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.

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.

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.

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.

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.

Ivermectin Does Not Protect against SARS-CoV-2 Infection in the Syrian Hamster Model.

Ivermectin, an FDA-approved antiparasitic drug, has been reported to have in vitro activity against SARS-CoV-2. Increased off-label use of ivermectin for COVID-19 has been reported. We here assessed the effect of ivermectin in Syrian hamsters infected with the SARS-CoV-2 Beta (B.1.351) variant. Infected animals received a clinically relevant dose of ivermectin (0.4 mg/kg subcutaneously dosed) once daily for four consecutive days after which the effect was quantified. Ivermectin monotherapy did not reduce lung viral load and even significantly worsened SARS-CoV-2-induced lung pathology. Additionally, it did not potentiate the activity of molnupiravir (LagevrioTM) when combined with this drug. This study contributes to the growing body of evidence that ivermectin does not result in a beneficial effect in the treatment of COVID-19. These findings are important given the increasing, dangerous off-label use of ivermectin for the treatment of COVID-19.

THE OFF-LABEL USE OF DRUGS IN PSYCHIATRY

Antipsychotic drugs have revolutionized the treatment of mental diseases. Although these drugs are more commonly used to treat schizophrenia, they are also prescribed to treat many other conditions, including bipolar disorder, depression, personality disorders, dementia, and autism. During the Covid-19 pandemic, antiviral activity was found to be characteristic of some psychotropic drugs. Recently, it has become common to prescribe antipsychotic drugs for diseases that are not in the instructions (off label), since clinical trials for them are more complex than for other medicines. Most often, off-label drugs in psychiatry are used for unapproved indications and in doses that are not indicated in the current instructions for medical use. One of the main reasons for prescribing psychotropic drugs off-label is the need to treat patients who do not respond to traditional psychotherapy, i.e. resistant to it. Specialized literature indicates that the percentage of the frequency of off-label drugs prescriptions in psychiatry in terms of pharmacological groups is as follows: anxiolytics-65%, antipsychotic drugs-69%, antidepressants-92%, antiepileptic drugs-51%, stimulants of the central nervous system (CNS)-30 %. Medicines most commonly prescribed off-label are risperidone (12%) [23], clobazam (12%), amitriptyline (11%), hydroxyzine (10%), diazepam (7%), clonazepam (12.4%), lorazepam (12%) and trihexyphenidyl hydrochloride (10%). Almost half (47%) of all off-label prescriptions were associated with symptoms such as anxiety (24%), behavioral disturbances (12%), and pain (11%) Thus, analyzing the problem of the off-label use of drugs in psychiatry, we can conclude that the insufficient number or absence of clinical large-scale comparative evidence for the off-label use of antipsychotic drugs, the insufficient validity of these data, and the poor awareness of doctors in the search for information on this problem makes it difficult to determine the credibility of effectiveness and the safety of such use. © 2021, SILAE (Italo-Latin American Society of Ethnomedicine). All rights reserved.

Pediatric Off-Label Use of Covid-19 Vaccines: Ethical and Legal Considerations.

When the U.S. Food and Drug Administration fully approved the Pfizer-BioNTech Covid-19 vaccine for people sixteen and older, questions arose. Parents, pediatricians, and the media wondered whether Covid-19 vaccines could be used off-label-and whether they should be. The American Academy of Pediatrics cautioned against pediatric off-label use of the vaccine, and the vaccine provider agreement from the Centers for Disease Control and Prevention appears to prohibit it. After briefly contextualizing ethical and legal precedents regarding off-label use, we offer an analysis of the ethical permissibility of and considerations for pediatric off-label Covid-19 vaccination based on individual benefits, risks, and available alternatives. Our analysis challenges the ethics of a blanket prohibition on off-label pediatric Covid-19 vaccination, as it limits clinician ability to provide care they may determine to be clinically and ethically appropriate. At the same time, our analysis acknowledges that Covid-19 creates population-level ethical considerations that are at times in tension with individual health interests.

Off-Label Use of COVID-19 Vaccines from Ethical Issues to Medico-Legal Aspects: An Italian Perspective.

During the COVID-19 outbreak, the lack of official recommendations on the treatment has led healthcare workers to use multiple drugs not specifically tested and approved for the new insidious disease. After the availability of the first COVID-19 vaccines (Comirnaty Pfizer-BioNTech and Moderna COVID19 vaccine), an authorization was issued by national and international Drug Regulatory Agencies in order to speed up their introduction on the market and their administration on a large scale. Despite the authorization, the off-label use of these vaccines may still be possible especially to answer specific concerns as the lack of vaccine doses, the delay in the delivery of planned doses or the pressure from public opinion and political influence also in relation to the evolution of the pandemic. This paper aims to assess the possible off-label use of COVID-19 vaccines and the ethical and medico-legal implications of this eventuality. The scope of this paper is to point out the possible consequences of off-label use of COVID-19 vaccines and possible mitigation and preventive measures to be taken by healthcare workers involved in vaccination procedures.

Phentolamine continuous infusion in a pediatric patient with uncontrolled hypertension.

PURPOSE: A case of uncontrolled hypertension nonresponsive to traditional pharmacologic management in a pediatric patient with a ventricular assist device awaiting a heart transplant is reported. SUMMARY: A 4-month-old male in heart failure was experiencing uncontrolled hypertension. Because of a lack of hemodynamic stability, he was unable to be listed as a heart transplant candidate. He received multiple antihypertensive agents (calcium channel blockers, ß-blockers, and direct-acting vasodilators) as both intermittent and continuous infusions over the course of several days without achieving normotension. The decision was then made to administer intravenous phentolamine as a continuous infusion to pursue a different mechanism than with traditional antihypertensive agents to achieve hemodynamic stability. Within 8 hours of initiation of the continuous phentolamine infusion, the patient became normotensive and was listed for a heart transplant. The continuous phentolamine infusion was administered over the next 4 days to maintain normotension, and on day 4 the patient underwent successful orthotopic heart transplantation. CONCLUSION: A 4-month-old male in heart failure with a ventricular assist device, experiencing uncontrolled hypertension nonresponsive to traditional pharmacologic management, was successfully treated with a continuous intravenous infusion of phentolamine.

Biologics for atopic diseases: Indication, side effect management, and new developments.

With the advent of biologicals, more and more therapeutics are available that specifically address specific switch points in the pathomechanism of immunologically dominated diseases. Thus, the focus of diagnostics and therapy (precision medicine) is more on the individual disease characteristics of the individual patient. Regarding the different phenotypes of atopic diseases, severe asthma was the first entity for which biologicals were approved, followed by urticaria, and finally atopic dermatitis and chronic rhinosinusitis with nasal polyps. Experience in the treatment of severe bronchial asthma has shown that the intensity of the response to biological therapy depends on the quality of clinical and immunological phenotyping of the patients. This also applies to different diseases of the atopic form, as patients can suffer from several atopic diseases at the same time, each with different characteristics. Biologics are already emerging that may represent a suitable therapy for allergic bronchial asthma, which often occurs together with severe neurodermatitis, and chronic rhinosinusitis with nasal polyps. In practice, however, the question of possible combinations of biologicals for the therapy of complex clinical pictures of individual patients is increasingly arising. In doing so, the side effect profile must be taken into account, including hypersensitivity reactions, whose diagnostic and logistical management must aim at a safe and efficient therapy of the underlying disease. Increased attention must also be paid to biological therapy in pregnancy and planned (predictable) vaccinations as well as existing infections, such as SARS-CoV-2 infection. Before starting a biological therapy, the immune status should be checked with regard to chronic viral and bacterial infections and, if necessary, the vaccination status should be refreshed or missing vaccinations should be made up for before starting therapy. Currently, reliable data on the effect of biologicals on the immunological situation of SARS-CoV-2 infection and COVID-19 are not available. Therefore, research and development of suitable diagnostic methods for detection of immunologically caused side effects as well as detection of potential therapy responders and non-responders is of great importance.

Clinical medication response under new major infectious disease: off-label use and compassionate use / 药学实践杂志

At present, there are no specific targeted drugs for the treatment of pneumonia (COVID-19) caused by the novel coronavirus (SARS-CoV-2). Interferon, lopinavir/ritonavir, ribavirin, chloroquine phosphate were chosen as off-label use, and remdesivir was chosen as compassionate use. This paper reviewed the behavior of the two medication response to the new major infectious disease.

Current regulatory approaches for accessing potential COVID-19 therapies.

This commentary aims to elaborate challenges in the regulatory approaches for accessing and investigating COVID-19 potential therapies either with off-label use, compassionate use, emergency use or for clinical trials. Since no therapies have been formally approved and completely effective and safe to date, the best clinical choice is acquired only after consistent and fair communication and collaboration between licensed clinicians, researchers, regulatory authorities, manufacturers and patients.

Delivering Benefits at Speed Through Real-World Repurposing of Off-Patent Drugs: The COVID-19 Pandemic as a Case in Point.

Real-world drug repurposing-the immediate "off-label" prescribing of drugs to address urgent clinical needs-is a widely overlooked opportunity. Off-label prescribing (ie, for a nonapproved indication) is legal in most countries and tends to shift the burden of liability and cost to physicians and patients, respectively. Nevertheless, health crises may mean that real-world repurposing is the only realistic source for solutions. Optimal real-world repurposing requires a track record of safety, affordability, and access for drug candidates. Although thousands of such drugs are already available, there is no central repository of off-label uses to facilitate immediate identification and selection of potentially useful interventions during public health crises. Using the current coronavirus disease (COVID-19) pandemic as an example, we provide a glimpse of the extensive literature that supports the rationale behind six generic drugs, in four classes, all of which are affordable, supported by decades of safety data, and targeted toward the underlying pathophysiology that makes COVID-19 so deadly. This paper briefly summarizes why cimetidine or famotidine, dipyridamole, fenofibrate or bezafibrate, and sildenafil citrate are worth considering for patients with COVID-19. Clinical trials to assess efficacy are already underway for famotidine, dipyridamole, and sildenafil, and further trials of all these agents will be important in due course. These examples also reveal the unlimited opportunity to future-proof our health care systems by proactively mining, synthesizing, cataloging, and evaluating the off-label treatment opportunities of thousands of safe, well-established, and affordable generic drugs.