Comparison of Safety and Treatment Continuity of Palbociclib and Abemaciclib for Hormone Receptor-Positive, HER2-Negative Metastatic/Recurrent Breast Cancer.

Background: Appropriate adverse event (AE) management and maintenance of therapeutic intensity are necessary to achieve therapeutic benefits of CDK4/6 inhibitors (palbociclib and abemaciclib) in hormone receptor-positive, HER2-negative metastatic/recurrent breast cancer. Objective: This study was aimed at clarifying the effect of AEs associated with palbociclib and abemaciclib on treatment. Methods: A total of 62 and 49 patients were prescribed palbociclib and abemaciclib, respectively, at our hospital from January 1, 2018 to June 30, 2023. The rate and reasons for treatment discontinuation, interruption of administration, and changes in dose and dosing schedule, treatment duration, and relative dose intensity (RDI) were compared between the groups of patients prescribed the 2 treatments. Results: Treatment discontinuation due to AEs occurred more frequently with abemaciclib (12 patients) because of interstitial lung disease and hepatic and renal events than with palbociclib (5 patients; P = .008). Administration was interrupted in 57 (91.9%) and 35 (71.4%) patients treated with palbociclib and abemaciclib, respectively (P = .004). Dose reduction occurred in 37 (67.3%) and 19 (47.5%) patients treated with palbociclib and abemaciclib, respectively (P = .053). The median [range] treatment duration was 301 [21-1643] days for palbociclib and 238 [70-1526] days for abemaciclib (log-rank test, P = .581). The median RDI was 59.7% and 59.6% for palbociclib and abemaciclib, respectively (P = .539). Although the AEs of palbociclib and abemaciclib affected the treatment considerably, the treatment duration and RDI were similar. Conclusion: CDK4/6 inhibitors should be selected based on the tolerability and manageability of each AE.

Association between CDK4/6 inhibitors and drug-related osteonecrosis of the jaw: A pharmacoepidemiological study using the FDA Adverse Events Reporting System.

The most common toxicities associated with cyclin-dependent kinase (CDK) 4/6 inhibitor therapy include decreased leukopenia and neutropenia due to the inhibition of CDK6 of leukocyte and neutrophil precursors in bone marrow. These hematological toxicities are more commonly observed with palbociclib administration than with abemaciclib administration, which is approximately 13 times more selective against CDK4 than CDK6. Thus, even though both successfully inhibit CDK4/6, the side effects of palbociclib and abemaciclib differ due to differences in selectivity. Recent reports have suggested an association between palbociclib and medication-related osteonecrosis of the jaw; however, reports on this association are inconsistent. This study investigated the potential association of palbociclib and abemaciclib with MRONJ using the FAERS. Signals of "Osteonecrosis of jaw" were detected only in females using palbociclib (cROR025: 2.08). Other signals detected included stomatitis-related adverse events with abemaciclib and intraoral soft tissue damage and infection with palbociclib. As previous exploratory studies have reported MRONJ signals for bisphosphonates and denosumab, we calculated the aROR for palbociclib-induced osteonecrosis of the jaw using concomitant bisphosphonates and denosumab as covariates. A signal was detected even after adjusting for sex, age, and concomitant medications as covariates (aROR0025: 5.74). A proper understanding of the differences in CDK selectivity is necessary for the appropriate use of CDK4/6 inhibitors. To the best of our knowledge, this is the first report on CDK4/6 inhibitors and drug-related osteonecrosis of the jaw. We believe that these results will offer new insights into adverse events related to the use of CDK4/6 inhibitors, and may aid in the proper use of CDK4/6 inhibitors.

Impact of Polypharmacy and Risk Factors for Exacerbation of Lower Urinary Tract Symptoms in Patients with Urological Conditions: A Retrospective Study in a Japanese Municipal Hospital.

Polypharmacy exacerbates lower urinary tract symptoms (LUTS). Japan exhibits a higher prevalence of concomitant medication use in drug therapy than other countries. Previous age- and sex-specific reports exist; however, none include patients of all ages. Therefore, this retrospective study determined the impact of polypharmacy and its associated risk factors on LUTS exacerbation in outpatients with urological conditions. We included patients receiving medication who visited the Department of Urology at the Gifu Municipal Hospital (Gifu, Japan) between January, 2018 and December, 2018. The association between LUTS and polypharmacy and the risk factors for LUTS exacerbation were investigated. Patients were categorized into two groups according to their polypharmacy status. We performed propensity score matching and compared the International Prostate Symptom Score (IPSS) between the groups using the unpaired t-test. Multiple logistic regression analysis was performed to examine the risk factors, including "polypharmacy" and "taking multiple anticholinergic medications" for LUTS exacerbation. When comparing the IPSS between the groups, the polypharmacy group was found to have significantly higher scores than the non-polypharmacy group in six items, including "total score" and "storage score." Multiple logistic regression analysis results showed high significance in three items, including "polypharmacy" (odds ratio (OR) = 1.67, 95% confidence interval (CI): 1.03-2.71) and "taking multiple anticholinergic medications" (OR = 8.68, 95% CI: 1.05-71.7). In conclusion, this study revealed that "polypharmacy" and "taking multiple anticholinergic medications" were risk factors for LUTS. Particularly, "polypharmacy" is associated with storage symptom exacerbation. Therefore, eliminating "polypharmacy" and "taking multiple anticholinergic medications" is expected to improve LUTS.

Detection Algorithms for Simple Two-Group Comparisons Using Spontaneous Reporting Systems.

Medical science has often used adult males as the standard to establish pathological conditions, their transitions, diagnostic methods, and treatment methods. However, it has recently become clear that sex differences exist in how risk factors contribute to the same disease, and these differences also exist in the efficacy of the same drug. Furthermore, the elderly and children have lower metabolic functions than adult males, and the results of clinical trials on adult males cannot be directly applied to these patients. Spontaneous reporting systems have become an important source of information for safety assessment, thereby reflecting drugs' actual use in specific populations and clinical settings. However, spontaneous reporting systems only register drug-related adverse events (AEs); thus, they cannot accurately capture the total number of patients using these drugs. Therefore, although various algorithms have been developed to exploit disproportionality and search for AE signals, there is no systematic literature on how to detect AE signals specific to the elderly and children or sex-specific signals. This review describes signal detection using data mining, considering traditional methods and the latest knowledge, and their limitations.

Pituitary-Related Adverse Events and Onset Patterns Caused by Immune Checkpoint Inhibitors: Analysis Using the Japanese Adverse Drug Event Report Database.

Background and Objectives: One type of immune-related adverse event caused by immune checkpoint inhibitors (ICIs) is pituitary-related adverse events. The management of pituitary-related adverse events is important because they can be fatal if not treated promptly. Therefore, this study was conducted to investigate the onset of pituitary-related adverse events using the Japanese Adverse Drug Report (JADER) database. Materials and Methods: Cases registered in the JADER database from 2004 to 2019 were used. The target drugs were ipilimumab, nivolumab, pembrolizumab, avelumab, atezolizumab, and durvalumab, and the target adverse events were the high-level terms "Anterior pituitary hypofunction," "Anterior pituitary hyperfunction," "Posterior pituitary disorder," and "Pituitary neoplasm" in the Medical Dictionary for Regulatory Activities, Japanese version (MedDRA/J). The information component (IC) was used for signal detection and IC delta (ICΔ) was used for women-related signals. Onset timing and patterns were analyzed using the Weibull distribution. Results: Signals were detected with ipilimumab, nivolumab, pembrolizumab, and atezolizumab in "Anterior pituitary hypofunction," with ICs and 95% credible intervals (95%CrI) of 5.53 (5.30-5.69), 4.96 (4.79-5.08), 4.04 (3.76-4.25), and 2.40 (1.53-3.00). Significant signals were detected in women, except for atezolizumab. Additionally, the time of onset was classified as the wear-out failure type. Inverse signals were detected with ipilimumab and nivolumab in "Posterior pituitary disorder," with ICs (95%CrI) of -1.24 (-2.80--0.26), and -0.89 (-1.64--0.37). Conclusions: Anterior pituitary hypofunction is likely to occur with the long-term administration of ipilimumab, nivolumab, and pembrolizumab. Further investigation is needed to determine the differences in the tendencies to detect signals in the anterior and posterior pituitaries between ipilimumab and nivolumab.

Evaluation of the therapeutic effects and tolerability of modified lenvatinib administration methods for unresectable hepatocellular carcinoma: A preliminary study.

Lenvatinib (LEN), a multitarget tyrosine kinase inhibitor, is a standard therapeutic agent for hepatocellular carcinoma, but the high incidence of adverse events (AEs) related to LEN treatment often necessitates treatment discontinuation. The present study aimed to clarify the therapeutic efficacy and tolerability of modified LEN dosing methods, such as alternate-day dosing, necessitated by AEs of LEN. A total of 66 patients who received LEN at Ogaki Municipal Hospital (Ogaki, Japan) between April 2018 and January 2022 were retrospectively evaluated. These patients were divided into those who completed treatment with the standard administration method (standard LEN, n=48) and those who changed from the standard administration method to a modified administration method in the middle of treatment [modified LEN (weekends off/alternate days), n=18]. The treatment duration and reasons for discontinuation of LEN treatment were analysed. The discontinuation rate due to AEs in the modified LEN group (1 patient) was less compared with that in the standard LEN group (16 patients) (P=0.022). The median treatment duration for patients in the standard LEN (n=48), modified LEN (weekends off, n=6) and modified LEN (alternate days, n=12) groups was 71 [95% confidence interval (CI) 55-134], 483 (95% CI: 193-644) and 222 (95% CI: 98-303) days, respectively (P=0.044). Modification of the administration method ensured fewer AE-related treatment discontinuations. However, weekends off dosing showed a longer treatment duration compared with standard dosing, whereas alternate day dosing showed no difference from standard dosing.

Analysis of pharmacological interventions among hospitalised patients with COVID­19: A focus on severe cases.

Existing recommendations regarding pharmaceutical interventions for patients with coronavirus disease 2019 (COVID-19) focus on outpatient, inpatient and post-discharge care. However, there are no studies examining the actual activities of pharmacists in relation to hospitalised patients. The present study aimed to identify pharmacists' roles by analysing cases of pharmaceutical interventions, particularly for patients admitted to high-care units. Pharmacological interventions were provided to patients with severe COVID-19 or patients at high risk of severe disease in 2021. These pharmaceutical interventions were analysed and evaluated. Pharmacists also developed a COVID-19 drug compatibility chart for use by care team members. In the present study, 54 patients were included, of which 33 were severe cases. A total of 28 patients (52%) received pharmacological interventions and 25 of them were severe cases. Out of 68 pharmacological interventions, interventions for antimicrobial agents were the most common (28 interventions), followed by nutrition and anti-COVID-19 drug-related interventions. In addition, the need for interventions relating to drug compatibility was reduced by ~43% after the drug compatibility chart was implemented. In conclusion, pharmacists have a responsibility to improve the quality of pharmacotherapy for patients with COVID-19. They should focus on creating specific pharmacotherapy tools for patients with COVID-19 and supporting appropriate antimicrobial use for secondary bacterial infections.

Analysis of adverse events leading to dose reduction/interruption of lenvatinib treatment in patients with Child-Pugh B unresectable hepatocellular carcinoma.

INTRODUCTION: We aimed to compare the safety of lenvatinib as first-line treatment for unresectable hepatocellular carcinoma (HCC) in patients with Child-Pugh A (CP-A) and Child-Pugh B (CP-B) and to determine the adverse events (AEs) that cause dose reduction/interruption of treatment in patients with CP-B. METHODS: Sixty-six patients with lenvatinib as a first-line treatment for HCC at Ogaki Municipal Hospital (Ogaki, Japan) between April 2018 and January 2022 were retrospectively evaluated. We analyzed the treatment duration, AEs, and reasons for dose reduction/interruption associated with lenvatinib treatment in patients with CP-A and CP-B HCC. RESULTS: The CP-B group had significantly more cases of grade ≥ 2 fatigue and anorexia than the CP-A group (p = 0.045 and p = 0.042, respectively). Regarding AEs that caused dose reduction/interruption of treatment, the CP-A group had significantly more cases of proteinuria than the CP-B group (p = 0.015), whereas the CP-B group had significantly more cases of hand-foot syndrome (HFS) than the CP-A group (p = 0.013). CONCLUSION: Patients with CP-B have greater difficulty than patients with CP-A in continuing treatment with repeated dose reductions/interruption of treatment due to intolerable grade ≥ 2 AEs (fatigue and anorexia). HFS is more likely to cause dose reduction/interruption of treatment in CP-B than in CP-A unresectable HCC.

Effects of Pharmacist-Led Dementia Care Round Interventions on the Use of Sleep Medications.

Objective: To investigate pharmacist-led dementia care rounds (PDRs) and their effect on the use of sleep medications, including the number and content of prescription suggestions during PDRs and use of sleep medications at the time of hospitalization and discharge.Methods: This was a retrospective observational study of inpatients who received PDR intervention at a hospital in Japan from January 1 to December 31, 2020. The PDR team, consisting of a pharmacist and dementia care nurse, made prescription suggestions through the attending nurse, and the attending physician made the decision to change the prescription. Use of sleep medication was investigated by classifying patients into 2 groups: those for whom prescription suggestions from PDRs were accepted and those for whom they were rejected.Results: PDRs were conducted 1,164 times with 418 patients, and prescription suggestions were made 330 times (28.4%) for 173 (41.4%) patients. Of these, 234 (70.9%) prescription suggestions were accepted. At the time of discharge, the percentage of patients using benzodiazepine-based sleep medications was 3.1% in the accepted group and 11.9% in the rejected group. The percentage of patients using non-benzodiazepine-based sleep medications was 22.1% in the accepted group and 9.5% in the rejected group. Further, the percentage of patients using non-γ-aminobutyric acid receptor agonist drugs as sleep medications was 9.2% in the accepted group and 2.4% in the rejected group. The results show that the percentage of patients using benzodiazepine-based sleep medications was significantly lower in the accepted group than in the rejected group (P = .022).Conclusions: PDR intervention contributed to the appropriate use of sleep medications, with nearly 30% of prescription suggestions. PDRs may play an important role in the appropriate use of sleep medications, and active participation of pharmacists in dementia care is necessary.

[Incidence of Immune-Related Adverse Events after Switching from a Conventional Regimen of Nivolumab and Pembrolizumab to the Extended Dosing Interval Regimen].

A new nivolumab and pembrolizumab monotherapy regimen with double the conventional dose and longer dosing intervals( the new regimen)has been approved. Here, we report the incidence of immune-related adverse events(irAEs)in the early phase of switching from the conventional regimen to the new regimen at Ogaki Municipal Hospital. Thirty-seven patients switched to the new regimen between October 2020 and February 2021: 7(18.9%)switched to nivolumab and 5 (14.3%)to pembrolizumab. Two of the 7 patients treated with nivolumab developed irAEs. One patient developed Grade 3 colitis on day 51 following the switch to the new regimen, and the treatment was discontinued. The other patient developed Grade 3 adrenal insufficiency on day 72 and was hospitalized. No irAEs were observed with pembrolizumab treatment. These results suggest that high-severity grade irAEs may occur early after switching to the new regimen.

[Comparative Safety Assessment of Ramucirumab plus FOLFIRI and Bevacizumab plus FOLFIRI in Second- and Later-Line Treatment in Japanese Patients with Metastatic Colorectal Carcinoma].

The addition of anti-angiogenic agents to cytotoxic agents to improve outcomes has become the standard treatment for metastatic colorectal carcinoma. In this study, we evaluated the safety of bevacizumab plus FOLFIRI with that of ramucirumab plus FOLFIRI in second- and later-line treatment in Japanese patients with metastatic colorectal carcinoma. Patients who received ramucirumab or bevacizumab as a second- and later-line treatment between January 2016 and March 2020 were included. Treatment regimens, body surface area, dosage, number of treatment courses, and adverse events( AEs) were evaluated. There were 66 and 17 patients in the bevacizumab plus FOLFIRI and ramucirumab plus FOLFIRI groups, respectively. All patients developed AEs. AEs of grade 3/4 were documented in 84.8% and 100% of the patients in the bevacizumab plus FOLFIRI and ramucirumab plus FOLFIRI groups, respectively. Progressive disease was the most common reason for treatment discontinuation in both groups. Twelve (18.2%) and 5 (29.4%) patients in the bevacizumab plus FOLFIRI and ramucirumab plus FOLFIRI groups, respectively, discontinued treatment due to AEs. The most common AEs leading to discontinuation were malaise and decreased performance status. The findings of our study indicated that both bevacizumab plus FOLFIRI and ramucirumab plus FOLFIRI groups have a high incidence of AEs, and that medical professionals need to be aware of the frequent development of malaise and decreased performance status.

Analysis of drug-induced hand-foot syndrome using a spontaneous reporting system database.

Purpose: The aim of our study was to assess the clinical features of hand-foot syndrome (HFS) associated with certain systemic chemotherapeutic drugs in a real-world setting using the Japanese Adverse Drug Event Report (JADER) database. Methods: HFS was defined using the preferred terms from the Medical Dictionary for Regulatory Activities. We used several indices, such as the reporting odds ratios (RORs) at 95% confidence interval (CI), the time-to-onset profile of HFS, and cluster analysis. Results: Of 646,779 reports (submission period: April 2004 to September 2020), 1814 reported HFS events. The RORs (95% CI) for axitinib, capecitabine, lapatinib, regorafenib, sorafenib, and sunitinib were 14.9 (11.1-20.1), 54.6 (49.2-60.6), 130.4 (110.7-153.6), 63.3 (55.2-72.6), 29.0 (25.8-32.7), and 13.9 (11.7-16.5), respectively. The analysis of time-to-onset profiles revealed that the median values (interquartile range: 25.0-75.0%) of drug-induced HFS caused by capecitabine, cisplatin, docetaxel, everolimus, regorafenib, sorafenib, and trastuzumab were 21.0 (13.0-42.0), 15.0 (10.0-82.0), 6.0 (3.0-25.0), 86.5 (67.0-90.5), 9.0 (6.0-14.0), 9.0 (6.0-14.0), and 70.0 (15.0-189.0) days, respectively. The number of clusters was set to 4. Among these, one cluster, which included capecitabine, regorafenib, and lapatinib, exhibited a higher reporting ratio and ROR of drug-induced HFS than other drugs. Conclusions: The RORs and results of time-to-onset analysis obtained in this study indicated the potential risk of HFS associated with chemotherapeutic drugs. Our results suggest that health care professionals must be aware of the potential onset of drug-induced HFS with docetaxel, regorafenib, and sorafenib for at least 4 weeks; therefore, careful observation is recommended. Plain Language Summary: Elucidation of the relationship between cancer drugs and risk of hand-foot syndrome: Purpose: Hand-foot syndrome (HFS) is an adverse effect of some cancer drugs, which is characterized by symptoms such as redness, swelling, blistering, and pain in the area of palms and soles. HFS reduces the quality of life of patients and can sometimes interfere with anticancer treatment plans. It is important to understand the clinical manifestations of HFS and gain knowledge that will allow for early intervention by clinicians.Methods: In this study, we used a large-scale side effect database of real-world cases for a comprehensive investigation of anticancer-drug-induced HFS. The database contained 646,779 adverse event reports from April 2004 to September 2020; among which, we identified 1814 HFS events. Using these data, we could obtain information on the relationship between 19 types of anticancer drugs and HFS, and the onset time of HFS and HFS prognosis related to each anticancer drug. Results: Our results suggest that clinicians should monitor the risk of HFS with docetaxel, regorafenib, and sorafenib for at least the first 4 weeks after drug administration. Conclusion: These findings are crucial for improving the management of the adverse effects caused by anticancer drugs.