Considerable paediatric drug dispensing - A nationwide study of more than 2 million Swedish children.

AIM: The aim of the nationwide study was to describe paediatric drug utilisation in Sweden. METHODS: Drug prescriptions dispensed to all children aged 0-17 years in 2019 were analysed using data from the Swedish National Prescribed Drug Register. RESULTS: We retrieved data on 2 180 508 unique children. Nearly 4.6 million prescriptions were dispensed to children aged 0-17 years, and 52% of these were to boys. Just under half of the children (47%) were dispensed at least one drug: 48% of girls and 45% of boys (p < 0.01). More than a third (34%) were dispensed three or more different drugs during 2019. The number of dispensed prescriptions per 1000 children was higher in boys than girls up to 12 years of age (p < 0.01), and the opposite trend was observed from 13 years and above, even when we excluded contraceptives (p < 0.01). The most common therapeutic areas were drugs for the respiratory tract (25%), namely antihistamines, antiasthmatics and cough medication. These were followed by psychoanaleptics and melatonin for the nervous system (19%) and dermatologicals (16%), namely cortisone creams and emollients. CONCLUSION: Paediatric drug use was common, and a considerable proportion of children were dispensed multiple drugs.

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.

Defined daily doses in pediatric dosing- a theoretical example.

A defined daily dose for children (cDDD) taking body weight into account, was proposed as a better measure of drug utilization in children than the World Health Organization's DDD. There is no global definition of DDDs for children, and it is unclear which standard doses should be used for children when conducting drug utilization studies. We used doses according to the authorized medical product information and body weight according to national pediatric growth curves to calculate theoretical cDDD for three common medicines in children in a Swedish setting. These examples demonstrate that the concept of cDDD may not be optimal for drug utilization studies in children, especially not for younger children and when dosing is done according to weight is crucial. Validation of cDDD in real-world data is warranted. When conducting pediatric drug utilization studies, accessibility to individual-level data on body weight and age combined with dosing information is needed.

Pediatric use of prescribed melatonin in Sweden 2006-2017: a register based study.

Sleep disturbances are common in the pediatric population and should primarily be treated non-pharmacologically. Most medicines for sleep disturbances are not approved for pediatric use and data on long-term safety is scarce. In Sweden, melatonin is classified as a prescription medicine. The aim of the present study was to characterize the prevalence and incidence of dispensed melatonin prescriptions, long-term treatment, concomitant dispensation of psychotropic medication, and psychiatric comorbidity, in children and adolescents aged 0-17 years living in Sweden during 2006-2017. Data was retrieved by linking the national population-based registers, the Swedish Prescribed Drug register and the National Patient register. In 2017, nearly 2% of the pediatric population 0-17 years was dispensed at least one prescription of melatonin, which was more than a 15-fold increase for girls and a 20-fold increase for boys, when compared to 2006. Among the children in the age group 5-9 who initiated a melatonin treatment in 2009, 15% of girls and 17% of boys were found to be continuously prescribed melatonin 8 years later. Nearly 80% of all children with dispensed melatonin had concomitant dispensations of psychotropic medications. The most common combination was melatonin together with centrally acting sympathomimetic medicines (23% of girls and 43% of boys). About half of the children (47% of girls and 50% of boys) had at least one registered diagnosis of mental or behavioral disorders. The most common diagnosis was attention deficit hyperactive disorder, across all age groups and genders. The continuous increase of use of melatonin in children, often concomitant with other psychotropic medications, together with a high proportion of younger children with prescriptions of melatonin on a long-term basis, suggests the need for further structured follow up studies, in particular of long-term use.

Evidence-based anti-seizure monotherapy in newly diagnosed epilepsy: A new approach.

OBJECTIVES: To describe the process and results of the updated Swedish practice guidelines for monotherapy in epilepsy. MATERIALS AND METHODS: The Swedish Medical Products Agency led the process together with medical experts. Evidence rating in accordance with the International League Against Epilepsy (ILAE) template was linked to the Cochrane group's GRADE system. Evidence from recently published trials and meta-analyses was added. A national expert panel participated in the project and contributed their clinical experience. RESULTS: In seizures with focal onset, carbamazepine, lamotrigine, or levetiracetam is recommended for children and adults (ILAE level A-C for adults/Cochrane level strong for children and adults). Oxcarbazepine is an alternative for children, although its level A evidence, in a single class I trial, could relate to poor phenytoin tolerability. Eslicarbazepine acetate, lacosamide, and zonisamide are alternatives for adults and gabapentin for the elderly (ILAE level A). Carbamazepine is not a first choice for the elderly due to its high potential for interactions. In generalized epilepsy with tonic-clonic seizures (GTC), lamotrigine, levetiracetam, and sodium valproate are recommended for children and adults (ILAE level C-D/Cochrane level moderate-strong) although sodium valproate is contraindicated in girls and women of childbearing age unless special considerations are met. Ethosuximide is the first choice in absence epilepsy without GTC (ILAE level A). CONCLUSIONS: Lamotrigine and levetiracetam can be used as first choice for focal seizures and generalized epilepsy with GTC, suitable in all age-groups and for both men and women. Recommendations for GTC seizures have lower evidence than those for focal seizures.

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.

Prevalence of potential drug-drug interactions in Swedish pediatric outpatients.

PURPOSE: To describe the occurrence of potential drug-drug interactions (DDIs) in prescribed drugs, dispensed to pediatric outpatients in Sweden. METHODS: A cross sectional study was conducted based on data from a national register of prescribed drugs, dispensed at pharmacies, to children 0-17 years old. The study period was January 1 to April 30, 2010. Drug dispensing data was linked to the DDI database SFINX. Prevalence and frequencies of potential interactions were investigated, and drugs commonly involved in interactions were identified. The study focused on clinically relevant potential interactions, class D (should be avoided), and class C (can be handled, e.g. by dose adjustment). RESULTS: In the Swedish pediatric population, 0 to 17 years of age, 12% (n = 231 078) of children had at least two dispensed drugs. In this group of patients, 0.14% had potential D-interactions and 1,3% had potential C-interactions. The number of D- and C-interactions that may lead to reduced effects were 181 (52%), and 1224 (32%) respectively. The ten most frequent drugs were involved in 78% and 65% of all potential D-, and C-interactions respectively. Furthermore, 80%, and 58% of the D-, and C-interactions respectively occurred in patients aged 12 to 17. CONCLUSIONS: We identified a limited number of drugs that were represented in the majority of potential interactions. Interactions that can lead to a reduced treatment effect constituted approximately half of D-interactions, and a third of C-interactions. The frequency of potential interactions was higher in older children. The results may contribute to increased prescriber awareness of important potential drug interactions among pediatric outpatients.

Children's views on taking medicines and participating in clinical trials.

INTRODUCTION: Limited information is available on the views of children taking medicines and participating in clinical trials. These views may contribute to a better understanding of what can be improved on in the development of medicines from their perspective. OBJECTIVE: To collect children's views on taking medicines and participating in clinical trials. MATERIALS AND METHODS: A question-based survey was conducted among children living in European Union countries between January and August 2015. RESULTS: Almost 900 children aged 10-17 years from Finland, Germany, Sweden, Spain and Hungary responded. Almost 40% had a chronic health condition. The most commonly used pharmaceutical forms were solid or liquid medicines for oral use and injectable medicines. Bad taste and pain during administration were reported as common problems. Of 785 respondents, 17% had been taking part in a clinical trial. Most respondents would potentially agree to take part in a clinical trial because the investigational medicine might improve their own health or that of other children. Concern that the investigational medicine might be harmful was the main reason to refuse participation, if asked to. Over half of the respondents were willing to learn more about clinical trials, preferably online. CONCLUSIONS: It is necessary to involve children in the development of age-appropriate pharmaceutical forms and in the design of clinical trials. Children and their carers should be provided with age-appropriate medical information in the most suitable channels. We have identified some common problems that children experience when taking medicines, and we conclude that children are interested in learning more and giving their opinions on clinical trials.

Recent drug history in children visiting a pediatric emergency room and documentation in medical records.

AIMS: We performed a systematic analysis of which drugs, prescribed, over the counter (OTC), and/or natural remedies, children had used prior to visiting a pediatric emergency room (ER), and to compare this information with the documentation of drug use in the medical records. METHODS: A questionnaire study was performed at a pediatric ER in a Swedish university hospital during 3 weeks in April 2008. The questionnaire was validated through an interview with a subgroup of participants. Only drug use associated with the time of that hospital visit was requested. Information was compared with information in medical records related to the same visit. RESULTS: Two hundred and seventy-four children aged 0-18 (median 2) years were enrolled, representing 28% of the total number of patients visiting the ER within the time frame. Forty% (n = 109) of participants reported use of prescribed drugs, 65% (n = 172) OTC drugs, and 8% (n = 17) natural remedies prior to the ER visit. The most common drugs in the three groups were salbutamol, paracetamol, and omega fatty acids, respectively. In the medical records, no more than 50% of the reported drug intake could be found, representing 74% of prescribed drugs but only 34% of OTC drugs and 27% of natural remedies. CONCLUSIONS: The majority of children had used drugs, both prescribed and OTC, before coming to the ER , but this drug intake, and especially that of nonprescribed drugs, was often not documented in the medical records.

Over-the-counter drug use--estimations within the Swedish paediatric population.

We have used three different sources to estimate the use of drugs sold over the counter (OTC) by the Swedish paediatric population during 2007-2008 as part of a European evaluation initiated by the European Medicines Agency. An estimation of the paediatric use from the total numbers of over-the-counter drugs (OTCD) packages sold by Swedish pharmacies and analyses of two separate questionnaires directed towards a population of 11- to 14-year-old children and another towards visitors to one of the paediatric emergency wards in Stockholm County were included in the study. In Sweden, 1.25 OTC packages are sold quarterly per child (0-18 years), and the children in both questionnaire studies use, on average, 0.9 OTC substances. Sixty-five percent of the children visiting an emergency ward and 67% of the 13-year-old Stockholm inhabitants had used at least one OTCD. OTCD use among children is common. Interpretation of OTCD data must be done carefully since questions with regard to OTCD use is subject to recall bias and the number of packages sold to children is hypothesised through a conversion factor.

Drug related problems and off-label drug treatment in children as seen at a drug information centre.

The aim of this work was to analyse the characteristics of Questions and Answers (Q&As) at a drug information centre (DIC) regarding drug related problems and off-label drug treatment in children. All questions concerning children 15 years or younger at a DIC in Stockholm, Sweden during the years 1995-2004 were analysed with respect to the main drug related problem, drug/s and drug group/s, whether the drugs were licensed or not, pediatric labelling of the drug/s and age and sex of the patient. Q&As were classified as whether or not they included evaluated literature information, adding to the labelling of the drugs. We identified 249 Q&As concerning pediatric drug treatment. Each question addressed an average of 1.5 drugs. More than two-thirds of the Q&As concerned adverse drug reactions and pediatric drug choice or dosing. Every second question was classified as off-label, psychotropic drugs being the most common. In half of all off-label Q&As, pediatric documentation on drug efficacy and safety outside the Swedish catalogue of medical products was found. Most Q&As concerned newborns and infants. However, the off-label proportion among questions was highest in adolescence as well as the evaluated literature information, adding to the labelling of the drugs. It was thus found that off-label drug treatment is common among pediatric questions at a DIC. This service can provide additional literature based information contributing to a safer use of drugs in children. There is still, however, a substantial need for clinical documentation of drug use in children.

Paediatric adverse drug reactions reported in Sweden from 1987 to 2001.

PURPOSE: To describe frequency, seriousness and recovery of the patient in reported suspected paediatric adverse drug reactions (ADRs) in Sweden using data from a nation-wide ADR reporting system. METHODS: Data from ADR reports submitted to the Swedish Medical Products Agency (MPA) were collected from the database SWEDIS and analysed for the period from 1987 to 2001. All reports with certain, probable or possible causality assessments referring to paediatric patients < 16 years of age were included. RESULTS: In 5771 children an ADR report was documented during the whole 15-year period in a paediatric population of about 1.7 million individuals. The annual reporting frequency was about 385 reports per year. The most frequently reported reactions were application site reaction (24%) followed by fever (12%) and exanthema (6.7%). The clearly most frequently reported group of drugs were the vaccines (63.8%) followed by antibiotics for systemic use (10.1%). The proportion of children that suffered from a serious ADR was 13.0% and that for drug related deaths 0.14%. Nine per cent of the children had not recovered at the time of reporting and 1% recovered with sequelae. A male overrepresentation was observed regarding the total number of reports. About two-third of the reports concerned outpatients less than 4 years of age. CONCLUSIONS: In respect of the limited number of paediatric drug safety studies or availability of record-linkage databases, nation-wide reporting systems of ADRs represent a valuable hypothesis generating tool in evaluating the characteristics of ADRs occurring in the orphan paediatric population.

Adverse drug reactions and off-label prescribing for paediatric outpatients: a one-year survey of spontaneous reports in Sweden.

PURPOSE: To investigate the extent and characteristics of off-label prescribing for paediatric outpatients among drugs reported to have caused an adverse reaction. METHODS: A retrospective, cross-sectional, observational analysis of spontaneous adverse drug reaction (ADR) reports in Sweden in the year 2000. We included all reports concerning drugs prescribed for outpatients younger than 16 years. Each ADR was classified with respect to its causality, seriousness and type of reaction. Off-label prescribing was evaluated with respect to age, dose, indication, formulation and route and frequency of administration. RESULTS: We identified 112 patient-linked reports corresponding to 158 ADRs of which 31% were serious. Antiasthmatic drugs were most frequently suspected as a cause of almost every third adverse reaction. The average proportion of off-label drug prescribing amounted to 42.4%. It was more frequently associated with serious than non-serious ADRs and mostly due to a non-approved age or dose. The most common clinical manifestations were psychiatric disorders and mucocutaneous inflammatory reactions. CONCLUSIONS: Off-label prescribing for paediatric outpatients is common among drugs reported to have caused an ADR. It is suggested to further identify unlabelled drugs frequently contributing to, in particular serious ADRs in children for a proper benefit-risk assessment of off-label drug use.

[An unusual case of a side effect. Cefotaxime-induced confusion in a patient with renal failure]. / Ovanligt fall av läkemedelsbiverkan. Cefotaximutlöst konfusion hos patient med njursvikt.

Third-generation cephalosporins in general have few adverse effects and cefotaxime (Claforan) particularly is considered to be a good choice because of the favourable side effect profile. In patients with severe renal failure there have been reports of confusion and psychosis. The manufacturer therefore recommends that half the ordinary dose should be given to patients with severe renal failure. Half the ordinary dose can still be too much. We describe a patient in hemodialysis who reacted with a reversible encephalopathy with psychosis in spite of reduced doses of cefotaxime. The plasma concentration of cefotaxime was high and the reaction was diagnosed as a dose dependent side effect.

Widespread off-label prescribing of topical but not systemic drugs for 350,000 paediatric outpatients in Stockholm.

OBJECTIVES: Many hospital-based studies throughout Europe have shown that a substantial number of children receive off-label prescribed drugs that lack marketing authorisation for paediatric use. Since information about the extent and characteristics of this prescribing pattern in paediatric primary health care is limited, we assessed the proportion of off-label drug prescribing for paediatric outpatients in a reference population of 350,000 children using a computerised prescription database. We also determined the adherence to a treatment guideline provided by the Stockholm county council as a quality of prescribing indicator. METHODS: All drugs prescribed for children younger than 16 years of age in the Stockholm county in the year 2000 were ranked by the number of prescription items. The retrospective, descriptive analysis was restricted to those drugs that accounted for 90% of total prescribing. We calculated the proportion of off-label drug prescribing for different age and therapeutic groups with respect to age, formulation and route of administration using the Swedish Physician's Desk Reference. The quality of prescribing was estimated as the proportion of prescription items corresponding to recommended drugs in the local treatment guideline Kloka Listan (The Wise List). RESULTS: Among the 317 drugs accounting for 90% of total prescribing, 575,526 prescription items were identified with an average proportion of off-label and recommended drug prescribing of 20.7% and 60.5%, respectively. The off-label proportion was similar in various age groups but widely different between therapeutic groups being much higher for topical (70.4%) than for systemic (5.4%) drugs. The extent to which recommended drugs were prescribed also greatly varied between therapeutic groups irrespectively of the off-label proportion. CONCLUSIONS: Off-label drug prescribing for paediatric outpatients is a common phenomenon. However, it mainly applied to topical drugs and was to a substantial extent recommended by the local treatment guideline. Thus, off-label prescribing might represent a more administrative rather than clinical problem in the paediatric outpatient setting.