1
Accepted Article
Adverse drug reactions in neonates and infants: a population tailored approach is needed1
Karel Allegaert1,2, Johannes N van den Anker3-6
1
Neonatal Intensive Care Unit, University Hospitals Leuven, Leuven, Belgium
2
Department of Development and Regeneration, KU Leuven, Belgium
3
Division of Pediatric Clinical Pharmacology, Children’s National Medical Center, Washington, DC, USA 4
Departments of Pediatrics, Pharmacology and Physiology, George Washington University School of Medicine and Health Sciences, Washington, DC, USA 5
Intensive Care, Erasmus MC- Sophia Children’s Hospital, Rotterdam, the Netherlands
6
Department of Paediatric Pharmacology, University Children’s Hospital Basel, Switzerland
Correspondence: Karel Allegaert, MD PhD Neonatal Intensive Care Unit, University Hospitals Leuven, Herestraat 49, 3000 Leuven, BELGIUM Tel
00-32-16-343850; Fax 00-32-16-343209
E-mail: [email protected]
Words full paper Words abstract
2 733
words
178
words
50 references, 1 figure, 2 tables
This article has been accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process, which may lead to differences between this version and the Version of Record. Please cite this article as doi: 10.1111/bcp.12430
This article is protected by copyright. All rights reserved.
2
Accepted Article
Running title: adverse drug reactions in neonates and infants
Summary
Drug therapy is a powerful tool to improve outcome, but there is an urgent need to improve pharmacotherapy in neonates through tailored adverse drug reaction (ADR) prevention and management. At present, infants commonly receive off label drugs, using doses extrapolated from those in children or adults. Besides the lack of labelling, inappropriate formulations, (poly)pharmacy, immature organ function and multiple illnesses further raise the risk for ADRs in neonates and infants. Pharmacovigilance to improve ADR prevention and management needs to be tailored to
neonates and infants. We will illustrate this using drug prescription and administration errors prevention (e.g. formulation, bedside manipulation, access) strategies, detection through laboratory or clinical outlier data signalling (e.g. reference laboratory values, overall high morbidity), assessment through algorithm scoring (e.g. Naranjo or population specific), as well as understanding of the developmental toxicology (e.g. covariates, developmental pharmacology) to avoid re-occurrence and in developing guidelines. Such tailored strategies need collaborative initiatives to combine the knowledge and expertise of different disciplines, but hold the promise to become a very effective tool to improve pharmacotherapy and reduce ADRs in infants.
This article is protected by copyright. All rights reserved.
Accepted Article
3
Introduction
An adverse drug reaction (ADR) has been defined by the World Health Organization (WHO) as ‘any noxious or unintended drug response at doses commonly used for prophylaxis, diagnosis, or treatment of a disease or condition’. Some ADRs are considered to be predictable based on the
known pharmacology and frequently relate to the dose (e.g. side effects, secondary effects, interactions or toxicity) while others remain unpredictable based on the currently available knowledge and are less dose related (e.g. idiosyncratic reactions, (pseudo)allergic reactions or intolerance)[1]. Despite the fact that this kind of ADR definition already includes a wide range of drug related complications, its application in the specific subpopulation of neonates and infants remains difficult because different ADR definition related assumptions (pharmacology and dose are known, interactions can be quantified, side- or secondary effects anticipated, active compound only or formulation) cannot be taken for granted. It may be more reasonable to use ‘an unintended and harmful effect resulting from the use of medications intended for diagnostic or therapeutic reasons (irrespective of the dose)’ as a broader definition, because of the common practice to prescribe drugs off label and unlicensed and the absence of dose guidance in this population [2-6]. Obviously, this definition results in overlap with errors related to inappropriate drug administration, commonly referred to as medication errors (e.g. wrong route, dose or patient). Finally, adverse drug reactions and medication errors relate to the broader and growing field of research on iatrogenesis, i.e. any adverse condition occurring as a result of a diagnostic procedure or treatment by a medical care provider (Figure 1)[2-6]. Although the research related to iatrogenesis is of obvious relevance to improve outcome and, despite the fact that some of the methods can also be applied to generate more insights in the incidence and prevention of ADRs in neonates or infants, this review aims to focus on the broader ADR definition
This article is protected by copyright. All rights reserved.
4
Accepted Article
including medication errors. Such an integrated approach and broader view on patient safety is in line with the trend of the authorities not only to focus on the medicinal product itself, but to integrate human factors (how is this medicine used and how do errors/ADR happen?) resulting in e.g. an action plan to reduce the burder of medication errors and ADR events supported by the European Medicines Agency, and of relevance for all stakeholders involved [7] First we like to focus on several important aspects of neonatal clinical pharmacology. We hereby refer to compound specific major ADRs to illustrate the impact of pharmacological, physiological and toxicological particularities on specific major ADRs in infancy. The burden of pharmaco-epidemiology and ADRs in infancy will subsequently be discussed, followed by suggestions for a population tailored approach to improve pharmacotherapy and reduce this ADR burden (prevention, detection, assessment, and understanding) in neonates.
Neonatal clinical pharmacology When a drug is prescribed, the overall aim is to attain specific, targeted effects (e.g., bactericidal, analgesic, blood pressure normalizing), preferably without disproportional side-effects (e.g. drug toxicity, hypotension, tachycardia). Neonatal clinical pharmacology aims to predict and estimate these (side)-effects at the level of the population or - preferably - the individual infant through integration of the covariates that explain the inter- and intra-individual variability [8,9]. The most obvious covariates in neonates relate to growth and maturation, reflected and quantified by birth weight, current weight, or age – either postnatal, gestational or postmenstrual age. There is already at least one order of variability in weight (
Accepted Article
Adverse drug reactions in neonates and infants: a population tailored approach is needed1
Karel Allegaert1,2, Johannes N van den Anker3-6
1
Neonatal Intensive Care Unit, University Hospitals Leuven, Leuven, Belgium
2
Department of Development and Regeneration, KU Leuven, Belgium
3
Division of Pediatric Clinical Pharmacology, Children’s National Medical Center, Washington, DC, USA 4
Departments of Pediatrics, Pharmacology and Physiology, George Washington University School of Medicine and Health Sciences, Washington, DC, USA 5
Intensive Care, Erasmus MC- Sophia Children’s Hospital, Rotterdam, the Netherlands
6
Department of Paediatric Pharmacology, University Children’s Hospital Basel, Switzerland
Correspondence: Karel Allegaert, MD PhD Neonatal Intensive Care Unit, University Hospitals Leuven, Herestraat 49, 3000 Leuven, BELGIUM Tel
00-32-16-343850; Fax 00-32-16-343209
E-mail: [email protected]
Words full paper Words abstract
2 733
words
178
words
50 references, 1 figure, 2 tables
This article has been accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process, which may lead to differences between this version and the Version of Record. Please cite this article as doi: 10.1111/bcp.12430
This article is protected by copyright. All rights reserved.
2
Accepted Article
Running title: adverse drug reactions in neonates and infants
Summary
Drug therapy is a powerful tool to improve outcome, but there is an urgent need to improve pharmacotherapy in neonates through tailored adverse drug reaction (ADR) prevention and management. At present, infants commonly receive off label drugs, using doses extrapolated from those in children or adults. Besides the lack of labelling, inappropriate formulations, (poly)pharmacy, immature organ function and multiple illnesses further raise the risk for ADRs in neonates and infants. Pharmacovigilance to improve ADR prevention and management needs to be tailored to
neonates and infants. We will illustrate this using drug prescription and administration errors prevention (e.g. formulation, bedside manipulation, access) strategies, detection through laboratory or clinical outlier data signalling (e.g. reference laboratory values, overall high morbidity), assessment through algorithm scoring (e.g. Naranjo or population specific), as well as understanding of the developmental toxicology (e.g. covariates, developmental pharmacology) to avoid re-occurrence and in developing guidelines. Such tailored strategies need collaborative initiatives to combine the knowledge and expertise of different disciplines, but hold the promise to become a very effective tool to improve pharmacotherapy and reduce ADRs in infants.
This article is protected by copyright. All rights reserved.
Accepted Article
3
Introduction
An adverse drug reaction (ADR) has been defined by the World Health Organization (WHO) as ‘any noxious or unintended drug response at doses commonly used for prophylaxis, diagnosis, or treatment of a disease or condition’. Some ADRs are considered to be predictable based on the
known pharmacology and frequently relate to the dose (e.g. side effects, secondary effects, interactions or toxicity) while others remain unpredictable based on the currently available knowledge and are less dose related (e.g. idiosyncratic reactions, (pseudo)allergic reactions or intolerance)[1]. Despite the fact that this kind of ADR definition already includes a wide range of drug related complications, its application in the specific subpopulation of neonates and infants remains difficult because different ADR definition related assumptions (pharmacology and dose are known, interactions can be quantified, side- or secondary effects anticipated, active compound only or formulation) cannot be taken for granted. It may be more reasonable to use ‘an unintended and harmful effect resulting from the use of medications intended for diagnostic or therapeutic reasons (irrespective of the dose)’ as a broader definition, because of the common practice to prescribe drugs off label and unlicensed and the absence of dose guidance in this population [2-6]. Obviously, this definition results in overlap with errors related to inappropriate drug administration, commonly referred to as medication errors (e.g. wrong route, dose or patient). Finally, adverse drug reactions and medication errors relate to the broader and growing field of research on iatrogenesis, i.e. any adverse condition occurring as a result of a diagnostic procedure or treatment by a medical care provider (Figure 1)[2-6]. Although the research related to iatrogenesis is of obvious relevance to improve outcome and, despite the fact that some of the methods can also be applied to generate more insights in the incidence and prevention of ADRs in neonates or infants, this review aims to focus on the broader ADR definition
This article is protected by copyright. All rights reserved.
4
Accepted Article
including medication errors. Such an integrated approach and broader view on patient safety is in line with the trend of the authorities not only to focus on the medicinal product itself, but to integrate human factors (how is this medicine used and how do errors/ADR happen?) resulting in e.g. an action plan to reduce the burder of medication errors and ADR events supported by the European Medicines Agency, and of relevance for all stakeholders involved [7] First we like to focus on several important aspects of neonatal clinical pharmacology. We hereby refer to compound specific major ADRs to illustrate the impact of pharmacological, physiological and toxicological particularities on specific major ADRs in infancy. The burden of pharmaco-epidemiology and ADRs in infancy will subsequently be discussed, followed by suggestions for a population tailored approach to improve pharmacotherapy and reduce this ADR burden (prevention, detection, assessment, and understanding) in neonates.
Neonatal clinical pharmacology When a drug is prescribed, the overall aim is to attain specific, targeted effects (e.g., bactericidal, analgesic, blood pressure normalizing), preferably without disproportional side-effects (e.g. drug toxicity, hypotension, tachycardia). Neonatal clinical pharmacology aims to predict and estimate these (side)-effects at the level of the population or - preferably - the individual infant through integration of the covariates that explain the inter- and intra-individual variability [8,9]. The most obvious covariates in neonates relate to growth and maturation, reflected and quantified by birth weight, current weight, or age – either postnatal, gestational or postmenstrual age. There is already at least one order of variability in weight (
