Amantadine / Symmetrel / Monograph

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Drug monograph
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Pharmacology

Antiparkinson

While the mechanism of action of amantadine in the treatment of Parkinson's=
 syndrome and drug-induced extrapyramidal reactions is not known, it is=
 believed to release brain dopamine from nerve endings making it more=
 available to activate dopaminergic receptors. The drug does not possess=
 anticholinergic activity in animal tests at doses similar to those used=
 clinically.

The antiviral activity of amantadine for the prophylaxis of Asian (A(2))=
 influenza in humans appears not to be related to the possible mode of=
 action of this drug in Parkinson's syndrome.

In man, amantadine is readily absorbed, passes the blood-brain barrier and=
 appears in the saliva and nasal secretions. The drug can be detected in the=
 blood and cerebrospinal fluid at relatively low, but dose-related, levels.=
 No evidence of metabolites has been found and 90% or more of the dose can=
 be recovered in the urine unchanged.

After oral administration of a single dose of 100 mg, maximum blood levels=
 are reached in approximately 4 hours, based on mean time of the peak=
 urinary excretion rate; the peak excretion rate is approximately 5 mg/hour;=
 the mean half-life of the excretion rate approximates 15 hours.

Compared with otherwise healthy adult individuals, the clearance of=
 amantadine is significantly reduced in adult patients with renal=
 insufficiency. The elimination half-life increases 2 to 3 fold when=
 creatinine clearance is less than 40 mL/min./1.73m(2) and averages 8 days=
 in patients on chronic maintenance hemodialysis.

The renal clearance of amantadine is reduced and plasma levels are increased=
 in otherwise healthy elderly patients age 65 years and older. The drug=
 plasma levels in elderly patients receiving 100 mg daily have been reported=
 to approximate those determined in younger adults taking 200 mg daily.=
 Whether these changes are due to the normal decline in renal function or=
 other age factors is not known.

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Indications

Amandatine is useful in the treatment of Parkinson's syndrome and in the=
 short-term management of drug-induced extrapyramidal symptoms.

In Parkinson's syndrome, amantadine has been used alone and in combination=
 with anticholinergic antiparkinson drugs and with levodopa. The final=
 therapeutic benefit seen with amantadine is significantly less than that=
 seen with levodopa. The maximal therapeutic benefit to be obtained with=
 amantadine is usually seen within 1 week. However, initial benefits may=
 diminish with continued dosing.

Amantadine is useful as an adjunct in patients who do not tolerate optimal=
 doses of levodopa alone or in combined therapy with a decarboxylase=
 inhibitor. In these patients, the addition of amantadine may result in=
 better control of Parkinson's syndrome and may help to smooth out=
 fluctuations in performance.

The comparative efficacy of amantadine and anticholinergic antiparkinson=
 drugs has not yet been established. When amantadine or anticholinergic=
 antiparkinson drugs are each used with marginal benefit, concomitant use=
 may permit the same degree of control, often with a lower dose of the=
 anticholinergic medication.

Amantadine is effective in reducing severity or abolishing drug-induced=
 extrapyramidal reactions including parkinsonism syndrome, dystonia and=
 akathisia. It is not effective in the management of tardive dyskinesia.

Although anticholinergic-type side effects have been noted when used in=
 patients with drug-induced extrapyramidal reactions, there appears to be a=
 lower incidence of these side effects than that observed with=
 anticholinergic antiparkinson drugs.

Antiparkinsonian agents should not usually be used prophylactically during=
 neuroleptic administration. However, they may be given when needed to=
 suppress extrapyramidal symptoms. Therefore, amantadine may be used in the=
 management of extrapyramidal symptoms which cannot be controlled by=
 reduction of neuroleptic dosage, but should be discontinued as soon as it=
 is no longer required. Amantadine should be withdrawn after a period of=
 time to determine whether there is recrudescence of extrapyramidal=
 symptoms.

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Contraindications

Known hypersensitivity to amantadine.

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Warnings

A small number of suicidal attempts, some of which have been fatal, have=
 been reported in patients treated with amantadine. The incidence of=
 suicidal attempts is not known and the pathophysiologic mechanism is not=
 understood. Suicidal attempts and suicidal ideation have been reported in=
 patients with and without prior history of psychiatric illness. Amantadine=
 can exacerbate mental problems in patients with a history of psychiatric=
 disorders or substance abuse.

Patients who attempt suicide may exhibit abnormal mental states which=
 include disorientation, confusion, depression, personality changes,=
 agitation, aggressive behavior, hallucinations, paranoia, other psychotic=
 reactions, and somnolence or insomnia. Because of the possibility of=
 serious adverse effects, caution should be observed when prescribing=
 amantadine to patients being treated with drugs having CNS effects, or for=
 whom the potential risks outweigh the benefit of treatment. Because some=
 patients have attempted suicide by overdosing with amantadine,=
 prescriptions should be written for the smallest quantity consistent with=
 good patient management.

Patients with a history of epilepsy or other seizures should be observed=
 closely for possible increased seizure activity.

Patients with a history of CHF or peripheral edema should be followed=
 closely as there are patients who developed congestive heart failure while=
 receiving amantadine.

Patients with Parkinson's disease improving on amantadine should resume=
 normal activities gradually and cautiously, consistent with other medical=
 considerations, such as the presence of osteoporosis or phlebothrombosis.

Occupational Hazards: Patients receiving amantadine who note CNS effects or=
 blurring of vision should be cautioned against driving or working in=
 situations where alertness and adequate motor coordination are important.

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Precautions

General: Amantadine should not be discontinued abruptly since a few patients=
 with Parkinson's syndrome experienced a parkinsonian crisis, i.e., sudden=
 marked clinical deterioration, when this medication was suddenly stopped.

Neuroleptic Malignant Syndrome (NMS): Sporadic cases of possible Neuroleptic=
 Malignant Syndrome (NMS) have been reported in association with dose=
 reduction or withdrawal of amantadine therapy. NMS is an uncommon but=
 life-threatening syndrome characterised by fever or hyperthermia;=
 neurologic findings including muscle rigidity, involuntary movements,=
 altered consciousness; other disturbances such as autonomic dysfunction,=
 tachycardia, tachypnea, hyper- or hypotension; laboratory findings such as=
 creatinine phosphokinase elevation, leukocytosis, and increased serum=
 myoglobin.

The diagnostic evaluation of patients with this syndrome is complicated. In=
 arriving at a diagnosis, it is important to identify cases where the=
 clinical presentation includes both serious medical illness (e.g.,=
 pneumonia, systemic infection, etc.) and untreated or inadequately treated=
 extrapyramidal signs and symptoms (EPS). Other important considerations in=
 the differential diagnosis include central anticholinergic toxicity, heat=
 stroke, drug fever, and primary CNS pathology.

The management of NMS should include: Intensive symptomatic treatment and=
 medical monitoring; and treatment of any concomitant serious medical=
 problems for which specific treatments are available. There is no general=
 agreement about specific pharmacological treatment regimens for=
 uncomplicated NMS.

Patients with Special Diseases and Conditions: Because amantadine is not=
 metabolized and is mainly excreted in the urine, it may accumulate in the=
 plasma and in the body when renal function declines. The dose of amantadine=
 should be reduced in patients with renal impairment and in patients who are=
 65 years of age or older (see Dosage). The dose of amantadine may need=
 careful adjustment in patients with congestive heart failure, peripheral=
 edema, or orthostatic hypotension.

Care shoud be exercised when administering amantadine to patients with liver=
 disease, a history of recurrent eczematoid rash, or to patients with=
 psychosis or severe psychoneurosis not controlled by chemotherapeutic=
 agents. Rare instances of reversible elevation of liver enzyme levels have=
 been reported in patients receiving amantadine, though a specific=
 relationship between the drug and such changes has not been established.

Pregnancy: Amantadine has been shown to be embryotoxic and teratogenic in=
 rats at 50 mg/kg/day, approximately 12 times the recommended human dose,=
 but not at 37 mg/kg/day. Embryotoxic and teratogenic drug effects were not=
 seen in rabbits that received up to 25 times the recommended human dose.

There are not adequate and well controlled studies in pregnant women.=
 Therefore, amantadine should not be used in women with childbearing=
 potential, unless in the opinion of the physician, the expected benefit to=
 the patient outweighs the possible risk to the fetus.

Lactation: Since amantadine is secreted in human milk, its use is not=
 recommended in nursing mothers.

Children: The safety and efficacy of use of amantadine in neonates and=
 infants less than 1 year old have not been established.

Drug interactions: The dose of anticholinergic drugs or of amantadine should=
 be reduced if atropine-like effects appear when these drugs are used=
 concurrently.

Careful observation is required when amantadine is administered concurrently=
 with CNS stimulants.

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Adverse Effects

Adverse reactions reported below have occurred in patients while receiving=
 amantadine alone or in combination with anticholinergic antiparkinsonian=
 drugs and/or levodopa.

The adverse reactions reported most frequently (5 to 10%) are: nausea,=
 dizziness (lightheadedness) and insomnia.

Less frequently reported (1 to 5%) are: depression, anxiety and=
 irritability, hallucinations, confusion, anorexia, dry mouth, constipation,=
 ataxia, livedo reticularis, peripheral edema, orthostatic hypotension,=
 headache, somnolence, nervousness, dream abnormality, agitation, dry nose,=
 diarrhea and fatigue.

Infrequently occurring adverse reaction (0.1 to 1%) are: CHF, psychosis,=
 urinary retention, dyspnea, skin rash, vomiting, weakness, slurred speech,=
 euphoria, confusion, thinking abnormality, amnesia, hyperkinesia,=
 hypertension, decreased libido, and visual disturbance, including punctuate=
 subepithelial or other corneal opacity, corneal edema, decreased visual=
 acuity, sensitivity to light, and optic nerve palsy.

Rarely occurring adverse reactions (less than 0.1%) are: instances of=
 convulsion, leukopenia, neutropenia, ezcematoid dermatitis and oculogyric=
 episodes. Other rare occurring adverse reactions are: suicidal attempt,=
 suicide, and suicidal ideation (see Warnings).

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Overdose

Symptoms: Deaths have been reported from overdose with amantadine. The=
 lowest reported acute lethal dose was 2 g. An elderly patient with=
 Parkinson's syndrome who took an overdose of 2.8 g of amantadine in a=
 suicidal attempt, developed acute toxic psychosis, urinary retention, and a=
 mixed acid-base disturbance. The toxic psychosis was manifested by=
 disorientation, confusion, visual hallucinations and aggressive behavior.=
 Convulsions did not occur, possibly because the patient had been receiving=
 phenytoin prior to the acute ingestion of amantadine.

Treatment: There is no specific antidote. Slowly administered i.v.=
 physostigmine in 1 and 2 mg doses at 1 to 2 hour intervals in an adult, and=
 0.5 mg doses at 5 to 10 minute intervals in a child up to a maximum of 2=
 mg/hour, have been reported to be effective in the control of CNS toxicity=
 caused by amantadine hydrochloride. For acute overdosing, general=
 supportive measures should be employed, along with immediate gastric lavage=
 or induction of emesis. Fluids should be forced, and if necessary, given=
 i.v.

Hemodialysis does not remove significant amounts of amantadine hydrochloride=
 in patients with renal failure; a 4 hour hemodialysis removed 7 to 15 mg=
 after a single 300 mg oral dose.

The pH of the urine has been reported to influence the excretion rate of=
 amantadine. Since the excretion rate of the drug increases rapidly when the=
 urine is acidic, the administration of urine-acidifying fluids may increase=
 the elimination of the drug from the body. The blood pressure, pulse,=
 respiration and temperature should be monitored. The patient should be=
 observed for the possible development of arrhythmias, hypotension,=
 hyperactivity, and convulsions; if required, appropriate therapy should be=
 administered. The blood electrolytes, urine pH and urinary output should be=
 monitored. If there is no record of recent voiding, catheterization should=
 be done. The possibility of multiple drug ingestion by the patient should=
 be considered.

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Dosage

Parkinson's Syndrome: The initial dose of amantadine 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. When=
 amantadine and levodopa are initiated concurrently, amantadine should be=
 held constant at 100 mg daily or twice daily while the daily dose of=
 levodopa is gradually increased to optimal dose. When used alone, the usual=
 dose of amantadine is 100 mg twice a day.

Patients whose responses are not optimal with amantadine at 200 mg daily may=
 benefit from an increase to 300 mg daily in divided doses. Patients who=
 experience a fall-off of effectiveness may regain benefit by increasing the=
 dose to 300 mg daily; such patients should be supervised closely by their=
 physicians.

Drug-Induced Extrapyramidal Symptoms: The usual dose of amantadine is 100 mg=
 twice a day. Occasionally, patients whose responses are not optimal with=
 amantadine at 200 mg daily may benefit from an increase up to 300 mg daily=
 in divided doses.

In the Presence of Impaired Renal Function: Table I outlines the recommended=
 dosage adjustments dependent upon creatinine clearance, based upon the=
 current National Advisory Committee on Immunization (NACI) Canada=
 Communicable Disease Report, May 29, 1992.

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Table I=20
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Creatinine Clearance (mL/min/1.73m(2))    Dosage=
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 >=3D80     100 mg twice daily=20
60-79     Alternating daily doses of 200 and 100 mg=20
40-59     100 mg once daily=20
30-39     200 mg twice weekly=20
20-29     100 mg thrice weekly=20
10-19     Alternating weekly doses of 200 and 100 mg=
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The recommended dosage for patients on hemodialysis is 20 mg every 7 days.

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Supplied

Capsules: Each red, soft gelatin capsule contains: Amantadine HCl 100 mg.=
 Also contains parabens. Alcohol-free, lactose-free, sodium-free,=
 sulfite-free and tartrazine-free. Bottles of 100. Store at room temperature=
 (15 to 30=B0C).

Syrup: Each 5 mL of clear colorless syrup contains: Amantadine HCl 50 mg.=
 Also contains parabens. Alcohol-free, lactose-free, sodium-free,=
 sulfite-free and tartrazine-free. Bottles of 500 mL. Store at room=
 temperature (15 to 30=B0C).

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Research

The research information is available separately on Internet Mental Health.

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Note: This information is from a Canadian monograph. There can be=
 differences in indications, dosage forms and warnings for this drug in=
 other countries.
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Internet Mental Health (<http://www.mentalhealth.com>)=20
copyright =A9 1995-1998 by Phillip W. Long, M.D.
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janet paterson - 51 now /41 dx /37 onset - almonte/ontario/canada
http://www.newcountry.nu/pd/members/janet/index.htm
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