Hydroxychloroquine safety in Covid-19 vs non-Covid-19 patients: analysis of differences and potential interactions.

BACKGROUND: The use of hydroxychloroquine (HCQ) in the first COVID-19 epidemic wave raised safety concerns. RESEARCH DESIGN AND METHODS: Adverse reactions (ADR) suspected to be induced by HCQ and submitted to the Spanish Pharmacovigilance Database were studied. A disproportionality analysis was performed to determine adverse effects reported in non-Covid and Covid patients. To explore potential drug-drug interactions, Omega (Ω) statistics was calculated. RESULTS: More severe cases were reported when used in COVID-19. Main differences in frequency were observed in hepatobiliary, skin, gastrointestinal, eye, nervous system and heart ADRs. During the COVID-19 pandemic, high disproportionality in reports was found for Torsade de Pointes/QT prolongation with a ROR (-ROR) of 132.8 (76.7); severe hepatotoxicity, 18.7 (14.7); dyslipidaemias, 12.1 (6.1); shock, 9.5 (6.9) and ischemic colitis, 8.9 (2.6). Myopathies, hemolytic disorders and suicidal behavior increased their disproportionality during the pandemic. Disproportionality was observed for neoplasms, hematopoietic cytopaenias and interstitial lung disease in the pre-COVID-19 period. Potential interactions were showed between HCQ and azithromycin, ceftriaxone, lopinavir and tocilizumab. CONCLUSIONS: The use of HCQ during the Covid-19 pandemic changed its ADRs reporting profile. Of particular concern during the pandemic were arrhythmias, hepatotoxicity, severe skin reactions and suicide, but not ocular disorders. Some signals identified would require more detailed analyses.

Hydrochlorothiazide use and risk of non-melanoma skin cancer in Spain: A case/non-case study.

OBJECTIVE: In 2018, the Pharmacological Risk Assessment Committee alerted to a potential relationship between accumulated hydrochlorothiazide dosage and the risk of non-melanoma skin cancer. To study this relationship we used data from the Spanish Pharmacovigilance System for Medicinal Products of Human Use. MATERIALS AND METHODS: Following a case search for every thiazide potentially associated with (SMQ/MedDRA) "Malignant Skin Neoplasms and not Otherwise Specified Skin Neoplasms", a series of disproportionality analyses were conducted by estimating the reporting odds ratio (95% confidence interval). Registered adverse drug reactions and disproportionality through the reported odds ratio were the main outcome measures. RESULTS: For basal cell carcinoma, reporting odds ratio was 4.8 (2.2 - 10.7); squamous cell carcinoma 3.2 (0.9 - 10.5); malignant melanoma, 0.8 (0.2 - 3.5). We found both disproportionality and association between hydrochlorothiazide and basal cell carcinoma, but none of these were found regarding malignant skin melanoma. In the case of squamous cell carcinoma, the lower confidence interval limit was below 1, thus the disproportionality value was not statistically significant. The accumulated hydrochlorothiazide dose was 36,714 mg for basal cell carcinoma; 98,288 mg for squamous cell carcinoma; and 38,444 mg for malignant melanoma. CONCLUSION: The results in Spain, where sun exposure is significant, are consistent with the data in the Pharmacological Risk Assessment Committee's alert, which were obtained in Denmark for both basal cell carcinoma and malignant melanoma. However, the results for squamous cell carcinoma did not reach statistical significance, although the reporting odds ratio value suggested a potential relationship between hydrochlorothiazide and squamous cell carcinoma.

Medicines under additional monitoring in the European Union.

OBJECTIVE: The objective of this study was to analyse the characteristics of  medicines subject to additional monitoring. We assessed the following aspects:  the criteria applied to approve a medicine as being subject to additional  monitoring; the authorized dispensing conditions; the pharmacological groups to which they belong; and their post-authorisation safety. METHOD: We analysed the list published by the European Medicines Agency in  January 2017 (EMA/245297/2013 Rev.41). Information for the analysis was  obtained from the web sites of the European Medicines Agency and the Spanish  Agency of Medicines and Medical Devices. RESULTS: We assessed 316 medicines subject to additional monitoring. The most  common criterion used to assign a medicine as being subject to additional  monitoring was it being a new active substance (n = 197 [62.3%]). Other  common criteria were requiring a post-authorisation safety study (n = 52  [16.5%]) and being a biologic medicine but not a new active substance (n = 49  [15.5%]). Regarding dispensing conditions, nearly 66% of these medicines were authorized under restricted conditions. Until January 2017, the Spanish Agency  of Medicines and Medical Device published 14 safety reports related to medicines subject to additional monitoring. CONCLUSIONS: The group of medicines subject to additional monitoring mainly  includes new active substances. The most common pharmacological group is antineoplastic and immunomodulating agents. The postauthorisation safety  study has already produced information published by the Spanish Agency of  Medicines and Medical Devices.

Objetivo: El objetivo de nuestro estudio fue analizar las características de los  medicamentos sujetos a seguimiento adicional. Para ello, estudiamos: los  criterios aplicados para su designación, los criterios de dispensación autorizados,  los grupos farmacológicos a los que pertenecen y su seguridad postcomercialización.Método: Se analizó la lista publicada por la Agencia Europea de Medicamentos en enero de 2017 (EMA/245297/2013 Rev.41). La información para el análisis se extrajo de las páginas web de la Agencia Europea  de Medicamentos y la Agencia Española de Medicamentos y Productos  Sanitarios.Resultados: Se estudiaron 316 medicamentos sujetos a seguimiento adicional.  El criterio de designación más común fue ser un nuevo principio activo (n = 197  [62,3%]). Otros criterios de designación comunes fueron: requerir un estudio  postautorización de seguridad (n = 52 [16,5%]) y ser un medicamento  biológico, aunque no un nuevo principio activo (n = 49 [15,5%]). Con respecto a las condiciones de dispensación, casi el 66% de estos medicamentos se  autorizaron con criterios de dispensación restringidos. Hasta enero de 2017, la  Agencia Española de Medicamentos y Productos Sanitarios había publicado 14  notas informativas de seguridad referidas a los medicamentos sujetos a  seguimiento adicional.Conclusiones: Los medicamentos sujetos a seguimiento adicional incluyen mayoritariamente nuevas sustancias activas. El grupo farmacológico más frecuente es el de los fármacos antineoplásicos e  nmunomoduladores. La revisión postcomercialización de su seguridad ha  generado ya alguna información publicada por la Agencia Española de  Medicamentos y Productos Sanitarios.

A polypharmacy risk prediction model for elderly patients based on sociodemographic and clinical factors.

OBJECTIVE: Elderly people take increasing amounts of medication. The aim of our study was to determine the effects of different sociodemographic and clinical factors on polypharmacy and to develop a risk prediction model in outpatients aged 65 years and older. MATERIALS AND METHODS: Cross-sectional, observational, descriptive study of outpatients aged 65 years and older scheduled for a specialist visit. Data on sociodemographic (age, sex, place of residence, and institutionalization) as well as on clinical variables (number of prescribing physicians and number of diagnoses) were collected. Polypharmacy was defined as the uninterrupted use of more than 5 medications within the last 3 months. To determine the risk factors for polypharmacy among these patients, a multivariate logistic regression model was developed and subsequently validated using bootstrap resampling techniques. The model was assessed for its discrimination accuracy using the area under the curve (ROC AUC). RESULTS: A total of 225 outpatients were included for development of the model. Polypharmacy was found in 46.7% of patients. The determinants that best predicted polypharmacy included: age, institutionalization, number of prescribing physicians, and number of diagnoses. The ROC AUC was 0.85. CONCLUSION: The predictive model developed in this study, which consists of 4 readily obtainable variables, may be a useful tool for identifying and monitoring elderly patients at risk for polypharmacy.
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Gynaecomastia associated with proton pump inhibitors: a case series from the Spanish Pharmacovigilance System.

OBJECTIVE: Proton pump inhibitors (PPIs) are widely used in the management of peptic ulcer and related symptoms. They have been linked to certain endocrine adverse reactions, including gynaecomastia. The aim of the present study is to investigate the association between the use of PPIs and the development of gynaecomastia. METHODS: Reports of cases of gynaecomastia that had putatively been induced by PPIs and that had been collected by the Spanish Pharmacovigilance System via the 'yellow card' scheme, were analysed. Reporting odds ratios (RORs) were calculated as a measure of disproportionality. RESULTS: Twenty-four cases of gynaecomastia associated with PPIs were identified in the database of the Spanish Pharmacovigilance System. Overall, there was a clear temporal sequence of events in all cases and the adverse effect disappeared after drug withdrawal in most of the cases; 14 patients were also receiving other drugs at the time of the adverse effect. The ROR for omeprazole exposure versus no exposure, but not that for other PPIs, showed a statistically significant elevation (ROR adjusted for age 5.23; 95% CI 3.32, 8.26). CONCLUSION: Considering the widespread use of PPIs, gynaecomastia may affect a large number of patients. In most cases, the condition seems to be reversible with drug withdrawal. Doctors should be aware of this potential adverse reaction when prescribing PPIs to their patients over long periods of time.