Neurological and Psychiatric Adverse Events Associated with Cyclin-Dependent Kinase 4/6 Inhibitors in Breast Cancer Patients: Insights from a Pharmacovigilance Study via the FDA Adverse Event Reporting System.

Cyclin-dependent kinase 4/6 (CDK4/6) inhibitors have revolutionised cancer therapy, particularly breast cancer therapy. However, concerns about their potential to cause neurological and psychiatric adverse events (AEs) have emerged, and these concerns remain underexplored. This study aimed to investigate the signals related to neurological and psychiatric AEs associated with CDK4/6 inhibitor use. A retrospective study was performed to analyse reports of AEs associated with the use of CDK4/6 inhibitors (abemaciclib, ribociclib and palbociclib) from the first quarter of 2015 to the fourth quarter of 2023 on the basis of the FDA Adverse Event Reporting System (FAERS). Both the reporting odds ratio (ROR) and the multi-item gamma Poisson shrinker (MGPS) were used for signal detection. The timing of events was assessed with the Weibull shape parameter (WSP). The management, analysis and presentation of the data were performed via Python (version 3.8) and R software (version 4.3.2). A total of 19,001 AE reports in which CDK4/6 inhibitors were identified as the 'primary suspect drug' were included in this study. These events were predominantly observed in patients aged 65 to 85 years. Through an ROR analysis, 85 positive signals for neurological and psychiatric AEs associated with CDK4/6 inhibitors were identified. The MGPS method revealed 61 positive AE signals for neurological and psychiatric AEs associated with CDK4/6 inhibitors. A total of 34 positive AE signals were identified by both the ROR and MGPS analyses. The WSP indicated that the onset times for AEs associated with all three CDK4/6 inhibitors tended to be early in drug therapy, suggesting a propensity for early failure type. The present study revealed neurological and psychiatric AEs associated with CDK4/6 inhibitors that often occur early in treatment. Significant signals include spinal cord herniation and cerebral microangiopathy. Close monitoring of these AEs is crucial. Further studies are necessary to verify the connection between CDK4/6 inhibitors and neurological and psychiatric AEs.

Yu Z ，Guan M ，Liao X 《-》

Musculoskeletal adverse events associated with CDK4/6 inhibitors: a real-world study using FDA Adverse Event Reporting System (FAERS) database.

Cyclin-dependent kinase (CDK)-4/6 inhibitors have significantly improved outcomes in several cancers but can also induce various organ system toxicities, including musculoskeletal disorders. This study aimed to comprehensively characterize the musculoskeletal adverse events (MSAEs) associated with CDK4/6 inhibitors based on real-world data. Reports of MSAEs linked to CDK4/6 inhibitors from the first quarter (Q1) of 2015 and 2023 Q4 were extracted from the FAERS. Descriptive analyses evaluated report frequencies over time and patient characteristics. Disproportionality analyses using reporting odds ratios (RORs) identified signals for specific musculoskeletal preferred terms (PTs). Time-to-onset analyses examined the temporal patterns of MSAEs. A total of 10,095 MSAE reports associated with CDK4/6 inhibitors were identified, most involving Palbociclib (n = 7819). The median age of patients was 64 years (IQR: 55-72), predominantly female (97.73%). Most reports were submitted by consumers (47.62%) and the majority of reports were from the United States (71.53%). Disproportionality analyses revealed distinct signals, with Ribociclib showing prominent signals for bone pain and bone lesions, and Abemaciclib for osteonecrosis of the jaw and pathological fractures. Palbociclib demonstrated a consistent but less pronounced signal across musculoskeletal PTs. Time-to-onset analyses demonstrated a significantly longer onset of MSAEs for Palbociclib (median 82 days, IQR[14-311]) compared to Abemaciclib (32.5 days, IQR[12-119]) and Ribociclib (34 days, IQR[8-177]) using the nonparametric Kruskal-Wallis test (P-value = 3.048e-11). Musculoskeletal toxicities is a significant adverse event that affects drug safety. Early identification and proper management of these events are crucial for patients receiving CDK4/6 inhibitors. Further research is warranted to elucidate the underlying mechanisms and improve risk mitigation strategies.

Chen Z ，Fu Z ，Zhang N ，Zou W ，Chen W ... -  《BMC Pharmacology & Toxicology》

A disproportionality analysis of CDK4/6 inhibitors in the FDA Adverse Event Reporting System (FAERS).

Peng Y ，Zhou Y ，Zhou X ，Jia X ，Zhong Y ... -  《-》

The drug risks of cilostazol: A pharmacovigilance study of FDA Adverse Event Reporting System database.

Cilostazol is indicated for alleviating intermittent claudication (IC) in stable-phase peripheral arterial disease (PAD) patients. Conducting data mining on adverse events (AEs) of cilostazol in the U.S. Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS) database to explore its potential medication risks and advance more rational and secure clinical medication practices. This study utilized the Open Vigil 2.1-MedDRA tool to retrieve and extract AE reporting data related to cilostazol from the FAERS database spanning the first quarter of 2004 to the first quarter of 2024. The primary methodology employed was the application of the reporting odds ratio (ROR) method to detect risk signals associated with AEs of cilostazol. A total of 2,130 AE reports involving cilostazol were identified as the primary suspect drug, with a total of 7,134 AEs reported. These reports were predominantly concentrated among patients aged 60 and above, with a higher occurrence in males compared to females. Japan ranked first among the reporting countries, and the majority of reports were submitted by healthcare professionals. Through the screening of cilostazol, a total of 323 positive risk signals for AEs were identified, encompassing 23 system organ classes (SOCs). A comparison with the existing cilostazol product label revealed 8 AEs that were not included based on the number of AE reports, and 19 AEs that were not included based on the strength of the risk signals. Cilostazol exhibited positive risk signals for AEs primarily affecting 8 organ systems based on the SOC classification. Among these, cardiac disorders ranked highest, with a total of 53 positive risk signals for cardiovascular-related AEs identified. In terms of the number of reports, cardiac failure ranked first, aligning with the black box warning issued by the FDA regarding cilostazol. The occurrence of adverse reactions related to cilostazol is primarily concentrated within the first month of treatment. However, a certain proportion of adverse reactions have been reported to occur after long-term use (exceeding 360 days) of cilostazol therapy. Our results have further enriched the observations from existing clinical and real-world studies, uncovering new AE signals for cilostazol, including fall, cerebral infarction, pneumonia, loss of consciousness, acute kidney injury, renal impairment, renal failure, cardiac vein perforation, basal ganglia haematoma, cerebral hyperperfusion syndrome, et al. This study also highlights the significant impact of cilostazol on the cardiovascular system, necessitating close attention to potential cardiovascular toxicities. In addition to focusing on the short-term adverse reactions following cilostazol administration, thorough research into its long-term safety profile is also imperative. This study provides recommendations and guidance for the rational and safe clinical use of cilostazol. In the future, prospective studies are needed to explore the occurrence of related AEs further.

Peng L ，Li X ，Li J ，Liu S ，Liang G ... -  《PLoS One》

Hematological toxicity of cyclin-dependent kinase 4/6 inhibitors in patients with breast cancer: a network meta-analysis and pharmacovigilance study.

Ding H ，Xu W ，Dai M ，Li S ，Xin W ，Tong Y ，He C ，Mi X ，Zhan Z ，Fang L ... -  《-》