The government is now operating in accordance with the Guidance on Caretaker Conventions, pending the outcome of the 2025 federal election.
The potentially fatal risk of gastrointestinal hypomotility in patients taking clozapine has been highlighted with a new boxed warning in the Product Information (PI) for this medicine. Health professionals should assess for constipation before and during treatment with clozapine, and manage suspected constipation promptly to prevent severe complications.
Safety update
The severe gastrointestinal effects of intestinal obstruction, severe constipation and gastrointestinal hypomotility are among the most serious adverse reactions experienced with clozapine. In post-marketing experience, severe complications of gastrointestinal hypomotility (such as intestinal obstruction, faecal impaction, megacolon, paralytic ileus and intestinal ischaemia or infarction) have resulted in hospitalisation, surgery and death.
The new boxed text and other changes to the PI expand on existing warnings about severe gastrointestinal adverse reactions associated with clozapine, which are primarily due to its potent anticholinergic effects.
The boxed warning states:
Clozapine-induced gastrointestinal hypomotility
Severe gastrointestinal adverse reactions have occurred with the use of clozapine resulting in potential outcomes of hospitalisation, surgery and death (see Section 4.4 Special warnings and precautions for use, and Section 4.8 Adverse effects (undesirable effects)). Prior to initiating and during treatment with clozapine, screen for constipation and, if necessary, manage as per current clinical guidelines.
The changes to the PI note that:
- the subjective symptoms of constipation may not accurately reflect the degree of gastrointestinal hypomotility. Therefore, health professionals should carefully monitor any changes in the frequency or character of a patient’s bowel movements, as well as signs and symptoms of complications of hypomotility, such as:
- nausea and/or vomiting
- abdominal distension and/or pain
- lack of urge and/or inability to defecate
- constipation
- patients with evidence of constipation or gastrointestinal hypomotility should be managed promptly to prevent severe complications
- clozapine should be used with caution and under careful supervision in patients with a current diagnosis or prior history of constipation
- concomitant use of clozapine with anticholinergic medicines should be avoided where possible because of the increased risk of severe gastrointestinal side effects or anticholinergic toxicity.
Please refer to the PI - external site for clozapine for more information.
Post-marketing adverse event data
The PI updates are based on evidence published in the literature and from post-market adverse event data in Australia and internationally.[1]
To 1 March 2022, there were 1,523 reports of gastrointestinal disorder for clozapine in the TGA’s Database of Adverse Event Notifications (DAEN), which included 260 reports of constipation, 146 of intestinal obstruction, 93 of abdominal pain and 41 of small intestinal obstruction. Of the 1,023 clozapine reports with a fatal outcome, 103 were due to gastrointestinal disorders.
The adverse reactions listed in the post-marketing experience category in the PI for clozapine are sourced from spontaneous reports and literature, and therefore their frequency is unknown. Megacolon, intestinal infarction/ischaemia, intestinal necrosis, intestinal ulceration and intestinal perforation are listed as potentially fatal adverse gastrointestinal reactions in this category; diarrhoea, abdominal discomfort, heartburn, dyspepsia and colitis are also listed as gastrointestinal adverse reactions, but not as potentially fatal.
Product background
Clozapine is a second generation or atypical antipsychotic with potent anticholinergic effects. It is marketed in Australia as Clozaril, as well as Clopine and various other generic brands.
Clozapine is indicated for treatment-resistant schizophrenia only − in patients with schizophrenia who are not responsive to, or are intolerant of, other antipsychotic drugs.
The Therapeutic Goods Administration (TGA) previously published information about clozapine and severe constipation in Medicines Safety Update in February 2011 and June 2018.
References
| [1] | Shirazi A et al. Prevalence and predictors of clozapine-associated constipation: a systematic review and meta-analysis - external site. Int.J.Mol.Sci. 2016;17:863. doi: 10.3390/ijms17060863. |
|---|---|
| [2] | Cohen D et al. Beyond white blood cell monitoring: screening in the initial phase of clozapine therapy - external site. J.Clin.Psych. 2012;73(10):1307-1312. doi: 10.4088/JCP.11r06977. |
What to report? You don't need to be certain, just suspicious!
The TGA encourages the reporting of all suspected adverse reactions to medicines, including vaccines, over-the-counter medicines, herbal, traditional or alternative remedies.
We particularly request reports of:
- all suspected reactions to new medicines (look for the Black Triangle in PI and CMI documents - this symbol identifies medicines that are new or being used differently)
- all suspected medicines interactions
- suspected reactions causing death, admission to hospital or prolongation of hospitalisation, increased investigations or treatment, or birth defects.
Reports may be submitted:
- online at www.tga.gov.au
- by fax to 02 6232 8392
- by email to ADR.Reports@tga.gov.au
For more information about reporting, visit www.tga.gov.au or contact the TGA's Pharmacovigilance and Special Access Branch ADR.Reports@tga.gov.au.
Disclaimer
Medicines Safety Update is aimed at health professionals. It is intended to provide practical information to health professionals on medicine safety, including emerging safety issues. The information in Medicines Safety Update is necessarily general and is not intended to be a substitute for a health professional's judgment in each case, taking into account the individual circumstances of their patients. Reasonable care has been taken to ensure that the information is accurate and complete at the time of publication. The Australian Government gives no warranty that the information in this document is accurate or complete, and shall not be liable for any loss whatsoever due to negligence or otherwise arising from the use of or reliance on this document.
© Commonwealth of Australia 2022
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For correspondence or further information about Medicines Safety Update, contact the TGA's Pharmacovigilance and Special Access Branch at ADR.Reports@tga.gov.au.
Medicines Safety Update is written by staff from the Pharmacovigilance Branch.
Editor: Dr Catherine Brogan
Deputy Editor: Mr Michael Pittman
Contributors: Richard Hill and Jovi van der Kallen