[Chinese expert consensus on off-label use of Tocilizumab in rheumatic diseases].

The interleukin-6 (IL-6) pathway plays a crucial role in various rheumatic diseases. Tocilizumab, a biologic targeting IL-6 receptor, has been widely used in clinical practice, though it's officially approved in China for only three indications. To address clinical challenges associated with the off-label use of tocilizumab in treating rheumatic diseases, the Committee of Chinese Primary Health Care Foundation for Rheumatologists and Immunologists engaged multidisciplinary experts and highlight 12 related clinical issues. We aggregated the drug specifications, the guidelines for clinical management of rheumatic diseases and the evidence from clinical research. Recommendations were formed through voting with the consensus conference method incorporating the Oxford evidence-based medicine criteria to evaluate the strength of evidence and recommendations. We have formulated 10 recommendations for off-label use of tocilizumab related to giant cell arteritis, polymyalgia rheumatica, Takayasu arteritis, systemic sclerosis, adult-onset Still's disease, rheumatoid arthritis, and juvenile idiopathic arthritis. This consensus aims to provide references for the rational use of tocilizumab in clinical practice and enhance pharmacovigilance monitoring.

Therapeutic Potential of Naltrexone in the Niche of Psychopharmacology.

NTX is FDA-approved for opiate and alcohol use disorders as anti-craving agent. It has been used successfully off-label in other psychiatric indications. Here, we shed some light on these while examining the extant evidence.

Age-related off-label drug prescribing in pediatric patients in South Korea and consistency of labeling compared to the United States, Europe, and Japan.

Insufficient labeling information regarding the appropriate age for prescribing drugs to the pediatric population is challenging. This study aimed to analyze the off-label prescription of age-related drugs for pediatric patients using claims data from South Korea and to assess the consistency of the approved age in South Korea, the United States, Europe, and Japan. In 2020, 1004 unique drugs were prescribed to the pediatric population in South Korea. We found that 641 drugs (63.8%, p < 0.0001) were related to off-label prescriptions for age-related use at least once, and the total number of off-label prescriptions was 2,236,669 (62.2%, p < 0.0001). Chlorpheniramine (28%) was the most frequently prescribed drug for pediatric patients with an age-related off-label, followed by budesonide (9%) and epinephrine (9%). The degree of agreement in the approved age range for 641 off-label drugs across countries was assessed using the overall kappa coefficient. We observed slight agreement in labeling across all countries (κ: 0.16, 95% confidence interval [CI]: 0.14-0.18). The highest degree of agreement was observed between the United States and Europe (0.41, 0.37-0.45) due to pediatric-population-specific legislation. South Korea showed the lowest degree of agreement with the United States and Europe (0.10, 0.06-0.14). The United States, Europe, and Japan showed fair agreement (0.23, 0.21-0.26). However, the degree of agreement between South Korea, the United States, and Japan (0.09, 0.06-0.11) and South Korea, Europe, and Japan (0.08, 0.05-0.10) was low. This study highlights the need for South Korean regulatory agencies to consider introducing pediatric legislation to prescribe evidence-based drugs for safe and effective use.

Role of IL-23 inhibitors including risankizumab and guselkumab in the treatment of pityriasis rubra pilaris.

Pityriasis rubra pilaris (PRP) is a rare and chronic inflammatory dermatologic condition characterized by hyperkeratotic salmon-colored plaques and palmoplantar keratoderma. Traditional therapeutic modalities have shown limited efficacy and often entail potential adverse effects, highlighting the need for alternative treatment options. Our review aims to summarize the current evidence on the off-label use of IL-23 inhibitors, risankizumab and guselkumab, in the treatment of PRP. These biologic agents have been approved for psoriasis, and their potential role in managing PRP has recently garnered interest. We conducted a comprehensive literature search on PubMed and Scopus databases, identifying relevant studies published in English up to June 2023 following PRISMA guidelines. A total of 10 studies were selected for data extraction and review. Results from the selected studies demonstrated encouraging outcomes with both risankizumab and guselkumab in managing PRP. Among 11 patients treated with risankizumab, 10 showed notable improvements in various disease manifestations, including pruritus, erythema, and affected body surface area. DLQI scores and BSA percentages reported a significant improvement before and after risankizumab treatment (p = 0.0322; p = 0.0216). However, two cases also reported symptom aggravation or even disease worsening. Patients treated with guselkumab exhibited ultimate improvement in all five cases, with complete clearance in three out of five cases. DLQI and BSA percentages also reported significant improvement with treatment with guselkumab (p = 0.0172; p < 0.0001). While most cases demonstrated positive outcomes, there were isolated instances of worsening symptoms, emphasizing the need for caution and further investigation. Further research with larger sample sizes and longer follow-up periods is necessary to establish the efficacy, optimal dosing, and long-term safety of risankizumab and guselkumab in treating PRP. Overall, we provide valuable insights into the potential use of IL-23 inhibitors, risankizumab, and guselkumab, as promising treatment options for PRP. These biologics have shown efficacy in improving symptoms in treatment-resistant cases, offering new avenues for clinicians to explore in the treatment of PRP.

Sotorasib as Fourth-Line Treatment in Pancreatic Cancer: A Case Report and Literature Review.

The molecular pathogenesis of exocrine pancreatic cancer involves mutations K-RAS, TP53, CDKN2A, and SMAD4. The KRAS oncogene leads to constitutively active tumor cell proliferation and is present in 90% of unresectable or metastatic pancreatic adenocarcinomas. Of these, the G12C variant of K-RAS genes accounts for 1-2% of mutations. A 65-year-old woman initially diagnosed with T3N0M0 pancreatic adenocarcinoma, underwent six cycles of neoadjuvant chemotherapy with mFOLFIRINOX followed by Whipple procedure. Her pathological stage was T4N2. She then received adjuvant mFOLFIRINOX but unfortunately her disease progressed through multiple lines of chemotherapy. Molecular analysis by Next Generation Sequence(NGS) panel revealed KRAS G12C mutation. Based on this mutational status, she was started on Sotorasib to which she had clinical response lasting for about 11 months prior to disease progression. Off-label use of Sotorasib as fourth-line treatment in our patient with KRAS G12C mutated pancreatic cancer was efficacious and relatively well tolerated.

Pediatric Pharmacology for the Primary Care Provider: Advances and Limitations.

Despite >1 in 5 children taking prescription drugs in the United States, off-label drug use is common. To increase the study of drugs in children, regulatory bodies have enacted legislation to incentivize and require pediatric drug studies. As a result of this legislation, novel trial approaches, and an increase in personnel with pediatric expertise, there have been numerous advancements in pediatric drug development. With this review, we aim to highlight developments in pediatric pharmacology over the past 6 years for the most common disease processes that may be treated pharmacologically by the pediatric primary care provider. Using information extracted from label changes between 2018 and 2023, the published literature, and Clinicaltrials.gov, we discuss advances across multiple therapeutic areas relevant to the pediatric primary care provider, including asthma, obesity and related disorders, mental health disorders, infections, and dermatologic conditions. We highlight instances in which new drugs have been developed on the basis of a deeper mechanistic understanding of illness and instances in which labels have been expanded in older drugs on the basis of newly available data. We then consider additional factors that affect pediatric drug use, including cost and nonpharmacologic therapies. Although there is work to be done, efforts focused on pediatric-specific drug development will increase the availability of evidence-based, labeled guidance for commonly prescribed drugs and improve outcomes through the safe and effective use of drugs in children.

[Off-label use of intravenous immunoglobulin g in a highly complex pediatric hospital in Argentina. A prospective observational study] / Uso "off label" de inmunoglobulina g endovenosa en un hospital pediátrico de alta complejidad de Argentina.

Introduction: The World Health Organization recommends prioritizing safe and effective drugs proven by clinical or epidemiological studies. However, in population groups with little research, a drug can be used for an indication or pharmaceutical form different from that approved by the regulatory agency (off-label), extrapolating data from studies in adults and exposing pediatric patients. to develop an Adverse Drug Reaction (ADR) due to safety considerations that have not been systematically studied. Intravenous immunoglobulin (IVIg), a high-cost drug, is used with scant evidence in some low-prevalence pathologies. This paper describes and analyzes the off-label use of IVIg at the J. P. Garrahan Pediatric Hospital. Methods: Observational, descriptive, prospective study on off-label indications of IVIg. The sampling technique was non-probabilistic and for convenience during 7 months. Results: 305 IVIg infusions were studied, corresponding to 111 patients. The indication classification showed that 22% (n=67) of the infusions were off-label. In neurology there was a higher percentage of off-label indications (46%) and within them 45% corresponded to the use in neurological disorders. 81% of the doses indicated off-label were in the range 0.8-1g/kg. The off-label infusions presented 61.5% (n=8) of the ADRs. Those from the Neurology service represented 87.5%; 75% being from the "Neurological disorders" group. Conclusion: In some cases, IVIg was indicated in an off-label manner, finding a statistically significant relationship with the appearance of ADR. This finding motivates the proposition of new hypotheses to carry out more studies.

Introducción: La Organización Mundial de la Salud recomienda priorizar fármacos seguros y eficaces comprobados mediante estudios clínicos o epidemiológicos. Sin embargo, en grupos poblacionales con escasa investigación, un fármaco puede utilizarse para una indicación o, forma farmacéutica diferente a la aprobada por la agencia reguladora ("off label"), extrapolando datos provenientes de estudios en adultos y, exponiendo a los pacientes pediátricos a desarrollar una Reacción Adversa Medicamentosa (RAM) por consideraciones de seguridad no estudiadas sistemáticamente. Inmunoglobulina G endovenosa (IgG EV), medicamento de alto costo, es utilizado con escasa evidencia en algunas patologías poco prevalentes. Este trabajo describe y analiza el uso "off label" de IgG EV en el Hospital de Pediatría J. P. Garrahan. Métodos: Estudio observacional, descriptivo, prospectivo sobre indicaciones "off label" de IgG EV. La técnica de muestreo fue no probabilística y por conveniencia durante 7 meses. Resultados: Se estudiaron 305 infusiones de IgG EV que correspondieron a 111 pacientes. La clasificación de la indicación mostró que 22% (n=67) de las infusiones fueron "off label". En neurología hubo mayor porcentaje de indicaciones "off label" (46%) y dentro de ellas el 45% correspondió al uso en desórdenes neurológicos. El 81% de dosis indicadas "off label" estuvieron en rango 0,8-1g/kg. Las infusiones indicadas "off label" presentaron el 61.5% (n=8) de las RAM. Las del servicio de Neurología, representaron el 87,5 %, siendo 75% del grupo "Desórdenes neurológicos". Conclusión: En algunos casos IgG EV fue indicada en forma "off label", encontrándose una relación estadísticamente significativa con la aparición de RAM. Este hallazgo motiva al planteo de nuevas hipótesis para realizar más estudios.

Safety and efficacy of new generation azole antifungals in the management of recalcitrant superficial fungal infections and onychomycosis.

INTRODUCTION: Terbinafine is considered the gold standard for treating skin fungal infections and onychomycosis. However, recent reports suggest that dermatophytes are developing resistance to terbinafine and the other traditional antifungal agents, itraconazole and fluconazole. When there is resistance to terbinafine, itraconazole or fluconazole, or when these agents cannot used, for example, due to potential drug interactions with the patient's current medications, clinicians may need to consider off-label use of new generation azoles, such as voriconazole, posaconazole, fosravuconazole, or oteseconazole. It is essential to emphasize that we do not advocate the use of newer generation azoles unless traditional agents such as terbinafine, itraconazole, or fluconazole have been thoroughly evaluated as first-line therapies. AREAS COVERED: This article reviews the clinical evidence, safety, dosage regimens, pharmacokinetics, and management algorithm of new-generation azole antifungals. EXPERT OPINION: Antifungal stewardship should be the top priority when prescribing new-generation azoles. First-line antifungal therapy is terbinafine and itraconazole. Fluconazole is a consideration but is generally less effective and its use may be off-label in many countries. For difficult-to-treat skin fungal infections and onychomycosis, that have failed terbinafine, itraconazole and fluconazole, we propose consideration of off-label voriconazole or posaconazole.

Promising immunomodulators for management of substance and alcohol use disorders.

INTRODUCTION: The neuroimmune system has emerged as a novel target for the treatment of substance use disorders (SUDs), with immunomodulation producing encouraging therapeutic benefits in both preclinical and clinical settings. AREAS COVERED: In this review, we describe the mechanism of action and immune response to methamphetamine, opioids, cocaine, and alcohol. We then discuss off-label use of immunomodulators as adjunctive therapeutics in the treatment of neuropsychiatric disorders, demonstrating their potential efficacy in affective and behavioral disorders. We then discuss in detail the mechanism of action and recent findings regarding the use of ibudilast, minocycline, probenecid, dexmedetomidine, pioglitazone, and cannabidiol to treat (SUDs). These immunomodulators are currently being investigated in clinical trials described herein, specifically for their potential to decrease substance use, withdrawal severity, central and peripheral inflammation, comorbid neuropsychiatric disorder symptomology, as well as their ability to improve cognitive outcomes. EXPERT OPINION: We argue that although mixed, findings from recent preclinical and clinical studies underscore the potential benefit of immunomodulation in the treatment of the behavioral, cognitive, and inflammatory processes that underlie compulsive substance use.

Systematic review of the utilization of botulinum toxin in Mohs micrographic surgery.

The use of botulinum toxin for off-label indications has become more prevalent, but the specific benefits in Mohs micrographic surgery (MMS) have not yet been fully elucidated. A systematic review was performed of PubMed, Cochrane, EMBASE, and Scopus databases to identify all articles describing the use of botulinum toxin in MMS. Analysis was subdivided into scar minimization, parotid injury, and pain management. A total of nine articles were included. Scar minimization and treatment of parotid injury were the most reported uses. One case reported the use of botulinum toxin for pain management. Off label uses of botulinum toxin are being explored. Additional research is warranted to determine the efficacy and utility of botulinum toxin in MMS.

Adverse drug reactions in paediatric surgery: prospective study on frequency and risk related factors.

BACKGROUND: Paediatric patients are especially prone to experiencing adverse drug reactions (ADRs), and the surgical environment gathers many conditions for such reactions to occur. Additionally, little information exists in the literature on ADRs in the paediatric surgical population. We aimed to quantify the ADR frequency in this population, and to investigate the characteristics and risk factors associated with ADR development. METHODS: A prospective observational study was conducted in a cohort of 311 paediatric patients, aged 1-16 years, admitted for surgery at a tertiary referral hospital in Spain (2019-2021). Incidence rates were used to assess ADR frequency. Odds ratios (ORs) were calculated to evaluate the influence of potential risk factors on ADR development. RESULTS: Distinct ADRs (103) were detected in 80 patients (25.7%). The most frequent being hypotension (N = 32; 35%), nausea (N = 16; 15.5%), and emergence delirium (N = 16; 15.5%). Most ADRs occurred because of drug-drug interactions. The combination of sevoflurane and fentanyl was responsible for most of these events (N = 32; 31.1%). The variable most robustly associated to ADR development, was the number of off-label drugs prescribed per patient (OR = 2.99; 95% CI 1.73 to 5.16), followed by the number of drugs prescribed per patient (OR = 1.26, 95% CI 1.13 to 1.41), and older age (OR = 1.26, 95% CI 1.07 to 1.49). The severity of ADRs was assessed according to the criteria of Venulet and the Spanish Pharmacovigilance System. According to both methods, only four ADRs (3.9%) were considered serious. CONCLUSIONS: ADRs have a high incidence rate in the paediatric surgical population. The off-label use of drugs is a key risk factor for ADRs development.

The Medicines Repurposing Program - a critical perspective.

The Medicines Repurposing Program was launched on 1 March 2024. It provides a pathway for registering and subsidising off-label medicines of significant public health benefit but which sponsors have no financial incentive to pursue. This article provides a short overview and critical analysis of the program. One concern that emerges is that commercial sponsors still retain de facto veto power over which off-label uses are prioritised and so have the capacity to sway the process. Simple suggestions are proposed to help mitigate this risk.

Off-label higher doses of serotonin reuptake inhibitors in the treatment of obsessive-compulsive disorder: Safety and tolerability.

OBJECTIVE: To examine the long-term safety and tolerability of off-label high-dose serotonin reuptake inhibitors (OLHD-SRIs) in the treatment of obsessive-compulsive disorder (OCD). METHODS: A retrospective longitudinal study was performed on 105 randomly selected outpatients diagnosed with OCD and were treated with OLHD-SRIs for at least 6 months. Patients received sertraline >200 mg/day, escitalopram >20 mg/day, fluvoxamine >300 mg/day, and fluoxetine >60 mg/day, combined with exposure and response prevention therapy. Patients were divided into three dosing groups: sertraline equivalent dose (SED) ≤ 200 mg/day (n = 26, 24.7%), 201-400 mg/day (n = 51, 48.5%) and 401-650 mg/day (n = 28, 26.6%). Safety and tolerability were assessed with an electrocardiogram, blood biochemistry, complete blood count, and side-effects monitoring. RESULTS: SED ranged from 100 to 650 mg/day and the mean duration of OLHD-SRI treatment was 20.8 months. The most common side-effects reported were sexual dysfunction (n = 36, 34%), weight gain (n = 28, 27%), sedation (n = 27, 26%), hyperhidrosis (n = 20, 19%), and tremor (n = 11, 10%). Abnormal ECG was documented in one patient, and another patient experienced a first-time seizure, whereas elevated liver enzymes were seen in 4.8% of the sample (n = 5). None of the patients had serotonin syndrome or drug-induced liver injury. Side-effects did not differ among the three dosing groups. CONCLUSION: OLHD-SRIs appear to be safe and well tolerated in OCD patients in SED ≤ 650 mg/day doses and the side-effects did not differ between the three dosing groups.

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

BACKGROUND: 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. OBJECTIVE: To describe the state of observational research and real-world evidence evaluating RTX in oncology, RA, and off-label use in MS. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

[Translated article] Syringes for intraocular administration: A systematic review.

OBJECTIVE: The off-label use in clinical practice of non-approved syringes for intravitreal drug administration has resulted in the detection of silicone oil drops in the vitreous of some patients. This situation derives from the lack of approved syringes for intraocular use in the Spanish market. The aim of this work is to review the use of syringes for intraocular administration, as well as to search for alternatives that meet the legal requirements for these unmet needs. METHOD: A systematic review was performed following the PRISMA 2020 guidelines by searching PubMed with the descriptors: (silicone) AND (syringes) AND ((intraocular) OR (intravitreal)) and filtering all existing publications from January 2006 to December 2023, including all those articles dealing with silicone oil release in intravitreal injections and analysing the possible consequences. RESULTS: Sixty-eight results were found, 23 of which were excluded because they did not deal with the subject under study, leaving a total of 45 articles for the systematic review. These were classified according to the conclusions obtained in 4 groups: the adverse reactions produced by silicone; the administration technique; the physicochemical aspects of silicone release; and the characteristics of the medical device. After reviewing the current manufacturers and technical data sheets of commercialised syringes, the existing syringes for this use have been collected, finding 2 that will probably be commercialised in Spain at the beginning of 2024: Zero Residual™ 0.2 ml SiO-free and VitreJect® Ophthalmic. CONCLUSIONS: From the results obtained, it can be interpreted that the use of syringes and needles with silicone for intravitreal use is a concern for health professionals due to the implications and consequences that may arise in patients, the most important being adverse reactions, so it is necessary to have silicone-free syringes on the market that are specific for intraocular use. Safety and legality in the use of intraocular syringes and needles is essential to guarantee ocular integrity and patient health.

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

OBJECTIVE: To examine the current prevalence and cost of paediatric off-label drug prescriptions in Gansu, China, and the potential influencing factors. DESIGN: The prevalence of off-label prescriptions in paediatrics was evaluated according to the National Medical Products Administration drug instructions in the China Pharmaceutical Reference (China Pharmaceutical Reference, MCDEX) database. The evidence of the prescription was determined by existing clinical practice guidelines and the Thomson Grade in the Micromedex 2021 compendium. We used logistic regression to investigate the characteristics that influence paediatric off-label drug use after single-factor regression analysis. SETTING: A multicentre cross-sectional study of outpatient paediatric prescriptions in 196 secondary and tertiary hospitals in Gansu Province, China, in March and September 2020. RESULTS: We retrieved 104 029 paediatric prescriptions, of which 39 480 (38.0%) contained off-label use. The most common diseases treated by off-label drugs were respiratory system diseases (n=15 831, 40.1%). A quarter of off-label prescriptions had adequate evidence basis (n=10 130, 25.6%). Unapproved indications were the most common type of off-label drug use (n=25 891, 65.6%). A total of 1177 different drugs were prescribed off-label, with multienzyme tablets being the most common drug (n=1790, 3.5%). The total cost of the prescribed off-label drugs was ¥106 116/day. Off-label prescriptions were less frequent in tertiary than in secondary hospitals. Topical preparations were more commonly prescribed off-label than other types of drugs. Senior-level clinicians prescribed drugs off-label more often than intermediate and junior clinicians. CONCLUSION: Off-label drug use is widespread in paediatric practice in China. Three-quarters of the prescriptions may potentially include inappropriate medication use, resulting in a daily economic burden of about ¥81 000 in 2020 in Gansu Province with 25 million inhabitants. The management of off-label drug use in paediatrics in China needs improvement.

Letermovir prophylaxis for cytomegalovirus in lung-transplant recipients: a comprehensive study with literature review of off-label use and real-world experiences.

Letermovir, initially approved for cytomegalovirus (CMV) prophylaxis in hematopoietic stem-cell transplantation, has gained attention for off-label use in lung-transplant (LTx) recipients. Given the high susceptibility of LTx recipients to CMV infection, this study explores the effectiveness and safety of letermovir prophylaxis. A retrospective analysis of using letermovir for LTx recipients at Tohoku University Hospital (January 2000 to November 2023) was conducted. Case summaries from other Japanese transplant centers and a literature review were included. Six cases at Tohoku University Hospital and one at Kyoto University Hospital were identified. Prophylactic letermovir use showed positive outcomes in managing myelosuppression and preventing CMV replication. The literature review supported the safety of letermovir in high-risk LTx recipients. Despite limited reports, our findings suggest letermovir's potential as prophylaxis for LTx recipients intolerant to valganciclovir. Safety, especially in managing myelosuppression, positions letermovir as a promising option. However, careful consideration is important in judiciously integrating letermovir into the treatment protocol.