Plasma Clozapine and Norclozapine After Use of Either Crushed Tablets or Suspension Compared With Tablets

Abstract

BackgroundWith clozapine, either crushed tablets suspended in an aqueous medium or proprietary suspension is sometimes prescribed as an alternative to tablets, but bioequivalence data are scant.MethodsWe compared clozapine dose, and plasma clozapine and N-desmethylclozapine (norclozapine) concentrations after use of either tablets or crushed tablets/suspension in samples submitted for clozapine therapeutic drug monitoring, 1993 to 2017.ResultsThere were 846 patients (1646 samples) given crushed tablets/suspension and 6065 patients (10,779 samples) given tablets. The median dose (mg d−1) was significantly higher in men (500 vs 450) and women (500 vs 400) given crushed tablets/suspension, but the median plasma clozapine and norclozapine concentrations (mg L−1) were significantly lower (men: 0.29 and 0.22 vs 0.39 and 0.28; women: 0.35 and 0.26 vs 0.50 and 0.32, respectively). A subgroup of 480 patients was prescribed either crushed tablets/suspension (1016 samples) or tablets (1259 samples) at different times. The median dose was again significantly higher in men (500 vs 500) and women (500 vs 450), but the median plasma clozapine and norclozapine concentrations were significantly lower (men: 0.29 and 0.22 vs 0.32 and 0.24; women: 0.30 and 0.24 vs 0.38 and 0.29, respectively).ImplicationsPoor adherence, sedimentation of suspension before use, and incomplete dosage are potential contributors to the lower median plasma clozapine and norclozapine concentrations observed after use of either crushed clozapine tablets or suspension as compared with tablets. Those administering crushed tablets/suspension should be aware of these factors.

Letter to the Editors in Response to: Flanagan RJ, Hunter S, Obee S, Reeves S. Plasma Clozapine and Norclozapine After Use of Either Crushed Tablets or Suspension Compared With Tablets

“…In addition, it seems that giving clozapine in this way would give rise, on average, to lower predose plasma clozapine and norclozapine concentrations than if the same dose were prescribed as tablets. [1][2][3][4] Hence, it is important to consider the mode of administration when reporting clozapine dose-to-plasma concentration relationships, for example.…”

“…Flanagan and colleagues 1 report that plasma concentrations of clozapine are lower in people receiving crushed tablets or clozapine suspension than in those receiving tablets. They suggest that one of the reasons for this is the sedimentation of suspended drug particles, leading to administration of doses lower than intended.…”

Patient with bipolar I disorder who presented with low blood lithium levels after receiving crushed tablets via a nasogastric tube: A case report

“…In the current case, drug loss could have occurred while making the pre-suspended solution. Further, Flanagan et al showed that only the supernatant liquid might have been administered due to drug sedimentation during suspension ( 9 ). According to the Japanese package insert, Li carbonate does not dissolve easily in water.…”

Response to Letter to the Editors From Prof D. Taylor

“…We thank Professor Taylor for his interest in our article 1 and for his helpful comments 2 . We feel that we all agree that clozapine administration as crushed tablets suspended in an appropriate medium or as a proprietary suspension or liquid formulation is a valuable dosing strategy in appropriate circumstances.…”

“…We feel that we all agree that clozapine administration as crushed tablets suspended in an appropriate medium or as a proprietary suspension or liquid formulation is a valuable dosing strategy in appropriate circumstances. In addition, it seems that giving clozapine in this way would give rise, on average, to lower predose plasma clozapine and norclozapine concentrations than if the same dose were prescribed as tablets 1–4 . Hence, it is important to consider the mode of administration when reporting clozapine dose-to-plasma concentration relationships, for example.…”