Effectiveness and safety profile of mepolizumab in chronic rhinosinusitis with nasal polyps: Real life data in a tertiary care.

BACKGROUND: Chronic rhinosinusitis with nasal polyps (CRSwNP) is characterized by a type 2 pattern of inflammation. Mepolizumab was approved for the treatment of CRSwNP in 2021, it may be useful to evaluate its safety profile in a real-world setting. AIM: This work aimed to prospectively highlight the effectiveness and safety profile of Mepolizumab in patients with CRSwNP enrolled in the Otorhinolaryngology Unit of the University Hospital of Messina. METHODS: An observational cohort study was carried out considering all patients treated with Mepolizumab. A descriptive analysis was conducted reporting all demographic characteristics, endoscopic evaluations, and symptom conditions. RESULTS: A total of 30 patients were treated with Mepolizumab, one patient discontinued the treatment. A statistically significant reduction in the Sino-Nasal Outcome Tests-22 (SNOT-22) and nasal polyp score (NPS) was shown at the 6th and 12th months compared to baseline values (SNOT-22, -33 and - 43, p < 0.001 for both comparisons; NPS, 0 and - 1, p < 0.001 for both comparisons). The median (Q1-Q3) sniffin' sticks test score increased from 7 (6-8) at the 6th month to 11 (10-13) at the 12th month. Seven patients (24.1 %) reported pain at the injection site, accompanied by redness, warmth, and tenderness within the first 24 h post-injection with a median duration of three days from the onset. CONCLUSIONS: Given the optimal treatment response and the minimal adverse effects observed, clinicians should consider Mepolizumab a safe and effective treatment in CRSwNP patients. Further studies in real-life setting are necessary to better understand the long-term effects.

Two Years of Active Pharmacovigilance Surveillance and Therapeutic Reconciliation in Frail Populations: The MEAP 3.0 Study.

Awareness related to the risk/benefit profile of therapies used in paediatric and elderly patients is limited. We carried out a study, called the MEAP 3.0 study, to collect and analyse evidence of adverse drug reactions (ADRs) and drug-drug interactions (DDIs) that occurred in frail populations under polypharmacy in a real-world setting. Data were retrieved from reports of ADRs and pharmacological counselling from patients treated in hospitals and territorial health services. We collected 2977 ADRs reports and identified 'anti-infectives for systemic use' and 'cardiovascular system' as the most frequently implicated pharmacological classes in under-18 and over-65 patients, respectively. We detected 2179 DDIs, of which 10.7% were related to at least one ADR: 22 were classified as 'contraindicated' (7 in the paediatric group and 15 in the elderly one), and 61 as 'major' (6 in the paediatric patients and 55 in the geriatric ones), while 151 DDIs were classified as 'moderate' (10 referred to paediatric population, and 109 to elderly patient) and as 'minor' (1 in paediatric patients, and 31 in the elderly ones). The MEAP 3.0 project demonstrates that pharmacovigilance surveillance and therapeutic reconciliation are valid strategies to avoid potential DDIs and the occurrence of ADRs, allowing for personalised medicine.

Neuropsychiatric adverse drug reactions with oral tyrosine kinase inhibitors in metastatic colorectal cancer: an analysis from the FDA Adverse Event Reporting System.

Introduction: New oral tyrosine kinase inhibitors (TKIs) are approved for metastatic colorectal cancer (mCRC). The aim of this study was to assess the neuropsychiatric adverse drug reactions (ADRs) of these drugs reported in the FDA Adverse Event Reporting System (FAERS) database. Methods: All reports with regorafenib (REG) and encorafenib (ENC) as the primary suspect, and reported in the FAERS between 2012 and 2022, were collected. A descriptive and disproportionality analyses were conducted. Results: Out of 4,984 cases, 1,357 (30.2%) reported at least one neuropsychiatric ADR. New potential signals for REG included neuropathy peripheral (n = 265; reporting odds ratio, ROR = 19.48, 95% confidence interval, CI 95% = 17.52-22.47; information component, IC = 2.89, IC025-IC075 = 2.77-3.02), hyperesthesia (n = 18; ROR = 12.56, CI 95% = 7.90-19.96; IC = 2.25, IC025-IC075 = 1.79-2.72), taste disorder (n = 41; ROR = 9.91, CI 95% = 7.29-13.49; IC = 2.18, IC025-IC075 = 1.88-2.49), poor quality sleep (n = 18; ROR = 6.56, CI 95% = 4.13-10.42; IC = 1.74, IC025-IC075 = 1.27-2.20), altered state of consciousness (n = 15; ROR = 5.50, CI 95% = 3.31-9.14; IC = 1.57, IC025-IC075 = 1.06-2.07), depressed mood (n = 13; ROR = 1.85, CI 95% = 1.07-3.19; IC = 0.58, IC025-IC075 = 0.04-1.13) and insomnia (n = 63; ROR = 1.48, CI 95% = 1.15-1.89; IC = 0.38, IC025-IC075 = 0.13-0.63). For ENC comprised depressed mood (n = 4; ROR = 5.75, CI 95% = 2.15-15.39; IC = 1.74, IC025-IC075 = 0.76-2.73) and cognitive disorders (n = 3; ROR = 4.71, CI 95% = 1.51-14.66; IC = 1.54, IC025-IC075 = 0.41-2.68). Discussion: This study identified new unknown potential neuropsychiatric ADRs. Further investigations are required to better define the neurotoxicity of TKIs in mCRC patients.

Renal Disorders with Oral Tyrosine Kinase Inhibitors in Metastatic Colorectal Cancer: An Analysis from the FDA Adverse Event Reporting System Database.

BACKGROUND: this study assessed the nephrotoxicity of regorafenib (REG) and encorafenib (ENC) in metastatic colorectal cancer (mCRC) through an analysis of reports from the US Food and Drug Administration's Adverse Event Reporting System (FAERS) database. METHODS: descriptive and disproportional analyses were performed for all reports using ENC and REG as the primary suspect. RESULTS: A total of 379 reports had at least one renal adverse drug reaction (ADR), and these ADRs were mainly related to REG (93.1%). Potential safety signals for REG included chromaturia (n = 44; ROR = 12.00, CI 95% = 8.92-16.16; IC = 2.36, IC025-IC075 = 2.06-2.66), hydronephrosis (10; 8.70, 4.67-16.19; 1.85, 1.23-2.47), nephrotic syndrome (7; 5.73, 2.73-12.03; 1.47, 0.73-2.21), renal impairment (53; 4.16, 3.17-5.45; 1.39, 1.12-1.66), dysuria (19; 3.06, 1.95-4.81; 1.06, 0.61-1.52), renal failure (38; 1.66, 1.20-2.28; 0.49, 0.17-0.81), and acute kidney injury (AKI) (43; 1.46, 1.08-1.97; 0.37, 0.07-0.67). For ENC, consistent disproportionalities were observed for AKI (n = 11; ROR = 3.79, CI 95% = 2.09-6.90; IC = 1.32, IC025-IC075 = 0.72-1.91) and dysuria (4; 6.50, 2.43-17.39; 1.86, 0.88-2.85). CONCLUSIONS: these findings highlight some not extensively reported renal ADRs that require further investigations to better characterize the safety profiles of REG and ENC in patients with mCRC.

Exploring low clozapine C/D ratios, inverted clozapine-norclozapine ratios and undetectable concentrations as measures of non-adherence in clozapine patients: A literature review and a case series of 17 patients from 3 studies.

BACKGROUND: Up to 1/2 of outpatients prescribed clozapine may be partially/fully non-adherent, based on therapeutic drug monitoring (TDM). Three indices for measuring partial/full non-adherence are proposed a: 1) clozapine concentration/dose (C/D) ratio which drops to half or more of what is expected in the patient; 2) clozapine/norclozapine ratio that becomes inverted; and 3) clozapine concentration that becomes non-detectable. METHODS: These 3 proposed indices are based on a literature review and 17 cases of possible non-adherence from 3 samples: 1) an inpatient study in a Chinese hospital, 2) an inpatient randomized clinical trial in a United States hospital, and 3) and a Uruguayan outpatient study. RESULTS: The first index of non-adherence is a clozapine C/D ratio which is less than half the ratio corresponding to the patient's specific ancestry group and sex-smoking subgroup. Knowing the minimum therapeutic dose of the patient based on repeated TDM makes it much easier to establish non-adherence. The second index is inverted clozapine/norclozapine ratios in the absence of alternative explanations. The third index is undetectable concentrations. By using half-lives, the chronology of the 3 indices of non-adherence was modeled in two patients: 1) the clozapine C/D ratio dropped to ≥1/2 of what is expected from the patient (around day 2); 2) the clozapine/norclozapine ratio became inverted (around day 3); and 3) the clozapine concentration became undetectable by the laboratory (around days 9-11). CONCLUSION: Prospective studies should further explore these proposed clozapine indices in average patients, poor metabolizers (3 presented) and ultrarapid metabolizers (2 presented).

Clozapine ultrarapid metabolism during weak induction probably exists but requires careful diagnosis. A literature review, five new cases and a proposed definition.

During weak induction (from smoking and/or valproate co-prescription), clozapine ultrarapid metabolizers (UMs) need very high daily doses to reach the minimum therapeutic concentration of 350 ng/ml in plasma; clozapine UMs need clozapine doses higher than: 1) 900 mg/day in patients of European/African ancestry, or 2) 600 mg/day in those of Asian ancestry. Published clozapine UMs include 10 males of European/African ancestry, mainly assessed with single concentrations. Five new clozapine UMs (two of European and three of Asian ancestry) with repeated assessments are described. A US double-blind randomized trial included a 32-year-old male smoking two packages/day with a minimum therapeutic dose of 1,591 mg/day from a single TDM during open treatment of 900 mg/day. In a Turkish inpatient study, a 30-year-old male smoker was a possible clozapine UM needing a minimum therapeutic dose of 1,029 mg/day estimated from two trough steady-state concentrations on 600 mg/day. In a Chinese study, three possible clozapine UMs (all male smokers) were identified. The clozapine minimum therapeutic dose estimated with trough steady-state concentrations >150 ng/ml was: 1) 625 mg/day, based on a mean of 20 concentrations in Case 3; 2) 673 mg/day, based on a mean of 4 concentrations in Case 4; and 3) 648 mg/day, based on a mean of 11 concentrations in Case 5. Based on these limited studies, clozapine UMs during weak induction may account for 1-2% of clozapine-treated patients of European ancestry and <1% of those of Asian ancestry. A clozapine-to-norclozapine ratio <0.5 should not be used to identify clozapine UMs.

Effectiveness and Safety Profile of Dupilumab in Chronic Rhinosinusitis with Nasal Polyps: Real-Life Data in Tertiary Care.

Chronic rhinosinusitis with nasal polyps (CRSwNP) is characterized by a type 2 pattern of inflammation resulting in the production of some cytokines. Dupilumab radically changes the treatment of CRSwNP, but, considering its recent approval, it may be useful to evaluate its safety profile in a real-world setting. This work aimed to prospectively highlight the effectiveness and safety profile of dupilumab in patients with CRSwNP enrolled in the Otorhinolaryngology Unit of the University Hospital of Messina. An observational cohort study was carried out considering all patients treated with dupilumab. A descriptive analysis was conducted reporting all demographic characteristics, endoscopic evaluations, and symptom conditions. A total of 66 patients were treated with dupilumab, but three patients were excluded due to a lack of adherence during the observational period. A statistically significant reduction in the Sino-Nasal Outcome Test 22 (SNOT-22) and nasal polyps score (NPS) was shown at the 6th and 12th months compared to baseline values (SNOT-22, -37 and -50, p < 0.001 for both comparisons; NPS, -3 and -4, p < 0.001 for both comparisons). During the follow-up, eight patients (12.7%) had a reaction at the site of injection, and seven (11.1%) had transient hypereosinophilia. Given the optimal treatment response and the minimal adverse effects observed, clinicians should consider dupilumab a safe and effective treatment. Further studies are necessary to better understand the long-term effects.

Neuropsychiatric Adverse Drug Reactions with Tyrosine Kinase Inhibitors in Gastrointestinal Stromal Tumors: An Analysis from the European Spontaneous Adverse Event Reporting System.

Tyrosine kinase inhibitors (TKIs) are widely used in gastrointestinal stromal tumors (GISTs). The aim of this study is to evaluate the reporting frequency of neuropsychiatric adverse drug reactions (ADRs) for TKIs through the analysis of European individual case safety reports (ICSRs). All ICSRs collected in EudraVigilance up to 31 December 2021 with one TKI having GISTs as an indication (imatinib (IM), sunitinib (SU), avapritinib (AVA), regorafenib (REG), and ripretinib (RIP)) were included. A disproportionality analysis was performed to assess the frequency of reporting for each TKI compared to all other TKIs. The number of analyzed ICSRs was 8512, of which 57.9% were related to IM. Neuropsychiatric ADRs were reported at least once in 1511 ICSRs (17.8%). A higher reporting probability of neuropsychiatric ADRs was shown for AVA. Most neuropsychiatric ADRs were known, except for a higher frequency of lumbar spinal cord and nerve root disorders (reporting odds ratio, ROR 4.46; confidence interval, CI 95% 1.58-12.54), olfactory nerve disorders (8.02; 2.44-26.33), and hallucinations (22.96; 8.45-62.36) for AVA. The analyses of European ICSRs largely confirmed the safety profiles of TKIs in GISTs, but some ADRs are worthy of discussion. Further studies are needed to increase the knowledge of the neuropsychiatric disorders of newly approved TKIs.

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

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

Effectiveness and Safety Profiles of Biological Therapies in Inflammatory Bowel Disease: Real Life Data from an Active Pharmacovigilance Project.

Post-marketing surveillance is essential to evaluate the risk/benefit profile of drugs; however, pharmacovigilance studies comparing persistence and safety of biologic therapies in patients with inflammatory bowel disease (IBD) are scant. The aim of this study was to prospectively investigate persistence together with safety profiles of biologics in a cohort of patients diagnosed with Crohn's Disease (CD) or ulcerative colitis (UC) followed by the IBD unit of Messina and treated with infliximab (IFX), adalimumab (ADA), golimumab (GOL), vedolizumab (VED), and ustekinumab (UST) from 2017 through 2021. Descriptive and treatment persistence analyses with predictors for discontinuation and occurrence of adverse drug reactions (ADRs) were performed. A total of 675 IBD patients were enrolled. A higher persistence rate was noted for UST and ADA in the first year (83.8% and 83.1%, respectively) and for IFX in the fifth year of treatment (58.1%). GOL, VED, and UST-all used as second/third-line therapies-seemed to have a higher risk of non-persistence than IFX (in order HR: 2.19; CI 95%: 1.33-3.61, 1.45; 1.04-2.04, 2.25; 1.25-4.07) as well as switchers and those who had at least one ADR (18.1; 13.22-24.68 and 1.55; 1.20-1.99, respectively). The reported ADRs, which were generally mild-moderate, were largely known. However, real-world data should be implemented to further study undetected safety concerns, including risk of malignancy.

Biosimilars in Pediatric Inflammatory Bowel Diseases: A Systematic Review and Real Life-Based Evidence.

Background: Many pediatric inflammatory bowel disease (IBD) patients are now using biosimilars of anti-tumor necrosis factor-α (TNF-α), with increasing trends in recent years. This study reviewed all available data regarding the use of biosimilars in children with IBD. Methods: PubMed, Google Scholar, Scopus, and CENTRAL databases were searched through keywords; inflammatory bowel diseases, Crohn's disease, ulcerative colitis, biosimilar and child were combined using "AND" and "OR." Original research articles involving pediatric patients receiving one of the biosimilar medications based on the anti-TNF-α biologic drugs approved for pediatric IBD treatment, independently from efficacy and drug response, were included. Results: Nine studies were included in the evidence synthesis. CT-P13 was the biosimilar used in all studies. Four studies assessed the induction effectiveness of CT-P13. Clinical response and remission rates of biosimilar treatment were 86-90% and 67-68%, respectively, and they were not significantly different to the originator group. Five prospective studies on patients elected to switch from originator IFX to CT-P13 yielded similar results. Adverse events related to CT-P13 were mostly mild. The most frequently reported were upper respiratory tract infections. The switch from the originator had no significant impact on immunogenicity. Conclusion: The current review showed reported CT-P13 effectiveness as measured by clinical response and/or remission rates after induction or during maintenance and suggest that there is no significant difference with that of the originator IFX. Further studies are warranted, including clinical, and pharmacovigilance studies.

Pharmacokinetic drug interactions with oral haloperidol in adults: dose correction factors from a combined weighted analysis.

INTRODUCTION: Pharmacokinetic (PK) drug-drug interactions (DDIs) of oral haloperidol, a first-generation antipsychotic, are systematically reviewed. AREAS COVERED: After exclusions, the search for DDIs with oral haloperidol provided 47 articles as victim and 7 as perpetrator. Changes in mean haloperidol concentration-to-dose (C/D) ratios after weighting each study's size were used to calculate the effects of other drugs (inhibitors/inducers) on haloperidol. These changes of haloperidol C/D ratio were used to estimate dose-correction factors (<1 for inhibitors and >1 for inducers). EXPERT OPINION: A box summarizes our recommendations for clinicians regarding our current knowledge of haloperidol PK DDIs, which will need to be updated as new information becomes available. Moderate to strong inducers (carbamazepine, phenobarbital, phenytoin, or rifampin) should be avoided since they required dose-correction factors of 2-5. Smoking appeared to be a weak inducer (dose-correction factor 1.2). Fluvoxamine, promethazine, and combinations of CYP3A4 and CYP2D6 inhibitors should be avoided. There are no long-term studies on fluoxetine to provide a dose correction factor. Limited information suggests that valproate may be an inhibitor (dose-correction factor 0.6). In most patients, haloperidol may not have clinically relevant effects as a perpetrator, but in vitro and clinical studies suggest it is a weak CYP2D6 inhibitor.

Adverse Drug Reactions with Drugs Used in Multiple Sclerosis: An Analysis from the Italian Pharmacovigilance Database.

Given the importance of inflammation at the onset of multiple sclerosis (MS), therapy is mainly based on the use of anti-inflammatory drugs including disease modifying therapies (DMTs). Considering the recent approval of some DMTs, pharmacovigilance becomes a fundamental tool for the acquisition of new safety data. The aim of the study was to analyze adverse drug reactions (ADRs) related to the use of drugs approved for MS. All national publicly-available aggregated ADR reports recorded from 2002 to 2020 into the Reports of Adverse Reactions of Medicines (RAM) system and all complete Sicilian data reported into the Italian spontaneous reporting system (SRS) database having as suspected drugs interferon ß-1a (IFN ß-1a), interferon ß-1b (IFN ß-1b), peginterferon ß-1a (PEG-IFN ß-1a), glatiramer acetate (GA), natalizumab (NTZ), fingolimod (FNG), teriflunomide (TRF), dimethyl fumarate (DMF), alemtuzumab (Alem), ocrelizumab (OCZ), or cladribine (Cladr), were collected. Descriptive analyses of national, publicly-available aggregated data and full-access regional data were performed to assess demographic characteristics and drug-related variables followed by a more in-depth analysis of all Sicilian ADRs with a case-by-case assessment and a disproportionality analysis of unexpected ADRs. A total of 13,880 national reports have been collected from 2002 to 2020: they were mainly not serious ADRs (67.9% vs. 26.1%) and related to females (71.7% vs. 26.3%) in the age group 18-65 years (76.5%). The most reported ADRs were general and administration site conditions (n = 6,565; 47.3%), followed by nervous (n = 3,090; 22.3%), skin (n = 2,763; 19.9%) and blood disorders (n = 2,180; 15.7%). Some unexpected Sicilian ADRs were shown, including dyslipidemia for FNG (n = 10; ROR 28.5, CI 14.3-59.6), NTZ (n = 5; 10.3, 4.1-25.8), and IFN ß-1a (n = 4; 8.7, 3.1-24.1), abortion and alopecia for NTZ (n = 9; 208.1, 73.4-590.1; n = 3; 4.9, 1.5-15.7), and vitamin D deficiency for GA (n = 3; 121.2, 30.9-475.3). Moreover, breast cancer with DMF (n = 4, 62.8, 20.5-191.9) and hypothyroidism with Cladr (n = 3; 89.2, 25.9-307.5) were also unexpected. The reporting of drugs-related ADRs in MS were mostly reported in the literature, but some unknown ADRs were also found. However, further studies are necessary to increase the awareness about the safety profiles of new drugs on the market.

Adverse Drug Reactions with HER2-Positive Breast Cancer Treatment: An Analysis from the Italian Pharmacovigilance Database.

BACKGROUND: Anti-HER2 therapy has evolved in the last years and an important role in this transformation was that of monoclonal antibodies and tyrosine kinase inhibitors. Considering their extended use in clinical practice, some toxicity problems have been highlighted around these drugs. OBJECTIVE: To analyze the onset of adverse drug reactions (ADRs) related to the use of HER2-positive breast cancer treatments through a spontaneous reporting system (SRS) database. METHODS: All ADR reports having as suspected drug trastuzumab, pertuzumab, lapatinib, or trastuzumab emtansine (TDM-1), recorded into the Report Reazioni Avverse dei Medicinali (RAM) system database for national data and into the Italian SRS database for Sicilian data and collected from 2006 to 2020 have been evaluated. A descriptive analysis of basal demographic and drug-related characteristics was performed. A case-by-case methodology was conducted paying particular attention to the serious ADR reports collected in Sicily, focusing on type of seriousness, age, sex, concomitant drugs, comorbidities, time to onset (TTO), and time to resolution (TTR). RESULTS: Of the 3609 Italian reports, 65.6% were related to trastuzumab (n = 2367), followed by pertuzumab, TDM-1, and lapatinib. Almost all reports occurred in female patients (94.3%) and were most frequent in the age group 18-65 years (69.6%). A higher number of cases were related to general disorders and administration site conditions (n = 1079; 29.9%), gastrointestinal disorders (n = 1037; 28.7%), skin disorders (n = 821; 22.7%), and blood disorders (n = 599; 16.6%). Cases involving trastuzumab and pertuzumab mainly reported general disorders (n = 788; 33.3% and n = 194; 32.1%, respectively) while more than half of the reports associated with lapatinib were related to gastrointestinal (n = 184; 59.7%) and skin diseases (n = 146; 47.4%). Regarding TDM-1, 40% of reports had at least one ADR belonging to blood and lymphatic system disorders. The case-by-case assessment of Sicilian ADR reports showed that 40 cases were serious (33.3%), with a median TTO of 37 (6-97) days. Serious ADR reports mainly involved the onset of thrombocytopenia (n = 8; 20.0%), diarrhea (n = 6; 15.0%), asthenia and cardiac failure (both with n = 5; 12.5%), vomiting, hypersensitivity, and ejection fraction decreased (all with n = 4; 10.0%) and stomatitis (n = 3: 7.5%). CONCLUSION: This study is fundamentally consistent with results from the literature. Given the serious clinical condition of breast cancer and taking into account the importance of preventing some clinically relevant ADRs related to the use of anti-HER2 therapy, further analyses are essential to better describe the safety profile of these target therapies.

European Whites May Need Lower Minimum Therapeutic Clozapine Doses Than Those Customarily Proposed.

PURPOSE/BACKGROUND: A nomogram from a British naturalistic study proposed that the clozapine dosing needed to reach a serum concentration of 350 ng/mL ranged from 265 mg/d (female nonsmokers) to 525 mg/d (male smokers). Some European reviews have used these dosing recommendations, which seem greater than what we found in an Italian White sample ranging from 245 mg/d (female nonsmokers) to 299 mg/d (male smokers). Five other published samples of European Whites were added to the Italian sample to estimate clozapine doses recommended for reaching 350 ng/mL. METHODS/PROCEDURES: Average clozapine metabolizers were obtained by eliminating outliers with confounding variables: (1) psychiatric inducers and inhibitors; (2) doses less than 100 mg/d; and (3) when possible, patients with inflammation, obesity, or using oral contraceptives. The study included 1363 average metabolizer European Whites: the Italian sample and 5 new samples. Mean averages that reached serum concentration levels of 350 ng/mL were calculated after stratification by sex and smoking status in each sample. Then, weighted mean averages were obtained by combining the 6 samples. FINDINGS/RESULTS: The estimated weighted mean clozapine dosages ranged from 236 to 368 mg/d (236 mg/d in 218 female nonsmokers, 256 mg/d in 340 male nonsmokers, 357 mg/d in 269 female smokers, and 368 mg/d in 546 male smokers). IMPLICATIONS/CONCLUSIONS: Our recommended dosages are less than those recommended in Europe. Future studies in European Whites need to replicate these recommended doses for average metabolizer patients after sex and smoking stratification and further explore clozapine dosing for those with relevant clinical confounders.

Safety profile of immune checkpoint inhibitors: An analysis of the Italian spontaneous reporting system database.

AIMS: To provide an overview of immune checkpoint inhibitors (ICIs) safety profile using the Italian spontaneous adverse drug reaction (ADR) reporting system. METHODS: We selected all ADR reports attributed to ipilimumab (CTLA-4 inhibitor), nivolumab, pembrolizumab, atezolizumab (PD-1/PD-L1 inhibitors) from the Italian spontaneous reporting system (2011-2018). Descriptive analyses of reports for ICIs have been conducted. Time to onset of adverse effects was stratified by system organ class. Reporting odds ratio was used as measure of ADR reporting disproportionality. ICI-related ADR reports were compared with 2 reference groups, i.e. all other suspected drugs or all other antineoplastic agents. RESULTS: Overall, 2217 (0.7%) reports were related to ICIs (nivolumab: 72.2% of those reports; ipilimumab: 14.3%; pembrolizumab: 10.3%; and atezolizumab: 3.5%). ICI-related ADR reports mostly involved males (65%) and median age was 67 (interquartile range 59-73) years. Serious reports accounted for 48.8%. Frequencies of endocrine, general, hepatobiliary, metabolism, musculoskeletal, respiratory disorders, infections and neoplasms were significantly higher for ICIs than for all other drugs (P < .001). Except for infections, similar results emerged through comparison with other anticancer drugs. Colitis, hypophysitis and skin disorders were more frequently reported for anti-CTLA-4 drugs than PD-1/PD-L1 ICIs, and the opposite for musculoskeletal effects, pneumonia, and thyroid dysfunctions. ICIs were disproportionally associated also with less known risks, e.g. ischaemic heart disease, cardiac failure and optic nerve disorders. CONCLUSION: The most frequently reported safety issues were probably immune-related adverse events including general, gastrointestinal and respiratory disorders. Potentially emerging safety signals, such as ischaemic heart disease and cardiac failure, requiring further investigation were detected.

Safety Profile of Biologics Used in Rheumatology: An Italian Prospective Pharmacovigilance Study.

Post-marketing surveillance activities are essential to detect the risk/benefit profile of biologic disease-modifying antirheumatic drugs (bDMARDs) in inflammatory arthritis. The aim of this study was to evaluate adverse events (AEs) in patients treated with bDMARDs in rheumatology during a prospective pharmacovigilance study from 2016 to 2018. Descriptive statistical analyses were performed to evaluate bDMARDs-related variables of patients without AEs/failures vs patients with AEs and failures. The risk profile among biologics was assessed by comparing patients treated with each bDMARD to patients treated with etanercept. A total of 1155 patients were enrolled, mostly affected by rheumatoid arthritis (46.0%). AEs and failures were experienced by 8.7% and 23.3%, respectively. The number of comorbidities significantly influenced the onset of AEs, while anxiety-depressive, gastrointestinal disease, and fibromyalgia influenced onset of failures. The probability of developing an AE was significantly lower in patients treated with secukinumab, while the probability of developing treatment failure was significantly lower in patients treated with golimumab, secukinumab and tocilizumab. A total of 216 AEs were reported (25.5% serious), mostly regarding infections (21.8%), musculoskeletal (17.6%) and skin (16.2%) disorders. Serious AEs included neutropenia (12.7%), lymphocytosis (9.1%) and uveitis (7.3%). The obtained results revealed known AEs but real-world data should be endorsed for undetected safety concerns.

Real-world use of biological drugs in patients with psoriasis/psoriatic arthritis: a retrospective, population-based study of years 2010-2014 from Southern Italy.

BACKGROUND: Biological drugs, such as infliximab, etanercept, adalimumab, ustekinumab, golimumab and certolizumab are third-line therapy for psoriasis (PsO) and psoriatic arthritis (PsA), but they may be used at earlier stage in severe forms. This study investigated the pattern of use and costs of biological drugs for PsO/PsA in a large population from Southern Italy during the years 2010-2014. METHODS: This was a retrospective, population-based, drug-utilization study, using healthcare administrative databases of the ASL (Local Health Unit) and two hospitals of Messina Province (Sicily) in the years 2010-2014. Incident users of adalimumab, ustekinumab, infliximab, etanercept and golimumab for PsO/PsA were characterized. Yearly prevalence of use and costs, as well as time to treatment discontinuation and switch were assessed. RESULTS: During the study period, 517 patients received at least one study drugs prescription for PsO/PsA and 304 (58.8%) were incident users, mostly treated with adalimumab (33.6%). Incident users were mostly males (59.8%), with a median age of 49 years. The prevalence of biological drugs users in PsO/PsA increased from 4.3 to 6.9 per 10,000 inhabitants from 2011 to 2014. Pharmaceutical expenditure of the study drugs almost doubled (from 2.6 to 4.7 million euros over 5 years of observation). During the first year of treatment, discontinuation occurred in 31.8% of incident users and switch was not infrequent (7.4%). CONCLUSIONS: Prevalence of use and costs of biological drugs for PsO/PsA substantially increased in recent years in a large population of Southern Italy. Larger uptake of lowest cost biological drugs, and biosimilars whenever available, may help access to the most innovative drugs.

Duloxetine in Psychiatric Disorders: Expansions Beyond Major Depression and Generalized Anxiety Disorder.

Background: Duloxetine hydrochloride (DUL) is an antidepressant included in the pharmacological class of serotonin-norepinephrine reuptake inhibitors approved for the treatment of major depressive disorder, generalized anxiety disorder, diabetic peripheral neuropathic pain, fibromyalgia, and chronic musculoskeletal pain. The aim of this review was to elucidate current evidences on the use of DUL in the treatment of a variety of psychiatric disorders. Methods: This systematic review was conducted according to PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines. PubMed database was searched from January 1, 2003, to September 30, 2018, using 11 key terms related to psychiatric disorders ("persistent depressive disorder," "dysthymic disorder," "bipolar disorder," "seasonal affective disorder," "obsessive-compulsive disorder," "social phobia," "panic disorder," "posttraumatic stress disorder," "schizophrenia," "eating disorders," "sexual disorders," "personality disorders") and one key term related to duloxetine ("duloxetine hydrochloride"). Article titles and abstracts were scanned to determine relevance to the topic. For additional studies, the authors also examined the reference lists of several of the included papers. Results: Duloxetine may be an effective treatment for mood spectrum disorders, panic disorder, several symptom clusters of borderline personality, and as add-on drug in schizophrenia. Modest or conflicting results have been found for the efficacy of duloxetine in obsessive-compulsive disorder, posttraumatic stress disorder, eating, and sexual disorders. Conclusion: Major limitations of the reviewed studies were short trial duration, small sample sizes, and the lack of control groups. Defining the potential role of DUL in the treatment of psychiatric disorders other than major depressive disorder and generalized anxiety disorder needs further randomized, placebo-controlled studies.

Characterization and preventability of adverse drug events as cause of emergency department visits: a prospective 1-year observational study.

BACKGROUND: Adverse drug events (ADEs) are a significant cause of emergency department (ED) visits, with a major impact on healthcare resource utilization. A multicentre observational study, aimed to describe frequency, seriousness and preventability of ADEs reported in four EDs, was performed in Sicily (Italy) over a 1-year period. METHODS: Two trained monitors for each ED supported clinicians in identifying ADEs of patients admitted to EDs between June 1st, 2013 and May 31st, 2014 through a systematic interview of patients or their caregivers and with an additional record review. A research team analyzed each case of suspected ADE, to make a causality assessment applying the Naranjo algorithm and a preventability assessment using Schumock and Thornton criteria. Absolute and percentage frequencies with 95% confidence interval (CI) and medians with interquartile ranges (IQR) were estimated. Logistic regression models were used to evaluate independent predictors of serious and certainly preventable ADEs. RESULTS: Out of 16,963 ED visits, 575 (3.4%) were associated to ADEs, of which 15.1% resulted in hospitalization. ADEs were classified as probable in 45.9%, possible in 51.7% and definite in 2.4% of the cases. Moreover, ADEs were considered certainly preventable in 12.3%, probably preventable in 58.4%, and not preventable in 29.2% of the cases. Polytherapy influenced the risk to experience a serious, as well as a certainly preventable ADE. Whilst, older age resulted an independent predictor only of serious events. The most common implicated drug classes were antibiotics (34.4%) and anti-inflammatory drugs (22.6%). ADEs due to psycholeptics and antiepileptics resulted preventable in 62.7 and 54.5% of the cases, respectively. Allergic reactions (64%) were the most frequent cause of ADE-related ED visits, followed by neurological effects (10.2%) that resulted preventable in 1.9 and 37.3% of the cases, respectively. CONCLUSION: ADEs are a frequent cause of ED visits. The commonly used antibiotics and anti-inflammatory drugs should be carefully managed, as they are widely involved in mild to severe ADEs. Polytherapy is associated with the occurrence of serious, as well as certainly preventable ADEs, while older age only with serious events. A greater sensitivity to drug monitoring programs among health professionals is needed.