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Psychiatric drugs have primacy for off-label prescribing. Among those, selective serotonin reuptake inhibitors (SSRIs) are highly versatile and, therefore, widely prescribed. Moreover, they are commonly considered as having a better safety profile compared to other antidepressants. Thus, when it comes to off-label prescribing, SSRIs rank among the top positions. In this review, we present the state of the art of off-label applications of selective serotonin reuptake inhibitors, ranging from migraine prophylaxis to SARS-CoV-2 antiviral properties. Research on SSRIs provided significant evidence in the treatment of premature ejaculation, both with the on-label dapoxetine 30 mg and the off-label paroxetine 20 mg. However, other than a serotoninergic syndrome, serious conditions like increased bleeding rates, hyponatremia, hepatoxicity, and post-SSRIs sexual dysfunctions, are consistently more prominent when using such compounds. These insidious side effects might be frequently underestimated during common clinical practice, especially by nonpsychiatrists. Thus, some points must be addressed when using SSRIs. Among these, a psychiatric evaluation before every administration that falls outside the regulatory agencies-approved guidelines has to be considered mandatory. For these reasons, we aim with the present article to identify the risks of inappropriate uses and to advocate the need to actively boost research encouraging future clinical trials on this topic.

Currently, due to the lack of specific etiotropic therapy, rituximab is widely used for the treatment of most autoimmune diseases of the central and peripheral nervous system. Rituximab is a chimeric monoclonal antibody with specificity for CD20, the antigen found on the surface of normal and malignant B-lymphocytes. It is used mainly in hematological practice. It is used off-label for the treatment of neurological diseases. The world literature describes the use of rituximab for the treatment of such pathologies as autoimmune encephalitis, neuromyelitis optica spectrum disorder, multiple sclerosis, primary angiitis of the central nervous system, immune-mediated inflammatory polyneuropathy, myasthenia gravis, refractory to basic immunosuppressive therapy. This article provides an overview of the world literature on the use of rituximab in neurological practice, describes our own experience of its use on the basis of the Department of Neurology № 1 of Pavlov University (Saint Petersburg, Russia).

Jan Anker Jahnsen,1– 3 Sofia Frost Widnes,1,2 Jan Schjøtt1– 3 1Regional Medicines Information and Pharmacovigilance Centre (RELIS Vest), Haukeland University Hospital, Bergen, Norway; 2Department of Clinical Biochemistry and Pharmacology, Haukeland University Hospital, Bergen, Norway; 3Department of Clinical Science, Faculty of Medicine and Dentistry, University of Bergen, Bergen, NorwayCorrespondence: Jan Anker JahnsenRegional Medicines Information and Pharmacovigilance Centre (RELIS Vest), Haukeland University Hospital, Bergen, NorwayTel +47-48182071Email jan.anker.jahnsen@helse-bergen.noPurpose: The second-generation antipsychotic quetiapine has been associated with misuse and dependency. We aimed to review questions to the Norwegian network of drug information centers concerning this potential drug safety problem.Methods: We conducted a Boolean search in the database of the Regional Medicines Information and Pharmacovigilance Centres in Norway (RELIS) combining the indexed categories “quetiapine” and “adverse drug reaction” with the text words “misuse” or “dependency”. Question–answer pairs (Q/As) in the full-text, searchable RELIS database were defined as cases. Cases were analyzed for drug safety issues linked to use of quetiapine, including off-label use, polypharmacy and other patient risk factors.Results: The search resulted in 54 cases. Forty-six cases (85%) were patient-related, and a majority came from physicians working in hospitals. Twenty-nine cases (54%) concerned patients with a history of addiction, 14 cases (26%) had polypharmacy, and off-label use of quetiapine for insomnia was identified in 14 of the cases (26%). Only three of the cases included a specific question about patient dependency of quetiapine, and these cases were all associated with insomnia.Conclusion: We conclude that our case series from the Norwegian network of drug information centres reflects that quetiapine frequently involves clinical narratives of a history of addiction, polypharmacy or insomnia (off-label use). However, the case series did not reveal new information about the drug’s addictive potential.Keywords: off-label, insomnia, drug safety, addiction, abuse

Purpose To describe the use of large-diameter balloon-expandable stent-grafts (BeGraft aortic stent-graft, Bentley InnoMed GmbH, Hechingen, Germany) in the treatment of infrarenal penetrating aortic ulcer (iPAU). Materials and Methods Retrospective analysis of patients undergoing endovascular treatment with the BeGraft aortic stent-graft in 8 European centers from January 2017 to October 2020. Demographics, perioperative data, and midterm outcomes were collected. Endpoints of the study were technical feasibility, early mortality, and morbidity. Results A total of 40 patients were included. The mean age was 73.9±7.05 years and 63.2% were male. Indications for treatment included size and morphology (65%), presence of symptoms (29.5%), and contained ruptures (5.5%). Urgent treatment was performed in 5% of cases. Technical success was 97.5%. Median operation time was 58 minutes (19–170 minutes), with 27.5% of patients having additional procedures during the main intervention (1 additional repair with a C-TAG (W.L. Gore & Associates, Inc, Flagstaff, AZ, USA) thoracic endoprosthesis, 5 covered endovascular reconstruction of aortic bifurcation procedures, 3 extensions with proximal cuffs, and 2 percutaneous angioplasties of the common iliac arteries). Percutaneous femoral access was used in 72.5%, while groin cut-down was performed in 27.5%. Repair was successful with only 1 stent in 45% of cases, while 37.5% required 2 stents and nearly 17.5% required 3/4 stent-grafts. The 30-day mortality was 0%, with a 2.5% reintervention rate (1 patient required evacuation of an intra-abdominal hematoma). Median follow-up was 13.9 months (2–39 months), during which no vascular-related reinterventions or deaths were reported. In 4 patients, a type II endoleak was observed. No cases of graft migration, thrombosis, or stent-fracture were observed. Conclusions The treatment of iPAU with the BeGraft aortic stent-graft in a selective patient group is feasible with low rate of perioperative morbidity and mortality. Balloon-expandable stent-grafts offer the option to repair iPAUs with a shorter coverage of the aorta using low-profile sheath, that enables treatment in the presence of calcified access vessels and small diameter aortic bifurcations.

Primary osteoporosis is rare in children and adolescents and its optimal pharmacological management is uncertain. Bisphosphonates are commonly used while denosumab has only been administered to a few children with osteogenesis imperfecta. We studied a treatment-naive 13.5-year-old boy with severe osteoporosis and multiple vertebral deformities who presented with back pain and difficulty in walking. Causes of secondary osteoporosis were excluded and there were no abnormalities in genes known to cause bone fragility. He was treated with denosumab 60 mg subcutaneously every 3 months for 30 months, and he was pain-free within 6 weeks after the first injection. Lumbar spine BMD and femoral neck BMD increased with treatment by 65.6% and 25.3%, respectively, and deformed vertebrae regained their normal shape; linear growth was not impaired. During the second year of treatment, transient hypercalcemia (maximum 3.09 mmol/l) before the denosumab injection was observed. In conclusion, denosumab was highly effective in this case of primary pediatric osteoporosis, with remarkable clinical and radiological response. Transient hypercalcemia was probably due to amplification of the effect of growth spurt and puberty on bone remodeling by the transient, short-term discontinuation of the drug. Furthermore, our data suggest that mobilization of calcium from treatment-induced sclerotic transverse lines in bone metaphyses may contribute to the development of hypercalcemia.

Introduction: Regulatory agencies are responsible for defining the use of off-label (OL) and unlicensed (UL) drug prescription in neonatal intensive care. However, these regulatory criteria may differ between agencies in different countries. The aim of this study was to establish the frequency of OL and UL drug prescription in a sample of patients in a neonatal intensive care unit applying the criteria of the Food and Drug Administration (FDA) of the United States and the Agência Nacional de Vigilância Sanitária (ANVISA) of Brazil, analysing the differences observed in the results based on the applied criteria. Methods: Prospective cohort study in neonates admitted for more than 24 h to the NICU of a teaching maternity hospital between August 2017 and July 2018. We obtained information concerning the drugs included in the analysis of OL and UL prescriptions from the DrugDex-Micromedex® and official information on pharmaceutical products in Brazil. We used the kappa correlation coefficient to assess the agreement between the FDA and ANVISA criteria. We defined disagreement as a kappa value of less than 0.200. Results: We evaluated 220 neonates admitted to the NICU and 17,421 items prescribed during the study period. We did not find a difference in the proportion of neonates in which at least 1 drug was prescribed under OL conditions applying the FDA versus the ANVISA criteria (96.4% vs. 98.6%). We found differences between the FDA and ANVISA in the OL classification based on the authorized age of use and indications for prescription, mainly in systemic antimicrobials and cardiovascular drugs. When we compared the prescribing information provided by the FDA and the ANVISA, we found that the criteria of the ANVISA were less specific. Conclusion: Off-label and unlicensed drug prescription are frequent in neonatal intensive care applying the criteria of either agency, although the FDA has established more detailed criteria in terms of the ages and indications for which prescription is authorized. Resumen: Introducción: Las agencias reguladoras son responsables de enmarcar la prescripción de fármacos en condiciones off-label (OL) y unlicensed (UL) en los cuidados intensivos neonatales. No obstante, los criterios de aprobación establecidos pueden variar entre las agencias de distintos países. El objetivo del estudio fue determinar la frecuencia de la prescripción de fármacos OL y UL en una muestra de pacientes en cuidados intensivos neonatales según los criterios establecidos por la Food and Drug Administration (FDA) de Estados Unidos y la Agência Nacional de Vigilância Sanitária (ANVISA) de Brasil, analizando las diferencias en los resultados obtenidos con los criterios de cada agencia. Métodos: Estudio prospectivo de cohortes en neonatos ingresados más de 24 horas en la unidad de cuidados intensivos neonatales (UCIN) de un hospital universitario materno infantil entre agosto de 2017 y julio de 2018. Se obtuvo información sobre los fármacos incluidos en el análisis de prescripción OL y UL de las bases de datos DrugDex-Micromedex® y de la información oficial sobre fármacos de Brasil. La concordancia entre los criterios de la FDA y de la ANVISA se evaluó por medio del índice kappa. Los valores de kappa < 0,200 se consideraron indicativos de discordancia. Resultados: Se evaluó a 220 neonatos ingresados en la UCIN y 17 421 prescripciones de fármacos individuales en el período de estudio. No hubo diferencias en la proporción de pacientes que recibieron al menos una prescripción OL según se aplicasen los criterios de la FDA o los de la ANVISA (96,4% vs. 98,6%). En cambio, se encontraron diferencias en el motivo de clasificación como OL en base a la edad o a la indicación entre las dos agencias reguladoras, principalmente en la prescripción de antiinfecciosos sistémicos y agentes cardiovasculares. Al comparar las condiciones de prescripción aprobadas por la FDA y la ANVISA, se observó que los criterios de la ANVISA eran menos específicos. Conclusiones: La prescripción de fármacos off-label y unlicensed es frecuente en los cuidados intensivos neonatales aplicando los criterios de cualquiera de las dos agencias, los criterios de la FDA son más específicos en cuanto a los grupos de edad y las indicaciones para los que se autoriza el uso de los fármacos.

Use of intrathecal gadolinium for contrast-enhanced myelography and cisternography remains off-label and is currently not FDA-approved. We report a 70-year-old male who underwent CT myelogram utilizing off-label high-dose intrathecal gadolinium who developed altered mental status and bilateral hearing loss. Workup ruled out meningitis (infectious and aseptic), infectious encephalopathy, encephalitis, and hypothyroidism. MRI of the brain and lumbar spine without contrast displayed fluid collection in L4-5 interspace and diffuse cerebrospinal fluid (CSF) hyperdensity consistent with intrathecal gadolinium. The patient eventually improved with high-dose IV dexamethasone and supportive care and resolution of diffuse CSF hyperdensity was observed on repeat MRI. There are limited data demonstrating the safety of low-dose intrathecal gadolinium due to which usage remains off-label. Our case highlights the need for caution when using substances for off-label indications and reinforces the usage of less invasive and noninvasive diagnostic modalities when possible.

The potent oral inhibitor of BCL2, venetoclax (VEN), used to treat adults with chronic lymphocytic leukaemia, has been approved in US for the treatment of naïve patients with acute myeloid leukemia (AML) unfit for intensive chemotherapy and recently in Europe, too. However, the drug has been used for years in combination with hypomethylating agents (HMAs) in patients not eligible to other treatment option, according to the so-called off-label use. We collected real-world data about patients treated with VEN + HMAs in the context of a pharmacovigilance project focused on the evaluation of the safety and effectiveness of drugs used for unapproved indication in Italian hospitals. From March to December 2020, 24 patients started treatment with VEN combined with HMAs. 21 patients have been assessed for response. Eleven (52%) patients reached complete remission (CR), and three patients (14%) CR with partial hematological recovery (CRh), with a median duration of response of 4.5 months (range 0.5–12.5). 19 patients experienced at least 1 adverse drug reaction (ADR), mostly serious, including 3 deaths (9% of ADRs; 12.5% of patients) in febrile neutropenia. Hematological toxicities and infections (cytopenia, neutropenia, febrile neutropenia, sepsis), were the most reported ADRs (84.4%). In general, neutropenic fever occurred more frequently in patients treated with decitabine (7 out of 9, 78%) compared to azacitidine (5 out of 15, 33%; p = 0.03), whereas response assessment did not differ based on used HMA (p = 0.1). These results confirm the benefit-risk profile of VEN in a real-world setting of patients with no adequate therapeutic options.

Off-label use is frequently practiced in primary and revision arthroplasty, as there may be indications for the application of implants for purposes outside the one the manufacturers intended. Under certain circumstances, patients may benefit from selective application of mix & match. This can refer to primary hip arthroplasty (if evidence suggests that the combination of devices from different manufacturers has superior results) and revision hip or knee arthroplasty (when the exchange of one component only is necessary and the invasiveness of surgery can be reduced). Within the EFORT ‘Implant and Patient Safety Initiative’, evidence- and consensus-based recommendations have been developed for the safe application of off-label use and mix & match in primary as well as revision hip and knee arthroplasty. Prior to the application of a medical device for hip or knee arthroplasty off-label and within a mix & match situation, surgeons should balance the risks and benefits to the patient, obtain informed consent, and document the decision process appropriately. Nevertheless, it is crucial for surgeons to only combine implants that are compatible. Mismatch of components, where their sizes or connections do not fit, may have catastrophic effects and is a surgical mistake. Surgeons must be fully aware of the features of the components that they use in off-label indications or during mix & match applications, must be appropriately trained and must audit their results. Considering the frequent practice of off-label and mix & match as well as the potential medico-legal issues, further research is necessary to obtain more data about the appropriate indications and outcomes for those procedures. Cite this article: EFORT Open Rev 2021;6:982-1005. DOI: 10.1302/2058-5241.6.210080

Purpose: Various solutions have been put forward for prescribing and reimbursing treatments outside their registered indications within universal healthcare systems. However, most off-label oncology prescriptions are not reimbursed by health funds. This study characterized the financing sources of off-label oncology use and the predictors of the decision to forego treatment.Materials and Methods: All 708 off-label oncology requests submitted for approval in a large tertiary cancer center in Israel between 2016 and 2018 were examined for disease and patient sociodemographic characteristics, costs and financing sources, and the factors predicting actual off-label drug administration using multivariate logistic regression analysis.Results: The mean monthly cost of a planned off-label treatment was ILS54,703 (SD = ILS61,487, median = ILS39,928) (approximately US$ 15,500). The main sources of funding were private health insurance (25%) and expanded access pharma company plans (30%). Approximately one third (31%) of the requests did not have a financing source at the time of approval. Of the 708 requests, 583 (or 82%) were filled and treatment was initiated. Predictors for forgoing treatment were the impossibility of out-of-pocket payments or the lack of a financing solution (OR = 0.407; p = 0.005 and OR = 0.400; p < 0.0005).Conclusion: Although off-label recommendations are widespread and institutional approval is often granted, a large proportion of these prescriptions are not filled. In a universal healthcare system, the financing sources for off-label treatments are likely to influence access.

Background: Understanding the prescription pattern of medications in a population can help reveal the potential usage scenarios, including off-label prescriptions, and the need for precision medicine implementation. Therefore, the aim of this study was to assess the prescription pattern and off-label use of antipsychotics in the Qatari population.Methods: We performed a cross-sectional study of Qatari patients who received antipsychotic prescriptions from the major healthcare providers in the country during the 2-year period between June 2018 and May 2020. The number of patients, prescriptions dispensed, and clinical indications were collected and statistical analysis using chi-square test was conducted.Results: Among the 9,349 Qatari patients prescribed with antipsychotics during the study period, the majority were female (57%; p < 0.001) and were in the age categories 20–39 and 30–39 years (both 22%; p < 0.001). Among the 35,938 antipsychotic prescriptions dispensed, second-generation antipsychotics were the most highly prescribed (59%), specifically, quetiapine (16%) and olanzapine (12%), but the first-generation antipsychotic prochlorperazine (13%) was also highly prescribed. Most of the indications of antipsychotics (69%) were for off-label use such as for controlling chronic diseases, sleeping disorders, benign paroxysmal positional vertigo and irritable bowel syndrome.Conclusion: Non-mental health and off-label prescriptions of several antipsychotics were observed. Integration of this data with pharmacogenomic and clinical outcome data will help in determining the course of action for implementing personalized and precision medicine in the country and beyond.

Background The off-label use of antipsychotic medications is common in many countries, and the extent of such use in psychiatric inpatients in China has not been sufficiently studied. The purpose of this study was to survey the incidence and examine the correlates of off-label antipsychotic use in a large, nationally–representative sample in China. Methods This study included discharged psychiatric patients between March 19 and 31, 2019 from 41 tertiary psychiatric hospitals across 29 provinces in China. Their socio-demographic and clinical data were collected and analyzed. Results After excluding patients with schizophrenia spectrum disorder or bipolar disorder, 981 patients were included in the analysis. Overall, antipsychotics were prescribed to 63.2% (95%CI 60.2–66.2%) of the sample. Antipsychotics were used in a wide spectrum of psychiatric disorders, with the rate being the highest among patients with dissociative (conversion) disorders (89.9, 95%CI 83.0–94.8%), organic mental disorders (81.7, 95%CI 73.1–88.7%), dementia (79.0,95%CI 67.8–87.9%), obsessive-compulsive disorder (77.8, 95%CI 55.7–92.5%), mental disorders due to psychoactive substances (75.3,95%CI 64.7–84.2%), behavioural and emotional disorders with onset usually occurring in childhood and adolescence (71.4, 95%CI 45.5–90.1%), somatoform disorders (63.2, 95%CI 40.8%–82..2%), major depression disorder (53.7,95%CI 48.8–58.6%), anxiety disorder (38.8,95%CI 30.5–47.7%), and insomnia (25.0, 95%CI 8.5–28.9%). The top three most commonly used antipsychotics were olanzapine (29.1%), quetiapine (20.3%) and risperidone (6.8%), and their corresponding average doses were 9.04 ± 5.80 mg/day, 185.13 ± 174.72 mg/day, and 2.98 ± 1.71 mg/day, respectively. A binary logistic regression showed that younger age, having the Employee Health Insurance or Residents Health Insurance, having psychotic symptoms and requiring restraint during hospitalization were significantly associated with off-label use of antipsychotics. Conclusion Off-label use of antipsychotics is very common in psychiatric inpatients in China, mainly with moderate-dose use of single agents. However, the efficacy and safety of this practice is uncertain for many diagnoses and for the elderly. Clinicians should be cautious about this practice while waiting for more research data.

Despite the availability of a lot of effective disease-modifying drugs, multiple sclerosis (MS) (in particular the progressive forms) still represents an important unmet medical need, because of issues in terms of effectiveness, duration of response, safety, and patient compliance. An increasing body of evidence from randomized clinical trials and real-world data suggest that rituximab is a highly effective alternative in both relapsing and progressive MS, with a low discontinuation rate, related to a good benefit/risk profile, and a good compliance. To date, the use of rituximab in patients with multiple sclerosis is not in accordance with the authorized product information (off-label use). However, the use of this medicine is widespread in several countries, and in some cases, it is the most commonly used disease-modifying drug for MS subtypes. This use could be officially recognized by national regulatory authorities, according to specific procedures, to ensure equal access for patients to a safe and effective option.

Teriparatide belongs to osteo-anabolic compounds and has been used in recent years to treat patients with osteoporosis, with the benefits of increased bone density. Its osteo-anabolic action has led to the investigation of the use of teriparatide for the improvement of bone quality. Apart from the enhancement of fracture union, teriparatide has been extensively studied in the promotion of fusion rate after spinal fusion. This study summarizes the preclinical and clinical results of the off-label use of teriparatide in the spine, and specifically its intermittent administration after instrumented spinal arthrodesis along with its impact on the spinal bone quality and spinal bone mineral density.

Recent randomized controlled clinical trials (RCTs) have revolutionized acute ischemic stroke care by extending the use of intravenous thrombolysis and endovascular reperfusion therapies in time windows that have been originally considered futile or even unsafe. Both systemic and endovascular reperfusion therapies have been shown to improve outcome in patients with wake-up strokes or symptom onset beyond 4.5 h for intravenous thrombolysis and beyond 6 h for endovascular treatment; however, they require advanced neuroimaging to select stroke patients safely. Experts have proposed simpler imaging algorithms but high-quality data on safety and efficacy are currently missing. RCTs used diverse imaging and clinical inclusion criteria for patient selection during the dawn of this novel stroke treatment paradigm. After taking into consideration the dismal prognosis of nonrecanalized ischemic stroke patients and the substantial clinical benefit of reperfusion therapies in selected late presenters, we propose rescue reperfusion therapies for acute ischemic stroke patients not fulfilling all clinical and imaging inclusion criteria as an option in a subgroup of patients with clinical and radiological profiles suggesting low risk for complications, notably hemorrhagic transformation as well as local or remote parenchymal hemorrhage. Incorporating new data to treatment algorithms may seem perplexing to stroke physicians, since treatment and imaging capabilities of each stroke center may dictate diverse treatment pathways. This narrative review will summarize current data that will assist clinicians in the selection of those late presenters that will most likely benefit from acute reperfusion therapies. Different treatment algorithms are provided according to available neuroimaging and endovascular treatment capabilities.

We present the case of a 62-year-old man who sustained a traumatic distal aortic injury associated with an adjacent lumbar vertebral body fracture resulting from a 20-ft fall. Given the site of injury, an iliac artery branched endograft was deployed off-label to preserve the aortic bifurcation and cover a limited amount of healthy aorta to preserve the collaterals. The procedure was successful, with no intraoperative complications or evidence of an endoleak. The aortic bifurcation and distal iliac arteries remained widely patent by computed tomography angiography at the follow-up examination without evidence of sequelae.

Background: Unlicensed (UL) and Off-label (OL) prescription of medications is common in paediatrics and does not constitute negligent practice since there is often no approved alternative according to FDA bulary. Aim: The study aimed to determine the current frequency of UL and OL prescriptions in children from one month to 12 years of age in a Paediatric Inpatient Unit (PIU). Methods: This is an observational, prospective study, reviewing the prescriptions of all patients admitted to the PIU in a university hospital in a single week in August 2014 and a single week in January 2015. Results: We included 157 patients of median age 18 months and median length of stay 24 days. There were 1,328 prescription items (average of 8.4 items/patient) and only two patients without UL/OL use. During the winter season (August), 27% of prescriptions were classified as UL and 44.6% as OL, and during summer (January), 29.6% as UL and 45.1% as OL. We identified 188 medications, of which the most prescribed were paracetamol (11%) and dipyrone (9.5%). The most frequent OL classification was regarding drug formulation (15.8%). In the winter week, the most frequent reasons for admission were respiratory (44%), followed by other clinical causes (CC) (17.3%), while in the summer week, they were CC (26.3%), followed by surgical and gastrohepatic (23.7%). Conclusion: The OL prescription of medicines for children in Brazil is in accordance with the international literature. The higher prevalence of OL due to formulation found in this study is related to the use of formulations other than those used by the FDA.

PURPOSE: Apremilast is a phosphodiesterase-4 inhibitor FDA approved for psoriatic arthritis and moderate to severe plaque psoriasis. In recent years, multiple studies have suggested other potential uses for apremilast in dermatology. A summary of these various studies will be a valuable aid to dermatologists considering apremilast for an alternative indication. MATERIALS AND METHODS: The PubMed/MEDLINE and ClinicalTrials.gov databases were queried with the term ‘apremilast,’ with results manually screened to identify published data on off-label uses of apremilast. The article was structured by the quality of evidence available. RESULTS: Apremilast use in dermatology beyond plaque psoriasis and psoriatic arthritis is frequently described in the literature, with a mixture of positive and negative results. Randomized controlled data is available for Behçet’s disease, hidradenitis suppurativa, nail/scalp/palmoplantar psoriasis, alopecia areata, and atopic dermatitis. CONCLUSION: The relatively safe adverse effect profile of apremilast and its broad immunomodulatory characteristics may make it a promising option in the future for patients with difficult to treat diseases in dermatology, refractory to first line therapies, but further studies will be necessary to clarify its role.

Aims Antipsychotics are primarily labelled for the treatment of severe mental illness and have documented clinical utility in certain neurological disorders or palliative care. However, off-label use of antipsychotics is common and increasing, and prior studies on antipsychotic utilisation have not specifically assessed users in neurology, palliative care or general practice. We aimed to explore diagnoses associated with antipsychotic use, treatment patterns and characteristics of users without diagnoses relevant to antipsychotic treatment. Methods Population-based study identifiying all users of antipsychotics in Denmark (pop 5.7 mio.) 1997–2018 in the Danish National Prescription Register (DNPR). Possible indications for antipsychotic therapy were evaluated using in- and outpatient contacts from the DNPR. Users were divided hierarchically into six groups: severe mental disorders (schizophrenia, bipolar-spectrum disorders), chronic mental disorders (dementias, mental retardation, autism), other mental disorders (depression-spectrum, anxiety and personality disorders, etc.), selected neurological diseases, cancer and antipsychotic users without any of these diagnoses. This last group was characterised regarding demographics, antipsychotic use, health care utilisation and likely antipsychotic treatment initiator in 2018. Results Altogether, 630 307 antipsychotic users were identified, of whom 127 649 had filled prescriptions during 2018. Users without diagnoses relevant to antipsychotic treatment comprised of the largest group (37%), followed by schizophrenia and bipolar-spectrum disorders (34%), other mental disorders (15%), dementia, autism and mental retardation (11%), cancer (2.2%) and neurological diagnoses (2.0%). Of 37 478 incident users in 2018, 39% had no diagnosis relevant to antipsychotic treatment, 7.9% had major depression, 7.7% neurotic/stress-related disorders and 7.5% dementia. Quetiapine was most commonly used, both overall (51%) and among users without diagnoses relevant to antipsychotic treatment (58%). Of 14 474 incident users in 2018 without diagnoses relevant to antipsychotic treatment, treatment was most likely initiated by a general practitioner (65%), with only 17% seeing a psychiatrist during the following year. As many as 18% of patients with adjustment disorders and 14% of those without relevant diagnoses for antipsychotic use, remained on antipsychotic treatment 5 years after their first prescription. Conclusions Over one-third of antipsychotic users in Denmark did not have psychiatric, neurological or cancer diagnoses as possible indications for antipsychotic therapy. Many antipsychotics are initiated or prescribed in general practice, and a concerningly large subgroup without documented diagnoses relevant for antipsychotics continued to receive them. Rational prescribing, adequate side effect monitoring and further research into reasons for the observed antipsychotic use patterns and their risk–benefit ratio are needed.

Fertility preservation represents one important goal of cancer patients’ management due to the high impact on health and quality of life of survivors. The available preventive measures cannot be performed in all patients and are not feasible in all health-care facilities. Therefore, the pharmacological treatment with GnRHa has become a valuable non-invasive and well-tolerated alternative, especially in those who cannot access to cryopreservation options due to clinical and/or logistic issues. Supporting data demonstrate a significant advantage for the survivors who received GnRHa in the long-term maintenance of ovarian function and preservation of fertility. The prevention of the risk of ovarian failure with GnRHa is a typical off-label use, defined as the administration of a medicinal product not in accordance with the authorized product information. Italy has officially recognized the off-label use of GnRHa in adult women at risk of premature and permanent menopause following chemotherapy. However, fertility preservation still represents an unmet medical need in adolescents who cannot access to other treatment options.

espanolIntroduccion. Determinar las indicaciones, tasa de exito y efectos adversos del tratamiento con ceftarolina fosamil en un hospital terciario. Material y metodos. Se analizaron retrospectivamente 84 casos desde febrero de 2018 a diciembre de 2019. No se aplicaron criterios de exclusion. Resultados. Ochenta y cuatro pacientes, con una mediana de edad de 70 anos, de los cuales el 6,7% (56) eran varones, fueron tratados con ceftarolina fosamil durante una mediana de 14 dias. La mayoria de las indicaciones se realizaron fuera de ficha tecnica, incluidas 29 endocarditis (34,5%), 14 bacteriemias (16,6%), 5 infecciones de sistema nervioso central (6%) y 19 infecciones osteoarticulares (22,6%). Staphylococcus aureus fue el microorganismo aislado con mas frecuencia, incluidos 28 S. aureus sensibles a meticilina (SASM; 33,3%) y 14 S. aureus resistentes a meticilina (SARM; 16,7%), seguidos por Staphylococcus coagulasa negativo (23, 27,4%). El principal motivo de prescripcion de ceftarolina fosamil fue el fracaso del tratamiento previo (41,7% de los casos). El tratamiento fue un exito en 60/84 pacientes (71,4%) y fracaso clinica o microbiologicamente en 14 (16,7%). Ocho pacientes murieron por una causa no relacionada con la infeccion y dos tenian un proceso no infeccioso. Veintidos de treinta y cinco (62,8%) pacientes a los que se les prescribio ceftarolina debido al fracaso del tratamiento previo mejoraron, incluidas ocho endocarditis y siete bacteriemias. Cinco pacientes (5,9%) presentaron efectos adversos que incluyen neutropenia, trombocitopenia, elevacion de transaminasas y elevacion de creatinina; todos excepto uno fueron leves y todos se resolvieron despues de la interrupcion del tratamiento. Conclusiones. Ceftarolina fosamil es una cefalosporina bien tolerada, eficaz contra microorganismos grampositivos multirresistentes y muchos gramnegativos. Nuestra experiencia sugiere que es eficaz como terapia de rescate o de primera linea en otras indicaciones distintas de las aprobadas actualmente. EnglishObjective. To determine the indications, success rate and adverse effects of ceftaroline fosamil treatment in a tertiary hospital. Material and methods. In total, 84 cases from February 2018 to December 2019 were retrospectively analysed. No exclusion criteria were applied. Results. Eighty-four patients, with a median age of 70 years, of which, 6.7% (56) were male, were treated with ceftaroline fosamil for a median of 14 days. Most indications were off-label, including 29 endocarditis (34.5%), 14 bacteraemia (16.6%), 5 Central nervous system (CNS) infections (6%) and 19 osteoarticular infections (22.6%). Staphylococcus. aureus was the most frequently isolated microorganism, including 28 methicillin-sensitive S. aureus (MSSA; 33.3%) and 14 methicillin-resistant S. aureus (MRSA; 16.7%), followed by coagulase-negative Staphylococcus (23, 27.4%). The main reason for ceftaroline fosamil prescription was the failure of previous treatment (41.7% of cases). Treatment was successful in 60/84 patients (71.4%) and failed clinically or microbiologically in 14 (16.7%). Eight patients died for a reason not related to the infection and two were found to have a non-infectious condition. Twenty-two of thirty-five (62.8%) patients prescribed ceftaroline because of failure of previous treatment improved, including eight endocarditis and seven bacteraemia. Adverse effects were reported in five patients (5.9%) including neutropenia, thrombocytopenia, transaminases elevation and creatinine elevation; all except one were mild and all resolved after discontinuation of treatment. Conclusions. Ceftaroline fosamil is a well-tolerated ceph alosporine, effective against multi- resistant gram-positive and many gram-negative microorganisms. Our experience suggests that it is effective as a rescue or first-line therapy in other indications than those currently approved.

The treatment landscape for multiple myeloma (MM) has dramatically changed over the last three decades, moving from no US Food and Drug Administration approvals and two active drug classes to over 19 drug approvals and at least eight different active classes. The advances seen in MM therapy have relied on both a structured approach to obtaining new labels and cautious off-label drug use. Although there are country and regional differences in drug approval processes, many of the basic principles behind off-label drug use in MM can be summarized into four main categories: 1) use of a therapy prior to the current approval regulations; 2) widespread use of a therapy following the release of promising clinical trial results but prior to drug approval; 3) use of a cheap therapy supported by clinical safety and efficacy data but without commercial backing; and 4) niche therapies for small well-defined patient populations where large clinical trials with sufficient power may be difficult to perform. This review takes a historical approach to discuss how off-label drug use has helped to shape the current treatment approach for MM.

Intravenous thrombolysis (IVT) represents the only systemic reperfusion therapy able to reverse neurological deficit in patients with acute ischemic stroke (AIS). Despite its effectiveness in patients with or without large vessel occlusion, it can be offered only to a minority of them, because of the short therapeutic window and additional contraindications derived from stringent but arbitrary inclusion and exclusion criteria used in landmark randomized controlled clinical trials. Many absolute or relative contraindications lead to disparities between the official drug label and guidelines or expert recommendations. Based on recent advances in neuroimaging and evidence from cohort studies, off-label use of IVT is increasingly incorporated into the daily practice of many stroke centers. They relate to extension of therapeutic time windows, and expansion of indications in co-existing conditions originally listed in exclusion criteria, such as use of alternative thrombolytic agents, pre-treatment with antiplatelets, anticoagulants or low molecular weight heparins. In this narrative review, we summarize recent randomized and real-world data on the safety and efficacy of off-label use of IVT for AIS. We also make some practical recommendations to stroke physicians regarding the off-label use of thrombolytic agents in complex and uncommon presentations of AIS or other conditions mimicking acute cerebral ischemia. Finally, we provide guidance on the risks and benefits of IVT in numerous AIS subgroups, where equipoise exists and guidelines and treatment practices vary.

In clinical practice, edoxaban is sometimes prescribed for off-label use based on the hypothesis that it is as safe and effective as warfarin. However, there is limited safety information on off-label use due to lack of clinical trial. We aimed to analyze the tolerability of off-label use of edoxaban and to identify patient characteristics associated with major bleeding as adverse effects. Patients under edoxaban treatment between January 2017 and December 2017 were enrolled in this retrospective cohort study. The incidence of major bleeding with off-label use compared with on-label use was analyzed using by log-rank test. Univariate and multivariate regression analysis were undertaken to detect independent variables with significant odds ratio that associated with major bleeding. After the exclusion criteria were applied, the patients were divided into two groups: off-label group (n = 30) and on-label group (n = 161). Incidence of major bleeding was found to be higher in the off-label group (13.3%) than in the on-label group (3.7%) (p

If an authorized drug is prescribed for a use that is not described in the Summary of Product Characteristics, this is defined as 'off-label use.' Methotrexate is often used off-label for dermatological indications. Off-label use is permitted if physicians can justify the treatment based on scientific evidence available to them. Our objective here was therefore to summarize the evidence for the effectiveness, efficacy, and safety of the dermatological off-label use of methotrexate in a systematic review. We searched MEDLINE, EMBASE, and CENTRAL for studies for evidence on the effectiveness, efficacy, and safety of the off-label use of methotrexate in dermatological indications up to November 2019. We used the GRADE system to rate the quality of the evidence. The search retrieved 34,583 hits of which 3566 were selected after the title and abstract screening. After the full-text screening, 143 studies were included, which involved 3688 patients in total. We found low-quality evidence for the effectiveness, efficacy, and safety of the off-label use of methotrexate in 31 dermatological diseases. To optimize the quality of evidence to support off-label use, we need high-quality studies in which well-characterized patients are treated with standardized treatments regimens using well-validated outcomes relevant to patients and physicians.

Background/Objectives: Atopic dermatitis (AD) affects up to 20% of the pediatric population, with a growing prevalence over the past 30 years. Topical corticosteroids (TCS) are commonly used as a first-line topical therapy for AD and are prescribed in 59% of all AD visits. However, some topical corticosteroids are prescribed outside of their age range indications. This paper aims to explore the frequency with which topical corticosteroids are prescribed for AD outside of their FDA-approved age range. Methods: Data on prescribing patterns for AD were obtained from the National Ambulatory Medical Care Survey (NAMCS). We assessed the frequency of off-label use of topical corticosteroids with respect to age indications in four specific age-groups, as delineated in the data (0-1, 2-7, 8-18, and 19+ years). Results: All prescribed topical corticosteroids found in the NAMCS database have an indication for AD or other inflammatory dermatoses or pruritic dermatoses. However, some medications were prescribed outside of their FDA-approved age indications. These off-label prescription rates ranged from 52% for desoximetasone to 0% for halobetasol and alclometasone, or rates lower than could be detected by our study. Conclusions: Much like other medications for AD treatment, TCS are sometimes used off-label. The off-label use of topical corticosteroids to treat pediatric AD highlights a gap between clinical practice and regulating guidelines. Additional pediatric studies would offer a greater body of evidence to maintain or expand label indications for the use of TCS in younger patients.

This work aimed to establish whether paediatric needs in cardiovascular diseases have been met by paediatric investigation plans (PIPs) produced since the development of the European Union Paediatric Regulation in 2007. The European Medicines Agency repository was searched for patterns in the development of paediatric medicines in general. Next, positive PIPs related to cardiovascular diseases were scrutinized for outcomes and compared to specific paediatric cardiovascular needs. In total, 1866 PIPs were identified with 12% corresponding to decisions taken for cardiovascular medicines. However, despite this therapeutic area having the greatest number of overall PIPs, only 14% of established needs in paediatric cardiovascular diseases were addressed by PIPs with positive decisions. Further, 71.9% of PIPs with decisions in cardiovascular disease corresponded to full waivers, so the product would not be studied in paediatrics. Despite the progress found in overall numbers of PIPs published, cardiovascular products are still commonly used off-label in paediatrics. Particularly, there is a need to develop products to treat heart failure and hypertension, two areas with clear unmet clinical needs in paediatrics. A case study on valsartan showed that industry, regulators, health technology assessment bodies, and prescribers should work together to reduce off-label use of paediatric cardiovascular diseases (CVD).

Itolizumab, an anti-CD6 monoclonal antibody, has been recently approved for the off-label indication of cytokine release syndrome in the background of COVID-19, by the Drug Controller General of India. However, this drug has not been included in the National Clinical Management Protocol for COVID-19 yet. The limited-to-no experience of the Indian health workforce with the drug urged us to conduct a situational analysis in the pre-COVID era to analyse the degree of use of the drug and the indications for which it has been employed.

The year 2020 is facing one of the worst public health situations in decades. The world is experiencing a pandemic that has triggered significant challenges to healthcare systems in both high and low‐middle income countries (LMICs). Government policymakers and healthcare personnel are experiencing real‐life ethical dilemmas and are pressed to respond to these situations. Many possible treatments are being investigated, one of which is the use of hydroxychloroquine or chloroquine. These drugs are approved for use by patients with systemic lupus erythematosus (SLE), rheumatoid arthritis, and malaria. The demand for these products has increased, and the stocks are depleting for the patient population for whom the drugs are intended initially. Although both innovator and generic pharmaceutical manufacturers are making plans for increased production, there are challenges with global supply chains disruption and the retention of supplies for local markets. This may cause countries that rely on the importation of pharmaceuticals to be out of stock of supplies for an extended period. There are allegations of off‐label prescribing and hoarding. Pharmacists are the custodians and dispensers of medications and are faced with the task of assessing prescriptions and making decisions about the allocation of these products. This paper seeks to 1) highlight some of the ethical challenges of dispensing hydroxychloroquine by pharmacists during the COVID‐19 pandemic, 2) identify some of the responses to these issues from various regulatory authorities in the USA, and 3) recommend approaches to assist pharmacists in their decision‐making process, especially in LMICs.

Background Recent reports suggest an important contribution from frequent off-label use of apixaban 2.5 mg twice daily to the higher rates of thromboembolic events observed in observational studies (OSs) relative to in randomized controlled trials (RCTs), and consequently, advocate against such use in all patients.Objectives To examine factors contributing to the higher thromboembolic event rates, we estimated the prevalence of off-label use in contemporary practice, and compared patient characteristics and rates of stroke/systemic embolism, major bleeding, and mortality by apixaban dose and by study design in a systematic review and meta-analysis.Results and Discussion We identified 18 OSs and 2 RCTs that included 155,228 and 11,928 patients, respectively. Patients in OSs more often received apixaban 2.5 mg twice daily (31.3% vs. 5.1%), were older (mean age 73.8 vs. 69.8 years), and had higher CHA2DS2-VASc scores (mean 3.6 vs. 2.9) versus those in RCTs. We observed a consistent pattern of higher rates of thromboembolic events, bleeding, and mortality in patients treated with 2.5 versus 5 mg twice daily apixaban in both OSs and RCTs.Conclusion The higher risk profiles of patients in OSs versus RCTs, and higher rates of both bleeding and mortality not attributable to thromboembolism in patients treated with apixaban 2.5 versus 5 mg twice daily suggest that differences in patient characteristics are additional important contributors to the higher than expected thromboembolic event rates in clinical practice.

BackgroundFurosemide is approved in full term neonates to treat edema associated with congestive heart failure, cirrhosis and renal diseases. It is often administered off-label in premature neonates, to treat respiratory conditions and at doses greater-than-recommended. We conducted a national survey on behalf of the Neonatal Pharmacotherapy Study Group of the Italian Society of Neonatology (SIN), to investigate its use in Italian neonatal intensive care units (NICUs), in conformity with current guidelines.MethodsBetween December 2016 and June 2017, a 14-item multiple-choice online questionnaire was sent to all NICU directors from the SIN directory.Gestational age, route of administration, posology, indications, referenced guidelines, adverse effects monitoring and the presence of Paediatric Cardiology or Cardiosurgery service on site were assessed. A chi-square test was performed 1) to evaluate differences in the distribution of responses between NICUs administering furosemide at doses higher-than-recommended; 2) to compare the proportion of NICUs administering furosemide at high doses in institutions with versus without a Paediatric Cardiology or Cardiosurgery service.ResultsThe response rate was 50% (57/114). The intravenous and oral routes were chosen primarily; the intravenous administration in single doses predominated over continuous infusion. Its main therapeutic indications were congestive heart failure/overload (94.7%) and oligo-anuria (87.7%) however furosemide was also frequently used for broncopulmonary dysplasia (50.9%) and respiratory distress syndrome and/or transient tachypnea of the newborn (24.6%).In 28/57 NICUs furosemide was administered at doses higher-than-recommended. In most NICUs the same posology was used in term and preterm neonates. Compared to the total sample, a larger proportion of NICUs administering doses greater-than-recommended referenced current literature for reasons to do so (19.3 and 32.1% respectively). The presence of a Paediatric Cardiology or Cardiosurgery service on site did not correlate with the chosen posology.The majority of NICUs performed acoustic test and renal ultrasound for furosemide exposure greater than 2 weeks.ConclusionsIn Italian NICUs, furosemide is commonly prescribed to term and preterm newborns for label and unlabeled indications. Doses greater-than-recommended are frequently administered. Such use is not necessarily inappropriate. More research is required to assess the efficacy and safety of unlabeled use.

Objectives. To provide a qualitative and a quantitative analysis of H1-antihistamines pharmacological uses pattern among children (

INTRODUCTION: Despite clinical trials, there are still no approved specific therapies or any vaccine against COVID-19 The only option available is using investigational drugs for compassionate use The update of the existing regulation regarding compassionate use is to ensure the effective and sustainable development of health policies and technologies over the COVID-19 pandemic and beyond AIM: The present short communication aimed to highlight the need for early and expanded access to investigational drugs for compassionate use as well as a call for an update of the existing regulation in Bulgaria concerning compassionate use in the era of COVID-19 MATERIALS AND METHODS: In EU and Bulgaria as well, the legal framework for compassionate use was introduced by Article 83 (1) of Regulation (EC) No 726/2004 of the European Parliament and of the Council;in principle, Regulations of the European Parliament and of the Council are mandatory for all Member States Remdesivir appears to have a favorable clinical and safety profile, as reported in a case involving patients with severe COVID-19 through a compassionate use programme RESULTS: The overall probability of clinical improvement observed in 36 of 53 COVID-19 patients received intravenous remdesivir as part of a compassionate use programme was 68% (95% CI 40% to 80%) Thirty two patients (60%) demonstrated at least one adverse event, twelve 12 patients (23%) experienced serious adverse events and seven patients (13%) died CONCLUSION: The global pandemic mandates Bulgarian Drug Agency for a reasonable update of the existing national regulation concerning compassionate use and off-label therapies In the era of COVID-19, it is important for Bulgarian patients to have early and expanded access to investigational drugs for compassionate use

The purpose of this essay is to inform others that it is possible to survive breast cancer with brain metastases. The second author is the subject patient and a long-term survivor of systemic metastatic breast cancer with numerous brain metastases (corresponding to 8% survivor group). We credit her survival to a combination of (1) medicine as practiced by an excellent oncologist with whom we developed a partnership to manage the patient’s health, (2) our informed exploration of the available scientific knowledge including a review of scientific research articles that go beyond conventional care, and (3) the patient’s supplementation with numerous repurposed drugs and other substances reported to have antitumor properties. Alongside her conventional treatment (the medical standard of care), it seems likely that this supplementation has been a key factor in the patient’s long-term survival. We also point out that the lack of follow-up magnetic resonance imaging brain scans for early detection of brain metastases poses substantial risks for patients with HER2+ metastatic breast cancer in non–central nervous system locations. Thus, we suggest that research be conducted on such early detection for possible inclusion in the recommendations for the medical standard of care. Finally, medical doctors and also patients with backgrounds in biological science may wish to consider potential options and advantages of repurposed drugs and other substances reported in scientific publications when the medical standard of care has limited options for advanced cancer and other severe chronic health conditions. However, any efforts along this line by patients should be in collaboration with their medical doctors.

This study used retrospective chart review and survey data to evaluate: (1) off‐label use of rituximab (MabThera®/Rituxan®) in autoimmune conditions and (2) patients’ receipt and knowledge of the Patient Alert Card (PAC), a risk minimization measure for progressive multifocal leukoencephalopathy (PML) and serious infections. Anonymized patient data were collected from infusion centers in Europe from December 2015 to July 2017. Adults receiving rituximab in the same centers were provided a self‐administered survey. Outcomes included patterns of off‐label rituximab use for nononcology indications, and evaluation of patients’ receipt and knowledge of the PAC and its impact. Of 1012 patients in the retrospective chart review, 70.2% received rituximab for rheumatoid arthritis or granulomatosis with polyangiitis/microscopic polyangiitis, and 29.8% received rituximab off label. Among 524 survey participants, 32.8% reported receiving the PAC, 59.3% reported not receiving the PAC and 7.9% did not know whether they received the PAC. A total of 72.4% of patients reported that they were unaware that some patients receiving rituximab experience PML. A higher proportion of PAC recipients identified PML as a potential risk of rituximab than nonrecipients (37.8% vs 19.9%); 58.3% of PAC recipients had poor awareness of PML. Most PAC recipients (90.0%) and nonrecipients (85.5%) correctly answered that they should seek medical attention for infection symptoms. In conclusion, approximately 30% of patients received off‐label rituximab. Most patients reported not receiving the PAC or having knowledge of PML but demonstrated understanding of the recommended action in the event of infection symptoms, regardless of PAC receipt.

Background: Tanreqing injection (TRQ) is a traditional Chinese medicine commonly used in China to treat pulmonary diseases presenting as phlegm-heat syndrome. Robust data on the safety of TRQ from real-world observational cohorts are currently lacking. Objective: To evaluate as the incidence, type, and predictors of adverse events (AEs) and adverse drug reactions (ADRs) of TRQ in clinical practice in China. Methods: We conducted a population-based cohort, multicenter study to evaluate the incidence, manifestation, outcomes, and risk factors of AEs and ADRs following TRQ use in China. Between April 2014 and May 2015 a total of 30,322 consecutive inpatients/emergency attendance patients from 90 hospitals across China administrated TRQ were followed-up for 7 days. Odds ratios (ORs) with 95% confidence intervals (CIs) were estimated using logistic regression to identify predictors of ADRs. Results: The incidence of AEs and ADRs was 1.4 and 0.3%, respectively. Skin and subcutaneous tissue disorders were the most common ADRs. All ADRs were mild or moderate in severity, except for one serious case of anaphylactic reaction. The majority of ADRs (72.8%) occurred in the first 2 h after TRQ administration. Two-thirds of patients (66.1%) in the study were prescribed TRQ off-label, including infants aged ≤24 months. A history of food allergy (OR 4.50, 95% CI: 1.35–15.00), drug allergy (OR 2.77, 95% CI: 1.56–4.94), and fast infusion speed (off-label use) (OR 2.10, 95% CI: 1.27–3.50) were associated with an increased risk of ADRs. Conclusion: TRQ is well tolerated in the general population, yet off-label use is prevalent. Efforts are required to educate prescribers to adhere to the drug label in order to minimize potential patient harm.

Background Massive bleeding is one of the commonest salvageable causes of death. The search for an ideal haemostatic agent during massive bleeding is still ongoing. One of the novel haemostatic medications is recombinant activated factor VII (rFVIIa). To date, the usage of rFVIIa during massive haemorrhage among non-haemophiliac patients remains off-label. The aim of this study is to report our experience in using rFVIIa to treat refractory bleeding. Methods Medical records of all patients treated with rFVIIa for massive bleeding over an eleven-year period in a single institution were recorded. Treatment indications, 24-h and 30-day mortality, changes in transfusion needs and coagulation profiles after rFVIIa administration were analysed. Results rFVIIa were administered in 76 patients. Of these, 41 (53.9%) were non-surgical bleeding, followed by 22 patients (28.9%) with trauma, other surgery bleedings in 9 patients (11.8%) and 4 patients (5.4%) with peripartum haemorrhage. Total survival rate was 78.9% within 24 h and 44.7% over 30 days. Among all these patients who had received rFVIIa due to life-threatening haemorrhage, blood and blood product requirements were significantly reduced (P

Non-steroidal anti-inflammatory drugs (NSAIDs) are liders in selling both in the Russian Federation and worldwide. The combination of analgesic, anti-inflammatory and antipyretic effects make the drugs of this group very popular in patients with various diseases. The realization of NSAIDs in pharmacies occurs both by prescription and over-the-counter, so the safety assessment of the use of this group of drugs remains relevant. In the current practice, self-administration (responsible selfmedication) of drugs of the NSAID group is an additional factor affecting the safety of their intake. According to the studies, about 40 % of patients taking NSAIDs consider that NSAIDS are absolutely safe, and more than 30 % of those taking OTC NSAIDs use them in excess of the recommended dosages. We analyzed 3963 individual case safety reports (ICSR) in the federal database «Pharmacovigilance» from 07.12.2008 to 31.08.2017. The inclusion criterions was the presence of information on the off-label application of NSAIDs in the ICSR, reports of adverse effects that may be associated with the use of this drug or erroneous reports on the active substance, which was not present in this drug. The most frequent mistakes in the application were an increase of the daily dose, a change in the method of administration to patient who are contraindicated with this drug. There were 9 ICSR of burning sensation in the anus with the introduction of ibuprofen suppositories (not in the label), and 7 ICSR of ineffectiveness of the active substance, which was not present in this drug.

In the 1980s, recombinant human erythropoietin (rhEPO) began to be used in clinical practice. In this study, the clinical application of rhEPO from single-center in recent ten years was reviewed, and the scope of indications and clinical efficacy were evaluated. The medical records of 35829 in-patients who were treated with rhEPO in the first Medical Center of the Chinese PLA General Hospital from 2009 to 2018 were collected. According to the scope of indications approved by CFDA (China Food and Drug Administration), curative effect and off-label of rhEPO were analyzed. Of the 35829 patients, 19013 (53.1%) were male and 16816 (46.9%) were female, with an average age of (52.1 ± 18.6) years. The usage of rhEPO is increasing year by year. The overall effective rate was 53.1%. The number of patients who met the indications accounted for 67.2%, and the effective rate patients with indications and Off-label were 48.8% and 50.7%. Among the patients with irregular use of rhEPO perioperative imperfect laboratory examination patients accounted for the highest proportion (7.1%). The volume of RBC(s) (red blood cell(s)) transfusion in patients with rhEPO was significantly less than that in patients without rhEPO (p

Psychosis after traumatic brain injury (TBI) occurs in up to 10% of cases. Although guideline consensus is lacking regarding drugs of choice for this condition, current literature points to the use of atypical antipsychotics. This case describes a 58-year-old male with major neurocognitive disorder due to TBI with behavioral disturbance that was successfully treated with paliperidone palmitate. In addition to the off-label use of paliperidone, this case also explores the use of forced medication as the initial injection was given per guardian consent. After completion of a literature review, this appears to be the first case report describing the use of a long-acting antipsychotic for the treatment of TBI-related psychosis. This case suggests that paliperidone palmitate may be efficacious for psychosis following TBI; however, further study is warranted.

Off-label use of rituximab is commonly requested for patients with resistant nephropathies. The outcomes and tolerability of rituximab in adult patients with nephropathy treated at our hospital (from 2013 to 2018) were described. Data were retrieved from electronic medical records. Response was classified as complete remission (CR), partial remission (PR), or no response (NR) according to the KDIGO criteria. A total of 89 requests were received for 61 patients. Median age was 58 years (45.9% female). Idiopathic membranous nephropathy (MN) (n = 30) was the most frequent indication, followed by minimal change disease (MCD) (n = 15) and secondary membranoproliferative glomerulonephritis (MPGN) (n = 12). Three patients with focal segmental glomerulosclerosis (FSGS) were included. After most treatment cycles in MN, a CR or PR was observed, median proteinuria levels significantly decreased for these patients (6000 mg/24h (IQR 3584–10,300) vs. 1468.8 (IQR 500–4604.25), p &lt, 0.01). In MPGN, no response was documented after 46.7% of rituximab cycles. A CR or PR was described with the majority of rituximab cycles in MCD, with a significant decrease in proteinuria (6000 mg/24 h (IQR 4007–11,426) vs. 196.8 (IQR 100–1300), p = 0.013). No cycles produced a response in FSGS. Mean CD19+ B-cell decreased in all types of nephropathy (10.44% vs. 0.29%, p &lt, 0.0001). Eleven patients presented infusion-related reactions, and 17 presented infectious complications. The majority of patients with MN and MCD had complete or partial responses, however, neither MPGN nor FSGS had encouraging results.

In oncology, preclinical and early clinical data increasingly support the use of a number of candidate "non-cancer" drugs in an off-label setting against multiple tumor types. In particular, metabolically targeted drugs show promise as adjuvant chemo and radiosensitizers, improving or restoring sensitivity to standard therapies. The time has come for large scale clinical studies of off-label drugs in this context. However, it is well recognized that high-cost randomized controlled trials may not be an economically viable option for studying patent-expired off-label drugs. In some cases, randomized trials could also be considered as ethically controversial. This perspective article presents a novel approach to generating additional clinical data of sufficient quality to support changes in clinical practice and relabeling of such drugs for use in oncology. Here, we suggest that a pluralistic evidence base and triangulation of evidence can support clinical trial data for off-label drug use in oncology. An example of an off-label drug protocol brought to the clinic for glioblastoma patients is presented, along with preliminary retrospective data from the METRICS study (NCT02201381). METRICS is a novel participant-funded, open-label, non-randomized, single-arm real-world study designed to gather high-quality evidence on the safety, tolerability, and effectiveness of four off-label metabolically targeted medicines as an adjunctive cancer treatment for glioblastoma patients.

The impressive potential of biologics has been demonstrated in psoriasis, hidradenitis suppurativa, and urticaria. Numerous biologicals are entering the field for a restricted number of skin disorders. Off-label use of biologics in other recalcitrant skin diseases has increased. Mounting data point to the potential of already existing biologics acting on the IL-17/IL-23 pathway in skin disorders with epidermal hyperkeratosis (e.g., pityriasis rubra pilaris), acneiform inflammation (e.g., hidradenitis suppurativa), and loss of mucosal integrity (e.g., aphthosis). TNF-alpha blockers are also effective in the latter conditions but seem of particular value in granulomatous (e.g., granuloma annulare) and neutrophilic disorders (e.g., pyoderma gangrenosum). Failure of IL-17 blockade in skin diseases resulting from immune-mediated cell destruction (e.g., alopecia areata and vitiligo) illustrates its limited involvement in Th1-dependent skin immunology. Overall, disappointing results of TNF-alpha blockers in alopecia areata and vitiligo point to the same conclusion although promising results in toxic epidermal necrolysis suggest TNF-alpha exerts at least some in vivo Th1-related activities. Acting on both the Th1 and Th17 pathway, ustekinumab has a rather broad potential with interesting results in lupus and alopecia areata. The efficacy of omalizumab in bullous pemphigoid has revealed an IgE-mediated recruitment of eosinophils leading to bullae formation. Reconsidering reimbursement criteria for less common but severe diseases seems appropriate if substantial evidence is available (e.g., pityriasis rubra pilaris). For other disorders, investigator-and industry-initiated randomized clinical trials should be stimulated. They are likely to improve patient outcome and advance our understanding of challenging skin disorders.

BACKGROUND: Off-label prescribing is encountered across various fields of medicine and creates alternative treatment options, but is associated with unknown safety risks. The use of off-label drugs for the treatment of patients with inflammatory bowel diseases (IBD) has not been characterised before.AIM: To assess the proportion and characteristics of off-label prescribing for IBD in tertiary care centres in the Netherlands.METHODS: A prospective database of IBD patients from all Dutch university hospitals was used to collect data on drug prescriptions for IBD and demographics. Drugs were classified as off-label if they were unlicensed for Crohn's disease and/or ulcerative colitis by the Medicines Evaluation Board. Uni- and multivariable analyses were used to identify patient-specific characteristics predictive of increased off-label use.RESULTS: For the induction and/or maintenance treatment of 4583 IBD patients, 12 651 historical and current drug records were available in the database. Of these, 2374 (19%) were considered off-label prescriptions. Out of 4583 IBD patients, 1477 (32%) were exposed to off-label drugs. Commonly prescribed off-label IBD drugs were mercaptopurine (18%), beclomethasone (12%), thioguanine (4%) and allopurinol (3%). Non-thiopurine/methotrexate off-label drugs were prescribed in 243 patients (6%), including biological agents or tofacitinib in 47 IBD patients (1%). Off-label prescriptions were more common in ulcerative colitis than Crohn's disease (37% vs 29%, P < 0.001). Smokers and patients that received ≥5 drug types during their disease course were more likely to be exposed to off-label drugs (smoking 33% vs 27% and multiple drug use 66% vs 22%, both P < 0.001).CONCLUSION: About one-fifth of prescriptions for IBD were off-label and one-third of IBD patients, especially ulcerative colitis patients, were exposed to off-label drugs.

The guidelines for borderline personality disorder (BPD) treatment suggest non-pharmacological treatment as the first option, but second-generation antipsychotics (SGAs) are among the overprescribed medications. This study aimed to explore Italian psychiatrists' attitudes toward off-label use of SGAs in BPD. A randomly selected sample of Italian psychiatrists completed a questionnaire regarding off-label prescription of SGAs. Most respondents reported the off-label use of SGAs. Among the reasons supporting the prescription of SGAs, the presence of strong published data was the most determining factor (51.5%). The SGA olanzapine is considered the most appropriate, followed by quetiapine and aripiprazole. Although off-label prescription of SGAs represents a common clinical practice in accordance with a worldwide trend, the use of long-acting injection formulations was considered inappropriate by 69% of psychiatrists in our sample. Our results reiterate the discrepancy between everyday clinical practice and international recommendations, and show how relevant the literature is in off-label drug prescription.

Ceftaroline fosamil is a fifth-generation cephalosporin with anti-methicillin-resistant Staphylococcus aureus (MRSA) activity. It has been approved by the EMA and FDA for the treatment of adults and children with community-acquired bacterial pneumonia (CABP) and acute bacterial skin and skin structure infections (ABSSSI). However, ceftaroline fosamil has a broad spectrum of activity, and a good safety and tolerability profile, so is frequently used off-label. The aim of this systematic review was to summarize the safety and efficacy of off-label use of ceftaroline. The review was conducted according to PRISMA guidelines. MEDLINE, EMBASE and CENTRAL databases (2010-2018) were searched using as the main term ceftaroline fosamil and its synonyms in combination with names of infectious diseases of interest. A total of 21 studies with 1901 patients were included: the most common off-label indications for ceftaroline use were bacteremia (n=595), endocarditis (n=171), osteoarticular infections (n=368), hospital-acquired pneumonia (n=115) and meningitis (n=23). The most common reasons for off-label use were persistent or recurrent infection after standard treatment or non-susceptibility to vancomycin and daptomycin. Clinical success was evaluated in 933 patients, and 724 (77%) of these reached this positive outcome. Incidence of adverse events (AEs) was reported in 11 studies. In 83 (9%) cases there were AEs related to the use of ceftaroline; the most common reported AEs were nausea, vomiting, diarrhea, rash and neutropenia. The review results show that ceftaroline may be used in clinical settings other than those currently approved; however, the use of ceftaroline in these contexts deserves further investigation.

Bipolar disorder (BD) is characterized by recurrent depressive and manic episodes. Lithium, valproate, lamotrigine, and some second-generation antipsychotics (SGAs) are the most typical pharmacological treatments for BD, the main goal being mood stabilization. However, despite these treatments, most patients continue to experience recurrent mood episodes and residual symptoms. Findings from several studies suggest that some SGAs may be beneficial beyond approved indications. The goal of the survey presented in this article was to examine Italian psychiatrists' attitudes concerning the off-label use of SGAs in depressive and maintenance phases of BD. A questionnaire about the off-label prescription of SGAs was e-mailed to 300 psychiatrists from Northern, Central, and Southern Italy affiliated with the Italian Society of Psychopharmacology (SINPF) to investigate the frequency of and motivation for off-label use of SGAs and evaluate the psychiatrists' attitude toward use of specific SGAs in BD; 202 questionnaires were completed. The respondents were equally distributed in terms of sex, and the mean age of respondents was 44.1 years. The majority of the sample reported use of SGAs for off-label indications either very often (16.7%), often (33.7%), or occasionally (34.7%). The main motivation for off-label use of the SGAs was the presence of published evidence (51.5%), followed by patients' nonresponse to previous treatment (37.1%). With regard to the use of specific SGAs in BD, off-label aripiprazole was considered appropriate for depressive episodes by 46% of the psychiatrists, followed by olanzapine which was considered appropriate by 33.7%. For maintenance treatment of BD, off-label asenapine was considered appropriate by 45% of the psychiatrists, followed by long-acting aripiprazole and olanzapine pamoate, which were considered appropriate by 37.1% and 23.8%, respectively. In summary, ~50% of Italian psychiatrists frequently (very often or often) prescribe SGAs for off-label indications. Given the relatively limited number of indicated effective treatments for BD, the use of some SGAs off-label may be considered appropriate when dealing with patients whose BD is resistant to medications with labeled indications for BD.

Introdução: Nos últimos anos, a terapêutica biológica expandiu de forma expressiva as opções terapêuticas disponíveis em Dermatologia. Ainda que o seu uso esteja apenas aprovado no tratamento da psoríase e psoríase atropática, a utilização off-label em diversas dermatoses inflamatórias tem sido descrita de forma crescente na literatura. Métodos: Efectuou-se um estudo retrospectivo dos doentes com dermatoses (que não a psoríase) tratados com terapêutica biológica entre Janeiro de 2005 e Dezembro de 2009, no nosso Serviço. Foram analisados os dados clínicos, as terapêuticas efectuadas, a eficácia e o perfil de segurança. Resultados: Foram incluídos 15 doentes e tratadas 7 diferentes patologias dermatológicas resistentes às terapêuticas convencionais. O etanercept foi utilizado em 4 casos: 3 doentes com Esclerodermia sistémica (2 doentes interromperam a terapêutica antes das 12 semanas por efeitos adversos graves; no 3º doente verificaram-se bons resultados) e um doente com granuloma elastolítico, no qual se registou uma boa resposta clínica. O infliximab foi utilizado com sucesso em 4 doentes (3 casos de doença de Behçet e 1 de pitiríase rubra pilar). O adalimumab foi utilizado num caso de dermatose pustulosa subcórnea com excelentes resultados. O efalizumab foi ineficaz em 2 casos de dermite atópica. O rituximab foi utilizado em 5 doentes: 3 casos de pênfigo (com excelentes resultados terapêuticos) e 2 casos de dermite atópica (numa doente houve uma boa resposta, mas interrompeu a terapêutica após 1 semana de tratamento por gravidez e na 2ª doente não se observou qualquer melhoria significativa). Conclusão: A terapêutica biológica tem demonstrado eficácia no tratamento de várias dermatoses; no entanto a maioria da informação disponível na literatura é referente a casos isolados ou a pequenas séries de casos. Apesar da nossa experiência ser limitada, estes resultados parecem-nos promissores na terapêutica de determinadas dermatoses inflamatórias refractárias aos tratamentos convencionais. Introduction: In recent years, the development of numerous biologic agents extended the therapeutic armamentarium available to dermatologists. Although they are currently approved only for psoriasis, experience is being accumulated with its use in the treatment of different inflammatory skin diseases. Methods: This was a retrospective study of all patients treated in our department with biologic agents for skin disease other than psoriasis. We analyzed the clinical data, previous and concomitant treatments, efficacy and safety profile of these agents in this setting. Results: 15 patients were included with 7 different skin diseases resistant to conventional therapies. Etanercept was used in 4 cases: 3 patients with scleroderma (2 patients developed major side effects and had to interrupt treatment, while the third patient had a good response) and one patient with elastolytic granuloma. Four patients were treated successfully with infliximab (3 cases of Behçet’s disease and 1 case of pytiriasis rubra pilaris). Adalimumab was used to treat a patient with subcorneal pustular dermatosis with excellent results. Efalizumab was ineffective in 2 cases of atopic dermatitis. Rituximab was used in 5 patients: 3 cases of pemphigus (with complete clinical improvement) and 2 patients with atopic dermatitis (1 patient had a good response but had to interrupt treatment because she become pregnant and in the other patient there wasn’t any clinical improvement). Conclusion: Biologic immunomodulators have demonstrated efficacy in the treatment of several dermatologic diseases; however, most of the available information are individual case reports or small case series. Despite our limited experience in this setting, these results seem promising in the treatment of some inflammatory skin diseases resistant to conventional therapies. info:eu-repo/semantics/publishedVersion

SummaryObjective In children many antiepileptic drugs (AEDs) are prescribed off-label due to a lack of well-designed randomized controlled trials (RCTs). We conducted a multicenter RCT in the Netherlands to compare levetiracetam and valproic acid as monotherapy in children with newly diagnosed epilepsy. After 2 years, we had to stop this investigator-initiated trial prematurely because the inclusion rate was too low. We analyzed the reasons for this failure, assessed the various issues involved in performing RCTs in children, and now give recommendations for future studies. Methods A questionnaire was completed by all investigators involved in the study. It included questions about the motivation to participate and the perceived reasons for recruitment failure. We also studied literature about financial, logistic, legal, and ethical aspects of RCTs in children. Results Main reasons for recruitment failure were overestimation of the number of eligible AED-naive children referred by general pediatricians; personal preferences of investigators for specific antiepileptic drugs; and the extensive administrative load due to extra regulations and guidelines for children. Fundraising for investigator-initiated trials is difficult and the majority of RCTs concerning AEDs are sponsored by pharmaceutical companies. Involving children requires balancing between protection and participation; the randomization procedure and obtaining informed consent are complex for both children and parents. Significance Performing RCTs with AEDs in children is important but complicated by logistic, regulatory, legal, and ethical restrictions. Based on our recent experience, our advice to colleagues who are planning a similar trial would be to perform a feasibility pilot study; to set up intensive collaboration with referring pediatricians; to arrange support of a clinical trials unit and a local research nurse during the complete trial period; and to incorporate the possibility of extending the recruitment period. Major investments, both financially from governmental organizations and in time, are imperative for independent RCTs in children.

ObjectivesThe aim of this study was to investigate the use of off-label (OL) and unlicensed (UL) medicines to hospitalised children in Norway, to add to the current knowledge on use of medicines in this vulnerable patient group.MethodsThe study was performed as a cross-sectional prospective study. Medication was classified as on- or off-label based on the comparison with the SmPC regarding age, indication, dosage, route of administration and handling of the product. UL products were classified as imported or pharmacy produced.Key findingsMore than 90% of children receiving medicines in our study were given OL or UL medicines. More patients received OL (83%) than UL (59%). Route of administration was the most frequently observed OL category. The vast majority of the OL prescriptions were for ‘off-patent’ products. One-third of products prescribed were UL.ConclusionsThe study confirms that medicines to children in hospital to a significant degree are being used outside or without authorisation, in spite of recent paediatric regulatory initiatives. More data are still needed on efficacy and safety of medicines used in children, data to be incorporated in the SmPC. In addition, suitable formulations are needed to ensure optimal dosing and adherence without risky manipulations.