Background:
Premarketing evaluation of side-effects of medication is too small to evaluate rarer side-effects. This requires effective postmarketing pharmacovigi-lance. While spontaneous reporting to a national center is encouraged, more active methods are required to recruit larger cohorts of known size so rates of rare adverse events can be estimated.
Methods:
The New Zealand Intensive Medicines Monitoring Programme (IMMP) prospectively examines the safety of marketed medicines using prescription-event monitoring methodology. Cohorts of patients are established using prescription data from pharmacies throughout the country. The IMMP obtains reports of adverse events from multiple sources, including from follow-up questionnaires sent to patients' doctors, spontaneous reports from health professionals, pharmaceutical company reports and linkage to national mortality and morbidity databases. An evaluation of atypical antipsychotics using this approach indicated high levels of GI side-effects with clozapine.
Results:
A large number of cases of constipation were identified, some severe. Two subjects suffered toxic megacolon, one paralytic ileus, one bowel ischemia requiring resection and one bowel perforation. The latter two subjects died of complications of surgery. Two other subjects were shown to suffer esophageal dys-motility, one requiring surgical intervention.
Conclusions:
Clozapine interacts with a range of muscarinic, serotonergic and other receptors to have particularly marked effects on the GI tract. These effects are predictable and can be managed provided adequate inquiry is made into symptoms. Only one New Zealander had died of clozapine agranulocy-tosis - at least three had died of consequences of constipation.
