Use Of Drugs In Neonates Research Articles

Introducing a Resource to Support Neonatal Nurse Engagement in Clinical Research©.

This paper introduces the Resource to Support Neonatal Nurse Engagement in Clinical Research© to educate and support engagement of nurses in study design and protocol review. The resource serves to promote collaboration between nurses and pharmaceutical researchers to advance the development of neonatal therapies. Neonates remain therapeutic orphans, underserved by the drug development community. Off-label use of drugs in neonates negatively impacts the evaluation of their safety and efficacy. Although NICU nurses' competencies are examples of expertise needed for well-designed clinical trials, nurses may have limited experience in providing insights. Resource development included a literature review and usability testing by multiple stakeholders. Usability testing indicated the resource was comprehensive and relevant to pharmaceutical and nonpharmaceutical studies. Reviewers commented resource prompts are beneficial in assessing study feasibility. Sponsors of research need nurse engagement to improve feasibility and flexibility and prevent protocol deviations in clinical trials. Leveraging the "Resource to Support Neonatal Nurse Engagement in Clinical Research©" can enhance research education and foster engagement of nurses in neonatal research. The resource has implications for the nursing profession, the pharmaceutical industry, and the advancement of new therapies. Individual nurses benefit from education and a framework for research engagement. The profession benefits from enhanced visibility through research collaboration. The pharmaceutical industry gains valuable insights on neonatal care, family dynamics, and NICU standard of care. A resource to foster collaboration in the study development process is an important step for advancing new therapies for neonates.

Machine Learning: A Potential Therapeutic Tool to Facilitate Neonatal Therapeutic Decision Making.

Bacterial infection is one of the major causes of neonatal morbidity and mortality worldwide. Finding rapid and reliable methods for early recognition and diagnosis of bacterial infections and early individualization of antibacterial drug administration are essential to eradicate these infections and prevent serious complications. However, this is often difficult to perform due to non-specific clinical presentations, low accuracy of current diagnostic methods, and limited knowledge of neonatal pharmacokinetics. Although neonatal medicine has been relatively late to embrace the benefits of machine learning (ML), there have been some initial applications of ML for the early prediction of neonatal sepsis and individualization of antibiotics. This article provides a brief introduction to ML and discusses the current state of the art in diagnosing and treating neonatal bacterial infections, gaps, potential uses of ML, and future directions to address the limitations of current studies. Neonatal bacterial infections involve a combination of physiologic development, disease expression, and treatment response outcomes. To address this complex relationship, future models could consider appropriate ML algorithms to capture time series features while integrating influences from the host, microbes, and drugs to optimize antimicrobial drug use in neonates. All models require prospective clinical trials to validate their clinical utility before clinical use.

Use of off-label drugs in the neonatal intensive care unit in India

Background: Off-label use of drugs is widespread in pediatrics and almost all neonates hospitalized in NICU are affected by the use of off-label drugs regardless of gestational age and birth weight. This is because of the lack of regulation for medications in the neonatal population and the delays in updating drug instructions. This is mainly due to the ethical difficulty in the research and difficulties in conducting clinical trials in this vulnerable population. Hence, the study was planned to assess the extent of the use of off-label drugs in the NICU. Methods: An observational study was carried out in the NICU of a tertiary care center from May 2021 to Oct 2022 and case records of neonates admitted to the NICU were evaluated. Results: Among 1745 drug prescriptions in 360 neonates, 1208 (69.22%) were off-label. Anti-infectives were the most commonly used off-label class of drug, Piperacillin+tazobactam was the most commonly used off-label drug and most common reason for off-label prescriptions was indication and administration. It was found that 79.44% of neonates received at least one off-label drug. Conclusions: Off-label use of drugs, specifically anti-infective drugs, is common in NICUs of India as in other countries. So, more research should be done to generate evidence-based guidelines for the rational use of drugs in neonates.

EXTENT AND PATTERN OF OFF-LABEL AND UNLICENSED DRUG UTILIZATION IN NEONATAL INTENSIVE CARE UNIT IN THE TERTIARY CARE TEACHING HOSPITAL

Background & Objectives: Many drugs that are used to treat children have not undergone evaluation to assure acceptable standards for optimal dose, safety and efcacy. As a result, drugs that are used to treat children are either not licensed for use in pediatric patients (unlicensed) or prescribed outside the terms of the product license (off-label).The extent of off-label and unlicensed drug use in neonates is unknown. Hence the purpose of the study is to determine the extent and pattern of off-label and unlicensed use of drugs amongst neonates in neonatal intensive care unit of a tertiary care hospital. A prospective study was carried Materials and Methods: out on 69 patients admitted in a tertiary care hospital for the period of ve months. Demographic data and complete prescriptions were noted in predesigned case record form. The off-label drugs were categorized by using National Formulary of India. Off-label drugs were classied in regards to their indications by using Anatomical Therapeutic Chemical Classication. The frequency was measured in terms of percentage and multiple binary logistic regressions were used for selecting confounding factors. A Results: total of 329 drugs were prescribed out of which 183(55.6%) were off-label and 65(19.8%) were unlicensed remaining 81(24.6%) labelled drugs. Most off-label drugs were prescribed for indication of alimentary tract (93.6%) and anti-infective (38.6%). Signicant confounding factors for prescription of unlicensed drugs were single diagnosis (OR 0.20, P<0.05) and hospital stay (OR 1.30, P<0.05) Common reasons for off-label prescribing were dosage 52.4% and age 23.2%. There was a high extent of utilization of off-label and unlicensed drugs. Hence Conclusion: , national drug regulatory authorities need to review and revise existing guidelines for safe administration of such drugs.

Off-label drug use in neonates and infants in Spain: A five-year observational study.

To provide information about the off-label rate of all drug prescriptions in neonates and infants up to 1year in Spain. Also, to analyse the off-label prescription of medicines under current practice in this age group according to different evidence sources. A five-year (2015-2019) exploratory observational study about off-label prescription in neonates and infants (0 to 1year) at primary health care in Spain. All drug prescriptions in this age group were analysed and classified according to their labelling in off-label or on-label. The drugs prescribed off-label were subsequently reviewed in national formularies and other databases to assess its evidence of use beyond what is recommended in the Summary of Product Characteristics (SmPC). On average 34.50% of total prescriptions were prescribed off-label according to the SmPC. 17.93% of total prescriptions in neonates and infants up to 1year old were not based on clinical evidence from SmPC, Pediamécum, BNF or DailyMed. In more than 88% of cases, off-label use was related to the posology section of the SmPC, followed by the therapeutic indications and contraindications sections, in 35.20% and 24.10% of cases, respectively. Almost 13% of off-label drugs were over-the-counter. Salbutamol followed by topical tobramycin and colecalciferol were the drugs most prescribed off-label. Off-label use of drugs remains as an important public health concern, especially for neonates and infants up to 1year, who receive the greatest proportion of off-label prescriptions. The evidence-based off-label prescription is a widespread practice that has shown a stable trend during the 5-year study period providing also a certain extent of flexibility to paediatricians in some therapeutic decisions.

Global Divergence of Antifungal Prescribing Patterns: Data From the Global Antimicrobial Resistance, Prescribing, and Efficacy in Neonates and Children Surveys.

Globally, invasive fungal diseases (IFDs) have a significant impact in human health. With an increasing pediatric population at risk of IFD, effective antifungal drugs access and affordability should be ensured universally. The aim of our study was to characterize the global antifungal drug use in neonates and children and its variability between countries in different income groups. Data were extracted from the Global Antimicrobial Resistance, Prescribing and Efficacy in Neonates and Children Point Prevalence Survey project, consisting in 1 pilot and four 1-day Point Prevalence Survey between 2015 and 2017. The data had been entered through a study-specific web-based data collection tool. From a total of 13,410 children included, 7.8% (1048/13,410) received at least 1 systemic antifungal drug: 9.5% (95% confidence interval: 8.9%-10.1%) in high income countries (HIC) versus 5.0% (95% confidence interval: 4.4%-5.6%) in low-middle income countries (LMIC) (P < 0.01). A significant proportion of patients on antifungals belonged to high-risk group for IFD (67.4%; 706/1048); most of these were managed in HIC (72.8%, P < 0.01). The likelihood of receiving antifungals being in high-risk group was higher in HIC compared with LMIC (ratio of 5.8 vs. 3.4, P < 0.01). Antifungal prophylaxis was more likely prescribed in HIC (67.2% vs. 30.4%, P < 0.01). Fluconazole was the most frequently prescribed drug. The proportional use of fluconazole was higher in LMIC compared with HIC. A significant variability of antifungal prescribing patterns was observed. The proportional use of systemic antifungals was twice as high in HIC compared with LMIC. More detailed data on access and antifungal use in limited-resource settings should be explored.

Intravenous drug use in neonatal intensive care units

ObjectivesIntravenous drug use in neonates is frequent and prone to medication errors. The aim of this study was to describe the intravenous drugs most frequently used in Spanish Neonatal Intensive...

Standardizing Safety Assessment and Reporting for Neonatal Clinical Trials

Standardizing Safety Assessment and Reporting for Neonatal Clinical Trials

Medicines prescription patterns in European neonatal units.

Background Hospitalized neonates receive the highest number of drugs compared to all other age groups, but consumption rates vary between studies depending on patient characteristics and local practices. There are no large-scale international studies on drug use in neonatal units. Objective We aimed to describe drug use in European neonatal units and characterize its associations with geographic region and gestational age. Setting A one-day point prevalence study was performed as part of the European Study of Neonatal Exposure to Excipients from January to June 2012. Method All neonatal prescriptions and demographic data were registered in a web-based database. The impact of gestational age and region on prescription rate were analysed with logistic regression. Main outcome measure The number and variety of drugs prescribed to hospitalized neonates in different gestational age groups and geographic regions. Results In total, 21 European countries with 89 neonatal units participated. Altogether 2173 prescriptions given to 726 neonates were registered. The 10 drugs with the highest prescription rate were multivitamins, vitamin D, caffeine, gentamicin, amino acids for parenteral nutrition, phytomenadione, ampicillin, benzylpenicillin, fat emulsion for parenteral nutrition and probiotics. The six most commonly prescribed ATC groups (alimentary tract and metabolism, blood and blood-forming organs, systemic anti-infectives, nervous, respiratory and cardiovascular system) covered 98% of prescriptions. Gestational age significantly affected the use of all commonly used drug groups. Geographic region influenced the use of alimentary tract and metabolism, blood and blood-forming organs, systemic anti-infectives, nervous and respiratory system drugs. Conclusion While gestational age-dependent differences in neonatal drug use were expected, regional variations (except for systemic anti-infectives) indicate a need for cooperation in developing harmonized evidence-based guidelines and suggest priorities for collaborative work.

Pediatric Ontogeny: Moving From Translational Science to Drug Development.

Pediatric Ontogeny: Moving From Translational Science to Drug Development.

Drug utilization pattern in a neonatal intensive care unit at tertiary care hospital attached to a medical college in Southern Karnataka, India

Background: Neonates and in particular preterm neonates belongs to the most vulnerable population. A neonatal intensive Care Unit (NICU) is a highly specialized unit that provides high quality skilled care to critically ill new newborn, premature or low birth weight babies. Apart from facilities for continuous clinical and biochemical monitoring, NICU management involves the use of wide range of medications. Irrational prescription of drug is common in clinical practice, important reason being lack of knowledge about drug prescription. Developing countries have limited funds available for health care and drugs so it becomes very important to prescribe drugs rationally. The present study was done to find out the drug utilization pattern and improve the rational use which aids in the improvement of neonatal care. Methods: The study was retrospective study in NICU of tertiary care hospital attached to MIMS, Mandya for a duration of 6 months. Data extraction sheet were used to collect the information regarding demographic details, maternal and delivery details, indication for admission, final diagnosis and medications administered. Data collected were evaluated for the category of prescribed, based on World Health Organization Anatomical Therapeutic Committee (WHO classification system and were analyzed using SPSS. WHO drug utilization core indicators were also evaluated.Results: Among 400 neonates admitted in NICU during the study period, 53.7% were males and 46.2% were females. There were 29.7% preterm born neonates. The maximum number of neonates were admitted in early neonatal period (87.25%). Neonatal sepsis (37.9%) and Birth asphyxia (11.6%) were the most common indications for admission. The total number of drugs prescribed was 1428 and the average number of drugs per neonate was 3.57. Preterm (&lt;37weeks) and low birth weight (&lt;2.5Kg) were exposed to significantly higher number of drugs. The most frequently prescribed therapeutic class of drugs was anti-infectives (60.36%), followed by drugs of central nervous system (7. 84%). Among the anti-infectives, the most commonly prescribed drugs were Ampicillin (59%), followed by gentamycin (42.5%). High end antibiotics like carbapenems, colistin’s and linezolid were used in less than 5% of cases.Conclusions: Drug use in neonates should be minimal and focus on the importance of therapeutic treatment guidelines establishment in hospital to control the over usage of antibiotics.

Off-label and unlicensed drug use in hospitalized newborns in a Saudi tertiary care hospital: a cohort study.

Objective To determine the extent of off-label and unlicensed prescribing in hospitalized newborns and to identify patient-related risk factors associated with off-label prescribing. Methods A prospective cohort study was conducted between January and March 2016 at a neonatology department of a tertiary-care hospital in the Eastern province. All consecutive admissions to all neonatal care levels meeting the inclusion and exclusion criteria were eligible for enrollment. All prescriptions were classified as off-label or unlicensed according to drug product monograph. Clinical and prescription data were extracted using a pilot-tested structured data collection sheet. Results During the study period583 prescriptions were made for 138 newborns, of which 29.7% (173/583) and 12.9% (75/583) were classified as off-label and unlicensed drugs respectively for use in neonates. Thirty-four percent (47/138) of patients received at least one off-label/unlicensed medicine. Mechanical ventilation, admission to the neonatal intensive care unit and length of hospital stay were identified as independent risk factors associated with prescribing of at least one off-label medication. Conclusion Use of off-label and unlicensed drugs in hospitalized newborns seems to be a common practicein this Saudi hospital. Future research should evaluate safety and efficacy of off-label and/or unlicensed use of drugs in neonates.

Large differences in neonatal drug use between NICUs are common practice: time for consensus?

AimsEvidence for drug use in newborns is sparse, which may cause large differences in drug prescriptions. We aimed to investigate the differences between neonatal intensive care units (NICUs) in the Netherlands in currently prescribed drugs.MethodsThis multicentre study included neonates admitted during 12 months to four different NICUs. Drugs were classified in accordance with the Anatomical Therapeutic Chemical (ATC) classification system and assessed for on/off‐label status in relation to neonatal age. The treatment protocols for four common indications for drug use were compared: pain, intubation, convulsions and hypotension.ResultsA total of 1491 neonates (GA range 23+6–42+2 weeks) were included with a total of 32 182 patient days, 181 different drugs and 10 895 prescriptions of which 23% was off‐label in relation to neonatal age. Overall, anti‐infective drugs were most frequently used with a total of 3161 prescriptions, of which 4% was off‐label in relation to neonatal age. Nervous system drugs included 2500 prescriptions of which 31% was off‐label in relation to neonatal age. Nervous system drugs, blood and blood forming organs, and cardiovascular drugs showed the largest differences between NICUs with ranges of 919–2278, 554–1465, and 238–952 total prescriptions per 1000 patients per ATC class, respectively.ConclusionsWe showed that drug use varies widely in neonatal clinical practice. The drug classes with the highest proportion of off‐label drugs in relation to neonatal age showed the largest differences between NICUs, i.e. cardiovascular and nervous system drugs. Drug research in neonates should receive high priority to guarantee safe and appropriate medicines and optimal treatment.

Drug use in neonates varies between NICUs in the Netherlands

Drug use in neonates varies between NICUs in the Netherlands

Collaboration in Regulatory Science to Facilitate Therapeutic Development for Neonates.

Historically, neonatal therapeutic interventions were derived from adult therapeutics, and tragedies resulting from this approach have demonstrated differences in the pathophysiologic and developmental processes between neonates and older patients. Over the past 3 decades, researchers and collaborative research networks have made progress in the systematic evaluation of neonatal therapies, yet most neonatal therapeutic products have been incompletely assessed for safety and efficacy, and remain unlabeled and unapproved. This work describes the legislative initiatives that have stimulated an increase in pediatric and neonatal studies. It highlights examples of successful neonatal drug studies that have resulted in informative neonatal labeling changes, as well as studies that have produced incomplete information. Strategies that support the design of successful studies, including targeting specific subpopulations, modeling and simulation to inform dose selection, innovative design strategies, biomarkers, and endpoints are discussed. Multi-stakeholder consortia such as the International Neonatal Consortium (INC), are working to improve the tools needed for the development of neonatal therapies. These research tools may be used by trial networks to inform consistent and efficient multicenter studies. More data are needed to support safe and effective use of drugs in neonates, and to obtain these data, a thorough understanding of pathophysiology, drug disposition, biomarkers, and clinically-meaningful endpoints is required. This information will be derived from clinical trials, registries, real-world evidence, and the medical literature. Collaboration of consortia and the development of research networks are essential to achieving these goals.

Drug Utilization on Neonatal Wards: A Systematic Review of Observational Studies

Despite limited evidence on safety and efficacy of drug use in neonates, drugs are extensively used in this age group. However, the availability of information on drug consumption in neonates, especially inpatient neonates, is limited. This paper systematically reviews published studies on drug utilization in hospitalized neonates. A systematic literature review was carried out to identify observational studies published from inception of databases used till August 2016. Four search engines, namely Medline, CINAHL, Embase, and PubMed, were used. Publications written in English that described drug utilization in neonatal wards were selected. Assessment of the data was based on the category of the study design, the objective of study and the method used in reporting drug consumption. A total of 20 drug utilization studies were identified, 12 of which focused on all drug classes, while the other eight evaluated antimicrobials. Studies were reported in Europe (n = 7), the United States (n = 6), India (n = 5), Brazil (n = 1), and Iran (n = 1). Substantial variance with regard to study types (study design and methods), data source, and sample size were found among the selected studies. Of the studies included, 45% were cross-sectional or retrospective, 40% were prospective studies, and the remaining 15% were point prevalence surveys. More than 70% of the studies were descriptive studies, describing drug consumption patterns. Fifteen per cent of the descriptive studies evaluated changes in drug utilization patterns in neonates. Volume of units was the most prevalent method used for reporting all drug categories. The ATC/DDD system for reporting drug use was only seen in studies evaluating antimicrobials. The most commonly reported drugs across all studies are anti-infectives for systemic use, followed by drugs for the cardiovascular system, the nervous system and the respiratory system. Ampicillin and gentamicin were the most prescribed antimicrobials in hospitalized neonates. The present review reveals that neonates are exposed to a high number of drugs and various methods are used to report drug consumption in this age group. The best measure of drug consumption to quantify prevalence of drug use in neonates remains to be identified and additional research in this area is warranted.

Neonatal drug therapy: The first frontier of therapeutics for children.

Knowledge about the safe and effective use of medicines in neonates has increased substantially but has resulted in few label changes. Drugs developed for use in adults are reshaped and tailored to specific neonatal indications. However, the use of drugs in neonates should not only mirror adult pharmacotherapy, but should be driven by their own specific needs. Therefore, building collaborative networks may assist to develop a newborn-driven research agenda addressing their clinical needs and diseases.

O-115 Relationship Between Adverse Drug Reactions And Off-label/unlicensed Drug Use In Hospitalised Neonates. Remineo Study

Background and aim Data regarding the association between the off-label drug use and adverse drug reactions (ADRs) in neonates is scarce. The main aims of this study are to evaluate prospectively the relationship between adverse drug reactions and off-label or unlicensed (OLUL) drugs in 2 neonatal centres in Lyon (France), and to provide more information on prescribing practice, the amplitude, nature and consequences of OLUL drug use. Methods The French summaries of product characteristics in Theriaque 2012 (a prescription products guide ) are being used as a primary reference source for determining drug labelling. Detection of ADRs is carried out by health care professionals and research groups using a trigger tool and patients’ electronic health records. The causality between suspected ADRs and drug is evaluated using the WHO and the French methods of imputability. Preliminary results for a 12 month period 910 neonates were included. 671 (73,7%) were preterm. 94,8% (CI 95: 93,3–96,3) of children received at least one OLUL drug, 66% of 8891 prescriptions were used in OLUL manner. 80% of the 96 validated ADRs were classified as severe. 84% of drugs related to ADRs were used in OLUL manner. Conclusion Our study confirmed that OLUL drug utilisation is common in neonates. This study will bring more evidence on the correlation between OLUL drug use and ADRs. Institutions and pharmaceutical industry should develop clinical trials for neonates, and ensure they do not remain a “therapeutic orphan”. A specific reference source for drug used in neonates would be helpful.

Clinical Trials of Drugs Used Off-Label in Neonates: Ethical Issues and Alternative Study Designs

The use of drugs for indications unapproved by the Food and Drug Administration (FDA), often called “off-label use,” is widespread in children, including neonates. The widespread off-label use of drugs in neonates presents ethical and safety challenges. Since the passage of the Best Pharmaceuticals for Children Act (BPCA) in 2002, both the FDA and National Institutes of Health (NIH) have taken initiatives to facilitate and encourage research to achieve the necessary labeling for drugs routinely used in infants and children. Federal regulations provide broad rules and guidance for the protection of human subjects in research. However, there are ethical issues that a physician may face when designing clinical trials of drugs in neonates that are routinely used off-label and widely believed to be beneficial. We attempt to describe these ethical challenges and provide recommendations, including alternative study designs, to resolve them in an ethical framework that takes into account the Belmont Report, the statement of the World Medical Association (WMA), and federal regulations.

Off-label use of antimicrobial agents in pediatrics

The majority of drugs, biological products, and devices used for children are done so off-label (ie, for age groups or indications that have not been approved by the Food and Drug Administration). Off-label use of drugs in neonates is particularly common, which makes caring for these children particularly difficult for physicians. The American Academy of Pediatrics (AAP) and other groups have been working actively for decades with the FDA and Congress to correct this problem. Last year, we published an overview of the problems that off-label use of drugs pose for children of all ages and discussed what was being done to correct this situation (Pediatr Infect Dis J 17:739-744, 1998).1 The purpose of this report is 0 to focus on how inadequate pediatric drug information negatively impacts the ability of physicians to safely treat diseases in children, especially neonates, and to update the reader on the status of recent legislation and regulations that have been put in place to solve this problem. Although inadequate pediatric information affects all classes of drugs, biological products, and devices, specific examples in this report focus on the use of antimicrobial agents.