Comprehensive Analysis of Bortezomib-Induced Adverse Events Using the Japanese Real-World Database

Background: Bortezomib is used as first-line therapy for multiple myeloma. Observational studies based on the FDA Adverse Event Reporting System (FAERS) database analysis and systematic reviews indicate that the incidence of peripheral neuropathy and tumor lysis syndrome (TLS) tends to be higher with bortezomib than that of other drugs. In a comprehensive analysis assessing drugs that cause peripheral neuropathy in Japanese patients, the incidence of bortezomib-induced adverse events (AEs) was reportedly high. However, a comprehensive assessment of bortezomib is lacking. Objectives: The purpose of this study was to determine the frequency of bortezomib AEs in Japanese patients and to determine the incidence, time to onset, and post hoc outcomes of unique AEs using the Japanese Adverse Drug Event Report (JADER) database. Method: To investigate the association between bortezomib and AEs, we analyzed the JADER database, which contains spontaneous AE reports submitted to the Pharmaceuticals and Medical Devices Agency from April 2004 to December 2020. Criteria indicating the presence of an AE signal were met when the following requirements were fulfilled: proportional reporting ratios (PRR) ≥ 2 and χ2 ≥ 4. Time to onset and post-event outcomes were analyzed for characteristic AEs. Results: Among 26 extracted AEs, 13 presented AE signals. The post-exposure outcomes of 12 AEs showed fatal outcomes at rates exceeding 10%, including cardiac failure (30%), lung disorder (24%), pneumonia (18%), and TLS (10%). Furthermore, a histogram of time to onset revealed that the 12 AEs were concentrated from the beginning to approximately one month after bortezomib administration. The median onset times for cardiac failure, lung disorder, pneumonia, and TLS were 28, 13, 42, and 5 days, respectively. Conclusions: Cardiac failure, lung disorder, pneumonia, and TLS had a higher rate of fatal clinical outcomes after onset than other AEs. These AEs exhibited a greater onset tendency in the early post-dose period. This study suggests that there is a need to monitor signs of cardiac failure, lung disorder, pneumonia, and TLS, potentially resulting in serious outcomes.

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Evaluation of pregabalin-induced adverse events related to falls using the FDA adverse event reporting system and Japanese Adverse Drug Event Report databases

Journal of Clinical Pharmacy and Therapeutics ◽

10.1111/jcpt.12790 ◽

2018 ◽

Vol 44 (2) ◽

pp. 285-291 ◽

Cited By ~ 3

Author(s):

Ririka Mukai ◽

Shiori Hasegawa ◽

Ryogo Umetsu ◽

Satoshi Nakao ◽

Kazuyo Shimada ◽

...

Keyword(s):

Adverse Event ◽

Adverse Events ◽

Adverse Drug Event ◽

Reporting System ◽

Adverse Event Reporting System ◽

Adverse Event Reporting ◽

Drug Event ◽

Event Report ◽

Event Reporting

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Analysis of chemotherapy-induced peripheral neuropathy using the Japanese Adverse Drug Event Report database

Scientific Reports ◽

10.1038/s41598-021-90848-6 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Misaki Inoue ◽

Kiyoka Matsumoto ◽

Mizuki Tanaka ◽

Yu Yoshida ◽

Riko Satake ◽

...

Keyword(s):

Monoclonal Antibodies ◽

Peripheral Neuropathy ◽

Confidence Interval ◽

Median Duration ◽

Adverse Drug Event ◽

Vinca Alkaloid ◽

Interquartile Range ◽

Drug Event ◽

Event Report ◽

Time To Onset

AbstractChemotherapy-induced peripheral neuropathy (CIPN) is a common adverse event associated with several antineoplastic drugs; however, the precise risks and time course of reactions of particular drugs are not clearly understood. The aim of this study was to evaluate the relationship between anticancer agents and CIPN development using data from the Japanese Adverse Drug Event Report (JADER) database and to characterize the time-to-onset and outcomes of CIPN. Chemotherapy-induced peripheral neuropathy was defined using the Medical Dictionary for Regulatory Activities preferred terms. Disproportionality analysis was performed by calculating the reporting odds ratio (ROR) with 95% confidence interval for signal detection. Data of nine Anatomical Therapeutic Chemical (ATC) drug categories correlated with CIPN development, in addition to the data of the time-to-onset and outcomes. Among 622,289 reports in the JADER database from April 2004 to March 2020, there were 1883 reports of adverse events corresponding to peripheral neuropathy. The ROR (95% confidence interval) for vinblastine, sorbent-based paclitaxel (sb-PTX), oxaliplatin, and bortezomib was 20.4 (12.5–33.4), 13.6 (11.9–15.7), 26.2 (23.6–29.1), and 30.8 (26.6–35.8), respectively. The median duration (interquartile range) to CIPN development after the administration of vinca alkaloids and analogues, taxanes, platinum compounds, and monoclonal antibodies was 11.0 (5.0–46.5), 22.5 (6.0–82.5), 22.0 (6.0–68.5), and 32.5 (11.3–73.8) days, respectively. The median duration (interquartile range) of sb-PTX and nanoparticle albumin-bound (nab)-PTX was 35.0 (7.0–94.0) and 5.5 (3.0–29.3) days, respectively. Our analysis of records in the JADER database revealed several drugs associated with a high risk for CIPN development. In particular, the development of CIPN after vinca alkaloid administration should be closely monitored for 2 weeks after administration. CIPN caused by nab-PTX showed significantly faster onset than that by sb-PTX. Patients who receive taxanes or monoclonal antibodies often do not show an improvement; accordingly, early treatment is required.

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Phase 2 Suzhou MM02 Study: Chidamide with VRD Versus VRD in Newly Diagnosed High Risk Transplant Eligible Multiple Myeloma Patients

Blood ◽

10.1182/blood-2021-152390 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 4765-4765

Author(s):

Weiqin Yao ◽

Lingzhi Yan ◽

Jingjing Shang ◽

Song Jin ◽

Xiaolan Shi ◽

...

Keyword(s):

Multiple Myeloma ◽

Peripheral Neuropathy ◽

High Risk ◽

Adverse Events ◽

Critical Role ◽

Tumor Lysis Syndrome ◽

Induction Treatment ◽

Cell Transplant ◽

Phase 2 ◽

Newly Diagnosed

Abstract Background Bortezomib with lenalidomide and dexamethasone (VRd) is a standard regimen for the induction treatment of multiple myeloma (MM) transplant eligible and ineligible patients. Deregulation of histone acetylation has been recognized to serve a critical role in the pathogenesis of MM, which histone deacetylase (HDACs) are overexpressed in plasma cells derived from patients with MM. Therefore, HDACs may promise targets for MM therapy, and panobinostat was approved by FDA for the treatment of relapsed/refractory MM in 2015. Chidamide, a novel oral benzamide type HDAC inhibitor independently developed and approved as anticancer drugs in China, selectively suppresses the activity of class I HDACs. Our studies have shown that chidamide can enhance cytotoxic effect of bortezomib or lenalidomide on MM cells in vitro, which suggested a synergistic combination of chidamide with bortezomib or lenalidomide at low dose. In ASH 2019 we reported Phase 1 Suzhou MM02 study in which chidamide at 4 dose levels (15mg/20mg/25mg/30mg d 0,3,7,10) were administered to 12 patients with VRd for 4-cycle induction therapy. No DLT in Chi-VRd group were observed. This phase 2 trial was designed to further assess the safety and efficacy of Chi-VRd versus VRd for induction treatment in patients with newly diagnosed high risk MM before autologous transplantation (NCT 04025450). Methods In this study, we enrolled patients from the First Affiliated Hospital of Soochow University and Soochow Hopes Hematology Hospital with newly diagnosed high-risk multiple myeloma who were aged 18 years or older and eligible for autologous stem-cell transplant (ASCT) according to International Myeloma Working Group diagnostic criteria. All the patients were randomly assigned to Chi-VRd and VRd group. Chi-VRd group patients received Chidamide 20mg orally on days -1,2,6 and 9 in combination with VRd (bortezomib 1.3mg/m2 subcutaneously on days 1,4,8,11; lenalidomide 25mg orally on days 1-14; dexamethasone 20mg iv or orally on days 1,2,4,5,8,9,11,12) for 4 cycles. VRd group patients received VRd (bortezomib 1.3mg/m2 subcutaneously on days 1,4,8,11; lenalidomide 25mg orally on days 1-14; dexamethasone 20mg iv or orally on days 1,2,4,5,8,9,11,12) for 4 cycles. All the patients proceed with ASCT after four cycles or continue VRd therapy for up to eight cycles, followed by maintenance therapy for up to 2 years. Primary efficacy endpoints were overall response rate (ORR), rate of very good partial response (VGPR) or better and rate of complete response (CR) for Chi-VRd and VRd. Safety data described rates of adverse events. Results Between Mar 16, 2020, and Jul 22, 2021, 40 patients were enrolled and randomly assigned to either the VRd regimen (n=20) or the Chi-VRd regimen (n=20). In the Chi-VRd group, 1 patient was discharged due to severe tumor lysis syndrome, and another 1 patient was discharged from sick sinus syndrome (considering lenalidomide related). By the deadline for submission, 18 patients in the VRd group and 11 patients in the Chi-VRd group had completed induction chemotherapy. The total adverse events were listed in the table below. The main treatment-related adverse events were hematological toxicity, hepatotoxicity, constipation, and peripheral neuropathy. ORR was 90.9% (10/11) for Chi-VRd and was 100% for VRd. Response of VGPR or better was 81.8% (9/11) for Chi-VRd and was 83.3% (15/18) for VRd. And rate of CR was 63.6%(7/11) for Chi-VRd and was 44.4%(8/18) for VRd. Conclusion The Chi-VRd group had more adverse events of thrombocytopenia, peripheral neuropathy and pulmonary. No treatment-related death was observed in two groups. Patients received Chi-VRd get more CR rate. Updated PFS and OS with comparison between VRd and Chi-VRd will be presented at the following study. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

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Peripheral Neuropathy In Multiple Myeloma Patients Treated with Lenalidomide

Blood ◽

10.1182/blood.v116.21.5024.5024 ◽

2010 ◽

Vol 116 (21) ◽

pp. 5024-5024

Author(s):

Carmen Castaneda ◽

Lilia Weiss ◽

Neil A. Minton ◽

Alex Kim ◽

John Freeman ◽

...

Keyword(s):

Multiple Myeloma ◽

Peripheral Neuropathy ◽

Adverse Events ◽

Median Time ◽

Study Drug ◽

Phase Iii ◽

Immunomodulatory Activity ◽

Pivotal Phase ◽

History Of ◽

Time To Onset

Abstract Abstract 5024 Background: Lenalidomide is an oral IMiD® immunomodulatory compound with a dual mechanism of action, namely tumoricidal and immunomodulatory activity. As demonstrated by 2 randomized, double-blind, placebo-controlled pivotal phase III registration trials, lenalidomide plus dexamethasone (Len/Dex) was well tolerated and achieved significant clinical efficacy and survival outcomes vs placebo plus Dex (PBO/Dex) in patients (pts) with relapsed/refractory multiple myeloma (MM) (Weber 2007; Dimopoulos 2007). In MM, the rate of symptomatic peripheral neuropathy (PN) is 3–13%, although the rate of subclinical neuropathy detected by electrophysiological studies or histopathological evaluation is estimated to be much higher (40-60%; Kwan 2007). Published incidence of PN has been notable with thalidomide (Thal) ranging from 0 to 90%, depending on pt characteristics, concomitant treatments, dose/exposure duration, and techniques for identifying PN. We present the result of our analysis of PN adverse events (AEs) reported with Len. Methods: Reports of PN from the 2 registration studies (MM-009, MM-010; data cutoff June and August 2005, respectively), and postmarketing safety reports (Dec 2005 to Dec 2009) were retrieved from Celgene clinical and safety databases utilizing the Preferred Terms for PN AEs within the PN Standardized MedDRA (v13.0) Query (SMQ) to obtain all possible cases. Severity grades were according to the NCI CTCAE (V3). Results: Clinical Studies 703 pts (353 Len/Dex; 350 PBO/Dex) from the 2 registration studies were included in this analysis. The proportion of pts with ≥1 Grade (G) 1–4 PN AEs and ≥1 serious adverse event (SAE) was similar between the Len/Dex and PBO/Dex arm (45.6% vs 44.9% and 1.1% vs 1.1%, respectively). However, the proportion of pts with ≥1 G3/4 PN was slightly higher with Len/Dex vs PBO/Dex (9.3% vs 5.1%). Among the Len/Dex pts with PN AEs, prior Thal or vincristine was reported in 39.1% and 60.9% of pts, respectively and 24.8% of pts had history of PN. Among the PBO/Dex pts with PN AEs, prior Thal or vincristine was reported in 46.5% and 58.0% of pts, respectively and 29.3% of pts had a history of PN. Within this SMQ analysis, the PN AEs reported in ≥5% of the pts were peripheral neuropathy, hypoaesthesia, paraesthesia, and muscle weakness in both treatment arms. 98.3% of PN AEs were not SAEs and 83.2% were G1/2 in the Len/Dex arm. Among pts in the Len/Dex arm and with PN AEs, PN resolved in 61.5% and study drug was continued in 78.9% of pts. Study drug was reduced due to PN in 12.4% and interrupted in 5.0% of pts in the Len/Dex arm. The median time to onset of PN event was longer in the Len/Dex arm compared with the PBO/Dex arm (41 vs 31 days). Postmarketing A total of 2857 PN AEs were reported in 2329 of an estimated 73,592 MM pts. The reporting rate of PN AEs is 3.2% in the MM indication. Within this SMQ analysis, the PN AEs reported in ≥0.5% of the pts were peripheral neuropathy, hypoaesthesia, and paraesthesia. 93.8% of PN AEs were not SAEs. Most pts were males and elderly with a median age of 66 yrs (range: 29–95). Among MM pts with PN AEs and available information, 13% had prior Thal, 5% had prior bortezomib, and 11% had a history of PN. In the majority of reports, outcome was unknown and Len was continued. The median time to onset of PN event was 60 days (range: 1–1460). Conclusion: In 2 pivotal phase III registration trials, the incidence rate of peripheral neuropathy adverse events was similar between the Len/Dex and PBO/Dex arms. Most pts had prior anti-myeloma therapies associated with PN and a quarter of the pts had a history of PN. Limited information in postmarketing reports on prior therapies and medical history may have underestimated pre-existing PN and exposure to prior anti-myeloma therapies associated with PN. PN AEs occurred within a median of 60 days of starting Len. In conclusion, peripheral neuropathy adverse events in MM pts treated with Len are generally not SAEs and did not commonly require dose modification or interruption. References Dimopoulos et al. NEJM 2007;357(21):2123-2132. Kwan JY. Neurol Clin 2007;25(1):47-69. Weber et al. NEJM 2007;357(21):2133-2142. Disclosures: Castaneda: Celgene: Employment. Weiss:Celgene: Employment. Minton:Celgene: Employment. Kim:Celgene: Employment. Freeman:Celgene: Employment. Yu:Celgene: Employment. Knight:Celgene: Employment.

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Assessment of the Potential Adverse Events Related to Ribavirin-Interferon Combination for Novel Coronavirus Therapy

Computational and Mathematical Methods in Medicine ◽

10.1155/2020/1391583 ◽

2020 ◽

Vol 2020 ◽

pp. 1-7

Author(s):

Wenya Shan ◽

Dongsheng Hong ◽

Jieqiang Zhu ◽

Qingwei Zhao

Keyword(s):

Adverse Event ◽

Adverse Events ◽

Adverse Event Reporting System ◽

Adverse Event Reporting ◽

Drug Event ◽

Reporting Odds Ratio ◽

Serious Adverse Events ◽

Bayesian Confidence Interval ◽

Novel Coronavirus ◽

Safety Signals

Purpose. We aimed to analyze and evaluate the safety signals of ribavirin-interferon combination through data mining of the US Food and Drug Administration Adverse Event Reporting System (FAERS), so as to provide reference for the rationale use of these agents in the management of relevant toxicities emerging in patients with novel coronavirus pneumonia (COVID-19). Methods. Reports to the FAERS from 1 January 2004 to 8 March 2020 were analyzed. The proportion of report ratio (PRR), reporting odds ratio (ROR), and Bayesian confidence interval progressive neural network (BCPNN) method were used to detect the safety signals. Results. A total of 55 safety signals were detected from the top 250 adverse event reactions in 2200 reports, but 19 signals were not included in the drug labels. All the detected adverse event reactions were associated with 13 System Organ Classes (SOC), such as gastrointestinal, blood and lymph, hepatobiliary, endocrine, and various nervous systems. The most frequent adverse events were analyzed, and the results showed that females were more likely to suffer from anemia, vomiting, neutropenia, diarrhea, and insomnia. Conclusion. The ADE (adverse drug event) signal detection based on FAERS is helpful to clarify the potential adverse events related to ribavirin-interferon combination for novel coronavirus therapy; clinicians should pay attention to the adverse reactions of gastrointestinal and blood systems, closely monitor the fluctuations of the platelet count, and carry out necessary mental health interventions to avoid serious adverse events.

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Novel Adverse Events of Iloperidone: A Disproportionality Analysis in US Food and Drug Administration Adverse Event Reporting System (FAERS) Database

Current Drug Safety ◽

10.2174/1574886313666181026100000 ◽

2019 ◽

Vol 14 (1) ◽

pp. 21-26 ◽

Cited By ~ 2

Author(s):

Viswam Subeesh ◽

Eswaran Maheswari ◽

Hemendra Singh ◽

Thomas Elsa Beulah ◽

Ann Mary Swaroop

Keyword(s):

Data Mining ◽

Adverse Event ◽

Adverse Events ◽

Reporting System ◽

Adverse Event Reporting System ◽

Adverse Event Reporting ◽

Disproportionality Analysis ◽

Positive Signal ◽

Data Mining Algorithms ◽

Mining Algorithms

Background: The signal is defined as “reported information on a possible causal relationship between an adverse event and a drug, of which the relationship is unknown or incompletely documented previously”. Objective: To detect novel adverse events of iloperidone by disproportionality analysis in FDA database of Adverse Event Reporting System (FAERS) using Data Mining Algorithms (DMAs). Methodology: The US FAERS database consists of 1028 iloperidone associated Drug Event Combinations (DECs) which were reported from 2010 Q1 to 2016 Q3. We consider DECs for disproportionality analysis only if a minimum of ten reports are present in database for the given adverse event and which were not detected earlier (in clinical trials). Two data mining algorithms, namely, Reporting Odds Ratio (ROR) and Information Component (IC) were applied retrospectively in the aforementioned time period. A value of ROR-1.96SE>1 and IC- 2SD>0 were considered as the threshold for positive signal. Results: The mean age of the patients of iloperidone associated events was found to be 44years [95% CI: 36-51], nevertheless age was not mentioned in twenty-one reports. The data mining algorithms exhibited positive signal for akathisia (ROR-1.96SE=43.15, IC-2SD=2.99), dyskinesia (21.24, 3.06), peripheral oedema (6.67,1.08), priapism (425.7,9.09) and sexual dysfunction (26.6-1.5) upon analysis as those were well above the pre-set threshold. Conclusion: Iloperidone associated five potential signals were generated by data mining in the FDA AERS database. The result requires an integration of further clinical surveillance for the quantification and validation of possible risks for the adverse events reported of iloperidone.

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PATIENT-REPORTED NUMBNESS AND TINGLING AUGMENTS COMMON TERMINOLOGY CRITERIA FOR ADVERSE EVENTS (CTCAE) TO DETECT CHEMOTHERAPY-INDUCED PERIPHERAL NEUROPATHY (CIPN) IN OLDER ADULTS WITH ADVANCED CANCER UNDERGOING SYSTEMIC TREATMENT

Journal of Geriatric Oncology ◽

10.1016/s1879-4068(19)31231-7 ◽

2019 ◽

Vol 10 (6) ◽

pp. S67-S68

Author(s):

E. Culakova ◽

M. Mohamed ◽

M. Flannery ◽

A. Patil ◽

S. Obrecht ◽

...

Keyword(s):

Older Adults ◽

Peripheral Neuropathy ◽

Adverse Events ◽

Advanced Cancer ◽

Systemic Treatment ◽

Patient Reported

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Early adverse events after the first administration of zoledronic acid in Japanese patients with osteoporosis

Journal of Bone and Mineral Metabolism ◽

10.1007/s00774-021-01231-4 ◽

2021 ◽

Author(s):

Junichi Takada ◽

Kousuke Iba ◽

Osamu Yamamoto ◽

Takayuki Dohke ◽

Akira Saito ◽

...

Keyword(s):

Zoledronic Acid ◽

Adverse Events ◽

Japanese Patients

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AB0249 SAFETY OF BARICITINIB IN JAPANESE PATIENTS WITH RHEUMATOID ARTHRITIS (RA): THE 2020 INTERIM REPORT FROM ALL-CASE POST MARKETING SURVEILLANCE IN CLINICAL PRACTICE

Annals of the Rheumatic Diseases ◽

10.1136/annrheumdis-2021-eular.433 ◽

2021 ◽

Vol 80 (Suppl 1) ◽

pp. 1150.1-1150

Author(s):

T. Fujii ◽

T. Atsumi ◽

N. Okamoto ◽

N. Takahashi ◽

N. Tamura ◽

...

Keyword(s):

Clinical Practice ◽

Adverse Events ◽

Aspiration Pneumonia ◽

Japanese Patients ◽

Research Support ◽

Serious Adverse Events ◽

Chugai Pharmaceutical ◽

Post Marketing Surveillance ◽

Otsuka Pharmaceutical ◽

Post Marketing

Background:An all-case post marketing surveillance (PMS) of baricitinib (Bari), that started in Sep 2017, collects safety and effectiveness for the first 24 wks of treatment and continues to collect serious adverse events (SAEs) for 3 yrs.Objectives:To evaluate Bari safety in RA patients (pt) in clinical practice.Methods:We report pt baseline demographics and adverse events (AEs) up to 24 wks for pts whose case report files for 24-wk data were completed as of Jun 2020.Results:Data from 3445 pts were analyzed (females=80%, mean age=64yr, mean RA duration 12yr). Bari dose regimen was as follows: 4mg, 60%, 2mg, 27%, 4mg→2mg, 5%, 2mg→4mg, 5%, and others, 2%. Concomitant use of MTX and glucocorticoid was 65% and 48%, respectively. 74% continued treatment for 24 wks. AE and SAE were recognized in 887 (26%) and 122 pts (4%), respectively. 6 pts died of pneumonia, aspiration pneumonia, bacterial pneumonia, cerebral infarction/ILD/aspiration pneumonia, adenocarcinoma, and colorectal cancer. Major AEs were as follows: herpes zoster=3%, liver dysfunction=3%, serious infection=1%, anemia=1%, hyperlipidemia=1%, malignancy=0.3%, interstitial pneumonia=0.2%, MACE=0.1%, and VTE=0.1%.Conclusion:Data do not show new safety concerns and encourage guideline-compliant use of Bari.Disclosure of Interests:Takao Fujii Speakers bureau: Chugai Pharmaceutical Co. Ltd.; Eisai Co. Ltd; Eli Lilly Japan K.K.; Janssen Pharmaceutical K.K.; Ono Pharmaceutical Co. Ltd., Consultant of: Asahikasei Pharma Corp, Grant/research support from: Asahikasei Pharma Corp; AbbVie Japan GK; Chugai Pharmaceutical Co. Ltd., Eisai Co. Ltd; Eli Lilly Japan K.K.; Mitsubishi-Tanabe Pharma Co.; Ono Pharmaceutical Co., Ltd., Tatsuya Atsumi Speakers bureau: AbbVie Japan GK; Astellas Pharma Inc.; Bristol-Myers Squibb Co. Ltd; Chugai Pharmaceutical Co. Ltd.; Daiichi Sankyo Co. Ltd.; Eisai Co. Ltd.; Eli Lilly Japan K.K.; Mitsubishi Tanabe Pharma Co.; Pfizer Japan Inc.; Takeda Pharmaceutical Co. Ltd., UCB Japan Co. Ltd., Consultant of: AbbVie Japan GK; AstraZeneca plc.; Boehringer Ingelheim Co. Ltd.; Medical & Biological Laboratories Co. Ltd.; Novartis Pharma K.K.; Ono Pharmaceutical Co. Ltd.; Pfizer Japan Inc., Grant/research support from: Astellas Pharma Inc., Alexion Inc.; Chugai Pharmaceutical Co. Ltd., Daiichi Sankyo Co. Ltd., Mitsubishi Tanabe Pharma Co., Otsuka Pharmaceutical Co., Ltd.Pfizer Japan Inc.; Takeda Pharmaceutical Co. Ltd., Nami Okamoto Speakers bureau: AbbVie Japan GK; Asahikasei Pharma Co.; AYUMI Pharmaceutical Co.Eisai Co. Ltd; Bristol-Myers Squibb Co. Ltd.; Eli Lilly Japan K.K.; Mitsubishi-Tanabe Pharma Co.; Pfizer Japan Inc.Sanofi K.K.; Chugai Pharmaceutical Co. Ltd.; Novartis Pharma Co.; Teijin Pharma Ltd.; Torii Pharmaceutical Co., Ltd., Nobunori Takahashi Speakers bureau: AbbVie Japan GK; Eisai Co. Ltd.; Mitsubishi Tanabe Pharma Co.; Pfizer Japan Inc.; Chugai Pharmaceutical Co., Ltd.; Eli Lilly Japan K.K.; Janssen Pharmaceutical K.K.; UCB Japan Co. Ltd.; Astellas Pharma Inc.; Bristol Myers Squibb Co. Ltd., Grant/research support from: Bristol Myers Squibb Co. Ltd., Naoto Tamura Speakers bureau: AbbVie Japan GK; Bristol Myers Squibb Co. Ltd.; Chugai Pharmaceutical Co. Ltd.; Eisai Co. Ltd.; Eli Lilly Japan K.K.; Glaxo Smith Kline K.K.; Janssen Pharmaceutical K.K.; Mitsubishi-Tanabe Pharma Co.; Novartis Pharma Co., Atsuo Nakajima: None declared, Ayako Nakajima Speakers bureau: AbbVie Japan GK; Actelion Pharmaceuticals Japan Ltd., Asahi Kasei Pharma Co., Astellas Pharma Inc., Ayumi Pharmaceutical Co., Bristol Myers Squibb Co., Ltd.,Chugai Pharmaceutical Co., Ltd., Eisai Co., Ltd., Eli Lilly Japan K.K., Glaxo Smith Kline K.K., Hisamitsu Pharmaceutical Co. Inc., Kyorin Pharmaceutical Co. Ltd., Mitsubishi Tanabe Pharma Co., Otsuka Pharmaceutical Co. Ltd., Pfizer Japan Inc., Teijin Pharma Ltd., Grant/research support from: Chugai Pharmaceutical Co., Ltd., Mitsubishi Tanabe Pharma Co., Pfizer Japan Inc., Hiroaki Matsuno Speakers bureau: Chugai Pharmaceutical Co., Ltd., Daiichi Sankyo Co., Ltd., Eli Lilly Japan K.K., Consultant of: Mochida Pharmaceutical Co., Ltd., Grant/research support from: Astellas Pharma Inc., Eli Lilly Japan K.K.; Janssen Pharmaceutical K.K, Naoto Tsujimoto Shareholder of: Eli Lilly, Employee of: Eli Lilly Japan K.K., Atsushi Nishikawa Shareholder of: Eli Lilly, Employee of: Eli Lilly Japan K.K., Taeko Ishii Shareholder of: Eli Lilly, Employee of: Eli Lilly Japan K.K., Tsutomu Takeuchi Speakers bureau: AbbVie Japan GK, Ayumi Pharmaceutical Co., Bristol Myers Squibb Co., Ltd., Chugai Pharmaceutical Co, Ltd. Daiichi Sankyo Co., Ltd. Eisai Co., Ltd. Eli Lilly Japan K.K.; Gilead Sciences, Inc. Janssen Pharmaceutical K.K.; Mitsubishi-Tanabe Pharma Co.; Novartis Pharma Co.; Pfizer Japan Inc.; Sanofi K.K.; UCB Japan Co., Ltd., Consultant of: AbbVie Japan GK, Astellas Pharma, Inc.; Chugai Pharmaceutical Co, Ltd.; Eli Lilly Japan K.K.; Eisai Co., Ltd.; Gilead Sciences, Inc.; Janssen Pharmaceutical K.K.; Mitsubishi-Tanabe Pharma Corp., Pfizer Japan Inc., Grant/research support from: AbbVie Japan GK, Asahikasei Pharma Corp., Chugai Pharmaceutical Co, Ltd., DNA Chip Research Inc.; Eisai Co., Ltd., Eli Lilly Japan K.K.; Mitsubishi-Tanabe Pharma Corp., UCB Japan Co., Ltd., Masataka Kuwana Speakers bureau: AbbVie Japan GK, Astellas Pharma Inc., Asahi Kasei Pharma Co., Boehringer-Ingelheim, Chugai Pharmaceutical Co., Ltd., Eisai Co., Ltd., Janssen Pharmaceutical K.K., Medical &Biological Laboratories Co., Ltd.; Mitsubishi Tanabe Pharma Co.; Mochida Pharmaceutical Co., Ltd., Nippon Shinyaku Co., Ltd.; Ono Pharmaceutical Co., Ltd.; Pfizer Japan Inc., Consultant of: Boehringer-Ingelheim, Chugai Pharmaceutical Co., Ltd., Corbus Pharmaceuticals Holdings, Inc.; Medical &Biological Laboratories Co., Ltd.; Mochida Pharmaceutical Co., Ltd., Grant/research support from: Boehringer-Ingelheim, Chugai Pharmaceutical Co., Ltd., Eisai Co., Ltd., Medical &Biological Laboratories Co., Ltd; Mitsubishi Tanabe Pharma Co., Ono Pharmaceutical Co., Ltd., Michiaki Takagi Speakers bureau: Yes, but sponsored lectures without COI in the academic meetings, only.

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