Sodium-glucose cotransporter 2 inhibitors (SGLT2is) remain underused in clinical practice, one of the reasons may be the fear of adverse events which have been emphasized during the first years of use. This comprehensive review aims to give an update on the safety and tolerability profile of SGLT2is. An extensive literature search identified randomized controlled trials, observational cohort studies and pharmacovigilance reports that investigated the safety of SGLT2is in patients with type 2 diabetes (T2D), with or without comorbidities or presenting at-risk conditions. Some adverse events pointed out initially have been confirmed, especially a higher risk of genital infections, though not the initial fear of urinary tract infections. A euglycemic diabetic ketoacidosis remains exceptional in patients with T2D. Volume depletion is a rare event that may be anticipated. Of note, several severe adverse events that led to warnings by regulatory agencies have not been confirmed in further studies: bone fractures, lower-limb amputations, severe perineal infections, acute renal injury. The safety profile of SGLT2is appears globally reassuring even in special at-risk populations. However, data remain rather scarce in patients with severe comorbidities and in very old or frail people, so that caution use is classically recommended. All medicines must be evaluated by weighing their effectiveness against their potential side effects. Gliflozins (SGLT2 inhibitors), originally developed to lower blood sugar in people with type 2 diabetes, have shown impressive benefits that go far beyond glucose control. They reduce the risk of major cardiovascular events, heart failure, and chronic kidney disease. Despite these strong advantages, they remain underused in clinical practice, even among patients who could benefit the most. One reason may be concerns about side effects that were initially reported when these drugs were introduced.Genital fungal infections are the most common side effect of SGLT2 inhibitors, but they are generally mild and easily treatable. In contrast, an increased risk of urinary tract infections has not been confirmed. Euglycemic diabetic ketoacidosis and volume depletion occur more often with gliflozins than with some other treatments, but these events remain rare and can usually be prevented with appropriate guidance. Some severe complications – such as bone fractures, lower-limb amputations, severe perineal infections, and acute kidney injury – were initially highlighted in pharmacovigilance reports and led to warnings by regulatory agencies. However, these risks have not been confirmed in more recent studies. Recent evidence shows that gliflozins are generally safe even in patients with diabetes and additional conditions such as chronic kidney disease, heart failure, or liver disease. Nevertheless, data remain limited for individuals with severe comorbidities and very old or frail patients. In these populations, cautious use, close monitoring, and personalized benefit – risk assessment are recommended when prescribing gliflozins.
Pulmonary arterial hypertension (PAH) has responded favorably to the new fusion protein named sotatercept. This study aimed to evaluate the safety and efficacy of sotatercept in PAH. The online databases like PubMed/Medline, Cochrane Library, and ClinicalTrials.gov were searched until 15 September 2024 for studies comparing sotatercept to placebo using keywords such as "sotatercept, pulmonary arterial hypertension, and 'fusion protein.' Of the 213 titles searched, after removing duplicates, 142 studies were evaluated for eligibility. Two RCTs were finally included. Subgroup analysis was conducted for the two doses (0.7 mg/kg and 0.3 mg/kg). In the safety analysis, there were no significant differences in total adverse events [RR = 1.03 (0.95, 1.12), I2 = 0, p = 0.50], serious adverse events [RR = 0.96 (0.38, 2.42), I2 = 56, p = 0.93], and mortality [RR = 0.39 (0.01, 11.81), I2 = 61%, p = 0.59]. However, a significant difference was observed with non-serious adverse events [RR = 1.15 (1.03-1.30), I2 = 0%, p = 0.02], telangiectasia [RR = 3.34 (1.26-8.83), p = 0.02], thrombocytopenia [RR = 3.69 (1.23-11.0), I2 = 0%, p = 0.02] and epistaxis [RR = 5.58 (2.20-14.13), p = 0.0003]. No significant difference was observed with headache, nasopharyngitis, hypotension, neutropenia, nausea, diarrhea, rash, anemia, and dizziness. A significant change was observed with the majority of efficacy parameters, like Pro BNP [MD = -1150.38 (-1846.44, -454.32), I2 = 79, p = 0.001], pulmonary vascular resistance [MD = -234.40 (-325.30, -143.51), I2 = 72, p < 0.00001], pulmonary arterial wedge pressure (p = 0.007) and improvement in WHO functional class [OR = 3.23 (1.25, 8.34), I2 = 61, p = 0.02]. This study demonstrates that sotatercept is more effective than placebo in treating PAH and has a fair safety profile. Identifier numbers: NCT04576988 and NCT03496207 PROSPERO: CRD42024534695. Based on current research, the pooled analysis of the studies demonstrates that sotatercept is a well-tolerated and helpful treatment option for managing pulmonary arterial hypertension (PAH). Sotatercept does not seem to worsen or increase the risk of overall side effects or serious health issues. The more common side effects of headache, sore throat, hypotension, nausea, diarrhea, skin rash, anemia, and dizziness did not differ to a clinically meaningful extent. Physicians, however, must pay attention to low platelet counts in some patients owing to the potential for bleeding and elevated hemoglobin levels, which may require dose modification.Sotatercept has demonstrated promising results in enhancing several important health metrics, including decreasing pulmonary blood pressure, enhancing physical functioning, and reducing levels of pro-BNP, a sign of cardiac strain. Sotatercept was used along with other standard treatments of PAH in the study. Since the available evidence stems from a limited number of studies, further research involving larger cohorts and extended observational periods is essential for clarifying long-term safety.
Placental abruption is a significant cause of fetomaternal mortality/morbidity. Management requires a difficult balance between opposing advantages/disadvantages for the fetus and mother. Remote from term, prompt delivery is best for the mother, but delayed delivery better for the fetus. Prevalence of fetomaternal morbidity/mortality; range of clinical situations: certainty of diagnosis, gestational age, labor status, fetal condition/viability, presence of maternal shock/consumption coagulopathy, feasibility of prompt delivery. Pathophysiology: maternal hypovolaemia; abruption size; impairment of placental oxygenation; intrauterine tone and pressure; safety, efficacy, and application of tocolytic therapy to abruption; potential role of atosiban with emphasis on safety. The fetomaternal morbidity/mortality of placental abruption deserves consideration of further interventions that may improve fetomaternal outcome. More information is now available about signs/symptoms that do not require invasive diagnostic procedures. The contribution of maternal uterine hypertonus/tachysystole and increased uterine tone/pressure that affects fetal hypoxia/acidosis and consumption coagulopathy, strengthens the case for the use of a tocolytic to relax the uterus and improve fetal oxygenation. Due to its safety and efficacy profile, we make the case for atosiban as an agent to reduce uterine contractile frequency, tone, and pressure to improve fetal oxygenation and improve fetomaternal outcome.
Hormonal therapy is the cornerstone of long-term endometriosis management, especially for women deferring surgery. In patients with comorbid migraine - a common, disabling condition - therapeutic choices must balance efficacy with neurological and vascular safety. This review summarizes hormonal therapies for endometriosis with a focus on safety in migraineurs. A comprehensive literature search was conducted using MEDLINE, EMBASE, and the Cochrane Library up to March 2025. Combined hormonal contraceptives (CHCs) and progestins remain first-line options for treating endometriosis-related pain. CHCs are contraindicated in patients with migraine with aura because of the increased risk of ischemic stroke, while their prescription in migraine without aura should be individualized, considering also the fact that evidence in women with concomitant endometriosis is still limited. Progestins generally show better tolerability and may improve migraine outcomes, despite the occurrence of breakthrough bleeding or mood changes. Gonadotropin-releasing hormone (GnRH) agonists and antagonists are second-line options, providing effective pain control, although their effects on migraine are variable and headaches are a frequent adverse event. Add-back therapy is essential to mitigate hypoestrogenic sequelae, particularly about bone health. Overall, treatment should be individualized according to migraine subtype and vascular risk profile to ensure long-term safety, adherence, and therapeutic effectiveness.
Acute ischemic stroke (AIS) is currently the leading cause of morbidity and mortality globally, and despite progress that has been made in treatment and prevention over the last 30 years, its burden is expected to increase in future decades, due to the growth and aging of the populations. Therein, a greater access and delivery of safe and effective better drugs will be needed to improve AIS management. This review highlights the current AIS care strategies, focusing on the efficacy and safety of antithrombotic drugs. Regarding AIS, reperfusion through IV thrombolysis remains the cornerstone of treatment, alongside mechanical thrombectomy in eligible patients. International guidelines recommend Alteplase within 4.5 hours of symptom onset; however, advanced neuroimaging may allow for the extension of this treatment window in selected patients. Tenecteplase, with its favorable pharmacokinetics and simplified administration, is emerging as an alternative. Early secondary prevention is strictly dependent on stroke etiology and consists of antiplatelets, oral anticoagulants, and aggressive risk factor control. Cardioembolic strokes require timely oral anticoagulation, while noncardioembolic minor ischemic strokes or high-risk transient ischemic attacks benefit from short-term dual antiplatelet therapy.
Several sarcomeric gene abnormalities associated with left ventricular thickening, hypercontractility, and high left ventricular ejection fraction define hypertrophic cardiomyopathy (HCM). Standard treatment options such as beta-adrenergic blockers, calcium channel blockers, and/or disopyramide improve symptoms in many patients, but have limited ability to modify disease progression. Two new cardiac myosin inhibitors (CMIs), mavacamten and aficamten, reduce the intensity of myosin - actin cross-bridge formation and could treat causes of HCM. Drug clearance concepts, relevant information pertaining to cytochrome P450 (CYP450) isoenzymes involved in the disposition of mavacamten and aficamten, genetic polymorphisms associated with CYP450 isoenzymes, and relevance of multi-drug interactions leading to changes in the systemic exposure of CMIs. Both mavacamten and aficamten exhibit complex disposition and are extensively metabolized by CYP450 isoenzymes including CYP2C9, CYP2C19, and CYP2D6, which exhibit genetic polymorphisms. CYP3A4 contributes less to the metabolism of mavacamten and aficamten. However, CYP3A4 can influence the disposition of these CMIs and other drugs, as CYP3A4 is subjected to induction and inhibition, and modulation by inflammatory factors. Therefore, multi-drug interactions due to changes in the metabolic clearances of CMIs are expected in HCM patients with other chronic conditions and polypharmacy.
Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder with limited treatment options and diverse symptoms necessitating active management. Anticholinergic medications are frequently used in ALS care, particularly for sialorrhea and mood disturbances. Their cumulative effects, termed anticholinergic burden, may pose underrecognized risks in this neurologically vulnerable population. This review highlights a plausible safety signal and outlines priorities for future research. This narrative review synthesizes evidence from non-ALS populations reporting associations between higher anticholinergic burden and cognitive decline, respiratory complications, functional deterioration, and mortality. Evidence was identified through targeted PubMed/MEDLINE and Embase searches with reference chaining, emphasizing recent and seminal studies. Mechanistic overlap with ALS pathophysiology, including neuromuscular junction disruption, impaired cholinergic signaling, and neuroinflammation, supports biological plausibility for harm. Current ALS guidelines do not address cumulative anticholinergic exposure, leaving clinicians without a framework for evaluating risk or deprescribing. This article proposes a testable hypothesis that anticholinergic burden may represent a clinically relevant yet unmeasured risk factor in ALS. Emerging pharmacoepidemiologic methods and validated burden tools offer approaches to quantify exposure and evaluate relationships with ALS outcomes, supporting safer symptomatic management. Prioritizing longitudinal studies and integrating burden assessment into multidisciplinary care may help clarify risk.
The United States Food and Drug Administration (FDA) requires post-marketing surveillance of approved drugs, and pharmaceutical manufacturers maintain comprehensive programs that include adverse event monitoring, internal safety assessments, and reporting to the FDA Adverse Events Reporting System (FAERS). This report provides an overview of FAERS within the broader framework of post-marketing surveillance by pharmaceutical manufacturers. It also identifies several limitations to FAERS public dashboard data for safety analyses. A PubMed search for published findings of FAERS safety analyses with vesicular monoamine transporter 2 (VMAT2) inhibitors provide a case study that illustrates the need for careful interpretation based on the limitations of the FAERS database. Using a case study of VMAT2 inhibitors, we identified factors in data quality and manufacturer pharmacovigilance programs that must be considered when interpreting published analyses of FAERS public safety data. The application of artificial intelligence methodologies may prove helpful in identifying novel safety signals more accurately and more rapidly. At the same time, as clinicians consider individual treatment choices with their patients, discussion of safety data from the FAERS public dashboard should be contextualized within each drug's known safety profile.
Asthma treatment has undergone a substantial change since monoclonal antibodies have been approved as treatment. IL-5 is a crucial player within the immunological pathways underlying asthma pathobiology. Selectively targeting IL-5 and its receptor demonstrated on long-term observations an optimal safety and efficacy profile in asthma patients. However, in some special populations, the evidence related to the safety data is still limited. The present review summarizes the currently available literature on the overall safety of anti-IL-5 compounds, including a focus on partial vs complete blood eosinophil depletion in response to the different therapies. Furthermore, data on anti-IL-5 antibodies in children, pregnant patients and old people in terms of safety profile have been critically reviewed. Limited data are available in children, pregnant women and elderly. The last two categories are usually excluded by the clinical trials enrollment, and a few randomized studies are available for children. However, the real-world evidence, aligned with the highly selective mechanism of action, supports the implementation of the anti-IL-5 therapies in the three subgroups mentioned above. Of course, an individualized approach carefully evaluating the risk-benefit balance and a close monitoring are highly recommended in those patients.
In patients with acute coronary syndromes (ACSs) undergoing percutaneous coronary intervention, 12 months of dual antiplatelet therapy (DAPT) with aspirin plus a P2Y12 inhibitor is the current standard. However, DAPT is associated with an increased risk of bleeding. DAPT duration and intensity should be modulated according to the patient's specific risk profile to optimize outcomes. Different DAPT regimens varying in intensity and duration have been shown to improve outcomes in specific settings. In patients at increased ischemic risk, DAPT escalation or prolongation can be considered, while de-escalation by discontinuing one of the antiplatelet drugs, reduction in the dose of the P2Y12 inhibitor, or switching to a less potent P2Y12 inhibitor should be considered in patients at increased risk of bleeding. Platelet function and genetic testing may help guiding the decision making. Antiplatelet agents also have specific drug-related adverse effects that clinicians should be aware of. Management of ACS patients has largely shifted over time, in order to achieve a patient-oriented approach. Development of specific scores based on genetic and clinical characteristics to predict patient's responsiveness to clopidogrel may allow to further reduce ischemic events, while technological and pharmacological advances are paving the way for further reduction of bleeding risk while preserving efficacy.
Glucagon-like peptide-1 (GLP-1)-based therapies elicit a clinically significant reduction in body weight, an effect that correlates with improved clinical outcomes in individuals with type 2 diabetes and/or obesity. However, a risk of excessive reduction in skeletal muscle mass (SMM), potentially leading to sarcopenia, could minimize the benefit/risk balance of this pharmacological class. Human studies that investigated the effects of GLP-1-based therapies on changes in SMM, muscle strength/function and muscle structure/quality. Mixed results were reported, some studies emphasizing an excessive SMM loss while others not but arguing for a protective effect against sarcopenia through improved muscle quality (less myosteatosis). This controversy may stem from the misinterpretation of changes in body composition, as well as from the scarcity of studies that rigorously assess SMM, muscle function, and structure in humans. At present, no definitive conclusion can be drawn regarding the potential detrimental or beneficial effects of GLP-1-based therapies on skeletal muscle. Even if most available results are reassuring, further investigations are warranted, especially among individuals at higher risk of sarcopenia as older patients. In any case, the overall benefit/risk ratio of GLP-1-based therapies appears positive in most patients living with type 2 diabetes and/or clinical obesity. Obesity is becoming a major health problem in many countries, because of its increasing prevalence and numerous associated comorbidities including type 2 diabetes and atherosclerotic cardiovascular disease. Incretin-based therapies (especially glucagon-like peptide-1 receptor agonists or GLP-1RAs) are increasingly used in clinical practice for the management of type 2 diabetes and obesity. These medications are associated with a pronounced weight reduction together with improved glucose control and reduced cardiovascular risk. A concern arose following some findings reporting a significant loss of muscle mass in people losing weight with GLP-1RAs. A risk of so-called sarcopenia, i.e. a condition characterized by a severe loss of skeletal muscle mass, strength and function, has been feared, especially in older or frailty patients. This might be a concern as maximizing fat loss while preserving skeletal muscle mass and function is a central goal of modern obesity treatments. Of note, most recent data are reassuring. If some muscle mass reduction may be observed, it does not appear to be disproportionate with GLP-1RAs compared to what is observed with other weight loss therapies. Furthermore, an improvement of muscle quality has been reported due to a reduction in fat infiltration inside the skeletal muscle, an anomaly frequently seen in people living with obesity or type 2 diabetes. As a result, muscle strength, function and performance do not appear to be altered with GLP-1RA therapy. Nevertheless, before having a final conclusion, further studies are required, especially in populations at greater risk of sarcopenia, i.e. older individuals and frail patients with severe comorbidities.
Most of the new agents in cancer therapy (referred to as targeted therapies in the paper) come to the market with limited and preliminary data concerning activity and tolerance. Although better tolerated than classical chemotherapy, safety issues of targeted agents must not be underestimated. The aim of this mini review is to present some pharmacological specifities of targeted anticancer agents and to examine tolerance challenges observed after approval through some examples. References were identified through searches of PubMed for articles published up to March 2025 using the term postmarketing safety AND anticancer agent. Relevant articles were also searched for in high impact journals and specialty journals. Considering the clinical immaturity of targeted agents at their launch, partly due to expedited approvals, the new mechanisms of cell killing and the novel technologies of manufacturing, the postmarketing safety surveillance is a critical feature to secure their use. Pharmacoepidemiologic studies based on electronic health-based data will help to identify emergent and late safety events and to investigate their etiology along with predisposition factors. Work is also needed to elucidate the sex differences in toxicity of targeted therapies and to harmonize withdrawal decisions of drug regulatory agencies for safety reasons.
This study aimed to assess the safety and effectiveness of vonoprazan, a potassium-competitive acid blocker, as long-term maintenance therapy in patients with healed reflux esophagitis (RE) in real-world settings. This prospective, observational study enrolled patients with healed RE from 122 sites in Japan. Patients received daily oral vonoprazan 10 mg as maintenance treatment for 12 months. Safety was assessed by monitoring adverse events (AEs) and adverse drug reactions (ADRs), and effectiveness was evaluated by endoscopic RE recurrence and symptom severity. Of the 1237 enrolled patients, 1174 were included in the safety analysis. ADRs were reported in 2.3% of patients. ADRs included diarrhea, constipation, and abnormal hepatic function. The severity of symptoms improved over time, and of those with endoscopic findings, the RE recurrence was 4.0% (17/425). A total of four serious ADRs were reported in two patients, which led to death, comprising pneumonia, acute leukemia, myelodysplastic syndrome, and decreased platelet count. This study demonstrates the effectiveness of vonoprazan in preventing RE recurrence during maintenance treatment in clinical practice. The incidence of ADRs was low, and no new safety signals were identified, supporting the established safety profile of vonoprazan.Clinical trial registration: NCT03214081; jRCT1080223147.
Pregnant women represent a vulnerable population during the COVID-19 pandemic, facing increased risks of severe disease and adverse obstetric outcomes, yet they have been largely excluded from pivotal therapeutic clinical trials, leaving a critical evidence gap for treatment decisions. This review examines the available evidence on the safety and efficacy of COVID-19 therapies during pregnancy, including oral antivirals (nirmatrelvir/ritonavir, molnupiravir), intravenous remdesivir, monoclonal antibodies, corticosteroids, and immunomodulators (tocilizumab, baricitinib). A literature search was conducted using MEDLINE/PubMed for English-language articles published from March 2020 to December 2023, including studies of any design reporting maternal and neonatal outcomes. The COVID-19 pandemic exposed a critical gap in clinical research through the systematic exclusion of pregnant women from therapeutic trials. Current evidence, though largely observational, supports vaccination as the primary preventive strategy, nirmatrelvir/ritonavir for outpatients at risk of progression, and remdesivir plus corticosteroids for hospitalized patients requiring oxygen supplementation.
Cardiotoxicity associated with HER2-targeted therapies represents an important clinical concern in the management of HER2-positive breast cancer, particularly as survival improves and patients are exposed to prolonged or sequential treatments. Trastuzumab has significantly enhanced outcomes but is associated with cardiac dysfunction, which may limit its use in patients with preexisting cardiovascular risk factors. With the expanding use of newer HER2-targeted agents, a clear understanding of their cardiac safety profiles is essential for optimizing long-term patient care. This review evaluates the incidence, mechanisms, and clinical relevance of cardiotoxicity associated with trastuzumab and novel HER2-targeted therapies, including monoclonal antibodies, antibody - drug conjugates, and tyrosine kinase inhibitors. A literature search was conducted using PubMed and major oncology meeting proceedings, including the American Society of Clinical Oncology (ASCO) Annual Meeting and the San Antonio Breast Cancer Symposium. Randomized clinical trials, pooled analyses, long-term follow-up studies, and selected real-world observational studies reporting cardiac outcomes were reviewed. Available evidence suggests that trastuzumab-related cardiotoxicity remains clinically relevant, whereas newer HER2-targeted agents generally demonstrate favorable cardiac safety profiles with mostly asymptomatic and reversible events. These findings support individualized, risk-adapted cardiac monitoring strategies to balance oncologic efficacy with cardiovascular safety.
GLP-1 receptor agonists (GLP-1RA) are glucose- and body weight-lowering therapies provided with cardio-renal benefits. Use of GLP-1RA in older adults with type 2 diabetes mellitus (T2DM) is increasing but concerns remain about their safety in this age group, particularly in light of multimorbidity, frailty, and polypharmacy, as well as age-related vulnerability to adverse events (AEs). We discuss the opportunities and challenges of GLP-1RA in older people with T2DM, focusing on real-world (RW) safety evidence. Available RW studies confirm the established GLP-1RA safety profile, with AEs in 10-30% of older users, predominantly gastrointestinal and mild-to-moderate in severity. Age-stratified analyses provide mixed results on AE susceptibility, but discontinuation due to intolerance appears more frequent in older adults. Weight loss is preserved across age groups, with no consistent evidence of harmful unintended reductions. However, the effects on muscle mass and sarcopenia risk remain largely unexplored. Current RW evidence supports GLP-1RA as a safe therapeutic option for older individuals with T2DM, without age-specific safety signals. Clinical phenotype-driven selection is essential to balance benefits and risks, particularly regarding nutritional status and frailty. Prospective, phenotype-stratified studies with body composition assessment are needed to guide optimal, individualized use in aging populations.
Teprotumumab (Tepezza), a monoclonal antibody targeting the insulin-like growth factor 1 receptor (IGF-IR), was approved in January 2020 by the US Food and Drug Administration for treatment of thyroid-associated ophthalmopathy (TAO). The drug was found to be effective and generally well-tolerated in two registered clinical trials and subsequent post-marketing trials. A search of PubMed and other databases of medical and scientific literature was conducted. Key search terms included 'teprotumumab,' 'Tepezza,' 'thyroid-associated ophthalmopathy treatment,' and 'Graves' disease treatment.' Two adverse events (AEs), auditory abnormalities and hyperglycemia, were the focus of this review. As of 7 December 2025, 392 citations were identified in PubMed using teprotumumab as the search term. Of these, 29 publications primarily reported AEs or safety concerns associated with teprotumumab. The two most consequential AEs, hearing dysfunction and hyperglycemia, were identified in phase 2 and phase 3 clinical trials. Teprotumumab, the only FDA-approved therapy for TAO, is generally effective. It has been associated with several side effects; the most concerning are hearing dysfunction and hyperglycemia. Due diligence in pretreatment, intra-treatment and post-treatment monitoring is essential. Detailed benefit-risk analysis should be shared with all patients for whom use of the drug is being considered.
Trigger tool methodologies have become important approaches for detecting adverse events in hospital care because they identify more harm than conventional incident reporting systems. Their role is particularly relevant for medication-related harm, which is often under-recognized or insufficiently documented in routine clinical practice. This structured narrative review examines the development, methodological foundations, performance, and clinical applications of trigger tools in hospital settings, with emphasis on their use in detecting adverse drug events. It also discusses population-specific adaptations, methodological variability, and recent advances in electronic health record - based, automated, and artificial intelligence-assisted trigger approaches. The literature search was conducted using PubMed and Google Scholar, with additional studies identified through manual screening of reference lists. Trigger tools should be viewed not only as methods for retrospective harm detection, but also as potential links between hospital patient safety monitoring and pharmacovigilance. Their future value will likely depend on greater standardization and on the development of hybrid, clinically validated systems that combine relevant triggers, electronic health record data, and clinician review. Importantly, trigger tool findings should be incorporated into closed-loop workflows that support pharmacovigilance reporting, clinician feedback, quality improvement, and measurable reduction of preventable medication-related harm.
Trastuzumab and its antibody-drug conjugates (ADCs) are pivotal in treating human epidermal growth factor receptor 2(HER2)-positive cancers. With the growing scope of clinical use, an increasing body of evidence from studies and case reports suggests that these agents can induce hepatotoxicity of varying severity. This review synthesizes evidence from published clinical trials, preclinical studies, pharmacovigilance data, drug labeling information, meta-analyses and clinical guidelines to comprehensively evaluate the potential mechanisms, risk factors, potential predictive methods, and preventive strategies associated with liver injury induced by trastuzumab and its ADCs. Trastuzumab-related liver injury is uncommon but occurs more frequently with its antibody-drug conjugates, particularly trastuzumab emtansine (T-DM1), which can cause hepatopulmonary syndrome (HPS), nodular regenerative hyperplasia (NRH), and sinusoidal obstruction syndrome (SOS). Risk factors include dosage, treatment duration, and drug interactions. T-DM1 shows dose-dependent hepatotoxicity, while cytochrome P450 3A4 (CYP3A4) inhibitors may increase hepatic accumulation of trastuzumab deruxtecan (T-DXd). Trastuzumab mainly induces hepatocellular and cholestatic injury, whereas T-DM1 involves both HER2-dependent and independent pathways. Diagnosis relies on causality assessment, and most cases are reversible with liver function monitoring and timely dose adjustment.
Drug utilization studies (DUS) provide important insights on how medications are used in routine clinical practice and can identify gaps between real-world use and existing evidence and guidance. While DUS are relevant across all therapeutic areas, they are particularly valuable in pediatrics as a substantial proportion of prescribing occurs off-label or with limited trial data. This paper describes five domains where pediatric DUS can contribute to improving safe and rational use of medications: (i) setting research priorities, (ii) supporting drug surveillance and stewardship, (iii) identifying and reducing unwarranted variation, (iv) assessing prescriber behavior, and (v) evaluating the impact of regulatory actions and clinical guidelines. The five domains are illustrated using examples of Danish register-based pediatric DUS. Despite their value, pediatric DUS remain underused in clinical and regulatory decision-making. DUS should be systematically integrated into the development and revision of clinical guidelines on medication use and used routinely to evaluate the effects of major regulatory initiatives. Establishing near-real-time monitoring systems and extending DUS to inpatient settings would further strengthen their ability to impact clinical practice and support safer and more evidence-based prescribing for children and adolescents.