Clozapine-induced gastrointestinal hypomotility: presenting features and outcomes, UK pharmacovigilance reports, 1992–2017

Abstract

Background Clozapine-induced gastrointestinal hypomotility (CIGH) affects some 75% of patients treated with clozapine. Aims To document the incidence of potentially harmful CIGH in the UK. Method We studied spontaneous UK pharmacovigilance reports recorded as clozapine-related gastrointestinal adverse drug reactions, 1992–2017. Results There were 527 patients reported with potentially harmful CIGH; 33% (n = 172) died. Deaths averaged 1 per year 1992–1999, 5 per year 2000–2009 and 15 per year 2010–2017. Those who died were older (median 52 years v. 49 years) and had been prescribed clozapine for longer than those who recovered (median 11.3 years v. 4.8 years), but there was no difference in prescribed dose. Within the first 4 years of clozapine treatment, there were 169 reports of CIGH, of which 3% (n = 5) were fatal. At 10–14 years there were 63 reports of CIGH, of which 25% (n = 16) were fatal. Among the deaths, males were younger (median 51, range 22–89 v. median 57, range 24–89 years) with higher clozapine doses (median 450, range 100–900 v. median 300, range 12.5–800 mg/d) than females. In non-fatal CIGH, surgery was the most frequent outcome (n = 92). The procedures included appendectomy, ileostomy, total/partial colectomy, colostomy/stoma and proctosigmoidectomy. Clozapine dosage was reduced in 6 patients, stopped and restarted in 23, ‘continued’ in 6 and discontinued permanently in at least 76 patients. Conclusions The risk of serious morbidity/mortality from CIGH is substantial. The need to actively monitor bowel function and give laxatives to patients treated with clozapine is clear.

Reflections on the Lack of Consideration of Ethnic Ancestry to Stratify Clozapine Dosing

“…The first 4 panels of Supplementary Table 13 (in the onlineonly Data Supplement) provide information that the author has gathered on the use of clozapine in the UK; the emphases are on guidelines, 39,127,159,160 the contribution of clozapine-induced agranulocytosis, 70,[161][162][163] what is known of UK fatal outcomes of clozapine-induced myocarditis, 67,104,164 clozapine-induced CIGH, 165 and clozapine-associated pneumonia. 166 Two months ago, the author' s understanding of clozapine use in the UK was completely shaken by discovering a VigiBase pharmacovigilance study focused on ADRs with fatal outcomes reported by physicians.…”

Lubiprostone for the Treatment of Clozapine-Induced Constipation: A Case Series

“…There is insufficient trial-based evidence to compare the effectiveness and safety of common laxatives for clozapine-induced constipation [4]. The risk of serious morbidity/mortality from clozapine-associated constipation is substantial, and there is a need for active monitoring of bowel function [5]. Due to the potential severity of clozapine-induced constipation, coadministration of laxatives is frequently encountered in clinical care [5,6].…”

“…The risk of serious morbidity/mortality from clozapine-associated constipation is substantial, and there is a need for active monitoring of bowel function [5]. Due to the potential severity of clozapine-induced constipation, coadministration of laxatives is frequently encountered in clinical care [5,6]. Lubiprostone is currently approved by FDA for treatment of opioid-induced constipation, irritable bowel syndrome with constipation, and chronic idiopathic constipation.…”

According to the WHO clozapine pharmacovigilance database, the United Kingdom accounts for 968 fatal outcomes versus 892 in the rest of the world

“…Furthermore, UK reports from all sources indicated 383 mean clozapine fatal outcomes every year (3828 in the last 10 years). 10…”