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Published: June 2011

Clozapine: impacts on the colon

Prescriber Update 32(2): 14–15
June 2011

Prescribers are reminded of the importance of treating constipation in patients taking clozapine to prevent potentially life-threatening complications.

Clozapine is indicated for use in patients with treatment-resistant schizophrenia. Constipation is a very common adverse effect related to clozapine use, occurring in 14-60% of patients.1 In rare cases complications can be fatal.1-4

Clozapine has potent anticholinergic effects. Although many anticholinergic medicines can cause gastrointestinal (GI) hypomotility, clozapine has a much more potent effect through its interaction with multiple receptors, including anticholinergic and serotonergic receptors.1

Clozapine can impair motility throughout the GI tract causing intestinal obstruction, bowel ischaemia, necrosis, perforation, toxic megacolon, and related aspiration pneumonia.1,3-7

Risk factors include recent initiation of clozapine treatment,1 higher clozapine doses,1 concomitant use of anticholinergics (e.g. benztropine and tricyclic antidepressants),1-3 and concurrent illness.1

Since 2007, when Medsafe last issued advice on this topic,7 CARM has continued to receive reports of clozapine-induced GI hypomotility-related adverse reactions. From 1 April 2007 to 31 March 2011, CARM received 14 reports of GI hypomotility for which clozapine was assessed as causally associated; two reports were life-threatening and two reported a fatal outcome.

Prior to initiation of treatment with clozapine, a gastrointestinal history and abdominal examination should be performed.1 Patients should be warned about the risks of constipation and given information on diet, exercise and fluid intake.1,3,6 Pre-existing constipation should be addressed before starting treatment with clozapine.1

Any patients taking clozapine should be asked about their bowel habits regularly, especially in the first few months of treatment.1,2,7 However the risk continues with ongoing use; therefore all patients taking clozapine need to be asked about their bowel habits on an ongoing basis.

Appropriate laxatives should be prescribed to treat constipation and need to be reviewed regularly.1 A combined stimulant and softening laxative may be helpful as a first-line treatment.1 However stimulant laxatives should be avoided if intestinal obstruction has already developed; these patients need to be referred urgently for treatment.1

The most commonly reported signs and symptoms of serious complications include: moderate to severe abdominal pain, abdominal distension, vomiting, paradoxical "overflow" diarrhoea, reduced appetite, nausea.1,4-6 Patients with these signs and symptoms require urgent medical referral and treatment as complications such as septic shock can occur.

Key messages:

  • Clozapine can impair motility of the entire GI tract
  • Constipation can lead to life-threatening complications
  • Ask clozapine patients about bowel function
  • Before prescribing clozapine:
    • Treat pre-existing constipation
    • Advise patients about the risks of constipation
    • Provide advice about diet, exercise and fluid intake
  • Refer patients early
  • Prescribe laxatives for constipation and regularly review treatment.
References
  1. Palmer SE, McLean RM et al. (2008). Life-threatening clozapine-induced gastrointestinal hypomotility: An analysis of 102 cases. J. Clin. Psychiatry. e1-e10.
  2. Medsafe. Clozapine data sheet. 22 September 2010. Available at: www.medsafe.govt.nz/profs/datasheet/c/Clozariltab.pdf Last accessed 15 May 2011.
  3. Committee on Safety of Medicines/Medicines Control Agency (1998). Clozapine (Clozaril) and gastrointestinal obstruction. Current Problems in Pharmacovigilance. 25: 5. Available at: http://www.mhra.gov.uk/Publications/Safetyguidance/CurrentProblemsinPharmacovigilance/CON007467 Last accessed 15 May 2011.
  4. Hibbard KR, Propst A et al. (2009). Fatalities associated with clozapine-related constipation and bowel obstruction: A literature review and two case reports. Psychosomatics. 50: 416-9. Available at: http://psy.psychiatryonline.org/cgi/content/full/50/4/416 Last accessed 15 May 2011.
  5. Lavi E, Rivkin L et al. 2009. Clozapine-induced colonic obstruction requiring surgical treatment. Isr Med Assoc J. 11(6):385-6. Available at: http://www.ima.org.il/imaj/ar09jun-18.pdf Last accessed 15 May 2011.
  6. De Hert M, Dockx L, et al. (2011). Prevalence and severity of antipsychotic related constipation in patients with schizophrenia: a retrospective descriptive study BMC Gastroenterol. 11: 17. Available at: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3062582/?tool=pubmed Last accessed 15 May 2011.
  7. Ellis P, McLean RM et al. (2007). Clozapine: Fatal 'constipation' more common than fatal agranulocytosis. Prescriber Update. 28(1): 7.