Adverse Drug Reactions of Intranasal Corticosteroids in the Netherlands:An Analysis from the Netherlands Pharmacovigilance Center

BACKGROUND: Intranasal corticosteroids are one of the cornerstone treatment options for allergic rhinitis and chronic sinusitis complaints. Safety information in the summary of product characteristics may not be representative for observations in daily clinical practice. The Netherlands Pharmacovigilance Center (Lareb) collects post-marketing safety information, using spontaneous reporting systems. OBJECTIVE: Our objective was to analyse reports of adverse drug reactions associated with intranasal corticosteroids reported in the Dutch spontaneous reporting database of the Netherlands Pharmacovigilance Center Lareb to obtain insight into real-world safety data. METHODS: We retrospectively examined all adverse drug reactions of intranasal corticosteroids reported to the Netherlands Pharmacovigilance Center Lareb, entered into the database from 1991 until 1 July, 2020. RESULTS: In total, 2263 adverse drug reactions after intranasal corticosteroid use were reported in 1258 individuals. Headache (n = 143), epistaxis (n = 124) and anosmia (n = 57) were reported most frequently. Nasal septum perforation (reporting odds ratio 463.2; 95% confidence interval: 186.7-1149.7) had the highest reporting odds ratio, followed by nasal mucosal disorder (reporting odds ratio 104.5; 95% confidence interval 36.3-301.3) and hyposmia (reporting odds ratio 90.8; 95% confidence interval 45.1-182.7). Moreover, 101 (4.5%) reports were classified as serious by Lareb, including reports of Cushing's syndrome, adrenal cortical hypofunction and growth retardation. CONCLUSIONS: Many side effects are consistent with the safety information in the summary of product characteristics of intranasal corticosteroids. Several serious (systemic) side effects are reported and it is important to realise that intranasal corticosteroids may contribute to the development. Healthcare providers and patients should be aware of the potential (individual) adverse drug reactions of intranasal corticosteroids. This information could help in discussing treatment options

Sex Differences in Adverse Drug Reactions of Metformin:A Longitudinal Survey Study

Introduction: In general, women more often experience metformin-associated adverse drug reactions (ADRs) than men. Objectives: We aimed to assess whether sex differences in reported ADRs for metformin are observed at different times after initiation, and to explore their concurrence with sex differences in the dose of metformin over time. This may guide future studies in assessing the involved mechanisms of sex differences in metformin-associated ADRs and may guide sex-specific management of ADRs in clinical practice. Methods: This study has a longitudinal design using data about patients initiating metformin collected by the Dutch National Pharmacovigilance Center Lareb through their Intensive Monitoring program. Patients were asked to complete a web-based questionnaire six times after initiation (i.e., at 2 weeks, 6 weeks and at 3, 6, 9, and 12 months). The outcome variables were the proportion of patients reporting any ADR (primary) and the dose of metformin (secondary). Sex differences in the proportions of ADRs and in the dose were tested at each assessment using Pearson Chi-Squared tests and Wilcoxon rank-sum tests, respectively. Using Bonferroni adjustment for multiple testing, a p value < 0.01 was considered statistically significant. Results: The number of included patients was 1712 (40.9% women). Women reported an ADR more often than men, which was statistically significant at the assessment at 2 weeks (34% vs 25%, p < 0.001), and 6 weeks (37% vs 28%, p = 0.001) after initiation. In general, women were reported to be prescribed a lower dose than men, which became statistically significant at the 9-month assessment (p < 0.01). Conclusions: Sex differences in reported ADRs were seen in the first weeks after metformin initiation, whereas statistically significant differences in self-reported prescribed dosing were observed after several months. Patients, in particular women, might benefit from being prescribed lower metformin doses at treatment initiation

Post-Marketing Safety Profile of Vortioxetine Using a Cluster Analysis and a Disproportionality Analysis of Global Adverse Event Reports

INTRODUCTION: Vortioxetine, a multimodal serotonergic drug, is widely used as treatment for major depressive disorder. Although on the market since late 2013, the data of the relative safety of vortioxetine, especially compared to selective serotonin reuptake inhibitors, are still scarce. OBJECTIVE: The aim of this study was to explore the adverse event reporting pattern of vortioxetine through a cluster analysis. Furthermore, to compare the adverse event reporting pattern for vortioxetine with that of the selective serotonin reuptake inhibitors. METHODS: Individual case safety reports for vortioxetine in VigiBase up to 1 November, 2019 were subjected to consensus clustering, to identify and describe natural groupings of reports based on their reported adverse events. A vigiPoint exploratory analysis compared vortioxetine to the selective serotonin reuptake inhibitors in terms of relative frequencies for a wide range of covariates, including patient sex and age, reported drugs and adverse events, and reporting country. Important differences were identified using odds ratios with adaptive statistical shrinkage. RESULTS: Thirty-six clusters containing at least five reports were identified and analysed. The two largest clusters included 48% of the vortioxetine reports and appeared to represent gastrointestinal adverse events and hypersensitivity adverse events. Other distinct clusters were related to, respectively, fatigue, aggression/suicidality, convulsion, medication errors, arthralgia/myalgia, increased weight, paraesthesia and anticholinergic effects. Some of these clusters are not labelled for vortioxetine, such as arthralgia/myalgia and paraesthesia, but are known adverse events for selective serotonin reuptake inhibitors. A vigiPoint analysis revealed a higher proportion of reports from consumers and non-health professionals for vortioxetine as well as higher relative reporting rates of gastrointestinal symptoms, pruritus and mood-related symptoms, consistent with the cluster analysis. CONCLUSIONS: A pattern of co-reported adverse events that is consistent with labelled adverse events for vortioxetine and the safety profile for selective serotonin reuptake inhibitors in general was revealed. Clusters of unlabelled adverse events were identified that reflect clinical entities that might represent signals of previously unknown adverse events. More extensive analyses of spontaneous reports may help to further understand the reporting pattern of adverse events. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s40264-021-01139-y

Analysis of Safety Concerns on Herbal Products with Assumed Phytoestrogenic Activity

Phytoestrogens (PEs) are plant-based compounds that can interact with estrogen receptors and are mainly used to treat menopausal complaints. However, the safety of products with assumed phytoestrogenic activity is not fully understood. This study aimed to identify plant species with assumed phytoestrogenic activity, review existing literature on their use and safety, and critically evaluate adverse reaction (AR) reports of single-herb, multi-herb, and mixed-multiple products, as submitted to the Netherlands Pharmacovigilance Centre Lareb and to VigiBase of the World Health Organization (WHO). In the Lareb database, the most commonly reported plant species to cause ARs (total of 67 reports) were Actaea racemosa L. (black cohosh) (47.8%), Humulus lupulus L. (hops) (32.8%), and Glycine max (L.) Merr. (soybean) (22.4%). In the VigiBase database (total of 21,944 reports), the top three consisted of Glycine max (L.) Merr. (71.4%), Actaea racemosa L. (11.6%), and Vitex agnus-castus L. (chaste tree) (6.4%). In the scoping review (total of 73 articles), Actaea racemosa L. (30.1%), Glycine max (L.) Merr. (28.8%), and Trifolium pratense L. (13.7%) were the most frequently mentioned plant species. ARs were most frequently reported in the system organ classes "gastrointestinal disorders", "skin and subcutaneous tissue disorders", "reproductive system and breast disorders", and "general disorders and administration site conditions". Furthermore, from the scoping review, it appeared that the use of products with assumed phytoestrogenic activity was associated with postmenopausal bleeding. It was concluded that, while the potential benefits of products with assumed phytoestrogenic activity have been extensively pursued, the potential occurrence of ARs after using these products is less well understood. This study highlights the need for further investigation and careful monitoring of these products to better understand their effects and ensure the safety and well-being of individuals using them. </p

Pharmacogenetics and Pharmacokinetics in high-dose alkylating chemotherapy

High-dose chemotherapy in combination with peripheral blood progenitor cell transplantation has been developed as a possible curative treatment modality in several solid tumours. A frequently used high-dose regimen in the Netherlands is the CTC regimen, which is a 4-day course of cyclophosphamide, thiotepa and carboplatin. High-dose chemotherapy is demanding for the patient. Severe and sometimes life-threatening toxicities may occur after high-dose chemotherapy. Therefore, treatment optimization in order to prevent or reduce toxicity is necessary. Pharmacogenetics focuses on the question to what extent variability in genetic background is responsible for the observed interindividual variability in pharmacokinetics and toxicity and might provide a tool for the a priori identification of patients at risk for severe toxicity. The objectives of this thesis were to identify relations between the genotype of the metabolising enzymes involved in cyclophosphamide, thiotepa and carboplatin metabolism, pharmacokinetics and toxicity in order to identify patients at risk for severe toxicity or under-treatment and, when possible, to develop a strategy for safe dosing of the agents included in the high-dose CTC regimen. Thiotepa is metabolised by cytochrome P450 and glutathione S-transferase enzymes. Polymorphisms of these enzymes may affect elimination of thiotepa and tepa, its main metabolite. Clearance of thiotepa and tepa was shown to be predominantly affected by the GSTP1 C341T polymorphism. Patients homozygous for the variant allele had an increased exposure to thiotepa and tepa of 45% compared to patients with the wild-type genotype. The presently evaluated variant alleles, however, only explained a small part of the substantial interindividual variability in thiotepa and tepa pharmacokinetics. Cyclophosphamide is metabolised by cytochrome P450, glutathione S-transferase and aldehyde dehydrogenase enzymes. The presently evaluated variant alleles in the genes encoding the enzymes important in cyclophosphamide metabolism did not explain the interindividual variability in cyclophosphamide and 4-hydroxycyclophosphamide pharmacokinetics. To obtain more insight into the interindividual variability in toxicity observed after treatment with CTC chemotherapy, relations between polymorphisms in drug metabolising enzymes and toxicity were studied. Sixteen selected polymorphisms in nine genes (CYP2B6, CYP2C9, CYP2C19, CYP3A4, CYP3A5, GSTA1, GSTP1, ALDH1A1 and ALDH3A1) of putative relevance in cyclophosphamide, thiotepa and carboplatin metabolism were assessed. Patients heterozygous for the ALDH3A1*2 and ALDH1A1*2 allele had an increased risk of haemorrhagic cystitis and liver-toxicity, respectively, compared to patients with wild-type alleles when treated with a high-dose chemotherapy combination of cyclophosphamide, thiotepa and carboplatin. The ALDH enzymes are important in the intracellular detoxification of cyclophosphamide. Therefore, although no effect of polymorphisms in these enzymes on the plasmapharmacokinetics of cyclophosphamide could be demonstrated, differences in susceptibility to toxicity might occur due to differences in intracellular detoxification of the active cyclophosphamide metabolites. In conclusion, although the pharmacokinetics of the components of the CTC regimen are not affected by the variability in the presently evaluated genes to a large extent, it is apparent that variability in genes encoding drug metabolising enzymes does affect the occurrence of toxicity. Pharmacogenetic approaches have potential for identifying patients who are at a higher risk of experiencing toxic side-effects in high-dose chemotherapy

First experiences with a tool to measure the level of clinical information present in adverse drug reaction reports

Background: To make a proper causality assessment of an adverse drug reaction (ADR) report, a certain level of clinical information is necessary. A tool was developed to measure the level of clinical information present in ADR reports. The aim of this study was to test the validity and reliability of the clinical documentation tool (ClinDoc) in an international setting. Methods: The tool was developed by a panel of pharmacovigilance experts. It includes four domains: ADR, chronology of the ADR, suspected drug and patient characteristics. The final score categorizes reports into: excellent, well, moderately or poorly documented. In two rounds, eight pharmacovigilance assessors of different countries made a total of 224 assessments using the tool, with the expert panels judgement as a standard. Sensitivity and specificity were calculated. Results: The tool with four outcome-categories demonstrated low sensitivity. A lack of distinctiveness was demonstrated between the categories moderate and well. Results for the second round were reanalysed using three categories. This demonstrated a better validity. Conclusion: This is the first tool to give insight in the level of relevant clinical information present in ADR reports. It can be used internationally to compare reports coming from different reporting methods and different types of reporters in pharmacovigilance

CYP450 genotype and aggressive behavior on selective serotonin reuptake inhibitors

AIM: Genetic variants for selective serotonin reuptake inhibitor (SSRI) metabolizing enzymes have been hypothesized to be a risk factor for aggression as adverse drug effect of SSRIs. Our aim was to assess the possible involvement of these polymorphisms on aggression when using SSRIs. MATERIALS & METHODS: A retrospective noninterventional case-control study was performed on 18 cases. The genetic profile of two main genes involved in the metabolism of SSRIs was determined, and predicted phenotype frequencies were compared with Dutch controls and literature data. RESULTS: Predicted CYP2C19 and CYP2D6 phenotypes for all SSRIs analyzed together did not show a significant difference between cases and controls. CONCLUSION: We found no supporting evidence for a significant relationship between CYP2C19 and CYP2D6 polymorphisms, and aggression in patients using SSRIs