Dataset Information

Clozapine and hematologic adverse reactions: Impact of the Risk Evaluation and Mitigation Strategy program.

ABSTRACT: Introduction:In October 2015, the Food and Drug Administration (FDA) instituted an update to the mandatory Risk Evaluation and Mitigation Strategy (REMS) program for clozapine to improve safety monitoring of hematologic events. However, the impact of the clozapine REMS program on reporting of hematologic adverse events has not been quantified. Methods:We assessed adverse event reports for agranulocytosis, granulocytopenia, leukopenia, and neutropenia from the FDA Adverse Event Reporting System (FAERS) for a 1-year time period before (October 2014 to September 2015, pre-REMS) and after (October 2015 to September 2016, post-REMS) the implementation of the clozapine REMS program. The AERSMine platform was used to capture historical effect estimates (October 2004 to September 2014). Reporting odds ratios (ROR), proportional reporting ratios (PRR), and corresponding Taylor series 95% confidence intervals (CIs) were calculated for hematologic events with clozapine compared with all other medications using OpenEpi. Results:Reporting rates for agranulocytosis, granulocytopenia, leukopenia, and neutropenia with clozapine all increased from the pre-REMS to post-REMS time frames, ranging from a 2-fold increase with leukopenia to a 40-fold increase with neutropenia; the composite measure of all hematologic reports had a 12-fold increase. During the post-REMS time frame, the ROR increased by 1691% (111.4, 95% CI 100.6-123.4) compared with the pre-REMS time frame (7.1, 95% CI 5.2-9.6), and the PRR increased by 1280% (83.1, 95% CI 76.8-90.0 vs 6.9, 95% CI 5.1-9.4) for the composite outcome. Discussion:We observed significant increases in reports of hematologic adverse events with clozapine after the introduction of the clozapine REMS program. Future research should explore the impact of the less stringent exclusionary and discontinuation criteria on utilization (eg, expanded access) and clinical outcomes (eg, treatment effectiveness and adverse events).

SUBMITTER: Borrelli EP

PROVIDER: S-EPMC7213944 | biostudies-literature | 2020 May

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Clozapine and hematologic adverse reactions: Impact of the Risk Evaluation and Mitigation Strategy program.

Borrelli Eric P EP Lee Erica Y EY Caffrey Aisling R AR

The mental health clinician 20200507 3

<h4>Introduction</h4>In October 2015, the Food and Drug Administration (FDA) instituted an update to the mandatory Risk Evaluation and Mitigation Strategy (REMS) program for clozapine to improve safety monitoring of hematologic events. However, the impact of the clozapine REMS program on reporting of hematologic adverse events has not been quantified.<h4>Methods</h4>We assessed adverse event reports for agranulocytosis, granulocytopenia, leukopenia, and neutropenia from the FDA Adverse Event Rep ...[more]

PMID: 32420002

Similar Datasets

Project description:Importance:Transmucosal immediate-release fentanyl (TIRF) drugs are potent, rapid-acting opioids approved to treat breakthrough pain in patients with cancer who are tolerant to other around-the-clock opioid analgesics. In March 2012, a US Food and Drug Administration-approved Risk Evaluation and Mitigation Strategy (REMS) was implemented, mandating prescribers, distributors, pharmacies, and patients to enroll in the REMS to prescribe, dispense, or receive TIRF drugs. Objective:To evaluate the association of the TIRF-REMS Access Program with TIRF prescribing. Design, Setting, and Participants:Cohort study using an interrupted time series analysis of TIRF prescriptions to Medicare Part D beneficiaries nationwide from 2010 to 2014. Data were analyzed from August 2017 through July 2018. Main Outcomes and Measures:Prescribing of TIRF per 100 000 Medicare Part D beneficiaries, overall and stratified by cancer status; percentage of TIRF prescriptions for patients without cancer, overall and by brand; and percentage of TIRF prescriptions for patients without known opioid tolerance, defined as patients prescribed at least 60 morphine milligram equivalents per day, overall and by brand. Results:There were 99 601 TIRF prescriptions written by 8619 clinicians to 10 472 patients. Most of the patients (79%) were younger than 65 years (mean [SD] age, 56 [13] years), and most (67%) did not have cancer. Implementation of TIRF-REMS was associated with a 26.7% relative level decrease in TIRF prescribing (95% CI, -33.3% to -19.4%; P < .001) but was followed by 2.0% monthly increases in prescribing (95% CI, 1.3% to 2.7%; P < .001). Sensitivity analyses that accounted for overall opioid prescribing trends were consistent with these findings. Furthermore, there were no significant changes associated with REMS implementation in the level (0.47%; 95% CI, -5.36% to 4.69%; P = .85) or trend (0.16%; 95% CI, -0.06% to 0.37%; P = .15) of the percentage of prescriptions for patients without cancer. However, a sensitivity analysis that used a broader cancer definition found implementation was associated with a 7.2% (95% CI, -13.5% to -0.48%; P = .04) level decrease in the percentage of TIRF prescriptions for patients without cancer. Lastly, the TIRF-REMS was associated with a 22.5% level decline in the percentage of TIRF prescriptions for patients without known opioid tolerance (95% CI, -36.1% to -5.95%; P = .01) followed by 1.98% monthly decreases (95% CI, -3.19% to -0.80%; P = .001). Conclusions and Relevance:Implementation of the TIRF-REMS Access Program, a restrictive drug distribution program, was associated with a temporary reduction in the rate of TIRF prescribing to Medicare Part D beneficiaries, and with a sustained decrease in the percentage of TIRF prescriptions for patients without known opioid tolerance. Implementation may have also been associated with a temporary decrease in the percentage of TIRF prescriptions for patients without cancer.

Project description:ImportanceTransmucosal immediate-release fentanyls (TIRFs), indicated solely for breakthrough cancer pain in opioid-tolerant patients, are subject to a US Food and Drug Administration (FDA) Risk Evaluation and Mitigation Strategy (REMS) to prevent them from being prescribed inappropriately.ObjectivesTo evaluate knowledge assessments of pharmacists, prescribers, and patients regarding appropriate TIRF use; to describe sponsor assessments, based on claims data, of whether the REMS program was meeting its goals; and to characterize how the FDA responded to REMS assessments.Design, setting, and participantsQualitative analysis of 4877 pages of FDA documents obtained through a Freedom of Information Act request, including 6 annual REMS assessment reports (2012-2017), FDA evaluations of these reports, and FDA-sponsor correspondence about safety issues.ExposureA REMS program to reduce the risk of adverse outcomes, including misuse, abuse, addiction, and overdose, arising from use of TIRFs.Main outcomes and measures(1) Knowledge assessments of pharmacists, prescribers, and patients; (2) survey and claims-based prescribing assessments; (3) FDA and TIRF sponsor communications; (4) modifications to the REMS program; and (5) disenrollment of noncompliant prescribers.ResultsTwelve months after initiation of the program, 24 of 302 pharmacists (7.9%), 35 of 302 prescribers (11.6%), and 5 of 192 patients (2.6%) incorrectly reported that TIRFs can be prescribed to opioid-nontolerant patients, with similar levels of misunderstanding maintained in the subsequent reports. At 60 months, product-specific analyses of claims data indicated that between 34.6% and 55.4% of patients prescribed TIRFs were opioid-nontolerant. In the 48-month survey, 106 of 310 prescribers (34.2%) reported prescribing TIRFs for opioid-tolerant patients with chronic, noncancer pain; at 60 months, 54 of 302 prescribers (18.4%) and 148 of 310 patients (47.7%) erroneously reported that TIRFs were FDA-approved for such use. Over the 60-month period examined, there were few substantive changes made to the REMS to address evidence of high rates of off-label TIRF use, and, although the REMS program had a noncompliance plan, there was no report of prescribers being disenrolled for inappropriate prescribing.Conclusions and relevanceIn this review of FDA documents pertaining to the TIRF REMS, surveys of pharmacists, prescribers, and patients reflected generally high levels of knowledge regarding proper TIRF prescribing, yet some survey items as well as claims-based analyses indicated substantial rates of inappropriate TIRF use. Despite these findings, the FDA did not require substantive changes to the program.

Dataset Information

Clozapine and hematologic adverse reactions: Impact of the Risk Evaluation and Mitigation Strategy program.

Publications

Clozapine and hematologic adverse reactions: Impact of the Risk Evaluation and Mitigation Strategy program.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets