The Modernization of Clozapine

Abstract

Purpose: Although clozapine was Food and Drug Administration (FDA) approved more than 3 decades ago, major barriers and gaps in knowledge continue to prevent its effective and safe use. We review modern-day problems encountered with clozapine in the United States (US).Methods: Information surrounding current administrative, clinical, research, and technological gaps or barriers related to clozapine use in the US was reviewed. Findings:The history of how clozapine became FDA approved likely contributes to gaps in knowledge. The frequency of safety warnings added to the FDA prescribing information may add to fears about clozapine, as evidence by numerous published survey studies. The clozapine Risk Evaluation and Mitigation Strategy (REMS) program has been modified several times in the last decade, causing access and safety issues for patients, which are discussed. Evidence may suggest that the FDA REMS requirements for hematologic monitoring are too cumbersome, and there may be ability to safely loosen requirements. The COVID-19 pandemic brought forth the ability for extended interval monitoring but also greater awareness of the clozapine-inflammation interaction. Newer guidelines published describe considerations in personalizing clozapine titration based on principles of ethnopsychopharmacology. Emerging technologies to support the use of clozapine are not widely available.Implications: Clozapine is a unique life-saving drug but it is underused in the US, despite its established efficacy. The 2021 REMS changes led to significant difficulties for providers and patients. We highlight the importance of the clozapine-inflammation interaction, therapeutic drug monitoring, and the ability for individual care based on patient-specific factors. There is an urgent need for advancing technology used for clozapine monitoring, evaluating barriers created by REMS, and establishing consistent practices throughout the US.

Escaping the Long Shadow Cast by Agranulocytosis

“…Even prescribers who are barely familiar with clozapine know that it can cause agranulocytosis, and most prescribers tend to overestimate, rather than underestimate, the agranulocytosis risk. 4 This worry about severe neutropenia is further perpetuated by regulatory bodies in many countries with rigid ad infinitum monitoring that is not evidence-based, given the decreasing risk of agranulocytosis over time. 4,23 After the generalized use of weekly hematological monitoring, during 2000-2019, there were only 433 deaths worldwide in VigiBase associated with all possible definitions of clozapineinduced agranulocytosis, providing a 1% relative fatality rate among 29,586 cases of potential agranulocytosis reported worldwide.…”

“…4 This worry about severe neutropenia is further perpetuated by regulatory bodies in many countries with rigid ad infinitum monitoring that is not evidence-based, given the decreasing risk of agranulocytosis over time. 4,23 After the generalized use of weekly hematological monitoring, during 2000-2019, there were only 433 deaths worldwide in VigiBase associated with all possible definitions of clozapineinduced agranulocytosis, providing a 1% relative fatality rate among 29,586 cases of potential agranulocytosis reported worldwide. 24 Clozapine prescribers around the world are highly sensitive to the risk of clozapine-induced agranulocytosis as evidenced by almost 30,000 ADR reports.…”

“…Recently, Leung et al 4 presented a perspective from the US point of view regarding the modernization of clozapine prescription. Leung et al 4 proposed loosening hematological requirements with a need to adopt new technologies and considering personalized approaches to avoid and manage clozapine-related ADRs including pneumonia and inflammation events (eg, myocarditis) 5 . In the US context, they also emphasize the importance of clozapine clinics and developing competency by clozapine prescribers.…”

“…Whereas Leung et al 4 offered a perspective focused on the United States, this article offers the perspective of an international group of collaborators that focuses on worldwide outcomes of clozapine that may be disproportionate and influenced by differing frequencies of clozapine ADRs. We briefly summarize (1) clozapine outcomes in Scandinavian national registries [7][8][9][10][11][12] and (2) clozapineassociated fatal outcomes according to recent pharmacovigilance studies [13][14][15][16][17][18] suggesting that outcomes may vary across countries based on current use.…”

Institutional Neglect of Anosognosia Is a Critical Barrier in the Treatment of Psychosis Related Disorders

“…In the United States, clozapine is woefully underused compared with other advanced countries. 12 Prescribers' concerns around the complexities of monitoring clozapine perpetuate what has been described in the literature as "clozaphobia." 13 This itself represents an obvious exclusion of the sickest patients from most psychiatric practices.…”