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Older people are often affected by impaired organ and bodily functions resulting in multimorbidity and polypharmacy, turning them into the main user group of many medicines. Very often, medicines have not specifically been developed for older people, causing practical medication problems for them like limited availability of easy to swallow formulations, easy to open packaging and dosing instructions for enteral administration. In 2020, the European Medicines Agency (EMA) published a reflection paper 'Pharmaceutical development of medicines for use in the older population', which discusses how the emerging needs of an ageing European population can be addressed by medicines regulation. The paper intends to help industry to better consider the needs of older people during pharmaceutical/clinical medicines development by summarising data on the most relevant topics, providing early suggestions on how to move forward and prompting expert discussions and studies into knowledge gaps. Topics include patient acceptability, (dis)advantages of an administration route, formulation, dosage form, packaging, dosing device and user instruction. While the paper is directed at older people and the pharmaceutical industry, the reflections are also relevant to younger patients with similar disease‐related needs and of value to other stakeholders parties, e.g., healthcare professionals, academics, patients and caregivers, as the paper makes clear what can be expected from industry and where collaborative work is needed. This commentary provides an overview of the different steps in the development of the reflection paper, discusses points considered most controversial and/or subject to (multidisciplinary) expert discussions and indicates their value for real world clinical practice. [ABSTRACT FROM AUTHOR]

Several papers have described hyponatraemia with tramadol. However, in most reports, several confounding factors can be found. We used the WHO pharmacovigilance database (VigiBase®) to investigate if tramadol alone could be associated with hyponatraemia. All 1992–2019 ICSRs (individual case safety reports) with the preferred term (PT) "hyponatraemia" and tramadol were included. Two disproportionality analyses were performed: (1) after inclusion of all reports, and (2) after exclusion of concomitant hyponatraemic drugs. Results are expressed as reporting odds ratios (ROR; 95% CI) and information component (IC). Of 19 747 604 ICSRs, 225 575 were included. A significant association was found between tramadol use and reports of hyponatraemia (ROR = 1.49 [1.39–1.60], IC = 0.57 [IC025 = 0.47]). After exclusion of hyponatraemic drugs, the previously found association disappeared. The study failed to find any pharmacovigilance signal of hyponatraemia with tramadol alone. We suggest that reports of hyponatraemia with tramadol can be explained principally by other underlying causes of hyponatraemia, especially other concomitant hyponatraemic drugs. [ABSTRACT FROM AUTHOR]

Introduction: Statins are widely prescribed drugs with established efficacy in primary and secondary prevention of cardiovascular events. Although they are mostly well tolerated, several authors have been emphasizing that the statins' safety profile is not totally clarified especially when considering risk of cancer in patients with long‐term exposure to statins. This meta‐analysis was aimed at evaluating the risk of cancer in patients with prolonged exposure to statins. Methods: Medline, Cochrane library, and clinicaltrials.gov were searched in order to identify studies with a minimum average follow‐up of 10 years of exposure to statins and a cancer‐related outcome reported. Relative risk (RR) of the primary outcomes and the combined effect was presented using a random‐effects model. In the selected randomized control trials (RCT), statin exposure was compared with placebo, and in the selected observational studies, it was compared with no exposure to statins. Results: We retrieved 1627 studies, of which 15 full‐papers were included for final review, five RCT, two cohort studies (CSs), and eight case‐control studies (CCs), representing a total of 358 544 patients. Five RCT, two cohort studies (CSs), and eight case‐control studies (CCs). No significant differences were found regarding risk of cancer occurrence (RR = 1.08, 0.96‐1.21) or cancer mortality (RR = 0.91, 0.80‐1.04) due to long‐term statin exposure. Regarding all‐cause mortality, a protective effect was found (RR = 0.93, 0.90‐0.97). Conclusions: According to available and published evidence, statins are not associated with an increased risk of cancer after prolonged exposure. These findings strengthen the role of statins in the primary and secondary prevention of cardiovascular events. [ABSTRACT FROM AUTHOR]

Pharmacovigilance studies based on spontaneous reporting systems use disproportionality analysis methods to identify drug‐event combinations with higher‐than‐expected reporting. Enhanced reporting is deemed as a proxy for a detected signal and is used to generate drug safety hypotheses, which can then be tested in pharmacoepidemiologic studies or randomized controlled trials. Higher‐than‐expected reporting means that the reporting rate of a drug‐event combination of interest is disproportionately higher than the rate in a specific comparator or reference set. Currently, it is unclear which comparator is the most appropriate for use in pharmacovigilance. Moreover, it is also unclear how the selection of a comparator may affect the directionality of the various reporting and other biases. This paper reviews commonly used comparators chosen for signal detection studies (active comparator, class‐exclusion comparator, and full data reference set). We give an overview of the advantages and disadvantages of each method based on examples from the literature. We also touch upon the challenges related to the derivation of general recommendations for the selection of comparators when mining spontaneous reports for pharmacovigilance. [ABSTRACT FROM AUTHOR]

Aims Previous systematic reviews have found that drug-related morbidity accounts for 4.3% of preventable hospital admissions. None, however, has identified the drugs most commonly responsible for preventable hospital admissions. The aims of this study were to estimate the percentage of preventable drug-related hospital admissions, the most common drug causes of preventable hospital admissions and the most common underlying causes of preventable drug-related admissions. Methods Bibliographic databases and reference lists from eligible articles and study authors were the sources for data. Seventeen prospective observational studies reporting the proportion of preventable drug-related hospital admissions, causative drugs and/or the underlying causes of hospital admissions were selected. Included studies used multiple reviewers and/or explicit criteria to assess causality and preventability of hospital admissions. Two investigators abstracted data from all included studies using a purpose-made data extraction form. Results From 13 papers the median percentage of preventable drug-related admissions to hospital was 3.7% (range 1.4–15.4). From nine papers the majority (51%) of preventable drug-related admissions involved either antiplatelets (16%), diuretics (16%), nonsteroidal anti-inflammatory drugs (11%) or anticoagulants (8%). From five studies the median proportion of preventable drug-related admissions associated with prescribing problems was 30.6% (range 11.1–41.8), with adherence problems 33.3% (range 20.9–41.7) and with monitoring problems 22.2% (range 0–31.3). Conclusions Four groups of drugs account for more than 50% of the drug groups associated with preventable drug-related hospital admissions. Concentrating interventions on these drug groups could reduce appreciably the number of preventable drug-related admissions to hospital from primary care. [ABSTRACT FROM AUTHOR]

Analyzing safety data from clinical trials to detect safety signals worth further examination involves testing multiple hypotheses, one for each observed adverse event (AE) type. There exists certain hierarchical structure for these hypotheses due to the classification of the AEs into system organ classes, and these AEs are also likely correlated. Many approaches have been proposed to identify safety signals under the multiple testing framework and tried to achieve control of false discovery rate (FDR). The FDR control concerns the expectation of the false discovery proportion (FDP). In practice, the control of the actual random variable FDP could be more relevant and has recently drawn much attention. In this paper, we proposed a two-stage procedure for safety signal detection with direct control of FDP, through a permutation-based approach for screening groups of AEs and a permutation-based approach of constructing simultaneous upper bounds for false discovery proportion. Our simulation studies showed that this new approach has controlled FDP. We demonstrate our approach using data sets derived from a drug clinical trial. [ABSTRACT FROM AUTHOR]

Purpose Because preapproval clinical trials typically exclude pregnant women, the evidence on drug safety during pregnancy required to inform drug labeling must come from postapproval controlled observational studies. Common designs have included pregnancy registries and case‐control studies. Recently, pregnancy cohorts nested within healthcare utilization databases are increasingly being used. Despite clear advantages, these databases share some important limitations that may threaten the validity of studies emerging from them. Methods: This paper describes the distinctive methodological aspects of conducting drug safety studies in healthcare utilization databases with special emphasis on design and analytic approaches to minimize biases. Results: We describe considerations for study design, cohort definition, and follow‐up. We then address issues related to exposure ascertainment based on prescription fills, including the importance of the etiologically relevant window and of properly accounting for preterm births. This is followed by a discussion of advantages and challenges when ascertaining maternal and infant outcomes based on secondary data. We then explore useful approaches to address confounding within the context of pregnancy research and of the potential for selection bias when restricting the cohort to live births. Finally, we consider issues related to external validity and statistical significance. The examples are mainly drawn from a pregnancy cohort nested in the Medicaid Analytic Extract. Conclusions: The approaches presented provide guidance regarding the important methodological considerations that need to be attended to in order to generate valid, minimally biased risk when using large healthcare utilization databases for drug safety surveillance in pregnancy. [ABSTRACT FROM AUTHOR]

Mitiperstat is a myeloperoxidase inhibitor in clinical development for treatment of patients with heart failure and preserved or mildly reduced ejection fraction, non‐alcoholic steatohepatits and chronic obstructive pulmonary disease. We aimed to assess the risk of QT‐interval prolongation with mitiperstat using concentration–QT (C‐QT) modeling. Healthy male volunteers were randomized to receive single oral doses of mitiperstat 5, 15, 45, 135, or 405 mg (n = 6 per dose) or matching placebo (n = 10) in a phase 1 study (NCT02712372). Time‐matched pharmacokinetic and digital electrocardiogram data were collected at the baseline (pre‐dose) and at 11 time‐points up to 48 h post‐dose. C‐QT analysis was prespecified as an exploratory objective. The prespecified linear mixed effects model used baseline‐adjusted QT interval corrected for the heart rate by Fridericia's formula (ΔQTcF) as a dependent variable and plasma mitiperstat concentration as an independent variable. Initial exploratory analyses indicated that all model assumptions were met (no effect on heart rate; appropriate use of QTcF; no hysteresis; linear concentration–response relationship). Model‐predicted mean baseline‐corrected and placebo‐adjusted ΔΔQTcF was +0.73 ms (90% confidence interval [CI]: −1.73, +3.19) at the highest anticipated clinical exposure (0.093 μmol/L) during treatment with mitiperstat 5 mg once daily. The upper 90% CI was below the established threshold of regulatory concern. The 16‐fold margin to the highest observed exposure was high enough to mean that a positive control was not needed. Mitiperstat is not associated with risk of QT‐interval prolongation at expected therapeutic concentrations. [ABSTRACT FROM AUTHOR]

GSK3640254 (GSK'254) is a novel HIV‐1 maturation inhibitor with pharmacokinetics supporting once‐daily (QD) therapy for HIV‐1 treatment. This thorough QT/corrected QT (QTc) study evaluated the effect of GSK'254 on cardiac repolarization. In this two‐part, randomized study, healthy participants received GSK'254 or placebo QD for 7 days (part 1) to determine safety and pharmacokinetics of a 500‐mg supratherapeutic dose. Four sequential treatment periods composed the main QTc study (part 2): GSK'254 100 mg, GSK'254 500 mg, placebo QD for 7 days, or placebo QD for 6 days with a 400‐mg moxifloxacin dose on Day 7 (all with a moderate‐fat meal). Concentration‐QTc analyses modeled the relationship between GSK'254 plasma concentrations and placebo‐adjusted change from baseline in QT interval corrected with Fridericia's formula (ΔΔQTcF). Of 50 participants enrolled, 48 completed the study (part 1, 8/8; part 2, 40/42). Least‐squares (LS) mean change from baseline in QTcF for GSK'254 100 mg followed the placebo pattern across time points (maximum LS mean ΔΔQTcF, 1.7 ms); the upper bound of the 90% CI remained <10 ms. Maximum LS mean ΔΔQTcF for GSK'254 500 mg exceeded the 10‐ms threshold: 10.6 ms (90% CI 7.75–13.38). Neither GSK'254 dose had clinically relevant effects on heart rate or cardiac conduction. By concentration‐QTc analysis, no effect on ΔΔQTcF >10 ms is expected up to GSK'254 concentrations of ~3070 ng mL−1. No clinically relevant effects on cardiac parameters were seen in healthy participants with GSK'254 at the 100‐mg dose. [ABSTRACT FROM AUTHOR]

Since the banning of ephedrine in over-the-counter nutritional supplements a decade ago, a plethora of untested and/or unsafe sympathomimetic stimulants have taken its place. This paper argues that these 'novel' stimulants in supplements recapitulate the work of synthetic chemists at commercial pharmaceutical firms during the 1930s and 1940s, all seeking substitutes for recently successful products based on ephedrine and amphetamine. Copyright © 2015 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

What is already known about this subject • Exercise is known to affect absorption of other inhaled substances, but so far there are no reports on the effect of exercise on the absorption of inhaled insulin in humans. What this paper adds • This report is the first to investigate the effect of exercise on the absorption of inhaled insulin. • In this study in healthy volunteers we found that exercise early after dosing increased absorption (15–20%) of inhaled insulin over the first 2 h after start of exercise, with an approximately 30% increase in maximal insulin concentration, and unchanged overall absorption. Aims To investigate the effect of moderate exercise on the absorption of inhaled insulin. Methods A single-centre, randomized, open-label, three-period cross-over trial was carried out in 12 nonsmoking healthy subjects. A dose of 3.5 mg inhaled human insulin was administered via a nebulizer and followed in random order by either 1) no exercise (NOEX), 2) 30 min exercise starting immediately after dosing (EX0), or 3) 30 min exercise starting 30 min after dosing (EX30). The study was carried out as a 10 h euglycaemic glucose clamp (90 mg dl−1 (5.0 mmol l−1)). Results The absorption of insulin over the first 2 h after start of exercise was 16% increased for EX0 (ratio (95%CI) 1.16 (1.04, 1.30), P = 0.01) and 20% increased for EX30 (1.20 (1.05, 1.36), P < 0.01), both compared with NOEX; the overall insulin absorption during 6 h and 10 h after dosing was not influenced by exercise. The maximum insulin concentration ( C max) increased by 32% for EX0 and 35% for EX30 (both P < 0.01) compared with NOEX, while the time to C max was 31 min faster for EX0 ( P < 0.01), but not significantly different after EX30, compared with NOEX. Conclusions A significant and clinically relevant increase of insulin absorption over the first 2 h after the beginning of exercise was observed. Until data from studies using the specific insulin inhalers exists, patients using inhaled insulin should be made aware of a potential increased absorption and higher concentration of insulin in connection with exercise. [ABSTRACT FROM AUTHOR]

Aims: Prescribing information should follow a defined structure to help prescribers easily find required information. Often information appears in different sections of Summaries of Product Characteristics (SmPCs) in an inconsistent way. Still unknown is how this inconsistency affects absolute contraindications and how it can be improved. Thisstudy aimed to evaluate the structure of absolute contraindications in SmPCs based on absolute drug–drug contraindications (DDCI) in the section 'contraindications' and references to sections 'special warnings and precautions for use' (here as 'warnings') and 'interaction with other medicinal products and other forms of interaction' (here as 'interactions'). Methods: SmPCs of 693 commonly prescribed drugs were analysed regarding absolute DDCI in 'contraindications' sections. References to sections on 'warnings' and 'interactions' were evaluated to characterize information provided about DDCI. Results: Of 693 analysed SmPCs, 138 (19.9%) contained ≥1 absolute DDCI. Of 178 SmPCs that referred to sections on 'warnings' or 'interactions', 131 (73.6%) did not contain further information on absolute DDCI, whereas 47 (26.4%) did. Such additional information was found in sections on 'interactions' and 'warnings' in 41 (87.2%) and 9 (19.1%) SmPCs, respectively. Conclusions: Information regarding absolute DDCI was found not only in sections on 'contraindications' but also in sections on 'warnings' and 'interactions'. Information was not given with consistently straightforward phrasing and structure and so can leave uncertainty for prescribers. To improve drug safety, clear definitions and wording for absolute and relative contraindications should be provided, ideally in tables. [ABSTRACT FROM AUTHOR]

Aims: Animal studies suggest that methylphenidate treatment for around 3 months may lead to less mineralized and weaker appendicular bones. A systematic review was conducted to summarize the evidence from observational studies, and a self‐controlled case series study was used to compare the risk before and after treatment initiation. Methods: Literature search was conducted using PubMed, Embase and the Cochrane Library to identify observational studies on methylphenidate and fractures. We also conducted a self‐controlled case series study with individuals aged 5–24 years who received methylphenidate treatment and experienced fractures from 2001 to 2020 in Hong Kong. Incidence rate ratios and 95% confidence intervals were calculated by comparing the incidence rate in the methylphenidate‐exposed period compared with nonexposed period. Results: Six cohort studies and 2 case–control studies were included in the systematic review. For all‐cause fractures, studies found a 39–74% lower risk in treated‐attention deficit hyperactivity disorder (ADHD) group compared with untreated ADHD but no difference between stimulants and nonstimulants. Differences between sexes and treatment duration were also found—significant results were shown in males and those with longer treatment duration. Among 43 841 individuals with ADHD medication before the year 2020, 2023 were included in the self‐controlled case series analysis. The risks of fractures were lower by 32–41% in different treatment periods when compared with 6 months before treatment initiation. Conclusion: Methylphenidate treatment may lower the risk of all‐cause fractures from both study designs; however, further evidence is needed about the treatment duration and sex effect. Conclusions on stress fractures are not yet established, and further research is required. [ABSTRACT FROM AUTHOR]

Aims: Recent case reports have suggested that sodium‐glucose co‐transporter 2 (SGLT2) inhibitors may interact with statins to increase their risk of myotoxicity. We assessed the risk of myotoxicity reporting associated with concomitant use of SGLT2 inhibitors and statins. Methods: We queried the US Food and Drug Administration Adverse Event Reporting System (FAERS) from 2013 to 2021 for reports including SGLT2 inhibitors, statins or both. We estimated several measures of disproportionate reporting of myopathy and rhabdomyolysis associated with concomitant use of SGLT2 inhibitors and statins: reporting odds ratio (ROR) with 95% confidence interval (CI), Ω shrinkage measure (safety signal if >0) and an extension of the proportional reporting ratio (PRR) (two‐criteria set, safety signal if both criteria are met), using the full FAERS dataset as the reference set. In sensitivity analyses, we focussed on specific SGLT2 inhibitor‐statin pairs with higher interaction potential (canagliflozin‐rosuvastatin, empagliflozin‐rosuvastatin) and accounted for stimulated reporting. Results: There were 456 myopathy and 77 rhabdomyolysis reports involving both an SGLT2 inhibitor and a statin. Concomitant use of SGLT2 inhibitors and statins was not associated with an increased risk of myopathy (ROR 0.79, 95% CI 0.70 to 0.89) or rhabdomyolysis (ROR 0.58, 95% CI 0.41 to 0.83) reporting. For both outcomes, the Ω shrinkage measure was negative and only one criterion of the PRR extension was met. SGLT2 inhibitor‐statin pairs with higher interaction potential yielded potential signals for rhabdomyolysis; these signals disappeared after accounting for stimulated reporting. Conclusion: There was no increased risk of myotoxicity reporting associated with concomitant use of SGLT2 inhibitors and statins or for specific drug pairs. [ABSTRACT FROM AUTHOR]

Aims: The aim of this study is to compare the Liverpool Causality Assessment Tool vs. Naranjo Scale for screening suspected adverse drug reaction (ADR) cases. Methods: We retrospectively reviewed patient charts with a history of suspected ADR, scored using both tools, and determined how each correlates with laboratory and other investigations. A total of 924 charts from the Clinical Pharmacology Clinic at the London Health Sciences Centre were reviewed, and 529 charts contained objective findings to support or against the diagnosis of ADR. The participant age ranged from 1 month to 93 years. We determined that the sensitivity (SN) and specificity (SP) of Liverpool and Naranjo tools for predicting ADRs with scores ranging from Possible to Definite were considered positive and Unlikely/Doubtful as negative for ADR. These results were confirmed by laboratory or clinical (re‐challenge) testing in 529 cases. Results: Liverpool causality tool had SN of 97.2 ± 2.4% and SP of 2.3 ± 1.57%. The positive (PPV) and negative predictive values (NPV) were 34.1 and 61.5%, respectively. The Naranjo Scale had SN of 81.2 ± 5.69% and SP of 13.2 ± 3.56%. PPV and NPV were 32.7 and 57.5%, respectively. Conclusion: The Liverpool Causality Assessment Tool is a more sensitive tool than the Naranjo Scale in the assessment of possible ADRs, but both tools have poor SP. The Liverpool Tool can be a useful screening tool in settings where other tests may not be readily available. However, the low PPV and NPV of both tools suggest that to pursue further testing is needed to confirm or deny an ADR. [ABSTRACT FROM AUTHOR]

Pharmaceuticals can reach the environment at all stages of their lifecycle and accumulate in the ecosystem, potentially reaching toxic levels for animals and plants. In recent years, efforts have been made to map and control this hazard. Assessing country‐specific environmental risks could drive regulatory actions towards eco‐friendlier drug utilization and disposal practices. By starting from a list of 25 environmentally hazardous pharmaceuticals developed by Region Stockholm, we integrated eco‐toxicological and 2019–2021 Italian drug utilization data to estimate the environmental impact of pharmaceuticals in Italy. We calculated the risk as the ratio between the predicted environmental concentration (PEC) and the predicted no‐effect concentration (PNEC). We found a high risk for levonorgestrel, ciprofloxacin, amoxicillin, azithromycin, venlafaxine, sertraline and diclofenac and a moderate risk for ethinyloestradiol, oestradiol and clarithromycin. This analysis can be periodically performed to identify the pharmaceuticals with the highest risk for the environment and ascertain if containment measures should be implemented. [ABSTRACT FROM AUTHOR]

Ensuring good storage practices (GSPs) of medicine outlets is important to maintain and ensure the safety, quality, and efficacy of dispensed medicines. The objective of this scoping review was to determine the most common GSP compliance issues within pharmacies and medicine outlets. PRISMA extension for scoping reviews guidelines were followed, and PubMed and Google Scholar were searched to identify the relevant primary literature from January 2016 and February 2022. All study designs in English were eligible for inclusion as long as they reported quantitative data for the fulfilment of individual GSP activities. Duplicate independent screening of the search results was undertaken. Quality assessment was performed on studies for final inclusion. Data extraction was performed by one reviewer, and the observed aggregate percentage compliance (% compliance), along with 95% confidence interval for the root GSP operation, was calculated. Of the 380 records identified, 15 articles were included. The studies were conducted in 10 countries and the majority were participatory research studies. Fire safety had the lowest aggregate % compliance (0.9%). Controlled substance, climate, light, ventilation and temperature and stock and bookkeeping operations all had overall aggregate % compliance levels below 50%. Despite evidence of basic controls and measures, we identified low compliance for many GSP operations. To ensure the integrity of medicines, it is important to increase the enforcement of security measures, invest resources in personnel training, account for informal vendor practices, and facilitate sharing global data publicly from external and governing body inspections and reviews of storage practices. [ABSTRACT FROM AUTHOR]

Setting-up a high quality, compliant and efficient pharmacovigilance (PV) system in multi-country clinical trials can be more challenging for academic sponsors than for companies. To ensure the safety of all participants in academic studies and that the PV system fulfils all regulations, we set up a centralized PV system that allows sponsors to delegate work on PV. This initiative was put in practice by our Inserm-ANRS MIE PV department in two distinct multinational European consortia with 19 participating countries: conect4children (c4c) for paediatrics research and EU-Response for Covid-19 platform trials. The centralized PV system consists of some key procedures to harmonize the complex safety processes, creation of a local safety officer (LSO) network and centralization of all safety activities. The key procedures described the safety management plan for each trial and how tasks were shared and delegated between all stakeholders. Processing of serious adverse events (SAEs) in a unique database guaranteed the full control of the safety data and continuous evaluation of the risk–benefit ratio. The LSO network participated in efficient regulatory compliance across multiple countries. In total, there were 1312 SAEs in EU-Response and 83 SAEs in c4c in the four trials. We present here the lessons learnt from our experience in four clinical trials. We managed heterogeneous European local requirements and implemented efficient communication with all trial teams. Our approach builds capacity for PV that can be used by multiple academic sponsors. [ABSTRACT FROM AUTHOR]

Aims: Many clinical decision support systems trigger warning alerts for drug-drug interactions potentially leading to QT prolongation and torsades de pointes (QTDDIs). Unfortunately, there is overalerting and underalerting because stratification is only based on a fixed QT-DDI severity level. We aimed to improve QT-DDI alerting by developing and validating a risk prediction model considering patient- and drugrelated factors. Methods: We fitted 31 predictor candidates to a stepwise linear regression for 1000 bootstrap samples and selected the predictors present in 95% of the 1000 models. A final linear regression model with those variables was fitted on the original development sample (350 QT-DDIs). This model was validated on an external dataset (143 QT-DDIs). Both true QTc and predicted QTc were stratified into three risk levels (low, moderate and high). Stratification of QT-DDIs could be appropriate (predicted risk = true risk), acceptable (one risk level difference) or inappropriate (two risk levels difference). Results: The final model included 11 predictors with the three most important being use of antiarrhythmics, age and baseline QTc. Comparing current practice to the prediction model, appropriate stratification increased significantly from 37% to 54% appropriate QT-DDIs (increase of 17.5% on average [95% CI +5.4% to +29.6%], padj = 0.006) and inappropriate stratification decreased significantly from 13% to 1% inappropriate QT-DDIs (decrease of 11.2% on average [95% CI -17.7% to -4.7%], padj ≤ 0.001). Conclusion: The prediction model including patient- and drug-related factors outperformed QT alerting based on QT-DDI severity alone and therefore is a promising strategy to improve DDI alerting. [ABSTRACT FROM AUTHOR]

Background: Tramadol, a weak opioid, inhibits the reuptake of serotonin, a key feature on vascular homeostasis. A suspected interaction exists between dabigatran and tramadol, which might trigger an excess on risk of bleeding however, there is a gap in knowledge on this topic. Purpose: To estimate the effects of tramadol, dabigatran and concomitant use on the risk of hospitalized major bleeds (Gastrointestinal bleeding and intra‐extracranial bleeds). Methods: Among a validated established cohort of new users of oral anticoagulants for non‐valvular atrial fibrillation (NVAF) aged 18 years or older, we identified all hospitalized bleed episodes (GIB and extra/intracranial bleeds) within 2008–2015. A nested case–control analysis was conducted using conditional logistic regression. Adjusted odds ratios (aORs) with 95% confidence intervals (CIs) were calculated for dabigatran, tramadol, and concomitant use. Several sensitivity analyses were carried out. Results: aORs (95%CIs) for current use of only dabigatran, only tramadol and concomitant users were 1.73 (1.37–2.18) and 1.38 (1.13–1.67) and 2.04 (0.74–5.67) compared with non‐users of both drugs (>365 days). aORs for current continuers and non‐continuer users of dabigatran were 1.36 (1.00–1.86) and 2.19 (1.61–2.98), respectively. For the latter, non‐continuer users with a short duration of dabigatran cumulated the highest risk (3.36 [1.88–5.99]). There also was an increased risk with concomitant use of tramadol and rivaroxaban (2.24 [1.19–4.21]), or antagonist of vitamin K (1.30 [1.00–1.69]). Conclusion: There was a trend towards and increased risk of excess bleeds when using concomitantly with dabigatran. The effect decreases with a narrower definition of current use. [ABSTRACT FROM AUTHOR]

Purpose In drug safety, there is a lack of guidance on how prioritization of safety issues should be performed. The aim of this literature review is to provide an overview of criteria used for signal prioritization and of the associated decision support frameworks. Methods A search strategy was constructed to identify relevant articles in Medline/Embase databases from the period from 1 January 1995 to 31 August 2015. The prioritization criteria were extracted and classified in relevant categories. Results From an initial set of 63 articles, 11 were retained for full review. The articles mentioned 48 criteria used in the prioritization process, with a median of six criteria per study [range: 1-16]. More than half of the criteria (63%), referred to strength of evidence while 19% related to public health impact, 14% to general public and media attention and 4% to novelty of the drug event association. Fifteen criteria were tested for predictive value with 11 showing positive results, most of them from the strength of evidence category. Six decision-making frameworks are presented, which incorporate criteria from various categories. Five of these frameworks were tested against expert decisions or by other means, but only in one database each and for a limited set of products. Conclusions There is a wide range of prioritization criteria described in the literature; however, few of them demonstrated predictive value. Many criteria with predictive value were related to strength of evidence category and to novelty. There were few attempts at integrating different criteria in decision support frameworks. Five of the frameworks were tested for validity and showed usefulness, while at least three are already in use for prioritization. Copyright © 2016 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

SUMMARY: Hydroxyurea (HU) (hydroxycarbamide) is used as a therapeutic option in β‐thalassaemia to increase fetal haemoglobin, which results in a reduced requirement for blood transfusion. However, a potential serious adverse effect of HU is neutropenia. Abnormal neutrophil maturation and function in β‐thalassaemia/HbE patients are well documented. This raises questions about the effect of the drug with regards to the immune response these patients. This study investigated the effects of HU treatment on both innate and adaptive immunity in a cross‐sectional study of 28 β‐thalassaemia/HbE patients who had received HU treatment (BE+HU) as compared with 22 β‐thalassaemia/HbE patients who had not received HU (BE‐HU) and 26 normal subjects. The expression of PU.1 and C/EBPβ, transcription factors, which are associated with neutrophil maturation, was significantly reduced in BE+HU patients as compared with BE‐HU patients and normal subjects. Interestingly, C3bR expression on neutrophils and their oxidative burst activity in BE+HU were restored to close to normal levels when compared with BE‐HU. There was no observed effect of HU on monocytes, myeloid derived suppressor cells (both granulocytic and monocytic subsets), CD4+T cells, CD8+T cells, complement levels and serum immunoglobulin levels in this study. The full immunophenotyping analysis in this study indicates that HU therapy in β‐thalassaemia/HbE patients does not significantly compromise the immune response. [ABSTRACT FROM AUTHOR]

Aims: Adverse drug reactions (ADRs) represent a significant public health burden. There are few data on fatal ADRs in children. This population is particularly at risk due to metabolic and physiological immaturity, frequent off‐label drug use and limited paediatric clinical pharmacology studies. The study investigated the main characteristics of drug‐related deaths registered in World Health Organization pharmacovigilance database, during the past decade. Methods: Fatal outcomes registered between 2010 and 2019 in children (<18 y) and reported by physicians were investigated. Age, sex and suspected drugs were described and disproportionality analyses investigated differences according to sex, age and continents with calculation of reporting odds ratio and its 95% confidence interval. Results: Among the 1 198 560 reports registered in children, 1585 (0.13%) were fatal. They occurred mainly in boys, aged 28 days–23 months. Reports mostly came from the Americas and Europe and involved, besides anti‐infectious drugs (mainly vaccines), central nervous system (vigabatrin, paracetamol, methylphenidate...) and antineoplastic/immunomodulating (mainly thalidomide) and cardiovascular (mainly bosentan) drugs without major differences between boys and girls. Large differences were found according to continents and age. The risk of reporting was higher in boys, in children aged <23 months, in the Americas and Africa. Conclusion: Fatal ADRs represented a small part (around 1/1000) of total registered ADRs, occurred more frequently in boys and during the first 2 years of life. Beside anti‐infectious drugs (vaccines), neuropsychiatric drugs were the most frequently involved, with large differences according to continents and classes of age. [ABSTRACT FROM AUTHOR]

Objective: To assess medicine use based on World Health Organization (WHO) core drug‐use indicators in selected public health facilities of the South Indian Union Territory. Methods: A prospective cross‐sectional study was conducted for period of one year (from March 2019 to February 2020) in 10 selected public health facilities based on the WHO document How to investigate drug use in health facilities. Total 900 prescriptions were analysed to study prescribing, patient care and health facility indicators. The results were compared with the WHO standard measures. Results: The overall average number of drugs per prescription was 3.2. Percentage of prescriptions with antibiotics and injections were found to be 36.6 and 11.4%, respectively. Percentage of drugs prescribed by generic name was 74.6%. Percentage of drugs prescribed from the National List of Essential Medicine was 93.3%. Average consultation and dispensing time were found to be 3.9 minutes and 49.3 seconds, respectively. The percentage of drugs dispensed in this study was 98.5 and 61.6% of medicines were properly labelled; 76.7% of patients had correct knowledge of each medicine dispensed to them. Mean availability of key essential medicine was 73.4%. Conclusion: Indicators such as percentage of drugs prescribed from the National List of Essential Medicine, availability of copy of essential medicine list and percentage of drugs dispensed were found to be as per WHO optimal value. Indicators such as average number of drugs per prescription, average consultation and dispensing time and percentage of medicines labelled were found below optimal value and need to be improved. [ABSTRACT FROM AUTHOR]

Diarrhoea is an adverse drug reaction of the angiotensin receptor neprilysin inhibitor (ARNI) sacubitril + valsartan. It was also described with olmesartan and more recently with other angiotensin receptor blockers. The study was performed to compare diarrhoea reports in pharmacovigilance databases with sacubitril + valsartan and valsartan. The study used reports of diarrhoea with the ARNI sacubitril + valsartan registered: first in the French PharmacoVigilance Database (FPVD) and second in Vigibase®, the WHO Global Individual Case Safety Report database. After description of the main characteristics, disproportionality analyses were performed. Results are reported as reporting odds ratios (ROR) with 95% confidence interval. We found 29 reports of diarrhoea with sacubitril + valsartan in the FPVD and 686 in Vigibase®. With sacubitril + valsartan, diarrhoea occurred more frequently in males around 70 years with a median delay of 3 days. With valsartan, diarrhoea occurred more frequently in females around 68 years with a median delay of 0.5 days. In the FPVD, a significant association was found with sacubitril + valsartan in comparison with valsartan alone before (ROR = 8.78 [5.19–14.85]) and after (ROR = 11.19 [5.89–21.25]) exclusion of concomitant drugs known to be associated with diarrhoea. A significant association was also found in Vigibase® after adjustment on age, sex, reporter and its location (ROR = 1.31 [1.14–1.50]). Diarrhoea reported with sacubitril + valsartan has marked differences in gender, delay of occurrence and frequency of reporting in comparison with diarrhoea with valsartan. From a pharmacodynamic point of view, these results suggest a specific role of sacubitril in diarrhoea. [ABSTRACT FROM AUTHOR]

Gruber and Tchetgen Tchetgen bring up many important limitations of p-value calibration as applied to the assessment of the safety and effectiveness of medications in secondary administrative data. In this discussion, I further examine the role of study design and selection of comparators in interpreting p-value calibration results, and we consider the advantages and disadvantages of automation in the epidemiology of medications, including p-value calibration. Copyright © 2016 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Aims: Medicines regulators issue post‐market safety warnings to advise of newly uncovered risks, but with mixed impacts. We aimed to identify factors influencing the use of regulatory warnings by primary care and specialist physicians in the US and Australia. Methods: Semi‐structured qualitative interviews were carried out with 40 primary care physicians, endocrinologists and other generalist specialists in Boston (USA) and Australia. Coding and analysis were performed inductively and iteratively to identify and examine key factors. Analysis centred around four areas: physicians' awareness of drug safety information, preferred information sources, opinion‐forming and sharing of information with patients. Results: Uncertainty, trust and clinical authority emerged as factors influencing use of advisories. Although regulators were trusted as authoritative institutions, they appeared to lack clinical authority, and physicians validated regulatory information against other trusted sources including evidence, expert opinion and experience. Specialists became aware of drug safety issues through specialised literature, using evidence and clinical consensus to form opinions. Primary care physicians, fielding high volumes of information, relied on convenient, accessible information sources including the media and the "clinical grapevine" for awareness, and on clinical colleagues, specialists and experience for interpretation. Communicating risk to patients was complicated by uncertainty; physicians tailored information to patients' health literacy and information needs. US physicians were more aware of their national regulator's post‐market safety role than Australian physicians of theirs. Conclusion: Drug safety warnings may not be optimally received or used. Regulators should consider strategies that increase trust, clinical relevance and accessibility, and address physicians' needs in communicating risk to patients. [ABSTRACT FROM AUTHOR]

Objectives: Creation of new algorithms to identify pregnancies in automated health care claims databases is of public health importance, as it allows us to learn more about medication use and safety in a vulnerable population. Previous algorithms were largely created using international classification of disease codes, but despite the U.S. code transition in 2015, few algorithms are available with the latest ICD‐10‐CM codes. Methods: Using U.S. IBM MarketScan® Commercial Claims and Encounters and Multi‐State Medicaid databases for women aged 10–64 years during 2014 and 2016, two pregnancy algorithms (ICD‐9‐CM and ICD‐10‐CM) were created using expert clinical review. The algorithms were evaluated by assessing the distribution of pregnancy outcomes (live birth and pregnancy losses) within each time‐based cohort and the ability of the algorithms to identify select medication use during pregnancy. Medication exposure, demographics, comorbidities, and pregnancy outcomes were compared to published literature estimates for the two time periods. Results: For the IBM MarketScan® Commercial database, the algorithms identified 687,228 pregnancies in 2014 and 444,293 in 2016. In the IBM MarketScan® Medicaid database, 389,132 pregnancies in 2014 and 406,418 in 2016 were identified. Percentages of most pregnancy outcomes identified using the algorithms were similar to national data sources; however, percentages of preterm births and pregnancy losses were not comparable. Most medication use estimates from the algorithms were similar to or higher than published estimates. Conclusions: By incorporating the latest ICD‐10‐CM codes, the new algorithms provide more complete estimates of medication use during pregnancy than algorithms using the outdated codes. [ABSTRACT FROM AUTHOR]

Aims: Adverse drug reactions (ADRs) are important causes of death. However, the main involved drugs are relatively unknown. The present study was performed to characterise death‐related drugs recorded in a large pharmacovigilance database during the last 10 years. Methods: A retrospective analysis of VigiBase, the World Health Organization pharmacovigilance database, was performed investigating fatal ADRs registered between 1 January 2010 and 31 December 2019 in male and female patients aged ≥18 years and reported by physicians. Analyses were descriptive investigating age, sex and suspected drugs. Differences in reporting according to sex, age and continents were investigated using disproportionality analysis with calculation of reporting odds ratio and its 95% confidence interval. Results: Among the 23 millions ADRs recorded in VigiBase, 3 250 967 were included with 43 685 fatal. They were reported mainly in patients older than 75 years. The 3 most frequently involved drug classes were antineoplastic/immunomodulating drugs followed by nervous system and cardiac drugs. The top 3 individual drugs were denosumab, lenalidomide and thalidomide with marked differences according to age, sex, continents and countries. The risk of reporting fatal ADRs was higher in males, in the Americas and in patients ≥65 years. Conclusion: Fatal ADRs registered in a large pharmacovigilance database during the last 10 years correspond to just over 1% of the total number of ADRs. They occurred more in males, after 65 years and with antineoplastic/immunomodulating drugs in general. Our study also highlighted, for the first time, important differences in fatal ADRs between continents and countries. [ABSTRACT FROM AUTHOR]

Rationale: Prescribed opioids are major contributors to the international public health opioid crisis. Such widespread iatrogenic harms usually result from collective decision failures of healthcare organizations rather than solely of individual organizations or professionals. Findings from a system‐wide safety analysis of the iatrogenic opioid crisis that includes roles of pertinent healthcare organizations may help avoid or mitigate similar future iatrogenic consequences. In this retrospective exploratory study, we report such an analysis. Methods: The study population encompassed the entire age spectrum and included those in whom opioids prescribed for chronic pain (unrelated to malignancy) were associated with death or morbidity. Root cause analysis, incorporating recent suggestions for improvement, was used to identify possible contributory factors from the literature. Based on their mandated roles and potential influences to prevent or mitigate the iatrogenic crisis, relevant organizations were grouped and stratified from most to least influential. Results: The analysis identified a chain of multiple interrelated causal factors within and between organizations. The most influential organizations were pharmaceutical, political, and drug regulatory; next: experts and their related societies, and publications. Less influential: accreditation, professional licensing and regulatory, academic and healthcare funding bodies. Collectively, their views and decisions influenced prescribing practices of frontline healthcare professionals and advocacy groups. Financial associations between pharmaceutical and most other organizations/groups were common. Ultimately, patients were adversely affected. There was a complex association with psychosocial variables. Limitations: The analysis suggests associations not causality. Conclusion: The iatrogenic crisis has multiple intricately linked roots. The major catalyst: pervasive pharma‐linked financial conflicts of interest (CoIs) involving most other healthcare organizations. These extensive financial CoIs were likely triggers for a cascade of erroneous decisions and actions that adversely affected patients. The actions and decisions of pharma ranged from unethical to illegal. The iatrogenic opioid crisis may exemplify 'institutional corruption of pharmaceuticals'. [ABSTRACT FROM AUTHOR]

Aims: Antipsychotics and lithium are widely used in psychiatry, particularly in schizophrenia and bipolar disorders. Recently, some cases of somnambulism or sleep‐related eating disorder (SRED) have been reported in patients treated with these drugs. This study investigated the risk of reporting somnambulism or SRED associated with the use of antipsychotics and lithium. Methods: The World Health Organization pharmacovigilance database (VigiBase), comprising >18 million adverse events, was queried. All somnambulism or SRED reports related to antipsychotics or lithium were identified. The association between antipsychotics or lithium and somnambulism or SRED was computed using the proportional reporting ratio (PRR) and information component. Results: Among the 5784 cases reporting somnambulism or SRED, 508 suspected at least 1 antipsychotic or lithium. Most patients were aged 18–64 years (62.0%), and 37.0% were men. In most cases (77.6%), antipsychotic or lithium were the only drug class involved, and 53.3% of cases suspected quetiapine. Somnambulism was reported in 88.6% of cases and SRED in 18.1%. A significant association was found for second‐generation antipsychotics (PRR 3.44, 95% confidence interval 3.13) and lithium (PRR 2.03, [1.22; 3.37]), but not for first‐generation antipsychotics (PRR 0.99, [0.68; 1.44]). Conclusions: We found a significant signal of somnambulism or SRED related to second‐generation antipsychotics and lithium. While case reports mentioned mostly quetiapine and olanzapine, almost all second‐generation antipsychotics were associated with somnambulism or SRED. [ABSTRACT FROM AUTHOR]

Background/Objectives: Gabapentinoids are commonly prescribed to relieve pain. The development of edema, an established adverse effect of gabapentinoids, may lead to a potentially harmful prescribing cascade whereby individuals are subsequently prescribed diuretics and exposed to diuretic‐induced adverse events. The frequency of this prescribing cascade is unknown. Our objective was to measure the association between new dispensing of a gabapentinoid and the subsequent dispensing of a diuretic in older adults with new low back pain. Design Population‐based cohort study. Setting: Ontario, Canada. Participants: A total of 260,344 community‐dwelling adults aged 66 years or older, newly diagnosed with low back pain between April 1, 2011, and March 31, 2019. Measurements Exposure status was assigned using dispensed medications in the 1 week after low back pain diagnosis. Older adults newly dispensed a gabapentinoid (N = 7867) were compared with older adults who were not newly dispensed a gabapentinoid (N = 252,477). Hazard ratios (HRs) with 95% confidence intervals (CIs) for dispensing of a diuretic within 90 days of follow‐up among older adults prescribed gabapentin relative to those who were not. Results: Older adults newly dispensed a gabapentinoid had a higher risk of being subsequently dispensed a diuretic within 90 days compared with older adults who were not prescribed a gabapentinoid (2.0% vs. 1.3%). After covariate adjustment, new gabapentinoid users had a higher rate of being dispensed a diuretic compared with those not prescribed a gabapentinoid (HR: 1.44, 95% CI: 1.23, 1.70). The rate of diuretic prescription among new gabapentinoid users increased with increasing gabapentinoid dosages. Conclusions: We have demonstrated the presence of a potentially inappropriate and harmful prescribing cascade. Given the widespread use of gabapentinoids, the population‐based scale of this problem may be substantial. Increased awareness of this prescribing cascade is required to reduce the unnecessary use of diuretics and the exposure of patients to additional adverse drug events. [ABSTRACT FROM AUTHOR]

Aims: GSK3640254, a novel, next‐generation maturation inhibitor effective against a range of HIV polymorphisms with no cross‐resistance to current antiretroviral therapy, could potentially be coadministered with dolutegravir as a 2‐drug regimen. In this phase I study, pharmacokinetics and tolerability of GSK3640254 plus dolutegravir were assessed. Methods: Healthy participants received dolutegravir 50 mg once daily (QD) on Days 1–5 in period 1, GSK3640254 200 mg QD on Days 1–7 in period 2, and dolutegravir 50 mg plus GSK3640254 200 mg QD on Days 1–7 in period 3. All treatments were administered with a moderate‐fat meal 30 minutes prior to dosing. Pharmacokinetics parameters were derived by noncompartmental methods, and geometric mean ratios (GMRs) and 90% confidence intervals (CIs) were derived using linear mixed effects models. Adverse events, laboratory measurements, electrocardiography and vital signs were monitored. Results: Sixteen participants completed the study. GMRs (90% CIs) for dolutegravir area under the plasma concentration–time curve from time 0 to the end of the dosing interval at steady state, maximum observed concentration and plasma concentration at the end of the dosing interval were 1.17 (1.118–1.233), 1.09 (1.044–1.138) and 1.24 (1.160–1.315), respectively. The GMRs (90% CIs) for GSK3640254 were 1.04 (0.992–1.094), 0.99 (0.923–1.065) and 0.10 (0.939–1.056), respectively. Dolutegravir plus GSK3640254 coadministration did not meaningfully alter steady‐state exposure to dolutegravir or GSK3640254. No clinically significant trends in tolerability or safety were observed. Conclusion: Coadministration of GSK3640254 with dolutegravir did not result in clinically significant drug interaction and was well tolerated. [ABSTRACT FROM AUTHOR]

Background: Some case reports have described parkinsonism with amiodarone. We investigated a putative association between parkinsonism and exposure to amiodarone. Methods: We used the WHO pharmacovigilance database (VigiBase®). All adverse drug reactions with 'Parkinson‐like events' and amiodarone were included. Four disproportionality analyses were performed: 1/after inclusion of all reports, 2/according to sex, 3/for the twenty last years (2000–2019), and 4/after exclusion of concomitant drugs known to induce parkinsonism (antipsychotic, antivertigo, antiemetic antinauseant drugs, flunarizine). Results are expressed as reporting odds ratios (ROR; 95% CI) and information component (IC). Results: No significant association was found in the whole population [ROR = 0.83 (0.65–1.06), IC = −0.7 (IC025 = −0.65)], in men, in women, for the 2000–2019 years, or after exclusion of drugs inducing parkinsonism. Conclusion: We failed to find any signal of parkinsonism with amiodarone. We suggest that reports of parkinsonism with amiodarone could be mainly explained by other underlying causes. [ABSTRACT FROM AUTHOR]

Aim: Meaningful and ethical phase I/II trials can only be conducted with supportive prospective risk‐benefit assessment. This relies largely on preclinical animal studies addressing the safety and efficacy of treatments. These studies are reported in an Investigator's Brochure (IB) to inform ethics review boards and regulatory authorities. Our study investigated the extent, reporting quality and accessibility of preclinical safety studies (PCSSs) compiled in IBs. Methods: We analysed a sample of 46 IBs for phase I/II trials approved at a leading German university medical centre from 2010 to 2016. We extracted all PCSSs presented in the 46 IBs and assessed them for reporting on methodological measures to reduce validity threats. Results: The 46 IBs included 777 PCSSs. Blinded outcome assessment, randomization and sample size calculation were reported for fewer than 1% of studies. Only 5% of the PCSSs provided a reference to published data. Compliance with Good Laboratory Practice (GLP) guidance was reported for 52% of PCSSs, but the GLP document itself does not include any relevant methodological requirements for the reduction of validity threats. Conclusion: Scarce reporting in IBs and the very limited publicly available data on PCSSs make it almost impossible for investigators to critically evaluate the robustness of preclinical evidence of drug safety. Combined with recent findings on the presentation of preclinical efficacy studies in IBs, we conclude that the current reporting patterns in IBs strongly limit the independent review of evidential support for early human trials. Regulatory authorities and IRBs should require better reporting in IBs. [ABSTRACT FROM AUTHOR]

Rationale, aims and objectives: The diversity of types of evidence (eg, case reports, animal studies and observational studies) makes the assessment of a drug's safety profile into a formidable challenge. While frequentist uncertain inference struggles in aggregating these signals, the more flexible Bayesian approaches seem better suited for this quest. Artificial Intelligence (AI) offers great promise to these approaches for information retrieval, decision support, and learning probabilities from data. Methods: E‐Synthesis is a Bayesian framework for drug safety assessments built on philosophical principles and considerations. It aims to aggregate all the available information, in order to provide a Bayesian probability of a drug causing an adverse reaction. AI systems are being developed for evidence aggregation in medicine, which increasingly are automated. Results: We find that AI can help E‐Synthesis with information retrieval, usability (graphical decision‐making aids), learning Bayes factors from historical data, assessing quality of information and determining conditional probabilities for the so‐called 'indicators' of causation for E‐Synthesis. Vice versa, E‐Synthesis offers a solid methodological basis for (semi‐)automated evidence aggregation with AI systems. Conclusions: Properly applied, AI can help the transition of philosophical principles and considerations concerning evidence aggregation for drug safety to a tool that can be used in practice. [ABSTRACT FROM AUTHOR]

Aim: To investigate the safety, tolerability, pharmacokinetics and pharmacodynamics of the highly selective oral p38alpha/beta mitogen‐activated protein (MAP) kinase inhibitor Org 48,775‐0 in a first‐in‐human study. Methods: In the single ascending dosing (SAD) study, an oral dose of Org 48,775‐0 (0.3‐600 mg) was evaluated in healthy males. In the multiple ascending dosing (MAD) study, levels of 30, 70 and 150 mg were dosed for six consecutive days, twice daily. Both studies were performed in a double‐blind, randomized, placebo‐controlled, cross‐over fashion and evaluated pharmacokinetics, pharmacodynamics (ex vivo inhibition of lipopolysaccharide [LPS]‐induced tumor necrosis factor (TNFα) release) and routine clinical and laboratory data. Pharmacokinetic and pharmacodynamic parameters of Org 48,775‐0 were compared between healthy males and postmenopausal females, and the effect of a standardized fat meal was evaluated. Results: All adverse events observed in the SAD (16; dizziness and headache, diarrhoea and catheter‐related phlebitis) and MAD (43; mainly somnolence, dizziness, headache and nasopharyngitis) cohorts were mild, transient and completely reversible. Pharmacokinetics were linear up to single doses of 400 mg. Median Tmax ranged from 0.5 to 1.8 hours, geometric mean for T1/2 from 7.0 to 14.4 hours. Org 48,775‐0 doses equal to and greater than 30 mg significantly inhibited LPS‐induced TNFα release (42.3%; 95% CI = −65.2, −4.3) compared to placebo. In the MAD study, Org 48,775‐0 treatment inhibited LPS‐induced TNFα release during the entire steady‐state period. Levels of inhibition amounted 30‐75% for 30 mg, 53‐80% for 70 mg and 77‐92% for 150 mg Org 48,775‐0. Conclusion: Org 48,775‐0 has the capacity to significantly inhibit MAP kinase activity in humans without safety concerns. [ABSTRACT FROM AUTHOR]

The assessment of safety is an important aspect of the evaluation of new therapies in clinical trials, with analyses of adverse events being an essential part of this. Standard methods for the analysis of adverse events such as the incidence proportion, that is the number of patients with a specific adverse event out of all patients in the treatment groups, do not account for both varying follow‐up times and competing risks. Alternative approaches such as the Aalen–Johansen estimator of the cumulative incidence function have been suggested. Theoretical arguments and numerical evaluations support the application of these more advanced methodology, but as yet there is to our knowledge only insufficient empirical evidence whether these methods would lead to different conclusions in safety evaluations. The Survival analysis for AdVerse events with VarYing follow‐up times (SAVVY) project strives to close this gap in evidence by conducting a meta‐analytical study to assess the impact of the methodology on the conclusion of the safety assessment empirically. Here we present the rationale and statistical concept of the empirical study conducted as part of the SAVVY project. The statistical methods are presented in unified notation, and examples of their implementation in R and SAS are provided. [ABSTRACT FROM AUTHOR]

Aims: The aim of this study was to evaluate the risk of trauma associated with the use of antidopaminergic antiemetics in a real‐world setting. Methods: A self‐controlled case series analysis was performed using the EGB database, the representative sample of the French national healthcare insurance system database. All subjects aged 18 years and over who presented with at least 1 trauma‐related hospitalization and 1 supply for domperidone, metoclopramide or metopimazine between 2009 and 2014 were included in the study. Associations were evaluated by incidence rate ratios. Results: Included exposed cases were 7610 for domperidone cohort, 2189 for metoclopramide and 3911 for metopimazine. Incidence rate ratio for trauma‐related hospitalization during the first 7 days of exposure period compared to unexposed period was 1.53 (95% confidence interval 1.29–1.80) for domperidone, 2.00 (1.37–2.91) for metoclopramide and 2.30 (1.71–3.09) for metopimazine. Conclusion: We found an increased risk of hospitalizations for traumatic injuries for the main marketed antidopaminergic antiemetics during the first days of use. The highest risk was observed for metopimazine, which could relate to its pharmacological profile and central effects. [ABSTRACT FROM AUTHOR]

TS‐1, an effective anticancer drug that consists of tegafur, gimeracil and oteracil, has been increasingly used for the treatment of many types of cancer. However, few studies investigate its cutaneous adverse reactions. Here, we report a female patient with gastric cancer treated with TS‐1 after a gastrectomy, who then developed Stevens–Johnson syndrome, a cutaneous and potentially life‐threatening adverse reaction. This is the first case report about a Grade IV toxic reaction associated with TS‐1. The patient presented with systemic symptoms of erythematous macules, vesicle formation, erosions, binocular ptosis and oedema of the lower eyelid conjunctiva. After 3 weeks of hospitalization with drug treatment and discontinuation of TS‐1, her symptoms were fully relieved and did not recur because the chemotherapy regimen was adjusted to modified FOLFOX6. According to the comprehensive analysis and the score of both the Naranjo assessment scale and algorithm of drug causality for epidermal necrolysis, we have drawn the preliminary conclusion that this is TS‐1‐induced Stevens–Johnson syndrome. [ABSTRACT FROM AUTHOR]

Aims: Polypharmacy increase the risk of drug–drug interactions (DDIs) in the elderly population living with human immunodeficiency virus (HIV). Several expert databases can be used to evaluate DDIs. The aim of the study was to describe actual DDIs between antiretroviral drugs and comedications in an elderly population and to compare grading of the DDIs in 3 databases. Methods: All treatments of HIV‐infected subjects aged 65 years and older were collected in 6 French HIV centres. Summary of Product Characteristic (SPC), French DDI Thesaurus (THES), and Liverpool HIV DDI website (LIV) were used to define each DDI and specific grade. DDIs were classified in yellow flag interaction (undefined grade in SPC and THES or potential weak interaction in LIV), amber flag interaction (to be considered/precaution of use in SPC and THES and potential interaction in LIV) and red flag interaction (not recommended/contraindication in SPC and THES and do not administer/contraindication in LIV). Results: Among 239 subjects included, 60 (25.1%) had at least 1 DDI for a total of 126 DDIs: 23/126 red flag DDIs were identified in 17 patients. All these 23 DDIs were identified in LIV. THES and SPC missed 6 and 1 red flag DDIs, respectively. Seven of 23 red flag DDIs were identified in the 3 databases concomitantly. Conclusion: Polypharmacy is frequent in this elderly HIV population leading to DDI in a quarter of the subjects. The discrepancies between databases can be explained by differences in analysis methods. A consensus between databases would be helpful for clinicians. [ABSTRACT FROM AUTHOR]

Objective: Due to cardiovascular safety concerns, the European Medicines Agency (EMA) recommended new contraindications and changes to product information for diclofenac across Europe in 2013. This study aims to measure their impact among targeted populations. Method: Quarterly interrupted time series regression (ITS) analyses of diclofenac initiation among cohorts with contraindications (congestive cardiac failure [CHF], ischaemic heart disease [IHD], peripheral arterial disease [PAD], cerebrovascular disease [CVD]) and cautions (hypertension, hyperlipidaemia, diabetes) from Denmark, the Netherlands, England and Scotland. Results: The regulatory action was associated with significant immediate absolute reductions in diclofenac initiation in all countries for IHD (Denmark −0.08%, 95%CI −0.13, −0.03; England −0.09%, 95%CI −0.13 to −0.06%; the Netherlands −1.84%, 95%CI −2.51 to −1.17%; Scotland −0.34%, 95%CI −0.38 to −0.30%), PAD and hyperlipidaemia, the Netherlands, England and Scotland for hypertension and diabetes, and England and Scotland for CHF and CVD. Post‐intervention there was a significant negative trend in diclofenac initiation in the Netherlands for IHD (−0.12%, 95%CI −0.19 to −0.04), PAD (−0.13%, 95%CI −0.22 to −0.05), hypertension, hyperlipidaemia and diabetes, and in Scotland for CHF (−0.01%, 95%CI −0.02 to −0.007%), IHD (−0.017, 95%CI −0.02, −0.01%), PAD and hypertension. In England, diclofenac initiation rates fell less steeply. In Denmark changes were more strongly associated with the earlier EMA 2012 regulatory action. Conclusion: Although significant reductions in diclofenac initiation occurred, patients with contraindications continued to be prescribed diclofenac, the extent of which varied by country and target condition. Understanding reasons for such variation may help to guide the design or dissemination of future safety warnings. [ABSTRACT FROM AUTHOR]

Aims: To provide an overview of immune checkpoint inhibitors (ICIs) safety profile using the Italian spontaneous adverse drug reaction (ADR) reporting system. Methods: We selected all ADR reports attributed to ipilimumab (CTLA‐4 inhibitor), nivolumab, pembrolizumab, atezolizumab (PD‐1/PD‐L1 inhibitors) from the Italian spontaneous reporting system (2011–2018). Descriptive analyses of reports for ICIs have been conducted. Time to onset of adverse effects was stratified by system organ class. Reporting odds ratio was used as measure of ADR reporting disproportionality. ICI‐related ADR reports were compared with 2 reference groups, i.e. all other suspected drugs or all other antineoplastic agents. Results: Overall, 2217 (0.7%) reports were related to ICIs (nivolumab: 72.2% of those reports; ipilimumab: 14.3%; pembrolizumab: 10.3%; and atezolizumab: 3.5%). ICI‐related ADR reports mostly involved males (65%) and median age was 67 (interquartile range 59–73) years. Serious reports accounted for 48.8%. Frequencies of endocrine, general, hepatobiliary, metabolism, musculoskeletal, respiratory disorders, infections and neoplasms were significantly higher for ICIs than for all other drugs (P <.001). Except for infections, similar results emerged through comparison with other anticancer drugs. Colitis, hypophysitis and skin disorders were more frequently reported for anti‐CTLA‐4 drugs than PD‐1/PD‐L1 ICIs, and the opposite for musculoskeletal effects, pneumonia, and thyroid dysfunctions. ICIs were disproportionally associated also with less known risks, e.g. ischaemic heart disease, cardiac failure and optic nerve disorders. Conclusion: The most frequently reported safety issues were probably immune‐related adverse events including general, gastrointestinal and respiratory disorders. Potentially emerging safety signals, such as ischaemic heart disease and cardiac failure, requiring further investigation were detected. [ABSTRACT FROM AUTHOR]

The field of pharmacogenomics has made great strides in oncology over the last 20 years and indeed a significant number of pre‐emptive genetic tests are now routinely undertaken prior to anticancer drug administration. Many of these gene–drug interactions are the fruits of candidate gene and genome‐wide association studies, which have largely focused on common genetic variants (allele frequency>1%). Examples where there is clinical utility include genotyping or phenotyping for G6PD to prevent rasburicase‐induced RBC haemolysis, and TPMT to prevent thiopurine‐induced bone marrow suppression. Other associations such as CYP2D6 status in determining the efficacy of tamoxifen are more controversial because of contradictory evidence from different sources, which has led to variability in the implementation of testing. As genomic technology becomes ever cheaper and more accessible, we must look to the additional data our genome can provide to explain interindividual variability in anticancer drug response. Clearly genes do not act on their own and it is therefore important to investigate genetic factors in conjunction with clinical factors, interacting concomitant drug therapies and other factors such as the microbiome, which can all affect drug disposition. Taking account of all of these factors, in conjunction with the somatic genome, is more likely to provide better predictive accuracy in determining anticancer drug response, both efficacy and safety. This review summarises the existing knowledge related to the pharmacogenomics of anticancer drugs and discusses areas of opportunity for further advances in personalisation of therapy in order to improve both drug safety and efficacy. [ABSTRACT FROM AUTHOR]

In X‐linked hypohidrotic ectodermal dysplasia, the most frequent ectodermal dysplasia, an inherited deficiency of the signalling protein ectodysplasin A1 (EDA1) impairs the development of the skin and its appendages, various eccrine glands, and dentition. The severe hypohidrosis common to X‐linked hypohidrotic ectodermal dysplasia patients may lead to life‐threatening hyperthermia, especially during hot weather or febrile illness. Fc‐EDA, an EDA1 replacement protein known to prevent the disease in newborn animals, was tested in 2 clinical trials (human adults and neonates) and additionally administered under compassionate use to 3 infants in utero. The data support the safety of Fc‐EDA and efficacy if applied prenatally. Anti‐drug antibodies were detected after intravenous administration in adult males and nonpregnant females, but not in pregnant women when Fc‐EDA was delivered intra‐amniotically. Most importantly, there was no detectable immune response to the investigational drug in neonates treated by intravenous infusions and in infants who had received Fc‐EDA in utero. In conclusion, the safety profile of this drug encourages further development of prenatal EDA1 replacement therapy. [ABSTRACT FROM AUTHOR]

We aimed to determine the reporting trends and characteristics of Individual Case Safety Reports (ICSRs) from the Zimbabwean national pharmacovigilance system. ICSRs submitted to VigiBaseTM, the World Health Organisation's ICSR database between January 1993 and December 2017 were retrospectively reviewed with respect to the suspected medicine, System Organ Class (SOC), adverse drug reaction (ADR) type and seriousness, Anatomic Therapeutic Chemical (ATC) group, age, and gender. In total, 4071 ICSRs were submitted to VigiBaseTM from targeted spontaneous reporting (n = 2909; 71.5%), vaccine surveillance (n = 679; 16.7%), and passive spontaneous reporting (n = 483; 11.9%), respectively. The median age, ICSR completeness score and timeliness of reporting were 34.0 years (IQR: 14.0; 43.0), 0.90 (IQR: 0.70; 1.00), and 548.0 days (IQR: 266:1131), respectively. More than half of the ICRS were from female patients (n = 2233; 54.9%). Antiretrovirals, antibiotics, vaccines, and anti-tubercular medicines were reported in 62.9%, 27.9%, 16.7%, and 13.3% of submitted ICSRs, respectively. The most frequent ADRs involved the skin and subcutaneous systems (n = 1111; 20.5%), nervous system (n = 733; 13.5%), and gastrointestinal disorders system (n = 654; 12.1%). The number of ADRs reported for each patient was significantly related to the reported medicine's ATC category (P = .001. The number of ADRs was significantly related to the use of antiretroviral agents. In conclusion, Zimbabwe has made significant progress in establishing a functional pharmacovigilance system. However, the present system reports on a limited therapeutic spectrum of medicines and potentially underestimates the national ADR burden. Further work is required to strengthen the more sustainable spontaneous reporting system which potentially captures a variety of therapeutic classes. [ABSTRACT FROM AUTHOR]

Intense efforts are underway to evaluate potential therapeutic agents for the treatment of COVID-19. In order to respond quickly to the crisis, the repurposing of existing drugs is the primary pharmacological strategy. Despite the urgent clinical need for these therapies, it is imperative to consider potential safety issues. This is important due to the harm-benefit ratios that may be encountered when treating COVID-19, which can depend on the stage of the disease, when therapy is administered and underlying clinical factors in individual patients. Treatments are currently being trialled for a range of scenarios from prophylaxis (where benefit must greatly exceed risk) to severe life-threatening disease (where a degree of potential risk may be tolerated if it is exceeded by the potential benefit). In this perspective, we have reviewed some of the most widely researched repurposed agents in order to identify potential safety considerations using existing information in the context of COVID-19. [ABSTRACT FROM AUTHOR]

The aim of this phase 1 study was to determine the effects of sapanisertib on the heart rate–corrected QT (QTc) interval in patients with advanced solid tumors. Adult patients with advanced solid tumors were enrolled to receive a single sapanisertib 40‐mg dose. Blood samples for pharmacokinetic analysis were collected and electrocardiogram readings were recorded at baseline and up to 48 hours after dosing. Patients could continue to receive sapanisertib 30 mg once weekly in 28‐day cycles for up to 12 months. The primary objective was to characterize the effect of a single dose of sapanisertib (40 mg) on the QT interval. Secondary objectives were to evaluate safety, tolerability, and pharmacokinetics. Following a single sapanisertib 40‐mg dose in 44 patients, the maximum least squares mean (upper bound of 1‐sided 95% confidence interval) changes from time‐matched baseline were 7.1 milliseconds (11.4 milliseconds) for individual rate‐corrected QT interval at 24 hours after dosing, and 1.8 milliseconds (5.6 milliseconds) for Fridericia‐corrected QTc at 1 hour post‐dose. There was no sapanisertib plasma concentration‐dependent increase in the change from time‐matched baseline individual rate‐corrected QTc interval or Fridericia‐corrected QTc. The most common adverse events following sapanisertib 30 mg once‐weekly dosing were nausea (80%), fatigue (61%), vomiting (57%), and decreased appetite (45%). A single sapanisertib 40 mg dose did not produce clinically relevant effects on QTc interval in patients with advanced solid tumors. The safety profile of sapanisertib 30 mg once weekly was favorable, and no new safety signals were observed (NCT02197572, clinicaltrials.gov). [ABSTRACT FROM AUTHOR]

Purpose Prior literature reviews have identified gaps in understanding of how postmarketing safety labeling changes and related FDA communications impact key clinical and behavioral outcomes. We conducted a review of newly published studies on this topic to determine what new evidence exists and to identify which gaps may still remain. We believe that this information can support FDA as it develops and implements future risk communication approaches. Methods: We searched PubMed and Embase for studies published between January 1, 2010, and August 7, 2017 that examined the impact of labeling changes or associated FDA safety‐related communications. For each study, we extracted information on research design and findings for key clinical outcomes and behaviors. We also conducted a ROBINS‐I review to identify potential for bias in the research design of each study. Results: We found that the estimated impacts of FDA labeling changes on several key outcomes—including adverse events—varied. Labeling changes also yielded unintended consequences on drug prescribing in some cases, despite low provider adherence. Finally, some studies we reviewed exhibited potential for bias due to confounding, among other factors. Conclusions: The new studies we reviewed contain many of the same limitations identified in previously published reviews. While there are several challenges to conducting this research there is substantial room for improvement in the quality of the evidence base. More information, particularly with respect to the types of populations and medications affected by labeling changes, is needed to support the development of more effective and targeted safety communications. [ABSTRACT FROM AUTHOR]

Little is known about the administration of direct‐acting oral anticoagulants (DOACs) and the occurrence of alopecia. Our aim was to analyse the reports of alopecia following DOAC administration received until 2 May 2018 from VigiBase, the World Health Organization database. A descriptive analysis of age, sex, seriousness and dechallenge/rechallenge outcome was carried out. For each report, the time‐to‐onset was evaluated and the causality was assessed by using Naranjo algorithm. Overall, 1316 reports were retrieved, most concerning rivaroxaban (58.8%); 80% of the reports were related to females, in particular to those aged ≥65 years (23.1%). The median value of the time‐to‐onset was 28 days, with an interquartile range of 63 days. In 54.3% of the reports the causality was assessed as possible. In conclusion, a possible association could exist between DOACs administration and alopecia, but further observational studies are needed to confirm these findings. [ABSTRACT FROM AUTHOR]