Tardive Dyskinesia

Tardive dyskinesia, a syndrome consisting of potentially irreversible, involuntary, dyskinetic movements, may develop in patients treated with neuroleptic (i.e. antipsychotics) drugs. (Amoxapine is not an antipsychotic, but it has substantive neuroleptic activitiy). Although the prevalance of the syndrome appears to be highest among the elderly, especially elderly women, it is impossible to rely upon prevalence estimates to predict, at the inception of neuroleptic treatment, which patients are likely to develop the syndrome. Whether neuroleptic drug products differ in their potential to cause tardive dyskinesia is unknown.

Both the risk of developing the syndrome and the likelihood that it will become irreversible are believed to increase as the duration of treatment and the total cumulative dose of neuroleptic drugs administered to the patient increase. However, the syndrorne can develop, although much less commonly, after relatively brief treatment periods at low doses.

There is no known treatment for established cases of tardive dyskinesia, although the syndrome may remit partially or completely, if neuroleptic treatment is withdrawn. Neuroleptic treatment, itself, however, may suppress (or partially suppress) the signs and symptoms of the syndrome and thereby may possibly mask the underlying disease process. The effect that symptomatic suppression has upon the long-term course of the syndrome is unknown.

Given these considerations, neuroleptics should be prescribed in a manner that is most likely to minimize the occurrence of tardive dyskinesia. Chronic neuroleptic treatment should generally be reserved for patients who suffer from a chronic illness that;

1. Is known to respond to neuroleptic drugs.
2. For whom alternative, equally effective, but potentially less harmful treatments are not available or appropriate.

In patients who do require chronic treatment, the smallest dose and the shortest duration of treatment producing a satisfactory clinical response should be sought.

General

In prescribing the drug it should be borne in mind that the possibility of suicide is inherent in any severe depression, and persists until a significant remission occurs; the drug should be dispensed in smallest suitable amount. Manic depressive patients may experience a shift to the manic phase. Schizophrenic patients may develop increased symptoms of psychosis; patients with paranoid symptomatology may have an exaggeration of such symptoms. This may require reduction of dosage or the addition of a major tranquilizer to the therapeutic regimen. Antidepressant drugs can cause skin rashes and/or "drug fever" in susceptible individuals. These allergic reactions may, in rare cases, be severe. They are more likely to occur during the first few days of treatment but may also occur later. Amoxapine should be discontinued if rash and/or fever develop. Amoxapine possesses a degree of dopamine-blocking activity which may cause extrapyramidal symptoms in < 1% of patients. Rarely, symptoms indicative of tardive dyskinesia have been reported.

Carcinogenesis, Impairment of Fertility

In a 21 month toxicity study at three dose levels in rats, pancreatic islet cell hyperplasia occurred with slightly increased incidence at doses 5-10 times the human dose. Pancreatic adenocarcinoma was detected in low incidence in the mid-dose group only, and may possibly have resulted from endocrine-mediated organ hyperfunction The significance of these findings to man is not known. Treatment of male rats with 5-10 times the human dose resulted in a slight decrease in the number of fertile matings. Female rats receiving oral doses within the therapeutic range displayed a reversible increase in estrous cycle length.

Pregnancy

Teratogenic Effects Pregnancy Category C: Studies perpormed in mice, rats, and rabbits have demonstrated no evidence of teratogenic effect due to amoxapine. Embryo toxicity was seen in rats and rabbits given oral doses approximating the human dose. Etotoxic effects (intrauterine death, stillbirth, decreased birth weight) were seen in animals studied at oral doses 3-10 times the human dose. Decreased postnatal survival (between days 0-4) was demonstrated in the offspring of rats at 5-10 times the human dose. There are no adequate and well-controlled studies in pregnant women. Amoxapine should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Nursing Mothers

Amoxapine, like many other systemic drugs, is excreted in human milk Because effects of the drug on infants are unknown, caution should be exercised when amoxapine is administered to nursing women

Pediatric Use

Safety and effectiveness in pediatric patients below the age of 16 have not been established.

Geriatric Use

Clinical studies of amoxapine were not adequate to determine whether subjects aged 65 and over respond differently from younger subjects.

Amoxapine is known to be substantially excreted by the kidney (see CLINICAL PHARMACOLOGY). Clinical circumstances, some of which may be more common in the elderly, such as hepatic or renal impairment, should be considered.

Greater sensitivity (e.g., tardive dyskinesia, sedation) of some older individuals cannot be ruled out (see WARNINGS and ADVERSE REACTIONS). In general, dose selection for an elderly patient should be cautious, usually starting at a lower dose (see DOSAGE AND ADMINISTRATION).

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