Repurposing of rituximab biosimilars to treat B cell mediated autoimmune diseases.

Rituximab, the first monoclonal antibody approved for the treatment of lymphoma, eventually became one of the most popular and versatile drugs ever in terms of clinical application and revenue. Since its patent expiration, and consequently, the loss of exclusivity of the original biologic, its repurposing as an off-label drug has increased dramatically, propelled by the development and commercialization of its many biosimilars. Currently, rituximab is prescribed worldwide to treat a vast range of autoimmune diseases mediated by B cells. Here, we present a comprehensive overview of rituximab repurposing in 115 autoimmune diseases across 17 medical specialties, sourced from over 1530 publications. Our work highlights the extent of its off-label use and clinical benefits, underlining the success of rituximab repurposing for both common and orphan immune-related diseases. We discuss the scientific mechanism associated with its clinical efficacy and provide additional indications for which rituximab could be investigated. Our study presents rituximab as a flagship example of drug repurposing owing to its central role in targeting cluster of differentiate 20 positive (CD20) B cells in 115 autoimmune diseases.

Differences in time to patient access to innovative cancer medicines in six European countries.

Patients across Europe face inequity regarding access to anticancer medicines. While access is typically evaluated through reimbursement status or sales data, patients can receive first access through early access programs (EAPs) or off-label use. This study aims to assess the time to patient access at the hospital level, considering different indications and countries. (Pre-)registered access to six innovative medicines (Olaparib, Niraparib, Ipilimumab, Osimeritinib, Nivolumab and Ibritunib) was measured using a cross-sectional survey. First patient access to medicines and indications were collected using the hospital databases. Nineteen hospitals from Hungary, Italy, the Netherlands, Belgium, Switzerland and France participated. Analysis showed that some hospitals achieved patient access before national reimbursement, primarily through EAPs. The average time from EMA-approval to patient access for these medicines was 2.1 years (Range: -0.9-7.1 years). Hospitals in Italy and France had faster access compared to Hungary and Belgium. Variation was also found within countries, with specialized hospitals (x̄: -0.9 years; SD: 2.0) more likely to provide patient access prior to national reimbursement than general hospitals (x̄: 0.4 years; SD: 2.9). Contextual differences were observed, with EAPs or off-label use being more prevalent in Switzerland than Hungary. Recent EMA-approved indications and drug combinations reached patients at a later stage. Substantial variation in patient access time was observed between and within countries. Improving pricing and reimbursement timelines, fostering collaboration between national health authorities and market authorization holders, and implementing nationally harmonized, data-generating EAPs can enhance timely and equitable patient access to innovative cancer treatments in Europe.

Progress report of a cross-organ and biomarker-based basket-type clinical trial: BELIEVE Trial.

Cancer genomic medicine using next-generation sequencers has been developing. However, the number of patients who could receive genomically matched therapy is limited because off-label use or patient-oriented compassionate use was not permitted under National Health Insurance in Japan. To improve patient drug accessibility, we initiated a biomarker-based basket-type clinical trial (NCCH1901) in October 2019 under patient-proposed healthcare services. We listed the drugs that had high medical needs but were not covered by National Healthcare Insurance. Then we included these drugs before patient proposal so that they could access off-label drugs soon after they had the results of CGP tests. All drugs were provided free of charge by pharmaceutical companies. The objective was to administer off-label drugs and to collect efficacy and safety data for these drugs. The primary endpoint was the response rate based on the best overall response for up to 16 weeks. As of January 31, 2022, we included 18 drug cohorts and 295 patients were treated in this study. The most common cancer was brain tumor, followed by carcinoma of endocrine organs and colorectal cancer. BRAF mutations and ERBB2 amplifications were the frequent genomic abnormalities to be enrolled. This study was one way to access off-label drugs, and contributed significantly to providing treatment opportunities for patients in Japan.

A national census for the off-label treatment of complex aortic aneurysms.

OBJECTIVE: Despite regulatory challenges, device availability, and rapidly expanding techniques, off-label endovascular repair of complex aortic aneurysms (cAAs) has expanded in the past decade. Given the lack of United States Food and Drug Administration-approved endovascular technology to treat cAAs, we performed a national census to better understand volume and current practice patterns in the United States. METHODS: Targeted sampling identified vascular surgeons with experience in off-label endovascular repair of cAAs. An electronic survey was distributed with institutional review board approval from the University of Rochester to 261 individuals with a response rate of 38% (n = 98). RESULTS: A total of 93 respondents (95%) reported off-label endovascular repair of cAAs. Mean age was 45.7 ± 8.3 years, and 84% were male. Most respondents (59%) were within the first 10 years of practice, and 69% trained at institutions with a high-volume of off-label endovascular procedures for complex aortic aneurysms with or without a physician-sponsored investigational device exemption (PS-IDE). Twelve respondents from 11 institutions reported institutional PS-IDEs for physician-modified endografts (PMEGs), in-situ laser fenestration (ISLF), or parallel grafting technique (PGT), including sites with PS-IDEs for custom-manufactured devices. Eighty-nine unique institutions reported elective off-label endovascular repair with a mean of 20.2 ± 16.5 cases/year and ∼1757 total cases/year nationally. Eighty reported urgent/emergent off-label endovascular repair with a mean of 5.7 ± 5.4 cases/year and ∼499 total cases/year nationally. There was no correlation between high-volume endovascular institutions (>15 cases/year) and institutions with high volumes of open surgical repair for cAAs (>15 cases/year; odds ratio, 0.7; 95% confidence interval, 0.3-1.5; P = .34). Elective techniques included PMEG (70%), ISLF (30%), hybrid PMEG/ISLF (18%), and PGT (14%), with PMEG being the preferred technique for 63% of respondents. Techniques for emergent endovascular treatment of complex aortic disease included PMEG (52%), ISLF (40%), PGT (20%), and hybrid-PMEG/ISLF (14%), with PMEG being the preferred technique for 41% of respondents. Thirty-nine percent of respondents always or frequently offer referrals to institutions with PS-IDEs for custom-manufactured devices. The most common barrier for referral to PS-IDE centers included geographic distance (48%), longitudinal relationship with patient (45%), and costs associated with travel (33%). Only 61% of respondents participate in the Vascular Quality Initiative for complex endovascular aneurysm repair, and only 57% maintain a prospective institutional database. Eighty-six percent reported interest in a national collaborative database for off-label endovascular repair of cAA. CONCLUSIONS: Estimates of off-label endovascular repair of cAAs are likely underrepresented in the literature based on this national census. PMEG was the most common technique for elective and emergent procedures. Under-reported off-label endovascular repair of cAA outcomes data appears to be limited by non-standardized PS-IDE reporting to the United States Food and Drug Administration, and the lack of Vascular Quality Initiative participation and prospective institutional data collection. Most participants are interested in a national collaborative database for endovascular repair of cAAs.

Emerging drugs in phase II and III clinical development for the treatment of alcohol use disorder.

INTRODUCTION: Alcohol Use Disorder (AUD) poses an ongoing significant global health burden. AUD is highly prevalent and affects not only the individuals with AUD, but also their communities and society at large. Even though pharmacotherapy is an integral part of AUD treatment, the few available substances show limited efficacy and limited clinical impact. Thus, there is a need for new innovative pharmacotherapeutic approaches. AREAS COVERED: This paper provides a comprehensive review of drugs approved for the treatment of AUD as well as those currently in phase II and III development. Data from recent clinical trials has been reviewed and supplemented by additional literature based on a systematic search of the PubMed database and clinical trials registries. Compounds discussed include disulfiram, naltrexone, nalmefene, acamprosat, baclofen, sodium oxybate, doxazosin, varenicline, zonisamide, gabapentin, apremilast, ibudilast, ivermectin, tolcapone, mifepristone, suvorexant, ketamine, psilocybin, semaglutide, oxytocin and cannabidiol. EXPERT OPINION: Even though the majority of the discussed compounds lack sufficient evidence to support their efficacy, multiple promising new treatment options are currently under investigation. Future research has to consider specific phenotypes and subgroups of AUD as well as a possible enhancement of the effects of psychotherapy through combination with pharmacotherapy. Practitioners should be encouraged to use available compounds to support existing therapeutic regimens.

Repurposing empagliflozin in individuals with glycogen storage disease Ib: A value-based healthcare approach and systematic benefit-risk assessment.

Off-label repurposing of empagliflozin allows pathomechanism-based treatment of neutropenia/neutrophil-dysfunction in glycogen storage disease type Ib (GSDIb). From a value-based healthcare (VBHC) perspective, we here retrospectively studied patient-reported, clinical and pharmacoeconomic outcomes in 11 GSDIb individuals before and under empagliflozin at two centers (the Netherlands [NL], Austria [AT]), including a budget impact analysis, sensitivity-analysis, and systematic benefit-risk assessment. Under empagliflozin, all GSDIb individuals reported improved quality-of-life-scores. Neutrophil dysfunction related symptoms allowed either granulocyte colony-stimulating factor cessation or tapering. Calculated cost savings per patient per year ranged between € 6482-14 190 (NL) and € 1281-41 231 (AT). The budget impact analysis estimated annual total cost savings ranging between € 75 062-225 716 (NL) and € 37 697-231 790 (AT), based on conservative assumptions. The systematic benefit-risk assessment was favorable. From a VBHC perspective, empagliflozin treatment in GSDIb improved personal and clinical outcomes while saving costs, thereby creating value at multiple pillars. We emphasize the importance to reimburse empagliflozin for GSDIb individuals, further supported by the favorable systematic benefit-risk assessment. These observations in similar directions in two countries/health care systems strongly suggest that our findings can be extrapolated to other geographical areas and health care systems.

Repurposing SGLT2 inhibitors: Treatment of renal proximal tubulopathy in Fanconi-Bickel syndrome with empagliflozin.

Renal proximal tubulopathy in Fanconi-Bickel syndrome is caused by impaired basolateral glucose transport via GLUT2 and consequently, intracellular accumulation of glucose and glycogen. SGLT2 inhibitors act on apical glucose reabsorption of renal proximal tubular cells. The purpose of this study was to retrospectively describe the first experiences with repurposing the SGLT2 inhibitor empagliflozin to treat the generalized tubulopathy in Fanconi-Bickel syndrome. A case series was conducted of seven persons from five families (five males, two females; three children, who were 14y5m, 2y9m, and 1y6m old) with genetically confirmed Fanconi-Bickel syndrome, off-label treated with empagliflozin. Median (range) age at start of empagliflozin was 27 years (1y6m - 61y) and duration of follow-up under empagliflozin treatment was 169 days (57-344). Under empagliflozin (up to 25 mg/d), biochemical parameters of tubular cell integrity (urinary N-acetyl-glucosaminidase) and/or tubular functions (including urinary α1-microglobulin) improved in all persons with Fanconi-Bickel syndrome, albeit to varying degrees. Clinically, supplementations (i.e., phosphate, alkali, carnitine, and alfacalcidol) could be completely discontinued in the three children, whereas results in the four adult patients were more variable and not as significant. Empagliflozin was well-tolerated and no symptomatic hypoglycemia was observed. In conclusion, SGLT2 inhibitors such as empagliflozin shift the metabolic block in Fanconi-Bickel syndrome, that is, they intervene specifically in the underlying pathophysiology and can thus attenuate renal proximal tubulopathy, especially when started in early childhood.

Is imiquimod a promising drug to treat oral mucosa diseases? A scoping review and new perspectives.

Imiquimod (IMQ) is a chemotherapeutic and immunostimulant drug that is applied topically, demonstrating antitumor and antiviral activities. The objective of this review was to compile data on the off-label use of IMQ in oral mucosal diseases. IMQ has exhibited effectiveness in the treatment of various oral mucosal conditions, including oral carcinogenic lesions, neoplasms, HPV-related lesions and autoimmune disorders. Although IMQ holds promise as a potential strategy for addressing oral mucosal lesions, it is important to note that significant side effects have been frequently reported. Nonetheless, it is crucial to develop and test new technological systems, such as the combination of nanotechnology with innovative drug delivery platforms. These advancements aim to minimize side effects and prolong the drug's contact time with the mucosa, preventing its removal by salivary flow.

PAttern of drug use in PEdiatrics: An observational study in Italian hOSpitals (the PAPEOS study).

AIMS: To assess the extent of off-label drug use and the occurrence of suspected adverse drug reactions (ADRs) among paediatric patients in Italian hospitals. METHODS: We conducted a 2-year prospective cohort study across 22 Italian hospital wards from September 2020 to September 2022. As part of the surveillance project, we performed a 6-month retrieval of all reported ADRs and evaluated all drug prescriptions for their possible off-label use. Following an educational project on pharmacovigilance addressed to healthcare professionals in participating wards, the same data collection was performed. RESULTS: Among the 892 patients included in the study, 64% were admitted to paediatric wards and 36% to neonatal wards. Fifty per cent of all drugs prescribed were used off-label and mainly concerned the administration of a different dose from the one authorized. In neonatal wards, off-label prescriptions occurred slightly more often, with antibacterials being the most frequently used off-label drugs. A total of 35 reports of suspected ADRs were collected, five before the educational project and 30 afterwards. Based on product licence, 10 of the total 35 reports concerned at least one off-label drug use. CONCLUSIONS: The off-label use of drugs in treating paediatric patients was extensive in Italian hospitals. Regulatory interventions are needed to promote the use of drugs based on the latest available literature and improve ADR reporting on children. Paediatric indications and dosages of the drugs most commonly used in children should be supported by appropriate ad hoc studies.

Plasma apixaban concentrations and thrombin generation assay parameters in response to dose reduction for atrial fibrillation.

AIMS: To investigate plasma apixaban concentrations and thrombin generation assay (TGA) parameters across different apixaban doses in atrial fibrillation patients who had dose-reduction criteria for apixaban. METHODS: This observational study included 374 patients (mean age 75.6 ± 7.7 years, 54.8% female) with dose-reduction criteria for apixaban. The patients were divided into 3 groups: (i) on-label standard dose (5 mg twice daily, n = 166); (ii) on-label reduced dose (2.5 mg twice daily, n = 55); and (iii) off-label underdose (2.5 mg twice daily, n = 153). Apixaban concentrations determined via the anti-Xa assay and TGA parameters were compared at trough levels. RESULTS: The off-label underdose group exhibited significantly lower apixaban trough concentrations than the on-label reduced-dose and standard-dose groups (56.7 ± 42.9 vs. 83.7 ± 70.4 vs. 129.9 ± 101.8 ng/mL, all P < .001). Less than 70% of all patients fell within the expected range of apixaban concentrations. Proportions exceeding the upper limit of the expected range were significantly lower in the off-label underdose group (1.3%) than in the on-label reduced-dose (9.1%, P = .005) and standard-dose (12.7%, P < .001) groups. The TGA parameters showed the on-label standard-dose group displaying the lowest thrombogenic profiles. Lower creatinine clearance was the most significant predictor of higher apixaban concentrations. CONCLUSION: Off-label underdosed apixaban resulted in lower apixaban concentrations than both on-label standard and reduced-dose regimens. A considerable proportion of the patients exhibited apixaban concentrations outside the expected range, suggesting the potential benefits of plasma concentration monitoring. Further studies are needed to compare dosages directly, investigate the impact of plasma apixaban concentration monitoring and validate the current dose-reduction criteria.

Upside-Down Gore Excluder as an Endoprosthesis for Aortoiliac Aneurysm Exclusion: A Retrospective Multicenter Study.

OBJECTIVE: The upside-down configuration of a Gore Excluder contralateral leg endoprosthesis has been used to overcome diameter differences in the endovascular treatment of aortoiliac aneurysms. Our goal was not to describe the technique but to study the applicability and safety. MATERIAL AND METHODS: Patients were retrospectively enrolled. The indication and details of the procedure were at the discretion of the treating physicians. A case report form was completed including baseline characteristics, indication for treatment, procedural data, and outcomes during follow-up. RESULTS: A total of 31 subjects were enrolled with a range of indications, including 3 patients treated in the emergency setting (9.7%). In 64.5% (n=20), it was a primary intervention for a common iliac aneurysm (n=10), internal iliac aneurysm (n=4), or abdominal aortic aneurysm (n=6). In 11 subjects (35.5%), treatment was performed after previous aortoiliac interventions, including anastomotic iliac artery aneurysm (n=5), type III endoleak (n=3), and endograft thrombus (n=3). Median follow-up was 13 months (range=1-142 months). During follow-up, 2 patients required an upside-down contralateral leg-related secondary intervention, one for an occlusion and another for a type Ia endoleak. There was no type Ib or III endoleak, and no migration, kinking/stenosis, or conversion to open repair was observed. The aneurysm-related mortality was 3.3% (n=1). CONCLUSION: An upside-down contralateral leg is a valuable technique that can be used to achieve adequate aneurysm exclusion or resolve complications. It is associated with a limited number of complications. CLINICAL IMPACT: This article studies the use of an upside-down iliac endograft. We describe a wide range of indications in which this previously published technique has been applied. In elective and acute settings and as primary and revision intervention an upside-down iliac endograft was performed successfully. Furthermore, follow-up data is presented showing the effectiveness of the technique. Knowledge of this procedure is a valuable addition to the skillset of every interventionalist.

Physician-Modified Reversed Iliac Branch Device to Prevent Spinal Cord Ischemia in an Urgent Branched Endovascular Aortic Repair.

PURPOSE: Repair of pararenal aneurysms poses a challenge, especially in an urgent setting. Despite the minimally invasive nature of the fenestrated/branched endovascular aortic repair, the technique may require extensive coverage of the aorta, increasing the risk of spinal cord ischemia. TECHNIQUE: A 68-year-old man was admitted with a rapid enlargement of an asymptomatic juxtarenal aortic aneurysm. A minimally invasive treatment with an off-the-shelf branched endovascular graft was planned. Before completing the aneurysm exclusion, an angiography highlighted a large lumbar artery, potentially significant for the perfusion of the spinal cord collateral network. Owing to this finding and an unsuccessful placement of the cerebrospinal fluid drainage, the procedure was staged and completed 5 days later using a physician-modified iliac branch device (IBD) for the segmental artery. The device was shortened and reversely loaded to obtain a cranially-oriented branch. A balloon-expandable covered stent was used to connect the retrograde branch (8 mm) to the lumbar artery (4 mm). Pre-discharge computed tomography (CT)-angiography confirmed the vessel patency. No neurological symptoms occurred. CONCLUSION: The use of a reversely-loaded IBD for segmental artery preservation appears feasible and safe. CLINICAL IMPACT: Intraoperative modification of an iliac branch device during an urgent branched endovascular aortic repair enabled preservation of a potentially critical segmental artery, thus reducing the risk of spinal cord ischemia. This adaptive interventional technique may also offer a strategy for preserving other anatomically significant vessels, such as accessory renal arteries, during complex aortic reconstructions in urgent settings.

Editor's Choice - Comparison of Open Surgery and Endovascular Techniques for Juxtarenal and Complex Neck Aortic Aneurysms: The UK COMPlex AneurySm Study (UK-COMPASS) - Peri-operative and Midterm Outcomes.

OBJECTIVE: Treatment of juxtarenal and complex neck abdominal aortic aneurysms (AAAs) is now commonly by endovascular rather than open surgical repair (OSR). Published comparisons show poor validity and scientific precision. UK-COMPASS is a comparative cohort study of endovascular treatments vs. OSR for patients with an AAA unsuitable for standard on label endovascular aneurysm repair (EVAR). METHODS: All procedures for AAA in England (November 2017 to October 2019) were identified, AAA anatomy assessed in a Corelab, peri-operative risk scores determined, and propensity scoring used to identify patients suitable for either endovascular treatment or OSR. Patients were stratified by aneurysm neck length (0 - 4 mm, 5 - 9 mm, or ≥ 10 mm) and operative risk; the highest quartile was considered high risk and the remainder standard risk. Death was the primary outcome measure. Endovascular treatments included fenestrated EVAR (FEVAR) and off label standard EVAR (± adjuncts). RESULTS: Among 8 994 patients, 2 757 had AAAs that were juxtarenal, short neck, or complex neck in morphology. Propensity score stratification and adjustment method comparisons included 1 916 patients. Widespread off label use of standard EVAR devices was noted (35.6% of patients). The adjusted peri-operative mortality rate was 2.9%, lower for EVAR (1.2%; p = .001) and FEVAR (2.2%; p = .001) than OSR (4.5%). In standard risk patients with a 0 - 4 mm neck, the mortality rate was 7.4% following OSR and 2.3% following FEVAR. Differences were smaller for patients with a neck length ≥ 5 mm: 2.1% OSR vs. 1.0% FEVAR. At 3.5 years of follow up, the overall mortality rate was 20.7% in the whole study population, higher following FEVAR (27.6%) and EVAR (25.2%) than after OSR (14.2%). However, in the 0 - 4 mm neck subgroup, overall survival remained equivalent. The aneurysm related mortality rate was equivalent between treatments, but re-intervention was more common after EVAR and FEVAR than OSR. CONCLUSION: FEVAR proves notably safer than OSR in the peri-operative period for juxtarenal aneurysms (0 - 4 mm neck length), with comparable midterm survival. For patients with short neck (5 - 9 mm) and complex neck (≥ 10 mm) AAAs, overall survival was worse in endovascularly treated patients compared with OSR despite relative peri-operative safety. This warrants further research and a re-appraisal of the current clinical application of endovascular strategies, particularly in patients with poor general survival outlook owing to comorbidity and age.

In-label, off-label prescription, efficacy and tolerability of dalbavancin: report from a National Registry.

PURPOSE: Although dalbavancin is currently approved for the treatment of ABSSIs, several studies suggest its efficacy and tolerance as long-term therapy for other off-label indications requiring prolonged intravenous antibiotic administration. METHODS: We conducted a prospective nationwide study of dalbavancin use in real-life settings for both approved and off-label indications analysing for each case the clinical and microbiological characteristics of infection the efficacy and safety of treatments. RESULTS: During the study period (from December 2018 to July 2021), the ID specialists from 14 different centres enrolled 223 patients treated with dalbavancin [141 males (63%) and 82 females (37%); male/female ratio 1.72; mean age 59 (SD 17.2) years, (range 15-96). Most patients in the study population (136/223; 61.0%) came from community rather than health care facilities and most of them were visited in Infectious Diseases wards (93/223; 41.7%) and clinics (55/223; 24.7%) even though some patients were cured in other settings, such as surgery wards (18/223; 8.1%), orthopaedic wards (11/223; 4.9%), Emergency Rooms (7/223; 3.1%) and non-surgical other than ID wards (6/223; 2.7%). The most common ID diagnoses were osteomyelitis (44 cases/223; 19.7%; of which 29 acute and 15 chronic osteomyelitis), cellulitis (28/223; 12.5%), cutaneous abscess (23/223; 10.3%), orthopaedic prosthesis-associated infection (22/223; 9.9%), surgical site infection (20/223; 9.0%) and septic arthritis (15/223; 6.7%). CONCLUSION: In conclusion, by virtue of its PK/PD properties, dalbavancin represents a valuable option to daily in-hospital intravenous or outpatient antimicrobial regimens also for off-label indications requiring a long-term treatment of Gram-positive infections.

Prescription habits and drugs accessibility for the treatment of non-tuberculous mycobacteria infections in Italy: a multicentric survey from the IRENE study group.

PURPOSE: Non-tuberculous mycobacteria (NTM) account for high clinical burden, and treatment can be challenging. Moreover, accessibility of NTM medications varies across centers. These challenges may lead to unplanned therapeutic changes, discontinuations, potentially affecting patient outcomes. Aim of this survey was to evaluate the accessibility of NTM-targeting drugs in Italy (with a particular focus on clofazimine) in centers associated with the IRENE Registry, a collaborative network of healthcare professionals. METHODS: A cross-sectional, internet-based, questionnaire-survey on the use and availability of clofazimineand other NTM-targeting drugs was sent to 88 principal investigators of the IRENE network in Italyin 2020. The questionnaires were designed with closed-ended and open-ended questions and distributed using the SurveyMonkey® platform. RESULTS: The surveys underscore the more frequent involvement of pulmonologists (42%) and infectious disease specialists (34%) in NTM treating strategies. Respondents were distributed across 18 out of20 Italian regions, with a significant concentration in the north, encompassing university hospitalsand outpatient clinics. Molecular testing is available in 40% of the involved centers, while phenotypic in 30% of the centers. Centers have a multidisciplinary team and an appointed pharmacy service for NTM drugs distribution in 10 and 75% of the cases, respectively. Substantial variability was observed in drug availability and accessibility, drug regimen composition, and drug dosage, particularly for medications like clofazimine. CONCLUSIONS: This study shows the high heterogeneity of anti-NTM drug availability in Italy and prompts toward a harmonization in antibiotic prescription and access; it also emphasizes the challenges in determining the optimal therapeutic strategies for treating NTM-infections.

Systemic calcineurin inhibitors tacrolimus and voclosporin: A review of off-label dermatologic uses.

BACKGROUND: Systemic calcineurin inhibitors, cyclosporine, tacrolimus, and voclosporin, have been utilized in various dermatologic conditions. Although there have been numerous off-label dermatologic indications with published guidelines for cyclosporine, there is no established strong consensus for tacrolimus and voclosporin. OBJECTIVE: To conduct a review of off-label use of systemic tacrolimus and voclosporin in various dermatoses to better inform treatment methods. METHODS: A literature search was conducted using PubMed and Google Scholar. Relevant clinical trials, observational studies, case series, and reports regarding off-label dermatologic uses of systemic tacrolimus and voclosporin were included. RESULTS: Tacrolimus shows promise for numerous dermatologic conditions, including psoriasis, atopic dermatitis/eczema, pyoderma gangrenosum, chronic urticaria, and Behcet's disease. Randomized controlled trial data are only available for voclosporin in psoriasis, which showed efficacy but did not meet noninferiority to cyclosporine. LIMITATIONS: Data were limited and extracted from published papers. Studies differed in methodology, and nonstandardized outcomes limited the conclusions drawn. CONCLUSIONS: In comparison to cyclosporine, tacrolimus can be considered for treatment-refractory disease or in patients with cardiovascular risk factors or inflammatory bowel disease. Voclosporin has only been utilized in psoriasis currently, and clinical trials in psoriasis show voclosporin's efficacy. Voclosporin can be considered for patients with lupus nephritis.

Off-label psychopharmacological interventions for autism spectrum disorders: strategic pathways for clinicians.

The prevalence of autism spectrum disorder (ASD) continues to see a trend upward with a noticeable increase to 1 in 36 children less than 8 years of age in the recent MMWR. There are many factors linked to the substantially increased burden of seeking mental health services, and clinically these individuals are likely to present for impairments associated with co-occurring conditions. The advances in cutting-edge research and the understanding of co-occurring conditions in addition to psychosocial interventions have provided a window of opportunity for psychopharmacological interventions given the limited availability of therapeutics for core symptomatology. The off-label psychopharmacological treatments for these co-occurring conditions are central to clinical practice. However, the scattered evidence remains an impediment for practitioners to systematically utilize these options. The review collates the crucial scientific literature to provide stepwise treatment alternatives for individuals with ASD; with an aim to lead practitioners in making informed and shared decisions. There are many questions about the safety and tolerability of off-label medications; however, it is considered the best practice to utilize the available empirical data in providing psychoeducation for patients, families, and caregivers. The review also covers experimental medications and theoretical underpinnings to enhance further experimental studies. In summary, amidst the growing clinical needs for individuals with ASD and the lack of approved clinical treatments, the review addresses these gaps with a practical guide to appraise the risk and benefits of off-label medications.

Use of Omalizumab for Pediatric Asthma After US Food and Drug Administration Expanded Indications.

PURPOSE: Research and regulatory approval for pediatric uses of prescription drugs often lag years after adult approvals, during which time substantial off-label use of medications in children can occur. We evaluated whether US Food and Drug Administration (FDA) regulatory actions affected the pediatric use of omalizumab, a biologic drug used to treat asthma. METHODS: In this serial cross-sectional study, we identified quarterly cohorts of children (0-18 years) with moderate-to-severe asthma within two large national claims databases of those with commercial insurance and Medicaid from 2003 to 2019. Using an interrupted time-series analysis, we fit segmented linear regression models to identify changes in the incidence of omalizumab use in 6-11-year-old children compared with 12-18-year-olds after two time points: (1) 2009Q3 when an FDA advisory committee voted against use for 6-11-year-old children and (2) 2016Q2 when FDA expanded omalizumab's labeling to include 6-11-year-old children. RESULTS: We identified 9298 new pediatric omalizumab users (84% Medicaid). Among 6-11-year-old children, the incidence of omalizumab use did not change following the FDA's initial review of evidence in 2009 and increased after 2016 Q2 FDA approval for this age group in both Medicaid (58 per 100 000 children with asthma, 95% confidence interval [CI] 27-89, p < 0.001) and commercial insurance (57 per 100 000, 95% CI 21-94, p = 0.003) compared with 12-18-year-old children. CONCLUSIONS: The use of omalizumab among asthmatic children aged 6-11 years remained steady after FDA advisory committee concerns in 2009 and increased after FDA expanded the indication to include this population in 2016. Additional market incentives may help to ensure the timely generation of evidence and regulatory approval of medications for children.

Research encouraging off-label use of quetiapine: A systematic meta-epidemiological analysis.

BACKGROUND: Researchers often conduct small studies on testing a drug's efficacy in off-label indications. If positive results from these exploratory studies are not followed up by larger, randomized, double-blinded trials, physicians cannot be sure of a drug's clinical value. This may lead to off-label prescriptions of ineffective treatments. We aim to describe the way clinical studies fostered off-label prescription of the antipsychotic drug quetiapine (Seroquel). METHODS: In this systematic meta-epidemiological analysis, we searched EMBASE, MEDLINE, Cochrane CENTRAL and PsycINFO databases and included clinical studies testing quetiapine for unapproved indications between May 1995 and May 2022. We then assessed the frequency with which publications providing low-level evidence suggesting efficacy of quetiapine for off-label indications was not followed up by large, randomized and double-blinded trials within 5 years. RESULTS: In total, 176 published studies were identified that reported potential efficacy of quetiapine in at least 26 indications. Between 2000 and 2007, publication of exploratory studies suggesting promise for off-label indications rapidly outpaced publication of confirmatory trials. In the 24 indications with a minimum of 5 years of follow-up from the first positive exploratory study, 19 (79%) were not followed up with large confirmatory trials within 5 years. At least nine clinical practice guidelines recommend the use of quetiapine for seven off-label indications in which published confirmatory evidence is lacking. CONCLUSION: Many small, post-approval studies suggested the promise of quetiapine for numerous off-label indications. These findings generally went unconfirmed in large, blinded, randomized trials years after first being published. The imbalance of exploratory and confirmatory studies likely encourages ineffective off-label treatment.

Effect of off-label targeted drugs on long-term survival in chronic thromboembolic pulmonary hypertension: Insights from a national multicentre prospective registry.

BACKGROUND AND OBJECTIVE: Off-label pulmonary arterial hypertension (PAH)-targeted drugs are commonly prescribed for non-operated chronic thromboembolic pulmonary hypertension (CTEPH), but their effect on the long-term prognosis of CTEPH remains unknown. This study investigated the effect of off-label PAH-targeted drugs on the long-term survival of CTEPH patients. METHODS: CTEPH patients were enrolled from a prospective multicentre national registry. Except for licensed riociguat and treprostinil, other PAH-targeted drugs were off-label. In the original and propensity score-matched (PSM) samples, five-year survival was compared in two groups: (a) patients not receiving off-label PAH-targeted drugs (control) versus (b) patients receiving off-label PAH-targeted drugs (treatment). The latter group was investigated for the effect of started off-label PAH-targeted drugs at baselines (initial) or during follow-up (subsequent). RESULTS: Of 347 enrolled patients, 212 were treated with off-label PAH-targeted drugs initially (n = 173) or subsequently (n = 39), and 135 were untreated. The 1-, 2-, 3- and 5-year survival of the treatment group was significantly higher than that of the control group (97.1% vs. 89.4%, 92.3% vs. 82.1%, 83.2% vs. 75.1% and 71.1% vs. 55.3%, respectively, log-rank test, p = 0.005). Initial treatment was correlated with better 5-year survival after excluding patients with subsequent treatment to reduce the immortal-time bias (hazard ratio: 0.611; 95% CI: 0.397-0.940; p = 0.025). In PSM samples, patients given initial treatment showed significantly better 5-year survival than untreated patients (68.9% vs. 49.3%, log-rank test, p = 0.008). CONCLUSION: Off-label targeted drugs contributed to improved long-term survival in CTEPH patients receiving pharmacotherapies.