Summary Safety Review - Clozapine - Assessing the effectiveness of monitoring for low numbers of white blood cells

March 9, 2018

Product

Clozapine

Potential Safety Issue

Low numbers of white blood cells (agranulocytosis)

Key Messages

  • Clozapine is a prescription drug authorized for sale in Canada for the management of the symptoms of schizophrenia in adults when other drugs have not helped.
  • One of the risks associated with clozapine use is that it causes a lowering of the number of white blood cells, which may lead to life-threatening infections. Therefore, white blood cell levels are monitored periodically in these patients to make sure that they do not become too low.
  • During routine safety review activities, concerns were raised about whether or not the processes to monitor for low numbers of white blood cells (i.e., agranulocytosis) were effective. Health Canada decided to review all of the available evidence related to the effectiveness of the white blood cell monitoring measures currently in place for clozapine.
  • Health Canada’s review concluded that the monitoring measures in place for low numbers of white blood cells are acceptable, and that the risk of agranulocytosis should continue to be monitored. Therefore, Health Canada has asked that the manufacturers of clozapine submit a report, in two years, of all the data collected, related to the risk of low numbers of white blood cells when clozapine is used.

Overview

Clozapine was developed in the 1960s. In 1975, clozapine was removed from the Canadian market because of reports of life-threatening infections (and deaths) linked with low numbers of white blood cells (i.e., agranulocytosis). Clozapine was re-introduced to the Canadian market in 1991, but with the requirement that patients be enrolled in a patient registry program to monitor their white blood cell levels before their next prescriptions can be filled. During routine safety review activities, concerns were raised about whether or not these processes to monitor for low numbers of white blood cells were effective. Health Canada decided to review all of the available evidence related to the effectiveness of the white blood cell monitoring measures currently in place for clozapine.

Use in Canada

  • Clozapine is a prescription drug authorized for sale in Canada for the management of the symptoms of schizophrenia, when other drugs have not helped. Clozapine is marketed under the brand name Clozaril and generic products are also available.

Safety Review Findings

  • From 1991 to the time of the review, Health Canada has received 92 Canadian reportsFootnote a of low numbers of white blood cells in patients using clozapine who later died. A review of these reports found that 11 of them were possibly linked to clozapine use. For the remaining reports, another cause of death was more likely.
  • Monitoring the risk of low white blood cell counts is still important for the safe use of clozapine. The evidence found in the published literature and from patient reports submitted to Health Canada showed that the risk of low numbers of white blood cells remains for over a year after starting treatment. In some cases, the ongoing monitoring was helpful in detecting the decrease in the number of white blood cells before the patient became too sick.
  • Concerns were also raised regarding patients potentially being switched from using one clozapine product to another without being appropriately monitored.

Conclusions and Actions

  • Health Canada’s review concluded that the monitoring measures in place for low numbers of white blood cells are acceptable, but that the risk should still be monitored. Therefore, Health Canada has asked that the manufacturers of clozapine submit a report, in 2 years, of all the data collected related to the risk of low numbers of white blood cells when clozapine is used.
  • Health Canada will continue to monitor safety information involving clozapine, as it does for all health products on the Canadian market, to identify and assess potential harms. Health Canada will take appropriate and timely action if and when any new health risks are identified.

Additional Information

The analysis that contributed to this safety review included scientific and medical literature, Canadian and international information, and what is known about the use of clozapine both in Canada and internationally.

For additional information, contact the Marketed Health Products Directorate.

Footnotes

Footnote a

Canadian reports can be accessed through the Canada Vigilance Online Database.

Return to footnote a referrer

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