Current Drug Safety - Volume 17, Issue 2, 2022

Background: Coronavirus disease 2019 (COVID-19) is a new strain of coronavirus. It is characterized by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). It has quickly influenced all over the world since it spreads easily. Common symptoms are fever, cough, difficulty in breathing and muscle aches. Despite the urgent need to find an effective antiviral treatment, already available agents are being used alone or in combination all over the world. At the beginning of the pandemic, death rates of infection caused by COVID-19 are high but “is COVID-19 responsible for all deaths?”, or “are there any contributions of the frequently used drugs in this period to these deaths?” Surely herd immunity plays a major role and has contributed to the decline in mortality rates. Meanwhile, it is kept in mind that due to safety concerns, changes have also been made in the dosage and combined use of frequently used drugs. Objective: In this review, answers to two questions above and the safety of treatments, toxicities of agents involving chloroquine, hydroxychloroquine, remdesivir, favipiravir, lopiravir/ritonavir, sarilumab, tocilizumab, siltuximab, corticosteroids and bromhexine which are the most frequently used in Turkey and all over the world will be summarized. Conclusion: Among these drugs, favipiravir seems the most promising drug due to more tolerable adverse effects. More clinical trials with large sample sizes are needed to find the most effective and safe drug for COVID-19 treatment.

A virus is an infectious agent that can only replicate within a host organism and can infect a variety of living organisms, including bacteria, plants, and animals. Viruses are so small that a microscope is necessary to visualize them, and they have a very simple structure. A coronavirus is a group of viruses that can cause diseases, for instance, the basic cold, severe acute respiratory syndrome (SARS), and the Middle East respiratory syndrome (MERS). The patients affected with the COVID-19 infection will encounter respiratory sickness and can recuperate without requiring normal therapy. Individuals with clinical issues like cardiovascular problems, diabetes, and respiratory illness will suffer from the ailment. COVID-19 disease spreads through aerosols or the nose when an infected individual hacks or sneezes. In 2019, a new disease, known as novel coronavirus disease 2019 (COVID-19), was discovered in China, and on March 11, 2020, it was declared a pandemic disease by the World Health Organization (WHO), spreading rapidly across 194 countries in Europe, North America, Asia, the Middle East, Latin America, and Africa. The best way to stop the spread of the transmission is to be instructed about COVID-19 and how it spreads. In this survey, we are endeavoring to focus on the drugs and vaccines that are used for the treatment and prevention of COVID-19.

Drug-induced QTc prolongation is a concerning electrocardiogram (ECG) abnormality. This cardiac disturbance carries a 10% risk of sudden cardiac death due to the malignant arrhythmia, Torsades de Pointes. The Arizona Center for Education and Research on Therapeutics (AzCERT) has classified QTc prolonging therapeutic classes, such as antiarrhythmics, antipsychotics, anti-infectives, and others. AzCERT criteria categorize medications into three risk categories: “known,” “possible,” and “conditional risk” of QTc prolongation and Torsades de Pointes. The list of QTc prolonging medications continues to expand as new drug classes are approved and studied. Risk factors for QTc prolongation can be delineated into modifiable or non-modifiable. A validated risk scoring tool may be utilized to predict the likelihood of prolongation in patients receiving AzCERT classified medication. The resultant risk score may be applied to a clinical decision support system, which offers mitigation strategies. Mitigation strategies including discontinuation of possible offending agents with a selection of an alternative agent, assessment of potential drug interactions or dose adjustments through pharmacokinetic and pharmacodynamic monitoring, and initiation of both ECG and electrolyte monitoring are essential to prevent a drug-induced arrhythmia. The challenges presented by the COVID-19 pandemic have led to the development of innovative continuous monitoring technology, increasing protection for both patients and healthcare workers. Early intervention strategies may reduce adverse events and improve clinical outcomes in patients identified to be at risk of QTc prolongation.

Background: The prevalence of potential drug-drug interactions (pDDIs) is indicative of the prevalence of actual drug-drug interactions and prescription quality. However, they are significantly understudied in Greece. Objective: The objective of the study was to determine the prevalence of pDDIs among outpatients and identify factors associated with their occurrence. Methods: Anonymous e-prescription data between 2012 and 2017 were obtained from community pharmacies in Thessaloniki, Greece. Patients taking more than one medication for at least three months were included. pDDIs were identified and categorized depending on their clinical significance using Drug Interactions Checker. Crude and adjusted odds ratios (ORs) with accompanying 95% confidence intervals (CIs) of risk factors of pDDIs occurrence were identified using multivariable logistic regression. Results: During the study period, 6,000 anonymous e-prescriptions (1,000 per year) satisfying the inclusion criteria were collected. The overall prevalence of major pDDIs was 17.4% (63.0% for moderate pDDIs). The most common major pDDIs were between amlodipine and simvastatin (22.8% of major interactions), followed by clopidogrel and omeprazole (6.4% of major interactions). Polypharmacy (≥5 concomitantly received medications) was associated with an increased risk of major pDDIs (adjusted OR, 5.72; 95% CI, 4.87-6.72); no associations were observed regarding age, sex, and number of prescribing physicians. Conclusion: The prevalence of pDDIs in this study was higher than previously reported in other European countries, with polypharmacy being a potential risk factor. Those results argue for a need for improvement in the area of prescribing in Greece.

Background: The use of Potentially Inappropriate Medications (PIMs) is common and negatively affects elderly health and disease prognosis. Objective: This study aims to analyze the frequency of PIMs in the elderly health records registered to a family health center and to identify risk factors, prescription/nonprescription distribution, distribution by healthcare institutions, number of doctors visits, and health literacy. Methods: In this cross-sectional study, a stratified sampling method was used to select individuals aged ≥ 65 years. The health records of the participants up to the last 12 months were examined, and medicines used by participants were evaluated according to Beers 2019 criteria. Results: Most of the participants (89.7%, n:183) had PIMs in health records. The mean number of PIMs used by the elderly was 2.9±1.9 (min:0, max:8). A positive linear relationship was observed between multimorbidity and the number of PIMs (p=0.001). There was no significant difference in terms of PIMs frequency among healthcare institutions. Prescription and non-prescription PIMs were found to belong to the same drug groups (Pain relievers and stomach medications). A linear and significant correlation was found between the number of PIMs and doctor visits (p=0.047). Conclusion: The doctor should examine prescription and over-the-counter medications used by the elderly during the visit. It will be useful to establish a warning system stating that PIMs are available while registering the medications in the electronic system. So, it will be possible for health authorities to re-evaluate the treatment and replace PIMs with rational drug options.

Background: Serious adverse reactions have been reported with the use of Chimeric Antigen Receptor (CAR) T-cell therapy in a clinical setting despite the success of these products in pre- clinical stages of development. Objective: We evaluated the quality of available pre-clinical safety data of CAR T-cell therapy products. Methods: A 21 items safety checklist was designed specifically for CAR T-cell. Literature was searched using search/MeSH terms in PubMed (October 2019 – February 2020). Studies were screened from title and abstract. Original pre-clinical researches related to CAR T-cell anti-cancer therapy were included. Results: Of the search results, 152 studies (3 in vivo, 39 in vitro, and 110 combined) were included. Only 7.9% of studies were specifically designed to evaluate/ improve product safety. Eleven studies included target antigen(s), and no study included co-stimulatory molecule(s) expressed exclusively by the tumor tissue and/or CAR T-cells. One study used CRISPR-Cas9 for CAR gene insertion. The use of switch-off mechanism and purity assessment of CAR T-cell products were reported in 13.2% and 8.6% studies, respectively. Of the 113 studies with in vivo components, immuno- competent animal models were used in 24.8%. Measurements of blood pressure, temperature, body weight, and serum cytokines were reported in 0, 2.7, 29.2, and 27.4% studies, respectively. The tissue distribution and CAR T-cells persistence were reported in 26.5% of studies. The surface expression level of CAR, functional characterization of the product, and use of control were reported in >90% of studies. Conclusion: The majority of the checklist parameters were not reported in the pre-clinical publications to be adequately predictive of the safety of CAR T-cells in a clinical setting.

Background: Anti-cancer agents are known to be toxic, leading to a number of adverse drug reactions (ADRs). ADRs not only increase the financial burden on the patient/healthcare system but also decrease the quality of life. Understanding the burden of ADR will help strengthen the knowledge on patient safety and implement intervention strategies to reduce it. Objectives: The objectives of the study are as follows: 1. To study the pattern of adverse drug reactions of anticancer agents of patients admitted in the oncology ward. 2. To assess the causality, severity, and preventability of the adverse drug reactions observed. Methods: This was a cross-sectional, observational study carried out in 200 adult patients in the daycare center for chemotherapy. Details of ADRs noted in the previous and current cycles were noted. Causality assessment was done using Naranjo and WHO scales. For severity and preventability assessment, Hartwig Siegel and Modified Schumock Thorton scale were used, respectively. Results: Out of the total 732 ADRs encountered, alopecia was the most common ADR. The average number of ADRs observed per patient was 3.66 + 1.59 (mean + SD). The maximum number of ADRs were seen in Paclitaxel-carboplatin 3 weekly regimen. Nausea and alopecia were the most common ADRs reported with most regimens. On causality assessment, 95 (12.97%) were definitely related according to Naranjo’s Causality scale, while 15.71% were certainly related according to the WHO scale. Of all the ADRs recorded, 47.81% were of moderate intensity, while 52.18% were of mild intensity. The majority of ADRs, i.e., 87.59%, were not preventable. Conclusion: Alopecia was the most common ADR reported. Most of the ADRs could be causally related to drugs. These ADRs were mild to moderate in severity and were not preventable. There is a need to identify the underlying factors that predispose patients to these ADRs and target them in future research.

Background: The treatment of COVID-19 disease remains a dilemma so far because there is no approved therapy for it. This study aimed to evaluate the use of hydroxychloroquine and azithromycin combination in treatment. Objectives: This study was carried out to determine the safety and effectiveness of hydroxychloroquine and azithromycin combination in COVID 19 patients. Methods: This study included 90 adult COVID 19 patients. Treatment of all patients followed Egyptian Ministry of Health COVID-19 protocols, receiving a combination of hydroxychloroquine 400mg twice on day 1, then 200 mg twice daily in addition to azithromycin 500mg/day for 5 days. ECG findings, especially the QTc interval, were assessed before and after 5 days from the administration. Results: All patients showed a statistically significant higher post-treatment QTc readings (433.6 ± 37.2) compared to baseline QTc (402.4 ± 31.3) at p<0.005 with a median QTc prolongation by 26 mSec and IQR (17.8-41.3), but without serious clinical complications. Only 5.6% of patients showed QTc more than 500 mSec and no torsade de points or cardiac arrest. Geriatric patients were at higher risk for QTc prolongation compared to patients aged less than 65 years but without a significant difference as regards the median max QTc difference p<0.65. The expected therapeutic effectiveness was 82.5% for moderate patients compared to 26% for severe patients (P<0.005). Conclusion: In a modest safety profile, we support the evidence that HQ/AZ therapy can be used to treat Covid-19 infection with more effectiveness in moderate rather than severe cases, which might be a reflection of the time of administration in the disease course.

Background: Colistin use has increased because of the emergence of infections caused by resistant gram-negative bacteria. Acute kidney injury (AKI) remains a treatment-limiting factor for widespread colistin clinical use. This study aimed at determining the incidence and the factors associated with the development of colistin-induced AKI. Methods: A retrospective observational study was conducted by reviewing files of adult patients with normal kidney function between January 2015 to March 2019 at a university hospital located in Beirut city. AKI was defined based on KDIGO criteria. Independent variables associated with colistin-induced AKI were also tested. Results: In this study, a total of 113 patients were included. AKI occurred in 53 patients (46.9%). The Charlson Comorbidity Index (CCI) was found to be significantly greater in the AKI group (2.26, P-value = 0.026). In the multivariate analysis, low serum albumen was found as an independent significant predictor for AKI (OR=.065, 95%CI: .013-.337, P-value=0.001). Moreover, the risk for AKI increased by 2 folds (OR=2.019, 95%CI: 1.094-3.728, P-value: 0.025), when two or more nephrotoxic agents were administered simultaneously with colistin. The patient’s age was also found as a significant predictor for AKI (OR=1.034, 95%CI:1-1.07), with a cut-off value of 58.5-year-old. Conclusion: This study demonstrated that the concomitant use of two or more nephrotoxic drugs, patient’s age of 58.5 or above, and the presence of hypoalbuminemia were independent factors for the development of colistin-induced AKI. These factors should be therefore taken into consideration when prescribing colistin in clinical practice to decrease the risk of AKI.

Remdesivir is an adenosine analogue drug that targets RNA-dependent RNA polymerase enzyme and inhibits viral replication. As of 22nd October, 2020, US FDA fully approved the drug Remdesivir for the treatment of COVID-19 patients who requires hospitalisation. Many clinical studies reported the derangement in hepatic and renal function tests, which is alarming considering the health conditions of the COVID-19 patients. In view of these results, the present study was envisaged to review the safety of Remdesivir in COVID-19 patients. The PubMed, Embase, and Cochrane databases were searched using the terms ‘Remdesivir,’ ‘veklury,’ ‘SARS’ and ‘COVID’ till 1st December, 2020. The studies included in this meta-analysis were either randomised or nonrandomised studies that evaluated Remdesivir for the treatment of COVID-19 against Placebo [standard of care]. The Adverse events [AEs], Serious adverse events [SAEs] and Treatment Discontinuation due to Adverse Events (TDAE) were used as primary outcome measures. The quality of studies was evaluated by using the Cochrane Collaboration’s tool for the assessment of RoB. Data analysis was performed by two authors (MK & DB) using statistical software Review manager [Revman] version 5.3. The pooled Risk Ratios (RR) and 95% Confidence Intervals (CI) were calculated by using a random-effects model for both primary and secondary outcomes. A total of four RCTs were included for the meta-analysis. Out of the four included clinical trials accepted for its methodological quality, three were of excellent quality and one study was of moderate quality. The pooled estimates of the three studies showed that Remdesivir had a 24% lower risk of SAEs compared to the placebo arm. However, the pooled estimates of two studies showed that 10 days of Remdesivir had 56% higher risk of SAEs compared to 5 days of Remdesivir regimen. Similarly, the 10 days of Remdesivir had two times higher risk of TDAEs compared to 5 days Remdesivir regimen. In conclusion, our meta-analysis demonstrated that Remdesivir is a safe therapeutic option. Our metanalysis revealed 5 days’ regimen have better safety profile than 10 days’ regimen of drug Remdesivir with respect to SAEs and TDAEs. For hospitalized patients, a 5-day course could be preferable with fewer safety concerns and lower drug costs. PROSPERO Registration ID: CRD 42020224272.