Off-label Research Articles

Status and trends of legislative and regulatory regulation of off-label use of drugs: A review

The off-label use of drugs is a common practice worldwide. The legal basis for off-label medical use varies from country to country. Regulatory control of the pharmaceutical market in the off-label preventive and therapeutic practice at the international and national levels has become a breakthrough with the emergence of the coronavirus pandemic. The prospects for off-label use in the context of innovations in the legislation of public health in the Russian Federation are crucial. Professionally significant aspects of the use of medicinal products outside the Summary of Product Characteristics and the off-label use have been introduced by supranational regulatory authorities for the common market of medicinal products of the Eurasian Economic Union. Special attention should be paid to the regulatory control of the use of extemporaneous medicines as part of improving the government regulation of drug compounding in pharmacies. The active development of pharmacy activities in drug compounding within the framework of improving regulatory practice determines the relevance of actual off-label prescriptions and the use of extemporaneous formulations. Aim – to perform a systematic analysis of national, transnational legislative and regulatory documents regulating off-label use of medicinal products, determine the main conceptual components of the current regulatory pool and directions for future development in this area. Systematic analysis of the national legislative and regulatory pool of documents and the regulatory framework of the common market of medicinal products of the Eurasian Economic Union on the regulation of various aspects of the off-label use of medicinal products. Study of the components and identification of the main trends in the regulatory practice of prescriptions outside the Summary of Product Characteristics and the off-label use. An analytical search was carried out in the reference legal systems "ConsultantPlus" and "Garant" on the official websites of the Ministry of Health of Russia, the Eurasian Economic Union, the RusMed information resource of the National Library resource of Russia in medicine and pharmacy "Central Scientific Medical Library" was used. A logical generalization of the results on the current state of the legal framework and the development of conceptual proposals on the key directions of the prospective development of regulation, control, and supervisory activities of the pharmaceutical off-label use of medicinal products was made.

B-10 | Off-label Use of KA Micro Plug in PDA Closure in Premature Infants Weighing Less than 1500 Grams: Tips for Success

B-10 | Off-label Use of KA Micro Plug in PDA Closure in Premature Infants Weighing Less than 1500 Grams: Tips for Success

Paediatric off-label use of drugs in Gansu, China: a multicentre cross-sectional study

ObjectiveTo examine the current prevalence and cost of paediatric off-label drug prescriptions in Gansu, China, and the potential influencing factors.DesignThe prevalence of off-label prescriptions in paediatrics was evaluated according to...

Evaluating the Safety and Efficacy of Capromorelin in Rhesus Macaques (Macaca mulatta).

Nonhuman primates used in biomedical research may experience clinically significant weight loss for a variety of reasons. Episodes of anorexia (complete loss of appetite) or hyporexia (decreased appetite) can result in significant weight loss, potentially altering animal welfare and scientific studies. The FDA has approved several appetite stimulants for use in domestic species, but currently none are approved for use in NHP. Treatment of inappetence and weight loss in NHP often relies on the extralabel use of these compounds. Capromorelin is a ghrelin receptor agonist. As a growth hormone secretagogue, capromorelin increases appetite, leading to weight gain. Studies in several species have shown a positive correlation between capromorelin administration and weight gain; in 2017, an oral solution of capromorelin received FDA approval for use in dogs. We tested this solution in healthy adult rhesus macaques (n = 3 males and 3 females) for its effects on body weight and insulin like growth factor-1 (IGF-1). A control group (n = 2 males and 2 females) was used for comparison. Treated macaques received a 3mg/kg oral dose daily for 7 d. Clinical signs were observed daily. Weights were collected before, during and at the end of treatment. Blood was drawn before, during and after treatment for measurement of IGF-1 levels and standard hematology and biochemistry parameters. Baseline-adjusted mean body weights and IGF-1 levels were significantly higher in treated as compared with control monkeys after 7 d of beginning treatment (body weight of 10.5±0.1kg (mean ± SEM) and 10.1±0.1kg, respectively; IGF-1 of 758±43ng/mL and 639±22ng/mL, respectively). Capromorelin administration was not associated with appreciable changes in hematologic and biochemical values in treated macaques. These findings suggest that capromorelin may be useful for treating inappetence and weight loss in NHP, and based on blood analysis, a 7-d course of treatment does not appear to cause acute toxicity.

Risankizumab as a Therapeutic Approach for Recalcitrant Pyoderma Gangrenosum.

Pyoderma gangrenosum (PG) is a neutrophilic dermatosis that is challenging to diagnose and treat. Clinicians frequently use fast-acting corticosteroids, which are subsequently combined with slower-acting immunosuppressants to progressively taper the corticosteroid dosage. Current research is focused on the use of monoclonal antibodies (mAbs) directed against target molecules involved in the pathogenesis of PG. However, available data on their efficacy are based on sporadic case reports and clinical experiences, so the authors aimed to evaluate the efficacy of risankizumab, an anti-interleukin-23 mAb, in the management of two complex PG cases. The authors enrolled two patients with PG who were already treated with immunosuppressive therapies. Their management was based on the off-label use of an mAb directed against the p19 subunit of interleukin-23: risankizumab. Patients received subcutaneous injections of 150 mg at the start of treatment, at week 4, and then every 10 weeks thereafter. Systemic therapy was combined with local management of ulcers, based on the principles of TIME (tissue, infection, moisture balance, and epithelialization) applied to the inflammatory and noninflammatory phases of PG. Clinical resolution was obtained at week 24 for patient 1 and week 16 for patient 2 and was maintained until week 40, without adverse effects or disease recurrence. These clinical cases demonstrate that risankizumab is a valid tool in terms of efficacy and safety for complicated cases of multirefractory PG when provided in parallel with local personalized wound management.

The landscape of real-world evidence of rituximab utilization and clinical outcomes in patients with cancer, rheumatoid arthritis, and multiple sclerosis: A scoping review.

Rituximab (RTX) is an anti-CD20 monoclonal antibody that is used to treat various conditions in cancer, rheumatoid arthritis (RA), and multiple sclerosis (MS). Although RTX has been used in the United States for almost 3 decades, questions remain regarding its real-world utilization and effectiveness. To describe the state of observational research and real-world evidence evaluating RTX in oncology, RA, and off-label use in MS. A broad search was conducted in MEDLINE, Embase, and CINAHL covering the period of January 2010 to June 2022. Two reviewers independently screened all identified records for each disease category (cancer, RA, MS) beginning with title review, followed by abstract, and full-text review to identify relevant publications to include in the final analysis. Data were extracted and summarized for each disease based on overall trends, similarities, and differences across included studies and stratified by disease state. A total of 260 studies met eligibility criteria, with 79 studies for the RA cohort, 144 for cancer, and 37 for MS. Across all disease cohorts, most studies (n = 189; 72.7%) were retrospective. 171 (65.8%) studies used hospital or electronic health record data as their data source and 65 (23.2%) used registry databases. Most studies (n = 153; 58.8%) assessed the effectiveness of RTX measured by disease-specific endpoints, followed by safety (n = 60; 23.1%), treatment patterns (n = 32; 12.3%), and descriptive analyses assessing treatment adherence and economic burden of disease (n = 16; 6.2%). Although safety was not the primary outcome for most studies, the majority of studies across all disease states still reported some form of safety measure. Conclusive statements on RTX's benefit varied across disease states, with MS having the most (n = 30; 81.1%) studies suggesting the drug's positive benefit. There were limited studies assessing RTX use, associated economic burden, and biosimilar switching. The findings underscore the need for health care providers to better understand the treatment landscape and utilization of RTX, particularly in terms of patient selection, timing of initiation, and long-term outcomes. Real-world evidence can help support health care decisions and treatment using rituximab.

Imrecoxib: Advances in Pharmacology and Therapeutics.

Imrecoxib, a cyclooxygenase-2 (COX-2) selective non-steroidal anti-inflammatory drug (NSAID), was discovered via the balanced inhibition strategy of COX-1/COX-2. It is indicated for the relief of painful symptoms of osteoarthritis. There have been some pharmacological and therapeutic advances since the approval of imrecoxib in 2011. However, an update review in this aspect is not yet available. Relevant literature until January 2024 was identified by search of PubMed, Web of science, Embase and CNKI. From the perspective of efficacy, imrecoxib provides relief of osteoarthritis symptoms, and potential off-label use for treatment of idiopathic pulmonary fibrosis, perioperative pain, hand-foot syndrome, axial spondyloarthritis, COVID-19, cartilage injury, and malignancies such as lung and colon cancer. From a safety point of view, imrecoxib showed adverse effects common to NSAIDs; however, it has lower incidence of new-onset hypertension than other types of selective COX-2 inhibitors, less gastrointestinal toxicities than non-selective NSAIDs, weaker risk of drug interaction than celecoxib, and more suitable for elderly patients due to balanced inhibition of COX-1/COX-2. From a pharmacoeconomic perspective, imrecoxib is more cost-effective than celecoxib and diclofenac for osteoarthritis patients. With the deepening of the disease pathophysiology study of osteoarthritis, new therapeutic schemes and pharmacological mechanisms are constantly discovered. In the field of osteoarthritis treatment, mechanisms other than the analgesic and anti-inflammatory effects of COX-2 inhibitors are also being explored. Taken together, imrecoxib is a moderate selective COX-2 inhibitor with some advantages, and there would be more clinical applications and research opportunities in the future.

“SEEK, AND YOU WILL FIND” - IMPLICATIONS OF PULMONARY HYPERTENSION DIAGNOSIS AND TREATMENT OF PATIENT WITH CHRONIC OBSTRUCTIVE PULMONARY DISEASE AND LEFT HEART FAILURE

Objective: The case report presents a patient with multimorbidity. A diagnosis of pulmonary hypertension was made during multiple hospitalizations due to bad compliance. The objective of this case report is to describe the difficulties involved in diagnosing pulmonary hypertension in a patient with chronic obstructive pulmonary disease and left heart failure. Design and method: Case report of patient with pulmonary hypertension, chronic obstructive pulmonary disease, left heart failure and multiple comorbidities. Observation of the patient's health condition during many hospitalizations led to further diagnosis of pulmonary hypertension and forced the modification of current treatment. Results: Patient went through many hospitalizations because of bad compliance to chronic obstructive pulmonary disease and left heart failure pharmacotherapy. The patient was hospitalized in our ward for chest pain. He also presented combination of nonspecific symptoms such as dyspnoea (including resting dyspnoea), exercise intolerance and peripheral oedema. Chest x-ray showed signs of pneumonia. Therefore, the diagnosis of pulmonary hypertension was not made during the first hospitalisations. Echocardiography was planned to exclude chronic coronary syndrome. It revealed patent ductus arteriosus, right ventriculum and pulmonary trunk dilation, tricuspid regurgitation and high probability of pulmonary hypertension (mean pulmonary artery pressure 46,5mmHg), without regional cardiac wall dysfunction. The next hospitalization was scheduled, during which cardiac catheterization was performed (pulmonary capillary wedge pressure 14,5 mmHg) and precapillary pulmonary hypertension was confirmed. After many consultations, excluding other causes, such as thromboembolic changes, chronic obstructive pulmonary disease was considered the most likely cause of precapillary pulmonary hypertension. Treatment of basal diseases has been modified, off-label treatment with sildenafil was started, and then due to ineffective treatment (deterioration of the patient's condition resulted in a transition from WHO functional class II to III) the patient was qualified for the bosentan clinical drug treatment program. Conclusions: Diagnosis of pulmonary hypertension can be difficult when symptoms of diseases from other systems are overlapping. This case shows the necessity of watchful observation of patients with multimorbidity, but also difficulties in maintaining good medical compliance. Pulmonary hypertension is still a rare diagnosis, but we should stay alerted about it.

Low-dose naltrexone for post-COVID fatigue syndrome: a study protocol for a double-blind, randomised trial in British Columbia

IntroductionA significant proportion of individuals suffering from post COVID-19 condition (PCC, also known as long COVID) can present with persistent, disabling fatigue similar to myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and...

Revealing the therapeutic potential of teriparatide: a review

Teriparatide is an FDA-approved medication for osteoporosis that presents promising results in treating various musculoskeletal conditions. It helps in improving the bone mineral density and preventing fractures in individuals with osteoporosis. Its effectiveness in treating non-union and delayed union fractures, atypical femoral fractures, and spinal fusion procedures makes it valuable in improving bone healing and reducing complications. Teriparatide also improves bone density and strength in individuals with osteogenesis imperfecta, helps prevent and treat hypocalcaemia post-thyroidectomy, and helps in the management of hypoparathyroidism. In MRONJ, teriparatide improves lesion resolution and reduces bony defects. Furthermore, it potentially prevents bone metastasis in cancer patients without stimulating tumour growth. Nevertheless, teriparatide may cause short-term side effects like nausea and long-term concerns pertaining to the risk of osteosarcoma. Recent European alliance of associations for rheumatology guidelines have highlighted teriparatide's superior effectiveness in achieving bone mineral density thresholds and reducing fracture risks. Further clinical trials are necessary to determine optimal dosages and treatment durations of teriparatide. The off-label use of teriparatide should be considered only under the guidance of a healthcare professional when standard options are unavailable or inadequate.

Coronary laser with simultaneous contrast injection for the treatment of stent underexpansion.

Stent underexpansion is a challenge in interventional cardiology. Some off-label treatments, such as rotational atherectomy, intravascular lithotripsy (IVL) and coronary lasing, have been used to overcome the problem. The purpose of this study is to evaluate the safety and efficacy of coronary laser atherectomy with simultaneous contrast injection and subsequent balloon dilation to optimize stent expansion. Coronary laser atherectomy with simultaneous contrast injection was used. After lasing, non-compliant balloon dilation at high pressure was performed to overcome the underexpanded point. The average increase in the minimum stent area (MSA) was measured by intravascular ultrasound (IVUS), and any complication related to the technique was evaluated. Additionally, major adverse cardiovascular events (MACE), consisting of death from any cause, new myocardial infarction (MI) and target lesion revascularization (TLR), were scrutinized in a long-term follow-up. Sixteen underexpanded stents were treated with laser between August 2017 and November 2022. In all cases but one, IVUS was used to evaluate the MSA before and after lasing. The MSA showed an average increase of 2.34 ± 1.57 mm² (95% confidence interval [CI]: 1.47-3.21; p < 0.001) after laser application and balloon inflation. No complication related to the technique was detected. During a follow-up period of a median (interquartile range) of 457 (50-973) days, the combined MACE assessed by Kaplan-Meier estimator showed an event-free rate of 0.82 (95% CI: 0.59-1). Coronary laser with simultaneous contrast injection is a safe method to optimize a stent underexpansion, with an acceptable event-free rate in long-term follow-up.

Off-Label Use of Balloon-Expandable Transcatheter Valves to Treat Pure Aortic Regurgitation

Transcatheter aortic valve implantation (TAVI) in native pure aortic regurgitation (AR) with off-label use of balloon expandable valves (BEV) has been reported. However, there are scant data regarding optimal oversizing and its safety and our study assessed BEV oversizing and outcomes of TAVI. Thirteen consecutive tricuspid aortic valve patients undergoing transfemoral TAVIs for pure AR with Sapien BEV at our centre between 2019 and 2023 (69.2% males, mean age 80.8 years, STS 4.0%) were divided into small annulus group (≤618mm2, SA) where ≥20% oversizing is achievable based on published data on BEV overexpansion, and larger annulus group (LA, >618mm2). Overexpansion and actual oversizing were measured on post-procedural CT scan. Technical success was 92.3% with one valve embolization in LA group. The post-procedural CT showed a mean 28.3% oversizing, significantly higher in SA (31.2%) then in LA group (19.4%), p= 0.0092. Oversizing ≥20% was achieved in 100% SA vs 33.3% LA patients (p=0.046). In conclusion, TAVI in pure AR with oversized Sapien BEV showed good procedural and short-term outcomes when ≥20% oversizing was predictably achievable.

The resolute Onyx in TIA management (ROTIA).

First-line treatment for symptomatic intracranial atherosclerotic disease (ICAD) is medical management; however, interventional approaches are increasingly considered for refractory disease. The Resolute Onyx in TIA management (ROTIA) study is a post-market evaluation of the Resolute Onyx (R-Onyx) drug-eluting stent in the treatment of recurrent transient ischemic attacks (TIAs) due to refractory ICAD (off-label use). This is a single-center, retrospective case series of consecutive patients who underwent angioplasty and stenting with R-Onyx for treatment of recurrent TIAs due to refractory ICAD from October 2019 to November 2022. Included patients were ages 22-80, had a baseline modified Rankin Scale of ≤2, and had recurrent TIAs attributed to intracranial artery stenosis >70% despite maximal medical therapy. Primary outcomes of interest were peri-procedural complications (TIA, stroke, intracranial hemorrhage, mortality) up to 72 h post-stenting and ischemic stroke up to 18 months post-stenting. Twenty patients (mean age 66.84 ± 14; 25% female; 80% Hispanic) were included. A total of 21 stents were successfully deployed with no peri-procedural complications. There were no recurrent ischemic events at 30 days post-stenting. At 18 months post-stenting, there were no ischemic events and no patient exhibited in-stent restenosis. ROTIA demonstrates the feasibility of using the Resolute Onyx drug-eluting stent for the management of TIAs due to refractory ICAD, with high technical success and low peri-procedural complications. Limitations include the retrospective and single-center nature of this study. Future prospective, multi-center, randomized trials with extended observation periods are needed.

115 Off-label treatment with the selective PI3Kδ inhibitor leniolisib in 2 pediatric patients with activated phosphoinositide 3-kinase delta syndrome 2 (APDS2)

115 Off-label treatment with the selective PI3Kδ inhibitor leniolisib in 2 pediatric patients with activated phosphoinositide 3-kinase delta syndrome 2 (APDS2)

Medicines management in children and young people: pharmacokinetics, drug calculations and off-label drug use.

Medicines management in children and young people presents specific challenges because children differ from adults in their response to medicines. The way in which medicines work inside the human body, or pharmacokinetics, varies according to age and stage of development. Accurate drug calculations for a child rely on the careful consideration of a series of factors, such as weight and height, pharmacokinetics and drug characteristics. This article focuses on three fundamental aspects: pharmacokinetics, drug calculations, and unlicensed and off-label drug use.

Imiquimod Is Effective in Reducing Cervical Intraepithelial Neoplasia: A Systematic Review and Meta-Analysis.

Topical Imiquimod is an immune response modifier approved for the off-label use of vulvar intraepithelial neoplasia. We conducted this systematic review and meta-analysis to investigate the efficacy and safety of Imiquimod in treating cervical intraepithelial neoplasia (CIN) and human papillomavirus (HPV)-positive patients. The study was prospectively registered (CRD420222870) and involved a comprehensive systematic search of five medical databases on 10 October 2022. We included articles that assessed the use of Imiquimod in cervical dysplasia and HPV-positive patients. Pooled proportions, risk ratios (RRs), and corresponding 95% confidence intervals (CIs) were calculated using a random effects model to generate summary estimates. Statistical heterogeneity was assessed using I2 tested by the Cochran Q tests. Eight articles reported on 398 patients who received Imiquimod out of 672 patients. Among CIN-2-3 patients, we observed a pooled regression rate of 61% (CI: 0.46-0.75; I2: 77%). When compared, Imiquimod was inferior to conization (RR: 0.62; CI: 0.42-0.92; I2: 64%). The HPV clearance rate in women who completed Imiquimod treatment was 60% (CI: 0.31-0.81; I2: 57%). The majority of side effects reported were mild to moderate in severity. Our findings indicate that topical Imiquimod is safe and effective in reducing cervical intraepithelial neoplasia and promoting HPV clearance. However, it was found to be inferior compared to conization. Imiquimod could be considered a potential medication for high-grade CIN patients and should be incorporated into guidelines for treating cervical dysplasia.

Off-label use of intravitreal bevacizumab: A global conundrum.

Bevacizumab is a monoclonal, humanized, full-length antibody targeting vascular endothelial growth factor(VEGF-A), known for its anti-angiogenic properties. The off-label use of bevacizumab has stirred legal, financial, industrial, and ethical complexities. With its potential to treat diverse ocular conditions, this commentary delves into the multifaceted dimensions of bevacizumab's off-label utilization, encompassing clinical trials, regulatory frameworks, safety considerations, comparative effectiveness, and economic implications.

Tailoring of Bilosomal Nanogel for Augmenting the Off-Label Use of Sildenafil Citrate in Pediatric Pulmonary Hypertension.

Pediatric pulmonary hypertension is a serious syndrome with significant morbidity and mortality. Sildenafil is widely used off-label in pediatric patients with pulmonary arterial hypertension. In this study, bile salt-stabilized nanovesicles (bilosomes) were screened for their efficacy to enhance the transdermal delivery of the phosphodiesterase type 5 inhibitor, sildenafil citrate, in an attempt to augment its therapeutic efficacy in pediatric pulmonary hypertension. A response surface methodology was implemented for fabricating and optimizing a bilosomal formulation of sildenafil (SDF-BS). The optimized SDF-BS formulation was characterized in terms of its entrapment efficiency (EE), zeta potential, vesicle size, and in vitro release profile. The optimized formula was then loaded onto hydroxypropyl methyl cellulose (HPMC) hydrogel and assessed for skin permeation, in vivo pharmacokinetics, and pharmacodynamic studies. The optimized SDF-BS showed the following characteristic features; EE of 88.7 ± 1.1%, vesicle size of 185.0 + 9.2 nm, zeta potential of -20.4 ± 1.1 mV, and efficiently sustained SDF release for 12 h. Skin permeation study revealed a remarkable improvement in SDF penetration from bilosomal gel compared to plain SDF gel. In addition, pharmacokinetic results revealed that encapsulating SDF within bilosomal vesicles significantly enhanced its systemic bioavailability (∼3 folds), compared to SDF oral suspension. In addition, pharmacodynamic investigation revealed that, compared to plain SDF gel or oral drug suspension, SDF-BS gel applied topically triggered a significant elevation (p < 0.05) in cGMP serum levels, underscoring the superior therapeutic efficacy of SDF-BS gel. Conclusively, bilosomes can be viewed as a promising nanocarrier for transdermal delivery of SDF that would grant higher therapeutic efficiency while alleviating the limitations encountered with SDF oral administration.

Safety of Off-Label Use of Anticancer Drugs in Oncology

Safety of Off-Label Use of Anticancer Drugs in Oncology

Cannabidiol Bioavailability Is Nonmonotonic with a Long Terminal Elimination Half-Life: A Pharmacokinetic Modeling-Based Analysis.

Background: Oral and inhalation-based cannabidiol (CBD) administration has been clinically evaluated for various therapeutic indications, alongside widespread off-label use. However, the long-term exposure kinetics and varied bioavailability have not been fully characterized. Methods: Human CBD plasma concentration-time profiles from six studies evaluating the oral administration of Epidiolex® and three studies evaluating inhalation-based delivery were obtained. A four-compartment pharmacokinetic (PK) model with Weibull-based oral absorption kinetics was employed to describe the long-term PKs of CBD. Furthermore, a Cedergreen-Ritz-Streibig model was applied to evaluate nonmonotonic oral bioavailability. Results: CBD was extensively distributed into tissue compartments with varied kinetics resulting in a long plasma terminal elimination half-life of >134 h in humans. For once-a-day oral dosing, the plasma trough concentrations require >70 days to reach a steady state. The oral bioavailability of CBD for different doses administered in fasted state follows a nonmonotonic pattern with an inverted U-shaped profile. Oral administration of CBD under fed state or subjects with hepatic impairment yields higher oral bioavailability with varied exposure. In contrast, inhalation-based delivery of CBD, while delivering a similar systemic delivered dose compared with oral dosing due to high device losses, bypasses first-pass metabolism and can be efficient. Conclusion: CBD PKs vary across different doses due to nonmonotonic oral bioavailability, and inhalation-based delivery could minimize such variability in humans. The delayed attainment of steady state and prolonged terminal half-life, resulting from differential but extensive tissue distribution, needs to be considered when dosing CBD in the long term. These fundamental findings are critical for establishing dose-exposure relationship for further clinical evaluation of novel CBD-based therapies.