Clozapine (Clozaril) and risk of serious bowel problems

FDA identified 10 cases of constipation that progressed to serious complications with clozapine use reported in the FDA Adverse Event Reporting System (FAERS) database from July 21, 2006, through July 20, 2016, and in the medical literature from July 21, 2006, through August 2, 2016. These cases resulted in hospitalization, surgery, and five deaths. Adverse events included necrotizing colitis2-5 (n=4), intestinal ischemia or necrosis6-8 (n=5), and volvulus (n=1). The total daily dose of clozapine administered ranged from 200 mg to 600 mg, with a median daily dose of 400 mg. The time to onset of serious bowel events ranged from 3 days to 6 months, with a median of 46 days. A preliminary review of additional FAERS data reported from July 21, 2016, through the end of 2019 found similar findings. Clozapine can do this alone; in contrast, serious complications of constipation have been identified with other antipsychotics (e.g., olanzapine) only when they were used with other anticholinergic medicines.

A New Zealand study of 37 patients conducted by Every-Palmer et al.9 objectively assessed and confirmed clozapine-induced gastrointestinal hypomotility by measuring colonic transit time (CTT) using radiopaque markers. The study reviewed the effects of clozapine (monotherapy and combination antipsychotic therapy, 20 patients) and non-clozapine antipsychotics (monotherapy and combination antipsychotic therapy, 17 patients) and concluded that nearly all patients receiving clozapine had increased CTTs, but most non-clozapine treated patients did not. An exposure-related increase in CTT was seen (that is, higher CTT with higher clozapine levels); however, patients did not report the hypomotility as subjective symptoms of constipation. The median CTT in patients treated with clozapine was more than four times longer than in patients not prescribed clozapine (104.5 hours vs. 23 hours, respectively).

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