Signs and Symptoms

Toxic manifestations of amoxapine overdosage differ significantly from those of other tricyclic antidepressants. Serious cardiovascular effects are seldom if ever observed. However, CNS effects, particularly grand mal convulsions, occur frequently, and treatment should be directed primarily toward prevention or control of seizures. Status epilepticus may develop and constitutes a neurologic emergency. Coma and acidosis are other serious complications of substantial amoxapine overdosage in some cases.

Renal failure may develop two to five days after toxic OVERDOSE in patients who may appear otherwise recovered. Acute tubular necrosis with rhabdomuolysis and myolobinurla is the most common renal complication in such cases. This reaction probably occurs in less than 5% of overdose cases, and typically in those who have experienced multiple seizures.

Treatment

Treatment of amoxapine overdosage should be Symptomatic and supportive but with special attention to prevention or control of seizures. If the patient is conscious, induced emesis followed by gastric lavage with appropriate precautions to prevent pulmonary aspiration should be accomplished as soon as possible. Following lavage, activated charcoal may be administered to reduce absorption, and repeated administrations may facilitate drug elimination. An adequate airway should be established in comatose patients and assisted ventilation instituted if necessary. Seizures may respond to standard anticonvulsant therapy such as intravenous diazepam and/or phenytoin. The value of physostigmine appears less certain. Status epilepticus, should it develop, requires vigorous treatment such as described by Delgado-Escueta et a (N Engl J Med 1982: 3061337-1340).

Convulsions when they occur, typically begin within 12 hours after suggestion. Because seizures may occur precipitously in some over dosage patients who appear otherwise relatively asymptomatic, the treating physician may wish to consider prophylactic administration of anticonvulsant medication during this period.

Treatment of renal impairment should it occur, is the same as that for nondrug-induced renal dysfunction.

Serious cardiovascular effects are remarkably rare following amoxapine overdosage, and the ECG typically remains within normal limits except for sinus tachycardia. Hence, prolongation of the QRS interval beyond 100 milliseconds within the first 24 hours is not a useful guide of the severity of over dosage with this drug.

Fatalities and rarely, neurologic sequelae have resulted from prolonged status epilepticus in amoxapine overdosage patients While the lethal dose appears higher than that of other tricyclic antidepressants (80% of lethal amoxapine overdosages have involved ingestion of 3 grams or more). Many factors other than amount ingested are important in assessing probability or survival. These include age and physical condition of the patient, concomitant ingestion of other drugs, and especially the interval between drug ingestion and initiation of emergency treatment.

Amoxapine tablets are contraindicated in patients who have shown prior hypersensitivity to dibenzoxazepine compounds. It should not be given concomitantly with monoamine oxidase inhibitors. Hyperpyretic crises, severe convulsions, and deaths have occurred in patients receiving tricyclic antidepressants and monoamine oxidase inhibitors simultaneous. When it is desired to replace monoamine oxidase inhibitor with amoxapine, a minimum of 14 days should be allowed to elapse after the former is discontinued. Amoxapine should then be initiated cautiously with gradual increase in dosage until optimum response is achieved. The drug is not recommended for use during the acute recovery phase following myocardial infarction.

The need for continued treatment should be reassessed periodically.

If signs and symptoms of tardive dyskinesia appear in a patient on neuroleptic drugs, discontinuation should be considered. However, some patients may require treatment despite the presence of the syndrome.

(For further information about the description of tardive dyskinesia and its clinical detection, please refer to the sections on PATIENT INFORMATON and ADVERSE REACTIONS.)

Neuroleptic Malignant Syndrome (NMS):

A potentially fatal symptom complex sometimes referred to as Neuroleptic Malignant Syndrome (NMS) has been has been reported in association with antipsychotic drugs and with amoxapine. Clinical manifestations of NMS are hyperpyrexia, muscle rigidity, altered mental status and evidence of autonomic instability ( irregular pulse or blood pressure, tachycardia, diaphoresis, and cardiac dysrhythmias).

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 (eg.,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 central nervous System (CNS) pathology.

The management of NMS should and primary central nervous System (CNS) include;

1. Immediate discontinuation of antipsychotic drugs and other drugs not essential to concurrent therapy.
2. Intensive symptomatic treatment and medical monitoring.
3. 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.

If a patient requires antipsychotic drug treatment after recovery from NMS, the potential reintroduction of the drug thereafter should be carefully considered. The patient should be carefully monitored, since recurrences of NMS have been reported.

Amoxapine should be used with caution in patients with a history of urinary retention, angle-closure glaucoma or increased intraocular pressure. Patients with cardiovascular disorders should be watched closely. Tricyclic antidepressant drugs, particularly when given in high doses, can induce sinus tachycardia, changes in conduction time, and arrhythmias. Myocardial infarction and stroke have been reported with drugs of this class.

Extreme caution should be used in treating patients with a history of convulsive disorder or those with overt or latent seizure disorders

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