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Introduction: The concept that children are therapeutic orphans emerged in the 1960s, triggering eventually worldwide legislation to facilitate pediatric studies, called 'Pediatric Drug Development (PDD).' However, PDD's true aim is not better medicines for children but labels in minors; minors are not another species., Areas Covered: Absorption, distribution, metabolism, and excretion (ADME) differ in preterm newborns, but babies mature. With the exception of neonatology, the justifications for clinical, pharmacokinetic, and safety studies were and are exaggerated., Expert Opinion: PDD reflects an artificial regulatory challenge, reflecting mankind's transition into a world of effective new drugs compared to previous millennia when only materials taken from nature were available. Minors need dose assessment and proof of safety; there is a tendency to exaggerate the scope of pharmacokinetic and safety studies before and after the eighteenth birthday, potentially motivated not by industry's greed, but by researchers' desire for funding and regulatory authorities' desire for recognition, specifically as since 2007 the European Medicines Agency (EMA) augmented and expanded PDD: a new type of conflict of interest in medicines' administration and mainstream medical science.

Introduction: The Woven EndoBridge (WEB) device is emerging as a novel therapy for intracranial aneurysms, but its use for off-label indications requires further study. Using machine learning, we aimed to develop predictive models for complete occlusion after off-label WEB treatment and to identify factors associated with occlusion outcomes., Methods: This multicenter, retrospective study included 162 patients who underwent off-label WEB treatment for intracranial aneurysms. Baseline, morphological, and procedural variables were utilized to develop machine-learning models predicting complete occlusion. Model interpretation was performed to determine significant predictors. Ordinal regression was also performed with occlusion status as an ordinal outcome from better (Raymond Roy Occlusion Classification [RROC] grade 1) to worse (RROC grade 3) status. Odds ratios (OR) with 95 % confidence intervals (CI) were reported., Results: The best performing model achieved an AUROC of 0.8 for predicting complete occlusion. Larger neck diameter and daughter sac were significant independent predictors of incomplete occlusion. On multivariable ordinal regression, higher RROC grades (OR 1.86, 95 % CI 1.25-2.82), larger neck diameter (OR 1.69, 95 % CI 1.09-2.65), and presence of daughter sacs (OR 2.26, 95 % CI 0.99-5.15) were associated with worse aneurysm occlusion after WEB treatment, independent of other factors., Conclusion: This study found that larger neck diameter and daughter sacs were associated with worse occlusion after WEB therapy for aneurysms. The machine learning approach identified anatomical factors related to occlusion outcomes that may help guide patient selection and monitoring with this technology. Further validation is needed., Competing Interests: Declaration of competing interest None., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Introduction: Amphotericin B is a polyene antibiotic that is used as an off-label eye drop to treat fungal keratitis. Poor solubility, permeability and high susceptibility to hydrolytic degradation make it challenging to formulate a drug delivery system. Despite its drawbacks, it is a potent antifungal drug against Candida and other fungal species. However, it has not been explored much in ocular drug delivery. Hence, this review brings into focus the potential and increasing significance of Amphotericin B in ocular drug delivery., Areas Covered: In this review, we have systematically summarized the use of Amphotericin B in ocular diseases, the various formulation challenges for Amphotericin B, along with its off-label ocular usage, and stability concerns. The degradation mechanism of Amphotericin B in different conditions was discussed in this article as well., Expert Opinion: In the last few decades, several nanocarriers have been explored to improve the formulation challenges associated with Amphotericin B. Also, due to insufficient clinical studies and unknown toxicity profile, there is no US Food and Drug Administration (FDA) approved Amphotericin B formulation for ocular drug delivery. This review aims to offer thorough information about Amphotericin B in ocular drug delivery.

Given its good tolerance and broad-spectrum, isavuconazole is increasingly used off-label as an empirical therapy of invasive fungal infections. We retrospectively reviewed isavuconazole empirical treatment during a 12-month period in four hospitals. During isavuconazole treatment (n=27), none of the patients had a mycological evidence for fungal infection, but 19% (5/27) developed liver test abnormalities without leading to isavuconazole discontinuation. Isavuconazole could be considered as an off-label empirical therapy only if patients cannot receive caspofungin or liposomal amphotericin B., (Copyright © 2024 Académie Nationale de Pharmacie. Published by Elsevier Masson SAS. All rights reserved.)

Antipsychotics (APs), especially second-generation antipsychotics, are being increasingly used around the world. At the same time their off-label use has also increased worldwide, as well as in Finland. The aim of our study was to find out the off-label prescribing of APs in Finland among physicians in different healthcare units. The study was conducted as a questionnaire survey. Particular attention was paid to practices between psychiatrists and other physicians (mostly general practitioners and occupational health doctors). Similar studies have not been conducted on this topic in Finland before. Altogether 216 physicians answered the questionnaire. The most common indications for off-label prescription were insomnia and anxiety, and this was evident for both psychiatrists as well as other physicians. Quetiapine was the one most commonly prescribed off-label AP. Over one-third of psychiatrists (39%) and about one-third of other physicians (30%) did not give instructions on the length of the treatment. The metabolic values were reported to be followed by 44% of the psychiatrists and by 18% of other physicians. Nearly two-thirds of all respondents thought that off-label use had more benefits than harms. Compared to other physicians, psychiatrists prescribed APs for off-label use more frequently and for more varied psychiatric conditions. Off-label use of APs seems to be a clinical reality in Finland. There is need for further studies on efficacy and adverse effects of APs in off-label use, and also a need for clinical guidelines on monitoring the patients using APs off-label.

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).

Background: Special approval medicines (SAMs) are medicines used with approval from the Director General of Health Malaysia when the therapeutic options within regulatory and formulary boundaries appear unsuitable or ineffective to treat the patients. Objectives: To examine and characterize the use of SAMs among children in a Malaysian tertiary care hospital. Methods: The named-patient basis SAM application forms, cover letter, pharmacist review summary and patient monitoring forms available at the Pharmacy Department between 1st January 2019 and 31st December 2020 were reviewed. Unprocessed, unapproved and stock-basis applications were excluded. The outcome measures were categories, scope, off-label use and cost of SAM. Per-patient data were analyzed descriptively. Results: Overall, 1010 patients (mean age of 8.7 ± 5.6 years) were involved in 328 SAMs applications. The most common SAMs pharmacological groups were nervous system (n = 371, 36.7%) and antineoplastic and immunomodulating agents (n = 332, 32.9%). Top three SAMs were melatonin (11.5%), scopolamine (7.6%) and cholecalciferol (7.1%). A total of 837 (82.9%) and 513 (50.8%) patients were involved in the SAMs applications for non-formulary and unregistered medicines, respectively. Unregistered, non-formulary medicines were applied for 47.3% (n = 478) of the patients. The majority of the scope for SAMs (64.7%) were to substitute the available alternatives in the national formulary which were ineffective or sub-optimal for the patients. Among the 262 patients with repeat applications, 93.8% reported disease or symptom improvement while 1.9% experienced side effects. Up to 17% of SAMs analyzed in this study were used for off-label indications. The total cost of the SAMs was RM8,748,358.38 (USD 2,090,418.86). Conclusion: The use of SAMs among children in this hospital involved unregistered, non-formulary medicines used to substitute the available alternatives in the formulary. A concerted effort is warranted in exploring supplementary mechanisms to enhance the medicine registration process and formulary system towards facilitating enhanced provision of treatment for children.

Background: This analysis describes the use of riluzole in amyotrophic lateral sclerosis (ALS) individuals with contraindications and off-label use for subjects with other motor neuron diseases (o-MND) in the Italian regions of Latium, Tuscany and Umbria.Methods: A cohort of adults with ALS prescribed with riluzole during the years 2016–2019 was enrolled from administrative healthcare databases, excluding subjects with o-MND in the preceding 5 years. Being affected by ALS for more than 5 years, presence of tracheostomy, renal or hepatic failure were considered as contraindications to the use of riluzole. A cohort of adults with o-MND was enrolled in 2016–2019 for whom off-label use of riluzole was retrieved up to 4 years, analysing over the time differences related to sex.Results: Among 206 ALS individuals prescribed with riluzole in Latium, 336 in Tuscany and 60 in Umbria, less than 1% were diagnosed with ALS for more than 5 years. Less than 2% were tracheotomised or affected by hepatic failure. Renal failure was documented for 1.9%, 2.7%, and 5.0% of ALS individuals in Latium, Tuscany and Umbria. The o-MND cohort comprised 264 subjects in Latium, 222 in Tuscany, and 66 in Umbria. Non-negligible off-label riluzole use was observed: 8.5%, 33.0%, and 4.2% in females, and 19.9%, 26.5% and 2.4% in males in Latium, Tuscany and Umbria.Discussion: Riluzole use in ALS individuals in the presence of contraindications is rare, with slightly higher numbers in presence of renal failure. Off-label use in o-MND was found to be non-negligible, with variations between sexes.

Compounds known to be successful in the treatment of alcohol use disorder include the aversive agent, Disulfiram, the glutamatergic NMDA receptor antagonist, Acamprosate, and the opioid receptor antagonists, Naltrexone and Nalmefene. Although all four are effective in maintaining abstinence or reduction of alcohol consumption, only a small percentage of patients receive pharmacological treatment. In addition, many other medications have been investigated for their therapeutic potential in the treatment of alcohol use disorder. In this review we summarize and compare Baclofen, Gabapentin, Topiramate, Ondansetron, Varenicline, Aripiprazole, Quetiapine, Clozapine, Antidepressants, Lithium, Neuropeptide Y, Neuropeptide S, Corticotropin-releasing factor antagonists, Oxytocin, PF-05190457, Memantine, Ifenprodil, Samidorphan, Ondelopran, ABT-436, SSR149415, Mifepristone, Ibudilast, Citicoline, Rimonabant, Surinabant, AM4113 and Gamma-hydroxybutyrate While some have shown promising results in the treatment of alcohol use disorder, others have disappointed and should be excluded from further investigation. Here we discuss the most promising results and highlight medications that deserve further preclinical or clinical study. Effective, patient-tailored treatment will require greater understanding provided by many more preclinical and clinical studies.

The second‐generation antipsychotic quetiapine is commonly used off‐label for its anxiolytic and hypnotic properties. However, quetiapine is associated with problematic side‐effects. We used Danish Medicinal Product Statistics and a 20% random sample of the Danish population's prescription fills (2001–2020) to describe the utilization of quetiapine and proportion of various prescriber types (general practitioner [GP], specialist in private practice, hospital physician and other prescribers) both in connection to first‐time and subsequent prescriptions. In 2020, 92% of all quetiapine was dispensed outside hospitals and the average daily dispensed quantity of quetiapine per user corresponded to 100 mg/user/d. A GP issued 53% of first‐time prescriptions and 75% of subsequent prescriptions for quetiapine in 2020. The proportion of quetiapine prescriptions issued by GPs varied by age group—from 14% among 0–17‐year‐olds to 93% among the ≥80‐year‐olds. Future initiatives on the rational use of quetiapine and related drugs, especially among adults, should target GPs. [ABSTRACT FROM AUTHOR]

Background: Given increasing community-based and off-label use of ketamine for psychiatric indications, we examined current informed consent processes from a convenience sample of outpatient ketamine clinics to identify areas of congruence with current evidence and opportunities for growth.Methods: Using a rubric developed from existing practice guidelines, we conducted an exploratory analysis of informed consent documents (IC-Docs) from 23 American clinics offering ketamine as a psychiatric treatment. Domains assessed included clinical content, procedures, and syntax.Results: Participating clinics (23/288) varied widely in their constitution, training, and services provided. We found that IC-Docs addressed a majority of consent elements, though did so variably on an item-level. Areas for improvement included communication around long-term adverse effects, treatment alternatives, medical/psychiatric evaluation prior to treatment, medical/psychological support during treatment, adjunctive psychological interventions, and subjective/dissociative-type effects. All forms were limited by poor readability.Limitations: Our study was limited by convenience sampling along with possible underestimation of verbal consent processes.Conclusions: As ketamine continues to emerge as a psychiatric intervention, both patients and providers will benefit from a deliberate consent process informed by scientific, ethical, and pragmatic factors toward the goal of shared decision-making regarding treatment. [ABSTRACT FROM AUTHOR]

The Domain Name System (DNS) is known to be one of the most widely abused protocols by threat actors to use in unconventional ways to hide under normal traffic. Apart from threat actors, DNS is being actively used or rather misused by many other service providers, vendors, and so on, to provide the intended services. An in-depth examination of the DNS logs collected over a long period revealed some very interesting legitimate use cases of the DNS protocol by the industry and other players, apart from its normal name resolution service function. We coin the term "Off-label use of DNS" to represent those use cases. Legitimate here simply means using DNS for non-malicious purposes other than what it was traditionally designed for, which is for providing domain resolution; a dictionary service mapping domain names to corresponding IP addresses. One of the main reasons DNS is used, or possibly misused, for these off-label use cases is the speed of data transfer and reduced overhead in terms of bandwidth. These off-label use cases of DNS can often leak important information about the clients and software they are running and can be leveraged in a variety of ways by the network security defenders/analysts to improve their detection on the network. This research will detail some of those legitimate off-label use cases and how they can be leveraged by the analysts to detect malware trends in the network and much more just by analyzing an enterprise's DNS logs. [ABSTRACT FROM AUTHOR]

Ustekinumab is approved for the treatment of psoriasis and Crohn's disease. Because many dermatological conditions are due to immune-mediated development, ustekinumab may be effective in other conditions. A systematic review of the off-label uses of ustekinumab, as well as on-label adverse effect, was performed, reporting on clinical improvement. MEDLINE, Embase, Web of Science, and Cochrane databases were searched for studies regarding ustekinumab treatment of rativa (HS), lichen planus (LP), pyoderma gangrenosum (PG), pityriasis rubra pilaris (PRP), cutalopecia areata (AA), atopic dermatitis (AD), Bechet's disease, bullous pemphigoid (BP), hidradenitis suppuaneous sarcoidosis, cutaneous systemic lupus erythematosus (SLE), and vitiligo. Descriptive statistics were performed. 74 articles of 4596 screened were included, and reported on 212 patients receiving ustekinumab treatment. Across all studies, ustekinumab showed promise in treating patients: AA (10/12 patients; 83.3% improvement), AD (28/74 patients; 37.8% improvement), HS (42/52 patients; 80.8% improvement), and PRP (25/27 patients; 92.6% improvement), among others. Adverse events were noted with the use of ustekinumab, including development of AA (four patients), AD (three patients), and BP (four patients), among others. Ustekinumab can be a promising option for patients with dermatological conditions refractory to traditional therapies. Adverse events must be monitored in certain patients. [ABSTRACT FROM AUTHOR]

Randomized controlled trials have demonstrated that noninsulin medications used to treat type 2 diabetes can improve health outcomes among patients with type 1 diabetes (T1D). This study assessed the effects of adjuvant diabetes medications on glycated hemoglobin (A1C), body mass index (BMI), or total daily insulin (TDI) among patients with T1D in a real-world setting. This was an analysis of the T1D Exchange Clinic Registry, using the study periods of 2010–2012, 2015–2016, and 2016–2017, to assess differences in A1C, BMI, and TDI between patients with and without adjuvant medications. The relationships between characteristics and A1C in 2015–2016 and 2016–2017 were determined. Analysis included 517 patients in the adjuvant medication cohort and 4968 in the insulin-only cohort. No significant improvement in A1C was observed. A significant difference in BMI and TDI between the insulin-only (median BMI: 25.5, 26.2, 26.4 and median TDI: 45, 44 units) and adjuvant medication cohorts (median BMI: 29.8, 30.5, 30.5 and median TDI: 51, 52 units) (p < 0.001) was observed. Patients with a continuous glucose monitor (CGM), higher education level, higher annual income, and older age were associated with lower A1C (p ≤ 0.001). Higher BMI and self-description as African American/Black were associated with higher A1C (p ≤ 0.01). Insulin pump use was associated with lower A1C (p < 0.01) in 2015–2016. Patients who used adjuvant medications did not demonstrate significant improvement in disease control. These data suggest that findings from well-designed research studies may not be consistently reproducible in real-world settings, due to patient-specific factors. [ABSTRACT FROM AUTHOR]

Sacubitril/valsartan is an angiotensin receptor/neprilysin inhibitor that the Food and Drug Administration has indicated to reduce the risk of cardiovascular hospitalization and death in patients with left ventricular ejection fraction below normal and with no specified ejection-fraction cut-off. However, clinically significant patient groups were excluded or minimally represented in sacubitril/valsartan's pivotal clinical trials. Clinicians often encounter scenarios in which a sacubitril/valsartan off-label use may be beneficial, but limited resources are available to evaluate the efficacy and safety in these patients. This state-of-the-art review describes contemporary literature for sacubitril/valsartan Food and Drug Administration off-label indications to help clinicians assess its appropriateness in these selected, clinically important groups of patients: those with acute decompensated heart failure, acute coronary syndrome, peripartum cardiomyopathy, chemotherapy-induced cardiomyopathy, adult congenital heart disease, cardiomyopathy in dialysis patients, right ventricular failure, or durable left ventricular assist device. [ABSTRACT FROM AUTHOR]

Practising the profession of a doctor involves high social recognition but also entails responsibility for the health and life of a patient. In this context, pharmacological treatment applied in compliance with the formal registration of a medicinal product does not raise any serious concerns. However, it is not always possible to administer medicine in a way that corresponds to its official characteristics. Clinical practice shows that it is often necessary to administer a medicine outside the requirements specified in the summary of product characteristics. In such cases, a legal, ethical, and typically medical problem arises. The aim of the study is to analyze the entire legal environment of the doctors’ use of medicines outside the summary of product characteristics in Poland, under Polish and European regulations. The discussion leads to the conclusion that medical personnel is fully authorized to administer a medicinal product outside its official characteristics. However, this may only take place if such a decision is based on current knowledge, the doctor’s individual experience, and acting in the best interest of the patient, as well as proper diagnosis of his/her current therapeutic needs. The legal regulations in force in Poland are sufficient in that sphere to ensure the well-being of the patient and protect the interests of the doctor, although – it should be admitted – their wording is not unambiguous enough to prevent more or less serious doubts as to their interpretation. Hence the proposal for legal clarification of the situation related to the administration of a medicine off-label. [ABSTRACT FROM AUTHOR]

Purpose: To examine trends in off‐label antipsychotic use for youth with attention‐deficit/hyperactivity disorder with and without a comorbid disruptive behavior disorder. Method: This cross‐sectional study of annual trends from 2007 through 2015 used the IQVIA PharMetrics® Plus for Academics data. We identified 165 794 commercially‐insured youth 3–18‐year‐old who had a diagnosis of attention‐deficit/hyperactivity disorder and classified them into subgroups with and without disruptive behavior disorders comorbidities. Antipsychotic use, with or without a stimulant, was the primary dependent outcome. Logistic regression estimated the odds of antipsychotic use associated with comorbid attention‐deficit/hyperactivity disorder and disruptive behavior disorders, adjusting for age, sex, study year, and other psychotropic use. Results: Over 70% of the 165 794 youth with attention‐deficit/hyperactivity disorder were 5–14‐year‐old and male, and 12% had disruptive behavior disorders. Antipsychotic prevalence, with or without a stimulant, was 4.4% in 2007 and 3.4% in 2015. Stimulants with antipsychotics increased significantly from 2007 to 2015 for females (19.5%–28.7%) and youth 15–18‐year‐old (25.9%–32.7%). Adjusting for age, sex, study year, and other psychotropic use, youth with a comorbid disruptive behavior had a 2.5 (95% CI: 2.3, 2.7) higher likelihood of receiving an antipsychotic than youth with attention‐deficit/hyperactivity disorder and no comorbidities. Conclusions: Antipsychotic use was associated with comorbid disruptive behaviors in youth with attention‐deficit/hyperactivity disorder. Off‐label antipsychotic use has increased for females and older adolescents. [ABSTRACT FROM AUTHOR]

(1) Background: The incidence of thromboembolic events is relatively low in the general population, but it increases in hospitalized children and those who underwent thrombogenic procedures. Although the evidence regarding direct oral anticoagulants (DOACs) in children with venous thromboembolism (VTE) is growing, DOACs were excluded from existing guidelines due to the lack of reliable data at that moment. Therefore, current evidence on VTE management in children needs to be critically reviewed. (2) Methods: We have conducted a literature search in the Scopus, EMBASE, and MEDLINE databases using prespecified keywords to retrieve studies published between 2010 and 2022. (3) Results: Clinical trials highlighted that rivaroxaban and dabigatran had predictable pharmacokinetic and pharmacodynamic profiles in children, similar to those observed in adults. Dabigatran and rivaroxaban had a similar safety profile to standard therapy but improved thrombotic burden and resolution during follow-up. Most studies involving apixaban and edoxaban are ongoing, and results are awaited. (4) Conclusions: Dabigatran and rivaroxaban could be valid therapeutic options for VTE management in children. In the case of apixaban and edoxaban, results from ongoing clinical studies are required before using them in pediatric VTE. [ABSTRACT FROM AUTHOR]

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

Abstract 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.

O metilfenidato é um medicamento capaz de causar alterações comportamentais, de humor e, devido seus efeitos psicoestimulantes, vem sendo utilizado de forma indiscriminada entre os estudantes para melhorar o desempenho acadêmico. O estudo teve como objetivo avaliar a prevalência do uso de metilfenidato entre estudantes universitários, bem como, seus efeitos. A pesquisa é uma revisão sistemática de literatura, em que foram reunidos artigos de forma abrangente e não tendenciosa sobre o uso indiscriminado de metilfenidato entre estudantes universitários. Os artigos foram escolhidos a partir das bases eletrônicas SCIELO, Google Acadêmico e LILACS e selecionados 27, publicados entre os anos de 2008 e 2019. O Rio Grande do Sul apresentou a maior quantidade de artigos sobre o tema, entretanto, os estados do Rio de Janeiro e São Paulo manifestaram os maiores números para o uso indiscriminado do medicamento entre os estudantes, nos anos de 2013 e 2014. Registraram-se 17 efeitos negativos em relação ao consumo da droga. São eles: taquicardia/palpitação, boca seca, perda de apetite, ansiedade, cefaleia, insônia, cansaço após uso, náuseas, aumento do estresse, dose dependência, tremores, tremores nas mãos, arritmia, anorexia, declínio da sensação de bem-estar, visão turva e euforia. Nesse sentido, foi possível verificar um levantamento geral, do período de 2008 a 2019, sobre a prática do uso inadequado do metilfenidato pelos acadêmicos brasileiros, verificando os benefícios e os malefícios dessa prática inconsequente. Os dados compilados servirão como parâmetro para outras pesquisas, assim como para o desenvolvimento de medidas preventivas e de conscientização.

• High prevalence of off-label psychotropic use was in adolescents with depression. • Off-label scenarios in high frequency are at a priority for digging evidence. • A significant gap is between limited evidence and pervasive off-label scenarios. • It is concerning to generalize adult use of psychotropic drugs to adolescence use. [ABSTRACT FROM AUTHOR]

Introduction: Information on the off–label use of Long–Acting Injectable (LAI) antipsychotics in the real world is lacking. In this study, we aimed to identify the sociodemographic and clinical features of patients treated with on– vs off–label LAIs and predictors of off–label First– or Second–Generation Antipsychotic (FGA vs. SGA) LAI choice in everyday clinical practice. Method: In a naturalistic national cohort of 449 patients who initiated LAI treatment in the STAR Network Depot Study, two groups were identified based on off– or on–label prescriptions. A multivariate logistic regression analysis was used to test several clinically relevant variables and identify those associated with the choice of FGA vs SGA prescription in the off–label group. Results: SGA LAIs were more commonly prescribed in everyday practice, without significant differences in their on– and off–label use. Approximately 1 in 4 patients received an off–label prescription. In the off–label group, the most frequent diagnoses were bipolar disorder (67.5%) or any personality disorder (23.7%). FGA vs SGA LAI choice was significantly associated with BPRS thought disorder (OR = 1.22, CI95% 1.04 to 1.43, p = 0.015) and hostility/suspiciousness (OR = 0.83, CI95% 0.71 to 0.97, p = 0.017) dimensions. The likelihood of receiving an SGA LAI grew steadily with the increase of the BPRS thought disturbance score. Conversely, a preference towards prescribing an FGA was observed with higher scores at the BPRS hostility/suspiciousness subscale. Conclusion: Our study is the first to identify predictors of FGA vs SGA choice in patients treated with off–label LAI antipsychotics. Demographic characteristics, i.e. age, sex, and substance/alcohol use co–morbidities did not appear to influence the choice towards FGAs or SGAs. Despite a lack of evidence, clinicians tend to favour FGA over SGA LAIs in bipolar or personality disorder patients with relevant hostility. Further research is needed to evaluate treatment adherence and clinical effectiveness of these prescriptive patterns. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Objectives: To analyze the current preferences of ophthalmologists for the treatment of macular edema and age-related macular degeneration (AMD) and to evaluate off-label use of bevacizumab in Turkey. Materials and Methods: All members of the Turkish Ophthalmological Association were contacted by e-mail to complete an anonymous, 47-question internet-based survey. The second part of the survey (questions 36-47) was evaluated. Results: When current legal regulations were considered, ophthalmologists used bevacizumab as the first-line agent in patients with diabetic macular edema (DME), AMD, and retinal vein occlusion (RVO) (58.25%, 55.89%, and 52.29%, respectively). When economic and legal constraints were disregarded, the participants' preference for bevacizumab in the treatment of DME, AMD, and RVO decreased (11.64%, 10.58%, and 10.93%, respectively). Approximately three-quarters (75.75%) of ophthalmologists stated that dispensing multiple syringes from a single bevacizumab bottle could increase the risk of endophthalmitis. Most participants (93.68%) did not feel legally safe from harm caused by off-label bevacizumab use. However, 66.43% of ophthalmologists stated that bevacizumab is as effective as other anti-vascular endothelial growth factor (anti-VEGF) drugs. Conclusion: Bevacizumab is widely used as a first-line treatment for all indications of anti-VEGF use in the current reimbursement conditions, which preclude the right of ophthalmologists to treat according to their own preferences. [ABSTRACT FROM AUTHOR]

Background & Objective: This study aimed to assess the clinical effectiveness of Hydroxychloroquine Sulfate (200 mg orally 8 hourlies thrice a day for 5 days), oseltamivir (75 mg orally twice a day for 5 days), and Azithromycin (500 mg orally daily on day 1, followed by 250 mg orally twice a day on days 2-5) alone and in combination (in seven groups). Methods & Analysis: An adaptive design is deployed, set within a comprehensive cohort study, to permit flexibility in fast-changing clinical and public health scenario. Primary outcomes include turning the test negative for coronavirus nucliec acid and in bringing about clinical improvement on day 7 of follow-up on a seven-point ordinal scale. The randomized study will recruit participants of either gender above 18 years of age who will test positive for SARS-CoV-2 on Quantitative Reverse Transcription Polymerase Chain Reaction (PCR). Pregnant or lactating females, and those with severe respiratory distress, or with serious comorbidities will be excluded. Randomization will be done maintaining concealment of allocation sequence using a computer-generated random number list. The sample size will be subjected to periodic reviews by National Data Safety and Monitoring Board. Ethics and Dissemination: The trial is approved by the National Bioethics Committee (No.4-87/NBC-471-COVID-19-05/20/) and institutional Ethical Review Committee. This clinical trial conducted under Good Clinical Practice is expected to inform patients clinical guidelines for the use of these drugs in newly diagnosed with SARS-CoV-2. [ABSTRACT FROM AUTHOR]

In recent years, off-label and unlicensed drug use has extensively developed in the paediatric population. For a long time, clinical trials in the paediatric population were considered complicated to perform because of ethical problems, causing frequent off-label use. Off-label drug use remains an important public health issue, especially for children with rare conditions or with diseases not responsive to conventional treatments. The present paper is a narrative review of the literature of off-label drug use in children. The aim of our study is to summarize the main works dealing with the off-label use of biological drugs in paediatrics. Further studies analyzing their efficacy, safety, and cost–benefit ratios are needed to extend the use of biological therapies to the paediatric population. [ABSTRACT FROM AUTHOR]

Background: The acquisition of proper and relevant pediatric clinical data is essential to ensure tolerable and effective pediatric drug therapies. In the field of pharmacological treatment of neuropsychiatric disorders, the lack of sufficient high quality scientific evidence for pediatric age results in the frequent need to prescribe off-label drugs. With the aim of improving knowledge about safety profile of off-label drug prescription in children and adolescent with neurological and/or psychiatric disorders, we realized a multidisciplinary pharmacovigilance study. Materials and methods: An observational retrospective study was conducted to assess the safety of off-label pharmacological therapies in patients aged 0–18 years, admitted to the Neuropsychiatry Unit of the Institute for Maternal and Child Health - IRCCS "Burlo Garofolo" between January 2016 and December 2018. Prescription patterns and adverse drug reactions were evaluated by a multidisciplinary team. Results: Overall, 230 patients were enrolled, 48% boys (N = 111), 52% girls (N = 119), average age of 10 years, and a total of 534 prescriptions was analyzed. 54.5% (N = 125) of patients had epilepsy, 37.5% (N = 86) suffered from psychiatric disorders, 8% (N = 19) had other neurological disorders. The prevalence of off-label prescriptions was 32% and 50% of the study population received at least one off-label drug. A total of 106 ADRs was detected: 57% of ADRs were due to drug-drug interactions, 30% were due to off-label prescriptions, 10% were due to overdose and 3% were due to improper use. No significant association between emerged ADRs and off label prescriptions was found (Fisher's exact two-tailed test, p = 1.000). There was significant association between increasing number of administrated drugs and risk of ADRs (OR 1.99; IC95% 1.58–2.5; p = 0.000). Psychiatric disorders were associated with at least three times higher risk to be treated with an off-label drug (OR 3.30; IC95% 2.26–4.83; p = 0.000). Conclusions: This study shows that off-label prescribing in neuropsychiatric disorders does not pose a greater risk of ADRs than on-label prescribing and highlights unmet clinical needs in pediatric neuropsychopharmacology. The multidisciplinary approach can provide important contributions to improve therapeutic path of these already complex pathologies by careful monitoring of therapeutic appropriateness and drug interactions. [ABSTRACT FROM AUTHOR]

Immunoglobulin E (IgE) and mast cells play a key role in various allergic diseases. Treatment with omalizumab, a monoclonal anti-IgE antibody, has significantly improved the control of these diseases and ushered in a new era in the treatment of severe allergic conditions. Long-term experience with omalizumab in severe allergic asthma has confirmed its effectiveness and safety, reducing the symptoms and incidence of severe exacerbations in patients. In addition to treating severe asthma, Omalizumab has been approved for the treatment of chronic spontaneous urticaria (CSU), and although the mechanisms underlying the action of omalizumab in CSU are not fully understood, almost 90% of CSU patients show complete or partial response to omalizumab treatment. Omalizumab has also recently been approved for the treatment of severe Japanese cedar pollinosis (JC) based on the successful results of a study of omalizumab in inadequately controlled severe hay fever treated with antihistamines and nasal corticosteroids. In recent years, there have been a number of scientific publications showing the successful off-label use of omalizumab in diseases in which IgE plays a key role such as allergic rhinitis, allergic bronchopulmonary aspergillosis, anaphylaxis, keratoconjunctivitis, food allergy, drug allergy, non-atopic asthma, mastocytosis, atopic dermatitis, nasal polyps, Churg-Strauss syndrome, eosinophilic otitis media, chronic rhinosinusitis, bullous pemphigoid, systemic lupus and contact dermatitis. Its safe use in pregnant women with asthma, as well as the concomitant use of omalizumab and allergen-specific immunotherapy, has already been confirmed. Therefore, the potential for omalizumab in other chronic conditions should be considered. [ABSTRACT FROM AUTHOR]

Background: The use of virus-neutralizing monoclonal antibodies has been approved in fragile populations, including kidney transplant recipients, who are at risk of developing severe COVID-19. Sotrovimab is the only currently available anti-SARS-CoV-2 neutralizing monoclonal antibody with activity against the new Omicron variant of concern. While sotrovimab has been approved in adolescents and adults, studies regarding its efficacy and safety in children aged less than 12 years old and weighing less than 40 kg are still lacking. Here, we report a first case of a child, who was treated early with sotrovimab after a kidney transplant. Case Report: At the end of January 2022, a 11-year-old male child underwent a deceased-donor kidney transplant and became infected with SARS-CoV-2 during the first day after surgery. Due to the increased risk of developing severe COVID-19, based on the predominance of Omicron and the patient's renal function, the child was treated with sotrovimab. The clinical course was successful and no adverse reactions were reported. Conclusions: For the first time, we report the well-tolerated use of sotrovimab in children under 12 years old. As the pandemic affects children across the globe, urgent data on sotrovimab dosing in children with a higher risk of developing severe COVID-19 are needed. [ABSTRACT FROM AUTHOR]

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

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.

The off-label use of medicines is neither prohibited nor explicitly allowed, according to the current European Union (EU) pharmaceutical legislation. This can cause confusion in physicians’ practice as well as lead to patients’ dissatisfaction. The purpose of this survey is to assess the knowledge and experience of Bulgarian physicians with the off-label use of medicines. The survey was performed at the beginning of 2020 in the biggest private hospital in South-Central Bulgaria. Ninety-six physicians from the inpatient and outpatient medical care participated in the survey and answered 10 questions. The data analysis was performed using the statistical program SPSS v19.0. The results are described as numbers and percentages for the qualitative variables and mean value (median due to their distribution) and a variance measure (range) for the quantitative ones. The distribution of the variables was tested with the Kolmogorov–Smirnov test. The evaluation of the relationships between the qualitative variables was performed using the χ2 test or the Fisher's exact test, where applicable. The results showed that most of the participants (81%) have never prescribed medicines off-label and believe it is not allowed to use medicines off-label (73%). Physicians strongly support the introduction of clear rules for the off-label use (88%). In conclusion, physicians practicing outside of the capital city demonstrated good level of knowledge, but relatively low awareness and little experience with the off-label use of medicines. They feel also, uncertainty in their prescribing activities when they use medicines off-label and strongly support introduction of clear rules for the off-label use.

Introduction Off-label use of antipsychotics has increased in many countries. In adult populations antipsychotics off-label prescriptions varied from 40 to 75% of all AP users. Objectives To examine the off-label prescribing practices and experiences of antipsychotic medication in Finland. Methods An electronic questionnaire on physicians’ prescription practices of antipsychotics, especially for off-label use, was sent in 2019 for physicians (n=1195) in different health care facilities including primary health care, occupational health care, in- and outpatient mental health services and services for substance abuse. The sample was selected by systematic and convenience sampling covering five university hospital areas in Finland. Results In total, 216 physicians (18% of the target sample) participated in the study, and 94% had prescribed antipsychotics for off-label use. The most common off-label indications were insomnia and anxiety. The most common antipsychotic used was quetiapine. Off-label antipsychotics was not prescribed as a first-choice medication: 99% of the physicians reported that the patients with off-label use have previously had other medications for the corresponding symptoms. In all, 88% of clinicians monitored the patients’ clinical condition, whereas metabolic values were followed more rarely. About 68% of physicians reported more benefit than harm from the antipsychotics off-label use. Conclusions Antipsychotics are often prescribed for off-label use, most commonly for insomnia and anxiety. Most of the physicians see more benefits than harms for the patient in off-label use. There is a need to analyse the long-term benefits and harms of off-label use of antipsychotics and create more detailed treatment algorithms and clinical recommendations for such use. Disclosure No significant relationships.

Background: The acquisition of proper and relevant pediatric clinical data is essential to ensure tolerable and effective pediatric drug therapies. In the field of pharmacological treatment of neuropsychiatric disorders, the lack of sufficient high quality scientific evidence for pediatric age results in the frequent need to prescribe off-label drugs. With the aim of improving knowledge about safety profile of off-label drug prescription in children and adolescent with neurological and/or psychiatric disorders, we realized a multidisciplinary pharmacovigilance study.Materials and methods: An observational retrospective study was conducted to assess the safety of off-label pharmacological therapies in patients aged 0–18 years, admitted to the Neuropsychiatry Unit of the Institute for Maternal and Child Health - IRCCS “Burlo Garofolo” between January 2016 and December 2018. Prescription patterns and adverse drug reactions were evaluated by a multidisciplinary team.Results: Overall, 230 patients were enrolled, 48% boys (N = 111), 52% girls (N = 119), average age of 10 years, and a total of 534 prescriptions was analyzed. 54.5% (N = 125) of patients had epilepsy, 37.5% (N = 86) suffered from psychiatric disorders, 8% (N = 19) had other neurological disorders. The prevalence of off-label prescriptions was 32% and 50% of the study population received at least one off-label drug. A total of 106 ADRs was detected: 57% of ADRs were due to drug-drug interactions, 30% were due to off-label prescriptions, 10% were due to overdose and 3% were due to improper use. No significant association between emerged ADRs and off label prescriptions was found (Fisher’s exact two-tailed test, p = 1.000). There was significant association between increasing number of administrated drugs and risk of ADRs (OR 1.99; IC95% 1.58–2.5; p = 0.000). Psychiatric disorders were associated with at least three times higher risk to be treated with an off-label drug (OR 3.30; IC95% 2.26–4.83; p = 0.000).Conclusions: This study shows that off-label prescribing in neuropsychiatric disorders does not pose a greater risk of ADRs than on-label prescribing and highlights unmet clinical needs in pediatric neuropsychopharmacology. The multidisciplinary approach can provide important contributions to improve therapeutic path of these already complex pathologies by careful monitoring of therapeutic appropriateness and drug interactions.

The chimeric anti-CD20 antibody rituximab has demonstrated good efficacy as an off-label treatment in chronic inflammatory demyelinating polyneuropathy (CIDP), while the humanized anti-CD20 antibody ocrelizumab has been approved for treatment of multiple sclerosis (MS), whereas there is no evidence for its use in CIDP so far. We present a patient suffering from CIDP and MS, both refractory to standard treatment and both showing marked improvement on ocrelizumab. To the best of our knowledge, this is a unique report of CIDP with an almost full electrophysiological recovery on ocrelizumab which could be considered as a potential treatment option for refractory CIDP. [ABSTRACT FROM AUTHOR]

Ruxolitinib is a Janus kinase (JAK) inhibitor that is FDA-approved for the treatment of myelofibrosis, polycythemia vera, and acute graft-versus-host disease. Its use in treating various dermatologic diseases has been a topic of growing interest due to its favorable safety profile and targeted inhibition of several cytokines that perpetuate inflammatory skin conditions. The PubMed/MEDLINE and ClinicalTrials.gov databases were searched for literature on off-label uses of ruxolitinib in dermatology and ongoing trials studying its safety and efficacy. There is randomized controlled trial (RCT) evidence for the successful use of ruxolitinib in treating alopecia, atopic dermatitis, and psoriasis, with ongoing RCTs for its use in vitiligo. Smaller studies have confirmed the success of ruxolitinib in treating conditions such as dermatomyositis and hypereosinophilic syndrome, among others. No serious adverse effects were reported with the use of ruxolitinib in dermatology, but further research is needed to determine its efficacy, delivery route, and optimal dosing for treating dermatologic conditions. [ABSTRACT FROM AUTHOR]

Introduction: Many efforts have been made to stimulate clinical trials (CTs) in pediatrics but most of the drugs are still authorized only in adults and used off-label in the pediatric population. Aim: To assess how widespread is the off-label prescription in Italy and to identify areas of unmet medical need by applying a model for the systematic collection and analysis of data. Methods: A study was performed using 2015 data from the Italian Medicines Utilization Monitoring Centre Health Database (OsMed). A study sample of 3,726,583 pediatric patients, was considered. Cardiovascular drugs were selected for this study. Assessment of the off-label use, the analysis of the pharmacovigilance signals, a bibliographic research and the analysis of ongoing CTs were carried out. Results: In 2015, 8,544 pediatric patients received treatment with a cardiovascular drug. Angiotensin converting enzyme inhibitors (ACE-I) followed by beta blockers agents are the most prescribed molecules. Eight molecules were selected and an in-depth analysis conducted. The PhV network showed only one record of adverse reaction as off-label in 2015. The results show several therapeutic areas of use in pediatrics. Conclusion: Off-label in pediatrics is largely widespread in Europe and US and our results show it is also present in Italy. Molecules selected are used off-label for therapeutic areas such as oncologic, hematological and rare diseases. Results of pharmacovigilance suggests underreporting. The analysis carried out in this study could be an open track for a systematic monitoring activity and of interest for prescribers, pediatricians and other healthcare professionals during the clinical practice. [ABSTRACT FROM AUTHOR]

The lack of appropriate medicines for children has a significant impact on health care practices in various countries around the world, including Thailand. The unavailability of pediatric medicines in hospital formularies causes issues regarding off-label use and extemporaneous preparation, resulting in safety and quality risks relating to the use of medicines among children. This research aimed to identify missing pediatric formulations based on the experience of healthcare professionals in a teaching hospital in northern Thailand. A cross-sectional survey was conducted to collect data on missing pediatric formulations, the reasons for their inaccessibility, their off-label uses, their reactions to the situation, and suggestions to improve access to these identified medications. The survey was distributed to all physicians, nurses, and pharmacists involved in prescribing, preparing, dispensing, and administering pediatric medicines. A total of 218 subjects responded to the survey. Omeprazole, sildenafil, and spironolactone suspension were most often identified as missing formulations for children by physicians and pharmacists. They are unavailable on the Thai market or in any hospital formulary. For nurses, sodium bicarbonate, potassium chloride, and chloral hydrate were the most problematic formulations in terms of preparation, acceptability, and administration. These medicines were difficult to swallow because of their taste or texture. [ABSTRACT FROM AUTHOR]

Anakinra (Kineret®) is an interleukin-1 receptor antagonist (IL-1Ra) FDA approved for use in rheumatoid arthritis and in neonatal-onset multisystem inflammatory disease (NOMID). It has been used off-label for a variety of dermatologic conditions. A review of the available studies and cases of these off-label uses would be valuable to the dermatologist considering alternative treatments for these oftentimes poorly studied conditions. The PubMed/MEDLINE, EMBASE, Scopus, and ClinicalTrials.gov databases were searched with the term 'anakinra.' Results were manually screened to identify published data on off-label uses of anakinra in dermatologic conditions and systemic conditions with prominent dermatologic manifestations. Anakinra appears to show efficacy for numerous dermatologic conditions, with the strongest evidence for hidradenitis suppurativa, Bechet's disease, Muckle-Wells syndrome, and SAPHO syndrome. Case reports and case series data are available for numerous other dermatologic conditions. Anakinra is a potential option for patients with certain difficult-to-treat dermatologic diseases, given its relatively benign adverse effect profile and its effectiveness in a wide array of conditions. Overall, anakinra appears to be a promising option in the treatment of numerous dermatologic inflammatory conditions refractory to first line therapies, but further and higher-quality data is needed to clarify its therapeutic role. [ABSTRACT FROM AUTHOR]

BACKGROUND: Governmental regulations of drug registration and licensing are not always followed by healthcare providers. OBJECTIVE: To explore the global research growth and patterns on systemic use of off-label and unlicensed drugs to gain knowledge about the magnitude of the problem and the main research themes encountered in this field. METHODS: SciVerse Scopus was searched for papers on off-label and unlicensed drug use from 1990 until December 31, 2020, without any language limitations. A bibliometric methodology was adopted to present the following indicators: top-cited documents, the most productive countries, top active journals, international research collaboration, the most frequent author keywords, and research themes. RESULTS: The search query returned 1320 papers with an h-index of 66, published in 721 different journals. The Hospital Pharmacy journal ranked first (n = 43, 3.3%). In total, 5777 authors (median = 3) from 85 different countries contributed to the retrieved papers. The USA (n = 381, 28.9%) ranked first, followed distantly by Germany and Italy. The percentage of documents with international authors for active countries was from 8.8% for China to 42.3% for the Netherlands. The most frequent author keyword next to off-label was children/pediatrics. The keyword unlicensed was less frequently encountered than that for off-label. Major research themes in the retrieved papers focused on off-label drug use in hospitalized children/pediatrics, biological drugs such as rituximab and rFVIIa, psychiatric disorders, regulations, and questionnaire-based knowledge/attitude studies among community pharmacists and physicians. CONCLUSIONS: Research activity on off-label drug use has witnessed a general increase in the past two decades. The major research theme was off-label drug use in hospitalized children/pediatrics/neonates. The USA and certain European countries made a major contribution to this field. [ABSTRACT FROM AUTHOR]

Botulinum toxin is a neurotoxic protein produced by Clostridium botulinum, the bacterium responsible for botulism. Botulinum toxin was first used for therapeutic indications in the 1970s for the treatment of strabismus. With greater understanding of its underlying physiology and safety profile, the use of botulinum toxin has now expanded to a range of cosmetic and medical indications. We performed a systematic review of current literature on the applications of botulinum toxin on off‐label esthetic uses. Electronic databases were searched for original published studies including randomized trials, observational or cohort studies, as well as relevant case reports. To add to the body of evidence, our review summarizes and synthesizes key study characteristics, results, and level of evidence for each use case. Although the body of evidence remains weak, there is increasing support for the use of botulinum toxin in emerging off‐label esthetic uses of botulinum toxin in dermatology. [ABSTRACT FROM AUTHOR]

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.

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.

Anteneh Belayneh Department of Pharmacy, College of Health Sciences, Debre Markos University, Debre Markos, EthiopiaCorrespondence: Anteneh Belayneh Tel +251 912844719Email antejour32@gmail.comAbstract: COVID-19 is continuing as a big challenge for the globe and several types of research are continued to find safe and effective treatment and preventive options. Although there is a lack of conclusive evidence of their benefit, there is worldwide controversy to use anti-malarial drugs, hydroxychloroquine and chloroquine, for the treatment of COVID-19. FDA issued an emergency use authorization to the use of these drugs for the treatment of COVID-19. On the contrary to the FDA, the European Medicines Agency has warned against the widespread use of these drugs to treat COVID-19. Finally, the WHO declared that clinical trials on these drugs are halted after the devastating findings of the study published in the medical journal called The Lancet. Against this fact, there are several rumors about the irresponsible use of these drugs in Africa for the treatment of COVID-19. This work aimed to review the off-label use of these drugs for the treatment of COVID-19 in African countries against WHO recommendation. Data on the use of these drugs for the treatment of COVID-19 in African countries were searched from credible sources including Scopus, PubMed, Hindawi, Google Scholar, and from local and international media. The study showed that many African countries have already approved at the national level to use these drugs to treat COVID-19 by opposing WHO warnings. In addition to this, falsified and substandard chloroquine products started to emerge in some African countries. The health sectors of the African government should critically compare the risks and benefits before using these drugs. The WHO and African drug regulatory organizations should intervene to stop the off-label use practice of these drugs against the licensed purpose and distribution of falsified and substandard products in the continent.Keywords: COVID-19, chloroquine, hydroxychloroquine, off-label, Africa

Alesha Wale,1 Mark Ireland,2 Rowan Yemm,1 Sarah Hiom,3 Alison Jones,3 John Paul Spark,3 Mark Francis,4 Karen May,5 Louise Allen,5 Steve Ridd,6 Efi Mantzourani1,7 1School of Pharmacy and Pharmaceutical Sciences, Cardiff University, Cardiff, Wales, UK; 2Community Pharmacy Wales, Cardiff, Wales, UK; 3St. Mary’s Pharmaceutical Unit, Cardiff, Wales, UK; 4Swansea Bay University Health Board, Swansea, Wales, UK; 5Cardiff and Vale University Health Board, Swansea, Wales, UK; 6Mayberry Pharmacy, Cardiff, Wales, UK; 7NHS Wales Informatics Service, Cardiff, Wales, UKCorrespondence: Efi Mantzourani Email MantzouraniE1@cardiff.ac.ukObjective: Community pharmacy staff are responsible for obtaining and supplying unlicensed “special” medicines to patients in primary care. Less well-defined parameters for safe and effective use of unlicensed compared to licensed medicines, along with issues around maintaining consistency between care settings or among manufacturers, have been associated with increased risks. This study aimed to explore the views and experiences of community pharmacy staff on accessing and supplying unlicensed “special” medicines to patients in Wales and the perceived impact of challenges faced on patient care.Methods: A qualitative, phenomenological approach was employed, involving semi-structured interviews with pharmacists and pharmacy technicians working at one small chain of community pharmacies in Wales. The interview schedule focused on the personal experiences and perceptions of the participants on the processes involved in accessing and supplying unlicensed “special” medicines from a community pharmacy. Interviews were audio-recorded and transcribed verbatim.Results: A total of six participants completed the interview. Three main themes were constructed from inductive thematic analysis of the transcribed interviews: requirement for additional patient responsibilities; influences on the confidence felt by pharmacy staff when accessing and supplying unlicensed “special” medicines; and continuity of supply.Conclusion: This study gives a preliminary insight into the views and experiences of community pharmacy staff in Wales when accessing and supplying unlicensed “special” medicines. Further research is required to see if these views and experiences are representative of community pharmacy staff across the country.Keywords: unlicensed medicines, “special” medicines, specials, community pharmacy, transfer of care, medicines supply, transmural care, off-label, compounding