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Aims: Pharmacovigilance signals of heart failure (HF) following exposure to protein kinase inhibitors (PKIs) have been detected in recent years. Our aim was to identify the PKIs most frequently associated with the development of HF. Methods: Using the French National Healthcare Database, all patients newly exposed to a PKI between January 2011 and June 2014 were followed up for 18 months. Specific hospitalization diagnosis and long-term HF-related disease codes were used to identify HF patients. HF incidence rate ratios (IRRs) were measured and adjusted hazard ratios (aHRs) were estimated using a Cox model. Sensitivity analyses were performed to limit the potential indication and competitive risk bias. Results: Thirteen PKIs were studied. Among the 49 714 new PKI users registered during the study period, the mean IRR of HF was 3.38 per 100 person-years, with a median time to onset of 155 days. We found a significant increase in the incidence of HF for six medicinal products: pazopanib (aHR = 2.42, 95% confidence interval [CI] 1.67-3.52), dasatinib (aHR = 2.22, 95% CI 1.42-3.44), ruxolitinib (aHR = 2.11, 95% CI 1.69-2.64), crizotinib (aHR = 1.71, 95% CI 1.07-2.72), everolimus (aHR = 1.45, 95% CI 1.26-1.67) and vemurafenib (aHR = 1.37, 95% CI 1.01-1.86). Sensitivity analyses were consistent with our primary analysis. Conclusions: The current study provides knowledge on HF following exposure to a PKI. Additional studies could confirm these results for dasatinib, everolimus, pazopanib and ruxolitinib, and particularly for the two medicinal products with results slightly above the significance threshold, namely, crizotinib and vemurafenib, in our sensitivity analyses. [ABSTRACT FROM AUTHOR]

We describe the safety profiles of all drug classes used for the treatment of advanced melanoma from the US Food and Drug Administration Adverse Event Reporting System over 2008–2018. Adverse reactions reported in 25 900 pharmacovigilance cases are described for chemotherapies, immunomodulators, targeted therapies and immunotherapies. There was a sharp increase in the number of cases over time, with peaks associated with the launch of new treatments. The adverse reactions diversified over time; notably, skin (alopecias, dermatitis) and retinal disorders were frequently associated with targeted therapies and endocrine disorders (hypothalamus, thyroid and adrenal dysfunctions) with immunotherapies. Less well‐known reactions were also detected, such as neuropsychiatric disorders with targeted therapies and gastrointestinal ulcers, pneumothorax and pleural effusions with immunotherapies. The findings highlight the need for various health professionals (including medical specialists or trained nurses) to enhance management of complications. [ABSTRACT FROM AUTHOR]

Aims: Although medicine misuse is a public health issue, it has multiple meanings in the medical literature. This study aimed to characterize, classify and identify the most appropriate definitions of medicine misuse. Methods: A systematic review was performed in Medline, ISI Web of Science, SocINDEX, PsycInfo, PsycArticles and Psychological and Behavioral Sciences Collection, using keywords related to "misuse", "appropriateness" and "medicine" between 1 November 2008 and 25 August 2020. Additional searches were conducted in websites of regulatory agencies and public health institutions. Two authors independently selected studies providing both definitions and examples of misuse, while a third resolved disagreements. Definitions were used to propose a hierarchical classification based on initiator, intent, purpose and context of medicine misuse. The study is registered on PROSPERO: CRD42018115789. Results: Of 3404 identified records, 51 were included. A total of 71 definitions and 74 examples of misuse were retrieved. When the prescriber is initiator and according to intent, potential medicine misuse referred to "intentional or unintentional prescribing not in line with clinical evidence". Based on context, they could prescribe medicines not clinically justified, i.e. overprescribing, or prescribe indicated medicines incorrectly, i.e. misprescribing. Among other groups of definitions, those overlapping with drug abuse or medication use errors were considered out‐of‐scope. Conclusion: This systematic review provides a comprehensive overview of the terms and definitions used to characterize medicine misuse and could serve as a basis for a terminology that makes clear distinctions between misuse, abuse and errors. [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]

Aims: Poor efficacy has been reported for patients with BRAF mutations for metastatic colorectal cancer (mCRC). Methods: EREBUS is a French cohort study of wild‐type (wt) KRAS unresectable mCRC patients initiating a first‐line treatment with cetuximab from 2009 to 2010, followed for two years (five years for vital status). Molecular genetics platforms have provided additional RAS and BRAF mutation testing results. Progression‐free survival (PFS) and overall survival (OS) were assessed according to tumour mutation (mt) status: RASmt/BRAFany, RASwt/BRAFmt and RASwt/BRAFwt. Multivariate Cox analyses were used to evaluate association between mutation status and death or progression. Results: A total of 389 patients were included in 65 centres and with a known tumour mutation status: 64 RASmt/BRAFany (21%), 33 RASwt/BRAFmt (13%) and 213 RASwt/BRAFwt (87%). Respective baseline characteristics were: median age 65, 64 and 63 years, male gender 63%, 64% and 69%, Eastern Cooperative Oncology Group performance status ≤ 1 75%, 76% and 79%, and liver‐only metastases 39%, 33% and 40%. Median progression‐free survival was 8.0 months [5.9–9.3] for patients with RASmt/BRAFany, 6.0 months [2.3–7.2] for patients with RASwt/BRAFmt, and 10.4 months [9.5–11.0] for patients with RASwt/BRAFwt. Respectively, median overall survival was 18.4 months [10.9–23.3], 9.7 months [6.9–16.6] and 29.3 months [26.3–36.1]. In multivariate analyses, progression (HR = 2.71 [1.79–4.10]) and death (HR = 2.79 [1.81–4.30]) were more likely for RASwt/BRAFmt vs RASwt/BRAFwt patients. Conclusions: BRAF mutations were associated with markedly poorer outcomes in initially unresectable RASwt mCRC patients treated by cetuximab in first‐line treatment. [ABSTRACT FROM AUTHOR]