A high plasma clozapine level was observed in a patient under concomitant diazepam treatment. Is th

Fråga: A high plasma clozapine level was observed in a patient under concomitant diazepam treatment. Is there a possible interaction?

Sammanfattning: We found no data on benzodiazepine therapy increasing plasma clozapine levels. However, several reports suggest that this combination might, in susceptible individuals, lead to serious adverse reactions. Caution is therefore warranted.

Svar: A comprehensive search including Medline, Drugline and pharmacological textbooks was done. We found no reports on benzodiazepines increasing clozapine levels. However, adverse effects, possibly due to interactions between benzodiazepines and clozapine have previously been addressed in Drugline (1). It was concluded that it is possible but not established that benzodiazepines may increase the risk of clozapine-induced respiratory arrest and circulatory collapse. Since then new cases were reported suggesting increased risk of adverse effects when clozapine is used together with benzodiazepines. Lorazepam was given for agitation in two patients on clozapine (2). Both developed delirium initially and after rechallenge. A third patient on clozapine was treated with clonazepam and also developed delirium. Sudden death was reported in a patient on clozapine 35 hours after receiving the last of three intravenous injections of lorazepam (2 mg) (3). The probable cause of death was respiratory arrest during sleep. It should, however, be mentioned that this was the only life-threatening event among 162 patients who were treated with the combination of clozapine and benzodiazepines between 1986 and 1991 at that hospital.

It should be pointed out that clozapine in the absence of benzodiazepines has been associated with isolated cases of respiratory arrest and orthostatic hypotension (4). Also, benzodiazepines are known to exert an inhibitory effect on the respiratory function (5).

A few other cases of circulatory collapse in patients receiving diazepam or lorazepam in combination with clozapine have been described (4). Although, a causal relationship has not been established in any of the reported cases, the severity of the reactions dictates that until further information is available, patients receiving clozapine and a benzodiazepine should be monitored closely for evidence of respiratory depression or hypotension.

Finally, higher-than-expected clozapine concentrations were recently reported in patients on clozapine alone. Levels of 1163 ng/ml and 1279 ng/ml were measured in two patients who received clozapine in doses of 250 mg and 750 mg respectively (6).