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Background Immune checkpoint inhibitors (ICIs) represent an effective cancer immunotherapy yet are associated with immune-related adverse events (irAEs). The aim of this study was to characterize irAEs involving the peripheral nervous system (PNS-irAEs) in a real-world cohort of ICI-treated patients. Methods Cancer patients treated with ICIs between January 2014 and March 2022 were included. Patients with PNS-irAEs were identified and divided into two groups: (1) cranial/peripheral neuropathies and (2) myasthenia gravis (MG) and/or myositis. Clinical characteristics and outcomes, measured with the modified Rankin Scale (mRS), were compared among the two groups. Results Among 920 ICI-treated patients, 20 patients (2.17%) developed a PNS-irAEs. The median latency from ICI exposure was 8.8 weeks and the median time from onset to clinical nadir was 3.5 weeks. Eleven patients developed a neuropathy: polyneuropathy (n = 4), cranial neuropathy (n = 3), small-fiber neuropathy (n = 3), brachial plexopathy (n = 1). Nine patients presented MG and/or myositis: concomitant MG and myositis (n = 6), isolated myositis (n = 2), exacerbation of MG (n = 1). Immunosuppressive treatment and/or ICI withdrawal determined a significant clinical improvement, expressed by a mRS reduction, in the neuropathy group (p = 0.004), but not in the MG/myositis group (p = 0.11). Overall, death due to irAEs occurred in four patients (20%), all with MG/myositis. Compared to patients with neuropathies, those with MG/myositis had a shorter latency onset (p = 0.036), developed more frequently concomitant non-neurologic irAEs (p = 0.028) and showed a higher mortality rate (p = 0.026). Conclusions In our large cohort of ICI-treated patients, 2.17% developed PNS-irAEs. Compared to ir-neuropathies, ir-MG/myositis tend to occur earlier from ICI exposure and present a worse response to treatment and a higher mortality.

Using 2 global postmarketing surveillance databases, Goldman and colleagues report that progressive multifocal leukoencephalopathy (PML), a viral disease associated with profound immunosuppression, occurs in approximately 0.9 cases per 1000 recipients of CD19-directed CAR T-cell therapy. The risk of PML appears higher with CAR T-cell therapy than other cancer therapies, but its precise role cannot be distinguished from antecedent therapies that these patients receive.

With the recent regulatory approvals, the relatlimab–nivolumab combination brings new expectations and opens avenues toward effective immunotherapy combination in advanced melanoma. This work provides a critical insight into the recent phase II–III RELATIVITY-047 trial (NCT03470922), including a comparison with the CheckMate 067 trial on the current standard ipilimumab–nivolumab combination, with a focus on immune-related adverse events. Some imbalances of rare toxicities were noted, deserving careful monitoring and assessment in the upcoming real-world use. The promising efficacy data, although still early, should be carefully balanced against these toxicities, thus making pharmacovigilance and global patient-level data sharing crucial to identify the target population, promote safer prescribing and eventually clarify its place in therapy.

IntroductionDeliberate self-poisoning (DSP) using drugs is the preferred method of suicide at a global level. Its investigation is hampered by limited sample sizes and data reliability. We investigate the role of the US FDA Adverse Event Reporting System (FAERS), a consolidated pharmacovigilance database, in outlining DSP habits and toxidromes.MethodsWe retrieved cases of 'intentional overdose' and 'poisoning deliberate' from the FAERS (January 2004-December 2021). Using descriptive and disproportionality analyses, we estimated temporal trends, potential risk factors, toxidromes, case-fatality rates and lethal doses (LDs) for the most frequently reported drugs.ResultsWe retrieved 42,103 DSP cases (17% fatal). Most cases were submitted in winter. Reports of DSP involved younger people, psychiatric conditions, and alcohol use, compared with non-DSP, and fatality was higher in men and older patients. Suspected drugs were mainly antidepressants, analgesics, and antipsychotics. Multiple drug intake was recorded in more than 50% of the reports, especially analgesics, psychotropics, and cardiovascular agents. The most frequently reported drugs were paracetamol, promethazine, amlodipine, quetiapine, and metformin. We estimated LD25 for paracetamol (150 g).ConclusionWorldwide coverage of the FAERS complements existing knowledge about DSP and may drive tailored prevention measures to timely address the DSP phenomenon and prevent intentional suicides.

Impulse control disorders (e.g., pathological gambling, hypersexuality) may develop as adverse reactions to drugs. Pathogenetic hypotheses have mainly focused on D3-receptor agonism, and switching to alternatives with different pharmacologic mechanisms represents a common management strategy. Nonetheless, treatment failure is common and gaining pathophysiological insights is needed.We aimed to identify targets potentially contributing to pathologic impulsivity.We performed a pharmacovigilance-pharmacodynamic study on dopamine agonists and antipsychotics using the Food and Drug Administration Adverse Event Reporting System (January 2004-December 2021). We estimated disproportionate reporting using the Bayesian information component. Using online public databases (IUPHAR, ChEMBL, PDSP, DrugBank), we calculated drug occupancies. To identify the targets potentially contributing to impulsivity, we fitted univariate regression models interpolating information components and occupancies within dopamine agonists and antipsychotics. Sensitivity analyses were performed to check for the robustness of the results.Among 19,887 reports of impulsivity, 5,898 recorded an antipsychotic, and 3,100 a dopamine agonist. The more robust signals concerned aripiprazole (N=3,091; median information component [95% confidence interval] = 4.51[4.45-4.55]) and brexpiprazole (229; 4.00[3.78-4.16]) for antipsychotics, pergolide (105; 5.82[5.50-6.06]) and pramipexole (2009; 5.43[5.36-5.48]) for dopamine agonists. Robust, significant positive associations between drug occupancy and impulsivity reporting were found for D3 within dopamine agonists (beta=1.52; p-value=0.047) and 5-HT1a within antipsychotics (1.92, 0.029).Our results supported the role of D3-receptor agonism in inducing impulsivity in dopamine receptor agonists and identified a potential role of 5-HT1a receptor agonism in antipsychotics. Investigating these receptors may drive towards a better management of drug-induced impulsivity. This article is protected by copyright. All rights reserved.

As chimeric antigen receptor T-cell therapies are becoming increasingly available in the armamentarium of the hematologist, there is an emerging need to monitor post-marketing safety.We aimed to better characterize their safety profile by focusing on cytokine release syndrome and identifying emerging signals.We queried the US Food and Drug Administration Adverse Event Reporting System (October 2017-September 2020) to analyze suspected adverse drug reactions to tisagenlecleucel (tisa-cel) and axicabtagene ciloleucel (axi-cel). Disproportionality analyses (reporting odds ratio) were performed by comparing chimeric antigen receptor T-cell therapies with (a) all other drugs (reference group 1) and (b) other onco-hematological drugs with a similar indication, irrespective of age (reference group 2), or (c) restricted to adults (reference group 3). Notoriety was assessed through package inserts and risk management plans. Adverse drug reaction time to onset and cytokine release syndrome features were investigated.Overall, 3225 reports (1793 axi-cel; 1433 tisa-cel) were identified. The reported toxicities were mainly: cytokine release syndrome (52.2%), febrile disorders (27.7%), and neurotoxicity (27.2%). Cytokine release syndrome and neurotoxicity were often co-reported and 75% of the events occurred in the first 10 days. Disproportionalities confirmed known adverse drug reactions and showed unexpected associations: for example, axi-cel with cardiomyopathies (reporting odds ratio = 2.3; 95% confidence interval 1.2-4.4) and gastrointestinal perforations (2.9; 1.2-7.3), tisa-cel with hepatotoxicity (2.5; 1.1-5.7) and pupil disorders (15.3; 6-39.1).Our study confirms the well-known adverse drug reactions and detects potentially emerging safety issues specific for each chimeric antigen receptor T-cell therapy, also providing insights into a stronger role for tisa-cel in inducing some immunodeficiency-related events (e.g., hypogammaglobulinemia, infections) and coagulopathies, and for axi-cel in neurotoxicity.

Aims: Impulse control disorders (ICDs) are iatrogenic and idiopathic conditions with psychosocial and economic consequences for the affected individuals and their families (e.g. bankruptcy and divorce). However, the definition of ICDs has changed over time, and ICDs are not consistently included within existing taxonomies. We discuss the origins of the ICD diagnostic construct and its unsolved tensions. Methods: To contextualize the ICD diagnostic construct, we provided an overview of its origins in past centuries and followed its development across multiple editions of the Diagnostic and Statistical Manual and the International Classification of Diseases, as well as its definition within emerging ontologies. Results: Two independent roots of the ICD construct emerged: (a) the interest in behavioral excess as expressed in encyclopedic compilations (18th century) and (b) the juridical debate on disruptive conduct and responsibility (19th–20th centuries). These roots underlie the repeated taxonomic remodeling observed throughout the 20th and 21st centuries and three critical issues persisting in both clinical practice and research. First, the number of ICDs keeps increasing across the spectrum of human behaviors, disregarding common pathogenetic and phenomenological grounds. Secondly, ICDs substantially overlap with other mental conditions. Impulsivity is often neglected as a minor inconvenience or side effect when co-occurring with major diagnoses (e.g. depression) and therefore inadequately managed. Finally, ICDs’ definitions display an unsolved tension between being conceived as hobby, moral fault or pathological drive, which may be responsible for stigma and delayed intervention. Conclusion: The reasons that made impulse control disorders (ICDs) difficult to define from their first conceptualization are the same reasons that now complicate taxonomic efforts and diagnosis. Tracing back ICDs’ roots and criticalities can help to define a common and less ambiguous theoretical framework, which may also result in the demise of the ICD construct and a move towards more clearly defined and more useful ontologies.

Pharmaceuticals can reach the environment at all stages of their lifecycle and accumulate in the ecosystem, potentially reaching toxic levels for animals and plants. In recent years, efforts have been made to map and control this hazard. Assessing country-specific environmental risks could drive regulatory actions towards eco-friendlier drug utilization and disposal practices. By starting from a list of 25 environmentally hazardous pharmaceuticals developed by Region Stockholm, we integrated eco-toxicological and 2019-2021 Italian drug utilization data to estimate the environmental impact of pharmaceuticals in Italy. We calculated the risk as the ratio between the predicted environmental concentration (PEC) and the predicted no-effect concentration (PNEC). We found a high risk for levonorgestrel, ciprofloxacin, amoxicillin, azithromycin, venlafaxine, sertraline and diclofenac and a moderate risk for ethinyloestradiol, oestradiol and clarithromycin. This analysis can be periodically performed to identify the pharmaceuticals with the highest risk for the environment and ascertain if containment measures should be implemented.

Following preterm birth, the immature kidney is exposed to several harmful conditions, with an increased risk of renal impairment. We aimed to assess urinary biomarkers of renal function in very preterm infants during early nephrotoxic treatments.Infants ≤32 weeks' gestation and ≤1500 g were enrolled in this observational prospective study. Urine samples were collected on day 1(T1), 2-4(T2), 5-7(T3), 8-10(T4), 11-13(T5). The following urinary biomarkers were determined: osteopontin (uOPN), epidermal growth factor (uEGF), neutrophil gelatinase-associated lipocalin (uNGAL), cystatin C (uCysC). The infants were grouped according to their exposure to amikacin or ibuprofen during the study period and a between-group comparison of urinary biomarkers at each time point was performed.Thirty-six infants were included. Urinary CysC, uOPN, and uNGAL rose significantly during ibuprofen or amikacin treatment, while no difference was observed for uEGF. After adjustment for possible influencing factors, amikacin administration was associated with higher uCysC at T1 (p = 0.007) and T2 (p = 0.016), whereas ibuprofen increased uOPN (p = 0.001) and uNGAL concentration (p = 0.009) at T3.Nephrotoxic therapies induce molecule-specific change patterns of renal function biomarkers in treated preterm infants. Serial assessments of these biomarkers may aid to identify neonates at risk of renal impairment and to develop tailored therapeutic approaches.Despite the wide use of nephrotoxic therapies in neonatal settings, little is known on their effect on renal function biomarkers in preterm infants. This study describes molecule-specific change patterns of urinary biomarkers during ibuprofen and amikacin administration, suggesting underlying pathophysiological effects on renal function. Given their low analytical costs and non-invasive collection, the urinary biomarkers investigated in this study represent a promising strategy for serial monitoring of renal function in at-risk neonates and may aid the early detection of renal function impairment at different kidney levels during nephrotoxic treatments.

In pregnancy, immune checkpoint pathways are involved in the maintenance of fetomaternal immune tolerance. Preclinical studies have shown that immune checkpoint inhibitors (ICIs) increase the risk of fetal death. Despite the fact that using ICIs in pregnant women and women of childbearing potential is not recommended, some case reports of ICI exposure in pregnancy have been published showing favorable fetal outcomes. This study aimed to gain further insight into ICI safety in pregnancy by querying VigiBase

Context Adrenal insufficiency (AI) is a life-threatening condition complicating heterogeneous disorders across various disciplines, with challenging diagnosis and a notable drug-induced component. Objective This work aimed to describe the spectrum of drug-induced AI through adverse drug event reports received by the US Food and Drug Administration (FDA). Methods A retrospective disproportionality analysis reporting trends of drug-induced AI was conducted on the FDA Adverse Event Reporting System (FAERS) (> 15 000 000 reports since 2004). AE reports were extracted from FAERS over the past 2 decades. Interventions included cases containing any of the preferred terms in the Medical Dictionary for Regulatory Activities describing AI, and signals of disproportionate reporting for drugs recorded in 10 or more cases as primary suspect. Results We identified 8496 cases of AI: 97.5% serious, 41.1% requiring hospitalization. AI showed an exponential increase throughout the years, with 5282 (62.2%) cases in 2015 to 2020. We identified 56 compounds associated with substantial disproportionality: glucocorticoids (N = 1971), monoclonal antibodies (N = 1644, of which N = 1330 were associated with immune checkpoint inhibitors—ICIs), hormone therapy (N = 291), anti-infectives (N = 252), drugs for hypercortisolism or adrenocortical cancer diagnosis/treatment (N = 169), and protein kinase inhibitors (N = 138). Cases of AI by glucocorticoids were stable in each 5-year period (22%-27%), whereas those by monoclonal antibodies, largely ICIs, peaked from 13% in 2010 to 2015 to 33% in 2015 to 2020. Conclusion We provide a comprehensive insight into the evolution of drug-induced AI, highlighting the heterogeneous spectrum of culprit drug classes and the emerging increased reporting of ICIs. We claim for the urgent identification of predictive factors for drug-induced AI, and the establishment of screening and educational protocols for patients and caregivers.

Amyotrophic lateral sclerosis is a fatal progressive disease with a still unclear multi-factorial etiology. This study focused on the potential relationship between drug exposure and the development of amyotrophic lateral sclerosis by performing a detailed analysis of events reported in the FDA Adverse Event Reporting System database.The FDA Adverse Event Reporting System quarterly data (January 2004-June 2020) were downloaded and deduplicated. The reporting odds ratios and their 95% confidence intervals were calculated as a disproportionality measure. The robustness of the disproportion was assessed accounting for major confounders (i.e., using a broader query, restricting to suspect drugs, and excluding reports with amyotrophic lateral sclerosis as an indication). Disproportionality signals were prioritized based on their consistency across analyses (reporting odds ratio stability).We retained 1188 amyotrophic lateral sclerosis cases. Sixty-two drugs showed significant disproportionality for amyotrophic lateral sclerosis onset in at least one analysis, and 31 had consistent reporting odds ratio stability, including tumor necrosis factor-alpha inhibitors and statins. Disproportionality signals from ustekinumab, an immunomodulator against interleukins 12-23 used in autoimmune diseases, and the anti-IgE omalizumab were consistent among analyses and unexpected.For each drug emerging as possibly associated with amyotrophic lateral sclerosis onset, biological plausibility, underlying disease, and reverse causality could be argued. Our findings strengthened the plausibility of a precipitating role of drugs primarily through immunomodulation (e.g., tumor necrosis factor-alpha, ustekinumab, and omalizumab), but also by impacting metabolism and the musculoskeletal integrity (e.g., statins and bisphosphonates). Complement and NF-kB dysregulation could represent interesting topics for planning translational mechanistic studies on amyotrophic lateral sclerosis as an adverse drug effect.

Importance: During the COVID-19 pandemic, urgent clinical management of patients has mainly included drugs currently administered for other diseases, referred to as repositioned drugs. As a result, some of these drugs have proved to be not only ineffective but also harmful because of adverse events associated with drug-drug interactions (DDIs). Objective: To identify DDIs that led to adverse clinical outcomes and/or adverse drug reactions in patients with COVID-19 by systematically reviewing the literature and assessing the value of drug interaction checkers in identifying such events. Evidence Review: After identification of the drugs used during the COVID-19 pandemic, the drug interaction checkers Drugs.com, COVID-19 Drug Interactions, LexiComp, Medscape, and WebMD were consulted to analyze theoretical DDI-associated adverse events in patients with COVID-19 from March 1, 2020, through February 28, 2022. A systematic literature review was performed by searching the databases PubMed, Scopus, and Cochrane for articles published from March 1, 2020, through February 28, 2022, to retrieve articles describing actual adverse events associated with DDIs. The drug interaction checkers were consulted again to evaluate their potential to assess such events. Findings: The DDIs identified in the reviewed articles involved 46 different drugs. In total, 575 DDIs for 58 drug pairs (305 associated with at least 1 adverse drug reaction) were reported. The drugs most involved in DDIs were lopinavir and ritonavir. Of the 6917 identified studies, 20 met the inclusion criteria. These studies, which enrolled 1297 patients overall, reported 115 DDI-related adverse events: 15 (26%) were identifiable by all tools analyzed, 29 (50%) were identifiable by at least 1 of them, and 14 (24%) remained nonidentifiable. Conclusions and Relevance: The main finding of this systematic review is that the use of drug interaction checkers could have identified several DDI-associated adverse drug reactions, including severe and life-threatening events. Both the interactions between the drugs used to treat COVID-19 and between the COVID-19 drugs and those already used by the patients should be evaluated..

Introduction: Sacubitril/valsartan is the first-in-class angiotensin-receptor neprilysin inhibitor approved in 2015 for the treatment of heart failure with reduced ejection fraction (HFrEF). On 16 February 2021, the Food and Drug Administration acknowledged that “Benefits are most clearly evident in patients with left ventricular ejection fraction below normal,” thus potentially extending the use in subjects with heart failure and preserved ejection fraction (HFpEF). Areas covered: The authors outline the regulatory history, pharmacokinetics, pharmacodynamics, and risk-benefit profile of sacubitril/valsartan in HFrEF and HFpEF. A critical cross-trial comparison is presented, including sodium-glucose cotransporter 2 inhibitors (SGLT2i), together with an insight into the latest European Society of Cardiology guidelines, where the new category of heart failure with mildly reduced ejection fraction is introduced. Expert opinion: Sacubitril/valsartan is a foundation of the pharmacological armamentarium in HFrEF to counteract the neuro-hormonal changes and reverse cardiac remodeling, together with beta-blockers, SGLT2i and mineralocorticoid receptor antagonists. The optimal sequence algorithm is an evolving issue, and the authors provide the reader with their personal perspective. A multidisciplinary management is encouraged to minimize the therapeutic inertia and manage tolerability issues, thus supporting adherence. Pragmatic trials, pharmacovigilance, and high-quality real-world evidence are crucial toward personalized safe prescribing of sacubitril/valsartan.

Background: Gam-COVID-Vac is the world's first registered vector vaccine against COVID-19 based on a combination of two heterologous adenoviruses. It was chosen by the Republic of San Marino as the main tool in its vaccination campaign, which started on 25 February 2021. Our aim was to build up on the ROCCA study, focused on the older population, by describing adverse effects following immunisation (AEFIs) rates and characteristics in all age groups for the first time in a real-world context. Methods: An active surveillance study on recipients of at least one dose of the Gam-COVID-Vac vaccine was conducted. Participants were administered online questionnaires through live/phone interviews with physicians, by e-mail or by scanning a QR code at different points in time after the first dose: one week (Q1) one month (Q2), and three months (Q3) between March and August 2021. Findings: Overall, 6190 vaccine recipients were recruited. Mean age was 52·4±18·2 years. After the first dose, systemic reactions were reported by 57·5% of the participants, while injection site reactions were reported by 46·7%. The most common AEFIs were pain at the injection site, fatigue and headache. Grade 3 or 4 AEFIs were reported by 0·8% and 0·3% of the participants, respectively. After the second dose, systemic reactions were reported by 63·1% of the participants, while injection site reactions by 54·7%. The most common AEFIs were malaise, pain at injection site and myalgia. Grade 3 or 4 AEFIs were reported by 2·7% and 1·1% of the participants, respectively. Multivariate analysis showed younger age, being a woman and food allergies are risk factors for more severe AEFIs. Interpretation: Our results confirm a good tolerability profile for the population aged 18 and over providing useful data for vaccination campaigns ongoing in countries planning to use Gam-COVID-Vac. Funding: None.

Background The dopaminergic partial agonism of the so-called third-generation antipsychotics (TGAs; aripiprazole, brexpiprazole, cariprazine) is hypothesized to cause impulse control disorders (ICDs). Relevant warnings by the Food and Drug Administration (FDA) were posted on aripiprazole (2016) and brexpiprazole (2018). Our study investigated the FDA Adverse Event Reporting System and the pharmacodynamic CHEMBL database to further characterize TGA-induced ICDs. Methods We downloaded and pre-processed the FDA Adverse Event Reporting System up to December 2020. We adapted Bradford Hill criteria to assess each TGA’s —and secondarily other antipsychotics’—causal role in inducing ICDs (pathological gambling, compulsive shopping, hyperphagia, hypersexuality), accounting for literature and disproportionality. ICD clinical features were analyzed, and their pathogenesis was investigated using receptor affinities. Results A total of 2708 reports of TGA-related ICDs were found, primarily recording aripiprazole (2545 reports, 94%) among the drugs, and gambling (2018 reports, 75%) among the events. Bradford-Hill criteria displayed evidence for a causal role of each TGA consistent across subpopulations and when correcting for biases. Significant disproportionalities also emerged for lurasidone with compulsive shopping, hyperphagia, and hypersexuality, and olanzapine and ziprasidone with hyperphagia. Time to onset varied between days and years, and positive dechallenge was observed in 20% of cases. Frequently, co-reported events were economic (50%), obsessive-compulsive (44%), and emotional conditions (34%). 5-Hydroxytryptamine receptor type 1a agonism emerged as an additional plausible pathogenetic mechanism. Conclusions We detected an association between TGAs and ICDs and identified a new signal for lurasidone. ICD characteristics are behavior specific and may heavily impact on life. The role of 5-Hydroxytryptamine receptor type 1a agonism should be further explored.

Background The development of anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors (TKIs) has improved the survival outcomes of patients with advanced ALK-rearranged non-small-cell lung cancer (NSCLC). The adverse events (AEs) related to ALK inhibitors are fairly well known; notably, about 20% of patients receiving lorlatinib experienced cognitive effects and behavioral alterations in pivotal trials. Therefore, psychiatric disorders could represent AEs of special interest for all ALK TKIs, deserving careful assessment in the post-marketing setting. Objective We conducted a real-world pharmacovigilance study on psychiatric AEs with marketed ALK inhibitors in subjects with advanced NSCLC. Patients and methods We performed an observational, retrospective analysis of spontaneous reports submitted to the Food and Drug Administration Adverse Events Reporting System (FAERS, as of December 2020), selecting psychiatric AEs to ALK TKIs approved in NSCLC (crizotinib, ceritinib, alectinib, brigatinib, lorlatinib). These AEs were independently scrutinized by three oncologists applying predefined exclusion criteria, described in terms of clinical/demographic features and assessed for drug-related causality according to an adaptation of the WHO–UMC system, a standardized probabilistic algorithm. Results Among 584 reported psychiatric AEs, 95 cases were selected as potentially treatment related, with higher reporting frequency for lorlatinib (26, 2.8%), followed by brigatinib (10, 1.2%), alectinib (18, 0.7%), ceritinib (12, 0.6%), and crizotinib (29, 0.3%). Reported psychiatric symptoms were mood disorders (39), psychotic disorders (24), and anxiety, agitation, and irritability (25). In the majority (74%) of cases, psychiatric AEs were serious and required hospitalization in about 32% of patients; 15.8% of retained cases were considered as highly probable and 69.5% as probable. Drug discontinuation was recorded in 31.6% of the reported cases, with the highest proportion for lorlatinib (65.4%). Conclusion Notwithstanding limitations, our study found a higher proportion of psychiatric AEs with lorlatinib, but also raised the hypothesis of psychiatric reactions as a class effect of ALK TKIs. Supplementary Information The online version contains supplementary material available at 10.1007/s11523-021-00865-8.

Background: We described clinical features of adrenal insufficiency (AI) reported with tyrosine kinase inhibitors (TKIs) targeting vascular endothelial growth factor receptor (VEGFR) in the Food and Drug Administration Adverse Event Reporting System (FAERS). Methods: Reports of AI recorded in FAERS (January 2004–March 2022) were identified through the high-level term “adrenal cortical hypofunctions”. Demographic and clinical features were inspected, and disproportionality signals were detected through the Reporting Odds Ratio (ROR) and Information Component (IC) with relevant 95% confidence/credibility interval (CI), using different comparators and adjusting the ROR for co-reported corticosteroids and immune checkpoint inhibitors (ICIs). Results: Out of 147,153 reports with VEGFR-TKIs, 314 cases of AI were retained, mostly of which were serious (97.1%; hospitalization recorded in 44.9%). In a combination regimen with ICIs (43% of cases), VEGFR-TKIs were discontinued in 52.2% of the cases (26% as monotherapy). The median time to onset was 72 days (IQR = 14–201; calculated for 189 cases). A robust disproportionality signal emerged, also in comparison with other anticancer drugs (ROR = 2.71, 95%CI = 2.42–3.04; IC = 0.25, 95%CI = 0.07–0.39). Cabozantinib, sunitinib and axitinib generated robust disproportionality even after ROR adjustment. Conclusions: We call pharmacologists, internists, oncologists and endocrinologists to raise awareness of serious AI with VEGFR-TKIs, and to develop dedicated guidelines, especially for combination regimens with immunotherapy.

Importance: Adrenal insufficiency is a life-threatening condition complicating heterogenous disorders across various disciplines, with challenging diagnosis and a notable drug-induced component. Objective To describe the spectrum and main features of drug-induced adrenal insufficiency through adverse drug event reports received by the Food and Drug Administration (FDA). Design: We conducted a retrospective disproportionality analysis within one of the largest publicly accessible spontaneous reporting system. Setting The FDA Adverse Event Reporting System (FAERS) collecting more than 15 million reports. Participants: Adverse event reports extracted from FAERS over the past 2 decades (2000-2020), with a focus on the 2015-2020 period. Main Outcomes and Measures: Descriptive statistics were used to assess the reporting trend of drug-induced adrenal insufficiency. Cases were selected if they contained any of the preferred terms in the Medical Dictionary for Regulatory Activities describing adrenal hypofunctions. We computed the reporting odds ratio (ROR) with relevant 95% confidence interval (CI) using Bonferroni correction to identify signals of disproportionate reporting for drugs recorded in at least 10 cases as primary suspect. Results We identified 8,496 cases (5,282 in the 2015-2020 period), 97.5% being serious and 41.1% requiring hospitalization. We identified 56 drugs (out of 164) associated with significant disproportionality within various pharmacological classes: glucocorticoids (N=1971, constant over time), monoclonal antibodies (1,330 out of 1,644 cases with immune checkpoint inhibitors, reaching 76% in 2020), hormone therapy (N=291), anti-infectives (N=252), drugs used for hypercortisolism or adrenocortical cancer diagnosis and/or treatment (N=169), protein kinase inhibitors (N=138). Conclusions and Relevance This comprehensive insight into the evolution of drug-induced adrenal insufficiency highlighted the heterogeneous spectrum of culprit drugs classes, including the consolidated role of topical and systemic corticosteroids and the emerging increased reporting of immune checkpoint inhibitors. Targeted screening and educational programs are needed to urgently identify predictive factors. Presentation: Saturday, June 11, 2022 1:00 p.m. - 3:00 p.m.