Prevalence and Appropriateness of Antipsychotic Prescribing in an Italian Prison: Is Everything Always Really Overprescribed?

PURPOSE/BACKGROUND: Although the prevalence of mental disorders in prisoners is known to be higher than in the general population, less is known about the antipsychotic (AP) prescribing rate in jail. The aim of this research was to investigate prevalence and appropriateness of AP prescription in an Italian prison to expand our understanding on this crucial area of clinical-forensic practice. METHODS/PROCEDURES: A cross-sectional (census day) design was used among male adults in the Parma Penitentiary Institutes (PPI). Sociodemographic, clinical and prescription data were collected from the PPI electronic clinical database management system. The AP prescribing appropriateness was examined in accordance with the therapeutic indications included in the Italian National Formulary. A descriptive statistical analysis was performed. FINDINGS/RESULTS: A total of 98 (14.1%) of 696 PPI prisoners were taking AP medications. Moreover, 90 (91.8%) of the 98 PPI participants were also taking other psychotropic medications concurrently. Quetiapine and olanzapine were the most common prescribed APs. Antipsychotic medications were most likely to be prescribed for off-label indications (74.4%). Less than one fifth of all AP prescriptions were for psychotic disorders. IMPLICATIONS/CONCLUSIONS: Antipsychotic medications are widely used in prison, often together with other psychotropic drugs. Considering their common adverse effects, it is crucial to longitudinally monitor their potential risk of metabolic, cardiovascular, and extrapyramidal symptoms and signs, as well as their early risk of mortality. Given the high prevalence of AP off-label prescription, the rationale for AP prescribing should be clearly documented and regularly reviewed within the prison by mental health professionals.

Medicamentos off-label e não licenciados no âmbito pediátrico: uma revisão descritiva dos últimos dez anos / Off-label and unlicensed drugs in the pediatric field: a descriptive review of the last ten years

A falta de medicamentos contendo bulas prevendo o tratamento de pacientes pediátricos representa um problema frequentemente observado em hospitais, principalmente nos setores de unidade de terapia intensiva (UTI) pediátrica e neonatais. Sabe-se que, para que um tratamento seja considerado seguro e eficaz, uma série de estudos clínicos são necessários, no entanto, relata-se um baixo número dessas pesquisas envolvendo crianças, principalmente devido a questões éticas que dificultam a condução das mesmas. Assim, poucos são os medicamentos que provam ser adequados para o tratamento desses pacientes, tornando necessário recorrer ao uso de medicamentos off-label e não licenciados. Os medicamentos são classificados como off-label quando seu uso se dá de maneira que difere de suas especificações aprovadas, por sua vez, produtos não licenciados são classificados desta forma por não possuírem aprovação para sua comercialização no país ou não possuírem comprovação de segurança e eficácia. O preparo de protocolos de estudo organizados, relato de informações aos pais e à criança de maneira clara e objetiva, aproximação entre pesquisadores e pais para o estabelecimento de uma relação de confiança e a condução das pesquisas em momentos de disponibilidade da família demonstram-se estratégias importantes para facilitar a realização dos ensaios clínicos.

The lack of medicines containing drug information leaflets considering the treatment of pediatric patients is a problem frequently observed in hospitals, especially in the pediatric and neonatal intensive care unit (ICU) sectors. It is known that, for a treatment to be considered safe and effective, a series of clinical studies are necessary; however, a low number of these studies involving children are reported, mainly due to ethical issues that make conducting them difficult. Thus, few drugs prove to be suitable for treating these patients, making it necessary to resort to using off-label and unlicensed drugs. Drugs are classified as off-label when their use differs from their approved specifications, in turn, unlicensed products are classified in this way due to not having approval for marketing in the country or do not have proof of safety and efficacy. Preparation of organized study protocols, reporting information to parents and the child in a clear and objective way, bringing researchers and parents closer to establish a relationship of trust and conducting research at moments when the family is available are important strategies to facilitate conducting clinical trials.

Off-label drugs in palliative care: a Group Delphi treatment recommendation process.

OBJECTIVES: The use of drugs beyond their marketing authorisation, that is, off-label use, is common practice in palliative care with over 70% of off-label use having little or no scientific support. The lack of evidence makes recommendations for off-label use essential, in order to increase the safety of drug therapy and thus patient safety. The aim of this study was to develop a guide for preparing and consenting drug-specific recommendations for off-label use in palliative care. METHODS: Group Delphi Study with three rounds and a prior online survey to identify topics of dissent. Participants represented professional groups working in palliative care involved in direct patient care and/or drug management and various care settings. Furthermore, representatives of relevant professional associations, experts with academic, non-clinical background and experts with international expertise were invited. RESULTS: 18/20 invited professionals participated in the prior online-survey. 15 experts participated in the Group Delphi process. Six domains, including identification of drugs, drug uses, assessment of evidence, formulation, consensus and updating of recommendations were generated and respective statements were included in the Group Delphi process. The consensus process resulted in 28 statements forming the guide for recommendations. CONCLUSIONS: The resultant systematic approach for preparing and consenting drug-specific recommendations for off-label use will allow the development of recommendations with transparent and reproducible monographs. This will help to increase treatment quality and patient safety as well as security of decision-making in palliative care. The developed guide is part of a larger project aiming to provide therapy recommendations for areas that have little or no scientific evidence.

COVID-19​ live Q&A with Dr Mike Ryan and Dr Maria Van Kerkhove. Ask WHO​ of 29 July 2020

#AskWHO​ series: This was the live discussion about the COVID-19 pandemic of 29 July 2020 with Dr Mike Ryan, Executive Director of WHO Health Emergencies Programme, and Dr Maria Van Kerkhove, WHO Technical Lead on COVID-19. Questions from the audience were taken.

Gaining insight into irrational off-label use of vidarabine through analysis of a spontaneous reporting system in China.

WHAT IS KNOWN AND OBJECTIVE: Although superseded by other antiviral agents in many Western countries, vidarabine is still widely used in some countries, including China; hence, the extent and appropriateness of vidarabine prescriptions in children require better characterization. This study examined the rationale, extent, and health risks associated with irrational off-label vidarabine use in China. METHODS: Data used in the study were extracted from a multi-provincial joint adverse drug reactions monitoring platform from 2002 to 2018. Descriptive statistics were used to analyse the characteristics of individual case safety reports (ICSRs) related to vidarabine use. RESULTS AND DISCUSSION: Among 2772 individual ICSRs related to vidarabine, 2223 (80.19%) cases occurred in patients aged 0-9. In all patients, the median age and interquartile range were 2 (0-6). Although most adverse events were mild, five deaths were recorded, all in children below 7 years of age. Paediatric use is the most prominent off-label use of vidarabine. Additionally, several other irrational off-label uses were identified, including 218 (7.86%) cases of overdosing and numerous applications beyond the approved indications, dosages, routes of administration, and solvents. WHAT IS NEW AND CONCLUSION: Data indicate that vidarabine was mainly prescribed for suspected common viral infections in paediatric patients, demonstrating serious inappropriate off-label uses. The problem was further complicated by the lack of sufficient information regarding safety, efficacy, and dosing regimens in children, as well as by several additional risk factors such as inappropriate solvents, routes of administration, and overdose. In the case of children, the physicians' lack of understanding of antiviral activities and compassionate prescriptions were mainly responsible for drug overuse. The health risks associated with the paediatric use of vidarabine in China require greater attention and further investigation.

Evolution of the AMCP Format for Formulary Submissions.

DISCLOSURES: No funding was required for this project. The authors are or have been members of the Format Executive Committee.

Reduced doses of dabrafenib and trametinib combination therapy for BRAF V600E-mutant non-small cell lung cancer prevent rhabdomyolysis and maintain tumor shrinkage: a case report.

BACKGROUND: A BRAF V600E mutation is found as driver oncogene in patients with non-small cell lung cancer. Although combined treatment with dabrafenib and trametinib is highly effective, the efficacy of reduced doses of the drugs in combination therapy has not yet been reported. CASE PRESENTATION: A Japanese man in his mid-sixties was diagnosed with unresectable lung adenocarcinoma and was unresponsive to cytotoxic chemotherapy and immune checkpoint inhibitors. The BRAF V600E mutation was detected by next generation sequencing, and the patient was subjected to treatment with dabrafenib and trametinib in combination. Although the treatment reduced the tumor size, he experienced myalgia and muscle weakness with elevated serum creatine kinase and was diagnosed with rhabdomyolysis induced by dabrafenib and trametinib. After the patient recovered from rhabdomyolysis, the treatment doses of dabrafenib and trametinib were reduced, which prevented further rhabdomyolysis and maintained tumor shrinkage. CONCLUSION: The reduction of the doses of dabrafenib and trametinib was effective in the treatment of BRAF V600E-mutant NSCLC, and also prevented the incidence of rhabdomyolysis.

Off-label use of medicines in neonates, infants, children, and adolescents: a joint policy statement by the European Academy of Paediatrics and the European society for Developmental Perinatal and Pediatric Pharmacology.

Health-care professionals who prescribe medicines have the professional duty to choose medicines that are in the best interest of their individual patient, irrespective if that patient is an adult or a child. However, the availability of medicines with an appropriate label for pediatric use is lagging behind those for adults, and even available pediatric drugs are sometimes not suitable to administer to children. Consequently, health-care professionals often have no other option than to prescribe off-label medicines to children. An important reason for use of off-label medicines is to improve access to (innovative) treatments or to address medical needs and preferences of patients, especially when no other options are available. However, off-label use of medicines is in general not supported by the same level of evidence as medicines licensed for pediatric use. This may result in increased uncertainty on efficacy as well as the risk for toxicity and other side effects. In addition, liability may also be of concern, counterbalanced by professional guidelines.Conclusion: The purpose of this joint EAP/ESDPPP policy statement is to offer guidance for HCPs on when and how to prescribe off-label medicines to children and to provide recommendations for future European policy.

Level of evidence used in recommendations by the National Comprehensive Cancer Network (NCCN) guidelines beyond Food and Drug Administration approvals.

BACKGROUND: A previous analysis of 113 National Comprehensive Cancer Network® (NCCN®) recommendations reported that NCCN frequently recommends beyond Food and Drug Administration (FDA)-approved indications (44 off-label recommendations) and claimed that the evidence for these recommendations was weak. METHODS: In order to determine the strength of the evidence, we carried out an in-depth re-analysis of the 44 off-label recommendations listed in the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®). RESULTS: Of the 44 off-label recommendations, 14 were later approved by the FDA and/or are supported by randomized controlled trial (RCT) data. In addition, 13 recommendations were either very minor extrapolations from the FDA label (n = 8) or were actually on-label (n = 5). Of the 17 remaining extrapolations, 8 were for mechanism-based agents applied in rare cancers or subsets with few available treatment options (median response rate = 43%), 7 were based on non-RCT data showing significant efficacy (>50% response rates), and 2 were later removed from the NCCN Guidelines because newer therapies with better activity and/or safety became available. CONCLUSION: Off-label drug use is a frequent component of care for patients with cancer in the United States. Our findings indicate that when the NCCN recommends beyond the FDA-approved indications, the strength of the evidence supporting such recommendations is robust, with a significant subset of these drugs later becoming FDA approved or supported by RCT. Recommendations without RCT data are often for mechanism-based drugs with high response rates in rare cancers or subsets without effective therapies.

Off-Label Use of Sirolimus and Everolimus in a Pediatric Center: A Case Series and Review of the Literature.

BACKGROUND: It has been 15 years since sirolimus, an mTOR inhibitor, received Food and Drug Administration approval to prevent acute rejection in kidney transplantation, and 8 years since its analog everolimus acquired the same status. Since then, these drugs have become more and more utilized and their immunosuppressive and antiproliferative properties have been tested in a great variety of clinical conditions, often achieving excellent results. Despite such positive evidence, the on-label indications for these rapalogs are still very restrictive, especially in children. AIMS: The aims of this study were to describe our center's experience with sirolimus and everolimus in managing rare pediatric conditions for which mTOR inhibitors have been reported as a therapeutic option, although without conclusive approval from regulatory agencies, and to evaluate safety and tolerability of the treatment at the prescribed doses. METHODS: All the subjects who received off-label sirolimus or everolimus at the Pediatric Department of the IRCCS Burlo Garofolo in the last 13 years were included. For each disease found in our case series, we reviewed the current scientific literature. RESULTS: Off-label treatment with rapalogs was prescribed in 16 children (11 males, 5 females, median age of 9.5 years, range 1-16 years). Seven had immunologic disorders: four autoimmune lymphoproliferative syndrome (ALPS), one multicentric Castleman disease (mCD), one activated PI3K delta kinase syndrome (APDS), and one immunodysregulation with polyendocrinopathy enteropathy X-linked (IPEX). Eight had proliferative disorders or vascular anomalies: one cystic lymphangioma, two Bannayan-Riley-Ruvalcaba syndrome (BRRS), one blue rubber bleb nevus syndrome (BRBNS), two tuberous sclerosis complex (TSC), and one low-flow mixed arterial and venous malformation. One case had congenital hyperinsulinism (CHI). The average dosage administered was 1 mg/m2 for sirolimus and 7 mg/m2 for everolimus. We experienced a good measurable clinical improvement in 14 patients. Nobody experienced serious adverse events (SAEs). The therapy was interrupted in two cases, for lack of efficacy and poor tolerance in one case and for occurrence of bacterial pneumonia in the other one. A review of the literature identified 101 published reports that met our inclusion criteria. CONCLUSIONS: Although use of mTOR inhibitors has been considered to be complicated, our experience shows that, using low dosages, it is possible to obtain relevant clinical improvements, with a good profile of safety and tolerability.

Off-Label Use of Clozapine in Children and Adolescents-A Literature Review.

BACKGROUND: Clozapine is a second-generation antipsychotic typically used for refractory schizophrenia or otherwise psychotic pathology. There are no FDA or manufacturer guidelines for use of clozapine in pediatric population. We investigated the current state of research concerning the use of clozapine in pediatric patients. AREAS OF UNCERTAINTY: We describe consistent calls for more research into the long-term and short-term effects of clozapine use in a young patient population. Despite the strongly supported efficacy, questions concerning clear indications for use and risk-benefit analysis persist. We acknowledge that a more comprehensive meta-analysis would greatly benefit the field. However, this is the first article of its kind for clozapine in recent history, and therefore, serves as a focus and reference point for future, more in-depth analyses. DATA SOURCES: We conducted a search of PubMed, ClinicalKey, PsycINFO, and MEDLINE databases. Keywords used included, in varying combinations: clozapine, off-label, indications, children and adolescent, pediatric, behavioral, suicidality, psychosis, early and very-early onset schizophrenia, side-effect profile, and long-term use. Further criteria and selection are described in Methods below. RESULTS: We describe the documented efficacy of clozapine for the management of refractory psychotic and nonpsychotic symptoms in the pediatric population. The authors highlight the risk of unmanaged early-onset schizophrenia, aggressive or suicidal behavior, and severe nonpsychotic pathology. Unfortunately, these studies are generally small. There is little consistency in when clozapine is prescribed, how long it is administered, and how long patients are followed. Despite the lack of FDA and manufacturer guidelines, clozapine continues to be used for the benefit of young patients. CONCLUSIONS: Indications for prescription of clozapine should be revisited, given the data presented in this manuscript of a low risk-benefit ratio for properly chosen patients. Larger studies should be conducted to provide more statistical power and determine clear guidelines for use, risk of side effects, and long-term adverse events that may arise.

Thesaurus for off-label indications for systemic antifungal agents.

OBJECTIVES: Following the removal of temporary treatment protocol procedures, we developed a thesaurus for off-label indications for systemic antifungals at our facility to update clinical practices and to control off-label prescriptions. MATERIALS AND METHODS: Clinical practice guidelines and literature data were analyzed. This work was part of an antifungal stewardship program. RESULTS: Off-label wording (prophylaxis, preemptive, empirical, curative) and corresponding antifungals and references were validated by the multidisciplinary group for antifungal agents under the aegis of the Commission for the use of drugs and sterile medical devices and of the anti-infective committee. CONCLUSION: Considering the complexity of invasive fungal infection management, this thesaurus needs to be shared and used as a helping tool to review off-label situations.