Off-label Drug Research Articles

Off‑label and unapproved pediatric drug utilization: A meta‑analysis.

Despite legislative enforcement on authorized drugs, off-label and unapproved pediatric drug use is prevalent. The present study aimed to assess the global prevalence of off-label and unlicensed prescriptions among hospitalized children via meta-analysis. A comprehensive examination of articles published between 1990 and 2023 from the PubMed, Scopus, Excerpta Medica Database, Web of Science and Google Scholar databases was conducted. Key word-based advanced searches were executed using the aforementioned databases. A total of 45 studies that reported the prescriptions of off-label and unlicensed drugs to pediatric patients were included. The global prevalence of off-label and unlicensed drug prescriptions to children in pediatrics or neonatal departments was 56%. Patient sample sizes varied from 40-13,426, with a range of 240-8,891 total prescriptions issued. Of the 45 studies examined, 22 studies originated from Europe, 13 from Asia, 3 from South America, 3 from Africa, and 2 each from North America and Australia. Africa had the highest prevalence rate at 66%, followed by Asia, South America, North America, Australia and Europe. The present meta-analysis demonstrated that the prevalence of off-label and unlicensed drug prescriptions given to pediatric patients was notably high and geographically diverse. Therefore, drug authorities should standardize pediatric prescription practices in future.

Adverse events associated with azithromycin and clarithromycin in adults aged ≥65: a disproportionality analysis of the FDA Adverse Event Reporting System (FAERS) database

ABSTRACT Background Azithromycin and clarithromycin are commonly used to treat community-acquired pneumonia in adults aged ≥ 65, such as mycoplasma pneumonia. This study aims to evaluate adverse events (AEs) associated with azithromycin and clarithromycin in this age group by analyzing the FDA Adverse Event Reporting System (FAERS), providing insights for clinical use and management of AEs in this population. Research design and methods We retrieved reports of AEs related to azithromycin and clarithromycin from the FAERS database. Disproportionality analysis was conducted using the Reporting Odds Ratio (ROR), Proportional Reporting Ratio (PRR), Bayesian Confidence Propagation Neural Network (BCPNN), and Multi-Gamma Poisson Shrinkage (MGPS) to identify AEs associated with azithromycin and clarithromycin in adults aged ≥ 65. Results A total of 2,019 adverse event reports were retrieved for azithromycin, and 2,392 for clarithromycin. Off-label use (n = 349) and drug interactions (n = 487) were the most reported AEs in adults aged ≥ 65 for azithromycin and clarithromycin, respectively. Prolonged QT interval showed the strongest signal among AEs for azithromycin in this age group. Drug interaction-related medication errors had the strongest signal for clarithromycin. Seven signals not explicitly included in the azithromycin package insert were identified in adults aged ≥ 65. Fourteen signals not explicitly included in the clarithromycin package insert were identified. Conclusions Among adults aged ≥ 65, cardiac-related adverse events are more closely associated with azithromycin than with clarithromycin. Conversely, AEs related to drug interactions and psychiatric symptoms are more associated with clarithromycin. Additionally, clinicians should be vigilant regarding AEs not specified in the package inserts. The findings of this study may help optimize the selection of azithromycin and clarithromycin based on patient circumstances and assist clinicians in focusing on relevant AEs for early intervention.

The Innate Immune Landscape of dMMR/MSI Cancers Predicts the Outcome of Nivolumab Treatment: Results from the Drug Rediscovery Protocol.

The treatment efficacy of nivolumab was evaluated in patients with advanced, treatment-refractory solid mismatch repair deficiency/microsatellite-instable (dMMR/MSI) tumors, and in-depth biomarker analyses were performed to inform precision immunotherapy approaches. Patients with dMMR/MSI tumors who exhausted standard-of-care treatment options were enrolled in the Drug Rediscovery Protocol, a pan-cancer clinical trial that treats patients with cancer based on their tumor molecular profile with off-label anticancer drugs (NCT02925234). Patients received nivolumab (four cycles of 240 mg every 2 weeks, thereafter 480 mg every 4 weeks). The primary endpoint was clinical benefit (CB: objective response or stable disease ≥16 weeks). Whole-genome sequencing and RNA sequencing were performed on pretreatment tumor biopsies. A total of 130 evaluable patients were enrolled with 16 different cancer types. CB was observed in 62% [95% confidence interval (CI), 53-70], with an objective response in 45% (95% CI, 36-54). After a median follow-up of 14.5 months (95% CI, 13-19), the median progression-free survival was 18 months (95% CI, 9-not reached), and the median overall survival was not reached. Whereas CB was not, or only weakly, associated with markers of adaptive immune cell infiltration, CB was strongly associated with expression of a broad set of innate immune receptors/ligands. This clearly contrasted findings in melanoma, in which markers of adaptive immunity dominated the biomarker landscape. Nivolumab proved highly effective in advanced dMMR/MSI tumors. Expression of key innate immune receptors/ligands was the main predictor of a good treatment outcome, contrasting findings in melanoma and strengthening the rationale for tumor type-specific biomarkers for guiding immunotherapy.

Determination of knowledge levels and attitudes of clinician veterinarians working in Thrace region towards antibiotic use

Antimicrobial resistance (AMR) has become a global problem due to widespread antimicrobial use in human and veterinary medicine. AMR affects health systems by leading to prolonged and severe illnesses, high mortality rates, and treatment failures caused by resistant microorganisms. As antibiotics are the most widely used drugs in veterinary medicine, veterinarians' knowledge, attitudes and practices regarding antibiotic use are crucial in combating AMR. In this cross-sectional study, an online questionnaire of 20 questions was administered to clinician veterinarians and members of the Trakya Chamber of Veterinarians and 60 participants answered the questionnaire. In the current survey, 98 % of veterinarians agree that AMR is an important public health problem and emphasize that focusing on rational antibiotic use in veterinary medicine is a critical area to slow the development of AMR. Only 10 % of the respondents stated that they take into account antibiotic requests from patient owners, 68.3 % stated that they rarely use off-label drugs and 16.7 % stated that they often use them. Of those respondents, 16.7 % stated that they routinely perform antibiograms. Regarding education, 41.7 % of veterinarians had received training on rational antibiotic use. When asked about their preferred type of training, 56.7 % favored online training, while 35 % preferred face-to-face sessions. The results indicate that veterinarians play a significant role in combating AMR and that more awareness and education are needed in this field.

Off-Label Pediatric Medication Prescribing and Dispensing: Awareness and Attitudes among Community Pharmacists: A Questionnaire-Based Study.

Off-label practice in pediatrics requires relentless engagement from all the health professionals involved. Community pharmacists are the last ones in the prescribing-dispensing chain; therefore, they have the key responsibility of verifying the correctness of a treatment. A cross-sectional study was conducted for assessing the awareness and views of Romanian community pharmacists, regarding off-label drugs in the pediatric population, through a 28-item questionnaire comprising five sections of different topics (general knowledge, frequency of prescribing and dispensing off-label medication, views, and attitudes). The sample size was 236 questionnaires with a response rate of 41.11%. A statistical analysis of the obtained data was performed with GraphPad Prism v.9. The results indicate that 55.1% of the community pharmacists have a good general knowledge and awareness regarding the off-label practice, although the legal frame is unclear. The responses highlight a high frequency of prescribing and request of medication for respiratory conditions (45.3%) and antibiotics (23.5%), with a concerning gap regarding the adverse events related to the off-label treatments (56.7%). A very small percentage of pharmacists (7.1%) contact a fellow healthcare professional when encountering an off-label prescription. In conclusion, in addition to the pharmacist's conduct towards the best interest of the patient, there is a clear need to improve the doctor-pharmacist collaboration in order to make an off-label treatment successful.

A foundation model for clinician-centered drug repurposing.

Drug repurposing-identifying new therapeutic uses for approved drugs-is often a serendipitous and opportunistic endeavour to expand the use of drugs for new diseases. The clinical utility of drug-repurposing artificial intelligence (AI) models remains limited because these models focus narrowly on diseases for which some drugs already exist. Here we introduce TxGNN, a graph foundation model for zero-shot drug repurposing, identifying therapeutic candidates even for diseases with limited treatment options or no existing drugs. Trained on a medical knowledge graph, TxGNN uses a graph neural network and metric learning module to rank drugs as potential indications and contraindications for 17,080 diseases. When benchmarked against 8 methods, TxGNN improves prediction accuracy for indications by 49.2% and contraindications by 35.1% under stringent zero-shot evaluation. To facilitate model interpretation, TxGNN's Explainer module offers transparent insights into multi-hop medical knowledge paths that form TxGNN's predictive rationales. Human evaluation of TxGNN's Explainer showed that TxGNN's predictions and explanations perform encouragingly on multiple axes of performance beyond accuracy. Many of TxGNN's new predictions align well with off-label prescriptions that clinicians previously made in a large healthcare system. TxGNN's drug-repurposing predictions are accurate, consistent with off-label drug use, and can be investigated by human experts through multi-hop interpretable rationales.

Pharmacological Management of Acute and Chronic Insomnia: A Cross-Sectional Study

Objective Insomnia is a frequent and difficult disease to treat. The objective was to determine the pharmacological management of a group of patients diagnosed with acute and chronic insomnia. Methods This is a cross-sectional study that identified patterns of prescription of drugs for outpatient use in patients with insomnia from a population database of 8.5 million individuals in the Health System of Colombia. Sociodemographic and pharmacological variables were considered. Results A total of 5825 patients with insomnia were identified. Acute insomnia was the most frequent complaint (85.2%). A total of 76.9% received pharmacological treatment, mainly through off-label drugs (70.7%), such as trazodone (20.2%), quetiapine (12.3%), and clonazepam (11.1%). The approved drugs were used in 9.9% of the patients, especially eszopiclone (4.7%) and zopiclone (3.6%). Benzodiazepines and Z compounds predominated in the elderly and individuals with chronic insomnia. Conclusions The pharmacological treatment of insomnia in this group of patients is heterogeneous, and medications not approved for this indication are very frequently used.

Efficacy and safety of tofacitinib on COVID-19 patients: A systematic review and meta-analysis

The use of drugs off-label for managing COVID-19 offers a potential approach. Among these potential drugs, tofacitinib, a JAK inhibitor, is strongly implicated in its ability to mitigate mortality by attenuating the cytokine storm syndrome. This study systematically reviewed and quantitatively assessed the effectiveness and safety profile of tofacitinib use through meta-analysis. Through searches of the PubMed, Scopus, and the Cochrane Library databases up to May 31, 2024, six articles meeting inclusion criteria were identified, encompassing 669 patients diagnosed with COVID-19. The review findings indicate that tofacitinib use demonstrates significant clinical efficacy, as evidenced by a reduced risk of mortality (P = 0.003), and a decreased need for invasive mechanical ventilation (P = 0.0002). Furthermore, tofacitinib use is not correlated with an increased risk of adverse drug reactions (P = 0.98), indicating a favorable safety profile. In conclusion, the evidence supports the clinical efficacy of tofacitinib for COVID-19 patients without concomitant risks of adverse effects. Further clinical studies, especially larger-scale randomized controlled trials, are necessary to validate the findings of this study.

Thrombopoietin Receptor Agonists as Second-Line Treatment in Children With Ongoing Immune Thrombocytopenia

What Is the Issue? Immune thrombocytopenia (ITP) is an autoimmune disorder characterized by low platelets and an increase in bleeding risk; in the pediatric population, the reported incidence rate varies between 2 and 5 per 100,000 children per year. Spontaneous remission may be observed in up to 70% of patients, while 20% of patients may experience severe bleeding symptoms. In children whose ITP does not respond to first-line corticosteroids, IV immunoglobulin (IVIG), or anti-D immunoglobulin, guidelines recommend the use of thrombopoietin receptor agonists (TPO-RAs), i.e., eltrombopag or romiplostim (avatrombopag did not have a marketing authorization and Notice of Compliance at the time that the review was initiated). Rituximab is considered a subsequent-line of therapy. Splenectomy is not usually considered an appropriate treatment option in children. The goal of therapy in pediatric patients with ITP is to reduce bleeding and improve quality of life. Platelet response is considered a valid and appropriate surrogate end point in studies and routine assessment in clinical practice. Children whose ITP does not respond to available first-line drugs may require subsequent treatment with off-label drugs because they do not have access to TPO-RAs. What Did We Do? We searched key resources, including journal citation databases, and conducted a focused internet search for relevant evidence. A systematic review of the literature identified 5 studies (4 randomized controlled trials [RCTs] and 1 observational study), which were synthesized narratively. The review addressed the following policy questions: In children with ongoing, active ITP, what is the overall body of evidence supporting the use of TPO-RAs and rituximab after failure of first-line therapies? Based on the level and quality of clinical evidence, should TPO-RAs be reimbursed for use earlier in the treatment sequencing for children with ongoing, active ITP, instead of being reimbursed only after a course of rituximab? What Did We Find? Evidence from 2 RCTs (n = 159) suggests that eltrombopag likely increases and maintains platelet response over time, in addition to decreasing the use of rescue medication and clinically significant bleeding compared to placebo, which were considered clinically meaningful outcomes for pediatric patients with ITP. There was a low risk of bias in the studies, but uncertainty was introduced due to the small sample sizes. Evidence from 1 RCT (n = 62) suggests that romiplostim may also increase and maintain platelet response, as well as reduce clinically significant bleeding compared to placebo. However, there was some concern due to a high risk of bias in the studies and uncertainty due to the small sample size, which suggests a need for caution in the interpretation of the findings. The effectiveness of rituximab was inconclusive due to the lack of evidence, as no comparative RCTs could be identified, while the observational study included presented only descriptive comparisons. No evidence was identified in support of trying rituximab before accessing TPO-RAs. What Does This Mean? Given that ITP is rare in children, there is a gap in available relevant evidence, and robust evidence from large RCTs in this patient population are unlikely to be conducted. Jurisdictions may consider requesting an implementation advice panel for use of eltrombopag and romiplostim after failure of first-line therapies in children with ongoing, active ITP.

Public Preference for Off-Label Use of Drugs for Cancer Treatment and Relative Importance of Associated Adverse Events: A Discrete Choice Experiment and Best-Worst Scaling.

Patients may get more treatment options with off-label use of drugs while exposed to unknown risks of adverse events. Little is known about the public or demand-side perspective on off-label drug use, which is important to understand how to use off-label treatment and devise financial assistance. This study aimed to quantify public preference for off-label cancer treatment outcomes, process, and costs, and perceived importance of associated adverse events. A discrete choice experiment and a best-worst scaling were conducted in Hong Kong in December 2022. Quota sampling was used to randomly select the study sample from a territory-wide panel of working-age adults. Preferences and willingness to pay (WTP) for treatment effectiveness, risk of adverse events, mode of drug administration, and availability of off-label treatment guidelines were estimated using a random parameter logit model and latent class model. The relative importance of different adverse events was elicited using Case 1 best-worst scaling. A total of 435 respondents provided valid responses. In the discrete choice experiment, the respondents indicated that extra overall survival as treatment effectiveness (WTP: HK$448,000/US$57,400 for 12-month vs 3-month extra survival) was the most important attribute for off-label drugs, followed by the risk of adverse events (WTP: HK$318,000/US$40,800 for 10% chance to have adverse event vs 55%), mode of drug administration (WTP: HK$42,000/US$5300 for oral intake vs injection), and availability of guidelines (WTP: HK$31,000/US$4000 for available versus not available). Four groups with distinct preferences were identified, including effectiveness oriented, off-label use refusal, oral intake oriented, and adverse event risk aversion. In the best-worse scaling, hypothyroidism, nausea/vomiting, and arthralgia/joint pain were the three most important adverse events based on the perceptions of respondents. Risk-averse respondents, who were identified from the discrete choice experiment, had different perceived importance of the adverse events compared with those with other preferences. Knowing the preference and WTP for cancer treatment-related characteristics from a societal perspective facilitates doctors' communications with patients on decision making and treatment goal-setting for off-label treatment, and enables devising financial assistance for related treatments. This study also provides important insight to inform evaluations of public acceptance and information dissemination in drug development as well as future economic evaluations.

Oral viscous budesonide solution for enhanced localized treatment of eosinophilic esophagitis through improved mucoadhesion and permeation

Eosinophilic esophagitis (EoE) is a chronic inflammatory disease of the esophagus that is immune/antigen-mediated and often requires targeted treatment. In clinical practice, an oral viscous budesonide suspension prepared by adding sucralose to a budesonide suspension for inhalation (Pulmicort®) is used to treat adult EoE and enhance retention in the esophageal mucosa. Inspired by this off-label drug use, oral viscous budesonide solutions (OVBSs) were developed in this study, and their capacities for adhesion, permeation, and stability were explored. Given the insolubility of budesonide as a BCS II drug, we first evaluated its equilibrium solubility and found that Transcutol® HP was an excellent choice for creating an OVBS at a concentration of 0.2 mg/g. The rheological properties of the OVBSs were evaluated with a rheometer, and shear-thinning, which aids in swallowing, was observed. The addition of hydroxyethyl cellulose (HEC) increased the adhesion strength of the preparation, which was associated with the hydration and thickening mechanism. This result was confirmed in a dynamic gelation study and in vitro elution experiment conducted with porcine esophagus tissue. Furthermore, the permeabilities of the OVBSs in the porcine esophagus were evaluated with a Franz diffusion cell device. >80 % of the budesonide was released after 24 h, and the release profile was similar to that of the solution. To explore the storage conditions of OVBSs, critical factors such as pH, content, and impurities were determined. It was found that OVBSs exhibited different behaviors at different pH values and temperatures. Notably, the OVBSs containing 1.7 % HEC could be stored for >6 months at a temperature of 5 °C ± 3 °C and a pH of 4.5 without significant degradation. Overall, this study demonstrated that OVBSs have the potential to adhere to the esophageal mucosa, permeate the tissue, and remain stable during storage. Moreover, OVBSs exhibit a distinct advantage over traditional converted inhalation-to-oral budesonide therapies by enabling flexible dose adjustment in clinical applications, thereby potentially minimizing systemic side effects commonly associated with oral glucocorticoid administration.

The implementation of the guideline for the management of pediatric off-label use of drugs in China: a cross-sectional study.

Previously, we developed the Guidelines for the Management of Pediatric Off-Label Use of Drugs in China in addressing the need for standardization of pediatric off-label drug use. As the implementation of recommendations in Guidelines among healthcare professionals is weak, it is important to identify barriers to guideline implementation for developing appropriate strategies for specific settings and target groups. This study aimed to assess the difficulty and urgency in implementing the recommendations in the Guideline, identifying the factors affecting the implementation of these recommendations to realize the clinical translation of the Guideline. A cross-sectional study was conducted from March 1 to June 17, 2022. Pediatricians, pharmacists, and health managers from all 31 mainland Chinese provinces were involved. The electronic questionnaires were distributed nationwide by The Clinical Pharmacology Group of the Pediatric Society of the Chinese Medical Association and the National Clinical Research Center for Child Health. Data analysis, including frequency, percentages, averages, and standard deviations was performed using Microsoft Excel 16.54. Chi-squared tests, multi-factor logistic regression, and linear regression were analyzed in SPSS 23.0. A Sankey diagram was constructed using R software. A total of 869 valid questionnaires were collected from 491 participating organizations. More than half of the recommendations were implemented, and 12 recommendations were implemented more in tertiary hospitals than in secondary hospitals. The mean urgency scores of all 21 recommendations were over 5. The mean difficulty scores of all 21 recommendations were over 4. The percentage of the most urgent was 44.33%, and the least urgent was 1.45%. The most difficult portion was 12.03%, and the least difficult was 5.74%. Factors impacting the urgency and difficulty of guideline implementation were different, with common influences including the position, education level of clinicians and hospital level. The recommendations in the Guideline for the Management of Pediatric Off-Label Use of Drugs are considered highly urgent for implementation in China. Nevertheless, the study revealed challenges in applying all 21 recommendations within clinical practice. The key factors affecting implementation include the position, education, experience, and hospital level of healthcare professionals. It is recommended to facilitate implementing the recommendations by sharing experience across various hospital levels, starting from high-level hospitals and extending to primary healthcare settings. Moreover, adjustments to the professional structure within hospitals are needed to enhance the management of off-label drug use in pediatric patients.

Computer Modeling of Bevacizumab Drug Distribution after Intravitreal Injection in Rabbit and Human Eyes.

Age-related macular degeneration (AMD) is a progressive eye disease that causes loss of central vision and has no cure. Wet AMD is the late neovascular form treated with vascular endothelial growth factor (VEGF) inhibitors. VEGF is the critical driver of wet AMD. One common off-label anti-VEGF drug used in AMD treatment is bevacizumab. Experimental efforts have been made to investigate the pharmacokinetic (PK) behavior of bevacizumab in vitreous and aqueous humor. Still, the quantitative effect of elimination routes and drug concentration in the macula are not well understood. In this work, we developed two spatial models representing rabbit and human vitreous to better understand the PK behavior of bevacizumab. This study explores different cases of drug elimination and the effects of injection location on drug concentration profiles. The models are validated by comparing them with experimental data. Our results suggest that anterior elimination is dominant for bevacizumab clearance from rabbit vitreous, whereas both anterior and posterior elimination have similar importance in drug clearance from the human vitreous. Furthermore, results indicate that drug injections closer to the posterior segment of the vitreous help maintain relevant drug concentrations for longer, improving bevacizumab duration of action at the fovea, which is located at the center of the macula. The rabbit and human models predict bevacizumab concentration in the vitreous and fovea, enhancing knowledge and understanding of wet AMD treatment.

A foundation model for clinician-centered drug repurposing.

Drug repurposing - identifying new therapeutic uses for approved drugs - is often serendipitous and opportunistic, expanding the use of drugs for new diseases. The clinical utility of drug repurposing AI models remains limited because the models focus narrowly on diseases for which some drugs already exist. Here, we introduce TXGNN, a graph foundation model for zero-shot drug repurposing, identifying therapeutic candidates even for diseases with limited treatment options or no existing drugs. Trained on a medical knowledge graph, TXGNN utilizes a graph neural network and metric-learning module to rank drugs as potential indications and contraindications across 17,080 diseases. When benchmarked against eight methods, TXGNN improves prediction accuracy for indications by 49.2% and contraindications by 35.1% under stringent zero-shot evaluation. To facilitate model interpretation, TXGNN's Explainer module offers transparent insights into multi-hop medical knowledge paths that form TXGNN's predictive rationales. Human evaluation of TXGNN's Explainer showed that TXGNN's predictions and explanations perform encouragingly on multiple axes of performance beyond accuracy. Many of TxGNN's novel predictions align with off-label prescriptions clinicians make in a large healthcare system. TXGNN's drug repurposing predictions are accurate, consistent with off-label drug use, and can be investigated by human experts through multi-hop interpretable rationales.

EU Avastin/Lucentis Case and Several Issues on Drug Off-label Use in Taiwan

EU Avastin/Lucentis Case and Several Issues on Drug Off-label Use in Taiwan

DRUGS SAFETY IN CHILDREN

Background: There is a need to promote drug-related safety in children and prevent them from drug-related toxicities. Understanding pediatric pharmacology, drug dosing, and physiological differences between children and adults is crucial for ensuring safe and effective pediatric care. Objectives: The focus of the current review is the safety and efficacy of drugs in children that involve medication errors and adverse drug reactions. The present study includes awareness of past medication-related incidents, off-label drug usage, inappropriate antibiotic prescriptions, adverse reactions to over-the-counter drugs, and cases of pharmaceutical poisoning in children. Methodology: Pertinent literature databases from search engines like Google Scholar and PubMed were retrieved and analyzed, and WHO and FDA guidelines were followed. Results: The literature survey showed that these problems can be overcome by taking safety measures and following evidence-based practice recommended by the FDA, reducing dosing errors, and preventing ADRs. The Best Pharmaceuticals for Children Act (BPCA) and Pediatric Research Equity Act (PREA) has made efforts in conducting drug research and improving pediatric labelling. Conclusion: A warning showing more recent information about contraindications must be mentioned in pharmaceutical labelling so the patient and doctors would be better aware of drug contraindications and their adverse effects.

Integrative Care for Challenging Behaviors in People with Intellectual Disabilities to Reduce Challenging Behaviors and Inappropriate Psychotropic Drug Prescribing Compared with Care as Usual: A Cluster-Randomized Trial.

People with intellectual disabilities (IDs) often present with challenging behaviors (CBs) mostly due to inappropriate environments and mental and physical disorders. Integrative care is recommended to address CBs. However, in clinical practice, psychotropic drugs are often prescribed off-label for CBs, although the effectiveness is unclear, and side effects frequently occur. We conducted a cluster-randomized controlled study to investigate the effect of integrative care provided by a collaboration of an ID specialized mental healthcare team and participants' own ID service providers' care team on reducing CBs and inappropriate off-label psychotropic drug prescriptions compared with care as usual. Participants (N = 33, aged 19-81 years) had a moderate, severe, or profound intellectual disability and used off-label psychotropic drugs. The primary outcome measures were the Aberrant Behavior Checklist and the total dose of psychotropic drug prescriptions. At the study endpoint of 40 weeks, we found no effect of the intervention on the total ABC score and on the total dose of psychotropic drug prescriptions. In the intervention group, however, the psychotropic drug dose decreased significantly, while CBs did not change. The small sample size and not-completed interventions due to organizational problems may have affected our findings. This study illustrates the difficulties in the implementation of integrative care.

A Non-Interventional, Multicenter Study to Characterize the Socio-Demographics, Clinical Characteristics, and Management of Generalized Pustular Psoriasis Patients in Spain: IMPULSE Study.

Generalized pustular psoriasis (GPP) is a chronic, rare, and potentially life-threatening skin condition characterized by flares comprising widespread sterile pustules and systemic inflammation. Both the rarity and heterogeneity of the disease have made GPP classification and standardization of clinical criteria challenging. Before the approval of spesolimab (IL-36R antibody) in 2022, there were no approved treatments in the USA or Europe for GPP flares. Treatment for GPP has amounted to off-label use of medicines approved to treat plaque psoriasis. Our aim was to describe the sociodemographics, clinical characteristics, and treatment patterns of patients with GPP in Spain. Non-interventional, descriptive, multi-center, retrospective chart review of patients diagnosed with GPP in Spain. 56 patients (50% women) were included, with a mean (standard deviation, SD) age at diagnosis of 53.7 (20.5) and a mean (SD) time of follow-up of 3.7 (3.1) years. In 80% of patients, GPP diagnosis was associated with a flare and 67.3% had known risk factors for GPP (such as previous diagnosis or family history of plaque psoriasis, comorbidities, smoking or stress). Hypertension and plaque psoriasis were the most frequent comorbidities (44.6% each). The number of GPP flares per patient-year was 0.55 with (range 0-4) a mean (SD) body surface area involvement of 21.3% (19.1). The most frequent manifestations of GPP flares were pustules (88.5%), erythema (76.9%), and scaling (76.9%). Additionally, 65.4% of patients had plaque psoriasis, 53.8% had unspecified skin lesions, and 30.8% experienced pain. The treatments used for GPP flares were off-label conventional systemic drugs (75%), mostly corticosteroids, cyclosporine, and acitretin. In the periods between flares, off-label biologics were used in 56.5% of patients. During the study period, 9 patients (16.1%) had at least one complication and 5 of them required hospitalization. This is the first multicenter study in Spanish GPP patients. Most patients were in their fifties, with personal or family history of plaque psoriasis, stress, smoking and a wide range of comorbidities and complications. Even though the number of flares per patient/year was 0.55, there was variability between patients. Both off-label conventional systemics and off-label biologics were used for flare management without a clear treatment pattern.

Perceptions and experiences of community pharmacists with off-label prescribing in the pediatric population.

This study aimed to investigate and provide insight into the prevalence and patterns of off-label drug use in the pediatric population from the perspective of community pharmacists, addressing the existing data gap in a developing setting. A questionnaire-based cross-sectional study was conducted on Albanian community pharmacists in June 2021. The online administered survey explored the participants' demographic details, perceptions, and experiences with off-label prescriptions in pediatric patients. The statistical analysis conducted on the survey data comprised the construction of frequency tables and the application of the chi-square test for independence. Three hundred and thirty-six community pharmacists nationwide completed the survey, out of which 186 (55.3%) were practiced in Tirana, the capital of Albania. Over 80% of surveyed pharmacists (n = 275) had encountered off-label drug prescriptions in pediatric patients, yet only 40% of participants reported dispensing medicines for off-label use. Community pharmacists reported that general pediatricians tended to prescribe off-label medications more frequently than pediatric subspecialists or general practitioners. It was found that off-label prescriptions were more frequently observed among children aged between 2 and 11 years. Antibiotics were the most reported medicines for off-label use in this study mentioned in almost all off-label categories. Prescribing medicines for unapproved uses for the treatment of pediatric patients is present in community settings in Albania. This indicates the need for further data collection and analysis to understand off-label practices in our country's pediatric population comprehensively.

Polypharmacy in Children with Medical Complexity: A Cross-Sectional Study in a Pediatric Palliative Care Center.

Children with medical complexity (CMC) often require multiple medications, leading to polypharmacy, which seems to be linked to adverse effects, administration errors, and increased caregiver burden. This study aimed to describe the prevalence of polypharmacy, medication burden, off-label drug use, and associated costs. Conducted at the Pediatric Palliative Care Center of Padua, Italy, from August to October 2021, this cross-sectional observational study included patients up to 23 years old with at least one prescribed drug. Data were collected from medical records and caregiver interviews. Drug costs were collected from the Italian Medicine Agency. Descriptive statistical analysis was performed. For comparisons among categorical variables, the Chi-square test was used, and for those among continuous variables, the ANOVA test was used. This study analyzed treatment regimens of 169 patients with a median age of 12.5 years (0.3-23). Polypharmacy was present in 52.7% of patients, and medication burden was observed in 44.4%, both varying significantly by primary diagnosis (p < 0.001). The median daily cost per patient was EUR 2.2 (IQR 0.9-7.1), with significant variation among subgroups. Only 34.6% of prescriptions were off-label. polypharmacy and medication burden are frequent among our CMC population, with some differences according to primary diagnosis.