Package Insert Research Articles

Brodalumab: 5-Year US Pharmacovigilance Report

Brodalumab: 5-Year US Pharmacovigilance Report

Review of drug-drug interactions in patients with prostate cancer.

The objective of this review is to provide an overview of common drug-drug interactions (DDIs) associated with prostate cancer treatments and outline recommendations for managing polypharmacy. A literature search of PubMed, Embase, and CINAHL was carried out to identify pharmacokinetic and pharmacodynamic changes caused by DDIs that are relevant for prostate cancer patients, DDIs between prostate cancer therapies and co-administered medications (both prescription and over-the-counter), and measures to prevent DDIs. Medication package inserts were used to identify the impact of DDI on the prostate cancer therapy and suggested interventions. No DDIs are expected for the LHRH agonists leuprolide acetate, histrelin, goserelin, or leuprolide mesylate. However, DDIs have been reported for GnRH antagonists, anti-androgens, PARP inhibitors, and taxanes. Although there are no confirmed DDIs for sipuleucel-T to date, it is not generally recommended to use sipuleucel-T concurrently with immunosuppressive medications. Interventions to prevent DDIs include the use of software that can detect clinically significant DDIs, up-to-date medication reconciliation, the inclusion of dedicated clinical pharmacists in cancer treatment teams, and patient/caregiver education. Prostate cancer patients have a high risk of potential DDIs due to numerous new anti-cancer therapies, the increased use of treatment combinations, and the likelihood of comorbid conditions also requiring drug therapy. Drug-drug interaction screening software, up-to-date medication reconciliation, inclusion of oncology pharmacists on healthcare teams, and patient/caregiver education will aid the development of treatment plans that focus on achieving an optimal risk-benefit profile whilst reducing the risk of DDIs.

Rapid Initiation of Injection Naltrexone for Opioid Use Disorder

Injectable extended-release (XR)-naltrexone is an effective treatment option for opioid use disorder (OUD), but the need to withdraw patients from opioid treatment prior to initiation is a barrier to implementation. To compare the effectiveness of the standard procedure (SP) with the rapid procedure (RP) for XR-naltrexone initiation. The Surmounting Withdrawal to Initiate Fast Treatment with Naltrexone study was an optimized stepped-wedge cluster randomized trial conducted at 6 community-based inpatient addiction treatment units. Units using the SP were randomly assigned at 14-week intervals to implement the RP. Participants admitted with OUD received the procedure the unit was delivering at the time of their admission. Participant recruitment took place between March 16, 2021, and July 18, 2022. The last visit was September 21, 2022. Standard procedure, based on the XR-naltrexone package insert (approximately 5-day buprenorphine taper followed by a 7- to 10-day opioid-free period and RP, defined as 1 day of buprenorphine at minimum necessary dose, 1 opioid-free day, and ascending low doses of oral naltrexone and adjunctive medications (eg, clonidine, clonazepam, antiemetics) for opioid withdrawal. Receipt of XR-naltrexone injection prior to inpatient discharge (primary outcome). Secondary outcomes included opioid withdrawal scores and targeted safety events and serious adverse events. All analyses were intention-to-treat. A total of 415 participants with OUD were enrolled (mean [SD] age, 33.6 [8.48] years; 205 [49.4%] identified sex as male); 54 [13.0%] individuals identified as Black, 91 [21.9%] as Hispanic, 290 [69.9%] as White, and 22 [5.3%] as multiracial. Rates of successful initiation of XR-naltrexone among the RP group (141 of 225 [62.7%]) were noninferior to those of the SP group (68 of 190 [35.8%]) (odds ratio [OR], 3.60; 95% CI, 2.12-6.10). Withdrawal did not differ significantly between conditions (proportion of days with a moderate or greater maximum Clinical Opiate Withdrawal Scale score (>12) for RP vs SP: OR, 1.25; 95% CI, 0.62-2.50). Targeted safety events (RP: 12 [5.3%]; SP: 4 [2.1%]) and serious adverse events (RP: 15 [6.7%]; SP: 3 [1.6%]) were infrequent but occurred more often with RP than SP. In this trial, the RP of XR-naltrexone initiation was noninferior to the standard approach and saved time, although it required more intensive medical management and safety monitoring. The results of this trial suggest that rapid initiation could make XR-naltrexone a more viable treatment for patients with OUD. ClinicalTrials.gov Identifier: NCT04762537.

Implementing a shared decision-making intervention to support treatment decisions for patients following an anterior cruciate ligament rupture — a protocol for the POP-ACLR feasibility study

BackgroundTreatment for anterior cruciate ligament (ACL) rupture may follow a surgical or nonsurgical pathway. At present, there is uncertainty around treatment choice. Two shared decision-making tools have been codesigned to support patients to make a decision about treatment following an ACL rupture. The shared decision-making tools include a patient information leaflet and an option grid. We report the protocol for a mixed-methods feasibility study, with nested qualitative interviews, to understand feasibility, acceptability, indicators of effectiveness and implementation factors of these shared decision-making tools (combined to form one shared decision-making intervention).MethodsA single-centre non-randomised feasibility study will be conducted with 20 patients. Patients diagnosed with an ACL rupture following magnetic resonance imaging will be identified from an orthopaedic clinic. The shared decision-making intervention will be delivered during a clinical consultation with a physiotherapist. The primary feasibility outcomes include the following: recruitment rate, fidelity, acceptability and follow-up questionnaire completion. The secondary outcome is the satisfaction with decision scale. The nested qualitative interview will explore experience of using the shared decision-making intervention to understand acceptability, implementation factors and areas for further refinement.DiscussionThis study will determine the feasibility of using a newly developed shared decision-making intervention designed to support patients to make a decision about treatment of their ACL rupture. The acceptability and indicators of effectiveness will also be explored. In the long term, the shared decision-making intervention may improve service and patient outcomes and ensure cost-effectiveness for the NHS; ensuring those most likely to benefit from surgical treatment proceed along this pathway.Trial registrationPending registration on ISRCTN.

Establishing hemolysis, icterus, and lipemia interference limits for body fluid chemistry analytes measured on the Roche cobas instrument.

The aims of this study were to (1) establish the maximum allowable interference limits for hemolysis, lipemia, and icterus for chemistry analytes tested in body fluid samples and (2) assess the effectiveness of serial dilution to mitigate spectral interferences. Residual body fluids from clinically ordered testing were mixed (<10% by volume) with stock solutions of interferent (spiked) and compared with a control spiked with an equal volume of 0.9% saline. The analytes were measured on the Roche cobas c501 instrument. Difference and percentage difference were calculated and compared with allowable total error limits. A subset of samples were serially diluted with 0.9% saline. Mean (SD) difference and percentage difference were calculated. The interference thresholds were lower than the package insert for lactate dehydrogenase, cholesterol, triglycerides, and total protein for hemolysis; amylase, cholesterol, and total protein for icterus; and albumin for lipemia. Only cholesterol and triglyceride results returned to baseline upon dilution of icteric samples. Interference thresholds in body fluids were lower than blood for 6 analytes. Diluting interferences that surpass these limits does not produce reliable results that are comparable to the baseline results before spiking in the interferent.

Application of intranasal dexmedetomidine in magnetic resonance imaging of preterm infants: The ED50, efficacy and safety analysis.

Infants undergoing magnetic resonance imaging (MRI) often require pharmacological sedation. Dexmedetomidine serves as a novel sedative agent that induces a unique unconsciousness similar to natural sleep, and therefore has currently been used as the first choice for sedation in infants and young children. To determine the 50% effective dose (ED50) and 95% confidence interval (95%CI) of intranasal dexmedetomidine for MRI in preterm and term infants, and to observe the incidence of adverse events. To explore whether there were differences in ED50 and 95%CI, heart rate (HR) and blood oxygen saturation (SpO2), the induction time and wake-up time and the incidence of adverse events between the 2 groups, so as to provide guidance for clinical safe medication for the meanwhile. A total of 68 infants were prospectively recruited for MRI examination under drug sedation (1 week ≤ age ≤ 23 weeks or weight ≤ 5kg). The children were divided into 2 groups according to whether they had preterm birth experience (Preterm group, Atterm group). The Dixon up-and-down method was used to explore ED50. The basic vital signs of the 2 groups were recorded, and the heart rate and SpO2 were recorded every 5 minutes until the infants were discharged from the hospital. The induction time, wake-up time and adverse events were recorded. The ED50 (95%CI) of intranasal dexmedetomidine in the Preterm group and the Atterm group were 2.23 (2.03-2.66) μg/kg and 2.64 (2.49-2.83) μg/kg, respectively (P < .05). the wake-up time was longer in Preterm group (98.00min) than in Atterm group (81.00 min) (P < .05), the incidence of bradycardia in Preterm group was 3/33, which was higher than that in Atterm group (1/35). There was no difference in the induction time between the 2 groups (P > .05), and there was no significant difference in other adverse events. Intranasal dexmedetomidine can be safely used for sedation in preterm infants undergoing MRI. Compared with term infants, preterm infants have a lower dose of dexmedetomidine, a higher incidence of bradycardia, and a longer weak-up time.

Status and trends of legislative and regulatory regulation of off-label use of drugs: A review

The off-label use of drugs is a common practice worldwide. The legal basis for off-label medical use varies from country to country. Regulatory control of the pharmaceutical market in the off-label preventive and therapeutic practice at the international and national levels has become a breakthrough with the emergence of the coronavirus pandemic. The prospects for off-label use in the context of innovations in the legislation of public health in the Russian Federation are crucial. Professionally significant aspects of the use of medicinal products outside the Summary of Product Characteristics and the off-label use have been introduced by supranational regulatory authorities for the common market of medicinal products of the Eurasian Economic Union. Special attention should be paid to the regulatory control of the use of extemporaneous medicines as part of improving the government regulation of drug compounding in pharmacies. The active development of pharmacy activities in drug compounding within the framework of improving regulatory practice determines the relevance of actual off-label prescriptions and the use of extemporaneous formulations. Aim – to perform a systematic analysis of national, transnational legislative and regulatory documents regulating off-label use of medicinal products, determine the main conceptual components of the current regulatory pool and directions for future development in this area. Systematic analysis of the national legislative and regulatory pool of documents and the regulatory framework of the common market of medicinal products of the Eurasian Economic Union on the regulation of various aspects of the off-label use of medicinal products. Study of the components and identification of the main trends in the regulatory practice of prescriptions outside the Summary of Product Characteristics and the off-label use. An analytical search was carried out in the reference legal systems "ConsultantPlus" and "Garant" on the official websites of the Ministry of Health of Russia, the Eurasian Economic Union, the RusMed information resource of the National Library resource of Russia in medicine and pharmacy "Central Scientific Medical Library" was used. A logical generalization of the results on the current state of the legal framework and the development of conceptual proposals on the key directions of the prospective development of regulation, control, and supervisory activities of the pharmaceutical off-label use of medicinal products was made.

Abstract PO5-14-11: Leveraging a pharmacokinetic/pharmacodynamic (PK/PD) model to guide dose optimization of palbociclib (palbo) in combination with vepdegestrant

Abstract Background: Vepdegestrant is a potent, selective, orally bioavailable PROteolysis TArgeting Chimeric (PROTAC) estrogen receptor (ER) degrader. A phase 3 study will evaluate the combination of vepdegestrant and palbo in participants with ER+, human epidermal growth factor receptor negative (HER2[-]) advanced/metastatic breast cancer (NCT05909397). The recommended starting dose of palbo is 125 mg once daily for 3 weeks followed by 1 week off treatment for each 28-day cycle in combination with aromatase inhibitors or fulvestrant.1 Neutropenia is the most frequently reported adverse event for patients receiving palbo in clinical trials.1 When co-administered with vepdegestrant in a phase 1b cohort of the first-in-human phase 1/2 study (NCT04072952), higher rates of medically manageable neutropenia and increased palbo concentrations were observed compared with historical studies of palbo administered with letrozole or fulvestrant.1 Reduced starting doses of palbo (100 mg, 75 mg) are planned to mitigate increased rates of Grade 4 neutropenia while maintaining similar palbo exposure when combined with vepdegestrant. The analysis objective was to leverage a PK/PD model to simulate palbo exposure and neutropenia taking into consideration the dose modification and management for hematologic toxicities provided in the palbo prescribing information.1 Methods: A Monte-Carlo simulation platform2 was utilized to monitor absolute neutrophil count (ANC) in 1000 patients with weekly monitoring over 4 cycles (112 days) of palbo administration. Simulated ANC was determined using a semi-mechanistic model of chemotherapy-induced myelosuppression as previously described.3 Palbo dose modification methods included both dose hold and reduction based on an individual’s ANC and thresholds for Grade 3 (&amp;lt; 1000 mm3) or Grade 4 (&amp;lt; 500 mm3) neutropenia. Simulated neutropenia and exposures from palbo starting doses of 100 mg and 75 mg in the presence of a 25%, 49%, and 67% increase in typical exposure were compared to a palbo starting dose of 125 mg in the absence of increased exposure (historical reference). Average concentration is calculated as the cumulative area under the curve divided by the simulation duration. Results: After a 4-cycle simulation, the 100 mg starting dose of palbo simulated across varying levels of increased exposure resulted in similar Grade 4 neutropenia incidence and average concentration compared to the reference simulation (&amp;lt; 12% difference). The 75 mg starting dose of palbo simulated across varying levels of increased exposure resulted in lower Grade 4 neutropenia incidence as well as lower average concentration compared to the reference simulation (Table 1). Conclusion: The PK/PD model simulation allows for relative comparison of Grade 4 neutropenia incidence and average palbo concentration between the planned reduced starting doses of palbo in the context of increased exposure relative to standard palbo dosing, i.e., without vepdegestrant. This simulation indicates a reduced dose of palbo (100 mg) in combination with vepdegestrant produces similar incidence of Grade 4 neutropenia and comparable average palbo concentration compared to historical reference providing additional support for the study lead-in of NCT05909397. Citations: 1. IBRANCE® (Palbociclib) [Package Insert]. New York, US: Pfizer, Inc. 2. Jermain et al. ACOP13 2023. 3. Friberg et al. J Clin Oncol 2002. Table 1. 4-cycle simulation results comparing reduced starting doses of palbociclib in the presence of increased typical exposure to a reference standard palbociclib dosing in the absence of increased exposure Citation Format: Brian Jermain, Derek Yang, Weiwei Tan, Julia Perkins-Smith, Justin Hoffman, Jason Williams. Leveraging a pharmacokinetic/pharmacodynamic (PK/PD) model to guide dose optimization of palbociclib (palbo) in combination with vepdegestrant [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO5-14-11.

Incidence of port site complications in relation to timing of bevacizumab infusion.

Bevacizumab is a monoclonal antibody that targets vascular endothelial growth factor, with a serious complication of wound healing complications. The package insert currently does not have recommendations on the management of bevacizumab administration around minor procedures, including port placements. Currently, there are only two trials that have examined the optimal timing of bevacizumab after port placement. This is a single-center retrospective trial aiming to evaluate the rate of wound dehiscence and other port site complications depending on the time between port placement and bevacizumab infusion. Eligible patients who have had at least one port place and have received bevacizumab for an oncologic indication were identified in a study period of 1/1/2016-3/31/2021. The primary outcome of this study was the incidence of wound dehiscence in relation to the timing of bevacizumab infusion. A total of 243 patients met the inclusion criteria, and 116 port placements had a port site complication. For wound dehiscence, 6% was observed 0 days from port placement, 10% was observed 1 day from port placement, 0% was observed 2 days from port placement, 0% was observed 3-7 days from port placement, 3% was observed 8-14 days from port placement, and 3% was observed 15-30 days from port placement. The results of this study show an inverse relationship between the risk of wound dehiscence and port site complication and the timing of bevacizumab infusion to port placement, with an increase in absolute risk of wound dehiscence when bevacizumab is given within 2 days of port placement.

A survey of community pharmacy customers’ use and views of patient information leaflets for medicines in paper and electronic formats

Abstract Introduction Paper patient information leaflets (PILs) are currently required to accompany licensed medicines in the European Union. As paper PILs fail to meet the needs of many end-users,[1] their routine use at the current extent remains questionable – especially with sustainability in mind.[2] With the growing scope of electronic product information (ePI) for medicines, there is a clear need for greater end-user input to inform future paper PIL and ePI usage. Aim To explore community pharmacy customers’ (CPCs’) use and views of paper PILs, their views on ePI, and to examine whether CPCs’ characteristics influence these parameters. Methods A survey was conducted amongst a convenience sample of CPCs (aged ≥18 years) recruited from eleven Irish community pharmacies across 4 weeks in November and December 2022. Respondents were recruited via the primary researcher, pharmacy staff, or by following a quick response (QR) code on a poster in the pharmacy. Descriptive and inferential statistics (including chi-squared tests) were used to analyse the data, whereby p&amp;lt;0.05 meant statistically significant differences. Results There were 226 valid responses (58.7% female and 41.3% male; 29.2% using ≥5 regular prescription medicines). The mean age was 49 years, with 38% aged &amp;lt;45 years and 23% aged ≥65 years. Only 26.1% indicated that they ‘always’ read the paper PIL when they start on a new medicine, whilst 15% said it was difficult or very difficult to read the paper PIL. When asked about reading the paper PIL other than the first time, 24.8% reported that they never read the PIL again. Approximately three-quarters agreed it would be okay if paper PILs were only provided to them on the first time they received a medicine (74.8%). Half of respondents had used the internet to check information about their medicines (50.9%). Approximately one quarter (25.7%) reported that they had accessed the official electronic PIL online previously, whilst 61.1% did not know that the official PILs for all licensed medicines are available freely on the internet for people in Ireland. Older adults (≥65 years) reported lower levels of confidence in using the internet and were less likely to use it for obtaining medicines information (p&amp;lt;0.05). Compared to those in older age categories (45-64 years, ≥65 years), younger respondents (&amp;lt;45 years) were significantly more likely to prefer using an electronic device to read the PIL in its electronic format instead of in its current paper format (69.3% versus 29.7%, p&amp;lt;0.05). Conclusion This study has highlighted that greater consideration is needed for the extent of paper PIL usage for medicines in future. These findings indicate a high level of wastage that is exacerbating the medicines-related carbon footprint globally, and emphasise the need for more sustainable strategies to communicate medicines information. While this study’s sample size was small, it comprised views ranging from younger people on no regular medicines to older people with polypharmacy. There is a clear need to raise awareness on ePI availability and to focus greater attention on older people and those less technologically competent when designing ePI going forward.

A survey of community pharmacists’ and healthcare advisors’ views and experiences on the provision of a Test and Treat Service for uncomplicated lower urinary tract infection in a retail pharmacy chain in Ireland

Abstract Introduction The use of Point of Care Testing (POCT) as an aid to guide antibiotic prescribing has been highlighted in Ireland’s second One Health National Action Plan on Antimicrobial Resistance 2021-2025 (iNAP2).[1] The role of community pharmacy is expanding with the introduction of antimicrobial stewardship (AMS) POCT strategies. Uncomplicated urinary tract infections (UTIs) are frequent and burdensome in the community. With antibiotic resistance on the rise amongst uropathogens, AMS efforts to reduce inappropriate antibiotic prescribing for urinary symptoms are paramount. Aim To evaluate community pharmacy staff views and experiences on the provision of a Cystitis Test-and-Treat Service for uncomplicated UTIs, while identifying opportunities for service improvement and expansion. Methods An electronic survey on Microsoft® Forms was distributed within a large retail pharmacy chain in Ireland during November 2021, with two reminders issued. Pharmacists and Healthcare advisors over the age of 18, working in 88 pharmacies that provided the Velieve Cystitis Test-and-Treat Service were eligible to participate. The survey was subdivided into participant demographics, local UTI information, views and experiences of participants on the Cystitis Test-and-Treat Service, the patient information leaflet and the training completed by pharmacy staff providing the service and included open-ended and closed-ended or Likert-scale questions. The survey was developed based on the literature and was revised following the contributions of pharmacy chain pharmacists and its Research Governance Committee who have a working knowledge of Service. Data were analysed using Microsoft® Excel and IBM® SPSS® statistics version 28.0. Qualitative data from the open-ended survey questions were analysed using thematic analysis. Results A total of 43 pharmacy staff (18 pharmacists and 25 healthcare advisors) participated in the study (overall participation rate of 10.2%). The majority of participants were female (83.7%) and most pharmacies were located in a town/suburb area (55.8%). The majority of participants (76.7%) estimated that service users with symptoms suggestive of UTI present to the pharmacy first, before visiting their GP. Participants believed that the Cystitis Test-and-Treat Service improved service user satisfaction in symptom management, reduced antimicrobial prescribing, alongside reduced general practitioner workload. High acceptability was attributed to the speed and convenience of the service, while time cost and time required explaining the service were identified as barriers. The associated smartphone application was identified as a service weakness. Participants recommended extended training on service user eligibility with perhaps training videos to improve overall confidence. While the low response rate and small sample size is a limitation of this study, the inclusion of participants from two differing pharmacy roles strengths the findings. Conclusion This study highlights that POCT are feasible AMS initiatives that enhance management of uncomplicated UTI and could be incorporated into community pharmacy practice. The perceived ‘poor public awareness of the service’ reported by the participants, suggests the need for increased promotion and advertising.

P006 A new digital front door for existing rheumatology patient queries

Abstract Background/Aims NICE guidelines recommend people with rheumatological conditions need rapid access to specialist care to manage flares and to advise on medication. With growing demand for NHS services, rheumatology advice lines are coming under pressure. We carried out an audit on our advice line queries over four clinics in summer 2021 with a view to developing a triaging system to improve response time. Over four advice line clinics, there were 44 calls averaging 13 minutes per call. The response time was two to three weeks. 34% of calls were deemed to be inappropriate. Inappropriate calls were considered ones that could be better directed elsewhere. Methods In 2022 we started working with DrDoctor, a digital health company to design a digital nurse advice line form to redirect inappropriate calls away from the nurse advice line call backs. This involved designing a digital pathway addressing common inappropriate themes from our audit including redirection of calls to secretaries, patient booking team, prescription management and a digital booking form for phlebotomy appointments. The new digital tool enabled us to expand the service and we used the opportunity to adopt patient assessment tools and educational videos as part of the service. We promoted the digital pathway through patient information leaflets, department website and sent a text with the link to all rheumatology patients. We continued to offer the traditional contact telephone number into the service as well. Results The digital nurse advice line went live at the end of July 2023 and after two months the response time has reduced to 1.5- 2 weeks. Since then there have been 529 form submissions from 417 unique patients. 47% of submissions were inappropriate and redirected. 97 patients called to book a blood test and 76 patients opted for the online self-service clinic. 151 patients had a query about their condition. 50% of patient had RA or inflammatory arthritis. 5% AS. 5% SLE. 17% PsA. 23% selected ‘other’ and a free text box captured conditions such as fibromyalgia, osteoporosis, PMR and OA. 26% of patients with rheumatoid arthritis opted to see the educational video on self-examination and 17% watched the educational video on rheumatoid arthritis. Based on 251 submissions that were inappropriate for the advice line, assuming each inappropriate call takes an average of nine minutes based from our previous audit, 39 hours of phone time was saved from avoiding booking inappropriate nurse advice line appointments in two months. Conclusion The digital rheumatology advice service is an efficient and effective method of responding to patient queries and can be a source of patient education and self assessment. Informal patient and staff feedback has been positive and we will be collecting formal feedback as the service becomes more established. Disclosure K. Nadesalingam: None. C. Short: None. K. Christian: None. P. Helliwell: None.

Factor Analysis of Patients Who Find Tablets or Capsules Difficult to Swallow Due to Their Large Size: Using the Personal Health Record Infrastructure of Electronic Medication Notebooks.

Understanding patient preference regarding taking tablet or capsule formulations plays a pivotal role in treatment efficacy and adherence. Therefore, these preferences should be taken into account when designing formulations and prescriptions. This study investigates the factors affecting patient preference in patients who have difficulties swallowing large tablets or capsules and aims to identify appropriate sizes for tablets and capsules. A robust data set was developed based on a questionnaire survey conducted from December 1, 2022, to December 7, 2022, using the harmo smartphone app operated by harmo Co, Ltd. The data set included patient input regarding their tablet and capsule preferences, personal health records (including dispensing history), and drug formulation information (available from package inserts). Based on the medication formulation information, 6 indices were set for each of the tablets or capsules that were considered difficult to swallow owing to their large size and concomitant tablets or capsules (used as controls). Receiver operating characteristic (ROC) analysis was used to evaluate the performance of each index. The index demonstrating the highest area under the curve of the ROC was selected as the best index to determine the tablet or capsule size that leads to swallowing difficulties. From the generated ROCs, the point with the highest discriminative performance that maximized the Youden index was identified, and the optimal threshold for each index was calculated. Multivariate logistic regression analysis was performed to identify the risk factors contributing to difficulty in swallowing oversized tablets or capsules. Additionally, decision tree analysis was performed to estimate the combined risk from several factors, using risk factors that were significant in the multivariate logistic regression analysis. This study analyzed 147 large tablets or capsules and 624 control tablets or capsules. The "long diameter + short diameter + thickness" index (with a 21.5 mm threshold) was identified as the best indicator for causing swallowing difficulties in patients. The multivariate logistic regression analysis (including 132 patients with swallowing difficulties and 1283 patients without) results identified the following contributory risk factors: aged <50 years (odds ratio [OR] 1.59, 95% CI 1.03-2.44), female (OR 2.54, 95% CI 1.70-3.78), dysphagia (OR 3.54, 95% CI 2.22-5.65), and taking large tablets or capsules (OR 9.74, 95% CI 5.19-18.29). The decision tree analysis results suggested an elevated risk of swallowing difficulties for patients with taking large tablets or capsules. This study identified the most appropriate index and threshold for indicating that a given tablet or capsule size will cause swallowing difficulties, as well as the contributory risk factors. Although some sampling biases (eg, only including smartphone users) may exist, our results can guide the design of patient-friendly formulations and prescriptions, promoting better medication adherence.

Automated radiolabelling of [68Ga]Ga-PSMA-11 (gallium (68Ga)-gozetotide) using the Locametz® kit and two generators

BackgroundSteps have been taken by pharmaceutical companies to obtain marketing authorisation of PSMA ligands in the European Union. Since December 2022, Locametz® (PSMA-11, gozetotide) is licensed as kit for manual radiolabelling with gallium-68 and commercially available since mid-2023. The Summary of Product Characteristic (SmPC) describes manual radiolabelling with a maximum activity after radiolabelling of 1369 MBq. We aimed for radiolabelling with a higher activity to increase production efficiency, and thus, automated radiolabelling is strongly preferred over manual radiolabelling to reduce radiation exposure to personnel. The aim of this study was to develop and validate a method for automated radiolabelling of the Locametz® kit using ~ 2000 MBq of gallium-68 eluate for radiolabelling.ResultsAutomated radiolabelling of [68Ga]Ga-PSMA-11 using the Locametz® kit provided a product which complies to the Ph. Eur., had a shelf-life of 6 h at room temperature, and theoretically reduced radiation exposure 5.7 times. Radiolabelling with one and two generator(s) resulted in a radiochemical yield of 91–102% and 96–101% after preparation, respectively. The radiochemical purity ranged from 98.0 to 99.6% for radiolabelling with one generator and ranged from 98.4 to 99.3% for radiolabelling with two generators with similar stability. The activity of the final product was much higher when using two generators, 1961–2035 MBq compared to 740–1260 MBq, which leads to ~ 1.5 times more patient syringes available per preparation.ConclusionAutomated radiolabelling of [68Ga]Ga-PSMA-11 using the Locametz® kit with higher gallium-68 activity than specified in the SmPC results in a product that is in compliance with the Ph. Eur. monograph and has a shelf-life of 6 h at room temperature. Radiolabelling with two generators proved possible and resulted in a product with similar quality but with much higher efficiency.

ShennongMGS: An LLM-based Chinese Medication Guidance System

ShennongMGS: An LLM-based Chinese Medication Guidance System

Increased risk of hypocalcemia with decreased kidney function in patients prescribed bisphosphonates based on real-world data from the MID-NET® in Japan: a new-user cohort study.

In the post-marketing stage, cases of hypocalcemia associated with bisphosphonate preparations (BPs) have been reported in patients with decreased kidney function, despite warning against use of BPs in such patients in the package insert (PI) of Japan. The purpose of this study was to investigate the safety of BPs in patients with decreased kidney function. The cohort study was conducted in patients with osteoporosis and newly prescribed bisphosphonate utilizing real-world data from MID-NET® in Japan. The adjusted hazard ratios (aHRs) for hypocalcemia (a corrected serum Ca level < 8.00mg/dL) relative to the normal group were calculated in each decreased kidney function group (mild, moderate or severe group). A total of 14,551 patients were included in the analysis, comprising 2,601 (17.88%) with normal (eGFR ≥ 90mL/min/1.73m2), 7,613 (52.32%) with mild (60 ≤ eGFR < 90mL/min/1.73m2), 3,919 (26.93%) with moderate (30 ≤ eGFR < 60mL/min/1.73m2), and 418 (2.87%) with severe kidney function (eGFR < 30mL/min/1.73m2). The aHRs (95% confidence interval) for hypocalcemia were 1.85 (0.75-4.57), 2.30 (0.86-6.21), and 22.74 (8.37-61.78) in the mild, moderate, and severe groups, respectively. The increased risk of hypocalcemia depending on kidney function was also observed even when calculating the aHR for each specific BP such as alendronate sodium hydrate, minodronic acid hydrate, and sodium risedronate hydrate. Furthermore, similar results were obtained in the sensitivity analysis by altering the outcome definition to a 20% or more reduction in corrected serum Ca level from the baseline, as well as when focusing on patients with more than one laboratory test result per 30days during the follow-up period. These findings suggest that the risk of hypocalcemia during BP prescription is higher in patients with decreased kidney function, particularly those with severely decreased kidney function. The quantitative real-world evidence on the safety risk of BPs obtained in this study has led to the PI revision describing a relationship between hypocalcemia risk and decreased kidney function as a regulatory action in Japan and will contribute to promoting the proper use of BPs with appropriate risk management in clinical practice.

Preventive and Therapeutic Effects of Crocetin in Rats with Heart Failure.

Gardenia is both a food and medicine plant. It is widely used for cardiovascular protection, and its main bioactive ingredient is crocetin. This study aims to observe the therapeutic effects of crocetin on chronic heart failure in rats induced by various etiologies. It further compares the efficacy differences between preventative and treatment administration, varying dosages, and treatment durations, to provide improved guidance for medication in heart failure rats and determine which categories of chronic heart failure rats might benefit most from crocetin. Chronic heart failure models induced by abdominal aorta constriction, renal hypertension, and coronary artery ligation were constructed. By examining cardiac function, blood biochemistry, and histopathology, the study assessed the preventive and therapeutic effects of crocetin on load-induced and myocardial ischemia-induced heart failure. The results showed that in all three models, both treatment and preventative administration of crocetin significantly improved chronic heart failure in rats, especially in preventative administration. The results indicate crocetin may be beneficial for improving symptoms and functional capacity in rats with heart failure. Furthermore, long-term administration was more effective than short-term administration across all three rat models, with therapeutic onset observed over 6 weeks.

Osteoporosis, Osteoarthritis, and Subchondral Insufficiency Fracture: Recent Insights.

The increased incidence of osteoarthritis (OA), particularly knee and hip OA, and osteoporosis (OP), owing to population aging, have escalated the medical expense burden. Osteoarthritis is more prevalent in older women, and the involvement of subchondral bone fragility spotlights its association with OP. Notably, subchondral insufficiency fracture (SIF) may represent a more pronounced condition of OA pathophysiology. This review summarizes the relationship between OA and OP, incorporating recent insights into SIF. Progressive SIF leads to joint collapse and secondary OA and is associated with OP. Furthermore, the thinning and fragility of subchondral bone in early-stage OA suggest that SIF may be a subtype of OA (osteoporosis-related OA, OPOA) characterized by significant subchondral bone damage. The high bone mineral density observed in OA may be overestimated due to osteophytes and sclerosis and can potentially contribute to OPOA. The incidence of OPOA is expected to increase along with population aging. Therefore, prioritizing OP screening, early interventions for patients with early-stage OA, and fracture prevention measures such as rehabilitation, fracture liaison services, nutritional management, and medication guidance are essential.

A disproportionality analysis of FDA adverse event reporting system (FAERS) events for ticagrelor.

Ticagrelor is a commonly used antiplatelet agent, but due to the stringent criteria for trial population inclusion and the limited sample size, its safety profile has not been fully elucidated. We utilized OpenVigil 2.1 to query the FDA Adverse Event Reporting System database and retrieved reports by the generic name "ticagrelor" published between 1 October 2010 and 31 March 2023. Adverse drug events (ADEs) were classified and described according to the preferred terms and system organ classes in the Medical Dictionary of Regulatory Activity. Proportional reporting ratio (PRR), reporting odds ratio (ROR) and Bayesian Confidence Propagation Neural Network (BCPNN) were used to detect signals. The number of ADE reports with ticagrelor as the primary suspect drug was 12,909. The top three ADEs were dyspnea [1824 reports, ROR 7.34, PRR 6.45, information component (IC) 2.68], chest pain (458 reports, ROR 5.43, PRR 5.27, IC 2.39), and vascular stent thrombosis (406 reports, ROR 409.53, PRR 396.68, IC 8.02). The highest ROR, 630.24, was found for "vascular stent occlusion". Cardiac arrest (137 reports, ROR 3.41, PRR 3.39, IC 1.75), atrial fibrillation (99 reports, ROR 2.05, PRR 2.04, IC 1.03), asphyxia (101 reports, ROR 23.60, PRR 23.43, IC 4.51), and rhabdomyolysis (57 reports, ROR 2.75, PRR 2.75, IC 1.45) were suspected new adverse events of ticagrelor. The FAERS database produced potential signals associated with ticagrelor that have not been recorded in the package inserts, such as cardiac arrest, atrial fibrillation, asphyxia, and rhabdomyolysis. Further clinical surveillance is needed to quantify and validate potential hazards associated with ticagrelor-related adverse events.

Evaluation of modified fixed dose four-factor prothrombin complex concentrate for warfarin reversal.

Non-activated four-factor prothrombin complex concentrate (4F-PCC) has emerged as the preferred reversal strategy for patients on warfarin with life-threatening bleeding. Current dosing recommendations for 4F-PCC require pre-treatment international normalized ratio (INR) and bodyweight values, resulting in ordering and administration delays. Studies have shown that alternative dosing regimens are safe and efficacious. This retrospective, single-center, pre- and post-protocol analysis was conducted to assess the efficacy of a pharmacist driven modified fixed-dose 4F-PCC regimen versus package insert weight- and INR-based dosing regimen for warfarin reversal. The primary outcome was achievement of INR less than two. Secondary outcomes included dose and cost of 4F-PCC, a time analysis, incidence of concomitant vitamin K administration, and incidence of thrombosis within seven days of 4F-PCC. There were 195 patients included in the analysis, with 74 in the pre-cohort and 121 in the post-cohort. Baseline characteristics were similar between cohorts with the most common indication for warfarin use being atrial fibrillation (48.6% versus 47.1%) and reversal being intracerebral hemorrhage (68.9% versus 43.0%). Achievement of the primary endpoint occurred in 92% versus 95% (p = 0.097) of patients. A statistically significant difference was seen between cohorts regarding median dose and cost of 4F-PCC administered (p < 0.001). Eleven thromboembolic events occurred with three events in the pre-cohort and eight events in the post-cohort (p = 0.453). A fixed-dose of 1500IU of 4F-PCC was effective in reversing INR to less than two in most patients regardless of reversal indication with minimal thrombotic risks.