Changes in Neutropenia Outcomes after the 2019 Clozapine Risk Evaluation and Mitigation Strategy Update

Background: In its February 2019 update, the Clozapine Risk Evaluation and Mitigation Strategy (REMS), originally introduced by the US Food and Drug Administration to mitigate clozapine-induced neutropenia risk, required certifications before prescribing or dispensing clozapine.

Objectives: This study examined the impact of the 2019 Clozapine REMS update on neutropenia outcomes among clozapine users.

Methods: This study used cross-sectional administrative data and claims from the Komodo Research Dataset linked to the Komodo Lab Results. Eligible members were adults who were 18 years or older, had >=1 observable absolute neutrophil count (ANC) value dated between Jan 2017 through July 2023, and had an outpatient clozapine dispensing in the prior 30 days. Clozapine users were allowed to enter the analytic cohort once per calendar month. Neutropenia outcomes (mild [ANC 1000-1499/μL], moderate [500-999/μL], severe [ <500/μL]) were calculated monthly based on the lowest ANC value observed for each patient. Patients with severe neutropenia were excluded from future months until a subsequent ANC >=1000μL was observed. Interrupted time series analyses comparing pre-update (Jan 2017-Nov 2018; 3-month anticipatory period excluded) and post-update (Mar 2019-July 2023) periods were conducted for each neutropenia outcome using quasi-poisson regression with monthly population offset to account for month-to-month changes in the at-risk population.

Results: Of 15,781 clozapine users with an ANC value reported, 59.3% were male, 85.3% were younger than 65 (mean age 47.9) years, 69.2% were White, and 89.7% were primary-insured by Medicaid or Medicare. Of the monthly eligible patients, 0.12-0.58% and 0.21-1.02% respectively in the pre- and post-update periods presented with neutropenia. The REMS update resulted in an immediate increase in any neutropenia outcome (incident rate ratio [IRR]=1.61 [95% CI 1.12-2.35]) and mild neutropenia (IRR=1.96 [1.32-2.98]), but no statistical significance was observed in moderate (IRR=1.11 [0.38-3.91]) and severe neutropenia outcomes (IRR=0.37 [0.13-1.16]). Month-to-month changes in the post-update period were small for all outcomes. No neutropenia trend was detected with statistically significant slope difference.

Conclusions: Preliminary findings suggest mild neutropenia increased among clozapine users after the 2019 Clozapine REMS update, which may reflect early detection of neutropenia as intended by the program. This study was limited to include only clozapine users with ANC result availability. Future research should consider longer-term follow-up and ANC monitoring adherence to complete evaluation of the program impact on neutropenia outcome.