Life-threatening Adverse Drug Reaction Research Articles

The role of corticosterone in nevirapine-induced idiosyncratic drug-induced liver injury.

Nevirapine, an antiretroviral used in the treatment of HIV, is associated with idiosyncratic drug-induced liver injury (IDILI), a potentially life-threatening adverse drug reaction. Its usage has decreased due to this concern, but it is still widely used in lower-resource settings. In general, the mechanisms underlying idiosyncratic drug reactions (IDRs) are poorly understood, but evidence indicates that most are immune-mediated. There is very limited understanding of the early immune response following administration of drugs associated with IDRs, which likely occurs due to reactive metabolite formation. In this work, we aimed to characterize the links between covalent binding of nevirapine, the development of an early immune response, and the subsequent liver injury using a mouse model. We describe initial attempts to characterize an early immune response to nevirapine followed by the discovery that nevirapine induced the release of corticosterone. Corticosterone release was partially associated with the degree of drug covalent binding in the liver but was also likely mediated by additional mechanisms at higher drug doses. Transcriptomic analysis confirmed metabolic activation, glucocorticoid signaling, and decreased immune activation; GDF-15 also warrants further investigation as part of the immune response to nevirapine. Finally, glucocorticoid blockade preceding the first dose of nevirapine attenuated nevirapine-induced liver injury at 3 weeks, suggesting that acute glucocorticoid signaling is harmful in the context of nevirapine-induced liver injury. This work demonstrates that nevirapine induces acute corticosterone release, which contributes to delayed-onset liver injury. It also has implications for screening drug candidates for IDILI risk and preventing nevirapine-induced IDILI.

Wound care in a child suffering from Stevens-Johnson syndrome in PICU: case report

Stevens-Johnson Syndrome is considered a life-threatening adverse drug reaction. The pathogenesis of these syndromesis still unclear, but several drugs, such as anticonvulsivants and antibiotics, and especially sulfonamides, non-steroidal anti-infiammatorydrugs, and allopurinol were predominantly suspected of triggering this reaction. A 5-year-old boy patient who came to hospital attention for an urticarial reaction developed after taking amoxicillin, then a recent scarlet fever acquired by brother. Due to the worsening of the lesions, he was admitted to our PICU after being intubated for deterioration of the respiratory dynamics and safe treatment of secretions. Nursing care is crucial: care of patient hospitalized with Stevens-Johnson syndrome and Toxic Epidermal Necrolysis consists of wound care, infection prevention, comfort management, hydration and nutrition, psychosocial support, and prevention of long-term complications. For all patients with SJS and TEN, it is essential to perform a total body daily evaluation of the skin. If the dressings remain intact, it is advisable to note the appearance of visible skin and any visible exudate or staining on the outside of the intact dressings. If dressings are being removed or need to be reapplied daily, a full skin evaluation is useful.

Meta-analysis of ACE inhibitor–induced angioedema identifies novel risk locus

Angioedema is a rare but potentially life-threatening adverse drug reaction in patients receiving angiotensin-converting enzyme inhibitors (ACEis). Research suggests that susceptibility to ACEi-induced angioedema (ACEi-AE) involves both genetic and nongenetic risk factors. Genome- and exome-wide studies of ACEi-AE have identified the first genetic risk loci. However, understanding of the underlying pathophysiology remains limited. We sought to identify further genetic factors of ACEi-AE to eventually gain a deeper understanding of its pathophysiology. By combining data from 8 cohorts, a genome-wide association study meta-analysis was performed in more than 1000 European patients with ACEi-AE. Secondary bioinformatic analyses were conducted to fine-map associated loci, identify relevant genes and pathways, and assess the genetic overlap between ACEi-AE and other traits. Finally, an exploratory cross-ancestry analysis was performed to assess shared genetic factors in European and African-American patients with ACEi-AE. Three genome-wide significant risk loci were identified. One of these, located on chromosome 20q11.22, has not been implicated previously in ACEi-AE. Integrative secondary analyses highlighted previously reported genes (BDKRB2 [bradykinin receptor B2] and F5 [coagulation factor 5]) as well as biologically plausible novel candidate genes (PROCR [protein C receptor] and EDEM2 [endoplasmic reticulum degradation enhancing alpha-mannosidase like protein 2]). Lead variants at the risk loci were found with similar effect sizes and directions in an African-American cohort. The present results contributed to a deeper understanding of the pathophysiology of ACEi-AE by (1) providing further evidence for the involvement of bradykinin signaling and coagulation pathways and (2) suggesting, for the first time, the involvement of the fibrinolysis pathway in this adverse drug reaction. An exploratory cross-ancestry comparison implicated the relevance of the associated risk loci across diverse ancestries.

Clinical Profiles of Japanese Patients with Stevens-Johnson Syndrome/Toxic Epidermal Necrolysis Collected by a Nationwide System from 2006 to 2023.

Stevens-Johnson syndrome and toxic epidermal necrolysis (SJS/TEN) are potentially life-threatening severe cutaneous adverse drug reactions. These diseases are rare, and their onset is difficult to predict because of their idiosyncratic reactivity. The Japan Severe Adverse Reactions Research Group, led by the National Institute of Health Sciences, has operated a nationwide to collect clinical information and genomic samples from patients with SJS/TEN since 2006. This study evaluated the associations of clinical symptoms with sequelae and specific causative drugs/drug groups in Japanese patients with SJS/TEN to identify clinical clues for SJS/TEN treatment and prognosis. Acetaminophen, antibiotics, and carbocisteine were linked to high frequencies of severe ocular symptoms and ocular sequelae (p < 0.05). For erythema and erosion areas, antipyretic analgesics had higher rates of skin symptom affecting <10% of the skin than the other drugs, suggesting narrower lesions (p < 0.004). Hepatic dysfunction, was common in both SJS and TEN, and antiepileptic drugs carried higher risks of hepatic dysfunction than the other drug groups (p = 0.0032). This study revealed that the clinical manifestations of SJS/TEN vary according to the causative drugs.

Prevalence and Correlates of Serotonin Syndrome in Real-World Inpatients.

Serotonin syndrome (SS) is a potentially life-threatening adverse drug reaction due to an increased central and peripheral serotonin activity, which usually presents as a triad of behavioral changes, neuromuscular excitability, and autonomic instability. Probably SS is often misdiagnosed, and its symptoms are mistaken for psychiatric symptoms or general medical issues: the true incidence of SS is not clear, and literature concerning potential risk factors is scarce. Our aims were to examine the prevalence of SS in a naturalistic sample of hospitalized patients and to evaluate potential factors related to the risk of developing the condition. The sample included 133 patients being treated with serotonergic medications admitted to the psychiatric inpatient unit of the San Luigi Gonzaga Hospital. All patients received a medical examination (including a neurological examination) within 24 hours of admission. Serotonin syndrome was diagnosed according to Hunter Criteria. Sixteen patients (12%) were diagnosed with SS. In the subgroup of subjects with SS, we found a higher rate of male patients when compared with subjects with no SS (62.5% vs 33.3%, P = 0.023). SS probably is an underestimated condition, which should be carefully assessed in patients on serotonergic medications. Male gender was the only factor found to be significantly related to a higher risk of developing SS. Further studies on larger samples are needed, to gain more information on possible risk factors and to identify subjects more prone to developing SS, given the potential risk for patients' health.

A Rare Case of TMP-SMX Induced DRESS and Clinical TSS in a Pediatric Patient

Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) is a rare and potentially life-threatening adverse drug reaction. We present a case of a 14-year-old girl with overlapping DRESS syndrome and Toxic Shock Syndrome (TSS) following Trimethoprim/Sulfamethoxazole treatment. The patient developed a generalized pruritic maculopapular rash, lymphadenopathy, fever, and facial swelling. Laboratory results showed leukocytosis, elevated liver enzymes, and C-reactive protein (CRP). Despite initial treatment with methylprednisolone, her condition worsened, necessitating a transfer to a higher level of care. She exhibited fever, hypotension, tachycardia, tachypnea, strawberry tongue, and perioral impetigo, consistent with TSS. Antibiotic therapy was initiated, but eosinophilia and an abdominal desquamative rash emerged, indicative of DRESS syndrome. Treatment involved discontinuing antibiotics, administering intravenous solumedrol for possible DRESS, and restarting antibiotics due to persistent TSS features. The patient’s symptoms improved, and she was discharged on tapering steroids and antibiotics. This case highlights the coexistence of DRESS and TSS in a pediatric patient and emphasizes the importance of promptly discontinuing the offending agent and appropriate management with steroids and antibiotics. Of the participants, 65.9% reported decreased activity levels, while 46.3% experienced weight gain. Notably, 64.2% of participants had an elevated risk score, signifying an increased vulnerability to T2D.

Definition and Clinical Evaluation for Trimethoprim-Sulfamethoxazole Severe Acute Respiratory Failure.

Trimethoprim-sulfamethoxazole (TMP-SMX)-associated severe acute respiratory distress syndrome (ARDS) has gone underrecognized. We propose the first disease definition and clinical evaluation for a novel adverse drug reaction (ADR) based on a series of recently identified rare cases of life-threatening ADRs. A retrospective study was conducted. All medical records were evaluated. Available pathology samples were sent to Massachusetts General for clinical consultation. Blood samples from surviving patients were obtained and human leukocyte antigen (HLA) analysis was performed by the Children's Mercy Hospital Genomic Center and Vanderbilt University Medical Center. U.S. ICUs, 1996-2021. Nineteen young patients (10-37) were identified. Patients were previously healthy, with no preexisting pulmonary disease, no other cause for respiratory failure, and no chronic history of smoking/vaping. None. Through our retrospective analysis, we analyzed clinical characteristics associated with TMP-SMX. Pathology samples were reviewed, and HLA analysis was performed on available samples by the study team or as standard of care at treatment hospitals in some cases. In 19 critically ill patients, we identified a pattern of severe respiratory failure requiring ICU admission, mechanical ventilation, and frequent extracorporeal membrane oxygenation use. We describe the first three-part clinical diagnosis and evaluation strategy: 1) Clinical definition: Unexplained severe respiratory failure in a patient receiving greater than or equal to 6 days of TMP-SMX at treatment dose (not prophylaxis). TMP-SMX ARDS is a diagnosis of exclusion. 2) Genetic association: One hundred percent of currently available TMP-SMX respiratory failure patient genomic data, ( n = 11) have been carriers of both HLA-B*07:02 and HLA-C*07:02 alleles. HLA allele evaluation could be considered in patients with suspected TMP-SMX respiratory failure. 3) Lung pathology: A unique pulmonary pathologic pattern of lung injury termed diffuse alveolar injury with delayed epithelialization has been observed in these cases. In suspected cases, surgical lung biopsy early in the clinical course could be considered. TMP-SMX is a commonly prescribed antibiotic. However, we find it imperative to share this relatively rare but life-threatening condition with clinicians as the mortality rate approaches 40%.

Heparin-induced thrombocytopenia after switching from unfractionated heparin to low-molecular-weight heparin: A case report and literature review.

Heparin-induced thrombocytopenia (HIT) is a severe, potentially life-threatening adverse drug reaction. It is an antibody-mediated process involving platelet activation. Heparin and low-molecular-weight heparin (LMWH) are routinely used in uremic patients undergoing hemodialysis. Here, we report a case of HIT that occurred in a hemodialysis patient after she switched from heparin to the LMWH nadroparin for anticoagulation during hemodialysis. The clinical features, incidence, mechanism, and treatment of HIT are discussed.

Analysis of adverse drug reactions (ADR) in fluorescein angiography (FAG) and indocyanine green angiography (ICGA) and indications before and during the COVID-19 pandemic at auniversity eye hospital

This study was an analysis of fluorescein angiography (FAG) and indocyanine green angiography (ICGA) at auniversity eye hospital. The primary objective of the study was to analyze adverse drug reactions (ADRs) and their severity (mild, moderate, severe). The secondary objective was to investigate the indications of FAG and ICGA before and during the COVID-19 pandemic. Aretrospective analysis of all FAG and ICGA at the University Eye Hospital in Würzburg from January 2016 to the end of December 2021 was performed. The ADRs, gender, age, examination time points and indications were evaluated. The ADRs were classified into mild, moderate, and severe, following the definition of Kornblau etal. [1] RESULTS: Atotal of 4900 examinations from 4193patients were analyzed. An FAG was performed slightly more frequently in men (54.8%) than in women (45.2%) and the mean age was 63.2 ± 16.9years (median: 65years). The ADRs occurred in only 1.65% of all FAG, of which 1.27% were mild and 0.39% were moderate. No severe ADRs occurred. The most common ADR was nausea at 59.26%. No ADR occurred in ICGA. The annual number of FAGs averaged 816.7 ± 91.1 and was relatively constant throughout the period except for asignificantly reduced number in 2016 (compared with 2018, 2019, and 2021). The most common indication for FAG was venous retinal occlusion at 22.93% (N = 774), showing asignificant increase in 2021 compared to 2018-2020. An ICGA was performed in 4.18% of cases, with the most common indication being uveitis at 31.82% (N = 63). Compared to other studies very few ADRs occurred and no life-threatening ADR occurred in any case. Venous retinal occlusions were very common indications for FAG, probably due to the frequent need for repeated examinations in this condition. Briefly, during the first lockdown (18 March-8 May 2020), adecrease in angiographies was observed, but over alonger period, no significant differences were seen compared with the prepandemic period.

Retrospective review of medication allergy labeling among patients admitted to a tertiary hospital in Qatar.

Background: Timely access to accurate, up-todate drug allergy information is critical to avoid potentially life-threatening adverse drug reactions (ADRs). However, the completeness and accuracy of allergy documentation remain a challenge. Inappropriate allergy documentation usually necessitates alternative treatments, increases costs, and may negatively impact patients' outcomes. Objectives: Review medication allergy labeling documentation, identify the most reported medication class, and describe allergic reactions based on the reported severity. Methods: A retrospective cross-sectional audit including all medication allergy labeling documentation for patients admitted to Hamad General Hospital (HGH) from January-December 2022 was conducted. A list of patients with medication allergies was generated from the pharmacy system, which included patients' demographics, medication names, documented allergy severity, and any other comments. The list was reviewed, and medications were categorized into different classes. Results: 2856 allergy documentation for 2431 unique patients were identified and included in the analyses. The mean age of included patients was 43 years old, with 73.2% (1780) being females. Among the reported allergic reactions, 11.8% (336) were documented as severe allergic reactions, 51.1% (1457) were moderate, and 37.1% (1060) were mild. Antibiotics were the most common documented allergens, representing 42.1% of all reported allergies, followed by non-steroidal anti-inflammatory drugs (20.7%, n=591), and paracetamol (5.3%, n=151). Of all the reported allergies, only 6 (0.21%) cases had documented confirmatory allergy tests done. Further analysis of the reported allergies revealed that 1.2% (34) of the allergies had documentation to counteract the allergy labeling through either revised patient history or re-challenging. Despite such, allergy labeling was kept in the medical profile without proper de-labeling. Conclusion: Allergy labeling documentation is a key to safe medication prescribing. However, standardized allergy documentation should be implemented to include a brief description and onset of the symptoms. Additionally, a safe de-labeling pathway should be adopted. Most of the allergy documentation was based on patients' or family/parents' reports, while actual allergies observed by a healthcare provider were limited.

A Case Report of Phenytoin-Induced Stevens-Johnson Syndrome

Stevens-Johnson syndrome and Toxic epidermal necrosis are acute, self-limited diseases, rare but life-threatening adverse drug reactions. Anti-epileptic drug-induced Steven-Johnson syndrome is a severe cutaneous adverse reaction, among anti-epileptic drugs carbamazepine and phenytoin are the major culprit. We report here a case of Steven-Johnson syndrome due to phenytoin. A 22-year-old female reported the chief complaint of fever and multiple rashes all over the body with skin peeling, gradual onset, and progressive in nature. The reaction was evoked after intake of T. Phenytoin for 1 ½ months. She started heavy skin eruption all over the body for 15 days. She was treated with corticosteroids, anti-microbial, and anti-fungal agents. Healthcare providers must carefully regard the adverse effect of the drug, especially the one that is Steven-Johnson syndrome which is a potentially fatal condition. The most commonly prescribed drug regimen should also be used and continuously monitored to prevent adverse drug reactions. Keywords: Steven-Johnson syndrome, Adverse drug reaction, Phenytoin, Skin eruption

CAR-T Cells and the Kidney: Insights from the WHO Safety Database.

Chimeric antigen receptor T (CAR-T) cells have proven to be a game changer for treating several hematologic malignancies. Randomized controlled trials have highlighted potential life-threatening adverse drug reactions (ADRs), including cytokine release syndrome (CRS). Acute renal failure (ARF) has also been reported in 20% of the patients treated. However, an analysis of renal safety supported by large-scale real-life data seems warranted. We queried VigiBase® for all reports of the Standardised MedDRA Query "acute renal failure" (ARF) involving a CAR-T cell, registered until 24 July 2022. Disproportionality for this ADR was analyzed through calculation of the Information Component [IC (95% confidence interval)]. A positive lower end of the 95% confidence interval of the IC is the threshold used in statistical signal detection in VigiBase®. The same analysis was carried out for various hydroelectrolytic disorders. We gathered 224 reports of ARF, and 125 reports of hydroelectrolytic disorders involving CAR-T cells. CAR-T cells were disproportionately reported with ARF [IC 1.5 (1.3-1.7)], even after excluding reports mentioning CRS. A significant disproportionate reporting was also found for hypernatremia [IC 3.1 (2.2-3.8)], hyperphosphatemia [IC 3.1 (1.8-3.9)], hypophosphatemia [IC 2.0 (0.6-2.9)], metabolic acidosis [IC 1.8 (1.2-2.2)], hyponatremia [IC 1.6 (1.1-2.0)], and hypercalcemia [IC 1.4 (0.5-2.1)]. There was no disproportionate reporting of dyskalemia. This study is limited by the inherent flaws of pharmacovigilance approaches. Nonetheless, our findings suggest that ARF and an array of hydroelectrolytic disorders are potential ADRs of CAR-T cell therapy, in real-life settings and in a nonselected population.

Validated ion exchange HPLC method for the quantification of levothyroxine – a narrow therapeutic index drug – used for the treatment of hypothyroidism

Drugs with narrow therapeutic index (NTI-drugs) have been defined by the FDA as drugs with small differences between therapeutic and toxic doses that might lead to serious therapeutic failures or life-threatening adverse drug reactions. Levothyroxine sodium pentahydrate (LT4), a synthetic T4 hormone used for the treatment of hypothyroidism (a condition where there is a hormonal imbalance in the thyroid gland that is responsible for the regulation of several physiological, metabolic, cardiovascular, and neurological processes). LT4 is designated by the FDA as a narrow therapeutic index drug and is available in the market in the form of very low dose pharmaceutical formulations ranging from 25 mcg to 150 mcg. This requires that the pharmaceutical dosage form should contain the exact labeled amount of the active ingredient, LT4, such that safety and efficacy are maintained. Therefore, it is necessary to develop an a precise, accurate and sensitive analytical method for LT4 quantification considering the treatment doses being in micrograms. In the present work, an ion exchange HPLC method has been developed and validated for the determination of LT4 as per ICH guidelines. The developed method was found to be simple, sepcific, precise and accurate. The low LOD and LOQ values allowed the quantitfication of the active ingredient in different pharmaceutical products qualifying the method to be applied in quality control assays.

Current understanding of genetic associations with delayed hypersensitivity reactions induced by antibiotics and anti-osteoporotic drugs.

Drug-induced delayed hypersensitivity reactions (DHRs) is still a clinical and healthcare burden in every country. Increasing reports of DHRs have caught our attention to explore the genetic relationship, especially life-threatening severe cutaneous adverse drug reactions (SCARs), including acute generalized exanthematous pustulosis (AGEP), drug reactions with eosinophilia and systemic symptoms (DRESS), Stevens-Johnson syndrome (SJS), and toxic epidermal necrolysis (TEN). In recent years, many studies have investigated the immune mechanism and genetic markers of DHRs. Besides, several studies have stated the associations between antibiotics-as well as anti-osteoporotic drugs (AOD)-induced SCARs and specific human leukocyte antigens (HLA) alleles. Strong associations between drugs and HLA alleles such as co-trimoxazole-induced DRESS and HLA-B*13:01 (Odds ratio (OR) = 45), dapsone-DRESS and HLA-B*13:01 (OR = 122.1), vancomycin-DRESS and HLA-A*32:01 (OR = 403), clindamycin-DHRs and HLA-B*15:27 (OR = 55.6), and strontium ranelate (SR)-SJS/TEN and HLA-A*33:03 (OR = 25.97) are listed. We summarized the immune mechanism of SCARs, update the latest knowledge of pharmacogenomics of antibiotics- and AOD-induced SCARs, and indicate the potential clinical use of these genetic markers for SCARs prevention in this mini review article.

APOA4 as a novel predictor of prognosis in Stevens-Johnson syndrome/toxic epidermal necrolysis: A proteomics analysis from two prospective cohorts

Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are rare but life-threatening adverse drug reactions. Conventional systemic therapies are of limited efficacy and often exhibit strong side effects. To assess the efficacy and safety of the combination treatment with a tumor necrosis factor-α antagonist adalimumab and delineate the underlying mechanisms. We evaluated the efficacy and safety of the combination therapy with adalimumab by comparing 2 treatment cohorts of SJS/TEN patients. Patient plasma samples were collected for proteomics analysis. The combination therapy with adalimumab significantly shortened the time to mucocutaneous re-epithelization and healing, with reduced side effects caused by corticosteroids. Plasma proteomic profiling showed that apolipoprotein A-IV (APOA4) was one of the most significant differentially expressed proteins. Multivariate regression analysis revealed that APOA4 level was significantly associated with prognosis parameter of SJS/TEN (P=.004), but not with disease severity score (severity-of-illness score for toxic epidermal necrolysis [SCORTEN]) (P=.118). Thus further research will be helpful to effectively incorporate APOA4 into current SCORTEN-driven protocols. The cohort size is relatively small. Both cohorts had low overall SCORTEN scores. Adalimumab in combination with corticosteroids demonstrates significant clinical benefits over corticosteroids alone in SJS/TEN patients. Moreover, APOA4 may serve as a novel prognostic marker of SJS/TEN.

Genetic predisposition for the development of lamotrigine-induced Stevens-Johnson syndrome/toxic epidermal necrolysis: a systematic review and meta-analysis.

Studies report an association between the expression of HLA alleles and lamotrigine (LTG)-induced Stevens-Johnson syndrome (SJS). This systematic review and meta-analysis evaluates the association between HLA alleles and LTG-induced SJS in different populations. Two alleles, HLA-B*0702 and HLA-C*0702, were deemed to be protective; five alleles, HLA-B*1502, HLA-B*4403, HLA-A*2402, CYP2C19*2 and HLA-B*38, may play a role in LTG-induced SJS, for which only data studying HLA-B*1502 could be extracted. The pooled odds ratio of 2.88, 95% CI of 1.60-5.17 and p-value of 0.0004 establish the presence of HLA-B*1502 as a major risk factor for the development of LTG-induced SJS/TEN. Although multiple alleles that may play a role in the development of LTG-induced SJS/TEN were identified, the expression of the risk alleles may be ancestry-specific, and genetic screening is warranted for preventing this life-threatening adverse drug reaction.

The role of DNA-profiling in predicting anticonvulsant-induced QT prolongation diseases based on pharmacogenetic aspects

Anticonvulsants or antiepileptic drugs (AEDs) are widely used for various neurological and psychiatric diseases and are often prescribed for a long period. In this regard, the issue of their safety profile is acute, including risk assessment for the development of life-threatening conditions and adverse drug reactions (ADRs). From the point of view of personalized medicine, it is important to develop an interdisciplinary approach to the development of a new strategy for a personalized approach to predicting AED-induced prolongation of the QT interval as one of the most unfavorable prognostic cardiac ADRs (including sudden death syndrome — SDS). We searched the databases of full-text publications for the period from 2012 to 2022 for keywords and their combinations. We have discovered and systematized monogenic and multifactorial forms of long QT syndrome (LQTS) and candidate genes that slow down AEDs metabolism in the liver. Identification of risk alleles of single nucleotide variants (SNV) of candidate genes predisposing to the development of AED-induced LQTS and SDS will allow adjusting the choice and dosage of these drugs and preventing the development of the ADR, which will improve the quality of life and help prevent SDS in patients with mental and neurological disorders

Characteristics of paediatric adverse drug reaction reports in Malaysia

During clinical trials, special populations such as children, pregnant women and elderly are excluded, creating lack of information on safety profile of medicines in these population. The lack of reliable efficacy and safety data often leads to under- or over-dosing in paediatric age groups which make them susceptible to adverse drug reactions (ADRs). This study was aimed to investigate the characteristics of ADR reports and serious ADRs among paediatric population in Malaysia. Descriptive analyses were undertaken for demographic characteristics and severity of the ADRs. Binary logistic regression was performed to identify association between selected variables and ADRs. A total of 3410 paediatric case reports for 6769 ADRs were reported within the 5-year period. Children aged one to 12 years old were the most frequently reported to experience ADRs (n=5488, 81%). Male gender exceeds more than half of the ADR reports (n=3812, 56.3%) and Malay race has the highest ADR reports (n=4780, 72%). Majority of the ADR reports were not serious (n=6285, 93%). Anti-infective medicines contributed most of the ADR reports (n=6024, 75%). The most common ADRs were from general disorders and administration site conditions (n=2879, 43%). A binary logistic regression showed male gender were more likely to experience nervous and respiratory system disorder ADRs (p &lt; 0.05). Surveillance of medicines marketed for use in children must be strengthened to prevent severe life-threatening ADRs. Effective support decision tool for prescribing in paediatric population with an integrated pharmacovigilance monitoring will support continuous safety monitoring for all marketed medicines.

Safety profile of tyrosine kinase inhibitors used in non-small-cell lung cancer: An analysis from the Italian pharmacovigilance database.

Non-small cell lung cancer (NSCLC) is often caused by molecular alterations that can be detected by predictive biomarkers including mutations or amplifications of several genes. Several tyrosine kinase inhibitors (TKIs) have been approved in Europe by the European Medicines Agency (EMA) for NSCLC. The aim of this study was to analyze the onset of adverse drug reactions (ADRs) related to TKIs in NSCLC through a spontaneous reporting system (SRS) database. All ADR reports having as suspected drug afatinib (AFT), alectinib (ALEC), brigatinib (BRG), ceritinib (CER), crizotinib (CRIZ), erlotinib (ERL), gefitinib (GEF), lorlatinib (LORL), nintedanib (NTB), and osimertinib (OSI) recorded into the Report Reazioni Avverse dei Medicinali (RAM) system database for national data and into the Italian SRS database for Sicilian data and collected from 2006 to 2021 have been evaluated. A descriptive analysis of basal demographic and drug-related characteristics was performed. A case-by-case methodology was conducted paying particular attention to all serious ADR reports collected in Sicily, focusing on type of seriousness, age, sex, concomitant drugs, and comorbidities. Of the 3,048 Italian reports, most of ADRs were related to ERL (n = 1,448), followed by AFT (n = 435) and GEF (n = 366). ADR reports were slightly more frequent in females (52.2%) and in the age group >65 years (53.0%). A higher number of cases were related to skin disorders (n = 1,766; 57.9%), followed by gastrointestinal disorders (n = 1,024; 33.6%), general disorders and administration site conditions (n = 536; 17.6%), and infections (n = 483; 15.8%). The case-by-case assessment of Sicilian ADRs showed that 33 cases were serious (12.5%) and mainly involved ERL (n = 17; 51.5%), occurring in males with a higher onset of respiratory diseases (30.3%) such as respiratory failure, interstitial lung disease and dyspnea. The analysis of spontaneous ADR reports of TKIs confirmed, in general, well-known risks, which often include skin, gastrointestinal, general, liver, and respiratory diseases as well as infections. However, more attention should be paid to the occurrence of serious life-threatening ADRs including respiratory failure, interstitial lung disease, and cardiogenic shock, especially in young patients.

Assessment of the Availability and Accuracy of Dosing Devices Packaged with Oral Liquid Medications in the Ho Municipality of Ghana.

Introduction Administering the right dose of medications is essential in avoiding potentially life-threatening adverse drug reactions. Industry guidelines for manufacturers of oral, over-the-counter, and liquid medications recommend including dose-delivery devices with packaging to limit dosing inaccuracy. This study describes the prevalence and accuracy of dosing devices packaged with oral liquid medications in the Ho municipality of Ghana. Methods Dosing device accuracy was determined after deviation of the measured volume from the expected volume was evaluated using the United States Pharmacopoeia criteria. Results A total of 78.6% of the oral liquid medications were packaged with a dosing device. The most common dosing devices were cups (83.6%), followed by spoons (14.3%), droppers (1.4%), and syringes (0.7%). The volumes measured with cups (5.14 ± 0.52 mL, p = 0.006) and spoons (5.3 ± 0.67 mL, p < 0.001) were significantly different from the desired 5 mL volume; this was dissimilar to the volume measured using syringes (5.01 ± 0.02 mL, p > 0.999). Further, the measured volumes for 38.6% and 72.2% of the cups and spoons, respectively, deviated by more than 15% of 5 mL. Conclusion Dosing cups and spoons are associated with significant inaccuracy. Yet, manufacturers continually favour them over syringes in packaging for oral liquid medications. This is unacceptable and of considerable concern due to the risk of variations in therapeutic outcomes. Therefore, strict regulatory directives on the inclusion of accurate dosing devices in the packaging of oral liquid medicines are needed to reduce the possibility of medication errors.