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Background: Atypical antipsychotic medications have often been used in the treatment of behavioral and psychological symptoms of dementia (BPSD). Recently, the US Food and Drug Administration (FDA) issued new safety information concerning atypical antipsychotic drugs, indicating that their use may increase the risk of cardiovascular adverse events among elderly adults with BPSD. Based on this information, the Japanese Ministry of Health, Labor and Welfare issued a similar warning against the use of atypical antipsychotic drugs licensed in Japan. We then sought to determine whether or not the use of typical antipsychotics should be recommended to replace atypical antipsychotics. In this paper, we discuss the influence of these warnings on the withholding of use of risperidone exemplified in seven case histories. Methods: Seven inpatients who exhibited BPSD received risperidone monotherapy in our hospital. In response to the FDA notice, the atypical antipsychotics used to treat these patients were replaced with typical antipsychotic agents. Results: During the period of risperidone administration, all patients exhibited clinical improvement compared with their baseline results and showed no adverse events. Two of our seven patients developed psychotic exacerbation and exhibited extrapyramidal symptoms coinciding with the replacement of risperidone with conventional antipsychotics. Conclusion: To the best of our knowledge, this is the first clinical report on the influence of the FDA alert on the use of atypical antipsychotics for psychotic symptoms in older patients with dementia in Japan. In two of our seven BPSD cases, there was no benefit from taking conventional antipsychotics. Our results lead to the conclusion that the use of typical antipsychotics should not be recommended to replace atypical antipsychotics. Although close attention should be paid to the FDA alert, clinicians must take into consideration the balance of benefits and risks when evaluating the appropriate use of antipsychotics in older patients with dementia. [ABSTRACT FROM AUTHOR]

Older patients are prone to multimorbidity or related polypharmacy, which may cause various adverse drug reactions (ADRs) and a high incidence of drug‐related health problems. Although not often noted, ADRs include nutrition‐related adverse reactions. Aging, multiple illnesses, mental and psychological problems, declining physical function, and environmental factors can lead to decreased food intake and increased metabolic stress in older people, resulting in energy imbalances that cause malnutrition. ADRs can lead to appetite loss, followed by decreased food intake, which in turn causes malnutrition and deficiencies of various nutrients. However, these nutrition‐related ADRs have received less attention. This review article describes drug–nutrition interactions, with a particular focus on older patients. Geriatr Gerontol Int 2023; 23: 465–477. Pharmacotherapy is a very important means of disease prevention and treatment for older patients. However, adverse drug reactions can have a significant negative impact on the health of older people. In this paper, the impact of drug therapy on nutritional status, dietary intake, the absorption and excretion of nutrients, and metabolism, with a focus on older people, is reviewed. [ABSTRACT FROM AUTHOR]

Objective: In a previous paper, we described the major health tragedy that occurred in Japan involving the use of gefitinib, and recommended steps to prevent such problems occurring again. In that paper, we argued that erlotinib should only be approved on the condition that all users are subject to surveillance. Erlotinib was subsequently approved for use in Japan on October 19, 2007. In the present paper, we examine whether our recommendations have been implemented in the safety measures established for erlotinib use. Methods: We comprehensively reviewed reports regarding erlotinib treatment published between 2007 and 2009 by regulatory agencies and the manufacturer of the erlotinib-containing drug. We evaluated the safety measures established for erlotinib in view of three problems we identified with the treatment of gefitinib marketing: (1) the results of animal experiments and pre-marketing clinical trials, and reports of adverse drug reactions from other countries were not properly incorporated into the product information; (2) indications for the drug were expanded without strict evaluation of the external validity of pre-marketing clinical trials; and (3) despite many serious cases of interstitial lung disease being spontaneously reported, well-designed post-marketing surveillance was not conducted immediately after these problems became evident. Results: We found that appropriate measures were taken for erlotinib in relation to each of the three above-mentioned problems. We found that there were fewer fatal adverse reactions to erlotinib after marketing relative to the pre-marketing period. Conclusions: Our recommendations following the health tragedy caused by gefitinib were implemented in the safety measures for erlotinib, which probably explains the smaller number of fatal adverse reactions to erlotinib in post-marketing surveillance than in pre-marketing trials. [ABSTRACT FROM AUTHOR]

The projected introduction of conditional automated driving systems to the market has sparked multifaceted research on human–machine interfaces (HMIs) for such systems. By moderating the roles of the human driver and the driving automation system, the HMI is indispensable in avoiding side effects of automation such as mode confusion, misuse, and disuse. In addition to safety aspects, the usability of HMIs plays a vital role in improving the trust and acceptance of the automated driving system. This paper aggregates common research methods and findings based on an extensive literature review. Empirical studies, frameworks, and review articles are included. Findings and conclusions are presented with a focus on study characteristics such as test cases, dependent variables, testing environments, or participant samples. These methods and findings are discussed critically, taking into consideration requirements for usability assessments of HMIs in the context of conditional automated driving. The paper concludes with a derivation of recommended study characteristics framing best practice advice for the design of experiments. The advised selection of scenarios and metrics will be applied in a future validation study series comprising a driving simulator experiment and three real driving experiments on test tracks in Germany, the USA, and Japan. [ABSTRACT FROM AUTHOR]

Patient profiles suitable for long-term lenvatinib treatment for unresectable hepatocellular carcinoma (uHCC) are yet to be fully understood. This post-hoc analysis aimed to identify such patient characteristics and explore the impact of treatment duration and relative dose intensity (RDI) on treatment outcomes. The data were obtained from 703 patients in a multicenter, prospective cohort study in Japan. Lenvatinib-naïve patients with uHCC were enrolled between July 2018 and January 2019 and were followed up for 12 months. Moreover, patients were dichotomized using the median treatment duration into the longer- (≥177 days; n = 352) or shorter-treatment (<177 days; n = 351) groups. The longer-treatment group often had better performance status, lower Child-Pugh score and better modified albumin-bilirubin grade than the shorter treatment group (p<0.05 for all). The objective response rate (47.6% vs. 28.2%; p<0.001) and disease control rate (92.4% vs. 60.2%; p<0.001) were both significantly higher in the longer-treatment groups than in the shorter-treatment groups. The proportion of patients with any adverse drug reactions was generally similar between the two treatment groups. Within the longer-treatment group, the disease control rate was high regardless of dose modification (i.e., RDI <100% vs. ≥100% during the initial 177 days) (91.2% vs. 98.0%). In conclusion, patients with longer treatment tended to have better overall conditions. Lenvatinib dose modifications at the physician's discretion, considering the balance between effectiveness and safety, may contribute to the long-term treatment. [ABSTRACT FROM AUTHOR]

Simple Summary: The efficacy of abiraterone plus prednisolone (ABI) against nonmetastatic castration-resistant prostate cancer (CRPC) remains unclear. To evaluate enzalutamide and ABI as the first-line treatment for CRPC, we conducted the randomized controlled trial including both metastatic and nonmetastatic CRPC. As a sub-analysis, we focused on nonmetastatic CRPC in this study. ABI and enzalutamide had similar efficacy and safety profiles in patients with nonmetastatic CRPC. Enzalutamide (ENZ) and abiraterone plus prednisolone (ABI) can improve the survival of patients with castration-resistant prostate cancer (CRPC). However, the agent that is more effective against nonmetastatic CRPC remains unclear. To evaluate the agent that can be used as the first-line treatment for CRPC, an investigator-initiated, multicenter, randomized controlled trial (ENABLE Study for PCa) including both metastatic and nonmetastatic CRPC was conducted in Japan. The prostate-specific antigen (PSA) response rate, overall survival, some essential survival endpoints, and safety of patients with nonmetastatic CRPC were also analyzed. In this subanalysis, 15 and 26 patients in the ENZ and ABI arms, respectively, presented with nonmetastatic CRPC. There was no significant difference in terms of the PSA response rate between the ENZ and ABI arms (80% and 64%, respectively; p = 0.3048). The overall survival did not significantly differ between the two arms (HR: 0.68; 95% CI: 0.22–2.14, p = 0.5260). No significant differences were observed in terms of radiographic progression-free survival and cancer-specific survival between the ENZ and ABI arms (HR: 0.81; 95% CI: 0.35–1.84; p = 0.6056 and HR: 0.72; 95% CI: 0.19–2.73; p = 0.6443, respectively). Only four and six patients in the ENZ and ABI arms, respectively, had ≥grade 3 adverse events. ABI and ENZ had similar efficacy and safety profiles in patients with nonmetastatic CRPC. [ABSTRACT FROM AUTHOR]

Background: Naldemedine is a peripherally acting μ-opioid receptor antagonist that is indicated to treat opioid-induced constipation. Objectives: To assess the potential for drug-drug interactions between a single oral dose of naldemedine and the oral P-glycoprotein inhibitor cyclosporine, cytochrome P450 (CYP) 3A inhibitors itraconazole and fluconazole, and CYP3A inducer rifampin. Methods: Three Phase 1, open-label studies were conducted in healthy subjects. In the P-glycoprotein inhibitor study, subjects received naldemedine 0.4 mg alone or coadministered with cyclosporine 600 mg. In the CYP3A inhibitors study, subjects in separate cohorts received naldemedine 0.2 mg alone or with itraconazole or fluconazole. In the CYP3A inducer study, subjects received naldemedine 0.2 mg alone or with rifampin 600 mg. Geometric mean ratios and 90 % confidence intervals were used to evaluate the effects of coadministered drugs on naldemedine maximum plasma concentration (Cmax) and the area under the concentration-time curve (AUC). Safety assessments included occurrence of adverse events (AEs), laboratory parameters, vital signs, and electrocardiography results. Results: A total of 56 subjects were enrolled (n = 14 in each cohort). Cyclosporine increased naldemedine AUC0–inf 1.78-fold and Cmax 1.45-fold. Itraconazole and fluconazole increased naldemedine AUC0–inf 2.91-fold and 1.90-fold, and Cmax 1.12-fold and 1.38-fold, respectively. Rifampin decreased naldemedine AUC0–inf by 83% and Cmax by 38%. Across studies, AEs were generally mild. Laboratory, vital sign, or electrocardiogram assessments produced no clinically significant findings. Conclusions: Coadministration of naldemedine with a P-glycoprotein inhibitor or a strong/moderate CYP3A inhibitor increases naldemedine exposure; coadministration with a strong CYP3A inducer decreases its exposure. Coadministration of naldemedine with cyclosporine, itraconazole, fluconazole, or rifampin was generally safe and well tolerated. Plain Language Summary: Naldemedine is a targeted medication approved in the USA, Europe, and Japan for the treatment of opioid-induced constipation. Symptoms of constipation may include passing fewer stools than usual, having lumpy or hard stools, and/or straining to have bowel movements. In some cases, these symptoms are side effects of regular opioid use, which is often medically necessary for the management of moderate-to-severe pain. For naldemedine to be prescribed safely, doctors must know what other medications a patient is taking and how these medications may affect one another. This is commonly known as drug-drug interactions. Some drug-drug interactions may decrease how well a medication works, while other drug-drug interactions may increase the side effects experienced by a patient. In this paper, researchers report the results of three Phase 1 studies in healthy subjects examining how naldemedine interacts with other drugs. The drugs chosen for investigation are commonly evaluated in DDI studies and may affect the transport or metabolic pathway of naldemedine, including the P-glycoprotein inhibitor cyclosporine, the CYP3A inhibitors itraconazole and fluconazole, and the CYP3A inducer rifampin. These studies demonstrate that co-administration of naldemedine with each of these drugs impacted the pharmacokinetics of naldemedine. Cyclosporine, itraconazole, or fluconazole all increased naldemedine exposure, while rifampin decreased naldemedine exposure. For all drug combinations, observed side effects were generally mild and well tolerated. Additional testing, including vital signs and heart monitoring, did not reveal any other safety concerns. In conclusion, these findings support the cautious use of naldemedine in combination with cyclosporine, itraconazole or fluconazole. Concomitant use with rifampin should be avoided. [ABSTRACT FROM AUTHOR]

Introduction: Idarucizumab, a monoclonal antibody fragment that rapidly reverses the anticoagulant effects of dabigatran, was approved in Japan in September 2016, at which time an all-case, postmarketing surveillance (PMS) study was initiated to collect data on idarucizumab in Japanese patients. Interim results were published previously, and the final results are reported herein. Methods: This multicenter, open-label, uncontrolled, non-interventional PMS study was conducted in Japanese patients who received idarucizumab at the approved dose (2 × 2.5 g/50 ml) and had uncontrolled bleeding (group A) or required an emergency procedure (group B). The primary endpoint was the frequency of adverse drug reactions (ADRs). The secondary endpoint was the maximum extent of reversal of the anticoagulant effects of dabigatran, within 4 h of idarucizumab administration, based on activated partial thromboplastin time (aPTT). Results: The final analysis included 804 patients. ADRs during the idarucizumab treatment and post-treatment periods were reported in 17 of 542 patients (3.1%) in group A and 12 of 240 patients (5.0%) in group B. Thrombotic events were reported in 22 patients (4.1%) in group A and 15 patients (6.3%) in group B, and hypersensitivity occurred in four (0.7%) and five patients (2.1%), respectively. Among 793 patients evaluated for effectiveness, 78 in group A and 26 in group B had aPTT data at baseline (immediately before idarucizumab administration) and within 4 h of idarucizumab administration; in these patients, median maximum percentage reversal within 4 h of idarucizumab administration was 100%. Conclusions: The final analysis from the PMS study confirms previous findings suggesting that idarucizumab can safely and effectively reverse the anticoagulant effects of dabigatran in Japanese patients in clinical practice. The results support the continued use of idarucizumab in Japan. Trial Registration: This study is registered with ClinicalTrials.gov (NCT02946931). Plain Language Summary: Atrial fibrillation is an irregular heart rhythm (arrhythmia), and the type of atrial fibrillation not caused by a heart valve problem is known as "non-valvular atrial fibrillation" or NVAF. People with NVAF have an increased risk of ischemic stroke, in which a blood clot (thrombus) blocks an artery in the brain. Drugs that inhibit blood clots, known as anticoagulants, are prescribed to people with NVAF to prevent ischemic stroke. Historically, warfarin has been one of the most prescribed anticoagulant drugs. However, a novel anticoagulant drug, known as dabigatran, has clinical advantages over warfarin and is approved in many countries for people with NVAF. People who take anticoagulants may experience life-threatening bleeding or need urgent surgery, and thus rapid and effective reversal of the anticoagulant effects is critical. The drug idarucizumab specifically binds to dabigatran to reverse its anticoagulant effects in people with uncontrolled bleeding or who require an urgent procedure. Idarucizumab was approved for use in Japan in September 2016. In Japan, drug companies are obligated to collect data after a new drug is launched as an approval condition, which is done through a postmarketing surveillance study. Here, we report the final results of a postmarketing surveillance study conducted between September 2016 and November 2020 to evaluate the safety and effectiveness of idarucizumab in Japanese patients receiving dabigatran. The results of our study show that idarucizumab can safely and effectively reverse the anticoagulant effects of dabigatran in Japanese patients, and support the continued use of idarucizumab in Japan in clinical practice. [ABSTRACT FROM AUTHOR]

Chronic kidney disease-associated pruritus (CKD-aP) is very common and sometimes refractory to treatment in hemodialysis patients. In a trial conducted in Japan, nalfurafine, effectively reduced itching of treatment-resistant CKD-aP. Our present bridging study aimed to evaluate the efficacy and safety of nalfurafine in Chinese cohort with refractory CKD-aP. In this phase III, multicenter bridging study conducted at 22 sites in China, 141 Chinese cases with refractory CKD-aP were randomly (2:2:1) assigned to receive 5 μg, 2.5 μg of nalfurafine or a placebo orally for 14 days in a double-blind manner. The primary end point was the mean decrease in the mean visual analogue scale (VAS) from baseline. A total of 141 patients were included. The primary endpoint analysis based on full analysis set (FAS), the difference of mean VAS decrease between 5 μg nalfurafine and placebo group was 11.37 mm (p =.041); the difference of mean VAS decrease between 2.5 μg and placebo group was 8.81 mm (p =.110). Both differences were greater than 4.13 mm, which met its predefined success criterion of at least 50% efficacy of the key Japanese clinical trial. The per protocol set (PPS) analysis got similar results. The incidence of adverse drug reactions (ADRs) was 49.1% in 5μg, 38.6% in 2.5 μg and 33.3% in placebo group. The most common ADR was insomnia, seen in 21 of the 114 nalfurafine patients. Oral nalfurafine effectively reduced itching with few significant ADRs in Chinese hemodialysis patients with refractory pruritus. [ABSTRACT FROM AUTHOR]

In April 2009, Japan Council for Quality Health Care (JCQHC) launched the Project to Collect Incidents within Community Pharmacies, a national project of self-and-voluntary reporting of incidents among community pharmacies. While there have been several studies and projects to collect and analyze incident reports among a set number of community pharmacies across the globe, it is still rare for an incident collecting project to exist at a national level. This paper introduces the new project in Japan. A retrospective analysis of community pharmacy participation across the country and cause of reported incidents based on the data released by JCQHC. Among the total number of reported incidents (1,460 cases), the most frequently reported incidents were related to the task of filling out prescriptions (92.0%). The most frequently answered cause of the incident was due to a "failure to check thoroughly" with 1,293 (96.3) out of 1,343 reported cases of incidents from community pharmacies. In a comparison of incidents reported between hospital pharmacies and community hospitals, both types of pharmacies reported a "failure to check thoroughly" as the leading cause of incidents. In hospital pharmacies, however, only 3,265 (84.7%) cases out of 3,857 were reported with "failure to check thoroughly" as the cause of incident. The rates between hospital pharmacy and community pharmacy for this cause differed significantly (P < 0.05). As the main cause of incidents was due to "the failure to check thoroughly", the need for confirmation systems within community pharmacies has become ever more evident. [ABSTRACT FROM AUTHOR]

In this paper, we present the third part of our ethnographic investigation including HIV-positive Latin Americans living in Japan. In order to investigate the relationship between psychological well-being and sexual activity among our informants, we interviewed 20 male HIV-positive Latin Americans living in Japan. From April to September, 2002 and August 2003, and 2004, we conducted a set of six 60-minute interviews with twenty 28- to 37-year-old HIV-positive males. Three of them were illegal aliens and seven of them claimed to be homosexual. Participants were contacted through a hospital, a NGO, (non-governmental organization) and by snowball sampling. Our analysis of the interviews indicates that concurrent with a negative attitude towards life informants feel disembodied and asexual after seroconversion. However, after resuming their sex life they experience a positive attitudinal change and emotional release. Drug side-effects on libido make them use stimulants and Viagra. Phallocentrism, fears of infection, and discrimination are obstacles to a full sex life. Informants look for casual sex and engage in prostitution in big cities. These findings have several implications for sex education practice. [ABSTRACT FROM AUTHOR]

Pharmacovigilance science has traditionally been a discipline focussed on the postmarketing or post-authorisation period, with due attention directed towards pre-clinical safety data, clinical trials and adverse events. As the biological sciences have evolved, pharmacovigilance has slowly shifted toward earlier, proactive consideration of risks and potential benefits of drugs in the pre- and peri-approval stages of drug development, leading to a maturing of drug safety risk management. Further advances in biology, pharmacology and improvements in computational applications to medicine have led to the development of more complex medicines previously unobtainable and have also permitted a more thorough assessment of risks and potential benefits even earlier in the development process. Elevated public concern with the safety of more sophisticated medicines, combined with new science, have led pharmaceutical innovators, regulators and healthcare professionals to collaborate to develop guidelines, which drive enhanced pharmacovigilance and safety risk management earlier in drug development.In this paper, we review international guidelines on pharmacovigilance planning applicable to the pre-approval phases of medicines development and provide author opinion on these guidelines’ potential drug safety implications. We discuss the possible evolution of a pharmaceutical industry model to respond to these guidelines; a view on multidisciplinary safety management teams is provided to encourage refinement of safety-signal identification and risk assessment early in drug development and to communicate important safety concerns to internal research efforts, patients, investigators and regulators. We further describe these functions in the context of the complexities of vulnerable populations, including the example of medicines research for paediatric populations. We also discuss the special role of epidemiology in pre-approval drug development and the impact on epidemiological science of changes to the pharmacovigilance paradigm. [ABSTRACT FROM AUTHOR]

Introduction: This study documents imprecision in Japanese reports of adverse events following immunization (AEFI). In doing so, it presents methods to analyze this imprecision. Methods: These methods include use of unique Japanese data on the validity of certain AEFIs. They also include ways to estimate AEFI rates, which allow comparison of AEFI data between countries. Using US AEFI data for comparison, we show how differences in AEFI reporting systems likely influence AEFI statistics. Results: Although our comparisons of AEFI rates are not precise, many of the difference we detected between Japanese and US statistics make sense and reflect differences in the societal and medical perspectives on various vaccines or can be explained by differences in the reporting systems including reporting sources. For example, differences in societal and medical perspective probably underly the extraordinarily high Japanese rates of anaphylaxis and other AEs following HPV immunizations from 2010 to 2016 compared to US rates and to Japanese rates for other vaccines. High US rates of reported Guillain–Barré syndrome following influenza vaccination relative to Japanese rates and to rates for other US vaccines are consistent with data suggesting that the index of suspicion for such reactions could affect AEFI rates. The findings that over half of Japanese anaphylaxis reports for every vaccine are erroneous, and that close to half of "serious" Japanese AEFI cases probably are not serious may be due in part not only to explanations unique to Japan, but also to factors that apply to the USA and other countries. Differences in reporting systems account for a much higher rate of non-serious AEFI reports in the USA compared to Japan. Japanese marketing authorization holders are probably at least as assiduous and timely in their reporting of AEFIs as health care providers, though granular level differences are apparent in reporting by various sources. Conclusion: The methods we used to analyze the validity of Japanese statistics can be used to analyze the validity of AEFI reports from other countries and aid the harmonization of adverse event reporting systems. Eventually, similar reporting systems might be adapted for drugs and medical devices. [ABSTRACT FROM AUTHOR]

The current study aimed to identify the crude drugs associated with drug-induced liver injury (DILI) in 148 Kampo medicines prescribed throughout Japan using the Japanese Adverse Drug Event Report (JADER) database, a large-scale spontaneous reporting system in Japan. First, we tabulated the number of DILI reports from the report-based dataset and the background information from the patient-based dataset. Thereafter, we combined the 126 crude drugs into 104 crude drug groups to examine multicollinearity. Finally, the reporting odds ratios (RORs), 95% confidence intervals, p values for Fisher's exact test, and number of reports were calculated for each crude group to identify those associated with DILI. Notably, the number of adverse event reports for DILI (63,955) exceeded that for interstitial lung disease (51,347), the most common adverse event. In total, 78 crude drug groups (90 crude drugs) were reported to have an ROR > 1, a p < 0.05, and ≥10 reported cases. Our results highlight DILI as an essential issue, given that it was among the most frequently reported adverse drug reactions. We were able to clearly identify the crude drugs associated with DILI, which could help manage adverse drug reactions attributed to Kampo medicines and crude drugs. [ABSTRACT FROM AUTHOR]

Introduction: Molnupiravir is an oral antiviral drug that received special approval for emergency use in Japan on December 24 2021 for infectious disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). This post-marketing surveillance (PMS) is underway to investigate the safety and effectiveness of molnupiravir in daily clinical practice in Japan. The interim PMS data collected from December 27 2021 to June 15 2022 are reported in this publication. Methods: This survey included adult Japanese patients treated with molnupiravir. For safety, adverse drug reactions (ADR) were assessed by physicians. Effectiveness was assessed by the composite endpoint of (1) hospitalization or (2) death in outpatients and by the composite endpoint of (3) death or (4) initiation of oxygen administration/mechanical ventilation in inpatients hospitalized for any reasons and without oxygen administration at the start of molnupiravir administration. The observation period was through 29 days from the start of molnupiravir administration. Results: Of the 1031 patients in the safety analysis set, 68 (6.60%) patients reported ADRs and four (0.39%) patients reported serious ADRs. The main ADRs observed were diarrhoea [26 patients (2.52%)], rash [six patients (0.58%)], dizziness [five patients (0.48%)], and faeces soft [four patients (0.39%)]. In the effectiveness analysis from the start date of molnupiravir administration to day 29, there were 16/612 (2.61%) hospitalizations and no deaths. Oxygen administration was newly initiated in 9/199 (4.52%) inpatients after the initiation of molnupiravir administration; 2/199 (1.01%) inpatients died. Conclusion: This interim analysis of molnupiravir in daily clinical practice use in Japan supports the safety and effectiveness profile of molnupiravir under pandemic conditions in which Omicron was the dominant SARS-CoV-2 variant. The results of this PMS will provide valuable information for daily clinical practice use. [ABSTRACT FROM AUTHOR]

Summary: This study aimed to describe the real-world efficacy and safety of the combination therapy of atezolizumab and bevacizumab (Atezo/Bev) for unresectable hepatocellular carcinoma (HCC). This retrospective analysis of a multicenter registry cohort included 268 patients treated with Atezo/Bev. The incidence of adverse events (AE) and its impact on overall survival (OS) and progression-free survival (PFS) were analyzed. Of the 268 patients, 230 (85.8%) experienced AE. The median OS and PFS in the whole cohort were 462 and 239 days, respectively. The OS and PFS were not different in terms of AE, but they were significantly shorter in patients with increased bilirubin level and those with increased aspartate aminotransferase (AST) or alanine aminotransferase (ALT). Regarding increased bilirubin level, the hazard ratios (HRs) were 2.61 (95% confidence interval [CI]: 1.04–6.58, P = 0.042) and 2.85 (95% CI: 1.37–5.93, P = 0.005) for OS and PFS, respectively. Regarding increased AST or ALT, the HRs were 6.68 (95% CI: 3.22–13.84, P < 0.001) and 3.54 (95% CI: 1.83–6.86, P < 0.001) for OS and PFS, respectively. Contrarily, the OS was significantly longer in patients with proteinuria (HR: 0.46 [95% CI: 0.23–0.92], P = 0.027). Multivariate analysis confirmed that proteinuria (HR: 0.53 [95% CI: 0.25–0.98], P = 0.044) and increased AST or ALT (HR: 6.679 [95% CI: 3.223–13.84], P = 0.003) were independent risk factors for a shorter OS. Furthermore, analysis limited to cases who completed at least 4 cycles confirmed that increased AST or ALT and proteinuria were negative and positive factors for OS, respectively. In the real-world setting, increased AST or ALT and bilirubin level during Atezo/Bev treatment were found to have a negative impact on PFS and OS, whereas proteinuria had a positive impact on OS. [ABSTRACT FROM AUTHOR]

Background: Drugs with new mechanisms of action are continually being developed, but it is difficult to capture whether a drug induces QT prolongation/torsade de pointes (TdP) in preclinical and preapproval clinical trials. Objective: To evaluate drugs associated with drug-induced QT prolongation/TdP using a real-world database in Japan. Patients and methods: A search was performed in the Japanese Adverse Drug Event Report (JADER) database for QT prolongation and TdP. The reporting odds ratio (ROR) was calculated to identify potential drug-induced QT prolongation/TdP association. Results: Among the reported 4,326,484 data entries, 3410 patients exhibited QT prolongation/TdP (2707 with QT prolongation, 703 with TdP) with the suspected drugs. Of these patients, 53.9% were females. The highest occurrence was in the 70- to 79-year-old age group (24.7%). The most common types of drugs involved were cardiovascular drugs, central nervous system (CNS) drugs, anticancer drugs, and anti-infective drugs; the rate of overdose was reportedly very low at 1.6%. The highest adjusted RORs were observed for nifekalant (351.41, 95% confidence interval (CI) 235.85–523.59), followed by vandetanib (182.55, 95% CI 108.11–308.24), evocalcet (181.59, 95% CI 132.96–248.01), bepridil (160.37, 95% CI 138.17–186.13), diarsenic trioxide (79.43, 95% CI 63.98–98.62), and guanfacine (78.29, 95% CI 58.51–104.74). Among the drugs launched in Japan during the last decade, vandetanib had the highest adjusted RORs. Conclusions: This study using the JADER database showed that antiarrhythmic drugs, calcium-sensing receptor agonists, small-molecule targeted anticancer drugs, and CNS drugs are associated with QT prolongation/TdP. Further pharmacoepidemiological studies, such as cohort studies using large databases, are needed to prove these causal relationships. [ABSTRACT FROM AUTHOR]

Aim: Previous reports suggest that the null genotype (*0/*0) of glutathione S‐transferase (GST) M1 and/or GSTT1 could be risk factors for drug‐induced liver injury (DILI). However, multi‐institutional pharmacogenetic research with various suspected drugs has rarely been performed in Japan. Therefore, the aim of this study was to investigate the role of GSTM1 and GSTT1 null genotype in the occurrence of DILI in Japanese patients. Methods: Blood samples of 270 DILI patients from 23 hospitals throughout Japan collected between 2010 and 2018 were subjected to genotyping of null genotypes of GSTM1 and GSTT1 using the SmartAmp‐2 method. We also collected information on DILI types, time to onset of DILI, pharmacological classification of suspected drugs and Digestive Disease Week‐Japan score, as well as genotypes of GSTM1 and GSTT1 in each patient with DILI. Results: The distribution of a combination of null genotypes of GSTM1 and GSTT1 in Japanese patients with DILI was significantly different from that reported in the general Japanese population. Notably, the incidence of the GSTM1 null genotype in patients with DILI was significantly higher than that of the control population. A significant relationship between the frequency of GSTM1 and GSTT1 null genotypes and pharmacological classification of suspected drugs, clinical laboratory data for liver function, time to onset of DILI, and Digestive Disease Week‐Japan scores was not observed. Conclusions: The GSTM1 null genotype was associated with an increased incidence of DILI in Japanese patients. [ABSTRACT FROM AUTHOR]

Many approved medicines are used with their adverse drug reactions (ADRs) appropriately managed in the clinical setting based on their risks and benefits. In this survey, the correlation between human ADR (specifically syncope/loss of consciousness and seizures/convulsions) and safety signals reported in animal studies has been investigated for 393 Japanese medicines which were approved between September 1999 and March 2013. Clinically important drug-induced ADR, syncope/loss of consciousness and seizures/convulsions are reported in this paper. Of 393 medicines, 101 (25.7%) showed syncope/loss of consciousness and 105 (26.7%) showed seizures/convulsions. Syncope/loss of consciousness and seizures/convulsions were reported for many medicines affecting the central nervous system. The animal toxicity concordance ratio with syncope/loss of consciousness and seizures/convulsions was 4.0% (4/101) and 23.8% (25/105), respectively. The underlying cases of syncope/loss of consciousness attributed to hypotension, arrhythmia, hypoglycemia or acute toxic reaction was 16.8%, 5.0%, 4.0% or 4.0%, respectively. Mechanism of seizures/convulsions for the remaining 101 medicines was not identified except for four local anesthetics. This survey suggested that the careful attention to and understanding of medicine profiles is necessary for the appropriate use of recently approved medicines in Japan. [ABSTRACT FROM AUTHOR]

Aim: We investigated adverse events (AEs) in a Japanese intensive care unit (ICU) and evaluated the impact of cause‐specific AEs on mortality and length of stay. Design: A retrospective observational study in the ICU of an academic hospital. Methods: We reviewed medical records with the Global Trigger Tool. Results: Of the 246 patients, 126 (51%) experienced one or more AEs with an incidence of 201 per 1000 patient‐days and 115 per 100 admissions. A total of 294 AEs were detected with 119 (42%) adverse drug events, 67 (24%) procedural complications, 63 (22%) surgical complications, 26 (9%) nosocomial infections, 5 (2%) therapeutic errors and 4 (1%) diagnostic errors. Adverse event (AE) presence was associated with length of ICU stay (β = 2.85, 95% confidence interval [CI]: 1.09–4.61). Adverse drug events, procedural complications and nosocomial infections were strongly associated with length of ICU stay (β = 2.38, 95% CI: 0.77–3.98; β = 3.75, 95% CI: 2.03–5.48; β = 6.52, 95% CI: 4.07–8.97 respectively). [ABSTRACT FROM AUTHOR]

Background: Rituximab is conditionally approved in Japan for use in patients with refractory nephrotic syndrome. To meet the conditions of approval, an all-case post-marketing surveillance study was conducted to confirm the real-world safety and efficacy of rituximab in patients of all ages with refractory nephrotic syndrome. Methods: All patients scheduled to receive rituximab treatment for refractory nephrotic syndrome were eligible to register (registration: August 29, 2014 through April 15, 2016); the planned observation period was 2 years from the initiation of rituximab treatment (intravenous infusion, 375 mg/m2 once weekly for four doses). The study was conducted at 227 hospitals throughout Japan. Adverse drug reactions (ADRs) were collected for safety outcomes. The efficacy outcomes were relapse-free period and the degree of growth in pediatric (< 15 years) patients. Results: In total, 997 (447 pediatric) patients were registered; 981 (445) were included in the safety analysis set; 852 (402) completed the 2-year observation period; and 810 (429) were included in the efficacy analysis set. Refractory nephrotic syndrome had developed in childhood for 85.0% of patients, and 54.6% were aged ≥15 years. ADRs were observed in 527 (53.7%) patients, treatment-related infection/infestation in 235 (24.0%) patients, and infusion reactions in 313 (31.9%) patients. The relapse-free period was 580 days (95% confidence interval, 511–664). There was a significant change in height standard deviation score (pediatric patients; mean change, 0.093; standard deviation, 0.637; P = 0.009). Conclusion: The safety and efficacy of rituximab treatment in patients with refractory nephrotic syndrome were confirmed in the real-world setting. Clinical trial registration: UMIN000014997. [ABSTRACT FROM AUTHOR]

Background: Data on real-world use of everolimus (EVR) in Japanese maintenance kidney transplant (KTx) patients are limited. This post-marketing surveillance study was conducted to assess the safety and effectiveness of EVR, and identify factors affecting renal impairment. Methods: Adult maintenance KTx patients were enrolled within 14 days of initiating EVR. Patient medical data were collected using electronic data capture case report forms at 6 months, 1, and 2 years after initiating EVR, or at discontinuation. Results: All patients receiving EVR in Japan during the surveillance period were enrolled (N = 263). Mean time from transplantation to EVR initiation was 75.7 months. Decreased renal function (31.56%) was the primary reason for initiating EVR. In combination with EVR, the mean daily dose of tacrolimus and cyclosporine could be reduced to ~ 79 and ~ 64%, by 2 years, respectively. Incidences of serious adverse events and adverse drug reactions were 15.97 and 49.43%, respectively. Two-year graft survival rate was 95.82% and low in patients with baseline estimated glomerular filtration rate (eGFR; modification of diet in renal disease) < 30 mL/min/1.73 m2 (69.57%; P < 0.0001) and urinary protein/creatinine ratio (UPCR) ≥ 0.55 g/gCr (84.21%; P = 0.0206). Throughout the survey, mean eGFR values were stable (> 55 mL/min/1.73 m2). Renal impairment was influenced by patient and donor age, eGFR, and UPCR at baseline. Conclusions: No new safety concerns for the use of EVR in adult maintenance KTx patients were identified. Early EVR initiation may be considered in these patients before renal function deterioration occurs. [ABSTRACT FROM AUTHOR]

Background: Among patients with advanced non-small-cell lung cancer who were treated with nivolumab monotherapy, the association of peripheral blood count data (at baseline and 2 weeks after treatment initiation) with the early onset of immune-related adverse events (irAEs) and treatment efficacy has not been clearly established. This study aimed to identify peripheral blood count data that may be predictive of the development of nivolumab-induced irAEs in a real-world clinical setting. Materials and Methods: This multicenter observational study retrospectively evaluated consecutive patients with advanced non-small-cell lung cancer undergoing nivolumab monotherapy in the second- or later-line setting between December 2015 and November 2018 at the National Cancer Center Hospital and Keio University Hospital in Japan. The primary endpoint was the association between peripheral blood count data and irAEs during the 6-week study period. Receiver operating characteristic curve and multivariable logistic regression analyses were performed. Results: Of the 171 patients evaluated, 73 (42.7%) had ≥1 irAE during the first 6 weeks following treatment initiation. The median time to irAEs from the initiation of nivolumab was 15 (interquartile range: 13–28) days. Receiver operating characteristic curve analyses revealed that the optimal cut-off values of the absolute lymphocyte count, neutrophil-to-lymphocyte ratio, and lymphocyte-to-monocyte ratio 2 weeks after treatment initiation for early irAE onset were 820, 4.3, and 2.2, respectively. In multivariable logistic regression analyses, absolute lymphocyte count >820 at 2 weeks after treatment initiation was significantly associated with an increased risk of early onset of any irAE. In contrast, no significant association was observed for the neutrophil-to-lymphocyte ratio (>4.3) or the lymphocyte-to-monocyte ratio (>2.2) at 2 weeks following treatment initiation. Conclusions: The absolute lymphocyte count >820 at 2 weeks following nivolumab initiation predicts early onset of irAEs during a 6-week study period. Routinely available absolute lymphocyte count, which is measured after the initiation of nivolumab, may be useful for identifying patients at risk of early onset of irAEs. [ABSTRACT FROM AUTHOR]

Purpose: We aimed to evaluate the efficacy and safety of 28‐day Cyclic and 84‐day Extended regimens of NPC‐16 (ethinylestradiol 0.02 mg plus levonorgestrel 0.09 mg) in patients with dysmenorrhea. Methods: This was a placebo‐controlled, double‐blind, randomized trial conducted in Japan. A total of 251 primary and secondary dysmenorrhea patients were randomly assigned to the NPC‐16‐Cyclic group, NPC‐16‐Extended group, or the Placebo group. The primary end point was a comparison of the efficacy and safety of the Cyclic and Extended NPC‐16 regimen for the treatment of dysmenorrhea relative to the Placebo. Main findings: Significantly greater reductions in total dysmenorrhea score and visual analog scale score were observed in the Cyclic and Extended groups compared with the Placebo group. Compared with the Cyclic regimen as a secondary end point, the Extended regimen exhibited greater efficacy in the treatment of dysmenorrhea over the course of the study period, particularly in patients with severe dysmenorrhea. The incidence of adverse drug reactions (ADRs) was significantly higher in the Cyclic and Extended groups than in the Placebo group. Conclusion: The Cyclic and Extended regimens of NPC‐16 significantly reduced dysmenorrhea severity compared to placebo. The Extended regimen was superior to cyclic regimen in reducing the dysmenorrhea. [ABSTRACT FROM AUTHOR]

This study aimed to characterize the safety and effectiveness of GH treatments, in usual clinical practice, in children with short stature born small for gestational age (SGA). This was a multicenter, open-label, non-interventional study (NCT01110928) conducted at 150 sites in Japan (2009-2018). The primary objective was to assess the type and frequency of serious adverse drug reactions (SADRs) associated with long-term GH use. Overall, 452 naïve and 46 non-naïve (previously treated) children were enrolled. GH treatment was well-tolerated, with SADRs occurring in 1.3% (6/452) and 0% (0/46) of naïve and non-naïve children, respectively. No new safety concerns or notable changes in glucose metabolism were identified during long-term treatment. Altogether, 57 children (32 naïve and 25 non-naïve) reached near adult height (NAH). In naïve and non-naïve children, mean ± standard deviation (SD) height standard deviation score (SDS) at NAH were -2.03 ± 0.77 and -1.53 ± 0.81, respectively, representing a change of +0.85 ± 0.72 and +1.24 ± 0.66 from baseline height SDS, respectively. Mean treatment duration to NAH was 4.29 (naïve) and 7.26 (non-naïve) yr. Thus, long-term GH treatment for short stature in children born SGA was confirmed to have a good safety profile and was effective for improving adult height. [ABSTRACT FROM AUTHOR]

Objective: Synthetic glucocorticoids cause various psychiatric symptoms. Prescription of psychotropic drugs could be considered to be a proxy for manifestation of psychiatric symptoms. The aim of this study was to investigate the prescriptions of psychotropics in outpatients receiving synthetic glucocorticoids. Methods: We used the claims sampling data during January 2015 from the National Database of Health Insurance Claims and Specific Health Checkups of Japan made by the Ministry of Health, Labor, and Welfare in Japan. We compared the prescription rates of psychotropics between outpatients receiving oral synthetic glucocorticoids and age‐ and sex‐matched controls and the prescription rates of psychotropics among the eight dosage groups of synthetic glucocorticoids by chi‐squared test, and chlorpromazine/imipramine/diazepam equivalent doses (or daily defined doses) of respective psychotropics among these groups using Welch's t‐test. Results: Synthetic glucocorticoids were prescribed to 3.1% (n = 18 122) of 581 990 patients. The prescription rates of psychotropics were significantly higher among the synthetic glucocorticoid recipients than among the non‐recipients: antipsychotics, 1.8% (n = 321) vs. 1.1% (n = 201) (P = 1.4 × 10−7); antidepressants, 4.0% (n = 724) vs. 2.0% (n = 359) (P = 8.7 × 10−30); anxiolytics/hypnotics, 16.7% (n = 3029) vs. 10.2% (n = 1841) (P = 2.7 × 10−75); and mood stabilizers, 1.3% (n = 238) vs. 0.7% (n = 120) (P = 3.6 × 10−10) respectively. There was no significant difference in the prescription rates of any psychotropic drugs, other than anxiolytics/hypnotics, among the eight synthetic glucocorticoid dosage groups. Conclusion: Prescriptions of oral synthetic glucocorticoids were found to be associated with the use of any of the types of psychotropic drugs, other than anxiolytics/hypnotics, although a causal relationship could not be confirmed due to the retrospective and cross‐sectional nature of this study. [ABSTRACT FROM AUTHOR]

Summary: Locally advanced or metastatic urothelial cancer is an aggressive form of cancer with high recurrence rates and low survival. Nectin-4 is a cell adhesion molecule commonly expressed in several tumors, including high expression in urothelial cancer. Enfortumab vedotin is an antibody–drug conjugate composed of an anti-Nectin-4 humanized monoclonal antibody linked to the microtubule disrupting agent, monomethyl auristatin E. In this phase I study (NCT03070990), Japanese patients with locally advanced/metastatic urothelial cancer treated with prior chemotherapy, or ineligible for cisplatin, were randomized 1:1 to receive 1.0 mg/kg (Arm A) or 1.25 mg/kg (Arm B) enfortumab vedotin on Days 1, 8, and 15 of each 28-day cycle. Assessing the pharmacokinetic and safety/tolerability profiles of enfortumab vedotin were primary objectives; investigator-assessed antitumor activity (RECIST v1.1) was a secondary objective. Seventeen patients (n = 9, Arm A; n = 8, Arm B) received treatment. Pharmacokinetic data suggest a dose-dependent increase in enfortumab vedotin maximum concentration and area under the concentration–time curve at Day 7. Enfortumab vedotin was well tolerated across both doses. Dysgeusia and alopecia (n = 9 each) were the most common treatment-related adverse events. Regardless of attribution, grade ≥ 3 adverse events occurring in ≥2 patients were anemia and hypertension (n = 2 each). One patient achieved a confirmed complete response (Arm A) and five achieved confirmed partial responses (n = 3, Arm A; n = 2, Arm B). Objective response and disease control rates were 35.3% and 76.5%, respectively. In Japanese patients with locally advanced/metastatic urothelial cancer, enfortumab vedotin is well tolerated with preliminary antitumor activity and a pharmacokinetic profile consistent with prior reports. [ABSTRACT FROM AUTHOR]

Background: The recommended starting dose of cabazitaxel for castration-resistant prostate cancer (CRPC) is 25 mg/m2 in Japan and Europe. Although lower doses are established alternatives based on randomized controlled trials, the safety and efficacy of 25 and 20 mg/m2 in real-world settings are not well established. Therefore, we investigated the safety and efficacy of cabazitaxel at the recommended starting dose or a lower dose (20 mg/m2) in real-world clinical practice.Methods: We compared the safety and efficacy of cabazitaxel between patients who received cabazitaxel at starting doses of 25 and 20 mg/m2 (C25 and C20, respectively) in a Japanese post-marketing surveillance study of 662 patients with docetaxel-refractory CRPC. Safety was assessed in terms of adverse drug reactions (ADRs). Prostate-specific antigen (PSA) response rate, overall survival (OS), and time-to-treatment failure (TTF) were compared between the C25 and C20 groups in unmatched patients and after applying propensity score matching.Results: The C20 and C25 groups comprised 190 and 159 patients without matching and 112 patients per group after matching. In unmatched patients, any-grade (C25 vs C20: 89.3% vs 78.4%, Fisher's p < 0.01) and grade ≥ 3 (81.1% vs 61.1%) ADRs were more frequent in the C25 group. Neutropenia (any grade: 61.6% vs 54.2%; grade ≥ 3: 55.3% vs 42.6%) and febrile neutropenia (grade ≥ 3: 30.2% vs 14.7%) were more frequent in the C25 group. In matched patients, the PSA response rate (reduction in PSA ≥30% from a baseline ≥5 ng/mL) was 26.4 and 32.0% in the C20 and C25 groups, respectively, median OS was 291 days (95% CI 230-not reached) versus not reached (hazard ratio 0.73, 95% CI 0.50-1.08), and TTF favored C25 (hazard ratio 0.75, 95% CI 0.57-0.99).Conclusions: Clinicians should consider the patient's risk of clinically significant ADRs and prophylactic granulocyte colony stimulating factor when selecting the starting dose of cabazitaxel for CRPC. Some patients at high risk of ADRs or unfit patients may benefit from a lower starting dose of 20 mg/m2, whereas fit patients may be candidates for a starting dose of 25 mg/m2.Trial Registration: Not applicable. [ABSTRACT FROM AUTHOR]

Introduction: Idarucizumab, a monoclonal antibody fragment, was developed to reverse the anticoagulant effect of dabigatran, and it was approved in Japan in September 2016. An all-case post-marketing surveillance is ongoing to collect data in Japanese patients treated with idarucizumab who had serious bleeding (Group A) or required an urgent procedure (Group B). Methods: The primary endpoint was the incidence of adverse drug reactions (ADRs). The secondary endpoint was the maximum extent of reversal of the anticoagulant effect of dabigatran based on activated partial thromboplastin time (aPTT) within 4 h after idarucizumab administration. Results: This interim analysis included 262 patients who received idarucizumab. Eighteen patients (6.9%) experienced ADRs within 4 weeks. The reversal effect of idarucizumab based on aPTT within 4 h after idarucizumab administration was assessed in 30 patients and the median maximum percentage reversal was 100%. In Group A, the median time to bleeding cessation in patients without intracranial bleeding was 3.3 h. In Group B, normal intraoperative hemostasis was reported in 63 patients (72.4%). Conclusions: The results of this interim analysis suggest that idarucizumab is safe and effective for the reversal of dabigatran in Japanese patients in a real-world setting, and support the continued use of idarucizumab. Trial Registration: ClinicalTrials.gov identifier, NCT02946931. [ABSTRACT FROM AUTHOR]

Introduction: Adverse event reporting patterns vary between countries, reflecting differences in reporting culture, clinical practice and underlying patient populations. Japan collects about 60,000 domestic adverse event reports yearly and shares serious reports with the World Health Organization (WHO) Programme for International Drug Monitoring in VigiBase, the WHO global database of individual case safety reports. Understanding these reports in the global context can be helpful for regulators worldwide and can aid hypothesis-generation for Japanese-specific vulnerabilities to adverse drug reactions.Objective: The objective of this study was to explore differences in the reporting of adverse events between Japan and other countries.Methods: vigiPoint is a method for data-driven exploration in pharmacovigilance. It outlines data subsets, pinpoints key features and facilitates expert review, using odds ratios subjected to statistical shrinkage to distinguish one data subset from another. Here, we compared 260,000 Japanese reports in E2B format classified as serious and received in VigiBase between 2013 and 2018 with 2.5 million reports from the rest of the world (of which 51% are from the USA). Reporting patterns for which the 99% credibility interval of the shrunk log-odds ratios were above 0.5 or below - 0.5 were flagged as key features. The shrinkage was set to the vigiPoint default corresponding to 1% of the size of the Japanese data subset. As a sensitivity analysis, additional vigiPoint comparisons were performed between Japan and, in turn, Africa, the Americas, the Americas except the USA and Canada, Asia and Europe.Results: There were higher reporting rates in Japan from physicians (83% vs. 39%) and pharmacists (17% vs. 10%). It was also more common to see reports with more than five drugs per report (22% vs. 14%) and with a single adverse event (72% vs. 45%). More than half of the Japanese reports had a vigiGrade completeness score above 0.8 compared with about one in five from the rest of the world. There were more reports than expected for patients aged 70-89 years and fewer reports for adults aged 20-59 years. Adverse events reported more often in Japan included interstitial lung disease, abnormal hepatic function, decreased platelet count, decreased neutrophil count and drug eruption. Adverse events reported less often included death, fatigue, dyspnoea, pain and headache. Drugs reported more often in Japan included prednisolone, methotrexate and peginterferon alfa-2b. Drugs reported less often included rosiglitazone and adalimumab as well as blood substitutes and perfusion solutions. The findings were generally robust to the sensitivity analysis except for the less often reported drugs, many of which were rarely reported in most countries, except in the USA.Conclusion: Analysis of Japanese adverse event reporting patterns in a global context has revealed key features that may reflect possible pharmaco-ethnic vulnerabilities in the Japanese, as well as differences in adverse event reporting and clinical practice. This knowledge is essential in the global collaboration of signal detection afforded by the WHO Programme for International Drug Monitoring. [ABSTRACT FROM AUTHOR]

Introduction: In 2010, nonacog alfa became the first recombinant factor IX (rFIX) available in Japan for patients with haemophilia B. Aim: To determine real‐world safety (adverse events, incidence of inhibitors) and effectiveness of nonacog alfa in Japan. Methods: This multicentre, prospective, observational, postmarketing surveillance study enrolled previously treated and untreated patients (PTPs and PUPs, respectively) who were observed for 1 and 2 years, respectively, after initiating nonacog alfa therapy. Safety and effectiveness were assessed for each treatment type. Annualized bleeding rate (ABR) and incremental recovery of rFIX were also evaluated. Results: Overall, 312 of 314 patients enrolled from 173 sites were eligible for the safety analysis set (PTPs, 281; PUPs, 28; other, 3). Mean age was 25.4 (PTPs) and 14.8 (PUPs) years. Haemophilic severity ranged from mild to severe, and 133 (42.6%) patients had haemophilic arthropathy. Of 285 patients (PTPs, 257; PUPs, 28) in the effectiveness set, 112 received on‐demand treatment for 1161 bleeding episodes (effectiveness rate, 93.7%) and 185 received routine prophylaxis (effectiveness rate, 95.5%). No spontaneous bleeding was observed in 52.4% of patients during prophylactic treatment. Median ABR was lower during routine prophylaxis (2.0) vs the rest of the observation period (8.3). A weak negative correlation was found between body weight and the reciprocal of rFIX recovery. Eleven adverse drug reactions occurred in 7 PTPs (2.2% [7/312]); recurrence of inhibitor was observed in 1 patient, but no new inhibitor developed in PTPs or PUPs. Conclusion: Nonacog alfa therapy is safe and effective in the real‐world scenario in Japan. [ABSTRACT FROM AUTHOR]

Objectives. Traditional Japanese Kampo medicines have been integrated into the Japanese national health-care system. In Japan, the Ministry of Health, Labor, and Welfare's website discloses adverse drug-event data that have been obtained from medical personnel reports investigated by the Pharmaceutical and Medical Devices Agency. Using these data, we investigated adverse events associated with ethical Kampo formulations. Methods. Reports of adverse events associated with ethical Kampo formulations from the domestic adverse-event data were obtained from July 30, 2003, to March 31, 2018. Adverse events were then categorized, and the relationships between categories of adverse events and crude drugs were analyzed. Results. There were 4,232 reported adverse events associated with ethical Kampo formulations. The numbers of events by category were as follows: events related to liver injury, 1,193; lung injury, 1,177; pseudoaldosteronism, 889; mesenteric phlebosclerosis, 223; drug eruption, 185; and others, 565. Among events related to both liver injury and lung injury, approximately 70% were suspected to be induced by Kampo formulations containing Scutellariae Radix. The pseudoaldosteronism-related events, which are induced by Glycyrrhizae Radix, included several events related to muscle injury, heart failure, and arrhythmia. Events related to mesenteric phlebosclerosis, believed to be induced by long-term use of Kampo formulas containing Gardeniae Fructus, increased remarkably during the study period. Among the events related to drug eruption, approximately 35% were suspected to be induced by Kampo formulations containing Ephedrae Herba. Conclusion. Kampo medicines may cause various adverse events. The present results provide valuable information regarding adverse events associated with Kampo medicines from the viewpoint of patient safety. [ABSTRACT FROM AUTHOR]

Background: Limited data regarding knowledge and factors related to understanding the adverse drug reaction (ADR) reporting system of health care professionals are available in Japan. Objective: The objective of this study was to identify factors related to understanding the ADR reporting system in Miyagi Cancer Center and to find ways to increase the number and quality of ADR reports. Methods: Self-administered questionnaire surveys were administered before and after the educational meeting among health care professionals who were working in our hospital during the study period. Subanalyses restricted to nurses were also performed. Main Outcome Measure: Understanding ADR reporting system among healthcare professionals. Results: The percentage of respondents who understood the ADR reporting system in the questionnaire after the educational meeting was significantly higher than that in the questionnaire before the educational meeting. In the questionnaire after the educational meeting, multivariate logistic regression analysis found that having over 30 years of practical experience (odds ratio [OR], 3.852; 95% confidence interval [CI], 1.228-12.081 for 20-29 years, 7.695; 1.650-35.881 for over 30 years), being a physician (8.071; 1.923-33.878), being a pharmacist (18.357; 3.847-87.585), and participating in the educational meeting (5.111; 1.700-15.365) were factors associated with understanding the ADR reporting system. Multivariate logistic regression analysis of the questionnaire results before the educational meeting among nurses showed that working at outpatient departments (8.330; 3.008-23.069) was significantly and independently associated with understanding the ADR reporting system. Conclusions: The present study demonstrated that many years of practical experience, profession (physicians, pharmacists), and educational interventions were associated with good understanding of the ADR reporting system among health care professionals. [ABSTRACT FROM AUTHOR]

Background: Kampo medicine is traditional Japanese medicine, which originated in ancient traditional Chinese medicine, but was introduced and developed uniquely in Japan. Today, Kampo medicines are integrated into the Japanese national health care system. Incident reporting systems are currently being widely used to collect information about patient safety incidents that occur in hospitals. However, no investigations have been conducted regarding patient safety incident reports related to Kampo medicines. The aim of this study was to survey and analyse incident reports related to Kampo medicines in a Japanese university hospital to improve future patient safety. Methods: We selected incident reports related to Kampo medicines filed in Toyama University Hospital from May 2007 to April 2017, and investigated them in terms of medication errors and adverse drug events. Results: Out of 21,324 total incident reports filed in the 10-year survey period, we discovered 108 Kampo medicine-related incident reports. However, five cases were redundantly reported; thus, the number of actual incidents was 103. Of those, 99 incidents were classified as medication errors (77 administration errors, 15 dispensing errors, and 7 prescribing errors), and four were adverse drug events, namely Kampo medicine-induced interstitial pneumonia. The Kampo medicine (crude drug) that was thought to induce interstitial pneumonia in all four cases was Scutellariae Radix, which is consistent with past reports. According to the incident severity classification system recommended by the National University Hospital Council of Japan, of the 99 medication errors, 10 incidents were classified as level 0 (an error occurred, but the patient was not affected) and 89 incidents were level 1 (an error occurred that affected the patient, but did not cause harm). Of the four adverse drug events, two incidents were classified as level 2 (patient was transiently harmed, but required no treatment), and two incidents were level 3b (patient was transiently harmed and required substantial treatment). Conclusions: There are many patient safety issues related to Kampo medicines. Patient safety awareness should be raised to prevent medication errors, especially administration errors, and adverse drug events in Kampo medicine. [ABSTRACT FROM AUTHOR]

The Japanese Postmarketing Relief System provides for compensation to patients with adverse reactions, based on the acknowledgment that unpredicted adverse events occur inevitably once a drug is marketed. The system also provides new knowledge about the benefit-risk profile of a drug that may be incorporated into product labeling. The system relies on causality assessments that are based on sound clinical pharmacology principles. The system may serve as a model for other countries' healthcare systems. [ABSTRACT FROM AUTHOR]

Oseltamivir is contraindicated for people aged 10-19 in principle in Japan, due to concern about abnormal behaviours. Sudden death is another concern. This review examines growing evidence of their association and discusses underlying mechanisms of these sudden-onset type reactions to oseltamivir. First, the importance of animal models and the concept of human equivalent dose (HED) is summarized. Second, the specific condition for oseltamivir use, influenza infection, is reviewed. Third, findings from toxicity studies conducted prior to and after the marketing of oseltamivir are reported on to provide context on the observation of a possible causal association. Fourth, similarity and consistency of toxicity in humans with that in other animals is described. Finally, coherence of toxicokinetic and molecular level of evidence (channels, receptors and enzymes), including differences from the toxicity of other neuraminidase inhibitors, is reviewed. It is concluded that unchanged oseltamivir has various effects on the central nervous system (CNS) that may be related to clinical findings including hypothermia, abnormal behaviours including with fatal outcome, and sudden death. Among receptors and enzymes related to CNS action, it is known that oseltamivir inhibits nicotinic acetylcholine receptors, which are closely related to hypothermia, as well as human monoamine oxidase-A (MAO-A), which is closely related to abnormal or excitatory behaviours. Receptors such as GABAA, GABAB and NMDA and their related receptors/channels including Na+ and Ca2+ channels are thought to be other candidates for investigation related to respiratory suppression followed by sudden death and psychotic reactions (both acute and chronic), respectively. [ABSTRACT FROM AUTHOR]

Introduction: The nature of medication errors (MEs) and the frequency of identified or intercepted MEs are not being scrutinized in daily practice in Japan.Objectives: The aim of this study was to clarify the epidemiology of MEs and the risk factors for non-intercepted and unidentified MEs.Methods: The Japan Adverse Drug Events (JADE) study was a prospective cohort study carried out at three tertiary-care teaching hospitals in Japan. Participants were consecutive patients (N = 3459) aged ≥15 years who were admitted to the study wards. MEs were identified by on-site reviews of all medical charts, self-reports, and prescription queries by pharmacists. Two independent physicians reviewed and classified all MEs and adverse drug events and determined the stages at which the MEs occurred and whether there was interception or identification of the MEs.Results: A total of 514 MEs were observed among 433 patients. Sixty-four percent of MEs occurred at the ordering stage. Among these, 60 % were due to duplicate drug orders. Overall, 63 % and 45 % of MEs were not intercepted or identified during hospitalization, respectively. The independent risk factors for non-intercepted MEs were hospitalization in the surgical ward (odds ratio [OR] 2.94) and the intensive care unit (OR 3.57). MEs by resident physicians were more likely to be intercepted (OR 0.52 for non-intercepted MEs).Conclusions: MEs frequently occurred and most at the ordering stage. Almost half of MEs were not intercepted or identified. Many MEs at the later stages were less likely to be intercepted and resulted in actual patient harm. Systems to improve the identification and interception of MEs should be implemented. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented which is concerned with research which investigated the factors associated with prolonged hospital stays in a geriatric ward in a university hospital in Japan.

Background: Rapid dissemination of information regarding adverse drug reactions is a key aspect for improving pharmacovigilance. There is a possibility that unknown adverse drug reactions will become apparent through post-marketing administration. Currently, although there have been studies evaluating the relationships between a drug and adverse drug reactions using the JADER database which collects reported spontaneous adverse drug reactions, an efficient approach to assess the association between adverse drug reactions of drugs with the same indications as well as the influence of demographics (e.g. gender) has not been proposed. Methods and Findings: We utilized the REAC and DEMO tables from the May 2015 version of JADER for patients taking antidepressant drugs (SSRI, SNRI, and NaSSA). We evaluated the associations using association analyses with an apriori algorithm. Support, confidence, lift, and conviction were used as indicators for associations. The highest score in adverse drug reactions for SSRI was obtained for "aspartate aminotransferase increased", "alanine aminotransferase increased", with values of 0.0059, 0.93, 135.5, and 13.9 for support, confidence, lift and conviction, respectively. For SNRI, "international normalized ratio increased", "drug interaction" were observed with 0.0064, 1.00, 71.9, and NA. For NaSSA, "anxiety", "irritability" were observed with 0.0058, 0.80, 49.9, and 4.9. For female taking SSRI, the highest support scores were observed in "twenties", "suicide attempt", whereas "thirties", "neuroleptic malignant syndrome" were observed for male. Second, for SNRI, "eighties", "inappropriate antidiuretic hormone secretion" were observed for female, whereas "interstitial lung disease" and "hepatitis fulminant" were for male. Finally, for NaSSA, "suicidal ideation" was for female, and "rhabdomyolysis" was for male. Conclusions: Different combinations of adverse drug reactions were noted between the antidepressants. In addition, the reported adverse drug reactions differed by gender. This approach using a large database for examining the associations can improve safety monitoring during the post-marketing phase. [ABSTRACT FROM AUTHOR]

Objective: Older people are more likely to have insomnia. One of the most prescribed hypnotics in Japan is triazolam. Although some studies showed the possibility of adverse effects of triazolam in older people, there have been few studies investigating these effects in a clinical setting. The aim of this study was to determine whether patients who used triazolam regularly had increased risks of pneumonia, trauma, and pressure ulcers.Methods: The research design was a retrospective cohort study using claim data. The subjects of the study were patients who were insured by Fukuoka Late Stage Elderly Healthcare Insurance. We defined patients who had received triazolam for 180 days or longer during fiscal year 2011 as the triazolam group, and those who had not received any hypnotics during the period as the non-triazolam group. Each patient in the triazolam group was then matched with a unique control from the non-triazolam group according to propensity score. Multivariate conditional logistic regression analyses were used to obtain adjusted odds ratios for pneumonia, trauma, and pressure ulcer in the triazolam group compared with the non-triazolam group.Results: The number of patients in the triazolam and non-triazolam groups in the unmatched cohort was 13,015 and 411,610, respectively. Adjusted odds ratios show that the risks for pneumonia, trauma, and pressure ulcer in the matched cohort increased by approximately 40%, 30%, and slightly less than 30%, respectively (all statistically significant).Conclusions: Regular use of triazolam is a risk factor for pneumonia, trauma, and pressure ulcer in older people. [ABSTRACT FROM AUTHOR]

Conclusion: Grade ≥ 3 mucositis/stomatitis and inability to feed orally were problematic for patients undergoing cetuximab-based bioradiotherapy (BRT) as well as platinum-based chemoradiotherapy (CRT). Severe mucositis/stomatitis and radiation dermatitis should be addressed carefully in patients undergoing cetuximab-based BRT as well. Objectives: The efficacy of cetuximab-based BRT in locally advanced head and neck squamous cell carcinomas has been established. However, the safety of cetuximab-based BRT in comparison with platinum-based CRT is currently under investigation. Method: This study retrospectively analyzed 14 patients undergoing cetuximab-based BRT and 29 patients undergoing platinum-based CRT to compare the incidence of acute toxicities. In the BRT group, an initial cetuximab loading dose of 400 mg/m2 was delivered 1 week before the start of radiotherapy. Seven weekly infusions of 250 mg/m2 of cetuximab followed during the definitive radiotherapy. In the CRT group, cisplatin was administered at a dose of 40 mg/m2 weekly during the definitive radiotherapy. Results: The BRT group had a higher incidence of Grade ≥ 3 radiation dermatitis than did the CRT group (43% vs 3%, respectively, p < 0.01). The incidence rate of Grade ≥ 3 mucositis/stomatitis was 64.3% and 41.4% in the BRT and CRT group, respectively ( p = 0.1484), while the incidence rate of the inability to feed orally was 38.5% and 55.2%, respectively ( p = 0.2053). [ABSTRACT FROM AUTHOR]

Background: Attitudes of healthcare professionals regarding spontaneous reporting of adverse drug reactions (ADRs) in Japan are not well known, and Japan’s unique system of surveillance, called early post-marketing phase vigilance (EPPV), may affect these reporting attitudes. Our objectives were to describe potential effects of EPPV and to test whether ADR seriousness, prominence, and frequency are related to changes in reporting over time. Methods: A manufacturer’s database of spontaneous ADR reports was used to extract data from individual case safety reports for 5 drugs subject to EPPV. The trend of reporting and the time lag between ADR onset and reporting to the manufacturer were examined. The following indices for ADRs occurring with each drug were calculated and analyzed to assess reporting trends: Serious:Non-serious ratio, High prominence:Low prominence ratio, and High frequency:Low frequency ratio. Results: For all 5 drugs, the time lag between ADR onset and reporting to the manufacturer was shorter in the EPPV period than in the post-EPPV period. All drugs showed higher Serious:Non-serious ratios in the post-EPPV period. No specific patterns were observed for the High prominence:Low prominence ratio. The High frequency:Low frequency ratio for peginterferon alpha-2a and sevelamer hydrochloride decreased steadily throughout the study period. Conclusions: Healthcare professionals may be more likely to report serious ADRs than to report non-serious ADRs, but the effect of event prominence on reporting trends is still unclear. Factors associated with ADR reporting attitude in Japan might be different from those in other countries because of EPPV and the involvement of medical representatives in the spontaneous reporting process. Pharmacovigilance specialists should therefore be cautious when comparing data between different time periods or different countries. Further studies are needed to elucidate the underlying mechanism of spontaneous ADR reporting in Japan. [ABSTRACT FROM AUTHOR]

Conclusion: Patients who received concurrent chemoradiation therapy or radiation therapy alone were followed over a long term. The complete response (CR), 10-year survival, and 10-year larynx preservation rates were 87.5%, 95.3%, and 75.1%, respectively. Statistically, concurrent chemoradiation therapy contributes to laryngeal preservation but not to the survival rate. Objective: To determine the additive and synergistic effects of anticancer chemotherapy combined with chemoradiation therapy for squamous cell carcinoma (SCC) of the glottic larynx. Methods: Eighty-nine patients with untreated T2N0M0 SCC of the glottic larynx were included. Thirty-two patients received treatment cycles consisting of intravenous cisplatin (CDDP) on day 1 (80 mg/m2) and intravenous 5-fluorouracil (5-FU) over 120 h on days 2-6 (600 mg/m2/day) every 4 weeks. Radiotherapy was delivered by a 4 MV linac X-ray machine at a dose of 66 Gy. Fifty-seven patients received radiotherapy alone. Results: After chemoradiation therapy, the overall response, CR, 10-year survival, and 10-year larynx preservation rates were 100%, 87.5%, 95.3%, and 75.1%, respectively. Side effects included leukopenia, neutropenia, mucositis, and dermatitis. Seven patients (21.9%) required salvage surgery. Pathological findings confirmed that the treatment regimen caused marked cancer tissue degeneration. Histologic examination of surgical specimens suggested that the safety margin for partial laryngectomy was 4 mm from the gross tumor. [ABSTRACT FROM AUTHOR]

Conclusion: Concurrent chemoradiation therapy with docetaxel (DOC) at a dose of 10 mg/m2 twice a week contributed to laryngeal preservation. Objective: To determine laryngeal preservation following concurrent chemoradiation therapy with DOC. Methods: A total of 141 patients with untreated T2N0M0 squamous cell carcinoma of the glottic larynx were included in the study. The treatments were either radiation therapy alone or DOC intravenously administered at a dose of 10 mg/m2 once or twice a week during radiotherapy with 4 MV linac X-ray (total of 66 Gy for 33 days). Results: The response and CR rates were 100% and 90.5% in the once-weekly combination group, and 100% and 97.6% in the twice-weekly combination group, respectively. The 5-year survival rates were 76.8% in the once-weekly combination group and 96.8% in the twice-weekly combination group. The 5-year laryngeal preservation rates were 83.8% in the once-weekly combination group and 97.6% in the twice-weekly combination group. The most common side effects were mucositis, dermatitis, and alopecia. The patients who received DOC twice a week showed more severe cancer tissue degeneration, and pathological examination of serial sections indicated that the safety margin for partial laryngectomy was considered to be 3 mm from the gross tumor with good glottal closure. [ABSTRACT FROM AUTHOR]

Background: Levofloxacin 0.5% ophthalmic solution is an antibacterial formulation, which was approved and marketed for the treatment of ocular infections in Japan in 2000. Objective: This study was designed to investigate the safety and efficacy of levofloxacin 0.5% ophthalmic solution in patients who received treatment for external ocular bacterial infections in regular clinical practice. Methods: Patients were recruited from more than 800 medical facilities in Japan, in accordance with Japanese Ministry of Health, Labour and Welfare ordinance guidelines. They were followed during three distinct time periods: April 2000 to December 2001, January 2002 to June 2003, and July 2003 to December 2004. Results: Information from 6760 patients receiving levofloxacin for the treatment of a variety of ocular infections was collected. Levofloxacin was well tolerated: adverse drug reactions (ADRs) were reported in 42 of 6686 patients (0.63%), with no serious ADRs reported. The most commonly reported ADRs were ocular disorders such as blepharitis, eye irritation, and punctate keratitis. The incidence of ADRs did not differ significantly with age, but it was significantly higher in females (0.82%) than in males (0.36%; p = 0.028). A clinical response was observed in 95.5% of patients receiving levofloxacin, with no difference in response between the three time periods. The rate of response to levofloxacin by bacterial disease ranged from 97.4% in keratitis to 88.3% in dacryocystitis. The rate was lower in patients with dacryocystitis, elderly patients, patients with a long duration of illness, and relapsing cases (all p < 0.001). Conclusion: This post-marketing surveillance of levofloxacin, conducted over 4 years, confirms the safety and efficacy of levofloxacin in regular clinical use and highlights that levofloxacin is a promising treatment for a variety of external ocular bacterial infections. [ABSTRACT FROM AUTHOR]

The Challenge-Stroke study was conducted in Japanese patients initiated on candesartan cilexetil therapy within 3 months of suffering a stroke to investigate the clinical use of candesartan and its efficacy/safety in this therapeutic setting. A total of 869 patients formed the safety analysis set. In total, 79.6% of patients with brain hemorrhage (BH) and 60.2% with brain infarction (BI) began candesartan before post-stroke day 3 and 7, respectively. Baseline average blood pressure (BP) was 152.0/83.2 mmHg in the BH group and 165.2/89.8 mmHg in the BI group; this was reduced to 125.8/75.4 mmHg and 136.3/78.1 mmHg, respectively, at 1 year. The incidence of adverse drug reactions was 6.7 and 8.0%, respectively. There were 12 recurrent strokes in the BH group and 11 in the BI group after 1 year. The risk of recurrent stroke was significantly higher for BH patients with a final systolic BP ≥150 mmHg than for those with a final systolic BP <130 mmHg (hazard ratio: 6.807; p = 0.004). Aggressive antihypertensive therapy is currently employed in Japanese patients with acute stroke. Candesartan was safe and effective for BP control in acute stroke patients. Strict BP management may be useful for secondary prevention of stroke after BH. [ABSTRACT FROM AUTHOR]

Lubiprostone is a prostone analog with a novel mechanism of action involving type-2 chloride channel activation. The aim of this work was to perform a dose-finding study for lubiprostone for the treatment of constipation with or without irritable bowel syndrome (IBS) in Japan. A total of 170 patients (128 without IBS and 42 with IBS) with chronic idiopathic constipation (CIC) randomly received a placebo ( n = 42) or 16 μg ( n = 41), 32 μg ( n = 43), or 48 μg ( n = 44) of lubiprostone daily for 2 weeks. There was a statistically significant and dose-dependent increase in change from baseline in the weekly average number of spontaneous bowel movements at week 1 (placebo: 1.5 ± 0.4; 16 μg: 2.3 ± 0.4, 32 μg: 3.5 ± 0.5; and 48 μg: 6.8 ± 1.1, per week, mean ± SE; P < 0.0001). These primary endpoint results were significant on stratified analysis when patients were limited to those without IBS ( P < 0.0001). The primary endpoint in patients with IBS treated with 48 μg of lubiprostone was significantly better than those given placebo ( P = 0.0086). Dose dependency was also seen for the secondary efficacy endpoints. Lubiprostone produced no serious side effects. Our results suggest that lubiprostone produced a steady and effective improvement in the symptoms of CIC with or without IBS in a dose-dependent manner with a good safety profile and tolerability in a Japanese population. [ABSTRACT FROM AUTHOR]

Evidence-based approach on the safety of acupuncture had been lagging behind both in the West and the East, but reliable data based on some prospective surveys were published after the late 1990s. In the present article, we, focusing on 'Japanese acupuncture', review relevant case reports and prospective surveys on adverse events in Japan, assess the safety of acupuncture practice in this country, and suggest a strategy for reducing the therapists' error. Based on the prospective surveys, it seems reasonable to suppose that serious adverse events are rare in standard practice by adequately trained acupuncturists, regardless of countries or modes of practice. Almost all of adverse reactions commonly seen in acupuncture practice-such as fatigue, drowsiness, aggravation, minor bleeding, pain on insertion and subcutaneous hemorrhage-are mild and transient, although we should be cautious of secondary injury following drowsiness and needle fainting. After demonstrating that acupuncture is inherently safe, we have been focusing on how to reduce the risk of negligence in Japan, as well as educating acupuncturists more about safe depth of insertion and infection control. Incident reporting and feedback system is a useful strategy for reducing therapist errors such as forgotten needles. For the benefit of acupuncture patients in Japan, it is important to establish mandatory postgraduate clinical training and continued education system. [ABSTRACT FROM AUTHOR]