Adverse Event Profile Research Articles

Delayed immune-related adverse events profile associated with immune checkpoint inhibitors: a real-world analysis

BackgroundImmune-related adverse events (irAEs) typically occur within 3 months of initiating immune-checkpoint inhibitors (ICIs), which has been extensively documented. But the clinical profiles of late-onset irAEs remain inadequately characterized. Therefore, this study aims to quantify the correlation between delayed irAEs and ICIs, and to delineate the profiles of delayed toxicities associated with ICIs using data from the Food and Drug Administration Adverse Event Reporting System (FAERS).MethodsData from the January 2011 to December 2023 in FAERS database were extracted. Four signal detection indices, reporting odds ratio (ROR), proportional reporting ratio (PRR), Bayesian confidence propagation neural network (BCPNN) and multi-item gamma Poisson shrinker (MGPS), were employed to evaluate the associations between ICIs and delayed irAEs.ResultsA total of 147,854 cases were included in this study, of which 3,738 cases related to delayed irAEs were identified. Generally, 8 signals at System Organ Class (SOC) level were found to be associated with ICIs. Males had a slightly higher reporting frequencies for respiratory disorders (ROR975 = 0.95) and blood and lymphatic system disorders (ROR025 = 1.22), but lower reporting frequencies for immune system disorders (ROR025 = 1.16). Three monotherapy (anti-PD-1, anti-PD-L1 and anti-CTLA-4) were all associated with significant increasing gastrointestinal disorders (ROR025 = 1.66, 1.16, 1.99) and metabolism disorders (ROR025 = 2.26, 1.74, 3.13). Anti-PD-1 therapy exhibited higher rates of respiratory toxicities (ROR025 = 1.46 versus 0.82) and skin toxicities (ROR025 = 1.27 versus 0.94) compared with anti-CTLA-4 therapy. At PT levels, pneumonitis (ROR025: from 11.85 to 29.27) and colitis (ROR025: from 2.11 to 24.84) were the most notable PT signals associated with all three ICI regimens. For outcomes of delayed irAEs, gastrointestinal disorders showed the highest proportion (51.06%) of death.ConclusionOur pharmacovigilance analysis indicates that a small percentage of patients receiving ICIs therapy experience delayed irAEs, which are challenging to manage and may result in severe consequences. Prompt identification and intervention of these delayed irAEs are crucial in clinical practice.

Pharmacogenomics of Lipid-Lowering Therapies in Obese Individuals with Dyslipidemia

Dyslipidemia is a key contributor to cardiovascular diseases, especially in obese individuals, where lipid metabolism is frequently impaired. Lipid-lowering therapies, such as statins, fibrates, and PCSK9 inhibitors, are commonly prescribed to manage dyslipidemia, but their efficacy and adverse effect profiles vary significantly across individuals. Pharmacogenomics, the study of how genetic variations influence drug response, has emerged as a powerful tool in predicting these inter-individual differences and optimizing treatment regimens. In obese individuals, genetic polymorphisms in genes involved in lipid metabolism, such as SLCO1B1, CYP3A4, APOE, and LDLR, have been linked to variable responses to lipid-lowering drugs. This review explores the impact of pharmacogenomics on lipid-lowering therapies in obese individuals with dyslipidemia, emphasizing the potential of personalized medicine in improving therapeutic outcomes. By understanding genetic influences on drug efficacy and safety, clinicians can tailor treatments to individual patients, thereby reducing adverse effects and improving lipid control. We also highlight current challenges in translating pharmacogenomic findings into clinical practice and discuss the future directions of this emerging field. Keywords: Pharmacogenomics, Lipid-Lowering Therapies, Dyslipidemia, Obesity, Statins, Fibrates, PCSK9 Inhibitors

English

Objectives: Direct-acting antivirals (DAAs) share pharmacokinetic pathways with many comedications commonly administered to patients living with chronic hepatitis C virus (HCV) infection (PLWHCV). International guidelines recommend a thorough drug-drug interaction (DDI) risk assessment prior to starting DAA therapy and before starting comedications. This study aims to evaluate the impact of potential multiple DDIs in the real-life adverse event (AE) profile of PLWHCV treated with DAAs. Material and method: This is a retrospective, observational study using electronic medical records. Patients included were PLWHCV and were treated with either the protease inhibitor (PI) free DAA sofosbuvir/velpatasvir (SOF/VEL) or glecaprevir/pibrentasvir (GLE/PIB) between 2017 and 2020. Potential (single and multiple) DDIs were identified using the Liverpool HEP Interaction Checker. AEs potentially associated to DDIs were identified during DAA treatment period. Results: 1620 patients with DAA prescriptions (SOF/VEL or GLE/PIB) were included. Of these, 123 were predicted to have multiple DDIs (multi-DDI). About 10% (123/1256) of the patients receiving ≥2 comedications were at risk of multi-DDI with DAA. Most comedication-associated AEs were recorded in this multi-DDI population (88.9%, 16/18), meaning that 13% (16/123) of the multi-DDI population suffered AEs. According to DAA regimen, more comedication-associated AEs were reported in GLE/PIB-treated as compared with SOF/VEL-treated patients (18.3% [13/71] vs 5.8% [3/52] p<0.05). These AEs were mainly reported by primary care physicians (62.5%). Discussion: PLWHCV predicted to have multiple DDIs are at high risk of AEs. Moreover, fewer comedication-associated AEs were identified with the PI-free DAA SOF/VEL as compared with GLE/PIB.

A Phase 1 Assessment of the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of (2R,6R)-Hydroxynorketamine in Healthy Volunteers.

(R,S)-Ketamine (ketamine) is a dissociative anesthetic that also possesses analgesic and antidepressant activity. Undesirable dissociative side effects and misuse potential limit expanded use of ketamine in several mental health disorders despite promising clinical activity and intensifying medical need. (2R,6R)-Hydroxynorketamine (RR-HNK) is a metabolite of ketamine that lacks anesthetic and dissociative activity but maintains antidepressant and analgesic activity in multiple preclinical models. To enable future assessments in selected human indications, we report the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of RR-HNK in a Phase 1 study in healthy volunteers (NCT04711005). A six-level single-ascending dose (SAD) (0.1-4 mg/kg) and a two-level multiple ascending dose (MAD) (1 and 2 mg/kg) study was performed using a 40-minute IV administration emulating the common practice for ketamine administration for depression. Safety assessments showed RR-HNK possessed a minimal adverse event profile and no serious adverse events at all doses examined. Evaluations of dissociation and sedation demonstrated that RR-HNK did not possess anesthetic or dissociative characteristics in the doses examined. RR-HNK PK parameters were measured in both the SAD and MAD studies and exhibited dose-proportional increases in exposure. Quantitative electroencephalography (EEG) measurements collected as a PD parameter based on preclinical findings and ketamine's established effect on gamma-power oscillations demonstrated increases of gamma power in some participants at the lower/mid-range doses examined. Cerebrospinal fluid examination confirmed RR-HNK exposure within the central nervous system (CNS). Collectively, these data demonstrate RR-HNK is well tolerated with an acceptable PK profile and promising PD outcomes to support the progression into Phase 2.

Adverse event profile of albumin-bound paclitaxel: a real-world pharmacovigilance analysis

BackgroundAbraxane plays a crucial role in the treatment of various types of cancer, despite the considerable attention it has garnered for its adverse drug events (ADEs). Nevertheless, there is currently a significant lack of comprehensive real-world pharmacovigilance studies on the ADEs associated with Abraxane.MethodsWe conducted a retrospective analysis of ADEs associated with Abraxane using data mining from the FAERS database, analyzing data from 2005 to 2023. In a real-world setting, we quantified and visualized the signals of these ADEs using four pharmacovigilance algorithms.ResultsThe FAERS database identified a total of 10,230 adverse event reports associated with Abraxane. The study revealed that Abraxane-related adverse drug events involved 27 system organ classes (SOC), with the strongest signals associated with the lymphatic and hematological systems and hepatobiliary disorders. Additionally, we identified 70 significant Preferred Terms (PT) signals, which included some critical adverse events not highlighted in the product labeling, such as cystoid macular edema. Further analysis of the timing of adverse reactions showed a median onset time of 41 days. Most adverse events (AEs) occurred within the first month of using Abraxane (43.5%), although some were still possible 1 year after treatment (3.5%). Gender-specific analysis indicated that high-risk AEs differed between females (nausea, vomiting, and erythema) and males (febrile neutropenia, disseminated intravascular coagulation, and upper gastrointestinal bleeding).ConclusionThe examined results provide crucial recommendations for optimizing the administration of Abraxane, enhancing its effectiveness, and mitigating potential adverse effects. This knowledge will substantially facilitate the implementation of the substance in clinical settings.

Systematic Review: Comparative Efficacy and Safety of Losartan vs. Candesartan for the Treatment of Hypertension

Hypertension is one of the most significant modifiable risk factors for cardiovascular disease (CVD) and remains a leading cause of morbidity and mortality globally. Effective management of hypertension is essential for preventing comp lications such as stroke, myocardial infarction, and heart failure. Angiotensin II receptor blockers (ARBs) like losartan and candesartan are well-established therapeutic options for blood pressure (BP) control and are widely prescribed due to their favorable side-effect profiles and organ-protective properties. Despite being members of the same drug class, these ARBs differ in their pharmacokinetics, receptor binding affinity, and clinical efficacy. This systematic review aims to provide a detailed comparison of the efficacy and safety of losartan versus candesartan in managing hypertension. We conducted a comprehensive search of the PubMed, Embase, and Cochrane databases, retrieving studies published from 2000 to 2024 that compared the two ARBs directly in hypertensive populations. A total of 25 randomized controlled trials (RCTs) and observational studies, comprising more than 12,000 participants, were included in the analysis. The primary outcomes evaluated were the reduction in systolic and diastolic blood pressure, cardiovascular event prevention, and adverse event profiles. The results suggest that both losartan and candesartan effectively lower BP, but candesartan consistently demonstrated greater reductions in both systolic and diastolic BP compared to losartan. Candesartan also appeared to have superior cardiovascular outcomes, with a lower incidence of major cardiovascular events such as stroke, myocardial infarction, and heart failure hospitalizations. The safety profiles of both drugs were comparable, though losartan was associated with a slightly higher incidence of cough and discontinuation due to adverse events. Overall, candesartan may offer a slight clinical advantage over losartan, particularly in patients requiring more potent or sustained BP control. However, both drugs remain valuable options in the management of hypertension. Further long-term studies are recommended to confirm these findings and to investigate the potential benefits of each drug in specific patient subgroups.

Efficacy and Safety of Ravulizumab in IgA Nephropathy: A Phase 2 Randomized Double-Blind Placebo-Controlled Trial.

Key Points This phase 2, double-blind, randomized controlled trial evaluated the complement C5 inhibitor, ravulizumab, in adults with IgA nephropathy.A 30.1% (90% confidence interval, 13.7% to 43.5%) relative reduction in proteinuria for ravulizumab versus placebo was observed at approximately 6 months.Treatment with ravulizumab was well tolerated. Background The complement system plays a central role in the pathogenesis of IgA nephropathy. We present findings from a phase 2 trial of ravulizumab, a complement C5 inhibitor. Methods The Study of Ravulizumab in Proliferative Lupus Nephritis or IgA Nephropathy (NCT04564339) was a randomized, double-blind, placebo-controlled trial of ravulizumab in addition to standard of care. Adults with IgA nephropathy, proteinuria ≥1 g/d, and eGFR ≥30 ml/min per 1.73 m2, and on stable renin-angiotensin blockade were randomized 2:1 to ravulizumab (intravenous every 8 weeks) or placebo for 26 weeks. From week 26–50, all participants received open-label ravulizumab. The primary end point was percentage change in proteinuria from baseline (BL) to week 26. Secondary end points included change in proteinuria at week 50 and eGFR. Safety, pharmacokinetics, and pharmacodynamics were evaluated. Results Forty-three patients were randomized to ravulizumab and 23 to placebo. At week 26, a statistically significant reduction in proteinuria was observed with ravulizumab versus placebo: −41.9% (95% confidence interval [CI], −50.2% to −32.0%) change in urine protein with ravulizumab and −16.8% (95% CI, −31.8% to 1.6%) change with placebo (30.1% treatment effect; P = 0.005). At week 50, there was a −44.8% (95% CI, −55.1% to −32.1%) change from BL in urine protein with ravulizumab, and in patients who crossed over from placebo to ravulizumab at week 26, the change from BL (week 0) to week 50 was −45.1% (−58.0% to −28.4%). The least squares mean change in eGFR from BL to week 26 with ravulizumab was 0.2 (95% CI, −2.3 to 2.7) ml/min per 1.73 m2 and with placebo was −4.5 (−7.9 to −1.1) ml/min per 1.73 m2. From BL to week 50, the least squares mean change in eGFR with ravulizumab was −3.9 (95% CI, −6.4 to−1.3) ml/min per 1.73 m2, and in patients who crossed over from placebo to ravulizumab at week 26, it was −6.3 (−9.7 to −2.9) ml/min per 1.73 m2. Ravulizumab was well tolerated, with an adverse event profile similar to that for placebo. Conclusions An early, sustained, and clinically meaningful reduction in proteinuria and trend toward stabilization of eGFR were observed with ravulizumab versus placebo. A phase 3 trial (NCT06291376) is enrolling. Clinical Trial registry name and registration number: Study of Ravulizumab in Proliferative Lupus Nephritis or IgA Nephropathy, NCT04564339.

The efficacy of cryotherapy compared to the other modalities for the management of palmoplantar warts: a systematic review and network meta-analysis

There are several treatment modalities for Palmoplantar Warts (PPW) introduced, but none have been proven to be significantly effective in all patients. The study aims to assess the efficacy and safety of cryotherapy compared to other modalities for PPW. Searches were conducted in Medline, Embase, Scopus, and CENTRAL databases, along with additional reference and citation tracking from included studies. Randomized Controlled Trials (RCTs) comparing various treatments for PPW were included. Two independent pairs extracted the data from the included studies. Outcomes assessed included cure rates, pain scores, recurrence rates, and adverse events. Network meta-analysis using Netmeta in R software was utilized, with treatments ranked by p-scores. A total of 27 RCTs that enrolled 2,539 participants were deemed eligible. As per p-scores, needling yielded the highest odd for the cure rate (p=1.00), followed by intralesional injection of the Measles, Mumps, and Rubella (MMR) vaccine (p=0.90). For the pain score, 76% topical monochloroacetic acid (p=0.13) showed the lowest mean pain score, while cryotherapy yielded the highest score (p=0.90). Furthermore, cryotherapy showed the highest odds for recurrence rate (p=0.75), followed by intralesional injection of Candida antigen (p=0.61). 0.05% intralesional bleomycin (p=0.93) was the highest agent for adverse events rate, followed by cryotherapy (p=0.61). Needling was the most effective in achieving a cure rate. Cryotherapy has the highest odds for pain score and recurrence rate, while 0.05% intralesional bleomycin has the highest adverse events profile.

Estimated cost of VEGFR TKI associated adverse events in metastatic renal cell carcinoma patients

IntroductionThe majority of metastatic renal cell carcinoma (mRCC) patients receive one or more VEGFR TKI agents, alone or in combination with an immune-oncology (IO) agent or an mTOR inhibitor. To date, the cost of adverse events (AEs) common to VEGFR TKIs has not been quantified. This study estimated the potential impact of differences in VEGFR TKI AE profiles on treatment cost efficiency in the relapsed/refractory (R/R) setting.MethodsPatients with documented mRCC who were treated with VEGFR TKI therapies between Jan 2015 and Mar 2021 were identified using EMR. ICD-10 diagnosis codes were used to identify the first occurrence of each class effect AE. Patients were matched to 3rd party insurance claims, and costs associated to TKI AEs within 90 days of index event were captured. Average per patient AE cost data was calculated and applied to published incidence data to estimate regimen-specific AE total cost burden within a hypothetical commercial plan for mRCC patients undergoing treatment in the R/R setting.ResultsThe highest total cost for AE management was attributed to lenvatinib and everolimus use at $13,303, followed closely by sunitinib at $13,092. Tivozanib treatment was associated with the lowest total cost of AE management at $7,523, driven by the relatively lower incidence of certain high-cost AEs.ConclusionsThe estimated costs of managing VEGFR TKI class-effect AEs were lowest with tivozanib, and highest with lenvatinib and everolimus, indicating potentially differential healthcare resource burden by TKI regimen. The use of tivozanib in the 3 L + mRCC setting suggests potential costs offsets when compared to other TKI regimens.

Upadacitinib in Adolescents With Moderate to Severe Atopic Dermatitis

The Measure Up 1, Measure Up 2, and AD Up studies demonstrated the efficacy and adverse events of upadacitinib through 52 weeks in adults and adolescents with atopic dermatitis (AD); however, longer-term outcomes (longer than 1 year) in adolescents have not previously been available. To evaluate the efficacy and adverse events of upadacitinib in adolescent patients with moderate to severe AD through 76 weeks. The Measure Up 1, Measure Up 2, and AD Up trials are ongoing double-blind, placebo-controlled phase 3 randomized clinical trials including adolescents (aged 12 to 17 years) with moderate to severe AD. Data were collected from August 2018 to April 2022, and data were analyzed from June 2022 to September 2023. Adolescents were randomized 1:1:1 to receive once-daily oral upadacitinib, 15 mg; upadacitinib, 30 mg; or placebo, either alone (Measure Up 1 and Measure Up 2 trials) or with topical corticosteroids (AD Up). At week 16, placebo-treated patients were rerandomized to receive upadacitinib, 15 mg, or upadacitinib, 30 mg, daily. Coprimary end points assessing efficacy included achievement of 75% reduction or more in the Eczema Area and Severity Index Score (EASI-75) from baseline, Validated Investigator Global Assessment for Atopic Dermatitis (vIGA-AD) score of clear (0) or almost clear (1) with 2 grades or more of improvement, and Worst Pruritus Numerical Rating Scale (WP-NRS) improvement of 4 points or greater through week 76 for participants with a WP-NRS score of 4 points or higher at baseline. From all studies, 542 adolescents were included; of these, 284 (52.4%) were female. At week 76, among patients in the Measure Up 1, Measure Up 2, and AD Up trials, EASI-75 was achieved by 89.1%, 84.4%, and 87.8% of adolescents taking upadacitinib, 15 mg, respectively, and by 96.1%, 93.6%, and 82.7% of adolescents taking upadacitinib, 30 mg, indicating maintenance or improvement of EASI-75 across 76 weeks with upadacitinib. Efficacy measured by achievement of vIGA-AD score of 0 or 1 and WP-NRS improvement of 4 points or more from baseline was similarly maintained or improved through week 76 for adolescents taking upadacitinib, 15 mg or 30 mg. Long-term outcomes in Measure Up 1, Measure Up 2, and AD Up participants were consistent with the known adverse event profile of upadacitinib (herpetic infection: 4.0, 1.9, and 1.1 events per 100 patient-years, respectively; creatine kinase elevation: 11.6, 11.0, and 7.1 events per 100 patient-years); no new signals were observed with either dose. In this study assessing 3 randomized clinical trials, long-term treatment of adolescents with moderate to severe AD with upadacitinib demonstrated a favorable benefit-risk profile, with sustained efficacy responses through 76 weeks. Measure Up 1 trial: ClinicalTrials.gov Identifier: NCT03569293; Measure Up 2 trial: NCT03607422; AD Up trial: NCT03568318.

The risks and benefits of managing obesity in older adults.

In an effort to expedite the publication of articles, AJHP is posting manuscripts online as soon as possible after acceptance. Accepted manuscripts have been peer-reviewed and copyedited, but are posted online before technical formatting and author proofing. These manuscripts are not the final version of record and will be replaced with the final article (formatted per AJHP style and proofed by the authors) at a later time. This review discusses weight loss considerations in overweight and obese older adults. Current US guidelines do not address weight loss in older adults. Waist circumference rather than body mass index (BMI) may be a more accurate assessment tool for obesity in older adults. Weight loss interventions are not recommended in overweight older adults due to the decreased mortality in this population (known as the "obesity paradox"). While weight loss in obese older adults may be beneficial, it is not without risks. The greatest risks include loss of muscle mass, decline in bone mineral density, and development of sarcopenic obesity. Weight loss interventions may be considered in older adults with a BMI of greater than 30kg/m2 who have metabolic derangements, cardiovascular disease, and/or functional impairments after carefully weighing the risks against the benefits of weight loss and the impact of interventions on the patient's quality of life. Medicare provides limited benefits for weight loss interventions. In older adults, there is no consensus on which lifestyle interventions are best for weight loss and there is a paucity of data on the use of weight loss medications. Careful consideration should be given before utilizing medications for weight loss in older adults given the enhanced adverse effect profiles, interactions, contraindications, and costs. Weight loss in older adults should be approached differently from that in the general adult population. More data are needed on the efficacy and safety of weight loss medications in older adults.

Thromboembolism adverse event profiles of thrombopoietin receptor agonists: a real-world, pharmacovigilance study

ABSTRACT Background Thrombopoietin receptor agonists (TPO-RAs) are currently approved for the treatment of thrombocytopenia in different conditions. The relationship between TPO-RAs and thromboembolic events (TEEs) remains controversial. Research design and methods We extracted TPO-RAs adverse reaction reports after their marketing until now, using the FDA adverse event reporting system (FAERS). Positive signals were detected by reporting odds ratios (RORs). And the Weibull shape parameter test was utilized to analyze the time-to-onset profiles. Result Thromboembolic events accounted for 8.97% among TPO-RAs reports. Increased reporting of TEEs was related to TPO-RAs treatment compared with the entire FAERS database [ROR = 2.65 (2.56, 2.73)]. In addition, venous thrombotic events [ROR = 4.13 (3.92, 4.35)] were reported more frequently than arterial events ROR = 1.81 (1.7, 1.93)]. Age over 60 years [odds ratio (OR) = 1.10 (1.01, 1.20), p = 0.029] and weight over 80 kg [OR = 1.36 (1.17, 1.58), p < 0.001] of patients might have higher risk of TEEs during TPO-RAs therapy. Conclusion Evidence from the real world suggested that TPO-RAs were associated with higher incidence of TEEs, particularly venous thrombosis. The risk of TPO-RAs-associated TEEs mostly happened in the early stages of treatment and decreased over time.

Comparison of abiraterone, enzalutamide, and apalutamide for metastatic hormone-sensitive prostate cancer: A multicenter study.

We aimed to assess the differential efficacy and safety of androgen receptor pathway inhibitors (ARPI), such as abiraterone, enzalutamide, and apalutamide, in patients with metastatic hormone-sensitive prostate cancer (mHSPC) in a real-world practice setting. We retrospectively reviewed the records of consequent 668 patients with mHSPC treated with ARPI plus androgen deprivation therapy between September 2015 and December 2023. Based on the LATITUDE criteria, the comparison among abiraterone, enzalutamide, and apalutamide was exclusively conducted in high-risk patients. Prostate-specific antigen (PSA) responses such as the achievement of 95% and 99% PSA decline, overall survival (OS), cancer-specific survival (CSS), time to castration-resistant prostate cancer (CRPC), and the incidence of adverse events (AEs) were compared. All two-group comparisons relied on propensity score matching (PSM) to minimize the effect on possible confounders. In total, 297 patients with high-risk mHSPC treated with abiraterone, 127 with enzalutamide, and 142 with apalutamide were compared. There were no differences in time to CRPC (p = 0.13), OS (p = 0.7), and CSS (p = 0.5) among the three ARPIs. No differences were observed in the achievement rates for 95% PSA decline at 3 months among the three ARPIs, while abiraterone was significantly better in 99% PSA decline achievement compared to apalutamide (72% vs. 57%, p = 0.003). The aforementioned oncologic outcomes were sustained even when performing PSM analyzes. Although skin rash for APA (34%) was the highest incidence of AEs, there were no differences in the rates of severe AEs across the three ARPIs. Enzalutamide resulted in the lowest treatment discontinuation rates (10%) other than disease progression compared to the other regimens. Abiraterone, enzalutamide, and apalutamide have comparable oncologic outcomes in terms of OS, CSS, and time to CRPC in patients with high-risk mHSPC. Our data on differential treatment discontinuation rates, PSA response, and AE profiles can help guide clinical decision-making.

Comparison of Adverse Event Profiles of Amphotericin B Formulations Using Real-World Data

Comparison of Adverse Event Profiles of Amphotericin B Formulations Using Real-World Data

Review article: Novel therapies in inflammatory bowel disease - An update for clinicians.

Several new treatments including small molecules and biologics have been approved for the treatment of inflammatory bowel diseases in recent years. Clinicians and patients now have a wide variety of therapeutic options to choose from and these novel therapies provide several advantages including oral administration, lower immunogenicity, better selectivity and arguably better safety profiles. An increase in treatment options has increased the complexity of decision-making. Both patients and clinicians have had to become rapidly familiar with efficacy of new medications balanced against a range of pre-initiation requirements, dosing schedules and adverse event profiles. To provide a simple guide to practising clinicians on recently approved and emerging therapies and address key challenges around treatment strategies such as optimal sequencing and timing of treatment. We comprehensively searched the published literature and major conference abstracts to identify phase III placebo-controlled and active comparator trials for Crohn's disease and ulcerative colitis. Data for recently approved therapies including selective Janus kinase inhibitors, sphingosine-1 receptor modulators and p19 interleukin (IL)-23 inhibitors have demonstrated improved patient outcomes in both Crohn's disease and ulcerative colitis. Further comparative head-to-head studies have improved our understanding of when and how to optimally use newer therapies, specifically for IL-23 inhibitors. Data for emerging treatment options and novel treatment strategies such as early effective treatment, combinations of treatments and implications for sequencing are continuing to transform IBD care continually. Recently approved novel therapies have expanded the range of medical options available to treat IBD. However, further data from long-term extension studies, real-world studies and head-to-head trials are warranted to better inform the long-term safety and optimal sequencing of treatments for patients living with IBD.

Differences in the Adverse Event Profiles of Sodium-Glucose Cotransporter 2 Inhibitors used in Patients with DiabetesMellitus and Heart Failure: An Analysis Using the Japanese Adverse Drug Event Report Database.

Sodium-glucose cotransporter 2 inhibitors (SGLT2i) have recently become a standard treatment for heart failure and renal failure. The number of patients using these drugs is expected to increase further. However, no adverse drug event profiles have been published for the use of SGLT2i in patients without diabetes. To analyze and clarify the differences in adverse event profiles associated with the use of SGLT2i in patients with diabetes or heart failure using the Japanese Adverse Drug Event Report (JADER) database, a Japanese reporting system for adverse events. The JADER database, containing reports submitted between April 2004 and January 2024, was used. Our study focused on patients with diabetes or heart failure, analyzing adverse events associated with empagliflozin and dapagliflozin. The reporting odds ratio (ROR) and 95% confidence interval (CI) were calculated for signal detection. We identified risks of adverse drug events such as ketoacidosis, urinary tract infection, dehydration, and acidosis in both patient groups. However, the risks of cerebral infarction and ischemic heart disease were identified only in patients with diabetes, while risks of renal dysfunction, hypoglycemia, and sepsis were identified only in those with heart failure. Adverse events should be managed appropriately for patients using SGLT2i, as the adverse event profiles differ between those with diabetes and those with heart failure. Understanding these differences is crucial for improving patient safety and optimizing treatment outcomes.

Therapeutic agents for the treatment of human mpox.

The aim of this study was to summarize the current knowledge of therapeutic options for mpox (formerly known as monkeypox) in the context of recent outbreaks and the ongoing evolution of the virus. Multiple therapeutic agents, including tecovirimat, cidofovir, brincidofovir, and vaccinia immune globulin, have been used during the multicountry outbreak of mpox caused by Clade 2b monkeypox virus that began in 2022. Tecovirimat has been most extensively used, based on efficacy against mpox lethal challenge in animal models, and human safety data. Real-world observational evidence has further supported safety with minimal adverse events in large cohorts and mixed reports of reductions in time to lesion resolution. Several prospective randomized controlled trials using tecovirimat are underway with headline results from a study in the Democratic Republic of the Congo showing no difference in lesion resolution compared to placebo. Other studies including in outpatient settings are underway in Europe and the Americas. Cidofovir and brincidofovir, limited by adverse event profiles, have been less extensively studied. Vaccinia immune globulin has been used predominantly in salvage therapy for severe mpox, with no large observational series available. The 2022 multicountry outbreak of mpox marked a public health emergency. Agents approved for smallpox management were widely used for mpox, supported by animal and in-vitro evidence, and human safety data. The large number of human cases has allowed retrospective observational study of these agents and facilitated recruitment in prospective trials. The ongoing evolution of the virus may pose challenges for therapeutic interventions, necessitating rigorous randomized controlled trials to guide clinical use.

The Adverse Effects of Commonly Prescribed Antiseizure Medications in Adults With Newly Diagnosed Focal Epilepsy.

Systematic screening can help identify antiseizure medication (ASM)-associated adverse events (AEs) that may preclude patients from reaching effective doses or completing adequate trial periods. The Adverse Event Profile (AEP) is a self-completed instrument to identify the frequency of common AEs associated with ASM use. This study aimed to compare the AE profile of commonly used ASMs in adults with newly diagnosed focal epilepsy. The Human Epilepsy Project is a prospective, international, observational study investigating markers of treatment response in newly diagnosed focal epilepsy. Participants were enrolled within 4 months of treatment initiation. Adult participants on levetiracetam, lamotrigine, carbamazepine, or oxcarbazepine monotherapy who completed the AEP and Mini International Neuropsychiatric Interview at enrollment were included. Multivariable generalized linear and penalized logistic regression models assessed differences in total and itemized marginal AEP scores and dichotomized responses ("never/rarely" vs "sometimes/always"). A total of 225 adults initiated on levetiracetam (n = 132, 59%), lamotrigine (n = 55, 24%), carbamazepine (n = 19, 8.4%), or oxcarbazepine (n = 19, 8.4%) were included. There were no significant differences in AEP total scores between ASMs. Patients with depression (adjusted marginal score ratio [aMSR] 1.23, 95% CI 1.09-1.39, p = 0.001) and anxiety (aMSR 1.15, 95% CI 1.04-1.26, p = 0.007) had worse AEP total scores than those without. After adjusting for depression and anxiety, levetiracetam users were >3 times more likely to report feelings of aggression (adjusted odds ratio [aOR] 3.38, 95% CI 1.07-10.7, p = 0.038) and almost half as likely to experience unsteadiness (aOR 0.45, 95% CI 0.21-0.99, p = 0.047) than lamotrigine users. Carbamazepine and oxcarbazepine had the highest rates of discontinuation (42.1%, each), followed by levetiracetam (34.8%) and lamotrigine (16.4%). Levetiracetam users had the highest proportion of discontinuations because of AEs alone (18%), and lamotrigine had the lowest (5%). Systematic screening for AEs in adults with newly diagnosed focal epilepsy on ASM monotherapy showed that those with comorbid psychiatric conditions report greater AEs overall, irrespective of ASM. Levetiracetam was associated with >3-fold risk of psychiatric AEs and half the risk of experiencing unsteadiness than lamotrigine. Levetiracetam had the highest proportion of discontinuations because of AEs alone, while lamotrigine had the lowest.

Capivasertib and fulvestrant for patients with HR-positive/HER2-negative advanced breast cancer: analysis of the subgroup of patients from Japan in the phase 3 CAPItello-291 trial.

In CAPItello-291, capivasertib-fulvestrant significantly improved progression-free survival (PFS) versus placebo-fulvestrant in the overall and PIK3CA/AKT1/PTEN-altered population with hormone receptor-positive (HR-positive)/human epidermal growth factor receptor 2-negative (HER2-negative) advanced breast cancer. Capivasertib-fulvestrant is approved in Japan for the treatment of patients with one or more tumor biomarker alterations (PIK3CA, AKT1 or PTEN). Here, we report outcomes in the CAPItello-291 subgroup of patients from Japan. Adults with HR-positive/HER2-negative advanced breast cancer whose disease had relapsed or progressed during or after treatment with an aromatase inhibitor, with or without previous cyclin-dependent kinase 4/6 (CDK4/6) inhibitor therapy, were randomly assigned (1:1 ratio) to receive capivasertib or placebo, plus fulvestrant. The dual primary endpoint was investigator-assessed PFS in the overall andPIK3CA/AKT1/PTEN-altered population. Safety was a secondary endpoint. Of 708 patients randomized in CAPItello-291, 78 were from Japan (37 randomized to capivasertib-fulvestrant and 41 to placebo-fulvestrant). In the Japan subgroup, PFS numerically favored the capivasertib-fulvestrant arm (hazard ratio 0.73; 95% CI 0.40-1.28), consistent with the analysis of PFS in the global population. Similarly, in the Japan subgroup of patients with PIK3CA/AKT1/PTEN-altered tumors, PFS favored the capivasertib-fulvestrant arm (hazard ratio 0.65; 95% CI 0.29-1.39), consistent with the global population. The adverse event profile of capivasertib-fulvestrant in the Japan subgroup was broadly similar to that in the global population; no new safety concerns were identified. Outcomes in the Japan subgroup were broadly similar to those of the global population, supporting the clinical benefit of capivasertib-fulvestrant in treating HR-positive/HER2-negative advanced breast cancer that has progressed on, or after, an endocrine-based regimen.

Adverse Event Profile of First-line Drugs for Treating Patent Ductus Arteriosus in Neonates: A Disproportionality Analysis Study of USFDA Adverse Event Reporting System.

Acetaminophen, ibuprofen, and indomethacin are widely used as first-line drugs for patent ductus arteriosus (PDA) closure in preterm neonates. However, their relative safety profiles remain unclear. Adverse event reports related to the first-line drugs used in PDA and neonates in general were retrieved from the US Food and Drug Authority (FDA) Adverse Event Reporting System. Deduplicated reports were analyzed using proportional reporting ratios and reporting odds ratios to identify disproportionality safety signals between drugs. A total of 969 unique reports related to the first-line drugs used in PDA and 499 reports in the neonatal period were included. Acetaminophen signals primarily involved the liver, while ibuprofen and indomethacin signals pertained to gastrointestinal, renal, vascular, and mortality outcomes. Higher occurrences of death were reported with indomethacin and ibuprofen compared with acetaminophen. This first comparison of PDA drug safety profiles from spontaneous reports highlights some differences, with acetaminophen potentially conferring a safer adverse effect profile overall. While limitations include missing data and reporting biases, the signals warrant further validation. Given its comparable efficacy to ibuprofen, as demonstrated in other studies, acetaminophen has the potential to be preferred as an initial medical therapy for PDA.