A Closer Look at Neutropenia Risk
Neutropenia receives the lion’s share of attention among clozapine’s potential side effects, but this focus may need to be re-evaluated, Dr. Cotes said.
He pointed out that recent data suggest the risk for severe neutropenia, 2-3 years after initiating clozapine, is comparable to that of other antipsychotics.
A study of 26,630 clozapine users in Australia and New Zealand showed that most cases of severe neutropenia leading to clozapine cessation peaked within 18 weeks and was negligible after 2 years. This suggests weekly hematologic monitoring could potentially be discontinued after the 2-year mark.
Another study reported earlier this year by this news organization showed a low risk for mild or moderate neutropenia and no severe cases in nearly 1000 people taking clozapine.
“I worry that we may be missing the forest for the trees by hyperfocusing on neutropenia and not considering clozapine’s other potential serious side effects like pneumonia, myocarditis, and gastrointestinal hypermotility,” Dr. Cotes said.
Importance of Vaccines
The findings of these studies highlight the importance of vaccines in this at-risk group, said Dr. Taquet, a point emphasized by investigators of the Danish study he reviewed.
“Inspired by the experience of COVID-19 vaccine prioritization in severe mental illness and based on our findings, there is momentum for preventive action,” the authors wrote. “Our findings do not suggest the avoidance of specific antipsychotics but rather a call for increased vigilance regarding this at-risk group.”
This includes recommending pneumococcal, influenza, COVID-19, and other anti-infective vaccines in those older than 40 years treated with, or due to start, an antipsychotic.
“It’s not mandatory, but we do recommend that patients on clozapine get the regular vaccines,” Dr. Taquet said.
Pointing to the recent study on pneumonia risk, Dr. Cotes said addressing underlying risk factors, such as smoking, obesity, and possibly sedation and excessive salivation caused by clozapine, is key.
“And to make sure that vaccinations are up to date, particularly heading into this fall,” he added.
Rethinking Clozapine REMS
One of the most challenging issues facing clinicians and researchers is how to help people understand the safety profile of clozapine and to use it with more confidence, Dr. Cotes said.
“A lot of people hear about clozapine and they think about neutropenia, they think about side effects, the REMS system, and all of these factors really drive down clozapine utilization,” he said.
Treatment-resistant schizophrenia affects about a quarter of those with schizophrenia, yet only 4% of these patients receive clozapine in the United States, Dr. Cotes said. That number may be even lower for its other indication of reducing suicidal behavior in patients with schizophrenia or schizoaffective disorder.
The clozapine REMS is viewed as a major barrier to utilization and requires certification of pharmacists and physicians and use of a central system to monitor absolute neutrophil counts for neutropenia in patients.
As previously reported by this news organization in November 2022, the FDA opted to temporarily exercise enforcement discretion for certain aspects of the drug safety program to ensure continuity of care for patients after concerns were raised by the American Psychiatric Association (APA) along with other professional organizations.
Even with that temporary enforcement discretion, “reports have shown that over half of those prescribed clozapine have trouble accessing the medication because of the REMS program,” a spokesperson for the APA told this news organization.
“Not only are patients having trouble accessing the medication, many have trouble finding a prescriber in their geographic locations and others because of the monitoring requirements have their treatment discontinued leading to negative outcomes,” the spokesperson said.
The FDA is currently reviewing the clozapine REMS and is holding a joint advisory committee meeting on November 19 to discuss the review and “possible changes to minimize burden on patients, pharmacies, and prescribers while maintaining safe use of clozapine.”
The APA plans to submit written and oral comments to the advisory committees.
“We are hopeful that the re-evaluation meeting in November will remove barriers and increase access to clozapine, which is currently highly underutilized, especially in marginalized communities,” the spokesperson said.
Dr. Cotes reported serving as a speaker and consultant for Saladax Biomedical and as a consultant for Syneos Health. Dr. Taquet reported having no competing interests.
A version of this article first appeared on Medscape.com.