Trends in Second Generation Antipsychotic Prescribing for Adolescents from 2013-2021

Objectives: To examine temporal trends of FDA-approved and off-label second-generation antipsychotic (SGA) prescribing for adolescents over time through the Covid-19 pandemic. Method(s): This is a new-user, retrospective longitudinal panel study using electronic health record data from a large, integrated health care system. Outpatient prescription orders for a new SGA (index date) for adolescents (age 10-17 years) during 2013-2021 were analyzed. Prescription orders were linked to diagnoses at time of encounter to examine prescribing behavior. A one-year lookback period was used for baseline inclusion and exclusion criteria, including one-year "washout" of SGAs and continuous insurance enrollment. FDA-approved use was determined by two outpatient diagnoses (one baseline diagnosis and the prescription order diagnosis) for autism, psychotic disorders, bipolar disorders, or Tourette's;the remaining proportion was considered potentially off-label. We report crude annual prescribing rates per 1,000 youths. Result(s): There were 8,145 unique patients with new SGA prescription orders, of which 5,828 (71.6%) had linked diagnoses available. Calendar year 2013 had the highest prescribing rate prior to Covid-19 onset (2.1 per 1,000) but then declined through 2016 (1.7 per 1,000). Prescribing rates in 2020 (2.0 per 1,000) and 2021 (2.2 per 1,000) were higher than those between 2017-2019. Across all study years, SGA prescriptions were mostly off-label and ordered for aripiprazole, quetiapine, or risperidone. The proportion of off-label indications was highest in 2013 (80.1%) and lowest (69.1%) in 2019. Off-label proportions increased again in 2020 (76.1%) and in 2021 (74.1%). At baseline, patients frequently had other psychotropic prescriptions (e.g., antidepressants 63.3%, stimulants 22.9%, and sedatives/hypnotics 20.7%). Conclusion(s): A general decline in SGA prescribing rates among adolescents was observed from 2013 to 2019, but then increased following Covid-19 onset. Despite known safety risks, off-label use of SGAs remains prominent. Future studies are needed to better understand prescribing outside of pediatric professional society guidelines.Copyright © 2023

COVID-19 off-label uses of medicines: the role of civil liability and regulation.

Physicians can prescribe medicines for different indications than the tested and authorised ones. Such 'off-label' uses expand therapeutic options but also create uncertainties. The COVID-19 pandemic triggered new off-label uses and, despite issues being reported in the literature, these have not resulted in substantial personal injury litigation in the EU. Against this backdrop, this article argues that civil liability plays, in fact, a limited role in off-label uses. In particular, civil liability may incentivise health actors to follow and react to the development of the evidence basis for off-label uses. However, it is ultimately unable to incentivise the conduct of additional research on off-label uses. This is problematic, as off-label research is key to protecting patients and is recommended by international medical ethics. The article concludes by critically discussing proposed mechanisms to incentivise off-label research. It argues that extending civil liability for unknown risks may have undesired effects on insurability and innovation, and most regulatory proposals seem ineffective. Building on the 2014 Italian reform of off-label uses, the article proposes the establishment of a fund financed by mandatory contributions from the industry, which should be used by pharmaceutical regulators to promote off-label research and develop guidelines for prescribers.

Pay attention to the medication safety of patients during the period of coronavirus disease 2019 epidemic prevention.

The coronavirus disease 2019 (COVID-19) epidemic is facing the most critical situation. As of January 11, 2021, there have been nearly 90 million confirmed cases worldwide and nearly 2 million deaths. The local epidemic situation in China is sporadic and locally clustered, and the situation of epidemic prevention is difficult and complicated. In this situation, there are many problems in medication safety of patients, such as safety issues in off-label medication and compassionate medication of COVID-19 treatment, safety problems in the combination use of drugs for COVID-19 and drugs for other diseases, monitoring of adverse drug reactions in COVID-19 treatment, the safety issues in self-purchased drugs for prevention and treatment of COVID-19, and the medication safety in patients with other diseases during the epidemic. Therefore, it is necessary to pay more attention to the medication safety of patients to fight the epidemic scientifically and to win a greater victory in the fight against the COVID-19 epidemic at a smaller price.Copyright © 2021 Chinese Medical Association

Off Label Medication to Combat COVID-19: Review Results to Date

Background: Severe viral pneumonia cases were observed in the people of Wuhan, China in December 2019. It has already affected almost every country around the globe and was declared a pandemic by the World Health Organization. We aim to evaluate the therapeutics and safety of various off label COVID-19 drugs. Method(s): PubMed, Research Gate, Science Direct, Google Scholar, Centre for Disease control and prevention (CDC) portal, Chinese Centre for Disease Control and prevention (CCDC) portal, World Health Organization (WHO) portal were searched for obtaining reliable data. Result(s): COVID-19 is creating a storm of deaths and active cases globally, which is forcing the pharmaceutical companies and scientists to work day and night to find an effective and safer anti-COVID-19 medication. Various in vitro and clinical trials had been performed as well as are currently ongoing to analyze the mechanisms and therapeutics of off label medications like Chloroquine, Hydroxychloro-quine, Amodiaquine, Azithromycin, Remdesivir, Favipiravir, Ritonavir/Lopinavir, Umifenovir, Osel-tamivir, Ribavirin, Nafamostat, Camostat, Tocilizumab, Ivermectin, Nitazoxanide, Famotidine, Vitamin D, Corticosteroids and Dexamethasone. In vitro studies were performed by utilizing Vero E6 cells and hSLAM cells while open/closed, randomized/non-randomized, single-centered/multi-centered and retrospective clinical trials and case studies were organized to determine their safety and efficacy. Conclusion(s): Although these drugs have shown promising results against COVID-19 patients, it cannot be concluded that these drugs are truly safe and effective because there are no conclusive evidence to support the facts since only limited researches and studies had been investigated.Copyright © 2021 Bentham Science Publishers.

Remdesivir (GS-5734) for COVID-19 Treatment: Past and Recent Updates

Background: SARS-CoV-2 is a pandemic now, and several measures have been taken by countries to prevent, control, and treat the disease. WHO has been working meticulously and has been providing up to date information and statistics on incidences and death. Several broad--spectrum anti-viral drugs are available and have been used in the past to fight against the viral out-break. Recently remdesivir, an experimental prodrug from Gilead Sciences, has been found to be a potential drug to be used as a therapy to treat COVID-19. Objective(s): Here, we have reviewed several previous findings from the literature and present an up to date information on remdesivir. Result(s): Remdesivir was initially invented for use against Ebola virus treatment and has proved ef-fective against different strains of Ebola, Nipah, and other strains of coronaviruses. Clinical trials with remdesivir for COVID-19 patients have begun, and several off label use of remdesivir have been reported recently. Currently, the drug seems to have an effect against the SARS-CoV-2 virus, with side effects among a few patients. Although the results are not conclusive, they are partly promising. This review provides past and recent updates on the use of remdesivir. Conclusion(s): From the review, we conclude that the drug remdesivir is known to exhibit its mechanism of action by terminating the RNA synthesis, and it is a potential drug against the novel coron-avirus.Copyright © 2021 Bentham Science Publishers.

Use of Intravenous Anakinra for Management of Pediatric Cytokine Storm Syndromes at an Academic Medical Center.

Background: Off-label intravenous (IV) route of anakinra is increasingly recognized to enable higher and faster maximal plasma concentrations than subcutaneous route for treatment of cytokine storm syndromes. Objective: To describe off-label indications of IV anakinra, corresponding dosing and safety profiles, particularly during the coronavirus disease 19 (COVID-19) pandemic. Methods: A retrospective, single-cohort study was conducted at an academic medical center to evaluate use of IV anakinra in hospitalized pediatric patients (age ≤21 years). Institutional Review Board review was considered exempt. The primary endpoint was the primary indication(s) for IV anakinra. The key secondary endpoints were dosing of IV anakinra, previous immunomodulatory therapies, and adverse events. Results: Of 14 pediatric patients, 8 (57.1%) received IV anakinra for treatment of multisystem inflammatory syndrome in children (MIS-C) associated with COVID-19, whereas 3 and 2 were treated for hemophagocytic lymphohistiocytosis (HLH) and flares of systemic onset juvenile idiopathic arthritis (SoJIA), respectively. The initial dosing regimen of IV anakinra for MIS-C associated with COVID-19 was a median dose of 2.25 mg/kg/dose with a median dosing interval of 12 hours for a median initial treatment duration of 3.5 days. Eleven (78.6%) patients received previous immunomodulatory therapies (IV immune globulin [n = 10; 71.4%] and steroids [n = 9; 64.3%]). No adverse drug events were documented. Conclusion: IV anakinra was used off-label for treatment of MIS-C associated with COVID-19, HLH and SoJIA flares in critically ill patients with no adverse drug events documented. This study helped ascertain the off-label indications of IV anakinra and corresponding patient characteristics.

Off-label Uses of Selective Serotonin Reuptake Inhibitors (SSRIs).

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

Recommendations for the so-called off-label use of medicinal products in covid-19 patients

During the epidemic of COVID-19, there often arises an urgent need for the so-called off-label use of medicinal products, i.e. use of a medicinal product that is not in accordance with its Summary of Product Characteristics (SPC). Most often, a medicinal product registered for a different indication is used. The goal of this paper is to provide the reader with an analysis of legal conditions under which the off-label use of medicinal products in COVID-19 patients is legally safe. If the provider of health services fulfils these conditions, they will not be held liable for immaterial harm that could potentially occur to the patient. Copyright © 2020, Czech Medical Association J.E. Purkyne. All rights reserved.

Early Treatments of Fragile Children with COVID-19-Results of CLEVER (Children COVID Early Treatment), a Retrospective, Observational Study.

(1) Background: SARS-CoV-2 infection is notably mild in children, though comorbidities may increase the risk of hospitalization and may represent a risk for increased disease severity. There is an urgent need for targeted therapies with an acceptable efficacy and safety profile. To date, most of the medicines for COVID-19-specific treatment are prescribed off-label for children due to a lack of clinical trials and consequent evidence in this population. (2) Methods: This was a retrospective, observational study investigating the safety of treatments for the prevention of severe COVID-19 in fragile pediatric patients who received monoclonal antibodies and antivirals for mild-to-moderate symptoms between December 2021 and July 2022. (3) Results: Thirty-two patients were included. Monoclonal antibodies were prescribed to 62%, intravenous antivirals to 22%, and oral antivirals to 16% of children. Sotrovimab was the most frequently prescribed drug among monoclonal antibodies and overall (59%). The second most prescribed drug was remdesivir (22%). No severe adverse drug reaction was reported. There was no progression to severe disease and no death cases due to COVID-19 or drug administration. At drug-type stratification, resolution of symptoms and swab positivity time showed no difference between the two groups at 7 and 28 days. Off-label prescriptions were 84% overall, and in similar proportions between the two groups. (4) Conclusions: in this small sample, antivirals seemed safe and showed no differences in efficacy as compared to MAbs for the early treatment of COVID-19 in fragile children, thus representing a valuable choice, even when administered off-label.

The Successful Treatment of COVID-19-Induced Bullous Pemphigoid With Dupilumab.

Bullous pemphigoid (BP) is a rare autoimmune blistering condition that predominantly affects the elderly population. Typical treatment regimens target the immune system and inflammatory response. We present a case of BP in a 78-year-old male patient that occurred following the coronavirus disease 2019 (COVID-19) vaccination. This case was refractory to topical steroids and immunosuppressants. However, it responded to treatment with dupilumab, a monoclonal antibody therapy. Dupilumab is classically indicated for the treatment of asthma, eosinophilic esophagitis, atopic dermatitis, and chronic rhinosinusitis with nasal polyposis. We highlight the importance of considering the off-label use of dupilumab and its success in treating BP.

Population Pharmacokinetic and Pharmacodynamic Analysis of Dalbavancin for Long-Term Treatment of Subacute and/or Chronic Infectious Diseases: The Major Role of Therapeutic Drug Monitoring.

A population pharmacokinetic analysis of dalbavancin was conducted in patients with different infection sites. Non-linear mixed effect modeling was used for pharmacokinetic analysis and covariate evaluation. Monte Carlo simulations assessed the probability of target attainment (PTA) of total dalbavancin concentration ≥ 8.04 mg/L over time (associated with ≥90% probability of optimal pharmacodynamic target attainment of fAUC24h/MIC > 111.1 against S. aureus) associated with a single or double dosage, one week apart, of 1000 or 1500 mg in patients with different classes of renal function. Sixty-nine patients with 289 concentrations were included. Most of them (53/69, 76.8%) had bone and joint infections. A two-compartment model adequately fitted dalbavancin concentration-time data. Creatinine clearance (CLCR) was the only covariate associated with dalbavancin clearance. Monte Carlo simulations showed that, in patients with severe renal dysfunction, the 1000 mg single or double one week apart dosage may ensure optimal PTAs of 2 and 5 weeks, respectively. In patients with preserved renal function, the 1500 mg single or double one-week apart dosage may ensure optimal PTAs of 2 and 4 to 6 weeks, respectively. Therapeutic drug monitoring should be considered mandatory for managing inter-individual variability and for supporting clinicians in long-term treatments of subacute and chronic infections.

BIBLIOMETRIC NETWORK ANALYSIS on TOCILIZUMAB TREATMENT for COVID-19 PATIENTS

Background: Tocilizumab is a humanized monoclonal antibody. It provokes inhibition of the proinfammatory signals by binding to IL-6 receptors [1]. Due to these properties, it is used in infammatory arthritis conditions and in cytokine release syndromes [2]. Notably, given its ability to intercept proinfammatory cascades, tocilizumab is an important option for patients with critical forms of COVID-19 [3]. Nevertheless, several aspects about the use of tocilizumab in this clinical setting should be better explained [4]. Objectives: This bibliometric analysis is aimed at dissecting the developed research in the subject. It could provide useful fndings for predicting the direction of future studies, implementing corrective measures, and enhancing research networks. Methods: The global literature on tocilizumab treatment for COVID-19 was scanned in the Web of Science (WOS) online database. The search terms applied to identify the closest matching articles included 'tocilizumab' and 'COVID-19'. All data were acquired on January 29, 2022. The information for the documents that met the requirements were extracted. The source was Journal Citation Reports™ 2020 (Clarivate Analytics). The literature analysis and knowledge visualization software tool VOSviewer (version 1.6.17) was used to analyze the co-occurrence of keywords (interconnection), co-citation (bibliographic coupling), co-citation analysis for sources, and countries, and analysis of the most productive organizations and networks. Results: A total of 1019 articles on tocilizumab treatment for COVID-19 patients were published from 2020 to January 2022, in WOS. Of those: 462 in 2020, 546 in 2021, 11 on January 29, 2022. About article types, 697 were research articles, 322 reviews. The analysis of keywords provided by authors showed that of 50 keywords, 17 met the threshold (interconnection 2). The most frequent keywords were EFFICACY, and OFF-LABEL USE (Figure 1) For the co-citation study, we used cited sources (journals) as unit (minimum numbers of citations of a source 1, maximum 3). Of 45 sources, 27 met the threshold. For each source, the total strength of the co-citation links with other sources was rated. The minimum number of documents per country was 2. Thus, 23 countries met the threshold. The largest number of partnerships regarded the US, and Italy. The analysis of affiliations was conducted by considering the cut-off 1 and 5 as the minimum and maximum number of documents. Out of 151 organizations, 94 met the threshold. Conclusion: This bibliometric network analysis on tocilizumab treatment for COVID-19 patients can be useful for planning future research. It highlights the strength of representative scholars and core research teams. Additional networks should be built, and high-value clinical studies are needed.

Pediatric Off-Label COVID-19 Vaccination: The Concerns of Healthcare Professionals in Pakistan.

Global health authorities have emphasized the vital role of healthcare professionals (HCPs) as a reliable source of vaccination information for patients in primary care. However, HCPs are concerned whether COVID-19 vaccinations can be used off-label. Hence, the current study was conducted to assess their perspectives towards off-label COVID-19 immunization in children. The study tool, consisting of 40 items, was utilized to evaluate HCPs' knowledge and attitudes towards the off-label use of the COVID-19 vaccine in children under 12 years of age. To assess the unfavorable attitudes regarding vaccinations, the Vaccination Attitudes Examination Scale was employed. Overall, 477 completed questionnaires were incorporated in the present study, with a response rate of 88.9%. The mean age of the respondents was 38.6 ± 7.5 years; among whom the majority were physicians, n = 209 (43.8%), and pharmacists, n = 112 (23.4%). Approximately 78% of the respondents had a general awareness of off-label vaccination. Around 80% knew the adverse drug reactions associated with the use of COVID-19 vaccines. Females showed more mistrust about vaccine benefits, n = 55 (16.9%), compared to males, n = 21 (13.8%), and concerns about commercial profits of vaccines, n = 59 (18.1%), compared to males, n = 19 (12.5%). By profession, physicians showed statistically significantly lower mistrust, n = 18 (8.6%), and higher concerns about unpredicted effects of vaccines, n = 41 (19.6%). A major portion of the respondents, n = 327 (68.5%), did not consider that HCPs should prescribe/administer off-label COVID-19 vaccination in children. The current findings demonstrated that respondents had an appropriate level of understanding about COVID-19 immunization in children. They showed higher levels of rejection for off-label use of the COVID-19 vaccination.

Early Use of Sotrovimab in Children: A Case Report of an 11-Year-Old Kidney Transplant Recipient Infected with SARS-CoV-2.

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

Inpatient Administration of Alpha-1-Adrenergic Receptor Blocking Agents Reduces Mortality in Male COVID-19 Patients.

Apha-1-adrenergic receptor antagonists (α1-blockers) can suppress pro-inflammatory cytokines, thereby potentially improving outcomes among patients with COVID-19. Accordingly, we evaluated the association between α1-blocker exposure (before or during hospitalization) and COVID-19 in-hospital mortality. We identified 2,627 men aged 45 or older who were admitted to Mount Sinai hospitals with COVID-19 between February 24 and May 31, 2020, in New York. Men exposed to α1-blockers (N = 436) were older (median age 73 vs. 64 years, P < 0.001) and more likely to have comorbidities than unexposed men (N = 2,191). Overall, 777 (29.6%) patients died in hospital, and 1,850 (70.4%) were discharged. Notably, we found that α1-blocker exposure was independently associated with improved in-hospital mortality in a multivariable logistic analysis (OR 0.699; 95% CI, 0.498-0.982; P = 0.039) after adjusting for patient demographics, comorbidities, and baseline vitals and labs. The protective effect of α1-blockers was stronger among patients with documented inpatient exposure to α1-blockers (OR 0.624; 95% CI 0.431-0.903; P = 0.012). Finally, age-stratified analyses suggested variable benefit from inpatient α1-blocker across age groups: Age 45-65 OR 0.483, 95% CI 0.216-1.081 (P = 0.077); Age 55-75 OR 0.535, 95% CI 0.323-0.885 (P = 0.015); Age 65-89 OR 0.727, 95% CI 0.484-1.092 (P = 0.124). Taken together, clinical trials to assess the therapeutic value of α1-blockers for COVID-19 complications are warranted.

VOLUNTARY ELECTRONIC REPORTING OF MEDICATION ERRORS AND ADVERSE DRUGS EVENTS DURING THE FIRST YEAR OF THE COVID-19 PANDEMIC

Background and importance Evidence regarding the rate of medication errors (ME) and adverse drugs events (ADE) during the COVID-19 pandemic is limited. In that period the risk of ME and unsafe medication practices was potentially higher than average. Thus, voluntary hospital reporting systems are valuable sources of information on ME and ADE. Aim and objectives To describe the ME and ADE registered in the voluntary electronic notification system of our centre (TPSC Cloud) during the first year of the COVID-19 pandemic and compare them with the same period in the previous year. Material and methods A retrospective observational study of ME and AE notifications in the TPSC Cloud from March 2020 to February 2021 compared to notifications recorded from March 2019 to February 2020. Five types of incidents were differentiated: situations with the capacity to cause ME, ME that do not reach the patient, ME that reach the patient without ADE, ME with ADE, and ADE without ME. The drugs involved in those incidents and the professional notifier also were identified. Results 249 incidents were reported from March 2020 to February 2021, which was 31.02% less than in the previous period (n=361) from March 2019 to February 2020. The most common ME was prescription error in both periods (70.4% vs 67.3%). The incident profile by typology was similar in both periods. The most frequent was ME that did not reach the patient (40.24% vs 43.47%), followed by ME that reached the patient without ADE (23.42% vs 28.53%). Systemic anti-infectives drugs were the most involved in both periods (n=57;22.89% vs n=73;20.22%). 84 ADE without ME were reported from March 2020 to February 2021, representing an increase of 500% compared with March 2019 to February 2020 (n=14). Emphasising the notification of 35 ADE of lopinavir/ritonavir and 4 of hydroxychloroquine used in the initial treatment of COVID-19. The main notifier in both periods was the pharmacist (80.48% vs 65.60%). Conclusion and relevance During the first COVID-19 pandemic year, notifications of ME decreased, due to care load pressure, but incident profile was similar. Otherwise, ADE notifications increased notably, due to active pharmacovigilance carried out by pharmacists on off-label drugs used to treat COVID-19.

Approach to management of cryoprecipitate inventory during pandemic-related shortages

Background: A surprising and disturbing feature of blood shortages in the United States during the COVID-19 pandemic is that they include Cryoprecipitate, a component that was not historically affected by seasonal shortages. Our blood suppliers provide Cryoprecipitate primarily as 5-unit pools. A few individual whole blood-derived units of Cryoprecipitate are also provided for use for infants and young children. The adult dose of Cryoprecipitate, standardized many years ago, has been two pools (10 units). In an average-sized adult, this dose is expected to increase plasma fibrinogen by 50-100 mg/dl. Over the 10-year period 2011- 2020, the number of single units transfused at our 1000 bed tertiary care hospital remained small and relatively stable, but the number of transfused pools increased approximately 60%, from a monthly average of 322-522. During the pandemic, Cryoprecipitate usage at our hospital remained high, possibly because high-use surgeries, such as urgent cardiovascular and liver transplant procedures, were not restricted. In the face of donor- and manufacturing-related shortages, our blood bank has been challenged to maintain an adequate inventory to support these services. Aims: To develop and implement a plan for ensuring sufficient availability of Cryoprecipitate units to meet our patients' needs. Methods: As with other blood components, the shortage of Cryoprecipitate was initially managed through prospective review and modification (if appropriate) of orders by the Transfusion Medicine resident physician, and regular communications with the blood suppliers regarding inventory requirements. Additional steps for Cryoprecipitate were: re-evaluating the standard dose of Cryoprecipitate, and exploring alternatives to the use of Cryoprecipitate pools. Results: Quality control data from our blood suppliers provided evidence that the fibrinogen content of Cryoprecipitate currently averages 524 mg per unit, more than twice the value of 250 mg per unit that is generally used for dosing calculations. These data justified halving the standard adult dose to 1 pool. An explanatory document was distributed to the clinical services, with comparisons of plasma fibrinogen increments expected with two pools versus one pool. An update to the electronic ordering system is in process, to change the default Cryoprecipitate order for adults from two pools to one pool. We increased the stock of single Cryoprecipitate units, whenever these were available, to build a buffer for adult use in case of ongoing shortage. We collaborated with the hospital pharmacy to maintain a reserve of purified fibrinogen concentrate, and develop a dosing and administration protocol for off-label use of this product. So far, there has not been an occasion to use either alternative. The efforts above have been supplemented with frequent, structured communication with the clinical services and hospital leaders regarding inventory levels of blood components, and the measures taken and requested to safeguard this precious resource. Summary/Conclusions: Meeting the challenge of extreme and prolonged blood shortages requires a multi-pronged approach that may include questioning assumptions, considering alternatives, and improving inter-disciplinary communications.

Safety of Drugs Used during the First Wave of COVID-19: A Hospital-Registry-Based Study.

The emergency of the coronavirus disease 2019 (COVID-19) pandemic led to the off-label use of drugs without data on their toxicity profiles in patients with COVID-19, or on their concomitant use. Patients included in the COVID-19 Patient Registry of a tertiary hospital during the first wave were analyzed to evaluate the adverse drug reactions (ADRs) with the selected treatments. Twenty-one percent of patients (197 out of 933) had at least one ADR, with a total of 240 ADRs. Patients with ADRs were more commonly treated with multiple drugs for COVID-19 infection than patients without ADRs (p < 0.001). They were younger (median 62 years vs. 70.1 years; p < 0.001) and took less medication regularly (69.5% vs. 75.7%; p = 0.031). The most frequent ADRs were gastrointestinal (67.1%), hepatobiliary (10.8%), and cardiac disorders (3.3%). Drugs more frequently involved included lopinavir/ritonavir (82.2%), hydroxychloroquine (72.1%), and azithromycin (66.5%). Although most ADRs recovered without sequelae, fatal cases were described, even though the role of the disease could not be completely ruled out. In similar situations, efforts should be made to use the drugs in the context of clinical trials, and to limit off-label use to those drugs with a better benefit/risk profile in specific situations and for patients at high risk of poor disease prognosis.

UK Market Access: The Evolving Scope of NICE and NHSE Specialised Commissioning

Objectives: Medicines are currently commissioned in England via Clinical Commissioning Groups (CCGs, following NICE appraisals) or national-level specialised services (that support people with rare, complex conditions) where commissioning is governed by NHS England (NHSE, who issue Clinical Commissioning Policies [CCPs] where there is a need, and no relevant NICE guidance exists). Under the 2019 Voluntary Scheme for Branded Medicines and Pricing and Access (VPAS), NICE committed to appraise all New Active Substances and significant new therapeutic indications by April 2020, except where there is a clear rationale not to do so. This research evaluates how the scope of NICE’s and NHSE’s CCP evaluations have evolved. Methods: Technologies considered under NICE Topic Selection or subject to NHSE CCP were identified from their respective websites and key information extracted (01-Jan-2015–21-Dec-2021). Results: 1,157 topics were considered, an average of 165/year (range:112[2021]–251[2018]). 80% were prioritised for potential NICE guidance, 15% not prioritised, 2% routed to specialised commissioning, and 3% to other programmes/processes. From 2019, 90% of topics were prioritised versus 74% pre-2019 whereas topics routed to specialised commissioning fell from 2.4% to 0.2%. 216 health technologies have been the subject of NHSE CCPs, 49% were for medicines (76% of which were routinely commissioned), at a mean of 11.7/year (range:1[2014]–23[2016]). The most common rationale for a medicine’s CCP was for off-label use (48%), followed by HIV indications (9%, not reviewed by NICE at that time). Conclusions: Since the 2019 VPAS, a greater proportion of (but by no means all) topics have been prioritised for potential NICE guidance and far fewer routed to specialised commissioning. However, NHSE CCPs are still developed for off-label/license considerations and medicines receiving routine licence extensions. Limitations of our analysis include the effects of the COVID-19 pandemic and any changes to Horizon Scanning, which may have acted as confounders.