Amantadine / Symmetrel / Monograph ---------------------------------------------------------------------------- Drug monograph ---------------------------------------------------------------------------- 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. ----------------------------------------------------------------------------= =20 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. ----------------------------------------------------------------=20 Table I=20 ----------------------------------------------------------------=20 Creatinine Clearance (mL/min/1.73m(2)) Dosage= ---------------------------------------------------------------- >=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= ---------------------------------------------------------------- The recommended dosage for patients on hemodialysis is 20 mg every 7 days. ---------------------------------------------------------------------------- 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). ---------------------------------------------------------------------------- Research The research information is available separately on Internet Mental Health. ---------------------------------------------------------------------------- Note: This information is from a Canadian monograph. There can be= differences in indications, dosage forms and warnings for this drug in= other countries. ---------------------------------------------------------------------------- Internet Mental Health (<http://www.mentalhealth.com>)=20 copyright =A9 1995-1998 by Phillip W. Long, M.D. ---------------------------------------------------------------------------- janet paterson - 51 now /41 dx /37 onset - almonte/ontario/canada http://www.newcountry.nu/pd/members/janet/index.htm [log in to unmask]