Background and Objective As of December 2017, 20 diabetic ketosis (DK)/diabetic ketoacidosis (DKA) cases associated with sodium–glucose co-transporter 2 inhibitors (SGLT2i) had been reported to the Health Sciences Authority (HSA), Singapore. We aimed to provide a detailed analysis of the profile of these cases. Methods As part of the emerging safety issue monitoring, the HSA followed up on SGLT2i-associated DK/DKA cases with the reporters to obtain the missing and/or supplementary information. Descriptive statistics were employed to summarise the data collected, while the Mann–Whitney test was employed to evaluate the differences between typical and euglycaemic DKA cases as well as between genders. Results All cases led to hospitalisation but were non-fatal. Where reported, the majority (71–85%) of DK/DKA cases occurred within 180 days of SGLT2i therapy initiation and involved female patients and/or patients with long-standing type 2 diabetes mellitus (T2DM). Apart from the difference in blood glucose levels, no differences in the profile between the typical and euglycaemic DKA cases were noted. Known precipitating factors were identified in all cases. Acute illnesses, particularly infections and abscesses, were the most commonly reported precipitating factors, followed by insulin dose reduction/cessation. Conclusions Based on the profile of the reported cases, it is imperative to maintain clinical vigilance for DK/DKA, especially during the first 6 months of SGLT2i treatment and more so in female patients and/or patients with long-standing T2DM. Prompt evaluation and management of underlying precipitating factors is also important to assess and mitigate the risk of developing DK/DKA during treatment with SGLT2i.

Introduction: Despite reports suggesting an association between COVID-19 mRNA vaccination and pericarditis and myocarditis, detailed nationwide population-based data are sparsely available. We describe the incidence of pericarditis and myocarditis by age categories and sex after COVID-19 mRNA vaccination from a nationwide mass vaccination programme in Singapore. Methods: The incidence of adjudicated cases of pericarditis and myocarditis following COVID-19 mRNA vaccination that were reported to the vaccine safety committee between January to July 2021 was compared with the background incidence of myocarditis in Singapore. All treatment was discontinued after 2 months. Average NAPSI score on each hand was analysed. Results: As of end July 2021, a total of 34 cases were reported (9 pericarditis only, 14 myocarditis only, and 11 concomitant pericarditis and myocarditis) with 7,183,889 doses of COVID-19 mRNA vaccine administered. Of the 9 cases of pericarditis only, all were male except one. The highest incidence of pericarditis was in males aged 12–19 years with an incidence of 1.11 cases per 100,000 doses. Of the 25 cases of myocarditis, 80% (20 cases) were male and the median age was 23 years (range 12–55 years) with 16 cases after the second dose. A higher-than-expected number of cases were seen in males aged 12–19 and 20–29 years, with incidence rates of 3.72 and 0.98 case per 100,000 doses, respectively. Conclusion: Data from the national registry in Singapore indicate an increased incidence of pericarditis and myocarditis in younger men after COVID-19 mRNA vaccination. Keywords: COVID-19 vaccine, myocarditis, pericarditis

Recalls of some batches of metformin have occurred due to the detection of N-nitrosodimethylamine (NDMA) in amounts above the acceptable intake (AI) of 96 ng per day. Prior to the recalls, an international regulatory laboratory network had been monitoring drugs for nitrosamine impurities with each laboratory independently developing and validating multiple analytical procedures to detect and measure nitrosamines in metformin drugs used in their jurisdictions. Here, we provide an overview of the analysis of metformin active pharmaceutical ingredients (APIs) and drug products with 1090 samples (875 finished dosage forms (FDFs) and 215 API samples) tested beginning in November of 2019 through July of 2020. Samples were obtained internationally by a variety of approaches, including purchased, received from firms via information requests or selected by regional regulatory authorities (either at wholesalers or during GMP inspections). Only one nitrosamine (NDMA) was detected and was only present in some batches of metformin products. For API samples, 213 out of 215 lots tested had no measurable level of NDMA. For FDF samples tested, the number of batches with NDMA above the AI amount for patient safety was 17.8% (156/875). Based on these data, although the presence of NDMA was of concern, 82.2% of the samples of metformin drug products tested met quality and safety standards for patients. Regulatory agencies continue to collaborate extensively and work with marketing authorization holders to understand root causes of nitrosamine formation and agree on corrective actions to mitigate the presence of NDMA in future metformin batches. Graphical abstract

The objective of this study is to collate and analyse adverse event reports associated with the use of complementary health products (CHP) submitted to the Health Sciences Authority (HSA) of Singapore for the period 2010–2016 to identify various trends and signals for pharmacovigilance purposes. A total of 147,215 adverse event reports suspected to be associated with pharmaceutical products and CHP were received by HSA between 2010 and 2016. Of these, 143,191 (97.3%) were associated with chemical drugs, 1,807 (1.2%) with vaccines, 1,324 (0.9%) with biological drugs (biologics), and 893 (0.6%) with CHP. The number of adverse event reports associated with Chinese Proprietary Medicine, other complementary medicine and health supplements are presented. Eight hundred and ninety three adverse event reports associated with CHP in the 7-year period have been successfully collated and analyzed. In agreement with other studies, adverse events related to the “skin and appendages disorders” were the most commonly reported. Most of the cases involved dermal allergies (e.g., rashes) associated with the use of glucosamine products and most of the adulterated products were associated with the illegal addition of undeclared drugs for pain relief. Dexamethasone, chlorpheniramine, and piroxicam were the most common adulterants detected. Reporting suspected adverse events is strongly encouraged even if the causality is not confirmed because any signs of clustering will allow rapid regulatory actions to be taken. The findings from this study help to create greater awareness on the health risks, albeit low, when consuming CHP and dispelling the common misconception that “natural” means “safe.” In particular, healthcare professionals and the general public should be aware of potential adulteration of CHP. The analysis of spontaneously reported adverse events is an important surveillance system in monitoring the safety of CHP and helps in the understanding of the risk associated with the use of such products. Greater collaboration and communication between healthcare professionals, regulators, patients, manufacturers, researchers, and the general public are important to ensure the quality and safety of CHP.

The expiration of patents on many biological medicinal products has prompted the development of these products as similar biological (biosimilar) products. The standard approach of demonstration of bioequivalence for chemical generic products is scientifically not applicable for biosimilar products. The biosimilar product approach, based on comparability (demonstration of similarity), should be adopted. In view of the impending submissions and to facilitate access of such products at a more affordable price in Singapore, the Health Sciences Authority (HSA) formalised the procedures and requirements for registration of biosimilar products in 2009. HSA has published the "Guideline on Registration of Similar Biological Products in Singapore" which describes the basic principles, submission procedure, and requirements pertaining to documentation, pharmacovigilance, and post-approval batch release for the registration of biosimilar products. This article provides a brief overview as well as key points on the registration of medicinal products and biosimilar products in Singapore.

Introduction Substandard medicines are medicines that fail to meet their quality standards and/or specifications. Substandard medicines can lead to serious safety issues affecting public health. With the increasing number of pharmaceuticals and the complexity of the pharmaceutical manufacturing supply chain, monitoring for substandard medicines via manual environmental scanning can be laborious and time consuming. Methods A web crawler was developed to automatically detect and extract alerts on substandard medicines published on the Internet by regulatory agencies. The crawled data were labelled as related to substandard medicines or not. An expert-derived keyword-based classification algorithm was compared against machine learning algorithms to identify substandard medicine alerts on two validation datasets ( n = 4920 and n = 2458) from a later time period than training data. Models were comparatively assessed for recall, precision and their F 1 scores (harmonic mean of precision and recall). Results The web crawler routinely extracted alerts from the 46 web pages belonging to nine regulatory agencies. From October 2019 to May 2020, 12,156 unique alerts were crawled of which 7378 (60.7%) alerts were set aside for validation and contained 1160 substandard medicine alerts (15.7%). An ensemble approach of combining machine learning and keywords achieved the best recall (94% and 97%), precision (85% and 80%) and F 1 scores (89% and 88%) on temporal validation. Conclusions Combining robust web crawler programmes with rigorously tested filtering algorithms based on machine learning and keyword models can automate and expand horizon scanning capabilities for issues relating to substandard medicines. Supplementary Information The online version contains supplementary material available at 10.1007/s40264-021-01084-w.

Introduction: Despite reports suggesting an association between COVID-19 mRNA vaccination and pericarditis and myocarditis, detailed nationwide population-based data are sparsely available. We describe the incidence of pericarditis and myocarditis by age categories and sex after COVID-19 mRNA vaccination from a nationwide mass vaccination programme in Singapore. Methods: The incidence of adjudicated cases of pericarditis and myocarditis following COVID-19 mRNA vaccination that were reported to the vaccine safety committee between January to July 2021 was compared with the background incidence of myocarditis in Singapore. All treatment was discontinued after 2 months. Average NAPSI score on each hand was analysed. Results: As of end July 2021, a total of 34 cases were reported (9 pericarditis only, 14 myocarditis only, and 11 concomitant pericarditis and myocarditis) with 7,183,889 doses of COVID-19 mRNA vaccine administered. Of the 9 cases of pericarditis only, all were male except one. The highest incidence of pericarditis was in males aged 12–19 years with an incidence of 1.11 cases per 100,000 doses. Of the 25 cases of myocarditis, 80% (20 cases) were male and the median age was 23 years (range 12–55 years) with 16 cases after the second dose. A higher-than-expected number of cases were seen in males aged 12–19 and 20–29 years, with incidence rates of 3.72 and 0.98 case per 100,000 doses, respectively. Conclusion: Data from the national registry in Singapore indicate an increased incidence of pericarditis and myocarditis in younger men after COVID-19 mRNA vaccination. Keywords: COVID-19 vaccine, myocarditis, pericarditis

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