Potential kidney damage associated with the use of remdesivir for COVID-19: analysis of a pharmacovigilance database

Potencial nefropatia associada ao uso do remdesivir para COVID-19: análise de uma base de dados de farmacovigilância

Potenciales lesiones renales asociadas con el uso de remdesivir para la COVID-19: análisis de una base de datos de farmacovigilancia

Nayara Aparecida de Oliveira Silva Ana Laura de Sene Amâncio Zara Albert Figueras Daniela Oliveira de Melo About the authors

Abstract:

The U.S. Food and Drug Administration (FDA) has stated that the prescription of remdesivir should be cautious for patients with estimated glomerular filtration rate (eGFR) < 30 and some studies reported risk of adverse renal events. The available information on the renal safety profile for remdesivir is limited, thus we analyzed the renal and urinary adverse reactions attributed to remdesivir reported in a large open pharmacovigilance database. We obtained reports of remdesivir and other drugs used to treat COVID-19 (tocilizumab, hydroxychloroquine, lopinavir/ritonavir) registered by September 30 2020, from the U.S. Food and Drug Administration Adverse Event Reporting System (FAERS). We analyzed the reporting odds ratios (RORs) for reports of adverse renal and urinary events for remdesivir and other drugs. We found 2,922 reports with remdesivir registered in FAERS for COVID-19. Among these, 493 renal and urinary adverse effects (16.9%) were reported. The most frequent events were acute kidney injury (338; 11.6%), renal impairment (86; 2.9%), and renal failure (53; 1.8%). Versus hydroxychloroquine, lopinavir/ritonavir, or tocilizumab, the use of remdesivir was associated with an increased chance of reporting renal and urinary disorders regardless of gender and age of patients (2.53; 95%CI: 2.10-3.06). The ROR remained significant when we restricted the analysis to hydroxychloroquine (4.31; 95%CI: 3.25-5.71) or tocilizumab (3.92; 95%CI: 2.51-6.12). Our results reinforce this already reported signal, emphasizing that it could be extremely useful for health professionals who prescribe this new antiviral to treat COVID-19, mainly knowing its low efficacy.

Keywords:
Coronavirus Infections; Pharmacovigilance; Adverse Drug Reaction Reporting Systems; Drug-Related Side Effects and Adverse Reactions

Resumo:

De acordo com a Agência de Controle de Alimentos e Medicamentos dos Estados Unidos (FDA), a prescrição do remdesivir deve ser feita com cautela em pacientes com taxa de filtração glomerular estimada (TFGe) < 30, sendo que diversos estudos relatam risco de eventos adversos renais. São limitados os dados disponíveis sobre o perfil de segurança renal do remdesivir. Assim, analisamos as reações adversas renais e urinárias atribuídas ao remdesivir e notificadas em um grande base de dados abertos de farmacovigilância. Obtivemos notificações sobre remdesivir e outros medicamentos usados para tratar a COVID-19 (tocilizumabe, hidroxicloroquina, lopinavir/ritonavir) registradas até 30 de setembro de 2020 do Sistema de Notificação de Eventos Adversos da FDA (FAERS). Analisamos as razões de chances de notificação (RORs) para notificações de eventos adversos renais e urinários referentes ao remdesivir e outros medicamentos. Encontramos 2.922 notificações sobre remdesivir registradas no FAERS para COVID-19. Entre esses casos, foram notificados 493 efeitos adversos renais e urinários (16,9%). Os eventos mais frequentes foram lesão renal aguda (338; 11,6%), comprometimento renal (86; 2,9%) e insuficiência renal (53; 1,8%). Comparado com a hidroxicloroquina, lopinavir/ritonavir ou tocilizumabe, o uso do remdesivir esteve associado com um aumento das chances de notificação de transtornos renais e urinários, independentemente do sexo e idade dos pacientes (2,53; IC95%: 2,10-3,06). A ROR permaneceu significativo quando limitamos a análise à hidroxicloroquina (4,31; IC95%: 3,25-5,71) ou ao tocilizumabe (3,92; IC95%: 2,51-6,12). Nossos resultados corroboram outros estudos e destacam a utilidade para profissionais da saúde que usam esse novo antiviral para tratar a COVID-19, sobretudo em função de sua baixa eficácia.

Palavras-chave:
Infecções por Coronavírus; Farmacovigilância; Sistemas de Notificação de Reações Adversas a Medicamentos; Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos

Resumen:

La Agencia Americana de Control de Alimentos y Medicamentos (FDA) ha destacado que la prescripción de remdesivir debe ser prudente con pacientes con tasa de filtración glomerular estimada (TGFe) < 30; además, algunos estudios informaron del riesgo de reacciones adversas renales. La información disponible sobre el perfil de seguridad renal, en el caso del remdesivir, es limitada. Por ello, analizamos las reacciones adversas renales y urinarias atribuidas al remdesivir e notificadas en una extensa base de datos abierta de farmacovigilancia. Obtuvimos las notificaciones de remdesivir y otros medicamentos usados para tratar la COVID-19 (tocilizumab, hidroxicloroquina, lopinavir/ritonavir) registrados el 30 de septiembre de 2020 por el Sistema de Notificación de Eventos Adversos de la FDA (FAERS). Analizamos las odds ratios informadas (RORs) en el caso de informes de eventos adversos renales y urinarios adversos relacionados con el remdesivir y otros medicamentos. En el FAERS, encontramos 2.922 notificaciones de remdesivir registradas como medicament sospechoso usado en COVID-19. De estos, habían 493 con efectos renales y urinarios adversos (16,9%). Los efectos adversos más frecuentes fueron lesiones renales agudas (338; 11,6%), insuficiencia renal (86; 2,9%), y fallo renal (53; 1,8%). Frente a hidroxicloroquina, lopinavir/ritonavir, o tocilizumab, el uso de remdesivir se asoció con un riesgo mayor de notificar alteraciones renales y urinarios, independientemente del género y edad de los pacientes (2,53; IC95%: 2,10-3,06). La ROR permaneció significativo al restringir el análisis a la hidroxicloroquina (4,31; IC95%: 3,25-5,71) o tocilizumab (3,92; IC95%: 2,51-6,12). Nuestros resultados corroboran datos previos, algo que podría ser extremadamente útil para los profesionales de la salud que decidan usar este nuevo antiviral para tratar la COVID-19, sobre todo conociendo su baja eficacia.

Palabras-clave:
Infecciones por Coronavirus; Farmacovigilancia; Sistemas de Registro de Reacción Adversa a Medicamentos; Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos

Introduction

Remdesivir received authorization for emergency use from the U.S. Food and Drug Administration (FDA), the European Medicines Agency (EMA) and the Brazilian Health Regulatory Agency (ANVISA) for treatment of severe coronavirus disease 2019 (COVID-19) 11. U.S. Food and Drug Administration. Coronavirus (COVID-19) update: FDA issues emergency use authorization for potential COVID-19 treatment. https://www.fda.gov/news-events/press-announcements/coronavirus-covid-19-update-fda-issues-emergency-use-authorization-potential-covid-19-treatment (accessed on 11/Oct/2020).
https://www.fda.gov/news-events/press-an...
,22. European Medicines Agency. First COVID-19 treatment recommended for EU authorisation. https://www.ema.europa.eu/en/news/first-covid-19-treatment-recommended-eu-authorisation (accessed on 11/Oct/2020).
https://www.ema.europa.eu/en/news/first-...
,33. Agência Nacional de Vigilância Sanitária. Anvisa aprova registro da vacina da Fiocruz/AstraZeneca e de medicamento contra o coronavírus. https://www.gov.br/anvisa/pt-br/assuntos/noticias-anvisa/2021/anvisa-aprova-registro-da-vacina-da-fiocruz-astrazeneca-e-de-medicamento-contra-o-coronavirus (accessed on 04/Jun/2021).
https://www.gov.br/anvisa/pt-br/assuntos...
. Although several countries have approved the emergency use of remdesivir, the World Health Organization (WHO) does not recommend the use of this drug for the treatment of COVID-19. According to a large, simple, international, open-label randomized trial conducted by the WHO, remdesivir, hydroxychloroquine, and lopinavir did not reduce the mortality, the need for mechanical ventilation, and the duration of hospitalization 44. Rochwerg B, Siemieniuk RA, Agoritsas T, Lamontagne F, Askie L, Lytvyn L, et al. A living WHO guideline on drugs for covid-19. BMJ 2020; 370:m3379.,55. WHO Solidarity Trial Consortium. Repurposed antiviral drugs for Covid-19 - Interim WHO Solidarity Trial Results. N Engl J Med 2021; 384:497-511.. Despite the lack of efficacy, these drugs continue to be used in the treatment of COVID-19 in some countries, such as Brazil 66. Santos-Pinto CDB, Miranda ES, Osorio-de-Castro CGS. "Kit-covid" and the Popular Pharmacy Program in Brazil. Cad Saúde Pública 2021; 37:e00348020..

In addition to efficacy, the safety of the drugs used to treat COVID-19 is a concerning aspect. The remdesivir formulation contains sulfobutylether-beta-cyclodextrin (SBECD) as an excipient, which accumulates in patients with kidney dysfunction 77. Luke DR, Tomaszewski K, Damle B, Schlamm HT. Review of the basic and clinical pharmacology of sulfobutylether-ß- cyclodextrin (SBECD). J Pharm Sci 2010; 99:3291-301.,88. Hoover RK, Alcorn H, Lawrence L, Paulson SK, Quintas M, Luke DR, et al. Clinical pharmacokinetics of sulfobutylether-ß-cyclodextrin in patients with varying degrees of renal impairment. J Clin Pharmacol 2018; 58:814-22.. In repeated dose toxicity studies in animals, dose-dependent kidney injury and/or reduced function was detected with remdesivir, however this was not observed in the phase I clinical studies 99. Fisher M, Neugarten J, Bellin E, Yunes M, Stahl L, Johns TS, et al. AKI in hospitalized patients with and without COVID-19: a comparison study. J Am Soc Nephrol 2020; 31:2145-57.,1010. European Medicines Agency. Summary on compassionate use: Remdesivir Gilead. https://www.ema.europa.eu/en/documents/other/summary-compassionate-use-remdesivir-gilead_en.pdf (accessed on 11/Oct/2020).
https://www.ema.europa.eu/en/documents/o...
. Patients with an estimated glomerular filtration rate (eGFR) < 30 were excluded from reported clinical trials of remdesivir 1111. Adamsick ML, Gandhi RG, Bidell MR, Elshaboury RH, Bhattacharyya RP, Kim AY, et al. Remdesivir in patients with acute or chronic kidney disease and COVID-19. J Am Soc Nephrol 2020; 31:1384-6., besides the FDA has stated that these patients should not receive remdesivir unless the potential benefit outweighs the potential risk 11. U.S. Food and Drug Administration. Coronavirus (COVID-19) update: FDA issues emergency use authorization for potential COVID-19 treatment. https://www.fda.gov/news-events/press-announcements/coronavirus-covid-19-update-fda-issues-emergency-use-authorization-potential-covid-19-treatment (accessed on 11/Oct/2020).
https://www.fda.gov/news-events/press-an...
. Post-marketing retrospective studies have indicated that the use of remdesivir in patients with severe renal impairment is safe 1212. Thakare S, Gandhi C, Modi T, Bose S, Deb S, Saxena N, Katyal A, et al. Safety of remdesivir in patients with acute kidney injury or CKD. Kidney Int Rep 2021; 6:206-10.,1313. Pettit NN, Pisano J, Nguyen CT, Lew AK, Hazra A, Sherer R, et al. Remdesivir use in the setting of severe renal impairment: a theoretical concern or real risk? Clin Infect Dis 2020; [Online ahead of print].,1414. Meshram HS, Kute VB, Patel H, Banerjee S, Navadiya V, Desai S, et al. Feasibility and safety of remdesivir in SARS-CoV2 infected renal transplant recipients: a retrospective cohort from a developing nation. Transpl Infect Dis 2021; 23:e13629.. On the other hand, a review of published studies describing the treatment with remdesivir 1515. Fan Q, Zhang B, Ma J, Zhang S. Safety profile of the antiviral drug remdesivir: an update. Biomed Pharmacother 2020; 130:110532. reported that four out of 53 patients with severe COVID-19 developed renal impairment 1616. Grein J, Ohmagari N, Shin D, Diaz G, Asperges E, Castagna A, et al. Compassionate use of remdesivir for patients with severe Covid-19. N Engl J Med 2020; 382:2327-36.. Acute kidney injury (AKI) was also reported in two studies 1616. Grein J, Ohmagari N, Shin D, Diaz G, Asperges E, Castagna A, et al. Compassionate use of remdesivir for patients with severe Covid-19. N Engl J Med 2020; 382:2327-36.,1717. Wang Y, Zhang D, Du G, Du R, Zhao J, Jin A, et al. Remdesivir in adults with severe COVID-19: a randomised, double-blind, placebo-controlled, multicentre trial. Lancet 2020; 395:1569-78.. A recent analysis of 363 notification with remdesivir and COVID-19 from VigiBase (the pharmacovigilance system of the WHO) has suggested that remdesivir may cause acute renal failure 1818. Gérard AO, Laurain A, Fresse A, Parassol N, Muzzone M, Rocher F, et al. Remdesivir and acute renal failure: a potential safety signal from disproportionality analysis of the WHO safety database. Clin Pharmacol Ther 2021; 109:1021-4..

The available information on the renal safety profile for remdesivir is still uncertain. Furthermore, concerning pharmacotherapy, COVID-19 itself may contribute to renal impairment. Between 20% and 40% of severe COVID-19 patients develop AKI and renal failure, mainly among those on mechanical ventilation due to a worse prognosis 1919. Hirsch JS, Ng JH, Ross DW, Sharma P, Shah HH, Barnett RL, et al. Acute kidney injury in patients hospitalized with COVID-19. Kidney Int 2020; 98:209-18.,2020. Gabarre P, Dumas G, Dupont T, Darmon M, Azoulay E, Zafrani L. Acute kidney injury in critically ill patients with COVID-19. Intensive Care Med 2020; 46:1339-48..

Thus, we designed a study to analyze the renal and urinary adverse reactions attributed to remdesivir reported in FDA Adverse Event Reporting System (FAERS) Public Dashboard (https://fis.fda.gov/sense/app/d10be6bb-494e-4cd2-82e4-0135608ddc13/sheet/7a47a261-d58b-4203-a8aa-6d3021737452/state/analysis), a large open pharmacovigilance database, from almost 3,000 notifications with remdesivir used for COVID-19.

Methods

The FAERS Public Dashboard is an open access database that includes reports of suspected adverse drug reactions (ADR) coordinated by the FDA. The reports for remdesivir and other drugs used in the treatment of COVID-19 (tocilizumab, hydroxychloroquine, and lopinavir/ritonavir) received by FAERS in September 30, 2020, were identified and characterized. Only reports describing its use to treat “COVID-19”, “Coronavirus Infection”, or SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) were selected. The occurrence of renal adverse events belonging to the “Renal and Urinary Disorders” organ system of the Medical Dictionary for Regulatory Activities (MedDRA; https://www.meddra.org/) was analyzed.

A disproportionality analysis was performed, and the reporting odds ratios (RORs) and corresponding 95% confidence intervals (95%CI) for the associations were calculated 2121. Faillie JL. Case-non-case studies: principle, methods, bias and interpretation. Therapie 2019; 74:225-32.: (a) potential increased risk of reporting renal disorders with remdesivir compared with other drugs prescribed to treat COVID-19 (tocilizumab, hydroxychloroquine, and lopinavir/ritonavir), and (b) potential increased risk of reporting renal disorders with remdesivir versus other drugs. For these analyses, reports were excluded if more than one of the drugs analyzed was considered suspected of causing the adverse reaction. The ROR of a drug-ADR combination was defined as the ratio between proportions of reports containing the drug of interest in the “case” (reports containing the ADR of interest; renal events) and in the “non-case” (reports containing other ADRs) group. All analyses were performed using counts of unique cases. An association was considered statistically significant when the limit of the 95%CI was greater (lower limit) or lower (upper limit) than 1.0.

For analysis of renal adverse reactions considering the groups of drugs (hydroxychloroquine, lopinavir/ritonavir, and tocilizumab combined and independent), a univariate logistic regression was performed from the estimate of the ROR and its 95%CI. Gender and age variables were considered to calculate the adjusted ROR in the logistic regression model, performed by the stepwise method, excluding the missing cases, both for the group with remdesivir and the other groups (hydroxychloroquine, lopinavir, tocilizumab combined and independent). The 5% significance level (p < 0.05) was considered for all statistical tests. The statistical analysis was conducted using the IBM SPSS Statistics program, version 25 (https://www.ibm.com/).

Results

We identified 2,922 notifications for remdesivir used to treat COVID-19. Almost all reports (2,859; 97.8%) originated in the United States, and most patients were male (1,769; 60.5%) and 46% of the individuals were aged 65 years or older. In 2,747 reports (94%), remdesivir was the only drug suspected of adverse events; in the remaining 128 reports, the suspected drugs were remdesivir and other drugs for COVID-19: hydroxychloroquine, tocilizumab, or lopinavir-ritonavir (90; 3.1%), and other drugs unrelated to the treatment of COVID-19 (38; 1.3%). Among the 2,922 reports analyzed, renal and urinary events were identified in 493 (16.9%), and the most frequent events were AKI (338; 11.6%), renal impairment (86; 2.9%), and renal failure (53; 1.8%).

Table 1 describes the number of adverse drug event reports associated with drugs used to treat COVID-19, when only one of the drugs was suspected of causing the adverse reaction. Lopinavir/ritonavir and remdesivir are the drugs with the highest proportion of renal adverse events among patients with COVID-19. The comparison of remdesivir with other drugs for COVID-19 showed an increased chance of reporting renal and urinary disorders (ROR = 2.50; 95%CI: 2.11-2.95), AKI (ROR = 2.77; 95%CI: 2.25-3.41), renal impairment (ROR = 3.36; 95%CI: 2.15-5.24), and renal tubular necrosis (ROR = 4.04; 95%CI: 1.51-10.82) for remdesivir. The chance of reporting was even higher for almost all reactions comparing remdesivir with other drug for COVID-19, except lopinavir/ritonavir (Table 2).

Table 1
Reports of adverse drug events associated with only one drug used to treat COVID-19. U.S. Food and Drug Administration Adverse Event Reporting System (FAERS), September 30, 2020.

Table 2
Disproportionality analysis of reports of renal adverse drug reactions (ADR) in patients treated with remdesivir compared with other drugs for COVID-19. U.S. Food and Drug Administration Adverse Event Reporting System (FAERS), September 30, 2020.

Versus hydroxychloroquine, lopinavir/ritonavir, or tocilizumab, we associated the use of remdesivir with an increased chance of reporting renal and urinary disorders regardless of the patients’ gender and age (adjusted ROR = 2.53; 95%CI: 2.10-3.06). The adjusted ROR of renal and urinary disorders regardless of patients’ gender and age remained significant when we restricted the analysis to hydroxychloroquine (adjusted ROR = 4.31; 95%CI: 3.25-5.71) or tocilizumab (adjusted ROR = 3.92; 95%CI: 2.51-6.12) but not for lopinavir/ritonavir (adjusted ROR = 1.01; 95%CI: 0.78-1.30) (Tables 3 and 4).

Table 3
Disproportionality analysis of reports of renal and urinary disorders in patients treated with remdesivir compared with other drugs for COVID-19, per age group.
Table 4
Disproportionality analysis of reports of renal and urinary disorders in patients treated with remdesivir compared with other drugs for COVID-19, per age group - crude and adjusted - on September 30, 2020.

Discussion

The evidence about the safety profile of remdesivir used to treat COVID-19 in clinical settings is still uncertain. Thus, we searched in a large pharmacovigilance database, such as FAERS, to quickly identify signals confirmed with observational studies and a recent analysis of VigiBase indicated a higher highest risk of acute renal failure in patients with COVID-19 treated with remdesivir compared to tocilizumab, lopinavir/ritonavir and hydroxychloroquine (ROR = 20.3; 95%CI: 15.7-26.3) 1818. Gérard AO, Laurain A, Fresse A, Parassol N, Muzzone M, Rocher F, et al. Remdesivir and acute renal failure: a potential safety signal from disproportionality analysis of the WHO safety database. Clin Pharmacol Ther 2021; 109:1021-4.. The FAERS analysis in this study and the VigiBase analysis conducted by Gérard et al. 1818. Gérard AO, Laurain A, Fresse A, Parassol N, Muzzone M, Rocher F, et al. Remdesivir and acute renal failure: a potential safety signal from disproportionality analysis of the WHO safety database. Clin Pharmacol Ther 2021; 109:1021-4. showed the increased chance of reporting renal disorders of different severity regardless of gender and age, even in a conservative analysis of the data, including only reports of adverse drug events associated with only one drug used to treat COVID-19. Thus, the FAERS result contributes to the strengthening of the renal disorder signal in patients with COVID-19 using remdesivir previously identified in VigiBase.

Kidney damage could be one of the consequences of the infection with SARS-CoV-2 and the immunological cascade prompted by the virus. It could also be a consequence of these patients’ comorbidities associated with COVID-19, by any means, the high proportion of renal and urinary reactions reported for patients using remdesivir are remarkable. Therefore, it generates a hypothesis to be confirmed in future studies and alerts health professionals to be aware of the potential nephrotoxic effect of remdesivir.

Renal adverse events may likely be associated with other nephrotoxic drugs used during the treatment of COVID-19, however in almost all reported cases, remdesivir was the only suspected drug and no other characteristic of the patients explained the observed difference. Despite the limitations of the disproportionality analyses of pharmacovigilance database reports, this method is well-known for identify unknown or poorly known adverse drug reactions, especially to new medicines or medicines used in situations different from those previously studied (signals). In fact, the EMA recently detected a safety signal about the use of remdesivir and the occurrence of kidney injury. The causal association has not yet been established and is under investigation 2222. European Medicines Agency. Meeting highlights from the Pharmacovigilance Risk Assessment Committee (PRAC) 28 September - 1 October 2020. https://www.ema.europa.eu/en/news/meeting-highlights-pharmacovigilance-risk-assessment-committee-prac-28-september-1-october-2020 (accessed on 11/Oct/2020).
https://www.ema.europa.eu/en/news/meetin...
.

Spontaneous reporting systems (SRS), such as FAERS, are important to detect signals in the post-marketing surveillance, however SRSs have important limitations arising with underreporting, incomplete reporting, and duplicate reporting 2323. Ventola CL. Big data and pharmacovigilance: data mining for adverse drug events and interactions. P T 2018; 43:340-51.. The sub-notification can overestimate the risk of an event with false-positive results. The quality of the report depends on the notifier’s ability to recognize a possible association between medication use and the development of ADR. The event may sometimes be related to the patient’s clinical condition (pre-existing diseases) or other medication not identified by the notifier as suspicious. Another recurring problem in the reports is the lack of information or the provision of incorrect information about the patient’s characteristics (sex and age), comorbidities, and concomitant drugs that compromise the data analysis. There may also be notification of a similar incident by different reports (e.g., event notified by both the patient and by the physician), thus increasing the false positive rate 2424. Hazell L, Shakir SAW. Determinants of under-reporting of adverse drug reactions: a systematic review. Drug Saf 2006; 29:385-96.. Besides the limitations inherent in the SRSs themselves, we also observed limitations related to the study design. The interference of pre-existing comorbidities in the disproportionality analysis was not evaluated.

The signals identified with the SRS do not reflect the real incidence of ADR, since we found no information about exposure of the general population to the drug 2323. Ventola CL. Big data and pharmacovigilance: data mining for adverse drug events and interactions. P T 2018; 43:340-51.,2525. Duggirala HJ, Tonning JM, Smith E, Bright RA, Baker JD, Ball R, et al. Use of data mining at the Food and Drug Administration. J Am Med Inform Assoc 2016; 23:428-34.. The signal has an exploratory character that serves as a starting point to emphasize early potential security problems and to instigate additional studies on these possible questions 2626. Coloma PM, Trifirò G, Patadia V, Sturkenboom M. Postmarketing safety surveillance: where does signal detection using electronic healthcare records fit into the big picture? Drug Saf 2013; 36:183-97..

Conclusion

Our findings emphasize the relevance of the EMA’s alert and stressed the analysis of this suspected safety concern, especially if the ongoing clinical trials recommend the use of remdesivir to treat COVID-19. Including a much larger number of notifications, our analysis reinforces the signal identified in VigiBase in a previous study. Thus, even though we found limitations, the analysis of the notifications allows us to infer the need of monitoring the renal function during remdesivir treatment, particularly in patients with risk factors (such as advanced age), pre-existing renal impairment or those receiving combination therapy with nephrotoxic drugs.

Acknowledgments

We thank Adalton Guimarães Ribeiro and Alfredo José Alves Rodrigues Neto for comments that greatly improved the manuscript and statistical analysis, respectively.

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Publication Dates

  • Publication in this collection
    12 Nov 2021
  • Date of issue
    2021

History

  • Received
    23 Mar 2021
  • Reviewed
    18 June 2021
  • Accepted
    02 July 2021
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