Identification of Cases
From Australia, there were 6323 clozapine ADR case reports in the TGA ‘Gastrointestinal’ System Organ Class, of which 157 met the inclusion criteria. A further 33 were excluded (3 duplicates and 30 with confounding pathology). The earliest eligible event occurred in 1994. This resulted in 124 Australian unique reports.
From the New Zealand data, there were 888 clozapine ADR reports in the CARM and IMMP ‘Alimentary class’, the earliest of which occurred in January 1999, of which 51 met the inclusion criteria. A further 15 were excluded (4 duplicates and 11 with confounding pathology). This resulted in 36 New Zealand unique reports.
Together, this gave a combined series of 160 cases from which data were extracted. Most key variables were reported in over 80% of cases (e.g., age and gender 94%; duration of treatment 86%; clozapine dose 84%), with the notable exception of outcome. Whether the patient ultimately recovered was unknown in 30.6% of New Zealand cases and 62.9% of Australian cases. See Box 1 for an example of a case reported to the TGA.
Of the 160 patients, 106 (66.3%) were male, 51 female (31.9%), and gender was unspecified for three. Age was reported for 150 (94%), with a mean of 46 ± 13.4 (SD) years, range 17–76.
Clozapine dose was documented for 135 patients (84%), M = 439 ± 221 (SD), range = 25–1000 mg/day. This is significantly higher than the mean clozapine dose (372 mg/day) in a large New Zealand epidemiological study  (p < 0.0001). Clozapine serum levels were seldom available in the ADR reports. The duration of clozapine treatment until serious CIGH, specified for 86%, was usually specific to the day, Md = 2.5 years (IQR 4 mo–5 y, 4 mo), range = 3 days–18 years. Data were positively skewed (skewness = 1.46, SE = 0.2). Thirty-seven percent of cases occurred within the first year. Duration of treatment until onset of serious CIGH was similar in both Australian and New Zealand populations (see Fig. 1).
Concomitant Use of Other Potentially Constipating Medication and of Laxatives
Only 11% were recorded as receiving other potentially constipating medications such as those with anticholinergic effects (like benztropine, or tricyclic antidepressants) or other constipating actions (like opioids). From the 70 reports of severe constipation (Table 1), only 6 (9%) were recorded as receiving laxatives prior to the evolution of symptoms.
The ADRs reported are summarized in Table 1. Constipation (70 reports) and intestinal obstruction (62 reports) were the most commonly reported features of the CIGH spectrum. A common theme was the late presentation to medical services when significant pathology had already evolved. Although many patients were reported as having massive fecal impaction at autopsy, prior complaints of constipation were not often recorded.
Twenty-nine patients were confirmed as having died from suspected CIGH (18%), 42 were reported as recovered (26%) and in 89 cases (56%) the outcome was recorded as ‘unknown’ or ‘not yet recovered’ at the time of reporting. The confirmed fatality rates differed significantly between countries: 36.1% for New Zealand, and 14.8% for Australia, χ
2 (1, n = 160) = 8.62, p < 0.001. This is likely to be strongly influenced by missing mortality data; outcomes were confirmed for more New Zealand patients (69.4%) than Australians (37.1%), χ
2 (1, n = 160) = 10.55, p < 0.001. This is presumably because while clozapine was under the IMMP in New Zealand, CIGH cases were proactively followed up after initial ADR reporting, leading to better classification of outcomes.
Subgroup analysis was performed comparing patients confirmed as having suffered a fatal outcome with the others. Those with fatal outcomes ranged in age from 22–73 years, with a mean age of 50 years. Unadjusted ORs for the various independent variables are reported in Table 2. A Mann–Whitney U test reveals those with fatal outcomes had significantly longer duration of treatment with clozapine (Md = 4.2 years, IQR = 1.5–8.6 years) than the rest of the group (Md = 1.9 years, IQR = 0.2–5 years), U = 968, z = −2.65 p = 0.008 (see Fig. 2). The OR of a fatal outcome increased by 1.21 (95% CI 1.02–1.44) for every 2 years on clozapine. Age, female gender, clozapine dose, and receiving other potentially constipating medication had positive, but non-significant associations with fatal outcomes (Table 2).
Using logistic regression methods to control for confounding, the only variable that remained significant was country: New Zealanders were more likely to have been confirmed as suffering fatal CIGH (OR 4.38, 95% CI 1.26–15.15).
Changes in Reporting Over Time
The number of reported serious CIGH-related drug reactions increased significantly over the 22-year period. The 3-year moving average of reported cases increased from below 5 throughout the first decade of clozapine use to consistently above 15 annual cases since 2010 (see Fig. 3). Plotting frequency against date gives a correlation coefficient of r
0.9 p < 0.001, indicating a strong positive linear correlation between reporting and time. While CIGH reports increase dramatically, the number of people taking clozapine has also increased. Unfortunately annual use data were not available.
From the time when clozapine first entered the New Zealand market (1988) and mid-2013, 7691 people were exposed to clozapine in New Zealand (personal correspondence: Novartis, New Zealand; and Clopine Services coordinator, Hospira, Australia). Our data show at least 36 of these patients developed serious CIGH, at a prevalence of 0.47%. From the time clozapine first entered the Australian market (1992) to mid-2013, 35,441 people were exposed to clozapine in Australia (personal correspondence: Novartis, Australia; and Clopine Services coordinator, Hospira, Australia). Our data show at least 124 developed serious CIGH, at a prevalence of 0.35%. Although there are limitations in such estimates (as discussed below), this suggests the prevalence of potentially life-threatening CIGH in Australia and New Zealand is at least 37 people for every 10,000 exposed to clozapine.
At least 29 patients died (7/10,000 clozapine users), 16 in Australia and 13 in New Zealand, a reported case fatality rate of 18%. The rates of reported fatal outcomes differed significantly between New Zealand (17/10,000) and Australian (5/10,000) datasets (χ
2 [1, n = 43,132] = 14.43, p < 0.001). We note that the disproportionate number of Australian patients recorded as ‘not yet recovered’ or outcome ‘unknown’ means it is likely some CIGH-related fatal outcomes were not captured, leading to greater underestimation of CIGH fatalities in Australian data.
International Pharmacovigilance Data
The analysis of CIGH-related data from the Uppsala Monitoring Centre is shown in Table 3. The Centre uses a Bayesian confidence neural network to detect ADR signals. The information component (IC) is a logarithmic measure of the disproportionality between the observed and the expected reporting of a drug–ADR pair. Signal detection is conducted using the IC025 metric, the lower limit of the 95% confidence interval for the IC. An IC025 above 0 indicates a statistically significant signal. We report the IC025 metric for associations between clozapine and a number of gastrointestinal symptoms. All the listed gastrointestinal ADR terms in Table 3 have significant positive associations with clozapine. Particularly strong associations exist (IC025 >2) with the terms megacolon, paralytic ileus, and intestinal obstruction.
For comparative purposes, the total number of suspected clozapine-induced agranulocytosis fatalities over the same time period was 168, with an IC025 of 3.44.
Clozapine Prescribing Information Provided by Regulators
Information provided by regulators about CIGH was uniformly poor in all four countries reviewed (see Table 4). While information about agranulocytosis, myocarditis, and other adverse effects was prominent and comprehensive (on the first page and under clear and informative headings), no datasheet had a specific section on CIGH, or even referred to this spectrum. Constipation was not mentioned until at least page 6 and was subsumed under an ‘anticholinergic side effects’ subheading. Serious CIGH conditions like paralytic ileus appeared toward the end of information sheets within long lists of possible side effects, and were reported as being ‘very rare’, which was defined as “isolated case reports or occurring in less than one in 10,000 users”. There was little, if any, reference to CIGH monitoring or treatment.