Adverse Drug Reactions during COVID-19 Treatment: A Comprehensive Analysis Focused on Hospitalized Patients, with the Use of a Survey in Cuba in 2020

Aims To evaluate the prevalence and type of adverse drug reactions (ADRs), together with associated risk factors, among Cuban COVID-19 patients treated with chloroquine (CQ), lopinavir/ritonavir (LPV/r), or interferon α2b (IFN α2b), according to the Cuban protocol. Materials and Methods A prospective descriptive analysis of ADRs was performed on 200 COVID-19 patients who were admitted consecutively to three hospitals in Havana and Pinar del Río from April to July 2020. Information on demographics, ADRs, outcomes, behavioral, and health-related factors was collected using a validated questionnaire and clinical records. Each potential ADR case was assessed for causality based on the WHO-UMC algorithm, concomitant drug influences, and the presence of any drug-drug interactions (DDI). Results The total frequency of ADRs was 55%, with predominantly gastrointestinal disorders and general symptoms (23% vs 20%). 95.1% of ADRs occurred within 10 days after treatment and 42 potential DDI in 55.5% of patients (61/110) were observed. The prevalence of ADRs was: 44%, 30.4%, and 26.4% for IFN α2b, LPV/r, and CQ, respectively. Sex (odds ratio (OR): 0.40 (95% confidence interval (CI): 0.211–0.742), age (OR: 2.36 (95% CI: 1.02–5.44)), and underlying diseases (OR: 0.12 (95% CI: 0.06–0.23)) were independently associated factors for ADRs (P < 0.05). Conclusions The frequency of ADRs and potential DDI was high compared to their use during nonpandemic times (e.g., for malaria, HIV, or inflammatory diseases). The safety profile of these drugs when used for COVID-19 treatment showed similar characteristics. Comorbidities, age >37 years old, and female sex were associated with ADRs.


Introduction
SARS-CoV-2, discovered in Wuhan, China, is a highly contagious pathogen that spread quickly throughout the world, and which caused a pandemic of global concern. According to the World Health Organization, 223 countries have been afected, with nearly 250 million people infected worldwide. Tere is a lack of a specifc treatment for SARS-CoV-2-induced severe acute respiratory syndrome, but effective vaccines became available by late 2020 [1][2][3].
People infected with SARS-CoV-2 can be asymptomatic or can present symptoms with varying severity, which is possibly associated with the patients' age and underlying comorbidities. Te most commonly reported symptoms are as follows: fever, dry cough, headache, myalgia, fatigue, and diarrhea. SARS-CoV-2 causes marked infammatory and immune responses that may activate a "cytokine storm," which results in apoptosis of epithelial and endothelial cells and, subsequently, vascular leakage and abnormal T cell and macrophage responses ensue [4,5].
Many host cellular factors have been identifed that are involved in the viral infection and in the various steps of the lifecycle or viral products that interfere with the homeostasis of cell metabolism. Tese factors cause signifcant cellular stress to the host cell, which induces cell and tissue damage [6].
Since the beginning of the pandemic, there have been several potential drug candidates for COVID-19 treatment, such as lopinavir/ritonavir, interferon alpha 2b, umifenovir, chloroquine, remdesivir, favipiravir, anti-infammatory drugs (such as corticosteroids and other molecules), and traditional medicines. Tese were considered to be drug repurposing or of-label, compassionate use drugs because there was a lack of clinical trial data supporting the use of these drugs in COVID-19 [7,8]. Hence, these drug treatment schemes and posologies must be carefully investigated to maximize their benefts with minimal toxicity or adverse drug reactions. Previous reports have shown that the treatment of COVID-19 patients with preexistent, noncommunicable diseases was complex [9] and that they had an increased risk for drug-related adverse reactions [10,11].
In early 2020, in Cuba, the option of drug repurposing and of-label, compassionate use was discussed and approved by an ad hoc commission of the Cuban Research and Science Ministry of Health. A consensus protocol of case management and treatment was approved in March 2020, which included compassionate use of lopinavir/ritonavir, interferon α, and chloroquine for all hospitalized patients that tested positive on a SARS-CoV-2 RT-PCR test, whether they were asymptomatic or not [12].
Te recommended drugs, such as HIV protease inhibitors, interferon, and chloroquine have previously shown complex DDI [13,14]. Drug safety must never be ignored, especially when there is still doubt about the drug's efcacy against the pathogen, as was the case for COVID- 19. Te drug's benefts must always outweigh its risks [15]. ADRs are described for the three recommended drugs, and they range from mild to life-threatening and short-to long-term efects, according to previous use worldwide [10,11,16]. Hence, evaluation of potential ADRs for the drugs used for the Cuban COVID-19 protocol was performed [12]. Little is known about the incidence of ADRs to these drugs when used in COVID-19 patients. In the literature, ADRs reaching 20-40% are reported when used for HIV, malaria, and infammatory diseases [10,11,16] but 40-70% of ADRs are reported in COVID-19 patients [9,13,17]. In low-and middle-income countries, the main priority is securing access to drugs for treatment, which leaves limited resources for pharmacovigilance [18,19]. Tus, it is clear that drug safety data should be collected and analyzed to obtain the necessary information for decision-making, to manage potential risks associated with certain drugs or their combinations.
Te "Institute Pedro Kouri" hospital in Havana, Cuba, is taking part in the Sentinel Surveillance on Pharmacovigilance. A specifc system was set up, where patient notifcation reports are routinely collected and analyzed for potential ADRs in infectious disease treatments [20]. Tis sentinel surveillance system aims to solve the problems of underreporting, undue delays, and miscommunication that were observed in the previous passive surveillance system on ADRs.
Better reporting systems and the rapid analysis of information will have a positive efect on rational drug use in hospitals [21]. In this study, we characterized the ADRs during the frst wave of COVID-19 in Cuba and analyzed possible drug-drug interactions. Our results obtained on drug safety will provide a solid basis for decision-making by the Cuban Ministry of Health about drug risk management in COVID-19 treatment. Moreover, our data are important for enhancing current treatment regimens by reconfguring the recommended therapeutic combinations and to provide potential information for personalized treatments.

Materials and Methods
Tis study was done in accordance with the principles of the Declaration of Helsinki and the Good Clinical Practice Guidelines of the International Conference on Harmonization. Te study protocol was approved by the Scientifc and Ethics Committee (by fast-track) of IPK, University of Informatics Science Hospital (UISH), and Pinar del Río Medical Science University Hospital (PRMUH), Cuba, on May 17, 2020. Tis study was also approved by and registered at the Cuban Ministry of Health (code number 2105028) in accordance with the regulatory Cuban agency (CECMED).

Setting.
Te frst cases were reported in Cuba in March 2020, and in accordance with the COVID-19 treatment protocols that were approved in April 2020 by the Cuban Ministry of Health Commission, all RT-PCR positive patients were admitted to diferent hospitals. All these hospitals were prepared with the necessary COVID-19 biosafety precautions. All patients were hospitalized and treated during acute COVID-19 with the three drugs: Kaletra (lopinavir/ritonavir), chloroquine, and interferon α2b, regardless of their clinical diagnosis (i.e., asymptomatic or symptomatic for COVID -19). COVID-19 cases were tracked by contacts with index cases, and all were isolated and tested with rapid tests or/and PCR. If patients tested SARS-CoV-2 positive, they were hospitalized and could be included in this study, dependent upon their time of presentation and admission to the hospital. All COVID-19 patients were hospitalized for the full duration of their treatment (30 days).
Inclusion criteria: all adult patients (>18 years old) with a SARS-CoV-2 positive RT-PCR test were included, with no sex restrictions. An exclusion criterion was participation in another clinical trial within the last three months.
All patients with SARS-CoV-2 infection confrmed by RT-PCR and hospitalized in IPK, UISH, or PRMUH were consecutively included in this study from April to July 2020.
Tere was no sample size estimated, as all patients in the study locations who gave consent were included in the study.

Questionnaire.
To evaluate the factors associated with ADRs, a 105-point paper-based questionnaire was used, which explored factors related to 11 domains, such as general health, demographics, and risk behaviors.
Aspect 1-patient demographic characteristics (age, sex, and ethnic group); Aspect 2-patient clinical status; Aspect 3suspected drugs and concomitant medications (for each one, administration route, therapy duration, dosage, and therapeutic indication were recorded); Aspect 4-ADR description; Aspect 5-ADR outcome (improvement, complete resolution, unchanged or worsened event, resolution with sequelae, and death).
Tis survey is a modifed version of the questionnaire on "Lifestyle Related Practices and Beliefs," designed, validated, and applied by Arrivillaga et al., to describe the healthrelated beliefs of a community of young university students in Cali, Colombia. It also assessed their attitudes toward risk and protective behaviors [22]. We obtained permission from Arrivillaga et al. to make a modifed version of their questionnaire.
Four members of our research team were trained as interviewers to ensure uniformity in data collection. When conducting the survey, they introduced themselves to the participants and explained by phone the purpose of the survey. Data related to aspects 1 and 2 were obtained from health records. Data for aspects 3, 4, and 5 were collected by phone. Te pharmacologists and physicians who reviewed the ADRs were specifcally involved in this study for this purpose. A "suspected drug" is defned as a drug which is potentially associated with the observed ADRs, while a "concomitant medication" is a drug that the patient is exposed to at the time of ADR occurrence. A concomitant medication may not necessarily be associated with the ADRs. Moreover, each case was evaluated with the aim of identifying the presence of DDI, which may have contributed to ADRs. DDI were identifed using the open access Drug Interaction Checker. For each case, the physicians consulted the source documents that were archived in the hospital medical record system.
A detailed written explanation of the questionnaire process, the researchers' names and institutions, and possible benefts for the patients and others were clearly explained to the participants, and additional information was provided upon request. Informed participants were asked to sign a written informed consent. All patients were codifed and anonymized to protect the confdentiality of individual participants.
Two hundred patients with SARS-CoV-2 infection, confrmed by RT-PCR, during April to July 2020, that were hospitalized (72 in IPK, 38 in UISH, and 100 in PRMUH), aged 19-85 years old at the time of inclusion, were interviewed by phone. Te questionnaire was performed while the patients were in the hospital, just before their discharge from the hospital. ADRs are defned by the WHO as noxious and unintended responses to drugs at standard doses. Te ADR reports were reviewed by pharmacologists and physicians that were specialized in pharmacovigilance. All the data collected for ADRs and their further characterizations were sent to the National Pharmacovigilance Unit.

Treatment Regimen.
All patients received the three drugs daily according to the following regimen: Kaletra (200 mg lopinavir and50 mg litonavir) 2 capsules per 12 hours for 30 days, chloroquine (250 mg � 150 mg base) 1 tablet per 12 hours for 10 days and 3 million units of interferon α2b, by intramuscular injection, 3 times a week for 4 weeks.

Data Collection.
Other characteristics of the COVID-19 patients (time of admission, length of stay, sex, age, disease diagnoses, etc.), history of drug allergies, the antiviral protocol, and the number of medications used during hospitalization were extracted manually from the study questionnaires.

Case Assessments.
Causality assessments were performed for all suspected ADRs using the World Health Organization-Uppsala Monitoring Centre (WHO-UMC) system. Te WHO-UMC system is a universally accepted method for causality assessment [23].
Te seriousness of the identifed suspected ADRs was determined according to the defnition of the ICH E2A guideline (ICH E2A Clinical Safety Data Management: Defnitions and Standards for Expedited Reporting), which includes and combines the severity classifcation that is evaluated with Hartwig's Severity Assessment Scale as mild (levels 1 and 2), moderate (levels 3 and 4), and severe (levels 5-7) [24]. Te Hartwig's Severity Assessment Scale contains the following levels: level 1: an ADR occurred but required no change in treatment with the suspected drug; level 2: the ADR required that treatment with the suspected drug be held, discontinued, or otherwise changed. No antidote or other treatment requirement was required. No increase in length of stay (LOS); level 3: the ADR required that treatment with the suspected drug be held, discontinued, or otherwise changed. AND/OR an antidote or Advances in Pharmacological and Pharmaceutical Sciences other treatment was required. No increase in LOS; level 4: any level 3 ADR which increases length of stay by at least 1 day. OR the ADR was the reason for the admission; level 5: any level 4 ADR which requires intensive medical care; level 6: the adverse reaction caused permanent harm to the patient; level 7: the adverse reaction either directly or indirectly led to the death of the patient. Te relationship between the reported ADRs and drugs was categorized as certain, probable, possible, unlikely, conditional/unclassifed, or unassessable/unclassifable. Only cases categorized as certain, probable, and possible were included in our study.

Potential Drug-Drug Interactions.
For the determination of potential DDI among chloroquine, Kaletra, interferon α2b, and other concomitant drugs, the Medscape and Liverpool Interaction Checker (https://reference.medscape. com/drug-interactionchecker) webpages were uniformly consulted, as recommended in the national and international treatment guidelines [25,26]. Potential DDI were those classifed according to risk level: X (contraindicated association), D (consider modifcation of therapy), and C (monitoring therapy). Subsequently, the DDI frequency was analyzed and each interaction was described according to its mechanism of action, the level of risk, if it afected LPV/r, the other drug involved in the interaction, or both, if it could compromise its efcacy or cause toxicity. and the recommendation in each case.

Data Processing and Statistical
Analyses. Data were stored digitally using an entry program developed with the WPS software package. All data were processed using Microsoft Access. Both descriptive and analytical analyses were carried out on the data using Microsoft Excel and Version 22, SPSS Inc., Chicago, IL, USA.
Bivariate analysis was carried out to evaluate the associations of potential risk factors with the presence of ADRs. Results were presented as percentages and frequencies. To test statistical signifcance, 95% confdence intervals and/or P-value were used. A P-value <0.05 was considered to be statistically signifcant. (Table 1). From these, 94 (47%) were female and 106 (53%) were male. Te mean age was 46 years old with (95% CI 20-76). Underlying diseases such as hypertension, cardiovascular disease, diabetes, asthma, cerebrovascular disease, cancer, chronic kidney disease, chronic liver disease, obesity, epilepsy, arthritis, and others were identifed in 70.5% of them. 72.5% of all patients were Caucasian.

Patient Characteristics. Two hundred (200) patients were included in this study
Of the 200 patients, 65 showed asymptomatic progression of COVID-19, and 135 presented low or moderate symptoms. A total of 232 ADR manifestations were identifed in 110 patients. Te overall cumulative incidence of ADRs was 55%.

Characteristics of ADRs.
Drug-related adverse reactions, as categorized by manifestations, are shown in Figure 1. Gastrointestinal (GI) disorders (diarrhea, vomiting, and nausea) were the most frequent ADRs with an occurrence of 23.0%, followed by general symptoms (fever, pain, decay, and general discomfort). For the onset of the ADRs, 9.57% (rash, diarrhea, and vomiting) occurred within the frst day of treatment, 79.8% occurred within 7 days of treatment, and 95.1% occurred within 10 days of treatment.
Suspected drugs with ADRs were associated with interferon α and lopinavir/ritonavir with 44% and 30.4%, respectively. CQ caused the lowest ADR incidence with (29/ 110) 26.4%, of which only 7.3% were found to be serious ( Table 2). Te causal relationship assessed by using the WHO-UMC system in the suspected ADR cases was found to be probable and possible (76% vs. 24%). Te prognoses of ADRs in these patients were favorable, with 75% cured and 25% improved.
Other drugs (in total, 63) used by patients for treatment of comorbidities are listed in Table 3, as well as the frequencies of DDI by drug, together with the descriptions of each interaction according to the following lists: mechanism of action, risk level, efect, and recommendations. Potential DDI with prescribed drugs for COVID-19 treatment was found in 61 patients using, in total, 29 drugs, which represent 46.0% (29/63). 55.5% of patients (61/110) who presented ADRs and comorbidities sufered from DDI. A risk level X was identifed in only 1 patient, the risk level D was identifed in 30 of 61 cases (49.2%), and the risk level C was observed in 30 of 61 cases (49.2%) ( Table 3). Te drug with the highest interaction frequency was lopinavir-ritonavir (n � 59), followed by CQ (n � 23). With respect to interferon α2b, no interactions were identifed, in concordance with the low or nonreports previously described for the studied drugs (41, 42). An exception was hydrochlorothiazide, which potentially interacts with interferon α2b, CQ, and ritonavir/ lopinavir. Only one type of DDI was identifed involving CQ, while 17 DDI were related to lopinavir/ritonavir. Potential interactions related to both CQ and LPV were identifed for 10 supportively prescribed drugs (45) ( Table 3). 4 Advances in Pharmacological and Pharmaceutical Sciences       Lopinavir + ritonavir Metamizole is a moderate inducer of CYP3A4 and a strong inducer of CYP2B6. Te risk or severity of nephrotoxicity can be increased when lopinavir is combined with metamizole also increased risk of haematological toxicity had to be considered Opioid Tramadol Lopinavir + ritonavir Levonorgestrel is metabolized by CYP3A4 and is glucuronidated to a minor extent; coadministration is predicted to increase levonorgestrel Source: completed surveys that were accessed in a digital database and printed surveys. ADR, adverse drug reaction. Risk level: X (contraindicated association), D (consider modifcation of therapy), and C (monitoring therapy). CYP450, Cytochrome 450. AUC, area under curse. C max : drug maximum (or peak) serum concentration that achieves in a specifed compartment. QTc: the interval is a measurement made on an electrocardiogram in relation to cardiac frequency using the beginning of the QRS complex to the end of the T wave. TdP: torsades-de pointes (French for "twisting of the points") is one of several types of life-threatening heart rhythm disturbances. mg: miligram.

Discussion
Te COVID-19 pandemic has overwhelmed healthcare systems worldwide. A more detailed stratifcation of the adverse-related events of prescribed drugs to treat COVID-19 is required [8]. In this study in Cuba, we used for the frst time a comprehensive survey to identify potential drug safety issues for of-label drugs that were used to treat COVID-19. We aimed to obtain evidence for a specifc combined drug approach that could be used for the prevention and treatment of COVID-19.
Our study actively recorded ADR symptoms in hospitalized patients in hospitals in Cuba under continuous monitoring, and data were directly reported to the National Pharmacovigilance Centre, to avoid any potential underreporting or miscommunication. As all patients with a positive RT-PCR test were hospitalized in Cuba, this provided an ideal opportunity to obtain data on the real incidence of ADRs in COVID-19 patients [18]. We ensured that there was no bias in the inclusion of COVID-19 patients in this study, so our study results may also be applicable in other contexts. Some of the main reasons for nonreporting in other settings included: a lack of time, no access to documentation, insufciently trained personnel, the personnel being busy with other tasks, failure to recognize an ADR, patient confdentiality concerns, biosafety resolution regarding clinical history use (quarantine), and fear of blame. Our study showed that ADRs in COVID-19 patients were mainly characterized by GI reactions and general symptoms such as fever and general discomfort, with an incidence of 23.0% and 20%, respectively. ADRs that occurred within 10 days represented 95.1%. As ritonavir/ lopinavir and chloroquine were orally administered, the GI manifestations associated with these drugs typically occurred within 7 days. Fever was presumably related to injections of interferon α2b, but this was not exclusive, and it typically appeared within 24 to 48 hours.
Various studies on drug safety monitoring in COVID-19 patients have been published [9,13,15,17,[27][28][29][30][31]. One study in China reported diarrhea that was associated with lopinavir/ritonavir use in COVID-19 [17] and showed that after using lopinavir/ritonavir in 33 patients with COVID-19 in the Nanchong area, 15 patients had diarrhea, rash, and other adverse reactions, with an incidence of 42.9%. In our study, the incidence of ADRs by lopinavir/ritonavir was 30.4% (34/110), which was lower than studies from China [9,17] but higher than the Melo study from Brazil [30] and the Maza Larrea study from Mexico [31]. Te proportion of ADRs caused by interferon α2b in our study (44%) was the highest, which was similar to other COVID-19 studies [9,30].
Results obtained from other studies difer slightly from ours. Tis may be due to diferences in population, context, and sex-age composition [32], or ancestry genotypic polymorphisms as have been observed in other viral diseases in Cuba [33]. Te safety monitoring data obtained in previous studies for lopinavir mainly focused on HIV patients and healthy people [13]. A randomized trial to evaluate the effcacy and safety of lopinavir/ritonavir in the treatment of HIV-1 infection reported that the incidence of diarrhea was high (26/40, 65%), resulting in 16% of moderate/severe adverse events [13]. Moreover, recent COVID-19 studies presented GI alterations as the main ADR [1,13,15].
In our study the incidence of adverse reactions by chloroquine was 29/110, and mainly manifested as GI reactions, general discomfort, and headache. No decreases in vision or cardiotoxicity were observed, which was in contrast to other studies [9,13,32], as this is induced by long-term use of chloroquine, which was not the case in our study as it was generally administered for less than 30 days [24].
In clinical trials with lopinavir/ritonavir recipients, hypertriglyceridemia and hypercholesterolemia were the most frequently observed alterations and were mainly seen in the frst month of treatment [27], which represents a potential reason for discontinuation of therapy [13]. Tis supports the need to closely monitor potential changes in blood lipids in patients undergoing treatment.
In our study, ten serious ADRs were observed in patients who each sufered from 3 or 4 underlying diseases. All these patients used polypharmacy with 5 potential DDI related to both chloroquine and ritonavir-lopinavir, had toxic habits (alcoholism and smoking), and showed ages higher than 37 years. Tese patients discontinued the drug therapy, after which their symptoms resolved in 1 to 3 days.
Te majority of ADRs observed in our study are in correspondence with previously reported adverse reactions or the recognized safety profles for these drugs [10,11,24]. Only 2 ADRs were identifed as rare and 3 as occasional in our study.
In accordance with our study, a signifcant association between age, sex, and comorbidities and the occurrence of ADRs was also observed in studies by Kojima et al. [34], Bandariz et al. [35], and Jing et al. [9]. Alterations in age are typically concomitant with underlying changes in the human body, such as a reduction in renal clearance, liver size, lean body mass, and other factors which may impact biological processes and, in consequence, alter drug distribution, metabolism, and pharmacodynamic responses [36].
In our study, an association of ADRs and sex was found, which was in concurrence with the results obtained by Jing et al. for lopinavir/ritonavir and Zekarias et al. for CQ and lopinavir/ritonavir [9,28]. Tis could be explained by differences in fat distribution, greater plasma volume, organ perfusion, and hormone-related regulation of drug metabolizing enzymes, as has been reported in other studies [37].

Advances in Pharmacological and Pharmaceutical Sciences
Preexisting or underlying diseases, or comorbidities, have also been identifed as associating factors. Comorbidities produce pathophysiological changes that could have an efect on drug pharmacodynamic and pharmacokinetic properties, and hence patients could be given unsuitable drug prescriptions [36]. Polypharmacy has been reported to be a strong risk factor for ADRs in several studies in relation to possible DDI [1,18]. Potential DDI was identifed in 63 patients for 29 drugs, mainly previously prescribed for COVID-19 infection, and could be a factor contributing to the high ADRs observed.
Te DDI identifed in our study are potentially related to the modifcations in drug concentrations, and this could afect their antiviral activity or infuence on comorbidities. Te DDI could also cause an increase in toxicities. Indeed, for 28 of the 29 drugs used, it is strongly recommended to monitor or avoid their use due to increased toxicities. For only one drug, concomitant administration with CQ, IFN, and LPV/r was contraindicated.
Diferent studies have reported that ADR incidence in hospitalized patients varies from 8 to 35%, which was mainly based on the physicians' spontaneous reports [14,18]. Te high incidence observed in our study (55%) could also be related to the nonexplored interactions among drugs-hostviruses in the new pandemic scenario that required an indepth study of the ADR-DDI in COVID-19 patients [14,32,35]. Some researchers have suggested that the application of a survey could be a useful method for collecting patient reported ADRs [21]. Reporting by the patients generally implies the use of the Internet or phone. For those patients who are not comfortable using Internet tools or where computers are not available in the hospitals involved in the study, another option should be made available, such as reporting by phone using a survey adapted to that case [21]. Te last variant was the one used in our study.
Te vast majority of COVID-19 patients in previous studies were hospitalized because of fever [9,15,17]. Hence, in this study, this bias was not present, as most of the hospitalized individuals were nonsymptomatic (contact tracing individuals). In univariate analysis from previous studies, the length of the hospital stay was reported to be signifcantly associated with the occurrence of ADRs [27,31]. No association was found in our study in relation to the duration of hospital stays, which was likely because hospitalization and duration of hospitalization were not dependent upon symptomatology or severity of infection.
Toxic habits such as alcoholism and smoking, which have a high incidence in the Cuban population, could also impact ADRs, but we found no association between ADRs and these toxic habits.
Te interpretation of our results is limited to the context from which participants were recruited. We mainly studied COVID-19 patients that were hospitalized in occidental provinces, which may not be representative for patients hospitalized across diferent regions in Cuba. In addition, a partial evaluation of possible ADRs does not completely exclude the infuence of COVID-19. In our study, both physicians and researchers made an efort to carefully make a distinction between drug efects and COVID-19 infection symptoms. Altered medical parameters and symptoms observed in patients, related to preexistent diseases diferent from COVID 19, cannot be included as ADRs. Furthermore, we only observed ADRs during hospitalization, after the drugs had been administered [30]. Also, late-stage retinopathy caused by chloroquine may occur many years after discontinuation of the treatment. Further studies with longer follow-up periods are required to assess the longerterm implications of ADRs. For DDI, some discrepancies were found compared to published drug guidelines, which could infuence recommendations for therapy. Another limitation is that the analysis of interactions was done with only two drugs. It needs to be considered that multiple drug combinations could result in additional ADR efects. Te sample size of this study was small, and most of the COVID-19 patients were asymptomatic. We excluded COVID-19 patients that were severely ill, as they were also treated with other drugs, and this would have afected our ADR analyses.
It still remains a challenge to design an efective, lowtoxicity, and well-tolerated drug regimen for COVID-19 using of-label drugs [7,13]. Our results have contributed to the modifcation of various aspects of the Cuban COVID-19 health guidelines. Additionally, our results have also provided data that could inform individualized therapies and could lead to better COVID-19 symptom management.

Conclusions
Te prevalence of ADRs was high in Cuban COVID-19 patients that were enrolled in this study. Te majority of the ADRs were drug-induced gastrointestinal disorders and general symptoms. Age, sex, and underlying diseases were the main independently associated factors for the occurrence of ADRs in patients. Te reported characterization and incidence refected the adverse reactions of patients with symptomatic and asymptomatic COVID-19, providing a reference for clinically safe medication.

Data Availability
Tere are specifc legal and ethical requirements related to Cuban populations that prohibit public sharing of a dataset. Data contains personal information on human subjects. Confdentiality and any specifc access restrictions are typically specifed by an Institutional Review Board. FFB, PSR, TP, WB, OOC, and LVL. Te data analysis was realized by LGV, MMDG, OELF, BS, ABP, RGH, XVO, WVB, and VVB. Manuscript writing was done by LGV, MMDG, OELF, BS, ABP, OOC, LVL, and MGGT. All coauthors revised the manuscript.