Abstracts

Introduction

During the COVID-19 pandemic, a set of drugs including azithromycin, hydroxychloroquine, and ivermectin was proposed as prophylactic or early treatment for COVID-19 in Brazil and other countries ¹1. Paumgartten FJR, Oliveira ACAX. Off label, compassionate and irrational use of medicines in Covid-19 pandemic, health consequences and ethical issues. Ciênc Saúde Colet 2020; 25:3413-9.^,22. Paumgartten FJR, Delgado IF, Pitta LR, Oliveira ACAX. Chloroquine and hydroxychloroquine repositioning in times of COVID-19 pandemics, all that glitters is not gold. Cad Saúde Pública 2020; 36:e00088520.^,33. Chaccour C, Hammann F, Ramón-García S, Rabinovich NR. Ivermectin and COVID-19: keeping rigor in times of urgency. Am J Trop Med Hyg 2020; 102:1156-7.^,44. Malik M, Tahir MJ, Jabbar R, Ahmed A, Hussain R. Self-medication during Covid-19 pandemic: challenges and opportunities. Drugs Ther Perspect 2020; 36:565-7.^,55. Kalil AC. Treating COVID-19-off-label drug use, compassionate use, and randomized clinical trials during pandemics. JAMA 2020; 323:1897-8.. As of April 2020, increasing evidence showed that these medicines were inefficient against the disease ⁶6. Axfors C, Schmitt AM, Janiaud P, Van't Hooft J, Abd-Elsalam S, Abdo EF, et al. Mortality outcomes with hydroxychloroquine and chloroquine in COVID-19 from an international collaborative meta-analysis of randomized trials. Nat Commun 2021; 12:3001.^,77. Deng J, Zhou F, Ali S, Heybati K, Hou W, Huang E, et al. Efficacy and safety of ivermectin for the treatment of COVID-19: a systematic review and meta-analysis. QJM 2021; 114:721-32.^,88. RECOVERY Collaborative Group. Azithromycin in patients admitted to hospital with COVID-19 (RECOVERY): a randomized, controlled, open-label, platform trial. Lancet 2021; 397:605-12.. Some groups, however, continued to advocate the off-label use of such drugs. Off-label administration is acceptable if no standard therapy is available for a serious condition and if its potential benefit is evidenced ⁹9. Le Jeunne C, Billon N, Dandon A; participants of round table Nº 3 of Giens XXVIII. Off-label prescriptions: how to identify them, frame them, announce them and monitor them in practice? Therapies 2013; 68:233-9.^,1010. Howland RH. Off-label medication use. J Psychosoc Nurs Ment Health Serv 2012; 50:11-3..

Potential adverse drug reactions (ADR) may occur even for recommended drugs. The World Health Organization (WHO) defines ADR as “a response to a drug which is noxious and unintended, and which occurs at doses normally used in man for the prophylaxis, diagnosis, or therapy of disease or for the modification of physiological function” ¹¹11. World Health Organization. The importance of pharmacovigilance: safety monitoring of medicinal products. Geneva: World Health Organization; 2002. (p. 40). In turn, Edwards & Aronson ¹²12. Edwards IR, Aronson JK. Adverse drug reactions: definitions, diagnosis, and management. Lancet 2000; 356:1255-9. (p. 1255) define it as “an appreciably harmful or unpleasant reaction, resulting from an intervention related to the use of a medicinal product, which predicts hazard from future administration and warrants prevention or specific treatment, or alteration of the dosage regimen, or withdrawal of the product”.

The Brazilian Health Regulatory Agency (Anvisa) has a national surveillance program on ADR. The agency reports on and discloses pharmacovigilance data on their website, an important resource to record the safety of medicines and the late ADRs that often escape clinical research ¹³13. Mota DM, Vigo A, Kuchenbecker RS. Reações adversas a medicamentos no sistema de farmacovigilância do Brasil, 2008 a 2013: estudo descritivo. Cad Saúde Pública 2019; 35:e00148818.. The website also presents data on release of controlled medicines, such as the ones used for the early treatment of COVID-19.

Melo et al. ¹⁴14. Melo JRR, Duarte EC, Moraes MV, Fleck K, Silva ASN, Arrais PSD. Adverse drug reactions in patients with COVID-19 in Brazil: analysis of spontaneous notifications of the Brazilian pharmacovigilance system. Cad Saúde Pública 2021; 37:e00245820. described the ADRs reported for patients with COVID-19 during the first half of 2020. On average, 1.6 ADRs were reported per patient, and the drugs frequently associated with were those included in the “COVID kit”. The authors also found that pharmacists notified the most ADRs whereas physicians notified the least, raising discussion on underreporting and the importance of training health professionals in pharmacovigilance. Also, Melo et al. ¹⁵15. Melo JRR, Duarte EC, Moraes MV, Fleck K, Arrais PSD. Automedicação e uso indiscriminado de medicamentos durante a pandemia da COVID-19. Cad Saúde Pública 2021; 37:e00053221. stress that notifications reported in the VigiMed system do not discriminate whether the drug was used by medical indication or self-medication.

This study aimed to analyze if the sales of azithromycin, hydroxychloroquine, and ivermectin increased after the onset of the COVID-19 pandemic and if this is correlated with increased reports of ADR.

Methodology

Data were obtained from the Anvisa website both for sales ¹⁶16. Agência Nacional de Vigilância Sanitária. Consultar dados de vendas de medicamentos controlados, antimicrobianos e outros. https://www.gov.br/pt-br/servicos/consultar-dados-de-vendas-de-medicamentos-controlados-antimicrobianos-e-outros (accessed on 02/Mar/2021).
https://www.gov.br/pt-br/servicos/consul... and for reported ADR ¹⁷17. Agência Nacional de Vigilância Sanitária. Notificações de farmacovigilância. https://www.gov.br/anvisa/pt-br/acessoainformacao/dadosabertos/informacoes-analiticas/notificacoes-de-farmacovigilancia (accessed on 02/Mar/2021).
https://www.gov.br/anvisa/pt-br/acessoai... . Drugs included in the search were azithromycin, hydroxychloroquine, and ivermectin. Sales history was selected considering both manipulated and industrialized drugs, and the number of sales was converted to grams if presented in another measurement. Chloroquine was not included since it lacked available industrialized sales data. The monthly history was obtained from March 2019 to February 2021 to analyze the 12 months before and after the onset of the COVID-19 pandemic (Brazil’s first case of COVID-19 was diagnosed on February 26, 2020, and WHO declared the pandemic on March 11, 2020).

The history was assessed by cross-correlation analysis to investigate correlation between sales and ADR within the same month (lag 0) and in the following month (lag 1) or two months (lag 2) after sales. The necessary adjustments for time series data were performed. Spearman’s correlation coefficient was used to assess the magnitude of the correlations. Such analyses were conducted for the whole country’s total data and by regions for each drug. Statistical significance was considered as p < 0.05. This research did not receive or use any funding.

Results

In the pre-pandemic period (from March 2019 to February 2020), azithromycin was the most sold drug nationwide. As a broad-spectrum antibiotic, it was mostly sold in the South and Southeast regions, which present more cases of respiratory infections ¹⁸18. Alonso WJ, Tamerius J, Freitas ARR. Respiratory syncytial virus causes more hospitalizations and deaths in equatorial Brazil than influenza (including during the 2009 pandemic). An Acad Bras Ciênc 2020; 92:e20180584.. After the pandemic onset, sales of azithromycin grew 60.18% in these regions and 69.75% nationwide (Table 1). On the other hand, before the pandemic, only the Northeast and Southeast regions of Brazil reported hydroxychloroquine sales. These sales increased nationwide from 72g to 7,816,738.60g (or 7.8 ton) in the next 12 months after the onset (10,856,481.39% increase). Sales of ivermectin, an antiparasitic drug, rose from 1.22g to 150,444.65g (12,291,129.32% increase).

Reported ADRs also increased. Before the pandemic, ADR levels were zero to must drugs but azithromycin, which went from 16 to 80 reported ADRs after the pandemic onset (Table 1). In the next 12 months, 150 ADRs of hydroxychloroquine and six ADRs of ivermectin were reported. Figure 1 shows the behavior of sales and reported ADRs in Brazil over the studies period.

The cross-correlation analysis showed that increased azithromycin sales were significantly correlated with increased ADR notifications in the following month both nationwide (correlation of 0.522, in lag 1) and in the Central-West Region (correlation of 0.517, in lag 1). Higher hydroxychloroquine sales were significantly correlated with increased ADRs within the same month for Brazil (correlation of 0.498, in lag 0) and regions South (correlation of 0.490, in lag 0) and Southeast (correlation of 0.562, in lag 0). Ivermectin sales also exploded, and the cross-correlation analysis with related ADR showed significant coefficients for a late correlation in Brazil (correlation of 0.681, in lag 2) and in the Central-West Region (correlation of 0.942, in lag 2) but an early correlation in the Southeast (correlation of 0.820, in lag 1). Figure 2 shows the observed cross-correlation analysis for the country.

Similarly, in Spearman’s correlation analysis (Table 2) azithromycin and hydroxychloroquine were moderately correlated to ADRs (according to Devore ¹⁹19. Devore JL. Probabilidade e estatística: para engenharia e ciências. São Paulo: Pioneira/Thomson; 2006.) during and one month after sales nationwide. By region, however, only hydroxychloroquine showed moderate levels of correlation in the South, Southeast, and Northeast regions. Ivermectin was not correlated to ADRs in any scenario.

Discussion and conclusion

ADRs are a major concern for all used drugs. However, they are underreported even in intra-hospital scenarios ²⁰20. Varallo FR, Guimarães SOP, Abjaude SAR, Mastroianni PC. Causes for the underreporting of adverse drug events by health professionals: a systematic review. Rev Esc Enferm USP 2014; 48:739-47.. In this study, we used a public database on drug dispensing and ADRs. Despite obvious limitations, we can assume that information for drug dispensing is more accurate due to legal constraints. Since 2008, Brazil has an online database, the National System for Management of Controlled Substances (SNGPC; http://sngpc.anvisa.gov.br/), which registers the sales of pharmacies ¹⁶16. Agência Nacional de Vigilância Sanitária. Consultar dados de vendas de medicamentos controlados, antimicrobianos e outros. https://www.gov.br/pt-br/servicos/consultar-dados-de-vendas-de-medicamentos-controlados-antimicrobianos-e-outros (accessed on 02/Mar/2021).
https://www.gov.br/pt-br/servicos/consul... ^,2121. Agência Nacional de Vigilância Sanitária. Resolução nº 174, de 15 de setembro de 2017. Dispõe sobre a atualização da lista de antimicrobianosregistrados na Anvisa. Diário Oficial da União 2017; 18 sep..

Among all drugs considered in this study, azithromycin and hydroxychloroquine are evidently associated with ADRs related to prolonged QT interval ²²22. Agstam S, Yadav A, Kumar-M P, Gupta A. Hydroxychloroquine and QTc prolongation in patients with COVID-19: a systematic review and meta-analysis. Indian Pacing Electrophysiol J 2021; 21:36-43.^,2323. Diaz-Arocutipa C, Brañez-Condorena A, Hernandez AV. QTc prolongation in COVID-19 patients treated with hydroxychloroquine, chloroquine, azithromycin, or lopinavir/ritonavir: a systematic review and meta-analysis. Pharmacoepidemiol Drug Saf 2021; 30:694-706.^,2424. Gérard A, Romani S, Fresse A, Viard D, Parassol N, Granvuillemin A, et al. "Off-label" use of hydroxychloroquine, azithromycin, lopinavir-ritonavir and chloroquine in COVID-19: a survey of cardiac adverse drug reactions by the French Network of Pharmacovigilance Centers. Therapie 2020; 75:371-9.. The literature shows that hydroxychloroquine is also related to neurotoxicity and retinopathy ²⁵25. Doyno C, Sobieraj DM, Baker WL. Toxicity of chloroquine and hydroxychloroquine following therapeutic use or overdose. Clin Toxicol (Phila) 2021; 59:12-23.. ADRs like gastrointestinal distress, confusion, ataxia, hypotension and seizures have been reported after high dosage exposure to ivermectin ²⁶26. Temple C, Hoang R, Hendrickson RG. Toxic effects from ivermectin use associated with prevention and treatment of Covid-19. N Engl J Med 2021; 385:2197-8.. In all cases, ADRs depend on dose and duration of exposure to the drug.

Drug label information for azithromycin suggests taking daily doses of 1,500mg for three days. Though hydroxychloroquine dosing depends on indication, the maximum initial dose is 1,600mg followed by daily doses of 400mg. Most common indications, however, recommend initial doses of up to 800mg followed by daily doses of up to 400mg. For ivermectin, the drug label recommends a single daily dose of up to 200mcg/kg a day according to the cause of the disease.

The Brazilian Commission for the Incorporation of Technologies in the Unified Health System (CONITEC) prepared a document called Brazilian Guidelines for Outpatient Drug Treatment of Patients with COVID-19²⁷27. Ministério da Saúde. Diretrizes brasileiras para tratamento hospitalar do paciente com COVID-19. Brasília: Ministério da Saúde; 2021., published in November 2021. The document does not recommend using medicines from the “COVID kit” (azithromycin, chloroquine, hydroxychloroquine, and ivermectin) in infected patients since randomized clinical trials and other national and international guidelines showed no evidence of efficacy of these drugs for the outpatient treatment of patients with COVID-19.

The recommended dose of these medicines for treating COVID-19 is difficult to find, especially considering the increasing evidence on their inefficacy. Some documents from municipalities or private health companies can be found in Portuguese ²⁸28. Comissão Covid 19 - Secretaria Municipal de Saúde e Saneamento. Tratamento precoce de pacientes COVID-19 (pré-hospitalar) e profilaxia nos trabalhadores em saúde. https://www.taquarussu.ms.gov.br/site/wp-content/uploads/2020/08/PROTOCOLO-TRATAMENTO-COVID-19-TAQUARUSSU-2020.pdf (accessed on 22/Nov/2020).
https://www.taquarussu.ms.gov.br/site/wp... ^,2929. Freitas TIS, organizadora. Protocolo para atendimento da COVID-19 na atenção primária e hospitalar. https://www.ufpi.br/arquivos_download/arquivos/PROTOCOLO_PARA_ATENDIMENTO_DA_COVID_Diagramado_paginado_justificadoNovo_PDF20200706211125.pdf (accessed on 22/Nov/2020).
https://www.ufpi.br/arquivos_download/ar... . They suggest 500mg of azithromycin per day for five days or, if symptoms persist, for ten days, along with simultaneous use of 400mg hydroxychloroquine every 12 hours for the first day and then 400mg/day for up to ten days. For ivermectin, the documents suggested daily doses of 6mg for four days then about 250mcg/kg per day.

Exposing patients to these risks with no confirmed benefits of the drugs contradicts the risk-benefit assumptions adopted in clinical practice. ADRs can threaten life and challenge the health system. Mota et al. ¹³⁰ showed that 9.2% of ADRs motivated or prolonged hospitalization and 4.7% threatened life. In Brazil, the estimated prevalence of suspected notified ADRs is 6.6% ³⁰30. Sousa LAO, Fonteles MMF, Monteiro MP, Mengue SS, Bertoldi AD, Dal Pizzol TS, et al. Prevalência e características dos eventos adversos a medicamentos no Brasil. Cad Saúde Pública 2018; 34:e00040017.. We emphasize that both manufacturers and regulatory agencies have condemned the use of such medicines for COVID-19 treatment ³¹31. Agência Nacional de Vigilância Sanitária. Nota de esclarecimento sobre a ivermectina. https://www.gov.br/anvisa/pt-br/assuntos/noticias-anvisa/2020/nota-de-esclarecimento-sobre-a-ivermectina (accessed on 22/Nov/2020).
https://www.gov.br/anvisa/pt-br/assuntos... ^,3232. Apsen Farmacêutica. Posicionamento. Informações sobre hidroxicloroquina. https://www.apsen.com.br/na_midia/posicionamento-informacoes-sobre-hidroxicloroquina/ (accessed on 22/Nov/2020).
https://www.apsen.com.br/na_midia/posici... ^,3333. EMS Pharma. Esclarecimentos sobre o uso da hidroxicloroquina. https://www.ems.com.br/esclarecimentos-sobre-o-uso-da-hidroxicloroquina-release,1082.html (accessed on 22/Nov/2020).
https://www.ems.com.br/esclarecimentos-s... . Merck-Sharp-Dohme, for example, stated that they do not believe that the data available support the safety and efficacy of ivermectin beyond the doses and populations indicated in the regulatory agency-approved prescribing information ³⁴34. Merck & Co. Merck statement on ivermectin use during the COVID-19 pandemic. https://www.merck.com/news/merck-statement-on-ivermectin-use-during-the-covid-19-pandemic (accessed on 22/Nov/2020).
https://www.merck.com/news/merck-stateme... .

ADR underreporting is a worldwide problem which limits our results. Several studies ³⁵35. Hazell L, Shakir SAW. Under-reporting of adverse drug reactions: a systematic review. Drug Saf 2006; 29:385-96.^,3636. Lopez-Gonzalez E, Herdeiro MT, Figueiras A. Determinants of under-reporting of adverse drug reactions: a systematic review. Drug Saf 2009; 32:19-31.^,3737. Varallo FR, Guimarães SOP, Abjaude SAR, Mastroianni PC. Causes for the underreporting of adverse drug events by health professionals: a systematic review. Rev Esc Enferm USP 2014; 48:739-47.^,3838. Mascarenhas FAS, Anders JC, Gelbcke FL, Lanzoni GMM, Ilha P. Facilities and difficulties of health professionals regarding the adverse event reporting process. Texto & Contexto Enferm 2019; 28:e20180040. indicate that underreporting is caused by the lack of knowledge about the process of notifying or identifying ADRs, insecurity, busy work routine, lack of interest, lack of incentive, guilt for having possibly harmed the patient, or the feeling that only safe drugs are allowed on the market. Many of these reasons overlap with the “seven deadly sins” list created by William Inman in the 1980s. According to the studies, continuous educational interventions and measures could mitigate several of these motivations and encourage health professionals to notify cases. Having a good notification instrument (easy to access, simple to fill out, anonymous, with little bureaucracy) also eliminates other possible obstacles ³⁸38. Mascarenhas FAS, Anders JC, Gelbcke FL, Lanzoni GMM, Ilha P. Facilities and difficulties of health professionals regarding the adverse event reporting process. Texto & Contexto Enferm 2019; 28:e20180040..

Another limitation of this study is the lack of an active search for ADRs to gather data closer to reality. However, this would be impractical considering the size of Brazil and the regional differences in using the “COVID kit”. Moreover, in some periods, data was not up-to-date and repressed data were logged into the system at once. Monthly data should thus be interpreted cautiously. Nevertheless, the use of these medicines and of ADRs over the year-long period increased overall.

Finally, though this type of analysis does not allow making causal inferences, it analyzes the association between the rising sales of off-label drugs for COVID-19 and side effects to these drugs. In short, our results show that, despite underreporting, the increased and indiscriminate use of azithromycin, hydroxychloroquine, and ivermectin during the pandemic correlates to an increased development of ADRs.

References

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History