Making Medicines Baby Size: The Challenges in Bridging the Formulation Gap in Neonatal Medicine.

The development of age-appropriate formulations should focus on dosage forms that can deliver variable yet accurate doses that are safe and acceptable to the child, are matched to his/her development and ability, and avoid medication errors. However, in the past decade, the medication needs of neonates have largely been neglected. The aim of this review is to expand on what differentiates the needs of preterm and term neonates from those of the older paediatric subsets, in terms of environment of care, ability to measure and administer the dose (from the perspective of the patient and carer, the routes of administration, the device and the product), neonatal biopharmaceutics and regulatory challenges. This review offers insight into those challenges posed by the formulation of medicinal products for neonatal patients in order to support the development of clinically relevant products.

High variability in the dosing of commonly used antibiotics revealed by a Europe-wide point prevalence study: implications for research and dissemination.

BACKGROUND: Antibiotic dosing in neonates varies between countries and centres, suggesting suboptimal exposures for some neonates. We aimed to describe variations and factors influencing the variability in the dosing of frequently used antibiotics in European NICUs to help define strategies for improvement. METHODS: A sub-analysis of the European Study of Neonatal Exposure to Excipients point prevalence study was undertaken. Demographic data of neonates receiving any antibiotic on the study day within one of three two-week periods from January to June 2012, the dose, dosing interval and route of administration of each prescription were recorded. The British National Formulary for Children (BNFC) and Neofax were used as reference sources. Risk factors for deviations exceeding ±25% of the relevant BNFC dosage recommendation were identified by multivariate logistic regression analysis. RESULTS: In 89 NICUs from 21 countries, 586 antibiotic prescriptions for 342 infants were reported. The twelve most frequently used antibiotics - gentamicin, penicillin G, ampicillin, vancomycin, amikacin, cefotaxime, ceftazidime, meropenem, amoxicillin, metronidazole, teicoplanin and flucloxacillin - covered 92% of systemic prescriptions. Glycopeptide class, GA <32 weeks, 5(th) minute Apgar score <5 and geographical region were associated with deviation from the BNFC dosage recommendation. While the doses of penicillins exceeded recommendations, antibiotics with safety concerns followed (gentamicin) or were dosed below (vancomycin) recommendations. CONCLUSIONS: The current lack of compliance with existing dosing recommendations for neonates needs to be overcome through the conduct of well-designed clinical trials with a limited number of antibiotics to define pharmacokinetics/pharmacodynamics, efficacy and safety in this population and by efficient dissemination of the results.

Adverse drug reactions and off-label and unlicensed medicines in children: a prospective cohort study of unplanned admissions to a paediatric hospital.

AIMS: To examine the impact of off-label and unlicensed (OLUL) prescribing on adverse drug reactions (ADRs) causing unplanned admissions to a paediatric hospital. METHODS: Prescription data from a 12 month prospective cohort study of ADRs detected in children admitted to a paediatric hospital were scrutinized. The relative risk for off-label and unlicensed medicines being implicated in an ADR was calculated. Logistic regression analyses were carried out with exposure to off-label and unlicensed medicines and number of off-label and unlicensed medicines administered as predictor variables. RESULTS: Off-label and unlicensed medicines were more likely to be implicated in an ADR than authorized medicines (relative risk 1.67, 95% CI 1.38, 2.02, P < 0.001). There was a 25% increase in ADR risk (95% CI 1.16, 1.35, P < 0.001) with each additional authorized medicine and 23% (95% CI 1.10, 1.36, P < 0.001) with each additional off-label or unlicensed medicine. Logistic regression analysis focusing on non-oncology patients demonstrated that the number of authorized medicines (odds ratio 1.33, 95% CI 1.23, 1.44, P < 0.001), but not the number of off-label and unlicensed medicine courses, was a predictor of ADR risk. CONCLUSIONS: In a heterogeneous population of children admitted to a secondary/tertiary hospital, off-label and unlicensed medicines are more likely to be implicated in an ADR than authorized medicines. This was largely driven by ADRs related to drugs used in oncological practice, where the usage of off-label or unlicensed medicines was associated with a higher ADR risk than in non-oncological areas.

Adverse drug reactions and off-label and unlicensed medicines in children: a nested case-control study of inpatients in a pediatric hospital.

BACKGROUND: Off-label and unlicensed (OLUL) prescribing has been prevalent in pediatric practice. Using data from a prospective cohort study of adverse drug reactions (ADRs) among pediatric inpatients, we aimed to test the hypothesis that OLUL status is a risk factor for ADRs. METHODS: A nested case?control study was conducted within a prospective cohort study. Details of all medicines administered were recorded, including information about OLUL status. The odds ratio for OLUL medicines being implicated in a probable or definite ADR was calculated. A multivariate Cox proportional hazards regression model was fitted to the data to assess the influence that OLUL medicine use had on the hazard of an ADR occurring. RESULTS: A total of 10,699 medicine courses were administered to 1,388 patients. The odds ratio (OR) of an OLUL medicine being implicated in an ADR compared with an authorized medicine was 2.25 (95% confidence interval (CI) 1.95 to 2.59). Medicines licensed in children but given to a child below the minimum age or weight had the greatest odds of being implicated in an ADR (19% of courses in this category were implicated, OR 3.54 (95% CI 2.82 to 4.44). Each additional OLUL medicine given significantly increased the hazard of an ADR (hazard ratio (HR) 1.3 95% CI 1.2 to 1.3, P <0.001). Each additional authorized medicine given also significantly increased the hazard (HR 1.2 95% CI 1.2 to 1.3, P <0.001). CONCLUSIONS: OLUL medicines are more likely to be implicated in an ADR than authorized medicines. The number of medicines administered is a risk factor for ADRs highlighting the need to use the lowest number of medicines, at the lowest dose for the shortest period, with continual vigilance by prescribers, in order to reduce the risk of ADRs.

Incidence, characteristics and risk factors of adverse drug reactions in hospitalized children - a prospective observational cohort study of 6,601 admissions.

BACKGROUND: Adverse drug reactions (ADRs) are an important cause of harm in children. Current data are incomplete due to methodological differences between studies: only half of all studies provide drug data, incidence rates vary (0.6% to 16.8%) and very few studies provide data on causality, severity and risk factors of pediatric ADRs. We aimed to determine the incidence of ADRs in hospitalized children, to characterize these ADRs in terms of type, drug etiology, causality and severity and to identify risk factors. METHODS: We undertook a year-long, prospective observational cohort study of admissions to a single UK pediatric medical and surgical secondary and tertiary referral center (Alder Hey, Liverpool, UK). Children between 0 and 16 years 11 months old and admitted for more than 48 hours were included. Observed outcomes were occurrence of ADR and time to first ADR for the risk factor analysis. RESULTS: A total of 5,118 children (6,601 admissions) were included, 17.7% of whom experienced at least one ADR. Opiate analgesics and drugs used in general anesthesia (GA) accounted for more than 50% of all drugs implicated in ADRs. Of these ADRs, 0.9% caused permanent harm or required admission to a higher level of care. Children who underwent GA were at more than six times the risk of developing an ADR than children without a GA (hazard ratio (HR) 6.40; 95% confidence interval (CI) 5.30 to 7.70). Other factors increasing the risk of an ADR were increasing age (HR 1.06 for each year; 95% CI 1.04 to 1.07), increasing number of drugs (HR 1.25 for each additional drug; 95% CI 1.22 to 1.28) and oncological treatment (HR 1.90; 95% CI 1.40 to 2.60). CONCLUSIONS: ADRs are common in hospitalized children and children who had undergone a GA had more than six times the risk of developing an ADR. GA agents and opiate analgesics are a significant cause of ADRs and have been underrepresented in previous studies. This is a concern in view of the increasing number of pediatric short-stay surgeries.

What can we learn from parents about enhancing participation in pharmacovigilance?

AIMS: To investigate parents' views and experiences of direct reporting of a suspected ADR in their child. METHODS: We audio-recorded semi-structured qualitative interviews with parents of children with suspected ADRs. Our sample included parents with (n = 17) and without (n = 27) previous experience of submitting a Yellow Card. RESULTS: Parents in both groups described poor awareness of the Yellow Card Scheme. Parents who had participated in the Yellow Card Scheme were generally happy to report their child's ADR via the Scheme and valued the opportunity to report concerns independently of health practitioners. They expressed motivations for reporting that have not previously been described linked to the parental role, including how registering a concern about a medicine helped to resolve uncomfortable feelings about their child's ADR. Parents who had not previously submitted a Yellow Card expressed uncertainty about the legitimacy of their involvement in reporting and doubts about the value of the information that they could provide. CONCLUSION: Promoting wider participation in pharmacovigilance schemes will depend on raising public awareness. Additionally, our findings point to the need to empower lay people to submitting reports and to reassure them about the value of their reports.

Prophylactic ranitidine treatment in critically ill children--a population pharmacokinetic study.

AIMS: To characterize the population pharmacokinetics of ranitidine in critically ill children and to determine the influence of various clinical and demographic factors on its disposition. METHODS: Data were collected prospectively from 78 paediatric patients (n = 248 plasma samples) who received oral or intravenous ranitidine for prophylaxis against stress ulcers, gastrointestinal bleeding or the treatment of gastro-oesophageal reflux. Plasma samples were analysed using high-performance liquid chromatography, and the data were subjected to population pharmacokinetic analysis using nonlinear mixed-effects modelling. RESULTS: A one-compartment model best described the plasma concentration profile, with an exponential structure for interindividual errors and a proportional structure for intra-individual error. After backward stepwise elimination, the final model showed a significant decrease in objective function value (-12.618; P < 0.001) compared with the weight-corrected base model. Final parameter estimates for the population were 32.1 l h(-1) for total clearance and 285 l for volume of distribution, both allometrically modelled for a 70 kg adult. Final estimates for absorption rate constant and bioavailability were 1.31 h(-1) and 27.5%, respectively. No significant relationship was found between age and weight-corrected ranitidine pharmacokinetic parameters in the final model, with the covariate for cardiac failure or surgery being shown to reduce clearance significantly by a factor of 0.46. CONCLUSIONS: Currently, ranitidine dose recommendations are based on children's weights. However, our findings suggest that a dosing scheme that takes into consideration both weight and cardiac failure/surgery would be more appropriate in order to avoid administration of higher or more frequent doses than necessary.

Manipulation of drugs to achieve the required dose is intrinsic to paediatric practice but is not supported by guidelines or evidence.

BACKGROUND: A lack of age-appropriate formulations can make it difficult to administer medicines to children. A manipulation of the dosage form may be required to achieve the required dose. This study aimed to describe medicines that are manipulated to achieve the required dose in paediatric practice. METHOD: A structured, undisguised observational study and postal survey. The observational study investigated drug manipulations occurring in clinical practice across three sites. The questionnaire, administered to a sample of paediatric nurses throughout the UK, surveyed manipulations conducted and nurses' experiences and views. RESULTS: The observational study identified 310 manipulations, of which 62% involved tablets, 21% were intravenous drugs and 10% were sachets. Of the 54 observed manipulations 40 involved tablets with 65% of the tablets being cut and 30% dispersed to obtain a smaller dose. 188 manipulations were reported by questionnaire respondents, of these 46% involved tablets, 12% were intravenous drugs, and 12% were nebuliser solutions. Manipulations were predominantly, but not exclusively, identified in specialist clinical areas with more highly dependent patients. Questionnaire respondents were concerned about the accuracy of the dose achieved following manipulations and the lack of practice guidance. CONCLUSION: Manipulations to achieve the required dose occur throughout paediatric in-patient settings. The impact of manipulations on the efficacy of the drugs, the accuracy of the dose and any adverse effects on patients is not known. There is a need to develop evidence-based guidance for manipulations of medicines in children.

A review of paediatric injectable drug delivery to inform the study of product acceptability - An introduction.

AIM: The EMA defines acceptability as "the overall ability and willingness of the patient to use, and their caregiver to administer, the medicine as intended" [1]. This paper seeks to outline issues of acceptability in relation to injectable therapy, namely intravenous (IV), intramuscular (IM) and subcutaneous (SC) administration routes, and to lay a foundation to identify a minimum set of data that would satisfy Regulatory Authorities when discussing the acceptability of an injectable product. In addition, it will alert drug product developers to other factors that might contribute to good practice, alternative administration strategies and overall adherence to achieve successful treatment. Whilst the term 'parenteral' means "outside the intestine" [2,3] and so potentially covers a range of administration routes including intranasal and percutaneous administration, this review focuses on IV, IM and SC administration by injection. The use of indwelling canulae or catheters to reduce venepuncture and facilitate prolonged treatment is common and may impact acceptability [4]. This may be influenced by information provided by the manufacturer but is not always in their direct control. Other injectable products suitable for routes such as intradermal, intra-articular, intraosseous and intrathecal, share the requirement to be acceptable but are not specifically covered in this paper [2,5].

WHO essential medicines for children 2011-2019: age-appropriateness of enteral formulations.

INTRODUCTION: The WHO Essential Medicine List for children (EMLc) is used for promoting access to medicines. The age-appropriateness of enteral (oral and rectal) formulations for children depend on their adaptability/flexibility to allow age-related or weight-related doses to be administered/prescribed and the child's ability to swallow, as appropriate. There is scant information on the age-appropriateness of essential enteral medicines for children. OBJECTIVE: To evaluate the age-appropriateness of enteral essential medicines. MATERIALS AND METHODS: Age-appropriateness of all enteral formulations indicated and recommended in the EMLc 3rd to 7th (2011-2019) editions were determined by assessing swallowability and/or dose adaptability for children under 12 years, stratified into five age groups. RESULTS: Enteral formulations in the EMLc were more age-appropriate for older children aged 6-11 years than for younger children. In the 3rd edition, for older children, 77%, n=342, of formulations were age-appropriate. For younger children, age-appropriateness decreased with age group: 34% in those aged 3-5 years, 30% in those aged 1-2 years, 22% among those aged 28 days to 11 months and 15% in those aged 0-27 days. Overall, similar proportions were found for the 7th edition. In contrast, the majority of medicines in the 7th list were age-appropriate in targeted diseases like HIV and tuberculosis. CONCLUSION: Most recommended enteral essential medicines in EMLc 2011 and 2019 were not age-appropriate for children <6 years. Medicines which are not age-appropriate must be manipulated before administration, leading to potential issues of safety and efficacy. Evaluation of the age-appropriateness of formulations for medicines to be included in EMLc could improve access to better medicines for children in the future.

Development and evaluation of an assessment of the age-appropriateness/inappropriateness of formulations used in children.

BACKGROUND: Medicines designed for adults may be inappropriate for use in children in terms of strength, dosage form and/or excipient content. There is currently no standardised method of assessing the age-appropriateness of a medicine for paediatric use. AIM: To develop and test a tool to assess whether a dosage form (formulation) is appropriate for children and estimate the proportion of formulations considered 'inappropriate' in a cohort of hospitalised paediatric patients with a chronic illness. METHOD: A multi-phase study: patient data collection, tool development, case assessments and tool validation. Inpatients aged 0-17 years at two UK paediatric/neonatal hospitals during data collection periods between January 2015 and March 2016. Written informed consent/assent was obtained. Medicines assessed were new or regularly prescribed to inpatients as part of their routine clinical care. All medicine administration episodes recorded were assessed using the Age-appropriate Formulation tool. The tool was developed by a consensus approach, as a one-page flowchart. Independent case assessments were evaluated in 2019. RESULTS: In 427 eligible children; 2,199 medicine administration episodes were recorded. Two assessors reviewed 220 episodes in parallel: percentage exact agreement was found to be 91.7% (99/108) and 93.1% (95/102). In total, 259/2,199 (11.8%) medicine administration episodes involved a dosage form categorised as 'age-inappropriate'. CONCLUSION: A novel tool has been developed and internally validated. The tool can identify which medicines would benefit from development of an improved paediatric formulation. It has shown high inter-rater reliability between users. External validation is needed to further assess the tool's utility in different settings.

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.

A Comprehensive List of Items to be Included on a Pediatric Drug Monograph.

OBJECTIVES: Children require special considerations for drug prescribing. Drug information summarized in a formulary containing drug monographs is essential for safe and effective prescribing. Currently, little is known about the information needs of those who prescribe and administer medicines to children. Our primary objective was to identify a list of important and relevant items to be included in a pediatric drug monograph. METHODS: Following the establishment of an expert steering committee and an environmental scan of adult and pediatric formulary monograph items, 46 participants from 25 countries were invited to complete a 2-round Delphi survey. Questions regarding source of prescribing information and importance of items were recorded. An international consensus meeting to vote on and finalize the items list with the steering committee followed. RESULTS: Pediatric formularies are most commonly the first resource consulted for information on medication used in children by 31 Delphi participants. After the Delphi rounds, 116 items were identified to be included in a comprehensive pediatric drug monograph, including general information, adverse drug reactions, dosages, precautions, drug-drug interactions, formulation, and drug properties. CONCLUSIONS: Health care providers identified 116 monograph items as important for prescribing medicines for children by an international consensus-based process. This information will assist in setting standards for the creation of new pediatric drug monographs for international application and for those involved in pediatric formulary development.

Development of the Liverpool Adverse Drug Reaction Avoidability Assessment Tool.

AIM: To develop and test a new tool to assess the avoidability of adverse drug reactions that is suitable for use in paediatrics but which is also applicable to a variety of other settings. METHODS: The study involved multiple phases. Preliminary work involved using the Hallas scale and a modification of the existing Hallas scale, to assess two different sets of adverse drug reaction (ADR) case reports. Phase 1 defined, modified and refined a new tool using multidisciplinary teams. Phase 2 involved the assessment of 50 ADR case reports from a prospective study of paediatric inpatients by individual assessors. Phase 3 compared assessments with the new tool for individuals and groups in comparison to the 'gold standard' (the avoidability outcome set by a panel of senior investigators: an experienced clinical pharmacologist, paediatrician and pharmacist). MAIN OUTCOME MEASURES: Inter-rater reliability (IRR), measure of disagreement and utilization of avoidability categories. RESULTS: Preliminary work-Pilot phase: results for the original Hallas cases were fair and pairwise kappa scores ranged from 0.21 to 0.36. Results for the modified Hallas cases were poor, pairwise kappa scores ranged from 0.06 to 0.16. Phase 1: on initial use of the new tool, agreement between the two multidisciplinary groups was found on 13/20 cases with a kappa score of 0.29 (95% CI -0.04 to 0.62). Phase 2: the assessment of 50 ADR case reports by six individual reviewers yielded pairwise kappa scores ranging from poor to good 0.12 to 0.75 and percentage exact agreement (%EA) ranged from 52-90%. Phase 3: Percentage exact agreement ranged from 35-70%. Overall, individuals had better agreement with the 'gold standard'. CONCLUSION: Avoidability assessment is feasible but needs careful attention to methods. The Liverpool ADR avoidability assessment tool showed mixed IRR. We have developed and validated a method for assessing the avoidability of ADRs that is transparent, more objective than previous methods and that can be used by individuals or groups.

A systematic review of the use of dosage form manipulation to obtain required doses to inform use of manipulation in paediatric practice.

This study sought to determine whether there is an evidence base for drug manipulation to obtain the required dose, a common feature of paediatric clinical practice. A systematic review of the data sources, PubMed, EMBASE, CINAHL, IPA and the Cochrane database of systematic reviews, was used. Studies that considered the dose accuracy of manipulated medicines of any dosage form, evidence of safety or harm, bioavailability, patient experience, tolerability, contamination and comparison of methods of manipulation were included. Case studies and letters were excluded. Fifty studies were eligible for inclusion, 49 of which involved tablets being cut, split, crushed or dispersed. The remaining one study involved the manipulation of suppositories of one drug. No eligible studies concerning manipulation of oral capsules or liquids, rectal enemas, nebuliser solutions, injections or transdermal patches were identified. Twenty four of the tablet studies considered dose accuracy using weight and/or drug content. In studies that considered weight using adapted pharmacopoeial specifications, the percentage of halved tablets meeting these specifications ranged from 30% to 100%. Eighteen studies investigated bioavailability, pharmacokinetics or clinical outcomes following manipulations which included nine delayed or modified release formulations. In each of these nine studies the entirety of the dosage form was administered. Only one of the 18 studies was identified where drugs were manipulated to obtain a proportion of the dosage form, and that proportion administered. The five studies that considered patient perception found that having to manipulate the tablets did not have a negative impact on adherence. Of the 49 studies only two studies reported investigating children. This review yielded limited evidence to support manipulation of medicines for children. The results cannot be extrapolated between dosage forms, methods of manipulation or between different brands of the same drug.

PAEDIATRIC ADVERSE DRUG REACTIONS (ADRS): A COMPARISON OF A NEWLY DEVELOPED AVOIDABILITY TOOL TO EXISTING HALLAS ASSESSMENTS.

AIM: To compare a newly developed avoidability assessment tool (AAT) to existing Hallas assessments1 for a set of paediatric ADR cases. METHOD: The new AAT was employed to assess 249 case reports of ADRs causing admission to hospital. The case reports contained a description of the ADR, details of suspected and concurrent medication and past medical history. Each case report was independently assessed and an avoidability category assigned. For ADRs categorised as either 'possibly' or 'definitely avoidable' a rationale was recorded. A second reviewer independently assessed a purposive sample (10%) for validation and quality assurance purposes.The final outcome was then compared to the Hallas assessments (1) previously completed as part of another study, which was carried out in a consensus group setting. Both tools used categorical scores with the same four point ordinal scale 'definitely avoidable', 'possibly avoidable', 'not avoidable' and 'unassessable'. RESULTS: Assessment of the 249 ADR case reports using the new AAT found that 19.3% were either possibly or definitely avoidable. This figure increased to almost 32% for the non-oncology cases (129/249) and decreased to 5.8% for the oncology cases (120/249). This was similar to the Hallas results (1), where overall, 22% of ADRs were deemed either possibly or definitely avoidable.Percentage exact agreement (%EA) was 90% overall; when subcategorised into oncology and non-oncology cases the %EA was found to be 94.2% and 86% respectively. Percentage extreme disagreement (%ED) was 0.8%. The kappa score was 0.71 (95% CI 0.60-0.82) for all cases, 0.54 (95% CI 0.40-0.68) for the oncology cases and 0.73 (95% CI 0.58-0.88) for the non-oncology cases. In total there were 25/249 cases with disagreement. %EA agreement from the validation check was 72%. CONCLUSION: Assessment with the new AAT showed that approximately 19% of all cases were either possibly or definitely avoidable. This was comparable to the Hallas assessments (1). The sub-categorisation of the analysis into oncology and non-oncology cases showed a change in the number of avoidable cases. The avoidability rate increased to almost 32% for the non-oncology cases and decreased to 5.8% for the oncology cases. The reason for this marked difference may be explained by the nature of the oncology ADRs. The most common oncology reactions were neutropenia, thrombocytopenia and anaemia; these are often expected and largely 'not avoidable' given the benefit risk ratio.The AAT was designed specifically for use in paediatrics following difficulty using other tools including Hallas (1). The AAT refers to guidelines and patient history rather than to abstract concepts such as "present-day knowledge of good medical practice" and "effort exceeding the obligatory demands" as per Hallas (1). Further work to identify potentially avoidable ADRs and strategies to prevent them is needed.

Product Substitution as a Way Forward in Avoiding Potentially Harmful Excipients in Neonates.

OBJECTIVES: Our objectives were to explore the possibility of avoiding neonatal exposure to potentially harmful excipients of interest (EOI)-parabens, polysorbate 80, propylene glycol, benzoates, saccharin sodium, sorbitol and ethanol-through product substitution in Europe. METHODS: We performed a 3-day service evaluation survey and a 1-day point prevalence study in 20 and 21 European countries, respectively. Analysis included active pharmaceutical ingredients (APIs) used in ≥10 % of units. We calculated the potential reduction in number of products with EOI through substitution in three stages: (1) similar API and route of administration, (2) plus similar dosage form and (3) plus similar strength. The reduction of individual exposure was analysed according to the second-stage criteria. RESULTS: We identified 137 products for 25 APIs that contained EOI. Substitution with EOI-free product(s) was available for 88 % (n = 120), 66 % (n = 91) and 31 % (n = 42) of products according to the first-, second- and third-stage criteria, respectively. Overall, 456 (63 % of 726) neonates received products containing EOI. Substitution of the products that had alternatives with similar API and dosage form would reduce the number of exposed neonates from 456 to 257 (44 % reduction). CONCLUSIONS: EOI-free formulations are available for a substantial number of products currently used in European neonates. Replacement of only the most frequently used products may spare almost half of neonates from unnecessary exposure to EOI.

Potentially harmful excipients in neonatal medicines: a pan-European observational study.

OBJECTIVES: We aimed to describe administration of eight potentially harmful excipients of interest (EOI)-parabens, polysorbate 80, propylene glycol, benzoates, saccharin sodium, sorbitol, ethanol and benzalkonium chloride-to hospitalised neonates in Europe and to identify risk factors for exposure. METHODS: All medicines administered to neonates during 1 day with individual prescription and demographic data were registered in a web-based point prevalence study. Excipients were identified from the Summaries of Product Characteristics. Determinants of EOI administration (geographical region, gestational age (GA), active pharmaceutical ingredient, unit level and hospital teaching status) were identified using multivariable logistical regression analysis. RESULTS: Overall 89 neonatal units from 21 countries participated. Altogether 2095 prescriptions for 530 products administered to 726 neonates were recorded. EOI were found in 638 (31%) prescriptions and were administered to 456 (63%) neonates through a relatively small number of products (n=142; 27%). Parabens, found in 71 (13%) products administered to 313 (43%) neonates, were used most frequently. EOI administration varied by geographical region, GA and route of administration. Geographical region remained a significant determinant of the use of parabens, polysorbate 80, propylene glycol and saccharin sodium after adjustment for the potential covariates including anatomical therapeutic chemical class of the active ingredient. CONCLUSIONS: European neonates receive a number of potentially harmful pharmaceutical excipients. Regional differences in EOI administration suggest that EOI-free products are available and provide the potential for substitution to avoid side effects of some excipients.

Clinical coding of prospectively identified paediatric adverse drug reactions--a retrospective review of patient records.

BACKGROUND: National Health Service (NHS) hospitals in the UK use a system of coding for patient episodes. The coding system used is the International Classification of Disease (ICD-10). There are ICD-10 codes which may be associated with adverse drug reactions (ADRs) and there is a possibility of using these codes for ADR surveillance. This study aimed to determine whether ADRs prospectively identified in children admitted to a paediatric hospital were coded appropriately using ICD-10. METHODS: The electronic admission abstract for each patient with at least one ADR was reviewed. A record was made of whether the ADR(s) had been coded using ICD-10. RESULTS: Of 241 ADRs, 76 (31.5%) were coded using at least one ICD-10 ADR code. Of the oncology ADRs, 70/115 (61%) were coded using an ICD-10 ADR code compared with 6/126 (4.8%) non-oncology ADRs (difference in proportions 56%, 95% CI 46.2% to 65.8%; p < 0.001). CONCLUSIONS: The majority of ADRs detected in a prospective study at a paediatric centre would not have been identified if the study had relied on ICD-10 codes as a single means of detection. Data derived from administrative healthcare databases are not reliable for identifying ADRs by themselves, but may complement other methods of detection.