HSA would like to bring the attention of healthcare professionals to a study recently published (online ahead of print) in the Journal of Clinical Psychiatry¹ to raise awareness of rare but potentially lethal clozapine-induced gastrointestinal hypomotility (CIGH). 

Although the adverse reaction of constipation with clozapine is not a new safety signal and there have been publications about this since the 1990s, CIGH is not readily distinguishable leading to its under-recognition. 

The electronic adverse drug reactions database of the Therapeutic Goods Administration, Australia and the New Zealand Intensive Medicines Monitoring Program (IMMP), which cited clozapine-related gastrointestinal side effects were analysed. In addition, databases like PsycINFO, MEDLINE and EMBASE were searched using relevant key words.

 

A total of 102 cases were identified for analysis; 66.7% of the patients were male and the age reported for 96 of the patients ranged from 17 to 73 years, with a median of 42 years. Of these 102 patients, 28 patients died, 42 recovered and the outcome was unknown in 32 cases. From the review, the dose of clozapine was known for 92 patients, with a range of 12 to 1000mg/day (mean of 428mg/day). The doses were noted to be higher among the fatal cases at 250 – 900mg/day (mean of 535mg/day).

 

The treatment duration with clozapine prior to onset of symptoms ranged from 3 days to 15 years with 20% of patients developing serious CIGH within the first month of treatment, 36.3% within the first 4 months, and just over 50% occurred within the first year of treatment. The mortality rate was found to be at 27.5% with considerable morbidity mainly due to bowel resection. Probable risk factors for CIGH were identified as new to clozapine therapy, higher doses of clozapine, co-prescription with other anticholinergic medication, concomitant medical illness, fever, and medications such as cytochrome P450 enzyme inhibitors which may inhibit metabolism of clozapine, thus increasing its serum concentration. History of bowel surgery, constipation or gastrointestinal pathology may also contribute to the risk of developing CIGH. 

The paper postulated three main mechanisms whereby CIGH can have a fatal outcome:

 

i)                  Untreated bowel obstruction/pseudo-obstruction leading to distension, necrosis,

                    perforation, or sepsis.

ii)                 Aspiration from inhalation of feculent vomitus or dysphagia.

iii)                Faecal stasis leading to infection.

 Even though it is known that clozapine can affect the entire digestive system causing esophageal to rectal hypomotility, the authors emphasized the need to prevent and manage CIGH-related constipation as it can result in bowel obstruction, ischaemia and necrosis, perforation, and aspiration pneumonia.

 

Suggestions for prevention include:

 There are three brands of clozapine registered in Singapore – Clozaril® (Novartis), Clozapine® (Delfi), Clozapin Hexal® (Novem Healthcare), and they are indicated for the management of treatment-resistant schizophrenia. The package inserts of all three products carry precautionary warnings of constipation and paralytic ileus, with Clozaril® and Clozapin Hexal® mentioning the association of clozapine with intestinal obstruction and faecal impaction, which on rare occasions have proven fatal.

HSA has not received any local report pertaining to clozapine and impairment of intestinal peristalsis. Healthcare professionals are encouraged to report cases of CIGH if they come across them. 

1. J Clin Psychiatry. 2008 April 29;e1-e10