Overview

Clozapine is an atypical antipsychotic agent which is indicated in patients with treatment-resistant schizophrenia.¹ It is also indicated to reduce the risk of recurrent suicidal behavior in patients with schizophrenia disorder. Currently, there are nine (9) products containing clozapine registered in Malaysia.

Background of Safety Issue

The National Pharmaceutical Regulatory Agency (NPRA) received information from United States Food and Drug Administration (US FDA) on the association of clozapine with the risk of serious bowel complications caused by constipation.

Constipation is a very common and known adverse drug reaction of clozapine.¹ However, untreated constipation may progress to serious but uncommon bowel complications, including complete bowel obstruction.²

In a safety review, US FDA has reviewed ten (10) local cases of constipation which lead to serious bowel problems resulting in hospitalisation, surgery and five (5) deaths. The time to onset for serious bowel events were between 3 days to 6 months after clozapine administration. The risk with clozapine is higher than with other similar agents due to its higher potency anticholinergic activity. The risk is also higher at increased doses of clozapine, and when clozapine is co-administered with other anticholinergic agents or other drugs that is known to cause constipation.

Based on all available evidence, US FDA are requiring all product registration holders of clozapine containing products to update their package insert with the risk of serious bowel complications.

Adverse Drug Reaction (ADR) Reports

The NPRA has received a total of 312 ADR reports with 534 adverse events suspected to be related to clozapine products.³ Adverse events related to serious bowel complications were intestinal obstruction (6), ileus paralytic (5), gastric hypomotility (3), faecaloma (2), ileus (1) and subacute intestinal obstruction (1).

Advice for Healthcare Professionals

• Be mindful on the risk of serious bowel complications when prescribing clozapine to patients.
• Assess patient’s bowel function prior to clozapine initiation and avoid prescribing other anticholinergic drugs that may cause constipation.
• Advise patients to seek immediate medical attention if the patient experiences symptoms of potential bowel complications such as nausea and vomiting, bloating and abdominal distension or pain. Emphasize that prompt treatment is critical to prevent serious complications.
• Counsel patients and their caregivers on high fibre dietary intake and lots of fluids to prevent constipation.
• Monitor patients on the frequency and character of bowel movements.
• Consider prophylactic laxative treatment when starting clozapine in patients with a history of constipation or bowel obstruction.
• Please report all suspected adverse events associated with clozapine products to the NPRA.

NPRA has completed a review of this safety issue and a directive [Ruj. Kami: NPRA.600-1/9/13 (13)] has been issued for registration holders of clozapine containing products to update the local package inserts and consumer medication information leaflets (Risalah Maklumat Ubat untuk Pengguna) to reflect this safety information.

References:

1. National Pharmaceutical Regulatory Agency. Malaysian Product Registration Database (Quest 3+). Clozapine local package insert [Internet]. Last revision date 2020 July [Cited 2020 November 30]. Available from https://www.npra.gov.my
2. United States Food and Drug Administration (US FDA). Drug Safety Communications: FDA strengthens warning that untreated constipation caused by schizophrenia medicine clozapine (Clozaril) can lead to serious bowel problems [Internet]. 2020 January 28 [Cited 2020 November 30]. Available from https://www.fda.gov/drugs/drug-safety-and-availability/fda-strengthens-warning-untreated-constipation-caused-schizophrenia-medicine-clozapine-clozaril-can
3. National Pharmaceutical Regulatory Agency. The Malaysian National ADR Database [Internet]. 2021 [Cited 2020 November 30]. Available from https://www.npra.gov.my

DISCLAIMER

This publication is aimed at health professionals. The information is meant to provide updates on medication safety issues, and not as a substitute for clinical judgement. While reasonable care has been taken to verify the accuracy of the information at the time of publication, the NPRA shall not be held liable for any loss whatsoever arising from the use of or reliance on this publication.