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 characterized 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. The dose of amantadine may need careful adjustment in patients with congestive heart failure, peripheral edema, or orthostatic hypotension.

Care should 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.

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 no 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.

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

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

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 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.