Off‐Label Use of Hydroxychloroquine in COVID‐19: Analysis of Reports of Suspected Adverse Reactions From the Italian National Network of Pharmacovigilance

Abstract

This study aimed to characterize adverse drug reactions (ADRs) to hydroxychloroquine in the setting of COVID-19, occurring in Italy in the period March to May 2020. The analysis of the combination therapy with azithromycin or/and lopinavir/ritonavir as well as a comparison with ADRs reported throughout 2019 was performed. ADRs collected by the Italian National Network of Pharmacovigilance were analyzed for their incidence, seriousness, outcome, coadministered drugs, and Medical Dictionary for Regulatory Activities classification. A total of 306 reports were gathered for the quarter of 2020: 54% nonserious and 46% serious, and half of the latter required either the hospitalization or its prolongation. However, most of them were either completely recovered (26%) or in the process of recovery (45%), except for 9 fatal cases. Throughout 2019, 38 reports were collected, 53% nonserious and 47% serious, but no deaths had been reported. Diarrhea, prolonged QT interval, and hypertransaminasemia were the most frequently ADRs reported in 2020, significantly higher than 2019 and specific for COVID-19 subjects treated with hydroxychloroquine. The logistic regression analyses demonstrated that the likelihood of serious ADRs, QT prolongation, and diarrhea significantly increased with hydroxychloroquine dosage. Coadministration of lopinavir/ritonavir and hydroxychloroquine showed a positive correlation with diarrhea and hypertransaminasemia and a negative relationship with the ADR seriousness. The combination therapy with azithromycin was another independent predictor of a serious ADR. Off-label use of hydroxychloroquine for COVID-19, alone or in combination regimens, was associated with increased incidence and/or seriousness of specific ADRs in patients with additional risk factors caused by the infection.

The Use and Safety Risk of Repurposed Drugs for COVID-19 patients: Lessons Learned Utilizing the Food and Drug Administration’s Adverse Event Reporting System

“…A study conducted in Italy found that prolonged QT/long QT syndrome was one of the most frequently reported ADRs (P < 0.0008) during the first wave of pandemic. (22) In our study, QT prolongation with hydroxychloroquine use was reported about five times more in 2020, compared to 2019 and 2021. This is because 2020 was the peak of the pandemic; based on our study, about 20% hydroxychloroquine use was related to coronavirus infection.…”

“…These reports are consistent with the ADRs reported in other studies. (20)(21)(22) For example, the disproportionality analyses in this study showed that hydroxychloroquine was associated with more QT prolongation compared to fluoroquinolone (ROR of 47.38 vs 9.32). A study conducted in Italy found that prolonged QT/long QT syndrome was one of the most frequently reported ADRs (P < 0.0008) during the first wave of pandemic.…”

Eventos adversos no sistema nervoso central potencialmente relacionados aos medicamentos utilizados na COVID-19: revisão de escopo

“…Embora a maioria das RAM identificadas no SNC e psiquiátricas tenha sido conhecida e não grave, a frequência de ocorrência pode ser maior em função da pandemia ( 25 , 26 ), da automedicação e do uso off-label dos medicamentos ( 27 ). Embora o número de notificações de eventos adversos associados ao uso off-label de medicamentos seja maior em relação à notificação de eventos adversos associados ao uso de acordo com as especificações em bula ( 28 ), não se pode excluir a possibilidade de subnotificação devido ao desconhecimento dos profissionais da saúde, tanto em relação ao evento propriamente dito quanto ao modo de notificação ( 29 ).…”

Drug repositioning in the COVID-19 pandemic: fundamentals, synthetic routes, and overview of clinical studies

“…Among the risks of using 1 and 2 are the increased likelihood of serious adverse events, diarrhea, elevated transaminase levels, and QT interval prolongation, especially in patients with cardiac comorbidities, which are more pronounced when associated with 10 [ 84 – 87 ].…”