Symmetrel
Du Pont Pharma
Amantadine
HCl
Antiparkinson

>>> Posting number 55289, dated 21 Jan 1999 10:06:37
Date:         Thu, 21 Jan 1999 10:06:37 -0500
From:         janet paterson <[log in to unmask]>
Subject:      Amantadine / Symmetrel / Monograph

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.

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.

Contraindications

Known hypersensitivity to amantadine.

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.

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.

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).

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.

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
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Creatinine Clearance (mL/min/1.73m(2))    Dosage
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 >3D80     100 mg twice daily
60-79     Alternating daily doses of 200 and 100 mg
40-59     100 mg once daily
30-39     200 mg twice weekly
20-29     100 mg thrice weekly
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 30B0C).

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 30B0C).

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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>
copyright 1995-1998 by Phillip W. Long, M.D.
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janet paterson
52 now / 41 dx / 37 onset
snail-mail: PO Box 171  Almonte  Ontario  K0A 1A0  Canada
website: a new voice <http://www.geocities.com/SoHo/Village/6263/>
e-mail: <[log in to unmask]>