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.

Relationship between Anaplastic Lymphoma Kinase Inhibitors and Epileptic Seizure Disorder: A Post-Marketing Surveillance Study.

INTRODUCTION: Anaplastic lymphoma kinase (ALK) has been to be involved in the uptake and regulation of dopamine 2 receptor (D2R), a G protein-coupled receptor expressed in various brain regions. Therefore, it is crucial to understand the relationship between ALK inhibitors and seizures is an important issue. This study investigated the relationship between ALK inhibitors and seizures. METHODS: This study investigated the relationship between ALK inhibitors and seizures through a disproportionality analysis using the US Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS). The target drugs were the ALK inhibitors crizotinib, ceritinib, alectinib, brigatinib, and lorlatinib. The seizures covered were defined high-level group term (HLGT): "Seizures (incl. subtype)" including high-level term (HLT): "seizures and seizure disorders NEC." This study used the information component (IC), a signal score, as a Bayesian statistical method for disproportionality analysis. The signal detection criteria used in this study were the same as those reported previously: a lower limit of 95% credible interval (CrI) for IC >0. RESULTS: The signal scores of '"seizures and seizure disorders not elsewhere classified (NEC)" "for each ALK inhibitor were crizotinib (IC: -0.00052, 95% CrI: -0.38-0.27), ceritinib (IC: 1.18, 95% CrI: 0.68-1.54), alectinib (IC: 0.68, 95% CrI: 0.19-1.02), brigatinib (IC: 1.04, 95% CrI: 0.32-1.54), and lorlatinib (IC: 0.82, 95% CrI: 0.11-1.32). On the other hand, "generalized tonic-clonic seizures," "partial simple seizures NEC," "absence seizures," and "partial complex seizures" had no or few reported cases, and no signal was detected. CONCLUSION: To our knowledge, this is the first report to evaluate the relationship between ALK inhibitors and seizures using post-marketing surveillance data. These results suggest that ceritinib, alectinib, brigatinib, and lorlatinib, which are highly brain-migrating drugs, are associated with seizures.

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.

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.

Medical Image Sharing in Japan.

This paper reports the history, background including politics, current status of Japan's health imaging study and other information sharing. Its realization was slow until the Ministry of Health, Labour and Welfare (MHLW) started paying digital image storage at the same rate as films in 2008. Information sharing was initiated in early 2010s, which was before vendors became ready for Integrating the Healthcare Enterprise (IHE) cross-enterprise document sharing (XDS), with the result that most of 34 large regional sharing systems are in non-standardized protocol. One standardized example is the Hamamatsu area where inexpensive online PDI (portable data for imaging) was introduced.

[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.

[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.

The utilization and challenges of Japan's MID-NET® medical information database network in postmarketing drug safety assessments: A summary of pilot pharmacoepidemiological studies.

PURPOSE: To examine the potential role of Medical Information Database Network (MID-NET® ), a newly established Japanese medical information database network, in postmarketing drug safety assessments through the characterization of its advantages and limitations in five pilot studies. METHODS: The pilot studies were designed to address three major objectives in postmarketing drug safety assessments, ie, the examination of actual drug utilization, the impact of safety-related regulatory actions, and drug-associated risks. The five studies were conducted on the following topics: (a) utilization of codeine-containing products and its relationship with respiratory depression, (b) impact of a Dear Healthcare Professional letter on hypocalcemia incidence associated with denosumab (Ranmark® ) use, (c) risk of acute myocardial infarction associated with antidiabetic drug use, (d) risk of glucose metabolism disorders associated with atypical antipsychotic drug use, and (e) prospective monitoring of abnormal laboratory test results during new drug prescriptions. RESULTS: The pilot studies were successfully conducted and demonstrated the value of MID-NET® in postmarketing drug safety assessments. In particular, the ability to utilize laboratory test results as objective clinical indicators is a major advantage of this database. Potential limitations include a relatively small sample size and a lack of patient-level data linkages among hospitals. CONCLUSIONS: MID-NET® was confirmed to be a valuable database for postmarketing drug safety assessments. The use of laboratory test results to define clinical outcomes may allow more objective and accurate analyses to be conducted. These studies furthered our understanding of the characteristics of MID-NET® , including its advantages and limitations.

Establishment of the MID-NET® medical information database network as a reliable and valuable database for drug safety assessments in Japan.

PURPOSE: To establish a new medical information database network (designated MID-NET® ) to provide real-world data for drug safety assessments in Japan. METHODS: This network was designed and developed by the Ministry of Health, Labour and Welfare and the Pharmaceuticals and Medical Devices Agency in collaboration with 23 hospitals from 10 healthcare organizations across Japan. MID-NET® is a distributed and closed network system that connects all collaborative organizations through a central data center. A wide variety of data are available for analyses, including clinical and administrative information. Several coding standards are used to standardize the data stored in MID-NET® to allow the integration of information originating from different hospitals. A rigorous and consistent quality management system was implemented to ensure that MID-NET® data are of high quality and meet Japanese regulatory standards (good post-marketing study practice and related guidelines). RESULTS: MID-NET® was successfully established as a reliable and valuable medical information database and was officially launched in April 2018. High data quality with almost 100% consistency was confirmed between original data in hospitals and the data stored in MID-NET® . A major advantage is that approximately 260 clinical laboratory test results are available for analysis. CONCLUSIONS: MID-NET® is expected to be a major data source for drug safety assessments in Japan. Experiences and best practices established in MID-NET® may provide a model for the future development of similar database networks.

The incidence and timing of leukocyte overshoot after pegfilgrastim administration.

INTRODUCTION: Pegfilgrastim is a PEGylated formulation of filgrastim with a long half-life. It is highly convenient and less burdensome for patients. However, white blood cell count may temporarily increase after administration; in particular, a leukocyte overshoot may be observed. The present study retrospectively examined the incidence and timing of leukocyte overshoot after pegfilgrastim administration. PATIENTS AND METHODS: Fifty-five patients (118 occasions of pegfilgrastim) were evaluated. Leukocyte overshoot was defined as white blood cell count ≥10,000/mm3 exceeding the reference value. RESULTS: Leukocyte overshoot was observed in 71.2% (84/118) occasions, in 76.4% (42/55) patients. The maximum white blood cell count ≥30,000/mm3 was observed in 30.5% (36/118) occasions in 45.5% (25/55) patients and was observed in 39.3% (33/84) occasions on day 1 after pegfilgrastim administration and 26.2% (22/84) on day 2. Leukocyte overshoot has been observed in only 23.1% (9/39) patients administered with normal granulocyte colony-stimulating factor. However, there were no patients with white blood cell counts ≥30,000/mm3. CONCLUSION: There was a higher frequency of occurrence of leukocyte overshoot in response to pegfilgrastim than in response to normal granulocyte colony-stimulating factor. High incidence of leukocyte overshoot was observed when blood was collected 1-2 days after administration of pegfilgrastim. It is important for patients to understand the characteristics of pegfilgrastim by conducting pharmaceutical guidance.

Identification of risk factors and development of detection algorithm for denosumab-induced hypocalcaemia.

WHAT IS KNOWN AND OBJECTIVE: This study used electronic medical records to identify risk factors and establish a detection algorithm for denosumab-induced hypocalcaemia. METHODS: We identified 201 patients with cancer who were initially prescribed denosumab. Hypocalcaemia was defined as an adjusted serum calcium level of ≤2.13 mmol/L. A diagnosis of denosumab-induced hypocalcaemia was confirmed by two physicians after reviewing patient medical records. We evaluated patient characteristics as potential screening factors. Moreover, a retrospective cohort study was conducted to identify risk factors for denosumab-induced hypocalcaemia. Odds ratios (ORs) were estimated using logistic regression analysis. RESULTS: We analysed 164 patients with a low risk of hypocalcaemia. Among these, 29 (17.7%) patients were suspected to have denosumab-induced hypocalcaemia. The times to onset of definitive hypocalcaemia were shorter among these patients than among patients with non-denosumab-induced hypocalcaemia. Based on receiver operating characteristic curve analysis, we used time to onset of hypocalcaemia of ≤90 days as a second screening factor. The positive predictive value of this factor was 87.5%. In the retrospective cohort study, a significant difference was observed among patients with serum alkaline phosphatase (ALP) levels of >5.95 µkat/L before initial prescription (P < 0.01). Patients with higher serum ALP levels had a 6.63 times higher risk of developing hypocalcaemia than those without increased serum ALP levels (OR: 6.63, 95% confidence interval [CI]: 1.79-29.31). The same results were observed in a sensitivity analysis using another database. WHAT IS NEW AND CONCLUSION: We developed a detection algorithm for denosumab-induced hypocalcaemia based on calcium levels and time to onset of hypocalcaemia. We also identified elevated ALP levels as a risk factor for hypocalcaemia. Clinicians should carefully monitor initial serum calcium levels and screen for signs of hypocalcaemia in patients receiving denosumab who demonstrate elevated serum ALP levels.

Evaluating the impact of regulatory action on denosumab-induced hypocalcaemia in Japan.

WHAT IS KNOWN AND OBJECTIVE: Since its introduction in April 2012, denosumab has been administered to approximately 7,300 patients as of August 2012, and 32 cases of serious hypocalcaemia after denosumab administration, including two deaths, have been reported in Japan. A Dear Healthcare Professional Letter of Rapid Safety Communication ('Blue letter') was released to warn about the risks of hypocalcaemia associated with denosumab. The goal of this study therefore was to measure the impact of regulatory action on denosumab-induced hypocalcaemia in Japan by using an electronic medical information database (MID). METHODS: We used two different aggregated data sets based on MIDs (data sets one and two). The patients studied were those who were newly prescribed denosumab or zoledronic acid between April 2012 and September 2014. We assessed four indicators: (a) the proportion of patients with calcium supplementation at the initial denosumab treatment, (b) the proportion of patients who underwent a serum calcium test, (c) the average number of serum calcium tests performed and (d) the prevalence of hypocalcaemia. All indices were aggregated by every 3 months. To evaluate the impact of regulatory action, we used difference in difference (DID) analysis. RESULTS AND DISCUSSION: The proportion of patients with calcium supplementation at the initial denosumab treatment increased year by year in both data sets. The average number of serum calcium tests increased year by year in data set two. There was a significant difference in the prevalence of hypocalcaemia in data set two. This suggests that the estimate of impact of the regulatory action may vary according to the database. In DID analysis, however, significant influences of the regulatory action on combination use with a calcium supplement were detected in both data sets. WHAT IS NEW AND CONCLUSION: There was a significant influence on combination use of denosumab with vitamin D and/or calcium supplement in both data sets. That there was no apparent increase in the prevalence of denosumab-induced hypocalcaemia, suggests that the regulatory action had an impact in the clinical setting studied. Such regulatory actions may play an important role in the promotion of drug safety.

Cost-effectiveness and safety of ramucirumab plus paclitaxel chemotherapy in the treatment of advanced and recurrent gastric cancer.

Introduction Weekly paclitaxel (PTX), irinotecan (CPT-11) and ramucirumab plus paclitaxel (Ram + PTX) are currently recommended as the standard second-line or later chemotherapies for advanced and recurrent gastric cancer. This study aims to compare the cost-effectiveness of using Ram + PTX vs. PTX or CPT-11. Furthermore, we investigated the safety and treatment continuity of Ram + PTX in Japan. Methods Expected costs were calculated based on data from patients with advanced and recurrent gastric cancer who were treated with PTX, CPT-11 and Ram + PTX. A literature review was performed to obtain clinical information so that the probability of the efficacy of each chemotherapy could be calculated. The cost-effectiveness ratio of each chemotherapy agent was calculated by dividing the expected cost by the median survival time (MST). Results The cost-effectiveness ratio per month was JPY 85,395.8/MST for the PTX regimen, JPY 132,735.4/MST for the CPT-11 regimen and JPY 657,175.4/MST for the Ram + PTX regimen (p < 0.001). The incremental cost-effectiveness ratio per month of the Ram + PTX regimen to the PTX regimen was JPY 2,780,432.4/MST. The incremental cost-effectiveness ratio of the Ram + PTX regimen to the CPT-11 regimen was JPY 2,185,179.0/MST. With regard to the reasons for discontinuation of treatment, the Ram + PTX regimen had only one case of being discontinued owing to adverse events, and had a profile similar to that of the PTX and CPT-11 regimens. Conclusion These findings show that the Ram + PTX regimen is less cost-effective compared to both the PTX and CPT-11 regimen, but the Ram + PTX regimen is a well-tolerated regimen with sufficient efficacy.

Evaluation of the role and usefulness of a pharmacist outpatient service for patients undergoing monotherapy with oral anti-cancer agents.

Introduction When rapid feedback to physicians must be provided, e.g. monitoring therapy with the oral anticoagulant warfarin or providing therapeutic support for patients undergoing cancer chemotherapy, the involvement of pharmacists is required for outpatients. We launched a pharmacist outpatient service for patients with cancer taking oral anti-cancer agents. We evaluated the role and usefulness of the pharmacist outpatient service for these patients undergoing oral monotherapy with anti-cancer agents. Methods Data regarding prescription recommendations were collected from the drug management guidance records of 154 patients who consulted the pharmacist outpatient service between July 2013 and September 2015. In addition, the rates of prescription recommendation adherence were calculated. Between April and August 2015, a self-reported questionnaire was administered to 47 patients undergoing therapy with oral anti-cancer agents who were visiting the pharmacist outpatient service at the Ogaki Municipal Hospital (Ogaki, Japan). Results Prescription recommendations were given to 235 cases. The total rate of adherence to the prescription recommendations was 94.9% (223/235 cases). The majority of prescription recommendations regarding supportive care were those for moisturizing agents (20.9%), analgesics (20.9%), steroid ointments (12.7%), and antihypertensive agents (10.8%). When continued guidance was provided, significant changes were observed for survey items 3 (knowing the side effects of the medication), 8 (worrying about side effects), and 12 (interest in prescribed medicine) ( p = 0.0049, p < 0.0001, and p = 0.0164, respectively). Conclusion Our study showed that continued pharmaceutical intervention resulted in a deeper understanding of the medications' side effects, and it reduced anxiety levels in patients undergoing monotherapy with oral anti-cancer agents.

[Medical Assistance Based on Interviews Conducted before Physician Examination by a Pharmacist for Outpatients with Thyroid Cancer Treated with Lenvatinib].

In municipal hospitals, there are few cases of thyroid cancer for which the multi-kinase inhibitor lenvatinib is used. Moreover, there are very few reports of lenvatinib use. We examined interventions related to the use of lenvatinib made at the pharmaceutical outpatient clinic in our facility. Seven patients received lenvatinib. The prescription proposals from the pharmacist( 45 cases)provided advice on dosage(15.6%), discontinuation of medication(11.1%), supportive care(64.4%), and other advice(9.0%). The prescription acceptance rate was 84.4%. Among the prescription proposals of supportive care, there were suggestions regarding blood pressure(26.7%), diarrhea(8.9%), nausea(8.9%), and oral hemorrhage(6.7%). Some patients also experienced side effects, such as abnormalities in equilibrioception and visual field defects; however, the relationship between such abnormalities and lenvatinib is unclear. In addition, we asked physicians to confirm if the outpatient pharmacists contributed to the examination process. We believe that lenvatinib administration can be continued safely with pharmaceutical outpatient clinic support for patients, even in municipal hospitals.

Prognosis of severe carpal tunnel syndrome with absent compound muscle action potential.

INTRODUCTION: Opponensplasty is a surgical option for patients with severe carpal tunnel syndrome (CTS). We investigated prognostic factors of patients who lack a preoperative compound muscle action potential (CMAP) of the abductor pollicis brevis (APB) muscle to determine the necessity for single-stage opponensplasty. METHODS: We retrospectively enrolled 22 hands of 22 CTS patients. Prognostic factors considered were age, diabetes mellitus, the median sensory nerve action potential, distal motor latency of the second lumbrical (2L) CMAP (2L-DML), and its amplitude (2L-Amp). Postoperative APB-CMAP amplitude (post APB-Amp) at 12 months was used as the outcome measure. RESULTS: Only 2L-DML showed a significant correlation with post APB-Amp (r = -0.56). The contribution of 2L-Amp was not significant, although 3 hands with absent 2L-CMAP had a poor electrophysiological recovery. CONCLUSIONS: Prolonged 2L-DML and absent 2L-CMAP seem to be poor prognostic factors. Concurrent opponensplasty may not be necessary in patients with 2L-DML of 8 ms or less. Muscle Nerve 54: 427-431, 2016.

[Economic Loss of Remaining Contents in Molecular Target Drug Preparation and the Simulation for Cost Saving].

While preparing an anticancer drug, even if it is an expensive molecular target drug, the remainder is not divided and saved for use in other patients; instead, it is discarded, resulting in waste of medical resources. In this study, we examined the economic loss in terms of medical costs by calculating the discarded amounts of 12 commonly used molecular target drugs at Ogaki Municipal Hospital, Japan between January 2012 and December 2014. We found, on average, that drugs valued at ¥ 52,593,182 were discarded annually. In particular, the discarded amounts of relatively expensive drugs, such as bevacizumab, bortezomib, and rituximab, were valued at ¥ 16,646,300, ¥ 15,866,289, and ¥ 8,401,324, respectively. Among these, the average amount of waste per administration of bortezomib was particularly expensive, at a cost of ¥ 67,325. Bortezomib is a commonly used treatment, resulting in excessive cumulative discarded cost. In an effort to save cost, we should consider using small capacity standard injections. Development of a simulation that used the remaining drug contents from only 1 day showed that bevacizumab alone accounts for an average cost saving of ¥1 2,542,191(75.3%) per year. This study suggests that effectively utilizing the remaining drug contents would ensure efficient use of medical resources, thereby reducing economic losses.

Prescription sequence symmetry analysis: assessing risk, temporality, and consistency for adverse drug reactions across datasets in five countries.

BACKGROUND: Prescription sequence symmetry analysis (PSSA) is a signal detection method for adverse drug events. Its capacity to consistently detect adverse drug events across different settings has not been tested. We aimed to determine the consistency of PSSA results for detecting positive and negative control adverse drug events across different settings. METHODS: Using a distributed network model, we analyzed prescription dispensing data using PSSA in Australia, Hong Kong, Japan, Korea, and Taiwan. Positive control was amiodarone and thyroxine, as a marker of amiodarone-induced hypothyroidism, a known adverse event with a clear temporal relationship to amiodarone initiation. Negative controls were amiodarone and allopurinol, as a marker of amiodarone-induced gout and thyroxine and allopurinol, as a marker of thyroxine-induced gout. Gout is not recorded as an adverse event in product information for either medicine. Adjusted sequence ratios (ASR) were calculated for each country. Pooled estimates were obtained by using the generic inverse variance method. RESULTS: A positive association was identified between amiodarone and thyroxine in all settings with a pooled ASR 2.63 (95% confidence interval (CI) 1.47-4.72). Temporal analysis showed the effect occurred within the first few weeks of treatment. No significant associations were found for the negative controls in any setting; pooled ASR were 0.76 (95%CI 0.62-0.93) and 0.98 (95%CI 0.85-1.12) for amiodarone-allopurinol and thyroxine-allopurinol, respectively. CONCLUSION: Despite different health settings, different populations, and different patterns of medicine utilization, PSSA gave consistent estimates across countries for a well-known positive association and two negative control adverse events.

Health checkup and telemedical intervention program for preventive medicine in developing countries: verification study.

BACKGROUND: The prevalence of non-communicable diseases is increasing throughout the world, including developing countries. OBJECTIVE: The intent was to conduct a study of a preventive medical service in a developing country, combining eHealth checkups and teleconsultation as well as assess stratification rules and the short-term effects of intervention. METHODS: We developed an eHealth system that comprises a set of sensor devices in an attaché case, a data transmission system linked to a mobile network, and a data management application. We provided eHealth checkups for the populations of five villages and the employees of five factories/offices in Bangladesh. Individual health condition was automatically categorized into four grades based on international diagnostic standards: green (healthy), yellow (caution), orange (affected), and red (emergent). We provided teleconsultation for orange- and red-grade subjects and we provided teleprescription for these subjects as required. RESULTS: The first checkup was provided to 16,741 subjects. After one year, 2361 subjects participated in the second checkup and the systolic blood pressure of these subjects was significantly decreased from an average of 121 mmHg to an average of 116 mmHg (P<.001). Based on these results, we propose a cost-effective method using a machine learning technique (random forest method) using the medical interview, subject profiles, and checkup results as predictor to avoid costly measurements of blood sugar, to ensure sustainability of the program in developing countries. CONCLUSIONS: The results of this study demonstrate the benefits of an eHealth checkup and teleconsultation program as an effective health care system in developing countries.

A detection algorithm for drug-induced liver injury in medical information databases using the Japanese diagnostic scale and its comparison with the Council for International Organizations of Medical Sciences/the Roussel Uclaf Causality Assessment Method scale.

PURPOSE: Drug-induced liver injury (DILI) is one of the primary targets for pharmacovigilance using medical information databases (MIDs). Because of diagnostic complexity, a standardized method for identifying DILI using MIDs has not yet been established. We applied the Digestive Disease Week Japan 2004 (DDW-J) scale, a Japanese clinical diagnostic criteria for DILI, to a DILI detection algorithm, and compared it with the Council for International Organizations of Medical Sciences/the Roussel Uclaf Causality Assessment Method (CIOMS/RUCAM) scale to confirm its consistency. Characteristics of DILI cases identified by the DDW-J algorithm were examined in two Japanese MIDs. METHODS: Using an MID from the Hamamatsu University Hospital, we constructed a DILI detection algorithm on the basis of the DDW-J scale. We then compared the findings between the DDW-J and CIOMS/RUCAM scales. We examined the characteristics of DILI after antibiotic treatment in the Hamamatsu population and a second population that included data from 124 hospitals, which was derived from an MID from the Medical Data Vision Co., Ltd. We performed a multivariate logistic regression analysis to assess the possible DILI risk factors. RESULTS: The concordance rate was 79.4% between DILI patients identified by the DDW-J and CIOMS/RUCAM; the Spearman rank correlation coefficient was 0.952 (P < 0.0001). Men showed a significantly higher risk for DILI after antibiotic treatments in both MID populations. CONCLUSIONS: The DDW-J and CIOMS/RUCAM algorithms were equivalent for identifying the DILI cases, confirming the utility of our DILI detection method using MIDs. This study provides evidence supporting the use of MID analyses to improve pharmacovigilance.