Drug treatment in children with focus on off-label drug use

ABSTRACT There is a lack of paediatric documentation concerning efficacy and safety of many drugs, which contribute to drug use outside the terms of the product license (off-label). In the present thesis, four studies (I-IV), using different settings and design to evaluate pharmacological treatment in children, with focus on off-label drug use, is presented. Outpatient records of purchased prescriptions were retrieved to investigate the frequency and characteristics of paediatric off-label prescribing (I). In Stockholm, 1.8 prescribed drugs per child were purchased in the year 2000. Every fifth drug was classified as an off-label prescription. The proportion of off-label prescriptions was highest for topical drugs, due to lack of paediatric information. A survey of all adverse drug reaction reports to the Medical Products Agency concerning paediatric outpatients in the year 2000 was performed, to investigate the frequency of off-label drug prescribing (II). One hundred and twelve paediatric cases, corresponding to 158 adverse reactions were reported. One third of the reports were regarded as serious, and these were more often associated with off-label drug prescribing. Antiasthmatic drugs were most commonly reported. Psychiatric symptoms were the most commonly reported adverse drug reactions. Paediatric questions and answers to a Drug Information Centre in Stockholm were retrieved and analysed regarding off-label drug use and paediatric literature information adding to the labelling of the drug (III). During a 10-year period, 249 paediatric questions were handled. Every third question concerned off-label treatment, often concerning psychotropic drugs. In every other response to off-label questions, additional paediatric documentation concerning the drug was found in the literature. In a prospective, nation-wide, cross-sectional study, paediatric prescriptions and offlabel drug use to children at hospitals in Sweden were analysed (IV). Enrolment of more than 200 hospital departments resulted in data from 2947 paediatric patients, that received altogether11294 prescriptions within two two-day-periods in 2008. Half of all administered prescriptions concerned either off-label drug use or unlicensed or extemporaneously prepared drugs. Paracetamol was the most common drug used both on- and off-label. Absence of paediatric information was the main reason for the large proportion of off-label prescribing of carbohydrates and electrolytes in hospitals. This thesis has demonstrated substantial off-label prescribing to children in both primary and hospital health care. A common reason for this is the lack of paediatric documentation. Children have the same right as adults to well documented and safe drug therapy. Therefore, it is necessary to improve paediatric documentation through harmonization of existing scientific knowledge and clinical experience, improved structure of SPC information, and more appropriate administration forms. Furthermore, the documentation of drug treatment and its outcomes, including the reporting of adverse drug reactions, need to be improved

Does the EU's Paediatric Regulation work for new medicines for children in Denmark, Finland, Norway and Sweden? : A cross-sectional study

Objective The aim of this study was to assess the marketing status of the new paediatric medicinal products listed in the 10-year report as initially authorised between 2007 and 2016, reflecting the product availability in four Nordic countries. Design This is a cross-sectional study. Setting Analysis of the national medicine agency's databases in Denmark, Finland, Norway and Sweden. Data source New medicinal products with paediatric indications and new paediatric formulations listed in the Annex of European Medicines Agency's EU Paediatric Regulation 10-year report. Data analysis The products were classified according to national marketing status between January 2019 and March 2019, whether a product was authorised and whether the product was marketed. Main outcome measures The percentages of the new medicinal products with paediatric indications and new paediatric formulations having a valid marketing authorisation and being marketed, both in terms of the sums of all countries and separately for each country. Results Across the four countries, 21%-32% (16/76-24/76) of the new medicinal products were not marketed. Of the new formulations relevant to children, 29%-50% (16/56-28/56) were not marketed, and a significant proportion of these products had never been marketed. Conclusions This study reflects the reality of the implementation of the Paediatric Regulation. The results show that several new paediatric medicines and new formulations are not marketed. This affects the product availability. Similar data from other countries are needed to evaluate the overall European status to find remedies to current situation and increase the availability of the medicines for children. ©Peer reviewe

Pharmacovigilance in children in Camagüey Province, Cuba

Purpose: Our aim was to describe the adverse drug reactions (ADRs) detected following increased education about pharmacovigilance and drug toxicity in children in Camagüey Province, Cuba. Methods: Over a period of 24 months (January 2009 to December 2010), all reports of suspected ADRs in children to the Provincial Pharmacovigilance Centre in Camagüey Province were analysed. ADRs were classified in relation to causality and severity. Results: There were 533 reports involving suspected ADRs in children in the period. Almost one third of the reports received were classified as moderate (155, 29%) or severe (10, 2%). There was one fatality in association with the use of ceftriaxone. Vaccines and antibiotics were responsible for most of the ADR reports (392, 74%) and for all ten severe ADRs. After an intensive educational package, both within the community and the Children’s Hospital, the number of reports increased from 124 in 2008 to 161 in 2009 and 372 in 2010. This was equivalent to a reporting rate of 879 and 2,031 reports per million children per year for 2009 and 2010, respectively. Conclusions: The incidence of ADRs in children Camagüey Province, Cuba, is greater than previously reported. An educational intervention about pharmacovigilance and drug toxicity in children can improve the reporting of ADRs

Pharmacokinetic-Pharmacodynamic Modeling in Pediatric Drug Development, and the Importance of Standardized Scaling of Clearance.

Pharmacokinetic/pharmacodynamic (PKPD) modeling is important in the design and conduct of clinical pharmacology research in children. During drug development, PKPD modeling and simulation should underpin rational trial design and facilitate extrapolation to investigate efficacy and safety. The application of PKPD modeling to optimize dosing recommendations and therapeutic drug monitoring is also increasing, and PKPD model-based dose individualization will become a core feature of personalized medicine. Following extensive progress on pediatric PK modeling, a greater emphasis now needs to be placed on PD modeling to understand age-related changes in drug effects. This paper discusses the principles of PKPD modeling in the context of pediatric drug development, summarizing how important PK parameters, such as clearance (CL), are scaled with size and age, and highlights a standardized method for CL scaling in children. One standard scaling method would facilitate comparison of PK parameters across multiple studies, thus increasing the utility of existing PK models and facilitating optimal design of new studies

Off-label drug treatment and related problems in children : A register based investigation

Introduction: There is a lack of pediatric documentation concerning efficacy and safety of many drugs, which may contribute to off-label drug treatment and increase the risk for adverse drug reactions (ADRs). Aims: To; (I) analyse the frequency and characteristics of pediatric off-label prescribing; (II) investigate frequency of off-label drug prescribing in pediatric ADR reports; (III) analyse drug related problems, the extent of off-label drug treatment in pediatric questions to a Drug Information Centre (DIC) and pediatric literature information adding to the labelling of the drug in DIC answers. Methods: Three retrospective register based investigations on drug treatment of children less than 16 years of age were performed. In study I, outpatient records of purchased prescriptions were retrieved and analysed. The analysis was restricted to the drugs that account for 90% of the total use (DU90%). In study II, a nation-wide survey of ADR reports to the Medical Products Agency in relation to prescriptions among suspected drugs in outpatients was performed. In study III, questions and answers (Q&A) to a DIC in Stockholm (1995-2004) were characterised and analysed. Results: In Stockholm 1.8 prescribed drugs per pediatric outpatient were purchased in the year 2000. Every fifth drug was classified as an off-label prescription. The proportion of off-label prescription was highest for topical drugs, followed by psychotropic drugs. In the year 2000, 112 pediatric ADR reports corresponding to 158 ADRs in outpatients were reported. The off-label proportion in ADR reports was more than 40%. One third of the reports was regarded as serious and these were more often associated with off-label drug prescribing. Antiasthmatic drugs were most commonly reported. Psychiatric symptoms were the most commonly reported ADRs. During a 10-year period DIC in Stockholm handled 249 pediatric questions and each question addressed on average 1.5 drugs. The questions mainly concerned drugs licensed in Sweden. Adverse drug reactions (ADRs), drug choice or dosing were the most common drug related problems. Every third question was off-label and among these the most common therapeutic group was psychotropic drugs. In every other response to offlabel questions, pediatric documentation concerning drug efficacy and safety was found. The most common reason for a drug to be classified as off-label was lack of pediatric labelling in the Swedish catalogue of medical products. Conclusion: This thesis has demonstrated substantial off-label prescribing in primary health care. Off-label prescribing were common in pediatric ADR reports from primary care. We also found literature information adding to the labelling of the drug. There is a great need for evidence based pediatric drug information, which can be retrieved from a DIC. A future challenge is to further diffuse this knowledge to pediatric prescribers through Internet, expert committees and medical journal databases

Melatonin Prescription in Children and Adolescents in Relation to Body Weight and Age

The prescription of melatonin to children and adolescents has increased dramatically in Sweden and internationally during the last ten years. In the present study we aimed to evaluate the prescribed melatonin dose in relation to body weight and age in children. The population-based BMI Epidemiology Study Gothenburg cohort has weight available from school health care records, and information on melatonin prescription through linkage with high-quality national registers. We included prescriptions of melatonin to individuals below 18 years of age where a weight measurement not earlier than three months before, or later than six months after the dispensing date, was available (n = 1554). Similar maximum doses were prescribed to individuals with overweight orobesity as to individuals with normal weight, and to individuals below and above 9 years of age. Age and weight only explained a marginal part of the variance in maximum dose, but were inversely associated and explained a substantial part of the variance in maximum dose per kg. As a result, individuals overweight or with obesity, or age above 9 years, received lower maximum dose per kg of body weight, compared with individuals with normal weight or below 9 years of age. Thus, the prescribed melatonin dose to individuals under 18 years of age is not primarily informed by body weight or age, resulting in substantial differences in prescribed dose per kg of body weight across BMI and age distribution