when the urine is acidic; administration of urine acidifying drugs may increase elimination of the drug.^{109 113 114 227}

Alterations of urine pH towards 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

Specific Drugs

Amantadine Hydrochloride (Antiparkinson) Pharmacokinetics

Absorption

Bioavailability

Well absorbed from the GI tract.^{109 113 114}

While peak plasma concentrations are directly related to dosages up to 200 mg daily, higher dosages may result in a greater than proportional increases in peak plasma concentration.^{109 113 114}

Following oral administration of extended-release capsules, dose-proportional pharmacokinetics observed over dose range of 68.5–274 mg.²²⁷ Time to peak plasma concentrations after a single dose is approximately 12 hours.²²⁷

Food

Food does not affect pharmacokinetics when given as the extended-release capsules; administration of capsule contents with applesauce also did not affect pharmacokinetics of the drug.²²⁷

Distribution

Protein Binding

Approximately 67% bound to plasma proteins.^{109 113 114 227}

Elimination

Elimination Route

Principally excreted unchanged in urine by glomerular filtration and tubular secretion; at least 8 metabolites have been identified in urine.^{109 113 114 116 227}

Not appreciably removed by dialysis.^{100 101 109 113 114 116 227}

Half-life

9–37 hours, with an average of 24 hours or less.^{109 113 114 117 119}

Stability

Storage

Oral

Conventional Preparations

20–25°C (excursions permitted between 15–30°C); dispense in tight, light-resistant container.^{109 113 114}

Extended-release Capsules

20–25°C (excursions permitted between 15–30°C); dispense in tight container.²²⁷

Actions

• Synthetic adamantane derivative.¹⁰⁹

• Exact mechanism of action not known.^{109 113 114 227}

• Weak uncompetitive antagonist of the NMDA receptor; may have direct and indirect effect on the dopaminergic system.^{109 113 114 227}

Advice to Patients

• Advise the patient to read the FDA-approved patient labeling (Patient Information).^{109 113 114 227}

• 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.

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

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Frequently asked questions

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