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Amantadine (Amantadine Hydrochloride) - Warnings and Precautions

 
 



WARNINGS

Deaths

Deaths have been reported from overdose with Amantadine Hydrochloride. The lowest reported acute lethal dose was 1 gram. Acute toxicity may be attributable to the anticholinergic effects of amantadine. Drug overdose has resulted in cardiac, respiratory, renal or central nervous system toxicity. Cardiac dysfunction includes arrhythmia, tachycardia and hypertension (see OVERDOSAGE).

Suicide Attempts

Suicide attempts, some of which have been fatal, have been reported in patients treated with Amantadine Hydrochloride, many of whom received short courses for influenza treatment or prophylaxis. The incidence of suicide attempts is not known and the pathophysiologic mechanism is not understood. Suicide attempts and suicidal ideation have been reported in patients with and without prior history of psychiatric illness. Amantadine Hydrochloride 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 Hydrochloride to patients being treated with drugs having CNS effects, or for whom the potential risks outweigh the benefit of treatment.

CNS Effects

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

Patients receiving Amantadine Hydrochloride who note central nervous system effects or blurring of vision should be cautioned against driving or working in situations where alertness and adequate motor coordination are important.

Other

Patients with a history of congestive heart failure or peripheral edema should be followed closely as there are patients who developed congestive heart failure while receiving Amantadine Hydrochloride. Patients with Parkinson’s disease improving on Amantadine Hydrochloride should resume normal activities gradually and cautiously, consistent with other medical considerations, such as the presence of osteoporosis or phlebothrombosis.

Because Amantadine Hydrochloride has anticholinergic effects and may cause mydriasis, it should not be given to patients with untreated angle closure glaucoma.

PRECAUTIONS

Amantadine Hydrochloride should not be discontinued abruptly in patients with Parkinson's disease since a few patients have experienced a parkinsonian crisis, i.e., a sudden marked clinical deterioration, when this medication was suddenly stopped. The dose of anticholinergic drugs or of Amantadine Hydrochloride should be reduced if atropine-like effects appear when these drugs are used concurrently. Abrupt discontinuation may also precipitate delirium, agitation, delusions, hallucinations, paranoid reaction, stupor, anxiety, depression and slurred speech.

Neuroleptic Malignant Syndrome (NMS)

Sporadic cases of possible Neuroleptic Malignant Syndrome (NMS) have been reported in association with dose reduction or withdrawal of Amantadine Hydrochloride therapy. Therefore, patients should be observed carefully when the dosage of Amantadine Hydrochloride is reduced abruptly or discontinued, especially if the patient is receiving neuroleptics.

NMS is an uncommon but life-threatening syndrome characterized by fever or hyperthermia; neurologic findings including muscle rigidity, involuntary movements, altered consciousness; mental status changes; other disturbances such as autonomic dysfunction, tachycardia, tachypnea, hyper - or hypotension; laboratory findings such as creatine phosphokinase elevation, leukocytosis, myoglobinuria, and increased serum myoglobin. The early diagnosis of this condition is important for the appropriate management of these patients. Considering NMS as a possible diagnosis and ruling out other acute illnesses (e.g., pneumonia, systemic infection, etc.) is essential. This may be especially complex if the clinical presentation includes both serious medical illness 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 central nervous system (CNS) pathology.

The management of NMS should include: 1) intense symptomatic treatment and medical monitoring, and 2) treatment of any concomitant serious medical problems for which specific treatments are available. Dopamine agonists, such as bromocriptine, and muscle relaxants, such as dantrolene are often used in the treatment of NMS, however, their effectiveness has not been demonstrated in controlled studies.

Renal Disease

Because Amantadine Hydrochloride is mainly excreted in the urine, it accumulates in the plasma and in the body when renal function declines. Thus, the dose of Amantadine Hydrochloride should be reduced in patients with renal impairment and in individuals who are 65 years of age or older (see DOSAGE AND ADMINISTRATION; Dosage for Impaired Renal Function).

Liver Disease

Care should be exercised when administering Amantadine Hydrochloride to patients with liver disease. Rare instances of reversible elevation of liver enzymes have been reported in patients receiving Amantadine Hydrochloride, though a specific relationship between the drug and such changes has not been established.

Other

The dose of Amantadine Hydrochloride may need careful adjustment in patients with congestive heart failure, peripheral edema, or orthostatic hypotension. Care should be exercised when administering Amantadine Hydrochloride to patients with a history of recurrent eczematoid rash, or to patients with psychosis or severe psychoneurosis not controlled by chemotherapeutic agents. Serious bacterial infections may begin with influenza-like symptoms or may coexist with or occur as complications during the course of influenza. Amantadine Hydrochloride has not been shown to prevent such complications.

Information for Patients

Patients should be advised of the following information:

Blurry vision and/or impaired mental acuity may occur.

Gradually increase physical activity as the symptoms of Parkinson’s disease improve.

Avoid excessive alcohol usage, since it may increase the potential for CNS effects such as dizziness, confusion, lightheadedness and orthostatic hypotension.

Avoid getting up suddenly from a sitting or lying position. If dizziness or lightheadedness occurs, notify physician.

Notify physician if mood/mental changes, swelling of extremities, difficulty urinating and/or shortness of breath occur.

Do not take more medication than prescribed because of the risk of overdose. If there is no improvement in a few days, or if medication appears less effective after a few weeks, discuss with a physician.

Consult physician before discontinuing medication.

Seek medical attention immediately if it is suspected that an overdose of medication has been taken.

Drug Interactions

Careful observation is required when Amantadine Hydrochloride is administered concurrently with central nervous system stimulants.

Agents with anticholinergic properties may potentiate the anticholinergic-like side effects of amantadine.

Coadministration of thioridazine has been reported to worsen the tremor in elderly patients with Parkinson's disease, however, it is not known if other phenothiazines produce a similar response.

Coadministration of Dyazide (triamterene/hydrochlorothiazide) resulted in a higher plasma amantadine concentration in a 61-year-old man receiving Amantadine Hydrochloride 100 mg TID for Parkinson's disease.1 It is not known which of the components of Dyazide contributed to the observation or if related drugs produce a similar response.

Coadministration of quinine or quinidine with amantadine was shown to reduce the renal clearance of amantadine by about 30%.

Carcinogenesis and Mutagenesis

Long-term in vivo animals studies designed to evaluate the carcinogenic potential of Amantadine Hydrochloride have not been performed. In several in vitro assays for gene mutation, Amantadine Hydrochloride did not increase the number of spontaneously observed mutations in four strains of Salmonella typhimurium (Ames Test) or in a mammalian cell line (Chinese Hamster Ovary cells) when incubations were performed either with or without a liver metabolic activation extract. Further, there was no evidence of chromosome damage observed in an in vitro test using freshly derived and stimulated human peripheral blood lymphocytes (with and without metabolic activation) or in an in vivo mouse bone marrow micronucleus test (140-550 mg/kg; estimated human equivalent doses of 11.7-45.8 mg/kg based on body surface area conversion).

Impairment of Fertility

The effect of amantadine on fertility has not been adequately tested, that is, in a study conducted under Good Laboratory Practices (GLP) and according to current recommended methodology. In a three litter, non-GLP, reproduction study in rats, Amantadine Hydrochloride at a dose of 32 mg/kg/day (equal to the maximum recommended human dose on a mg/m2 basis) administered to both males and females slightly impaired fertility. There were no effects on fertility at a dose level of 10 mg/kg/day (or 0.3 times the maximum recommended human dose on a mg/m2 basis); intermediate doses were not tested.

Failed fertility has been reported during human in vitro fertilization (IVF) when the sperm donor ingested amantadine 2 weeks prior to, and during the IVF cycle.

Pregnancy Category C

The effect of amantadine on embryofetal and peri-postnatal development has not been adequately tested, that is, in studies conducted under Good Laboratory Practice (GLP) and according to current recommended methodology. However, in two non-GLP studies in rats in which females were dosed from 5 days prior to mating to Day 6 of gestation or on Days 7-14 of gestation, Amantadine Hydrochloride produced increases in embryonic death at an oral dose of 100 mg/kg (or 3 times the maximum recommended human dose on a mg/m2 basis). In the non-GLP rat study in which females were dosed on Days 7-14 of gestation, there was a marked increase in severe visceral and skeletal malformations at oral doses of 50 and 100 mg/kg (or 1.5 and 3 times, respectively, the maximum recommended human dose on a mg/m2 basis). The no-effect dose for teratogenicity was 37 mg/kg (equal to the maximum recommended human dose on a mg/m2 basis). The safety margins reported may not accurately reflect the risk considering the questionable quality of the study on which they are based. There are no adequate and well- controlled studies in pregnant women. Human data regarding teratogenicity after maternal use of amantadine is scarce. Tetralogy of Fallot and tibial hemimelia (normal karyotype) occurred in an infant exposed to amantadine during the first trimester of pregnancy (100 mg P.O. for 7 days during the 6th and 7th week of gestation). Cardiovascular maldevelopment (single ventricle with pulmonary atresia) was associated with maternal exposure to amantadine (100 mg/d) administered during the first 2 weeks of pregnancy. Amantadine Hydrochloride should be used during pregnancy only if the potential benefit justifies the potential risk to the embryo or fetus.

Nursing Mothers

Amantadine Hydrochloride is excreted in human milk. Use is not recommended in nursing mothers.

Pediatric Use

The safety and efficacy of Amantadine Hydrochloride in newborn infants and infants below the age of 1 year have not been established.

Usage in the Elderly

Because Amantadine Hydrochloride is primarily excreted in the urine, it accumulates in the plasma and in the body when renal function declines. Thus, the dose of Amantadine Hydrochloride should be reduced in patients with renal impairment and in individuals who are 65 years of age or older. The dose of Amantadine Hydrochloride may need reduction in patients with congestive heart failure, peripheral edema, or orthostatic hypotension (see DOSAGE AND ADMINISTRATION).

Page last updated: 2006-08-09

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