Pharmacology
AntiparkinsonWhile
the mechanism of action of amantadine in the treatment of Parkinson's
disease 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 Disease, 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 disease, 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 Disease 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 Disease--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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>=80 100 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.
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°C).
--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°C).
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