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

March 9, 2018, update: July 26, 2018

Product

Clozapine

Potential Safety Issue

Effectiveness of measures to monitor low numbers of white blood cells (agranulocytosis) with clozapine use

Key Messages

• Clozapine is a prescription drug authorized for sale in Canada to manage symptoms of schizophrenia in adults when other drugs have not helped.
• One of the known risks of clozapine use is that it can lower the number of white blood cells (i.e., agranulocytosis), which may lead to life-threatening infections. Patients must be enrolled in a registry program to monitor their white blood cell levels before their prescriptions can be refilled.
• During routine safety review activities, concerns were raised about whether the processes to monitor for low numbers of white blood cells were effective. Health Canada decided to review all 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, but that the risk of agranulocytosis should continue to be monitored.
• Therefore, Health Canada is reminding healthcare professionals to follow the recommendations regarding switching of a patient from one brand of clozapine to another, as highlighted in the current product safety information.
• The Department has also asked manufacturers of clozapine to submit, in two years, a report of all data collected related to the risk of low numbers of white blood cells when clozapine is used.

Overview

Clozapine is a prescription drug authorized for sale in Canada to manage symptoms of schizophrenia when other drugs have not helped.

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 patients must be enrolled in a patient registry program to monitor their white blood cell levels before their next prescription can be filled.

Between 1991 and 2003, clozapine was distributed by a single manufacturer, and patients were monitored by this manufacturer's specific registry. The introduction of generic clozapine has led to the establishment of other registries. In June 2004, Health Canada issued a safety communication to inform healthcare professionals that the product safety information had been revised related to concerns about information sharing between registries. 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.

In 2017, Health Canada decided to review all available evidence related to the effectiveness of the white blood cell monitoring measures currently in place for clozapine.

Use in Canada

• 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 in 2017, Health Canada received 92 Canadian reports^{Footnote a} of low numbers of white blood cells in patients using clozapine who later died. A review of these reports found that 11 of the deaths 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. Therefore, the monitoring should continue throughout the duration of use. 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 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 of all the data collected related to the risk of low numbers of white blood cells when clozapine is used. Health Canada has requested that the report be submitted in two years rather than one, given that the risk is rather low due to the monitoring system (around 1 case/1000 patient-year) and the limited information that could be obtained after 1 year.
• Health Canada reminds healthcare professionals to follow the recommendations regarding switching of a patient from one brand of clozapine to another. These recommendations are highlighted in the current product safety information and in the safety communication issued in 2004.
• 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.