Current Drug Safety - Volume 17, Issue 1, 2022

Causality assessment for idiosyncratic ADRs mainly relies on epidemiology, signal detection and less often on proven or plausible mechanistic evidence of the drug at a cellular or organ level. Distinct clones of cells can exist within organs of individual patients, some conferring susceptibility to well-recognised Adverse Drug Reactions (ADRs). Recent advances in molecular biology have allowed the development of single-cell clonal techniques, including single-cell RNA sequencing (scRNA-seq) to molecularly fingerprint ADRs and distinguish between distinct clones of cells within organs in individuals, which may confer differing susceptibilities to ADRs. ScRNA- seq permits molecular fingerprinting of some serious ADRs, mainly in the skin, through the identification of Directly Expressed Genes (DEG) of interest within specific clones. Overexpressed DEGs provide an opportunity for targeted treatment strategies to be developed. scRN A-seq could be applied to a number of other ADRs involving tissues that can be biopsied/sampled (including skin, liver, kidney, blood, stem cells) as well as providing a molecular basis for rapid screening of potential therapeutic candidates, which may not otherwise be predictable from a class of toxicity/organ involvement. A framework for putative assessment for ADRs using scRNA-seq is proposed as well as speculating on potential regulatory implications for pharmacovigilance and drug development. Molecular fingerprinting of ADRs using scRNA-seq may allow better targeting for enhanced pharmacovigilance and risk minimisation measures for medicines with appropriate benefit-risk profiles, although cost-effectiveness and other factors, such as frequency/severity of individual ADRs and population differences, will still be relevant.

Medication errors are amongst the most frequently occurring healthcare-related incidents and have the potential to lead to life-threatening harm to patients. An incident reporting system is a traditional approach to the improvement of patient safety and entails the retrieval of information from incident reports. This not only provides a better understanding of causes and contributing factors but also enables the collection of data on the severity of incidents, system deficiencies and the role of human factors in safety incidents. Medication error reporting systems are often developed as a part of larger incident reporting systems that deal with other types of incidents. Although a rise in the prevalence of medication errors has led to an increased demand for medication error reporting, little is known about the characteristics and limitations of medication error reporting systems. The authors broach the subject of medication error reporting systems and propose a more robust and standardized approach.

Background: QTc prolongation is common in dangerous clinical conditions, associated with an increased risk of life-threatening arrhythmia torsades de pointes. The goal of this short communication is to evaluate the principal causes of risk of QTc prolongation that are observed in an emergency department and discuss the differences between drug- and non-drug-associated factors. Methods: The retrospective analysis was carried out on 130 patients that presented a QTc prolongation (>480 ms for man and >470 for female, respectively), admitted to the emergency department of a single Italian hospital. Patients with pace-maker (22) were excluded from this study. For each patient, a minimum of 3 ECGs (12 leads) were recorded. Attention was paid on electrolytes disturbances and to the pharmacotherapy, with a particular emphasis to the use of antibiotics. Results: Mean age of the patients was 79.6 years (SD=11.3) and females and males were almost equally present (46.6% F, 53.7% M). The average QTc value was 492.2 ms (493.3 ms F, 492.8 M). The patients were divided in those with electrolytes disturbances (24.0%), antimicrobial therapy (35.2%), both antimicrobial therapy and electrolytes disturbances (24.1%), and other causes of QTc prolongation (16.7%). Conclusion: This analysis shows the relevance of the empirical therapy established at the admission, in particular for infective diseases, as an important risk factor for the prolongation of QTc. Other factors that can increase the risk are electrolytes alterations, advanced age, cardiovascular diseases, and drug-drug interaction.

Introduction: Respiratory tract infections (RTIs) are a common cause of antibiotic usage in hospitalized pediatric patients. Inappropriate use of antibiotics may lead to the emergence of multidrug-resistant microorganisms and increased treatment costs. Objective: This study was designed to assess antibiotic usage in hospitalized pediatric patients with RTIs. Methods: Medical charts of the patients admitted to the pediatric ward (PW) and pediatric intensive care unit (PICU) of a tertiary respiratory center were reviewed. Patients’ demographic and clinical data, including gender, age, weight, history of allergy, length of hospital stay, clinical diagnosis, and prescribed antibiotics (indication, dose, and frequency of administration) were collected. The appropriateness of antibiotic usage was evaluated in each patient according to international guidelines. Results: Two hundred seventy-nine hospitalized patients were included in the study. The most common reason for hospitalization was pneumonia (38%), followed by cystic fibrosis (20.1%) and bronchitis (5%). The most commonly used antimicrobial agents were ceftriaxone, azithromycin, and clindamycin which guideline adherence for their usage was 85.3%, 23.3%, and 47%; respectively. Inappropriate dose selection was the main reason for non-adherence to the guidelines. The adherence rate to RTIs’ guidelines (considering all parameters for each patient) was 27.6%. Multivariate logistic regression analysis demonstrated CF and prescription of azithromycin are predictors of guideline non-adherence. Conclusion: We found relatively low adherence to international guidelines in our center that could be related to restricted definitions of optimal antibiotic therapy. Despite most patients received logical antimicrobial therapy, actions should be taken into account to reach optimal antibiotic usage.

Background: Inappropriate medication use poses a sizable health safety hazard in the elderly owing to aging-associated physiological and anatomic changes. Inappropriate drug prescribing and polypharmacy in this population elevate the risk of adverse drug reactions (ADR). The study aimed at assessing the prevalence and predictors of Potentially Inappropriate Medication (PIM) use in elderly patients according to updated Beers Criteria 2019. Methods: Medical records of 402 patients aged ≥65 years admitted to a tertiary care hospital from June 2018 to May 2019 were analyzed. The patients who received at least one PIM based on the 2019 Updated Beers Criteria were considered as test cases and others as control. Data were presented as descriptive statistics, and logistic regression was performed to assess the factors affecting the outcomes. Results: The mean age was found to be 73.7 ±6.4 years in the test and 70.5±5.5 years in the control group. The prevalence of PIMs to be used with caution was found to be 54%. Whereas the prevalence of PIMs to be avoided and to be used with reduced dose was found to be 45% and 1%, respectively. The most prescribed PIMs were aspirin, diuretics, long-acting sulfonylureas, and proton pump inhibitors (PPIs). Increasing age, polypharmacy, and the number of drugs in medication history were significantly (p<0.05) correlated with a substantial risk of PIM use. The risk of developing serious and moderate drug-drug interactions (DDIs) was significantly high in the test group (p<0.05) when compared to the control group. Conclusion: A high prevalence of PIMs was observed in this study. Age, polypharmacy, and ≥ 3 drugs in medication history were identified as risk factors for PIM use, and at a higher risk of developing DDIs. Continuous medication reviews by clinical pharmacists can aid in reducing the occurrence of PIMs amongst geriatrics.

Introduction: An adverse drug reaction case report refers to a scientific publication that is written by a health care professional who suspects a casual relationship between a drug and an adverse drug reaction (ADR). ADR case reports help to identify potential risks associated with the use of drug. Most of the case reports do not mention about reporting the ADR to regulatory authorities. With this objective, the aim of this study was to analyze the number of Adverse Drug Reactions (ADR) published as case reports (PubMed indexed journals) from January 2018 to June 2019, and observe if they are translated in regulatory frameworks like Vigibase, and package inserts. Materials and Methods: 321 ADRs were obtained with the keywords “Adverse Drug Reaction”. Out of those, 158 were independently extracted by two investigators, observed and categorized according to classes of the drugs, geographic location, severity, hospitalization, Completeness of ADR, whether reported to the regulatory authority (Vigibase), or listed in the package insert. Literature review articles were excluded. Results: Out of the 158 ADRs, antibiotics accounted for 12.65%, CNS drugs and monoclonal antibodies11.39%, anticancer drugs 9.49%, CVS drugs 4.43%, anti-viral 3.79%, others 45.56%, respectively. According to geographic region, 26 ADRs published were from USA, Australia 4, Italy 3, India 17, Turkey 9, Singapore and UK 1, China 20, Denmark and Canada 2, Japan 10, France 9, Austria 1, Korea 5, South America 3, Switzerland 2, respectively. Depending upon the severity, causality assessment was done only for 45 ADRs, and not done for 113 ADRs. 41.13% patients (from 65 case reports) were hospitalized. Among the 158 ADRs, 14 ADRs were not found in Vigibase. 32 ADRs were not mentioned in the Drug package inserts. When categorized according to the completeness of case reports, weight accounted for1.89%, lab values and procedure for diagnosis, 96.8%, risk factors, 95.56%, prior exposure, 88.60%, Post ADR status, 60.12%, start-stop medication, route of administration, first dose, last dose, duration of illness accounted for 100%, respectively. Conclusion: Depending upon our observation, we have noticed that there is deficiency in reporting of suspected ADRs to regulatory authorities. Reporting can be included as mandatory criteria for ADR case reports. Also, there is an increased need to aware various healthcare workers for reporting ADR.

Background and Objective: Identification of the offending drug is crucial and challenging in cases of severe cutaneous adverse drug reactions (CADR) like Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN). Poor reproducibility and varying levels of agreement have been observed among different causality assessment tools (CATs) in assessing severe CADRs. This study was conducted to examine the agreement among four different CATs in assessing cases of drug-induced SJS, TEN and SJS/TEN overlap. Methods: All cases of drug-induced SJS, TEN and SJS/TEN overlap, which were reported between January 2012 and January 2020, were identified from the ADR register at an ADR monitoring centre. Causality assessment was done in these reported cases using the following CATs: The World Health Organization–Uppsala Monitoring Centre (WHO–UMC) scale, Naranjo algorithm, Liverpool algorithm and Algorithm of drug causality for epidermal necrolysis (ALDEN). Weighted kappa (Κw) test was used to evaluate the agreement among four CATs. Results: A total of 30 cases of drug-induced SJS, TEN and SJS/TEN overlap were included in our analyses. The most common offending groups of drugs were anticonvulsants (46.7%), antimicrobials (40%) and nonsteroidal anti-inflammatory drugs (13.3%). Of the anticonvulsants, phenytoin (13.3%), carbamazepine (10%), and valproate (10%) were the commonly reported offending drugs. Poor agreement was observed among the four different causality assessment scales. Conclusion: Discrepancies were observed among four different CATs in assessing drug-induced SJS and TEN. A CAT, which is more specific to drug-induced SJS and TEN, simple, user-friendly with limited subjective interpretation, incorporating new immunological and pharmacogenetic markers, is necessary.

Aims: The aim of this study was to determine if there are discrepancies among various agency-approved labels for the same active ingredient and where the labels approved by the Turkish Medicines and Medical Devices Agency (TMMDA) stand regarding the inclusion of PGx and discuss these ethical implications. Background: The efficacy and safety of drugs can be improved by rational prescription and personalization of medicine for each patient. Pharmacogenomics information (PGx) in Drug Labels (DL) is one of the important tools for the personalization of medications because genetic differences may affect both drug efficacy and safety. Providing adequate PGx to patients has ethical implications. Objective: The study aims to evaluate PGx in the DLs approved by TMMDA and other national agencies provided by the Pharmacogenomics Knowledgebase. Methods: DL annotations from the Pharmacogenomics Knowledgebase and DLs approved by the TMMDA were analyzed according to information and action levels, which are “testing required”, “testing recommended”, “actionable”, and “informative”. Results: There are 381 drugs listed in PharmGKB drug label annotations with pharmacogenomics information, and 278 of these have biomarkers. A total of 242 (63.5%) drugs are approved and available in Turkey. Of these, 207 (85.5%) contain the same information as in or similar to that in the labels approved by the other agencies. The presence and level of information varied among the DLs approved by different agencies. The inconsistencies may have an important effect on the efficacy and the safety of drugs. Conclusion: These findings suggest a need for the standardization of PGx information globally because it may not only affect the efficacy and safety of medications but also essential ethical rules regarding patient rights by violating not sufficiently sharing all available information.

Background: The Black-Box Warning (BBW) is the most serious warning that US-FDA can ask for on a drug’s labelling. BBWs represent key safety concerns uncovered either during dossier review or post-approval. We have conducted the present study with the primary objective of assessing BBWs issued by the US-FDA. Methods: BBWs were identified on US-FDA’s website from 1st January 2015 to 31st December, 2019. Prescribing information was used to identify and characterize BBWs into new and minor/major updates on a previous BBW. The therapeutic class of the drug, nature [Biological/New Molecular entity (NME)], formulation type, expected duration of use, along with the year of first approval of the molecule with BBWs were evaluated. Results: A total of n = 167 BBWs were issued by the FDA of which 53 (31.7%) had major updates, 57(34.1%) had minor updates and 57(34.1%) were new BBWs. A total of 137(82%) of BBWs were with NME’s whereas 30(18%) were with biologics. Drugs for neurology 40(25.5%)had the highest number of BBWs, followed by oncology 38(24.2%). Among the type of BBWs, cardiovascular risk 31 (15%) were the highest. Conclusion: Practicing physicians need to understand that benefit-risk of a drug is dynamic and keep abreast of new data related to it.

Background: Although it takes more time, the Glucagon Stimulation Test (GST) is a reliable measure for assessing growth hormone (GH) and Adrenocorticotropic Hormone (ACTH) secretion. The GST is considered to be a safe test; however, it still has mild side effects and potential risks. Objectives: The objective of this study was to analyze the side effects of the GST while testing adrenal-insufficient patients. Methods: This was a prospective study in which GST was performed in eighty-one patients (44 men, 37 women, mean age: 35.83A9.62 years) with the pituitary disorder. The GST consisted of an intramuscular injection of 1 mg of glucagon. Blood samples were collected at baseline, and 30, 60, 90, 120, 150, 180, and 210 min after glucagon injection for cortisol measurements. All patients were asked to report side effects associated with this test. Results: The mean peak blood glucose level under GST was 9.01A.03 mmol/L, and the mean glycemic nadir was 4.34A.75 mmol/L most frequently found during the 30th minute (p <10-3). During the test, 35 subjects (43.2%) had side effects with a mean age of 42.89 A19.75 years. Frequent side effects included: nausea (29.62%), vomiting (27.16%), abdominal cramps (18.51%) and hunger (13.58%). All patients tolerated the test until the end. Adverse effects were significantly more prevalent in patients older than 50 years (p=0.012). Conclusions: The GST is a reliable alternative to assess the hypothalamic pituitary adrenal axis but should be cautiously used especially in the elderly, despite minor side effects.

Background and Objective: Subclinical hypothyroidism can potentially develop into overt hypothyroidism. Thyroid hormones have substantial roles in metabolism and glucose homeostasis and thus, are closely related to determinant factors of metabolic syndromes, such as obesity and insulin resistance. Osteocalcin is considered a predictor of metabolic conditions in thyroid diseases. This study aimed to investigate the effect of levothyroxine vs. placebo on serum osteocalcin levels in patients with subclinical hypothyroidism. Methods: This randomized clinical trial was performed on 30 patients with subclinical hypothyroidism, who were referred to the endocrine clinics of Ghaem and Imam Reza hospitals in Mashhad, Iran. After giving informed consent, patients were randomly divided into intervention (50 μg/- day levothyroxine for 2 months) and control (placebo) groups. Serum levels of osteocalcin, thyroid hormones, lipid profile, insulin, and fasting glucose, as well as other clinical and anthropometric data, were measured at baseline and at the end of the study. SPSS was used to analyze the data, and p < 0.05 was considered significant. Results: Mean age in the intervention and control groups was 35.07 ± 9.94 and 31.30 ± 4.30, respectively (p = 0.20). There was no significant difference between osteocalcin levels before and after the intervention in either of the groups (p = 0.54). TSH level was significantly decreased in the levothyroxine group after the intervention (p < 0.01). T4 level was significantly increased in the intervention group (p = 0.02). Conclusion: Levothyroxine had no significant effect on the increasing levels of serum osteocalcin in patients with subclinical hypothyroidism.

Introduction: Gemcitabine is a commonly used antimetabolite that has been effective in a broad spec- trum of tumors so far. The main grade three and four known toxicity of this drug is myelosuppres- sion. Cardiac adverse events have been rarely reported and gemcitabine-induced Atrial-Fibrillation (AF) has been described in only five previous cases so far. Here we report the 6th case of gemc- itabine-related AF. Case Presentation: A 68-year-old man diagnosed with metastatic nasopharyngeal cancer was referred to our oncology department. He started first-line chemotherapy with gemcitabine and cisplatin. He presented poorly tolerated atrial fibrillation related to gemcitabine infusion that lasted for six days. The treatment was then withdrawn, and the patient received the best supportive care. Conclusion: We conclude that medical oncologists and cardiologists should be aware of such toxicities of gemc- itabine, especially in the elderly who seem to be at a higher risk of such adverse events and which may dictate discontinuation of the drug.

Background: Angioedema, like anaphylaxis, has been reported as a rare adverse event of alteplase infusion in acute ischemic stroke. Objective: We report the case of a patient with acute ischemic stroke who, after treatment of alteplase, developed angioedema. Methods: We report the case of an 81-year-old woman who presented to our observation with acute ischemic stroke. The patient was on therapy with 100 mg acetylsalicylic acid and a triple combination antihypertensive drug (perindopril 10 mg + 2.5 mg indapamide + 5 mg amlodipine). The patient was treated with alteplase infusion. Results: Five minutes after the end of the alteplase infusion (0.9 mg/kg for 1 hour), the patient developed isolated angioedema of the lips and tongue. Conclusion: Although the incidence of alteplase-induced angioedema in these patients is rare, this case report suggests the need for a routine inspection of the tongue in an acute ischemic patient in treatment with alteplase infusion, especially in female patients in treatment with ACE inhibitors.

Background: Pantoprazole is a Proton Pump Inhibitor, commonly used by clinicians all over the world as a gastric acid synthesis inhibitor for a wide variety of gastrointestinal disorders. The efficacy and the safety of the drug are unsurmountable. PPIs are being prescribed nowadays for unapproved indications. It is one of the widely used medications in the world. Consequently, adverse events are commonly reported nowadays with proton pump inhibitors, and it is essential to improve physician awareness regarding judicious prescribing practice. Objective: To report a case of anaphylaxis to pantoprazole, that occurred in a patient admitted with gastrointestinal complaints. Case Summary: Within few minutes of intravenous infusion of pantoprazole, a 75-year-old female developed anaphylaxis. The adverse drug reaction was promptly diagnosed, and the patient was resuscitated. Conclusion: It is imperative that clinicians should be aware of this adverse effect that might occur with pantoprazole and hence be more cautious while prescribing the drug, especially in the elderly.