Eye-tracking-based analysis of pharmacists' thought processes in the dispensing work: research related to the efficiency in dispensing based on right-brain thinking.

BACKGROUND: Pharmacists should be aware of their thought processes in dispensing work, including differences in the dispensing complexities owing to different drug positions in the left, center, and right areas. Dispensing errors associated with "same-name drugs (a pair of drugs with the same name but a different ingredient quantity)" are prevalent and often negatively affect patients. In this study, using five pairs of comparative models, the gaze movements of pharmacists in dispensing work were analyzed using an eye-tracking method to elucidate their thought processes. METHODS: We prepared verification slides and displayed them on a prescription monitor and three drug rack monitors. The dispensing information (drug name, drug usage, location display, and total amount) was displayed on a prescription monitor. A total of 180 drugs including five target drugs were displayed on the three drug rack monitors. Total gaze points in the prescription area, those in the drug rack area, total vertical movements between the two areas, and time required to dispense drugs were measured as the four classifications Gaze 1, Gaze 2, Passage, and Time, respectively. First, we defined the two types of location displays as "numeral combination" and "color/symbol combination." Next, we defined two pairs of models A1-A2 (numerals) and B1-B2 (color/symbol) to compare differences between the left and right areas. Moreover, three pairs of models C1-C2 (left), D1-D2 (center), and E1-E2 (right) were established to compare differences between "numeral combination" and "color/symbol combination." RESULTS: Significant differences in the complexities of dispensing work were observed in Gaze 2, Passage, and Time between the models A1-A2 (A1B2), and in Gaze 2 and Time between the models C1-C2, D1-D2, and E1-E2 (C1>C2, D1>D2, and E1>E2, respectively). CONCLUSIONS: Using the current dispensing rules, pharmacists are not good at dispensing drugs located in the right area. An effective measure for reducing the dispensing complexity is to introduce visual information in the prescription content; the utilization of the right brain facilitates reducing the complexity in the right dispensing area.

Evaluation of time-to-onset and outcome of cardiac adverse events related to pembrolizumab using post-marketing surveillance in Japanese patients.

BACKGROUND: Pembrolizumab has been widely used in patients since its release, but information on cardiac Adverse Events (AEs) related to pembrolizumab remains lacking, particularly in Japanese populations. OBJECTIVES: This study aims to evaluate time to onset, incidence rates, and outcomes for pembrolizumab-induced cardiac AEs in patients with cancer using the Japanese Adverse Drug Event Report database. METHODS: We analysed data for the period from April 2004 to March 2022. Data on cardiac AEs were extracted and relative risks of AEs were estimated using the reporting odds ratio. RESULTS: We analysed 2,021,907 reports and identified 15,306 reports of AEs caused by pembrolizumab. Of these, 399 cardiac AEs were associated with pembrolizumab. Signals were detected for six cardiac AEs: myocarditis, immune-mediated myocarditis, pericardial effusion, cardiac tamponade, pericarditis, and pericarditis malignant. A histogram of median times to onset showed occurrence from 33 (21-97) days for immune-mediated myocarditis to 138 (67-168) days for pericarditis malignant, but some cases occurred even more than 1 year after the start of administration. Among these, myocarditis was the most frequently reported (27.1%), with fatal cases also reported. CONCLUSION: This study focused on cardiac AEs caused by pembrolizumab as post-marketing AEs. Patients should be monitored not only at the time of administration, but also over time for signs of these AEs, especially myocarditis, as some patients may have serious outcomes.

Medical Economic Effect of Pharmaceutical Interventions by Board-Certified Pharmacists in Palliative Pharmacy for Patients with Cancer Using Medical Narcotics in Japan: A Multicenter, Retrospective Study.

BACKGROUND: The Japanese Society for Pharmaceutical Palliative Care and Sciences specializes in pharmacology in the field of palliative medicine. More than 700 board-certified pharmacists in palliative pharmacy (BCPPP) are actively involved in palliative pharmacotherapy at various hospitals and pharmacies. The purpose of this study was to determine the economic effect of pharmaceutical interventions by BCPPPs. METHODS: This multicenter retrospective study included 27 medical centers and analyzed the medical economic effect of interventions by BCPPPs (17 pharmacists) and non-BCPPPs (24 pharmacists) on patients using medical narcotics for cancer pain in September 2021. RESULTS: The percentage of patients who received a pharmaceutical intervention and whose drug costs were reduced by pharmacist intervention was significantly higher in the BCPPP group than in the non-BCPPP group. Although there was no significant difference between the two groups in drug cost reduction per patient per month (BCPPP group: $0.89 [-$64.91 to $106.76] vs. non-BCPPP group $0.00 [-$1,828.95 to $25.82]; P = 0.730), the medical economic benefit of pharmacist intervention in avoiding or reducing adverse drug reactions was higher in the BCPPP group ($103.18 [$0.00 to $628.03]) than in the non-BCPPP group ($0.00 [$0.00 to $628.03]) (P = 0.070). The total medical economic benefit-the sum of these-was significantly higher in the BCPPP group ($88.82 [-$14.62 to $705.37]) than in the non-BCPPP group ($0.66 [-$1,200.93 to $269.61]) (P = 0.006). CONCLUSION: Pharmacological intervention for patients with cancer using medical narcotics may have a greater medical economic benefit when managed by BCPPPs than by non-certified pharmacists in Japan.

Disproportionality analysis of stomatitis associated with anticancer drugs using Japanese Adverse Drug Event Reporting Database.

INTRODUCTION: Anticancer drug-induced stomatitis can affect a patient's quality of life and the continuation of drug treatment. Although there have been reports of the occurrence of stomatitis associated with anticancer agents in clinical trials, few Japanese participants have been enrolled in clinical trials and have not been sufficiently investigated. In addition, there has been little attention on research on anticancer drugs associated with stomatitis by patient stratification with different carcinogenic sites. Therefore, the aim of this study was to determine the disproportionality associated with stomatitis for various types of anticancer drugs in different types of cancer patients using the Japan Spontaneous Adverse Event Reporting Database (JADER). METHODS: The aim of this study was to identify the disproportionality of stomatitis by analyzing the type of anticancer drug and cancer patients using the Japanese Pharmacovigilance Database. Data obtained from spontaneous reports of adverse events with more than 10 stomatitis outbreaks reported in the Japanese Adverse Drug Event Report database (JADER) between April 2004 and March 2023 were analyzed. The safety signal for an adverse event was defined as the lower limit of the 95% confidence interval of the reporting odds ratio of >1. RESULTS: There were 6178 reports of drugs associated with stomatitis. Among these, 41 drugs were suggested to be associated with stomatitis, and 41 drugs were detected as signals. These drugs were classified based on their efficacy: antipyrimidines (six drugs), folate metabolism antagonists (three drugs), alkylating agents (four drugs), platinum (three drugs), topoisomerase inhibitors (three drugs), microtubule inhibitors (three drugs), mTOR inhibitors (two drugs), kinase inhibitors (seven drugs), anti-growth factor antibodies (five drugs) immune checkpoint inhibitors (one drug), and others (four drugs). CONCLUSION: The drugs that may be associated with stomatitis were cell cycle-dependent drugs, epidermal growth factor receptor-tyrosine kinase inhibitors, and mTOR inhibitors. Thus, the use of JADER suggests that anti-growth factor antibodies and immune checkpoint inhibitors may be associated with stomatitis development.

Evaluation of Time to Onset and Outcome of Lung Adverse Events Related to Pembrolizumab Using Marketing Surveillance.

BACKGROUND: Pembrolizumab has been widely used in patients since its release, but detailed information on lung-specific adverse events (AEs) from post-marketing monitoring has not been reported. OBJECTIVES: This study was undertaken to determine the risk of pembrolizumab-induced lung AEs, time to onset, and post hoc outcomes using the Japanese Adverse Drug Event Report database. METHOD: We analyzed data for the period between April 2004 and March 2022. Data on lung AEs were extracted and the relative risks of AEs were estimated using reporting odds ratios. RESULTS: We analyzed 2,021,907 reports and identified 15,306 reports of AEs caused by pembrolizumab, including 3,004 lung AEs. Signals were detected for 14 lung AEs. Interstitial lung disease was the most frequently reported (62.3%) and included fatal cases. A histogram of median time to onset showed occurrence ranging from 2 to 73 days, but some cases of interstitial lung disease occurred after 2 years of administration. The AEs showing the highest fatality rates were interstitial lung disease, respiratory failure, and pneumonia aspiration. CONCLUSIONS: This study focused on lung AEs caused by pembrolizumab as post-marketing AEs. Some cases could potentially involve serious outcomes, so patients should be monitored for signs of AE onset not only at the start of administration but also over an extended period, especially for interstitial lung disease.

Evaluation of Time to Onset and Outcome of Cardiac Adverse Events Associated with Nilotinib using Post-Marketing Surveillance.

INTRODUCTION: Cardiac adverse events (CAEs) have become a concern as serious adverse events (AEs) of nilotinib administration. No reports have described the incidence of CAEs associated with nilotinib in Japanese patients. Thus, we conducted this study to evaluate the risk of nilotinib-induced CAEs, time to onset, incidence rates, and post hoc outcomes using the Japanese Adverse Drug Event Report database. METHODS: We analysed data for the period between April 2004 and March 2022. Data on CAEs were extracted, and relative risk of AEs was estimated using the reporting odds ratio. RESULTS: We analysed 2,021,907 reports and identified 3,545 reports of AEs caused by nilotinib. Of these, 511 reports involved CAEs. Signals were detected for 19 CAEs. Of these, electrocardiogram QT prolonged was the most frequently reported (30.9%). Fatal outcomes were observed in eight AEs: cardiac failure, atrial fibrillation, acute myocardial infarction, pericardial effusion, myocardial infarction, cardiac arrest, pericarditis, and cardiac tamponade. Of these, acute myocardial infarction, myocardial infarction, pericarditis, and cardiac tamponade exhibited mortality rates >10%. A histogram of median times to onset showed nilotinib-associated AEs occurring 3-485 days after nilotinib administration. CONCLUSION: We focused on CAEs caused by nilotinib as post-marketing AEs. Some cases resulted in serious outcomes. Patients should be monitored for signs of onset of these AEs not only at the start of administration but for a long period of time.

Improvement of Medication Guidance Sheet for Total Body Irradiation/Cyclophosphamide Followed by Allogeneic Hematopoietic Stem Cell Transplantation Based on Real Monitoring Data.

BACKGROUND/AIM: Adverse events (AEs) must be managed during cancer therapy. We had previously developed a medication guidance sheet (MGS) to monitor AEs after conditioning therapy with allogeneic hematopoietic stem cell transplantation (HSCT). However, it remains unclear whether this sheet can accurately predict the type, onset, and duration of AEs in clinical practice. In this study, we evaluated the clinical utility of the original MGS in patients receiving total body irradiation (TBI) and cyclophosphamide (CY). PATIENTS AND METHODS: Fifty-eight patients who underwent TBI/CY were included. The types, onsets, and durations of AEs observed during real monitoring were compared with those listed in the original MGS. RESULTS: A total of 361 subjective AE symptoms were observed, all of which were predictive, as listed in the MGS. However, the durations of several AEs were longer than expected. Thus, the prediction accuracy for all AEs was 67.0%. The accuracy rate was the lowest for anorexia (6.7%), followed by diarrhea (42.6%), and nausea/vomiting (55.6%). Acute graft versus host disease (GVHD) most likely caused the prolongation of AEs. Subsequently, the original MGS was revised to account for the possible occurrence of acute GVHD. CONCLUSION: When monitoring AEs in patients receiving a TBI/CY conditioning regimen for HSCT, the involvement of acute GVHD-associated AEs should be considered. In this respect, the present modified MGS is particularly useful for rapid and accurate monitoring of AEs.

Multicenter prospective observational study on hospital pharmacist interventions to reduce inappropriate medications.

Background: In Japan, the involvement of hospital pharmacists in inappropriate medications (IMs) practices has not been sufficiently reported. Therefore, this prospective study described the interventions of hospital pharmacists in discontinuing inappropriate drugs or reducing drug doses. Methods: We conducted a prospective, multicenter, observational study to investigate the intervention of hospital pharmacists in inappropriate prescriptions for inpatients in September 2018. Fifty pharmacists from 45 hospitals in Japan participated in this study. IMs were defined as medications that pharmacists deemed inappropriate for patient treatment. The subjects of the study were patients who interacted with the participating pharmacists. Results: During the study period, the median number of beds in hospitals where the 50 participating pharmacists worked was 380, and the average number of beds for which the pharmacists were responsible was 49. The enrolled hospital pharmacists recommended that doctors discontinue or reduce the doses of their regular drugs for 347 out of 1,415 (24.5%) patients. Among the 391 pharmacists' recommendations to reduce IMs for 347 patients, physicians accepted 368 (94.1%) recommendations, and 523 drugs were discontinued as a result. Pharmacist intervention also led to improvements in hypnotic sedation, delirium, and hypotension. The most common reasons for IMs identified by pharmacists were "long-term administration of irresponsible or aimless medications" (44.5%), "adverse effects caused by medications" (31.5%), and "medications-mediated duplication of the pharmacological effect" (15.3%). Approximately 90% of pharmacists' suggestions to reduce medications were accepted for each reason. The average number of regular medications used by patients involved in drug reduction was 8.2, and the average number of medications reduced was 1.7. A sub-analysis showed that patients using opioids tended to take more medications, and these patients were able to reduce the amount of medications taken. Interventions by pharmacists certified in palliative pharmacies tended to reduce adverse drug events. Conclusion: This was the first multicenter prospective observational study conducted in Japan to demonstrate hospital pharmacist intervention's effectiveness in promoting appropriate prescription and, consequently, a reduction in the number of medications in use and polypharmacy.

Adverse Event Profile of Azacitidine: Analysis by Route of Administration Using Japanese Pharmacovigilance Database.

INTRODUCTION: Azacitidine is a useful drug for myelodysplastic syndromes and acute myeloid leukemia. In clinical trials, hematologic toxicity and infection have been observed as adverse events (AEs) of this drug. However, information on the time to onset of high risk AEs and subsequent outcomes, as well as differences in the frequency of AEs due to the route of administration is lacking. In this study, we investigated azacitidine-induced AEs comprehensively using the Japanese Adverse Event Reporting Database (JADER) published by the Pharmaceuticals and Medical Devices Agency, with disproportionate analysis of AE incidence trends, time to onset, and subsequent outcomes. In addition, we analyzed the differences in AEs by route of administration and the number of days until the occurrence of AEs and generated hypotheses. METHODS: The study used JADER data reported from April 2004 to June 2022. Risk estimation was conducted using reported odds ratio. A signal was detected when the lower limit of the 95% confidence interval of the calculated ROR was ≥1. RESULTS: A total of 34 signals were detected as AEs due to azacitidine. Among them, 15 were hematologic toxicities and 10 were infections, which demonstrated a particularly high rate of death. Signals of AEs such as tumor lysis syndrome (TLS) and cardiac failure, which have been described in case reports, were also detected, and the rate of death after onset was high. In addition, more AEs generally occurred within the first month of treatment. CONCLUSION: The results of this study suggest that more attention should be paid to cardiac failure, hematologic toxicity, infection, and TLS. Because many patients in clinical trials have discontinued treatment due to serious AEs before the therapeutic effect became apparent, appropriate supportive care, dose reduction, and drug withdrawal are important for the continuation of treatment.

Development of Real-world Data-based Medication Instruction Sheet for Acute Myeloid Leukemia Patients Receiving High-dose Cytarabine Consolidation Therapy.

BACKGROUND/AIM: For quick and accurate monitoring of potential adverse events (AEs) during concurrent chemotherapy, we had previously developed innovative medication instruction sheets (MIS) for a variety of chemotherapy regimens. However, it is still unclear whether these sheets correctly predict the type and time course of the onset and recovery of AEs. Therefore, we monitored AEs in patients with acute myeloid leukemia (AML) receiving high-dose cytarabine (HD-AraC) using the original MIS. PATIENTS AND METHODS: Patients who received HD-AraC following remission induction chemotherapy were included in this study. Data obtained from AE monitoring were evaluated, and the original MIS was modified as appropriate. RESULTS: Among 41 patients, a total of 203 AEs (139 non-hematological and 64 hematological) were observed after chemotherapy. By contrast, all but one patient (97.6%) experienced 102 AEs (43 non-hematological and 59 hematological) before chemotherapy. The AEs that appeared after chemotherapy were all predicted items described in the original MIS; however, their onset and duration were not consistent with the predicted data, in which the prediction accuracy was 69.1% for non-hematological AEs and 1.6% for hematological events. Based on these monitoring data, the original MIS was revised, which led to an increase in the prediction accuracy to 94.2% for nonhematological events and 100% for hematological events. CONCLUSION: Preexisting AEs should be considered when preparing MIS for consolidation therapy with HD-AraC. The modified MIS based on AE monitoring exhibited a sufficiently high prediction accuracy.

Ameliorating effects of cystine and theanine in a cancer cachexia mouse model.

Cachexia is a common cancer complication and is associated with weight loss and anorexia. In this study, we investigated the ameliorating effects of cystine and theanine on cancer cachexia using a mouse model. In mice carrying the colon cancer cell line C-26, there was a suppression of body weight increase and reduction in both internal fat and lower limb muscles. Repeated cystine and theanine administration significantly prevented weight loss, internal fat loss, lower limb muscle loss, and serum IL-6 increase in the cachexia model. These results suggested that cystine and theanine may be effective in ameliorating cancer cachexia.

Evaluation of lung adverse events with nivolumab using the spontaneous reporting system in Japan.

This study was conducted to examine times to onset, incidence rates, and outcomes of nivolumab-induced lung adverse events (AEs), using the Japanese Adverse Drug Event Report database. We analysed data for the period between April 2004 and March 2021. Data on lung AEs were extracted, and relative risks of AEs were estimated using the reporting odds ratio. We analysed 5,273,115 reports and found 18,721 reports of nivolumab-related AEs, including 3084 lung AEs. Signals were detected for nine lung AEs: interstitial lung disease; pneumonitis; lung disorder; organising pneumonia; pleural effusion; pneumonia aspiration; pneumonia bacterial; radiation pneumonitis; and infectious pleural effusion. Among these, interstitial lung disease was the most frequently reported (68.7%) and included some fatal cases. A histogram of median times to onset showed AEs occurring from 34 to 79 days after the first dose, but some cases occurred even more than one year after starting administration. In conclusion, we focused on lung AEs caused by nivolumab as post-marketing AEs. Some cases could potentially involve serious outcomes, particularly in interstitial lung disease. Patients should be monitored for signs of the development of these AEs not only at the start of administration, but also over an extended time.

Evaluation of Cardiac Adverse Events with Ponatinib Using a Spontaneous Reporting Database.

INTRODUCTION: The efficacy of ponatinib was demonstrated in patients resistant or intolerant to prior BCR-ABL tyrosine kinase inhibitors. However, cardiac adverse events (CAEs) have become a concern as a serious side effect of ponatinib administration. No reports have described the incidence of CAEs associated with ponatinib in Japanese patients. Thus, this study aimed to determine the risk of ponatinib-induced CAEs, time to onset, and post hoc outcomes using the Japanese Adverse Drug Event Report database. METHODS: We analyzed data for the period between April 2004 and March 2021. Data on CAEs were extracted, and relative risk of AEs was estimated using the reporting odds ratio. RESULTS: We analyzed 1,772,494 reports and identified 1,152 reports of AEs caused by ponatinib. Of these, 163 CAEs were reportedly associated with ponatinib. Signals were detected for thirteen CAEs: hypertension, cardiac failure, acute cardiac failure, atrial fibrillation, increased blood pressure, coronary artery stenosis, myocardial infarction, angina pectoris, pulmonary hypertension, prolonged QT on electrocardiography, cardiomyopathy, cardiac dysfunction, and acute myocardial infarction. Among these, hypertension was the most frequently reported AE (27.6%). A histogram of times to onset showed occurrence from 4.5 to 150.5 days. DISCUSSION/CONCLUSION: Hypertension, cardiac failure, coronary artery stenosis, and myocardial infarction could potentially result in serious outcomes and some cases occurred earlier or even more than 1 year after starting administration. Patients should be monitored for signs of the onset of these AEs not only at the start of ponatinib administration but also over the longer term.

Evaluation of the Time to Onset and Outcome of Lenalidomide-induced Thrombosis and Embolism Using Spontaneous Reporting Database.

BACKGROUND/AIM: Lenalidomide (LND) is an oral antineoplastic agent used in the treatment of various malignant hematologic diseases, including multiple myeloma. Major adverse events of LND include myelosuppression, pneumonia, and thromboembolism. Thromboembolism is an adverse drug reaction (ADR) associated with poor outcomes, therefore anticoagulants are administered prophylactically. However, LND-induced thromboembolism has not been clearly characterized from clinical trials. The purpose of this study was to evaluate the incidence, timing, and outcome details of thromboembolism caused by LND using the JADER (Japanese Adverse Drug Event Report) database. PATIENTS AND METHODS: ADRs due to LND reported from April 2004 to March 2021 were selected. Data on thromboembolic adverse events were analyzed and relative risks were estimated using reported odds ratios (RORs) and 95% confidence intervals (CIs). In addition, the time of onset and outcome of thromboembolism were analyzed. RESULTS: There were 11,681 adverse events attributed to LND. Of these, 306 were thromboembolisms. The most frequently reported thrombosis with the highest ROR was deep vein thrombosis (DVT) (165 cases, ROR=7.12, 95%CI=6.09-8.33). The median onset of DVT (quartiles, 25-75%) was 80 (28-155) days. The parameter value (ß) was 0.87 (0.76-0.99), suggesting the onset of DVT early in treatment. The prognosis of DVT due to LND was recovery and remission in 34% and 43% of patients, respectively, but 7.9% did not recover. CONCLUSION: DVT is the most frequent thromboembolism in LND, and early treatment is important.

Assessment of Time-to-onset and Outcome of Lung Adverse Events With Pomalidomide from a Pharmacovigilance Study.

BACKGROUND/AIM: Pomalidomide is an immunomodulatory drug that is used to treat multiple myeloma. We examined the time-to-onset and outcome of lung adverse events (LAEs) related to pomalidomide in Japanese patients based on information obtained from the spontaneous reporting system of the Japanese Adverse Drug Event Report database (JADER) of the Pharmaceuticals and Medical Devices Agency. PATIENTS AND METHODS: We analyzed adverse events (AEs) reports recorded between April 2004 and March 2021 from JADER. Data on LAEs were extracted, and the relative risk of AEs was estimated using the reporting odds ratio and 95% confidence interval. We analyzed 1,772,494 reports and identified 2,918 reports of AEs caused by pomalidomide. Of these, 253 LAEs were reportedly associated with pomalidomide. RESULTS: Signals were detected for five LAEs: pneumonia, pneumocystis jirovecii pneumonia, bronchitis, pneumonia bacterial, and pneumonia pneumococcal. Pneumonia was the most frequently mentioned condition (68.8%). The median time-to-onset of pneumonia was 66 days, but some cases of pneumonia occurred as late as 20 months after the start of administration. Fatal outcomes were observed in two of the five AEs wherein signals were detected and were due to pneumonia and bacterial pneumonia. CONCLUSION: Serious outcomes can occur after pomalidomide administration. It has been suggested that these LAEs occur relatively early after pomalidomide administration. Since some situations can result in fatal consequences, patients should be monitored for the emergence of these AEs over a prolonged period of time, especially for pneumonia.

Usefulness of a Medication Instruction Sheet for Patients Receiving Cytarabine and Idarubicin Induction Therapy for Acute Myeloid Leukemia.

BACKGROUND/AIM: To monitor adverse events rapidly and accurately during combination chemotherapy, we established an innovative medication instruction sheet (MIS) including cytarabine and idarubicin induction therapy. However, it is unclear whether this MIS allows for the accurate prediction of adverse events and their onset timing in a clinically significant manner. We therefore evaluated the clinical usefulness of our MIS for monitoring adverse events. PATIENTS AND METHODS: Patients who received cytarabine and idarubicin induction therapy for acute myeloid leukemia (AML) at the Department of Hematology, Kyushu University Hospital between January 2013 and February 2022 were included. The real-world clinical data were compared to the MIS to determine the accuracy of the MIS for predicting the onset and duration of adverse events in patients with AML during induction chemotherapy. RESULTS: Thirty-nine patients with AML were included in this study. Overall, 294 adverse events were noted, all of which were predicted items in the MIS. Among the 192 non-hematological adverse events, 131 (68.2%) occurred during a similar period as that listed in the MIS, whereas among the 102 hematological adverse events, 98 (96.1%) appeared earlier than expected. For the non-hematological events, the onset and duration of elevated aspartate aminotransferase levels and nausea/vomiting coincided well with those listed in the MIS, whereas the predictive accuracy for rashes was the lowest. CONCLUSION: Hematological toxicity was not predicted because of the bone marrow failure associated with AML. Our MIS was useful for rapidly monitoring non-hematological adverse events in patients with AML receiving cytarabine and idarubicin induction therapy.

Cardiac Adverse Events Associated with Multiple Myeloma Patients Treated with Proteasome Inhibitors.

BACKGROUND: Proteasome inhibitors (PIs) are standard treatments for multiple myeloma (MM). The risk of cardiac adverse events (CAEs) with PIs has been documented with bortezomib and carfilzomib; however, only a few studies have been reported on ixazomib. Furthermore, the effects of concomitant medications including dexamethasone and lenalidomide remain unclear. OBJECTIVES: This study aimed to determine the safety signals of adverse events related to CAEs, the effect of concomitant medications, the time to the occurrence of CAEs, and the incidence of fatal clinical outcomes after the occurrence of CAEs for three PIs using the US Pharmacovigilance database. METHODS: We examined 1,567,240 cases of 231 drugs registered as anticancer drugs in the US Food and Drug Administration Adverse Event Reporting System (FAERS) database from January 1997 to March 2021. We compared the odds of developing CAEs between patients who received PIs and those who received non-PI anticancer drugs. RESULTS: Bortezomib treatment resulted in significantly higher reporting odds ratios (RORs) for cardiac failure, cardiac failure congestive, and atrial fibrillation. Carfilzomib treatment resulted in significantly higher RORs for cardiac failure, congestive cardiac failure, atrial fibrillation, and QT prolonged. However, no adverse event CAE signals were observed with ixazomib treatment. A signal was detected for the safety of cardiac failure with bortezomib or carfilzomib, regardless of the presence or absence of concomitant medications. Safety signals for cardiac failure congestive with bortezomib and for cardiac failure congestive, atrial fibrillation, and QT prolonged with carfilzomib were observed only with dexamethasone combination therapy. Co-administration of lenalidomide and its derivatives did not affect the safety of bortezomib and carfilzomib. CONCLUSION: We identified CAE safety signals for bortezomib and carfilzomib exposure when compared with 231 other anticancer agents. The safety signal for developing cardiac failure for both the drugs did not differ between patients with and without concomitantly administered medications.

Evaluation of Cardiac Adverse Events with Nivolumab Using a Japanese Real-World Database.

BACKGROUND: Nivolumab has been used for the treatment of various types of cancers and has achieved improvements in overall survival. However, nivolumab can cause a variety of adverse events (AEs). Among these, cardiac-specific AEs have received little attention in clinical trials, despite their life-threatening potential. OBJECTIVE: The present study aimed to determine the risk of nivolumab-induced cardiac AEs, time to onset, incidence rates, and post hoc outcomes using the Japanese Adverse Drug Event Report database. METHODS: We analyzed data for the period between April 2004 and March 2021. Data on cardiac AEs were extracted and relative risk of AEs was estimated using the reporting odds ratio (ROR). RESULTS: We analyzed 1,772,494 reports and identified 18,721 reports of AEs caused by nivolumab. Of these, 409 reports involved cardiac AEs. Signals were detected for four cardiac AEs: myocarditis; pericardial effusion; pericarditis; and immune-mediated myocarditis. Among these, myocarditis was the most frequently reported (35.0%) and included fatal cases. A histogram of times to onset showed nivolumab-associated AEs occurring 41-127 days after starting administration, with outlier cases of myocarditis or pericardial effusion occurring after more than one year, both with catastrophic consequences. CONCLUSION: This study focused on cardiac AEs caused by nivolumab as post-marketing AEs. Myocarditis and pericardial effusion have been associated with some fatal cases after administration of nivolumab. Patients should be monitored for signs of onset for these AEs, not only at the start of administration, but also over an extended period after nivolumab administration.

Efficacy and safety of mycophenolate mofetil in treating immune-related hepatitis induced by immune checkpoint inhibitor use: A retrospective study.

Background and Aim: To investigate the outcomes in eight Japanese patients with cancer treated with mycophenolate mofetil (MMF) and corticosteroids for immune checkpoint inhibitor treatment-induced severe immune-related hepatitis (ir-hepatitis) and the efficacy and safety of MMF. Methods: We retrospectively examined patient background, treatment course, as well as examination and imaging data using electronic medical records. Results: The ratio of male to female patients was 7:1, and the median age was 60 years (27-72 years). There were five and two cases of kidney cancer and malignant melanoma, respectively, and one case of lung cancer. The median number of days until MMF administration in addition to systemic corticosteroid therapy after the onset of ir-hepatitis was 14.5 (2-42). The patients were categorized as four "good responders" who showed an improvement in the liver function tests following MMF treatment and four "poor responders" who did not. Furthermore, the time from the onset of ir-hepatitis to initial MMF administration was significantly shorter in good responders (median 3 days, range 2-15 days) than in poor responders (median 25.5 days, range 14-42 days) (P = 0.042). No significant intergroup difference was observed in other clinical factors. No serious adverse events caused by MMF were observed in any case. Conclusions: According to these findings, early recognition of corticosteroid refractoriness and the use of MMF may be beneficial in patients with ir-hepatitis.

The Influence of the Rapid Increase in the Number of Adverse Event Reports for COVID-19 Vaccine on the Disproportionality Analysis Using JADER.

BACKGROUND/AIM: The COVID-19 prophylactic vaccine for the prevention of coronavirus infection was approved in Japan on February 14, 2021. Adverse event reports for the vaccine were collected from the Japan Adverse Drug Event Relief (JADER) database, similar to those for drugs. Reported odds ratios (RORs) and proportional reporting ratios (PRRs) are commonly used in disproportionality analysis to detect safety signals. Therefore, adverse event reports from the vaccinated population may affect the detection of safety signals for the registered drugs. This study determined the impact of adverse event reports on the detection of safety signals for a COVID-19 prophylactic vaccine by analyzing the JADER database using disproportionality analysis. PATIENTS AND METHODS: We extracted data from the JADER dataset, in which the COVID-19 vaccine was reported as a suspected drug, and selected the top 10 adverse events in terms of the number of reports. We then extracted the top 30 drugs by the amount of information in the selected 10 adverse events and compared the changes in the number of signal detections with and without the COVID-19 vaccine report data. RESULTS: The total number of adverse events reported in the JADER database during the study period was 2,002,564. Of the total number of reports, 85,489 (4.3%) reported adverse events related to the COVID-19 vaccine. Of the top 30 drugs reported in the 10 selected adverse events, the ROR and PRR were found to be lower with the inclusion of COVID-19 vaccine data than without. Detection by ROR excluded 23 out of 245 drugs, and detection by PRR excluded 34 out of 204 drugs. CONCLUSION: The rapid increase in the number of adverse event reports for the COVID-19 vaccine in JADER may affect the detection of safety signals by disproportionality analysis.