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Objective Results Conclusion A post‐marketing surveillance was conducted to evaluate the safety and efficacy of the buprenorphine transdermal patch under actual clinical practice.Of the 3017 patients included in the safety analysis, adverse drug reactions (ADRs) were observed in 1524 (50.5%), the most common being nausea, skin symptoms at the site of application, constipation, and vomiting. The incidences of respiratory depression and withdrawal symptoms were low, and no drug dependence was observed. Among the 2573 patients included in the efficacy analysis, the efficacy (≥2‐point improvement in the numerical rating scale) rate was 74.4%, which was significantly higher in older adults (≥65 y.o) than in younger adults. Discontinuation was mostly caused by ADRs during the early initiation phase.This study demonstrated the safety and efficacy of long‐term administration of buprenorphine transdermal patches, suggesting that pain control is possible over the long term if attention is paid to ADRs in the early stages of administration. [ABSTRACT FROM AUTHOR]

Introduction: Satralizumab, an anti-interleukin-6 receptor antibody, is approved in Japan for relapse prevention in neuromyelitis optica spectrum disorder (NMOSD) and is undergoing post-marketing surveillance (PMS) of clinical use. We aimed to describe the real-world safety and effectiveness of satralizumab in Japanese patients with NMOSD. Methods: This is an ongoing PMS (planned completion: February 2027). This 6-month interim analysis assessed the safety and effectiveness of satralizumab in Japanese patients with NMOSD using data collected from August 2020 to July 2021. Results: Among 570 patients who participated, 523 (91.75%) were female and the mean ± standard deviation (SD) age was 52.4 ± 14.1 years. At baseline, NMOSD expanded disability status scale mean ± SD was 4.19 ± 2.19; 490 (85.96%) patients used glucocorticoids and 277 (48.59%) patients used immunosuppressants concomitantly. Of 570 satralizumab-treated patients, 85 (14.91%) had discontinued satralizumab treatment at 6 months. For the overall adverse drug reactions (ADRs), 76.22 (66.07–87.48) events/100 person-years occurred in 118 (20.70%) patients, and infections occurred in 28 (4.91%) patients. Serious infections occurred in 18 (3.15%) patients, with an event rate of 9.05 (5.80–13.47) events/100 person-years. Of the 24 events of serious infections, respiratory tract infections (29.17%; 7) and urinary tract infections (25.00%; 6) were the most common serious infection events. One fatal ADR (septic shock) suspected to be related to satralizumab was reported. The mean ± SD glucocorticoid dose reduced from 12.28 ± 10.17 mg/day at the index date to 8.11 ± 7.30 mg/day at 6 months. The Kaplan–Meier cumulative relapse-free rate (95% confidence interval) was 94.59% (92.25–96.23) at 6 months. Conclusion: In this study, satralizumab was found to be safe, well tolerated, and effective in patients with NMOSD in routine clinical practice. The results are consistent with those of previous clinical trials. The safety and effectiveness of satralizumab in Japanese patients with NMOSD will be analyzed over the 6-year surveillance period. Trial Registration: UMIN Clinical Trials Registry, UMIN000041047. [ABSTRACT FROM AUTHOR]

Objective Methods Results Conclusion Fingolimod is the first oral sphingosine‐1‐phosphate receptor modulator approved in Japan for multiple sclerosis (MS). A large Japanese observational study of fingolimod in patients with MS was carried out to support its safety and effectiveness in a real‐world setting.This 2‐year, prospective, multicenter, single‐cohort, observational study included all Japanese patients with MS who initiated fingolimod (0.5 mg/day). Safety endpoints included adverse events and adverse drug reactions. Effectiveness endpoints included the annualized relapse rate, Kurtzke's Expanded Disability Status Scale score and physician clinical global impression. All endpoints were analyzed in fingolimod‐naïve patients.Of the 1792 patients who started fingolimod between 28 November 2011 and 31 May 2013, 1624 and 1623 fingolimod‐naïve patients were included in the safety and effectiveness analysis sets, respectively. The most common MS type was relapsing–remitting MS (89.47%). Adverse events, adverse events leading to discontinuation of fingolimod, adverse drug reactions and serious adverse drug reaction incidences were 64.10%, 15.33%, 57.88% and 23.46%, respectively. No new/unexpected safety signals were identified. The annualized relapse rate was 0.97 during the 1 year before baseline, and decreased to 0.22 after treatment. The mean Expanded Disability Status Scale score remained stable throughout treatment, irrespective of the baseline Expanded Disability Status Scale score (≥3 or <3). Physician clinical global impression was classified as ‘effective’ in the majority of patients (70.3%–90.1%) throughout the treatment period.Fingolimod was well tolerated and no new safety concerns were identified in this Japanese 2‐year post‐marketing study. Additionally, fingolimod was effective in preventing MS relapse and physical disability progression in this real‐world population comprising mainly relapsing–remitting MS patients. [ABSTRACT FROM AUTHOR]

Valbenazine is commonly used to treat tardive dyskinesia, and we conducted a pharmacovigilance analysis using the Food and Drug Administration Adverse Event Reporting System (FAERS) to evaluate neurological safety signals associated with valbenazine. Data was collected in FAERS from the second quarter of 2017 to the fourth quarter of 2023 for data cleaning. Neurological adverse event (AE) signals of valbenazine were mined by calculating reporting odds ratios (ROR), information component (IC) and empirical Bayesian geometric mean (EBGM). The serious and non-serious cases and signals were prioritized using a rating scale. The number of neurological AE reports where the primary suspect (PS) drug was 8981 for valbenazine. Significant AE signals were identified by the preferred term (PT) analysis for valbenazine, including somnolence (ROR 19.69), tremor (ROR 15.17), and tardive dyskinesia (ROR 236.91), among which 18 AEs were identified as new signals. Patient age (p < 0.009) and sex (p = 0.197) might be associated with an increased risk of neurological AE severity. Notably, the association between valbenazine and neurological disorders remained when stratified by sex, age, and reporter type. AE timing analysis was performed for the drug and four moderate clinical priority signals [i.e., somnolence, balance disorder, parkinsonism, and akathisia (priorities 7)], showing the same early failure type profiles. The increase in neurological safety signals is identified in the post-marketing research of valbenazine. Clinicians need to pay attention to not only common AEs but also be alert to new neurological AE signals when using valbenazine. • This study provides the latest valbenazine-related neurological safety profiles, and eighteen AEs were identified as new signals. • Neurological AEs most commonly identified for valbenazine were somnolence, tremor, dizziness, drooling, dyskinesia, and balance disorder. • Our findings could potentially prompt improved awareness of valbenazine-related toxicities and help healthcare professionals mitigate the risk of neurological events. [ABSTRACT FROM AUTHOR]

Trastuzumab emtansine (T-DM1) is widely utilized as a second-line and subsequent treatment for metastatic HER2+ breast cancer and has shown promise in early breast cancer treatment, particularly in adjuvant settings for residual disease after neoadjuvant chemotherapy. However, concerns have arisen regarding long-term hepatic adverse drug reactions (ADRs) not identified in clinical trials. We investigated potential safety signals of T-DM1 in hepatobiliary disorders and the time-to-onset of ADRs using the FDA Adverse Event Reporting System (FAERS) database. Suspected ADRs were extracted and divided into two groups: T-DM1 (N = 3387) and other drugs (N = 11,833,701). Potential signal for T-DM1 in hepatobiliary disorder were identified (reporting odds ratio [ROR] = 5.66, 95% confidence interval [CI] = 5.11–6.27; information component [IC] = 2.35, 95% Credibility Interval [Crl] = 2.18–2.51). A breast cancer indicated subgroup analysis (2519 T-DM1; 172,329 other drugs) also identified a potential safety signal (ROR = 3.28, 95% CI = 2.92–3.68; IC = 1.53, 95%CrI = 1.35–1.71). The median time-to-onset for T-DM1-associated hepatobiliary disorders was 41 days. For prolonged and chronic hepatobiliary disorders, median times were 322.5 and 301.5 days, respectively. These findings highlight the need for further research to inform clinical decisions on optimal T-DM1 treatment duration, balancing benefits with potential adverse reactions. [ABSTRACT FROM AUTHOR]

Objectives: An interim analysis of post-marketing surveillance data to assess the safety and effectiveness of sarilumab in Japanese patients with rheumatoid arthritis refractory to previous treatment. Methods: The interim analysis included patients who initiated sarilumab therapy between June 2018 and January 2021. The primary objective of this surveillance was safety. Results: In total, 1036 patients were enrolled and registered by 12 January 2021 (interim cut-off date). Of these, 678 were included in the safety analysis [75.4% female; mean age (± standard deviation) 65.8 ± 13.0 years]. Adverse drug reactions, defined as adverse events classified as possibly or probably related to sarilumab, were reported in 170 patients (incidence: 25.1%), with white blood cell count decreased (4.4%) and neutrophil count decreased (1.6%) most frequently reported. Serious haematologic disorders (3.4%) and serious infections (including tuberculosis) (2.5%) were the most frequently reported priority surveillance items. No malignant tumour was reported. An absolute neutrophil count (ANC) below the minimum standard value did not increase the incidence of serious infections. Conclusions: Sarilumab was well tolerated, and no new safety signals were noted in this analysis. There was no difference in the frequency of serious infections between patients with an ANC below or above normal. [ABSTRACT FROM AUTHOR]

Objectives: This interim report presents the 12‐week results of a post‐marketing surveillance evaluating the safety of desmopressin orally disintegrating tablets 25 and 50 μg in Japanese men with nocturia due to nocturnal polyuria. Methods: Of the planned study population of 1000 Japanese men receiving desmopressin for the first time for nocturia due to nocturnal polyuria, 971 cases were enrolled. In this interim analysis, 9 cases, including 6 registry violations and 3 cases of unconfirmed desmopressin dosing, were excluded from the 354 case report forms collected and fixed by the end of December 2021, and data up to 12 weeks after administration in 345 cases were defined as the safety analysis set. Results: The mean age was 74.5 ± 9.9 years and 88.7% of the survey participants were aged ≥65 years. Desmopressin was started at a dose of 25 μg in 153 cases (44.3%). There were 102 adverse drug reactions (ADRs) reported in 71 cases, including 6 serious ADRs in 3 cases (0.9%). The most common ADR was hyponatremia occurring in 29 cases (8.4%). Eight of the hyponatremic cases were asymptomatic. Symptoms were resolved or slightly improved within 4 weeks of onset in 13 of 29 cases of hyponatremia. In addition, hyponatremia occurred in 11 of 217 cases (5.1%), with a serum sodium level before the administration of desmopressin of ≥140 mmol/L, and in 13 of 87 cases (14.9%), with a level of 135–139 mmol/L, and was not measured in 5 hyponatremia cases. Patient characteristics that showed significant differences in the occurrence of hyponatremia included body weight, body mass index, renal function, and pretreatment serum sodium level. Regular monitoring of serum sodium is necessary for early detection of hyponatremia. Conclusions: Hyponatremia was the most common ADR when desmopressin orally disintegrating tablets were used to treat nocturia due to nocturnal polyuria over a 12‐week period. [ABSTRACT FROM AUTHOR]

Rabies presents with a high fatality rate, which imposes a significant global public health challenge, and therefore the use of post-exposure prophylaxis (PEP) is crucial for prevention. Monoclonal antibodies (mAbs) have emerged as a promising substitute for rabies immunoglobulins (RIGs) due to their high efficacy and standardized manufacturing process. A prospective, open-label, post-marketing surveillance study (PMS) was conducted at Byramjee Jeejeebhoy Medical College (BJMC), Pune. The study included patients aged more than 2 years who had recently sustained Category III-suspected rabid animal bite exposures. These patients were administered TwinRabTM at a dosage of 40 IU/ kg in and around the wound as intralesional transfer, along with the anti-rabies vaccine (ARV). Adverse events (AEs) grading was performed with reference to the Food and Drug Administration (FDA) toxicity grading. In this study, 215 subjects received the TwinRabTM mAb with a 100% completion rate. Out of 215 patients, three (1.3%) patients in the range of 18 to 65 years of age showed solicited local AEs, which were resolved after the appropriate treatment intervention, but causality assessment was non-assessable. The overall tolerability assessment showed positive ratings from doctors (91.63%) and patients (67.91%) for the mAb cocktail. The PMS demonstrated the safety of TwinRabTM in patients who experienced Category III-suspected rabid animal bites, thereby supporting its potential as an alternative option for post-exposure prophylaxis in the management of animal bites for the prevention of rabies [ABSTRACT FROM AUTHOR]

Simple Summary: In post-irradiated recurrent head and neck cancer (R-HNC), the treatment safety margin is limited by accumulated toxicity. Despite the development of aggressive curative treatment methods, such as reirradiation with photon or particle beam therapy with or without chemotherapy, sufficient clinical outcomes have not been achieved in various prospective trials due to the limitations imposed by toxicity. Boron neutron capture therapy (BNCT), with its selective cell-by-cell dose delivery, may be an effective and safe treatment option for patients with a prior radiotherapy history, as the previous Phase II trial of BNCT in unresectable locally recurrent or locally R-HNC has shown encouraging results. In this study, we analyzed the results of a Japanese nationwide post-marketing surveillance of BNCT for R-HNC conducted under the national health insurance system and found that toxicity was well-tolerated with preferable efficacy. BNCT is suggested to be a promising treatment option in post-irradiated R-HNC. Background: This study was conducted to evaluate the real-world safety and efficacy of boron neutron capture therapy (BNCT) with borofalan(10B) in Japanese patients with locally advanced or locally recurrent head and neck cancer (LA/LR-HNC). Methods: This prospective, multicenter observational study was initiated in Japan in May 2020 and enrolled all patients who received borofalan(10B) as directed by regulatory authorities. Patient enrollment continued until at least 150 patients were enrolled, and adverse events attributable to drugs, treatment devices, and BNCT were evaluated. The patients with LA/LR-HNC were systematically evaluated to determine efficacy. Results: The 162 patients enrolled included 144 patients with squamous cell carcinoma of the head and neck (SCCHN), 17 patients with non-SCCHN (NSCCHN), and one patient with glioblastoma. Treatment-related adverse events (TRAEs) were hyperamylasemia (84.0%), stomatitis (51.2%), sialoadenitis (50.6%), and alopecia (49.4%) as acute TRAEs, and dysphagia (4.5%), thirst (2.6%), and skin disorder (1.9%) as more common late TRAEs. In patients with LA/LR-HNC, the overall response rate (ORR) was 72.3%, with a complete response (CR) in 63 (46.0%) of 137 patients with SCCHN. Among 17 NSCCHN patients, the ORR was 64.7%, with eight cases (47.1%) of CR. One- and two-year OS rates in patients with recurrent SCCHN were 78.8% and 60.7%, respectively. Conclusions: This post-marketing surveillance confirmed the safety and efficacy of BNCT with borofalan(10B) in patients with LA/LR-HNC in a real-world setting. [ABSTRACT FROM AUTHOR]

Objectives: The objectives of this study were to describe the knowledge, attitudes and practices of Adverse Drug Reactions (ADR) reporting among healthcare professionals at Teaching Hospital Karapitiya (THK), a tertiary care hospital in Sri Lanka. Methodology: A descriptive cross-sectional study was conducted at THK. The healthcare professionals working in THK who were available during the study period were invited to the study. A self-administered pre-tested questionnaire was administered to the participants. Respondents were evaluated for their knowledge, attitudes and practices related to ADR reporting. The data were analyzed using SPSS statistical software. Results: Of the total 444 respondents, 31% were doctors and 69% were nurses. The majority of respondents, 90% (n = 400) were aware of the term ADR, while 64.8% (n = 288) could correctly define it. Among the respondents, 30.8% (n = 137) knew about the types of ADR and only 15.5% (n = 70) were able to mention a drug that is banned due to ADR correctly. Among the respondents, only 38.7% (n = 172) were aware of a formal process of reporting ADR and, only 35.3% (n = 157) stated that they had seen the ADR reporting form. Further, only 33.7% (n = 150) respondents have recognized ADR during their clinical practice and only a small proportion 18.2% (n = 81) have ever reported an ADR during their practice. Regarding attitudes toward ADR reporting, overall 84.1 (n = 373) had positive attitudes toward ADR reporting, while 13.54% (n = 60) of them stayed neutral and 2.25% (n = 10) had negative attitudes toward ADR reporting. Conclusions: Although the majority were aware of ADR, the knowledge and practices regarding spontaneous reporting of ADR are inadequate. However, most respondents have shown a positive attitude toward ADR reporting. A sincere and sustained effort should be made by concerned bodies to enhance the healthcare professionals' knowledge, attitudes, and practices regarding ADR reporting. [ABSTRACT FROM AUTHOR]

Objectives: Atopic dermatitis (AD) is a common chronic inflammatory skin disorder in Japan. Dupilumab, a fully human monoclonal antibody, targets a shared subunit of the interleukin (IL)‐4 and IL‐13 receptors. Post‐marketing surveillance of the safety and effectiveness of dupilumab in adult AD patients was conducted in Japan, where the drug is also allowed for use in older adolescents (i.e., ≥15 years), and interim results are reported here. Methods: This observational, multicenter study enrolled Japanese patients with AD who initiated dupilumab between July 2018–June 2020 (UMIN‐CTR Trials Registry: UMIN000032807). Baseline demographics, clinical history, medication data and dupilumab safety and effectiveness data were collected. Results: By the data cut‐off date of March 26, 2021, information from 600 patients has been collected. All the available safety and 1‐year effectiveness data are presented. The mean (standard deviation) age was 42.0 (15.9) years, the majority (69.1%) were male, and asthma was present in 12.2%. Adverse drug reactions (ADRs) were observed in 98 patients (16.4%), including conjunctivitis (n = 40; 6.7%), conjunctivitis allergic (n = 30; 5.0%), blepharitis (n = 5; 0.8%), headache and eye pruritus (n = 4; 0.7% each) and eosinophilia (n = 3; 0.5%). Six patients experienced asthma, all of whom had a history of, or concurrent, asthma. Disease severity improved remarkably at 4 months in most patients, which was maintained up to 1 year. Conclusion: Dupilumab appears to be a safe and effective treatment for patients aged ≥15 years with moderate‐to‐severe AD in routine clinical practice in Japan. Dupilumab was well tolerated, with no new safety signals and no new‐onset asthma. [ABSTRACT FROM AUTHOR]

Objectives: To report 24-week safety and effectiveness of certolizumab pegol (CZP) in Japanese patients with rheumatoid arthritis from a post-marketing surveillance study. Methods: Enrolled patients were newly receiving CZP. All adverse events (AEs) and adverse drug reactions (ADRs) were recorded for patients who received ≥1 CZP dose. Effectiveness outcomes included: 28-joint Disease Activity Score with erythrocyte sedimentation rate (DAS28-ESR) and European Alliance of Associations for Rheumatology (EULAR) response. Missing data were imputed using the last observation carried forward. Results: 3727 patients were enrolled; safety and effectiveness were evaluated in 3586 and 1794 patients, respectively. 24.9% of patients reported AEs (893/3586), 14.7% reported ADRs (528/3586), 8.3% (298/3586) reported serious AEs and 5.3% (190/3586) reported serious ADRs. Selected serious ADRs of interest: infections (110; 3.1%), tuberculosis (6; 0.2%), interstitial pneumonia (15; 0.4%), malignancy (8; 0.2%), and hepatic function disorder (7; 0.2%). No allergic reactions, autoimmune disease, cardiac failure, demyelinating diseases, or pancytopenia were reported. Mean DAS28-ESR reduced from 4.8 (baseline) to 3.4 (final evaluation). At final evaluation, 34.7% of patients achieved EULAR good response. Conclusions: These real-world safety and effectiveness results were consistent with previously reported data, with no new safety signals identified. Long-term, real-world CZP safety and effectiveness data are needed. [ABSTRACT FROM AUTHOR]

Introduction: SB4 is the first approved biosimilar of etanercept, a biologic tumor necrosis factor inhibitor, to treat various autoimmune diseases including axial spondylarthritis (axSpA), rheumatoid arthritis (RA), psoriatic arthritis (PsA), and plaque psoriasis (PsO). This post-marketing surveillance (PMS) study of SB4 investigated safety and effectiveness in routine clinical practice and is part of the drug approval process in Korea. Methods: This prospective, multi-center, open-label, observational, phase IV PMS study was designed to enroll patients with axSpA, RA, PsA, and PsO in Korea from September 2015 to September 2019. Both etanercept-naïve patients or patients switched from reference etanercept were included. SB4 was administered weekly via subcutaneous injections using pre-filled syringes. Safety was assessed by the incidence of adverse events (AEs), adverse drug reactions (ADRs) and serious adverse events (SAE). Effectiveness was assessed by the change from baseline of investigator-rated Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) in patients with ankylosing spondylitis (AS) and disease activity score-28 (DAS28) in patients with RA. Results: Among 316 enrolled patients, 314 were included in the safety analysis (176 with AS and 138 with RA). The overall incidence of AEs, ADRs and serious AEs were 17.8, 9.9, and 1.3%, respectively. Most AEs were mild (66.7%) or moderate (31.1%) and not related to SB4 (58.9%). Most common AEs were injection site pruritus (1.9%) and injection site rash (1.3%). At week 24, mean disease activity scores significantly decreased compared to baseline in naïve patients with AS and RA (BASDAI 2.7 vs. 6.2, p < 0.0001; DAS28 3.8 vs. 5.7, p < 0.0001) and in switched patients with AS and RA (BASDAI 1.0 vs. 1.3, p = 0.0018; DAS28 2.4 vs. 2.9, p = 0.0893). Conclusion: This first real-world evidence of SB4 from a phase IV PMS study in Korea shows comparable effectiveness to historical SB4 real-world evidence without any new significant safety signals. [ABSTRACT FROM AUTHOR]

Although the immunotherapy advent has revolutionized cancer treatment, it, unfortunately, does not spare cancer patients from possible immune-related adverse events (irAEs), which can also involve the peripheral nervous system. Immune checkpoint inhibitors (ICIs), blocking cytotoxic T-lymphocyteassociated protein 4 (CTLA-4), programmed cell death protein 1 (PD-1), or programmed cell death ligand 1 (PD-L1), can induce an immune imbalance and cause different peripheral neuropathies (PNs). Considering the wide range of PNs and their high impact on the safety and quality of life for cancer patients and the availability of large post-marketing surveillance databases, we chose to analyze the characteristics of ICI-related PNs reported as suspected drug reactions from 2010 to 2020 in the European real-world context. We analyzed data collected in the European pharmacovigilance database, Eudravigilance, and conducted a systematic and disproportionality analysis. In our study, we found 735 reports describing 766 PNs occurred in patients treated with ICIs. These PNs included Guillain-Barré syndrome, Miller-Fisher syndrome, neuritis, and chronic inflammatory demyelinating polyradiculoneuropathy. These ADRs were often serious, resulting in patient disability or hospitalization. Moreover, our disproportionality analysis revealed an increased reporting frequency of PNs with tezolizumab compared to other ICIs. Guillain-Barré syndrome is a notable potential PN related to ICIs, as it is associated with a significant impact on patient safety and has had unfavorable outcomes, including a fatal one. Continued monitoring of the safety profile of ICIs in real-life settings is necessary, especially considering the increased frequency of PNs associated with atezolizumab compared with other ICIs. [ABSTRACT FROM AUTHOR]

Objectives: To describe the characteristics of safety alerts issued by the Spanish Medicines Agency (AEMPS) and the Spanish Pharmacovigilance System over a 7-year period and the regulatory actions they generated. Methods: A retrospective analysis was carried out of drug safety alerts published on the AEMPS website from 1 January 2013 to 31 December 2019. Alerts that were not drug-related or were addressed to patients rather than healthcare professionals were excluded. Results: During the study period, 126 safety alerts were issued, 12 of which were excluded because they were not related to drugs or were addressed to patients and 22 others were excluded as they were duplications of previous alerts. The remaining 92 alerts reported 147 adverse drug reactions (ADRs) involving 84 drugs. The most frequent source of information triggering a safety alert was spontaneous reporting (32.6%). Four alerts (4.3%) specifically addressed health issues related to children. ADRs were considered serious in 85.9% of the alerts. The most frequent ADRs were hepatitis (seven alerts) and congenital malformations (five alerts), and the most frequent drug classes were antineoplastic and immunomodulating agents (23%). Regarding the drugs involved, 22 (26.2%) were "under additional monitoring." Regulatory actions induced changes in the Summary of Product Characteristics in 44.6% of alerts, and in eight cases (8.7%), the alert led to withdrawal from the market of medicines with an unfavorable benefit/risk ratio. Conclusion: This study provides an overview of drug safety alerts issued by the Spanish Medicines Agency over a 7-year period and highlights the contribution of spontaneous reporting of ADRs and the need to assess safety throughout the lifecycle of medicines. [ABSTRACT FROM AUTHOR]

Objective: Adverse Drug Reactions (ADR) add a significant clinical and economic burden to the healthcare system of a country. We present an overview of the different approaches of ADR reporting systems worldwide and their evolution over time. Methods: A systematic review of the literature was made based on PubMed and the Cochrane database of systematic reviews. The articles searched for included original articles, WHO and FDA reports and institute of medicine reports. Summary: Reporting ADRs is the cornerstone of detecting uncommon ADRs once the drugs are on the market. In many countries, ADR reporting is regulated by national regulatory bodies and various methods are employed to report ADRs. Direct reporting by healthcare professionals has been adopted by many developed and developing countries. With emerging new technologies in the field of medicine, there is a great potential to develop better ADR reporting systems in the countries where they have poor reporting. Conclusion: Development and acquisition of newer technologies to promote ADR monitoring and reporting is a necessity for an effective pharmacovigilance system in a country. [ABSTRACT FROM AUTHOR]

Schizophrenia is an unexplained, complex and serious mental illness. Blonanserin (BNS) is a new antipsychotic drug widely used in the treatment of schizophrenia. However, large-scale clinical studies have not been conducted in China. A multi-center, prospective, open-label, 12-week surveillance was carried out to evaluate the safety and effectiveness of BNS in patients with schizophrenia in China. Safety assessments included adverse drug reactions (ADRs), extrapyramidal symptoms (EPS), akathisia, concomitant medications for EPS by the end of treatment, and the changes in body weight from baseline by the end of treatment. The effectiveness was evaluated by the Brief Psychiatric Rating Scale (BPRS). From September 2018 to May 2020, of the 1,060 patients enrolled, 1,018 were included in the full analysis set (FAS) and safety set (SS), respectively. ADRs were developed in 205 patients among the included, the incidence being 20.1%. ADRs of EPS occurred in 169 patients, the incidence being 16.6%, ADRs of akathisia occurred in 90 patients, the incidence being 8.8%; concomitant therapeutic and prophylactic agents for EPS accounts for 19.2%; 4.0% of patients had a =7% increase in body weight from baseline at 12 weeks after initiating treatment. Using the last-observation-carried-forward (LOCF) method, the changes in total BPRS scores were -11.2 ± 10.17 (N = 1,018), -16.8 ± 12.69 (N = 1,018) and -20.6 ± 13.99 (N = 1,018) after 2/4, 6/8, or 12 weeks, respectively. 53.5% (545/1,018) patients showed response to blonanserin treatment in week 12. The post-marketing surveillance results of BNS demonstrates safety profile and effectiveness of the drug. [ABSTRACT FROM AUTHOR]

Introduction: TETRAXIM™ (Sanofi), a combined diphtheria, tetanus, acellular pertussis, and inactivated poliovirus (DTaP-IPV) vaccine, has been licensed in South Korea since 2009. In accordance with the Ministry of Food and Drug Safety regulations, this post-marketing surveillance (PMS) study evaluated the safety of the DTaP-IPV vaccine in real-world clinical practice in infants and children who received it as either a part of the three-dose primary series dose at 2, 4, and 6 months or school entry booster between 4 and 6 years of age. Methods: This multicenter, observational, PMS study was conducted in real-world practice in South Korea for 6 years (2009–2015) in participants aged between 2 months and 6 years. The study outcomes included solicited reactions, unsolicited adverse events (AEs)/adverse drug reactions (ADRs), unexpected AEs/ADRs, and serious AEs (SAEs)/ADRs. Results: Data from 647 participants was included in the safety analysis. Overall, 268 AEs were reported by 181 (28%) participants: 47 (17.5%) solicited reactions, 220 (82.1%) unsolicited AEs, and 1 (0.4%) unsolicited ADR. A total of 48 AEs (including 47 solicited reactions) were reported to have a causal relationship with the DTaP-IPV vaccine and were reported by 36 (5.6%) participants. A total of 212 unexpected AEs were reported by 152 (23.5%) participants, none of which had a causal relationship with the DTaP-IPV vaccine. Neither immediate AEs nor SAEs were reported during the study. Among the participants who reported AEs, 220 (34%) were on concomitant medications. Most AEs were of mild intensity, and all participants recovered. Conclusion: No safety concerns related to the DTaP-IPV vaccine in a real-world setting were raised in participants aged 2–6 months for the primary series and 4–6 years for the school-entry booster dose in the Korean population. The DTaP-IPV vaccine was well tolerated and can be continued as part of routine immunization programs in infants and children. Trial Registration: NCT01437423. [ABSTRACT FROM AUTHOR]

Background: Adverse events identified during clinical trials can be important early indicators of drug safety, but complete and timely data on safety results have historically been difficult to access. The aim was to compare the availability, completeness, and concordance of safety results reported in ClinicalTrials.gov and peer-reviewed publications. Methods: We analyzed clinical trials used in the Food and Drug Administration safety assessment of new drugs approved between 1 July 2018 and 30 June 2019. The key safety outcomes examined were all-cause mortality, serious adverse events, adverse events, and withdrawals due to adverse events. Availability of safety results was measured by the presence and timing of a record of trial-level results in ClinicalTrials.gov and a corresponding peer-reviewed publication. For the subset of trials with available results, completeness was defined as the reporting of safety results for all participants and compared between ClinicalTrials.gov and publications. To assess concordance, we compared the numeric results for safety outcomes reported in ClinicalTrials.gov and publications to results in Food and Drug Administration trial reports. Results: Among 156 trials studying 52 drugs, 91 (58.3%) trials reported safety results in ClinicalTrials.gov and 106 (67.9%) in peer-reviewed publications (risk difference = −9.6%, 95% confidence interval = −20.3 to 1.0). All-cause mortality was reported sooner in published articles compared with ClinicalTrials.gov (log-rank test, p = 0.01). There was no difference in time to reporting for serious adverse events (p = 0.05), adverse events (p = 0.09), or withdrawals due to adverse events (p = 0.20). Complete reporting of all-cause mortality was similar in ClinicalTrials.gov and publications (74.7% vs 78.3%, respectively; risk difference = −3.6%, 95% confidence interval = −15.5 to 8.3) and higher in ClinicalTrials.gov for serious adverse events (100% vs 79.2%; risk difference = 20.8%, 95% confidence interval = 13.0 to 28.5) and adverse events (100% vs 86.8%; risk difference = 13.2%, 95% confidence interval = 6.8 to 19.7). Withdrawals due to adverse events were less often completely reported in ClinicalTrials.gov (62.6% vs 92.5%; risk difference = −29.8%, 95% confidence interval = −40.1 to −18.7). No difference was found in concordance of results between ClinicalTrials.gov and publications for all-cause mortality, serious adverse events, or withdrawals due to adverse events. Conclusion: Safety results were available in ClinicalTrials.gov at a similar rate as in peer-reviewed publications, with more complete reporting of certain safety outcomes in ClinicalTrials.gov. Future efforts should consider adverse event reporting in ClinicalTrials.gov as an accessible data source for post-marketing surveillance and other evidence synthesis tasks. [ABSTRACT FROM AUTHOR]

We conducted a drug use investigation to investigate the safety and efficacy of tigecycline, which has been approved for clinical use for the treatment of multidrug-resistant gram-negative infections in Japan. This was an open-label, observational, multicenter cohort study that included all patients who received tigecycline. A total of 116 patients were registered between December 2012 and April 2016 and all of them were evaluated for safety and efficacy. Among them, 64 patients aged ≥65 years (55.2%) and five children aged <15 years (4.3%) were included. Of these patients, 47 (40.5%) met the approved indications of tigecycline. Adverse drug reactions (ADRs) were observed in 41 patients (35.3%) with a total of 74 events. Serious ADRs were observed in 15 patients (12.93%) with a total of 33 events. There were 42 deaths, and 6 of these were considered to be caused by ADRs. Among the 116 patients, 65 achieved clinical response at the end of the observation period, and the efficacy rate was 73.9%. Furthermore, 46 patients were assessed as "cure" at the test of cure visit, and the cure rate was 59.0%. The eradication rate was 47.5% at the end of the observation period. Classified by pathogenic bacteria, the eradication rate of patients infected with the approved pathogens was 54.5%. Tigecycline was well-tolerated, and no additional safety concerns were noted. It was effective considering that most patients had poor physical conditions. The overall benefit–risk balance of tigecycline was favorable. [ABSTRACT FROM AUTHOR]

Background: Nalfurafine (Remitch®, Toray Industries, Inc.) is a selective κ-receptor agonist approved in Japan for the improvement of pruritus in patients with chronic liver diseases (only when existing treatments bring insufficient efficacy) in May 2015. Methods: A post-marketing Specific Drug Use Survey was conducted in Japan (March 1, 2016 to June 30, 2020) of the safety and efficacy of nalfurafine for the improvement of pruritus in patients with chronic liver disease. Results: Among 1186 cases analyzed for safety, the incidence of adverse drug reactions was 9.4% (112/1186 cases), lower than 61.4% reported in pre-marketing surveillance (297/484 cases). No specific safety issues were found and no cases of concern for drug dependence identified. Efficacy (itch improvement) was demonstrated in 73.16% (815/1114 cases; 12-week analysis set) and in 85.67% (520/607; general assessment of itch improvement at 1-year analysis set). A significant difference was found in 4 items of itch improvement at 12 weeks and 8 items of itch improvement at 1 year. No noteworthy issues were identified. Mean Visual Analog Scale (VAS) values after 12 weeks and 1 year after the first dose were significantly lower than the baseline (p < 0.0001 for both treatment durations). Mean severity scores (Kawashima's classification scheme) were significantly lower than the pretreatment score at 12 weeks and 1 year after the first dose (both p < 0.0001). No concerns were identified in the efficacy and safety of nalfurafine in patients with specific background, ie, the elderly (aged ≥ 65 years), those with renal impairment, and those on long-term treatment (≥ 365 days) compared with patients without corresponding background. Conclusion: No new safety issues of concern or cases of insufficient efficacy were identified in this Specific Drug Use Survey of the safety and efficacy of nalfurafine for the improvement of pruritus in patients with chronic liver diseases. [ABSTRACT FROM AUTHOR]

Purpose: This prospective post-marketing surveillance (PMS) was designed to collect data on the safety and effectiveness of naldemedine in routine clinical practice in patients with opioid-induced constipation (OIC) and cancer pain in Japan and explore the characteristics of patients prone to diarrhea. Methods: The enrolled patients received naldemedine (0.2 mg, once a day) orally for up to 12 weeks. In the safety analysis, adverse drug reactions (ADRs), including diarrhea as a special interest, were assessed. Effectiveness was evaluated, especially regarding the frequency and condition of bowel movement. Results: In the safety analysis set (n = 1177), 145 ADRs occurred in 133 (11.30%) patients, and diarrhea was the most frequent event (n = 107, 9.09%). Most cases of diarrhea were non-serious (98.1%). Most ADRs were non-serious (93.8%), and they resolved within 2 weeks (75.9%). No patient characteristics influenced the risk of diarrhea development or aggravation. Both the frequency (75.0% and 83.2%) and condition of bowel movement (80.0% and 88.0%) were improved at 2 and 12 weeks, respectively in the effectiveness analysis set (n = 953). Frequency and condition of bowel movement were also improved in patients excluded (e.g., Eastern Cooperative Oncology Group performance status was ≥ 3) or with very small numbers (e.g., received weak opioid) in the clinical trials. Conclusions: This PMS indicates that naldemedine is well tolerated and effective in patients of various backgrounds in routine clinical practice who have OIC and cancer pain. Trial registration: UMIN000042851. [ABSTRACT FROM AUTHOR]

Immune checkpoint inhibitors (ICIs) are widely used improving clinical outcomes in many cancer patients. However, they can induce serious consequences, like neurological immune-related adverse drug reactions (NirADRs). Although these are rare complications, they can be serious with important impact on patients' quality of life. Our purpose is to describe these adverse events observed in the European clinical practice context. We carried out a descriptive analysis of individual case safety reports (ICSRs) related to ICIs collected until February 7, 2020, in the European spontaneous reporting database, EudraVigilance, and reported nervous disorders as suspect adverse drug reactions (ADRs). NirADRs were classified according to the Medical Dictionary for Regulatory Activities (MedDRA). In order to identify a hypothetical different reporting probability of the NirADR types between the ICI classes, we carried out a disproportionality analysis. The reporting odds ratio (ROR) with 95% CI was computed comparing the different ICI classes to each other based on their pharmacological target [the cytotoxic T-lymphocyte antigen-4 (CTLA-4), the programmed death-1 (PD-1) or its ligand (PD-L1)]. Finally, we researched in the literature the hypothesized mechanisms, which could explain the onset of these ICI-related neurological complications. Overall, we found 4,875 cases describing 6,429 ICI-related suspected NirADRs. ICI-related neurotoxicities include a wide range of central and peripheral events. These were mainly related to anti-PD-1 agents and occurred in male patients (59%). Our analysis confirmed a gender difference of NirADRs. Twenty-three percent of the events (comprising myasthenia gravis, neuropathy peripheral, and cerebral infarction) had unfavorable fallouts, including fatal outcome (7%). Majority of the NirADRs were categorized as "Neurological disorders NEC" HLGTs MedDRA (2,076; 32%). In 1,094 cases (22%), more NirADRs overlapped with other neurologic complications. An interesting overlapping of myasthenia gravis with myositis or myocarditis emerged. From our disproportionality analysis, an increased reporting probability of peripheral neuropathies and headaches emerged with ipilimumab when compared to anti-PD-1 and anti-PD-L1 agents. However, neuromuscular disorders were more probably reported with anti-PD-1. Several pathogenic mechanisms, including neuronal damage by T cells and autoantibodies and/or cytokine-mediated inflammation processes, have been hypothesized. However, the pathogenesis of these ICI-related complications is not completely understood. Considering the recent marketing authorizations of ICIs, further studies are strongly needed to monitor their neurologic safety profile. [ABSTRACT FROM AUTHOR]

Introduction: Seasonal influenza poses a major public health burden worldwide. Influenza vaccines, updated yearly to match circulating strains based on World Health Organization (WHO) recommendations, are the cornerstone of prevention and require regular monitoring. The COVID-19 pandemic is expected to cause logistical, site access and medical staff constraints and could affect the safety profile of influenza vaccines. Methods: Following European Medicines Agency guidance, an enhanced safety surveillance (ESS) study assessed the frequency and severity of predefined and other adverse events (AEs) occurring within 7 days of receiving GSK's inactivated quadrivalent seasonal influenza vaccine (IIV4), in Belgium, Germany and Spain in 2020/21, using adverse drug reaction (ADR) cards. Results: During the 2020/21 influenza season, 1054 participants vaccinated with GSK's IIV4 were enrolled (all adults in Belgium and Germany, 30% adults/70% children in Spain); 96 eligible children received a second dose. Overall, 1042 participants completed the study. After doses 1 and 2, 98.9% and 100% of participants, respectively, returned their completed ADR card. After doses 1 and 2, 37.8% (398/1054) and 13.5% (13/96) of participants, respectively, reported at least one AE. The most frequently reported categories of AEs were "general disorders and administration site conditions" (e.g. injection site pain) and "nervous system disorders" (e.g. headache). There were no deaths or serious AEs deemed related to GSK's IIV4. Conclusion: This ESS study assessed AEs in near real time. The COVID-19 pandemic did not alter the safety profile of GSK's IIV4. No safety signals were detected during the study, which confirms the excellent safety profile of GSK's IIV4. [ABSTRACT FROM AUTHOR]

Background and Aim: Ustekinumab, a human anti‐interleukin‐12/23 monoclonal antibody, has been approved in Japan for the treatment of Crohn's disease. Here, we report the findings from an 8‐week interim analysis of post‐marketing surveillance to evaluate the safety and effectiveness of ustekinumab in Japanese patients with Crohn's disease. Methods: Patients initiating ustekinumab treatment were prospectively evaluated from May 2017 to June 2020 at 91 medical centers in Japan. Adverse drug reactions (ADRs) and serious ADRs (SADRs) were monitored. Effectiveness was evaluated by clinical response, clinical remission, and changes in Crohn's Disease Activity Index (CDAI) and C‐reactive protein (CRP) from baseline to week 8. Presence of perianal disease was documented at baseline and week 8. Results: In total, 341 patients were enrolled in the study, of which 339 were included in the safety analysis while 334 were included in the effectiveness analysis. The overall incidences of ADRs and SADRs were 5.3% and 2.1%, respectively. Worsening of Crohn's disease was the most common event. The clinical response and clinical remission rate at week 8 were 40.0% and 48.5%, respectively. Significant improvements in CDAI and serum CRP (P < 0.001) were observed at week 8. CDAI decreased significantly (mean difference: −31.4; 95% confidence interval: −61.1, −1.7; P = 0.038) in biologics‐naïve patients versus patients who had received two or more biologics. Conclusions: This 8‐week interim analysis of the real‐world study confirmed the effectiveness of ustekinumab‐based therapy in Japanese patients with Crohn's disease. No new safety concerns were found during 8‐week induction period in the Japanese clinical settings. [ABSTRACT FROM AUTHOR]

Background: Oxaliplatin (OXA), a third-generation platinum derivative, has become one of the main chemotherapeutic drugs for colorectal cancer and other cancers, but reports of adverse reactions are also increasing with the extensive application of OXA. In this study, post-marketing surveillance was carried out to investigate the safety profile of OXA in a real-world setting in Chinese cancer patients to provide a reference for the rational application of OXA. Methods: All patients with cancer who received OXA-based chemotherapy in 10 tertiary hospitals in Hubei Province, China, between May 2016 and November 2016 were enrolled. A central registration method was used to document patients' demographics, clinical use, and any incidence of adverse reactions to OXA. All adverse drug reactions (ADRs) were collected and analyzed to assess causality, severity, treatment, and outcome. Results: In total, 3687 patients were enrolled in this study. Approximately 64.6% of the patients were male, and 68.8% were aged 50-70 years, with a mean age of 55.3 years. The proportions of patients diagnosed with colorectal and gastric cancers were 59.3% and 31.6%, respectively. In this study, the overall incidence of ADRs and serious ADRs was 42.7% and 1.3%, respectively. The most common ADRs were gastrointestinal disorders (25.7%), blood disorders (21.1%), and peripheral nervous system disorders (8.0%). The serious ADRs identified were hypersensitivity reactions, thrombocytopenia, abnormal hepatic function, and leukopenia/neutropenia. The median onset of gastrointestinal toxicity, myelosuppression, peripheral neurotoxicity, and abnormal hepatic function was 1 d, 5 d, 1 d, and 14 d, respectively. The majority (84.7%) of hypersensitivity reactions were mild to moderate, and the median time to onset of these reactions was within the first 20 min of OXA infusion. Almost 88.0% of patients who experienced ADRs recovered or improved with treatment. Conclusion: Our data suggest that OXA-induced ADRs are very common in Chinese patients with cancer; however, more attention should be paid to hypersensitivity reactions caused by OXA. This study provides a valuable reference regarding the safe application of OXA in a real-world setting. [ABSTRACT FROM AUTHOR]

Introduction: Golimumab is a human monoclonal antibody that inhibits tumor necrosis factor-α (TNF-α). Inhibition of TNF-α by golimumab inhibits the inflammatory response, thereby modulating the immune response in immune-mediated inflammatory diseases. Although the efficacy of golimumab has been demonstrated in randomized controlled trials (RCTs), various patient populations, such as those at high risk of infection, including those with latent tuberculosis and various comorbidities, or on co-administered medications, were excluded from the RCTs. Therefore, safety cannot be sufficiently evaluated by RCTs in the patient group with heterogenous characteristics. The aim of this study was to assess the safety and effectiveness of golimumab in patients with rheumatoid arthritis (RA), psoriatic arthritis (PsA), and ankylosing spondyloarthritis (AS) in a real-world setting in Korea. Methods: We conducted an open-label, prospective, non-interventional study as post-marketing surveillance. Safety was evaluated by collecting and recording adverse events, and effectiveness was evaluated by assessing disease activity using DAS28-CRP, DAS28-ESR, ACR20, and ASAS20 outcome measures. Multiple logistic regression was performed to identify factors associated with the incidence of adverse events, and changes in disease activity scores from baseline were analyzed using the Wilcoxon signed-rank test. Results: A total 673 patients were enrolled, of whom 621 were included in the safety analysis. During the study, 97 adverse drug reactions (ADRs) were reported in 62 patients (10.0%). The most frequently reported ADRs were related to infection, including nasopharyngitis (0.8%), upper respiratory tract infection (0.6%), and herpes zoster (0.5%). The mean (± standard deviation) changes from baseline in global disease activity at weeks 12 and 24 were − 3.37 ± 2.529 and − 3.68 ± 2.404, respectively, with statistical significance. In those patients with RA, 72.5 and 47.0% of individuals had a good response based on DAS28-CRP and DAS28-ESR outcomes at week 24. At week 24, 71.4% of patients with PsA had an ACR20 response and 72.9% of patients with AS had an ASAS20 response. Conclusion: In the real-world setting, golimumab was safe and effective in Korean patients with RA, PsA, and AS. [ABSTRACT FROM AUTHOR]

Omalizumab is approved as add-on therapy for pediatric asthma since 2013 in Japan, however, its data in clinical practice is limited. This post-marketing surveillance aimed to evaluate long-term safety and effectiveness of omalizumab in Japanese pediatric patients with severe allergic asthma in real-life setting. This 104-week, multicenter surveillance was conducted from September 2013 to May 2019 by central registration method. Patients with severe allergic asthma aged ≥6 and < 15 years at initiation of treatment who were first-time omalizumab users were included. The primary endpoints included incidence of adverse drug reactions and physician's Global Evaluation of Treatment Effectiveness (GETE). The secondary endpoints included incidence of serious adverse events, adverse events and adverse drug reactions of special interest and asthma exacerbation-related events. Of the 128 patients enrolled, 127 completed the surveillance and were included for safety and effectiveness analysis. Thirteen patients experienced 20 adverse drug reactions with an incidence rate of 10.2%. The most frequent adverse drug reactions were pyrexia (2.4%) and urticaria (1.6%). In total, adverse events and serious adverse events occurred in 60 (47.2%) and 30 patients (23.6%) respectively. Two patients experienced anaphylactic reaction and 1 patient experienced type 1 hypersensitivity. 77.2% had an effective response to omalizumab according to GETE at final assessment, and frequency of all asthma exacerbation-related events decreased in post-treatment versus pre-treatment. Long-term omalizumab treatment showed no new safety signals in pediatric patients with severe allergic asthma. The observed safety and effectiveness profile was consistent with previous studies. [Display omitted] [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]

Objective: To evaluate the safety and effectiveness of Qishe Pill (芪麝丸) on neck pain in real-world clinical practice. Methods: A multi-center, prospective, observational surveillance in 8 hospitals across Shanghai was conducted. During patients receiving 4-week Qishe Pill medication, Visual Analogue Scale (VAS) and Neck Disability Index (NDI) assessments have been used to assess their pain and function, while safety monitoring have been observed after 2 and 4 weeks. Results: Results from 2,023 patients (mean age 54.5 years) suggest that the drug exposure per unit of body mass was estimated at 3.41 ± 0.62 g/kg. About 8.5% (172/2,023) of all participants experienced adverse events (AEs), while 3.8% (78/2,023) of all participants experienced adverse reaction. The most common AEs were gastrointestinal events and respiratory events. The VAS score (pain) and NDI score (function) significantly decreased after 4-week treatment. An effect-quantitative analysis was also conducted to show that the normal clinical dosage may be consider as 3–4 g/kg, at which dosage the satisfactory pain-relief effect may achieve by 40-mm reduction in VAS. Conclusion: These findings showed that patients with cervical radiculopathy who received Qishe Pill experienced significant improvement on pain and function. (Registration No. NCT01875562) [ABSTRACT FROM AUTHOR]

Objectives: To explore whether the duration of prior low-dose methotrexate treatment (MTX; ≤8 mg/week) influences the safety and effectiveness of high-dose MTX (>8 mg/week) in Japanese patients with rheumatoid arthritis (RA).Methods: This post-hoc sub-analysis of a Japanese post-marketing surveillance study evaluated patients initiating high-dose MTX with ≥1 year or <1 year prior low-dose MTX use. Over 24 or 52 weeks, adverse drug reactions (ADRs) were monitored, and effectiveness was assessed using the Disease Activity Score in 28 joints, erythrocyte sedimentation rate (DAS28-4[ESR]).Results: 1292 MTX ≥1 year and 1001 MTX <1 year patients were included. The incidence of ADRs during the 24- and 52-week follow-up period was significantly more frequent in MTX <1 year than ≥1 year patients and serious ADRs were significantly higher in MTX <1 year than ≥1 year patients during the 52-week follow-up period (all p < 0.05). Over both follow-up periods, the mean DAS28-4(ESR) significantly decreased from baseline for all groups. Remission and low disease activity rates (DAS28-4[ESR] < 2.6 and <3.2, respectively) increased from baseline for all groups. Conclusions: High-dose MTX reduced disease activity regardless of prior treatment duration, but ADRs occurred more frequently among MTX <1 year patients compared to MTX ≥1 year patients. [ABSTRACT FROM AUTHOR]

Introduction: STELLA-LONG TERM is a post-marketing surveillance study evaluating the safety and effectiveness of ipragliflozin in Japanese patients with type 2 diabetes mellitus. Methods: Patients were classified by age at ipragliflozin initiation (< 65 and ≥ 65 years), and elderly patients were subclassified by baseline body mass index (BMI) < 25.0 or ≥ 25.0 kg/m2. Incidence of adverse drug reactions (ADRs) and effectiveness were evaluated over 3 years. Results: Among 11,051 patients, 7894 (71.4%) were aged < 65 years and 3157 (28.6%) ≥ 65 years. The 3-year ADR incidence was similar in patients aged ≥ 65 (19.04%) and < 65 years (19.36%; P = 0.701). Serious ADRs were more frequent in the subgroup ≥ 65 years (2.79% vs 1.55%; P < 0.001). In terms of ADRs of special interest, a significantly greater proportion of elderly patients had skin complications (2.22% vs 1.62%, P = 0.033), renal disorders (2.28% vs 1.51%, P = 0.005), hypoglycemia (0.73% vs 0.43%, P = 0.048), or malignant tumors (1.01% vs 0.24%, P < 0.001), while the incidence of polyuria/pollakiuria (5.97% vs 4.47%, P = 0.002) and hepatic disorders (1.39% vs 0.73%, P = 0.004) was significantly higher in non-elderly than elderly patients. In patients aged ≥ 65 years, the incidence of ADRs was higher when baseline BMI was ≥ 25 kg/m2 versus < 25 kg/m2 (24.40% vs 17.68%; P < 0.001). Glycosylated hemoglobin, fasting blood glucose, and body weight significantly decreased from baseline in both age groups at each evaluation up to 3 years (all P < 0.001). Conclusions: Ipragliflozin was well tolerated and effective for 3 years in routine clinical use in elderly and non-elderly patients, although elderly patients had a higher rate of serious ADRs. No new safety concerns were identified. Clinical Trial Registration: ClinicalTrials.gov identifier NCT02479399. [ABSTRACT FROM AUTHOR]

Background: Sodium hyaluronate/chondroitin sulfate fixed combination plays an essential role in the treatment of keratoconjunctivitis sicca, a multifactorial disease accompanied by ocular symptoms like alteration of the tear film. Despite low or no absorption of such drugs, these can cause secondary effects. An essential tool in the study of medication behavior is active pharmacovigilance. Unlike spontaneous reporting pharmacovigilance, this tool allows an appraisal of adverse drug reactions (ADRs)' real incidence, a higher capacity to identify safety signals, the relationship with concomitant drugs and pathologies prevalent in the study population. This study aimed to evaluate the safety profile and identify and/or assess adverse reactions in an uncontrolled population. Methods: Active pharmacovigilance by Drug Event Monitoring was performed. A total of 3 follow-up calls were made for 30 days for the identification of the ADRs, tolerability (ADR severity, seriousness, long term sequelae, and duration) and the possible risks (safety signals, medical interactions) of sodium hyaluronate and chondroitin sulfate (HUM). Results: Thirty-five ADRs were identified in the 212 patients included in the study (0.17 ADR/patient). The 35 ADRs were classified into 3 System Organ Class (SOC) groups: general disorders and administration site conditions (74.2%), eye disorders (22.9%), and nervous system disorders (2.9%); and 4 Preferred Term (PT) groups: burning sensation (74.2%), followed by blurred vision (20%), ocular pain (2.9%) and headache (2.9%). All the ADRs were categorized as mild and not serious. No statistically significant differences were found in concomitantly medications, posology and age groups. Conclusion: Good tolerability to the solution was identified, with a low incidence of ADRs. Just the same, all the associated ADRs were consistent with the information found in HUM's physicochemical profile and the physiopathology of DED. No unknown risks were identified, reinforcing HUM's safety profile. [ABSTRACT FROM AUTHOR]

Background: The purpose of this study was to evaluate the post-marketing safety and effectiveness of aripiprazole in treating irritability in pediatric patients (6–17 years) with autism spectrum disorder (ASD) in actual clinical sites of Japan. Methods: In this post-marketing surveillance, patients were enrolled into the multicenter, prospective, non-interventional, observational study for 52 weeks, and were dosed with aripiprazole (1–15 mg/day) under daily clinical settings in Japan. Results: In 510 patients, the continuation rate of aripiprazole treatment was 84.6% at day 168 (week 24) and 78.1% at day 364 (week 52). Adverse drug reactions (ADRs) occurred in 22.7% of patients (n = 116), and the most common ADRs were somnolence (9.4%), followed by weight increased (3.3%). At week 4, the mean change from baseline in the irritability subscale score for the Aberrant Behavior Checklist Japanese version (ABC-J) was − 5.7 ± 6.8 (n = 288). Based on multiple regression analysis, comorbid attention deficit and hyperactivity did not affect the ABC-J irritability subscale score at endpoint. At week 24, the mean change from baseline for the Strengths and Difficulties Questionnaire was − 3.3 ± 4.9 (n = 215) for the total difficulties score and 0.6 ± 1.7 (n = 217) for the prosocial behavior subscale score. Conclusions: Aripiprazole was well tolerated and effective in the long-term treatment of irritability associated with ASD in Japanese pediatric patients in the real-world clinical practice. Trial registration: This surveillance was registered with Clinical Trial.gov (no. NCT03179787) on June 7, 2017 (retrospectively registered). [ABSTRACT FROM AUTHOR]

Objectives: Primary: Analyze the Adverse Events (AEs) reported to the Food and Drug Administration (FDA) after use of mifepristone as an abortifacient. Secondary: Analyze maternal intent after ongoing pregnancy and investigate hemorrhage after mifepristone alone. Methods: Adverse Event Reports (AERs) for mifepristone used as an abortifacient, submitted to the FDA from September 2000 to February 2019, were analyzed using the National Cancer Institute's Common Terminology Criteria for Adverse Events (CTCAEv3). Results: The FDA provided 6158 pages of AERs. Duplicates, non-US, or AERs previously published (Gary, 2006) were excluded. Of the remaining, there were 3197 unique, US-only AERs of which there were 537 (16.80%) with insufficient information to determine clinical sever-ity, leaving 2660 (83.20%) Codable US AERs. (Figure 1). Of these, 20 were Deaths, 529 were Life-threatening, 1957 were Severe, 151 were Moderate, and 3 were Mild. The deaths included: 9 (45.00%) sepsis, 4 (20.00%) drug toxicity/overdose, 1 (5.00%) ruptured ectopic pregnancy, 1 (5.00%) hemorrhage, 3 (15.00%) possible homicides, 1 (5.00%) suicide, 1 (5.00%) unknown. (Table 1) Retained products of conception and hemorrhage caused most morbidity. There were 75 ectopic pregnancies, including 26 ruptured ectopics (includes one death). There were 2243 surgeries including 2146 (95.68%) D&Cs of which only 853 (39.75%) were performed by abortion providers. Of 452 patients with ongoing pregnancies, 102 (22.57%) chose to keep their baby, 148 (32.74%) had terminations, 1 (0.22%) miscarried, and 201 (44.47%) had unknown outcomes. Hemorrhage occurred more often in those who took mifepristone and misoprostol (51.44%) than in those who took mifepristone alone (22.41%). Conclusions: Significant morbidity and mortality have occurred following the use of mifepristone as an abortifacient. A pre-abortion ultrasound should be required to rule out ectopic pregnancy and confirm gestational age. The FDA AER system is inadequate and significantly underestimates the adverse events from mifepristone. A mandatory registry of ongoing pregnancies is essential considering the number of ongoing pregnancies especially considering the known teratogenicity of misoprostol. The decision to prevent the FDA from enforcing REMS during the COVID-19 pandemic needs to be reversed and REMS must be strengthened. Conflict of Interest Statement: The authors did not report any potential conflicts of interest. Authors note that although Dr. Harrison is an associate editor for Issues in Law and Medicine, she recused herself from any involvement in the peer review process for this manuscript. [ABSTRACT FROM AUTHOR]

Aims/Introduction: Tofogliflozin is a sodium–glucose cotransporter 2 (SGLT2) inhibitor that lowers plasma glucose levels by enhancing urinary glucose excretion. After its approval in Japan in 2014 for the treatment of type 2 diabetes mellitus, we carried out a 3‐year prospective observational post‐marketing surveillance study in Japanese patients (Japanese Study of Tofogliflozin with Type 2 Diabetes Mellitus Patients/Long Term [J‐STEP/LT]). Materials and Methods: This surveillance was carried out between September 2014 and February 2019, and recorded safety in terms of adverse drug reactions (ADRs) and ADRs of special interest, and effectiveness in terms of changes in glycated hemoglobin and bodyweight from baseline to last observation carried forward. Results: Of 6,897 patients with type 2 diabetes mellitus registered, 6,711 and 6,451 were analyzed for safety and effectiveness, respectively. ADRs were reported in 846 patients (12.61%), with serious ADRs in 101 patients (1.5%). ADRs of special interest included hypoglycemia (62 patients [0.9%]), polyuria/pollakiuria (90 [1.3%]), volume depletion‐related disorders (135 [2.0%]), urinary tract infections (91 [1.4%]), genital infections (117 [1.7%]) and skin diseases (53 [0.8%]). One case of diabetic ketoacidosis was reported. The mean ± standard deviation changes from baseline to last observation carried forward in glycated hemoglobin and bodyweight were −0.68 ± 1.34% (n = 6,158, P < 0.0001) and −3.13 ± 4.67 kg (n = 5,213, P < 0.0001), respectively. Conclusions: J‐STEP/LT, a 3‐year, prospective, observational, post‐marketing study in Japan, found no unprecedented ADRs, and consistent reductions from baseline in glycated hemoglobin and bodyweight over the observation period. The present results provide further evidence regarding the safety and tolerability of tofogliflozin in Japanese patients with type 2 diabetes mellitus. [ABSTRACT FROM AUTHOR]

Invasive fungal diseases are crucial causes of morbidity and mortality among patients with febrile neutropenia (FN). Though liposomal amphotericin B (L-AMB) is one of the agents recommended for first-line empirical antifungal therapy in patients with FN, large-scale clinical studies have not been performed in Japan. An open-label prospective multi-center study was carried out to evaluate the safety and efficacy of L-AMB in Japanese patients with FN suspected of having fungal infection. Of the 426 patients registered, safety and efficacy evaluations were conducted for 424 and 399, respectively. By clinical response criteria using 5 composite endpoints, the response rate was 46.6% (186/399). The response rate by age were 54.5% (child: 30/55), 47.5% (adult: 97/204), 42.1% (elderly: 59/140) respectively. Regarding the composite endpoints, resolution of fever was observed in 61.2% (244/399), no breakthrough fungal infection in 99.0% (395/399), survival for 7 days or longer after the completion of treatment in 83.7% (334/399), no discontinuation of treatment due to toxicity or lack of efficacy in 60.9% (243/399), and successful treatment of any baseline fungal infection in 10/18. Adverse drug reactions (ADRs) developed in 61.1% (259/424), and frequent ADRs were hypokalemia, kidney dysfunction, and liver dysfunction, as previously reported. The safety and efficacy profile of L-AMB in Japanese patients with FN suspected of having fungal infection were elucidated for the first time, through the analysis of a large number of cases including pediatric patients under real-world clinical settings collected in this nationwide study. [ABSTRACT FROM AUTHOR]

Background: Etelcalcetide is a second-generation calcimimetic for the management of secondary hyperparathyroidism (SHPT) in patients on dialysis. We performed a post-marketing surveillance (PMS) to obtain information on the safety and efficacy of etelcalcetide in clinical practice in Japan. Methods: This PMS enrolled SHPT patients who started initial treatment with etelcalcetide between April 1, 2017 and February 28, 2018 in Japan. Safety [adverse drug reactions (ADRs)] and efficacy [serum intact parathyroid hormone (iPTH), corrected calcium (cCa), phosphorous (P), and alkaline phosphatase (ALP)] were recorded for up to 52 weeks or until treatment discontinuation. Treatment decisions were at the physician's discretion. Results: Of 1226 patients enrolled across 282 centers, safety and efficacy data were available for 1195 and 1192, respectively, while 933 continued treatment to Week 52. The starting dose was 5 mg in 82.0% of patients. There were 218 ADRs in 169 patients (14.1%). Metabolism and nutrition disorders (8.8%), adverse laboratory test results (1.8%), and gastrointestinal disorders (1.6%) were the most frequent classes of ADRs. Hypocalcemia-related ADRs occurred in 104 patients (8.7%). The percentage of patients with iPTH levels within the target range (60–240 pg/mL) steadily increased from 19.5% at Week 0 to 64.1% at Week 52 or last dose. cCa, P, and ALP levels remained well controlled. Conclusion: This was the first real-world, large-scale, long-term observational PMS of etelcalcetide in Japan. We did not observe any new safety concerns. Etelcalcetide was associated with clinically relevant improvements in serum iPTH and maintenance of serum cCa, P, and ALP levels. [ABSTRACT FROM AUTHOR]

Purpose: Eculizumab, a drug that blocks activation of the terminal complement pathway, is useful in the treatment of several rare diseases. However, eculizumab-related meningococcal disease is a serious problem. Because of the difficulty diagnosing meningococcal disease, deaths from meningococcal disease may have been overlooked. The purpose of this study was to clarify the trend of meningococcal infection in patients on eculizumab and to evaluate the effectiveness of risk communication. Methods: Pharmacovigilance analysis was conducted using the Japanese Adverse Drug Event Report database between the first quarter of 2010 and the second quarter of 2019. Of the reports of deaths, those with adverse event terms of fever, shock, altered state of consciousness, loss of consciousness, sepsis, organ failure, and disseminated intravascular coagulation were analyzed as deaths with suspected meningococcal infection. Results: Of the 3559.2 person-years of eculizumab-exposed patients, 17 patients died with symptoms of meningococcal disease (including two confirmed cases). The mortality rate of meningococcal disease in patients exposed to eculizumab in Japan was estimated to be 0.56 (confirmed cases) to 4.8 (suspected cases) per 1000 person-years. Based on data from the National Epidemiological Surveillance of Infectious Disease, the mortality rate of meningococcal disease in the general population in Japan is 0.0042 per 100,000 person-years. Thus, the mortality rate from meningococcal disease in eculizumab-exposed patients is estimated to be 13,000 to 114,000 times the mortality rate from meningococcal disease in the general population of Japan. Academic societies warned of deaths from meningococcal disease in the first quarter of 2018, calling for appropriate action. Thereafter, only one death with symptoms of meningococcal disease has been reported. Conclusion: The analysis of the database showed that death from meningococcal disease in eculizumab-exposed individuals may occur more often than expected. This study also showed that appropriate risk communication reduced the fatality rate of meningococcal disease. [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]

Background: Ripasudil is approved in Japan for glaucoma or ocular hypertension (OH) when other treatments are ineffective or cannot be administered. Its long-term safety and efficacy are being examined in a post-marketing surveillance study; 12-month data are described here.Methods: This prospective, open-label, observational study enrolled patients with glaucoma or OH who started ripasudil during routine care. The key safety outcome was the incidence of adverse drug reactions (ADRs), focusing on allergy and/or inflammation-related ADRs such as blepharitis (including allergic) or conjunctivitis (including allergic). The primary efficacy endpoint was least squares mean (LSM) ± standard error (SE) change in intraocular pressure (IOP) from baseline to 12 months in all patients and in diagnostic groups. Secondary endpoints were change in IOP in groups stratified by treatment initiation pattern, number of concomitant drugs, and baseline IOP.Results: Overall, 3359 patients (48% male, mean age ± standard deviation [SD] 69.1 ± 12.7 years) were evaluated for safety and 3323 for efficacy. Diagnoses were primary open-angle glaucoma (43.9%), normal-tension glaucoma (36.6%), secondary glaucoma (8.7%), OH (4.2%), and primary closed-angle glaucoma (2.4%). Mean ± SD observation period was 300.1 ± 122.4 days; 1010 patients (30.1%) discontinued ripasudil by 12 months. ADRs occurred in 626 patients (18.6%); the most common were conjunctival hyperemia and blepharitis. Allergy and/or inflammation-related ADRs occurred in 388 patients (11.6%), most commonly blepharitis (5.6%) and conjunctivitis (4.2%). IOP decreased significantly from a mean ± SD 18.1 ± 6.1 mmHg at baseline; the LSM ± SE IOP change throughout 12 months of ripasudil treatment was - 2.6 ± 0.1 mmHg (- 14.0 ± 0.4%; p < 0.001). A significant decrease in IOP at 12 months was seen in all categories of baseline IOP (p < 0.001), and all types of glaucoma (p < 0.001), except neovascular glaucoma. Ripasudil was associated with a significant reduction in IOP at 12 months whether initiated as monotherapy or in combination with ≤4 concomitant glaucoma therapies (p < 0.001).Conclusions: Ripasudil was safe and effective in patients with glaucoma or OH during routine care. No new safety signals were identified, and significant reductions in IOP were maintained over 12 months. [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]

Objective: Fosamprenavir, a protease inhibitor (PI) to treat human immunodeficiency virus (HIV)-infected patients, has been approved in more than 40 countries and mainly used with nucleoside reverse transcriptase inhibitors. In Japan, Lexiva tablet (fosamprenavir calcium hydrate) has been marketed since January 2005 and used in clinical practice. The safety and effectiveness of fosamprenavir in HIV-infected Japanese patients were evaluated in an observational surveillance study (OTH112334).Methods: A post-marketing surveillance study (PMS) of fosamprenavir usage in HIV-infected Japanese subjects evaluating drug safety was conducted under Good Post-marketing Study Practice from January 2005 to December 2014.Results: Of 364 patients receiving fosamprenavir, 51% received emtricitabine/tenofovir disoproxil fumarate. Adverse events whose causal relationship could not be completely ruled out (adverse drug reactions; ADRs) were reported in 43.7%; the most common were diarrhoea (10.4%), hyperlipidaemia (8.5%) and hypertriglyceridaemia (6.9%). Serious ADRs were reported in 26 patients (32 events), including 1 death attributed to hepatic failure. Most ADRs occurred within 180 days after fosamprenavir was started. ADRs were more frequent in patients with the Centers for Disease Control and Prevention category B (AIDS or lipid disorders) or in those taking fosamprenavir combined with abacavir and lamivudine. Although spontaneous bleeding has been reported in hemophiliac patients taking other PIs, in this survey, only one muscle haemorrhage case was reported in 24 hemophiliac patients.Conclusions: The results of this PMS analysis in Japan support its known safety profile and identified no new safety risks for people living with HIV/AIDS in Japan currently on, or beginning treatment with, fosamprenavir. [ABSTRACT FROM AUTHOR]

Introduction: Clinical trials of linagliptin in Japanese patients conducted to date have had limited observational periods; therefore, there is a need for additional longer-term real-world data. The aim of this study was to investigate the long-term safety and effectiveness of linagliptin in routine clinical practice. Methods: This was a prospective, observational, post-marketing surveillance study conducted over 156 weeks in patients with type 2 diabetes mellitus who started linagliptin monotherapy. The primary endpoint was the incidence of adverse drug reactions (ADRs). The secondary endpoint was the change in glycated hemoglobin (HbA1c) from baseline to last available observation. Other effectiveness endpoints included the change in HbA1c and change in fasting plasma glucose (FPG) from baseline to week 26 and over the course of the treatment period. Results: Overall, 2235 and 2054 patients were included in the safety and effectiveness analysis sets, respectively. Patients were mostly male (58.4%), and the mean age was 66.7 years. The incidence of ADRs was 10.7% (n = 240). The most frequent ADRs according to MedDRA preferred terms were diabetes mellitus (n = 35 patients, 1.6%), constipation (n = 21, 0.9%), diabetes mellitus inadequate control (n = 13, 0.6%) and hypertension (n = 13, 0.6%). The mean change in HbA1c from baseline to last observation was − 0.67% [standard deviation (SD) 1.27%, 95% confidence interval − 0.72, − 0.61]. At week 26, HbA1c and FPG showed mean ± SD changes from baseline of – 0.73 ± 1.20% and − 21.02 ± 44.33 mg/dL, respectively, that were sustained until week 156. Conclusions: In Japanese patients with type 2 diabetes mellitus, linagliptin produced sustained reductions in HbA1c and had a safety profile consistent with the established safety profile of linagliptin. Trial Registration: ClinicalTrials.gov (NCT01650259). [ABSTRACT FROM AUTHOR]

Fabry disease is a rare X-linked inherited multisystem disorder resulting from deficiency of the lysosomal enzyme alpha-galactosidase A. Currently, specific therapies, including enzyme replacement therapies, are available for Fabry disease, but clinical trials provide limited information on long-term safety and effectiveness. Agalsidase alfa was approved in Japan in 2006. The post-marketing surveillance study of all patients receiving agalsidase alfa to evaluate its long-term safety and effectiveness as a mandatory condition for its approval had been conducted for 8 years (from February 2007 to March 2015). A total of 493 patients were included in this analysis of safety and effectiveness. The overall mean follow-up period was 3.5 years (range, 0.0–7.9 years). The percentage of patients with adverse drug reactions was 24.5% (121/493) and 12.6% had infusion-related reactions (62/493). In the 256 patients without prior enzyme replacement therapy whose IgG antibody data were available, 17 were IgG antibody positive (6.6%). However, the chronological correlation between seroconversion and the incidence of infusion-related reactions was not clear. The mean brief pain inventory score of the worst pain decreased in patients with moderate and severe pain at baseline. Plasma Gb 3 and urine sediment Gb 3 in males with classical Fabry disease without prior enzyme replacement therapy significantly decreased. The mean yearly changes in eGFR (mL/min/1.73 m2) ranged from −2.88 to +1.00 in males with classical Fabry disease, from −2.04 to −0.95 in males with non-typical variant and from −2.64 to −1.02 in females. The lower eGFR or the more proteinuria at baseline, the faster the decrease in eGFR of the patients was observed. There was no substantial difference in cardiac parameters (left ventricular mass index, E/A wave ratio, ejection fraction, and QRS duration). In conclusion, agalsidase alfa, 0.2 mg/kg every other week, was well tolerated and controlled the progression of symptoms (especially renal and cardiac) of Fabry disease in adults. Enzyme replacement therapy should be started in Japanese patients before cardiac and/or renal symptoms of Fabry disease develop. [ABSTRACT FROM AUTHOR]

Objectives: Post-marketing surveillance (PMS) was conducted to assess the safety and effectiveness of tacrolimus (TAC) add-on therapy for patients with rheumatoid arthritis (RA) and an inadequate response to biological disease-modifying anti-rheumatic drugs (DMARDs). Methods: Patients with RA from 180 medical sites across Japan were registered centrally with an electronic investigation system. The observational period was 24 weeks from the first day of TAC administration concomitantly with biological DMARDs. Results: Safety and effectiveness populations included 624 and 566 patients, respectively. Patients were predominantly female (81.1%), with a mean age of 61.9 years. Overall, 125 adverse drug reactions (ADRs) occurred in 94 patients (15.1%), and 15 serious ADRs occurred in 11 patients (1.8%). These incidences were lower compared with previously reported incidences after TAC treatment in PMS, and all of the observed ADRs were already known. A statistically significant improvement was observed in the primary effectiveness variable of Simplified Disease Activity Index after TAC treatment; 62.7% of patients achieved remission or low disease activity at week 24. Conclusions: TAC is well tolerated and effective when used as an add-on to biological DMARDs in Japanese patients with RA who do not achieve an adequate response to biological DMARDs in a realworld clinical setting. [ABSTRACT FROM AUTHOR]

Introduction: Natalizumab, a humanized anti-α4 integrin monoclonal antibody, received marketing approval in Japan in 2014 for the treatment of multiple sclerosis (MS). Because the previous large-scale clinical trials of natalizumab were mainly conducted in Europe and North American countries, and data in patients with MS from Japan were limited, we conducted an all-case post-marketing surveillance of natalizumab-treated MS patients from Japan to investigate the safety and effectiveness of natalizumab in a real-world clinical setting in Japan. Here, we report the results of an interim analysis. Methods: During the observation period of 2 years, all patients who were treated with natalizumab subsequent to its approval in Japan were followed. The effectiveness of natalizumab was assessed by examining the changes in expanded disability status scale (EDSS) score and annualized relapse rate (ARR) from baseline. Safety was assessed by analyzing the incidence of adverse drug reactions (ADRs). Results: The safety analysis included 106 patients (mean age 39.3 years; women 62.3%) whose data were collected until the data lock point (February 7, 2016). The effectiveness analysis included 75 patients. The majority of patients had relapsing-remitting MS (93/106 patients; 87.7%). The mean length of treatment exposure in the present study was 6.6 months. During the 2-year observation period, no significant change in the EDSS was observed, while the ARR decreased significantly from baseline (72.9% reduction, p = 0.001). ADRs and serious ADRs were observed in 11.3% and 3.8% of patients, respectively; however, no new safety concerns were detected. No patient had progressive multifocal leukoencephalopathy (PML) during the present study period. Conclusion: The safety and effectiveness of natalizumab were confirmed in Japanese patients with MS in clinical practice. Nevertheless, potential risks including PML require continuous, careful observation. Funding: Biogen Japan Ltd (Tokyo, Japan). [ABSTRACT FROM AUTHOR]

Background This large-scale study was conducted to evaluate the safety and effectiveness of eribulin for the treatment of inoperable or recurrent breast cancer in real-world settings in Japan. Methods Between July and December 2011, eligible patients with inoperable or recurrent breast cancer receiving eribulin for the first time were centrally registered and observed for 1 year. Eribulin was administered intravenously (1.4 mg/m) on days 1 and 8 of every 3-week cycle. The primary endpoint was the frequency and intensity of adverse drug reactions (ADRs). Secondary endpoints included overall response rate (ORR) and time to treatment failure (TTF). Results Of 968 patients registered at 325 institutions, 951 and 671 were included in the safety and effectiveness analyses, respectively. In the safety population, ADRs were observed in 841 patients (88.4%). The most common (≥15% incidence) were neutropenia (66.6%), leukopenia (62.4%), lymphopenia (18.4%), and peripheral neuropathy (16.8%). The most common grade ≥ 3 ADRs (>5% incidence) were neutropenia (59.8%), leukopenia (50.5%), lymphopenia (16.1%), and febrile neutropenia (7.7%). In the effectiveness population, ORR was 16.5% (95% confidence interval: 13.7, 19.4). The median TTF was 127 days (95% confidence interval: 120, 134). Conclusions The safety and effectiveness profile of eribulin was consistent with prior studies. Eribulin had a favorable risk-benefit balance when used in real-world clinical settings. [ABSTRACT FROM AUTHOR]

Background and objective: The use of contrast media in Italy has exponentially increased in the past 3 decades. However, it is unknown whether there has been an increase in clinical research evaluating the risks associated with contrast media usage, especially regarding contrast-induced nephropathy. To fill this gap in knowledge, we performed a systematic review.Study eligibility criteria: Meta-analyses, observational studies, and clinical trials assessing contrast media-induced nephropathy as the safety outcome, in which at least one author was affiliated with an Italian university/health care structure, were eligble.Data sources: Ovid MEDLINE, Ovid Embase, Cochrane Methodology Register, and Web of Science were screened.Participants: Men and women exposed to contrast media.Results: In total, 60 original articles were retrieved with an incremental trend between 1990 and 2017. Cohort studies were the most common study design represented. In total, 45 of 60 (75.0%) studies were monocenter studies and 41 of 60 (68.3%) received no funding. In all, 91.7% of studies disclosed no conflicts of interest and 81.7% had no external collaboration. Most of the studies provided a level of evidence of III-2 (32/60; 53.3%) and II (23/60; 38.3%). In total, 50 of 60 studies (83.3%) were published in a scientific journal ranked in the first quartile of their subject area.Conclusion: There was an increased number of studies evaluating contrast-induced nephropathy in Italy during the last three decades. These studies covered procedures to prevent contrast-induced nephropathy or aimed to identify risk factors, biomarkers, and scores, and their related prognosis. [ABSTRACT FROM AUTHOR]

Peramivir, the only injectable anti-influenza neuraminidase inhibitor medically available in Japan at present, is considered first-line treatment in patients with high risk factors for influenza exacerbation. We conducted a drug-use investigation of peramivir in inpatients with high risk factors (old age, pregnancy, and underlying disease such as chronic respiratory disease) from January 2010 to March 2013. Data of 772 patients from 124 facilities across Japan were collected; peramivir's safety in 770 patients and effectiveness in 688 patients were examined. In total, 412 adverse events were observed in 219 patients (28.4%). Of these, 155 events were adverse drug reactions (ADRs) observed in 98 patients (12.7%). Major ADRs (≥2%) were increased aspartate aminotransferase (5.1%), increased alanine aminotransferase (3.8%) and decreased white blood cell count (2.5%). Fourteen serious ADRs were observed in 12 patients (1.6%). All serious ADRs were resolved or improved except for two events for which outcomes were unknown. Multivariate analyses revealed that ADR incidences were significantly associated with these four backgrounds of patients: medical history, no influenza vaccination, renal impairment and other infection(s). With regard to its effectiveness, the median time to alleviation of both influenza symptoms and fever was 3 days, including the first day of administration, which was the same as in other previous surveillance studies. This surveillance study indicated the safety of peramivir in the treatment of influenza inpatients with high risk factors under routine clinical settings. [ABSTRACT FROM AUTHOR]