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RESEARCH WEEKLY: The Clozapine REMS
By Shanti Silver
(August 2, 2023) Clozapine is the only FDA-approved medication for treatment-resistant schizophrenia but remains underutilized in the United States and around the world. In this week’s “Research Weekly,” two articles are summarized that discuss the Clozapine Risk Evaluation and Mitigation Strategy (REMS).
What is the Clozapine REMS?
A REMS is a program that the U.S. Food and Drug Administration (FDA) can require for medications that have serious safety concerns to help reduce the risk of any severe side effects. The Clozapine REMS is in place because of the risk of severe neutropenia. Severe neutropenia is a blood condition that is characterized by a shortage of white blood cells, making people vulnerable to severe infections. Because of the risk of severe neutropenia, people receiving clozapine in the United States are required to come in for weekly blood tests for the first six months of treatment, every two weeks for the second six months, and monthly for the rest of their lives while they are taking clozapine.
Does the frequency of testing required by the Clozapine REMS keep people safe?
While the risk of severe neutropenia is a concern that must be taken seriously, the Clozapine REMS may be creating some unnecessary barriers to accessing this lifesaving medication. According to the authors of these two studies, the risk of developing fatal neutropenia because of exposure to clozapine is approximately the same as the risk posed by other medications for which the FDA does not require a lifetime of blood tests.
In fact, evidence suggests that the risk of developing severe neutropenia due to clozapine decreases substantially after 18 weeks, leading other countries such as the United Kingdom, the Netherlands, Denmark, New Zealand, and Romania to require weekly testing for only the first 18 weeks after beginning clozapine, a much shorter period of time than the six months required in the United States. Additionally, there is little evidence to suggest that lifetime blood tests are necessary for people using clozapine, as the risk of neutropenia after one year on the medication is roughly equivalent to that found with other antipsychotic medications.
The FDA’s decision that people who use clozapine should be subjected to more extensive long-term testing than people using other medications with similar risks has real consequences on health care providers’ attitudes toward prescribing clozapine. Surveys of health care providers have repeatedly found “gaps in prescribers’ and psychiatric trainees’ knowledge, unfounded negative perceptions of clozapine, and a general discomfort with clozapine prescribing,” according to the authors of an article published in “Journal of Clinical Psychopharmacology.” This unscientific discomfort with clozapine, also sometimes called clozaphobia in the literature, is only made worse by the complex administrative barriers that clinicians need to navigate in order to prescribe clozapine under the REMS.
Implications
According to the authors of these articles, the current Clozapine REMS provide a level of protection against severe neutropenia. However, evidence suggests that the current precautions put forth by the REMS are likely overburdensome when weighed against the risk of developing severe neutropenia and that conducting blood tests less often than what is currently required by the REMS may be appropriate.
When considering changes to the REMS, the authors note that the benefits of clozapine in reducing suicidality and mortality for people with SMI should be emphasized. The authors conclude one paper by noting that changes to the Clozapine REMS will likely only be possible through the continued advocacy of researchers, public health systems, health care providers, people with SMI who are impacted directly by the Clozapine REMS, and their families.
To read more “Research Weekly” blogs on clozapine, click here, and if you would like to read stories of individuals and family members impacted by the Clozapine REMS, you can visit “The Angry Moms” website through clicking the link here.
References
Leung, J. et al. (February 2023). Improving clozapine utilization will require continued advocacy, drug sponsor interest, and FDA support to address REMS issues. Expert Review of Clinical Pharmacology.
Leung, J., et al. (November 2022). The Modernization of Clozapine. Journal of Clinical Psychopharmacology.
The Angry Moms. (2023). End the Clozapine REMS.
U.S. Food and Drug Administration (November 2022). Frequently Asked Questions | Clozapine REMS Modification.
Gurrera R. J. (2021). A commentary on improving clozapine accessibility and reducing treatment cost. Psychiatry Research.
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