Sharon Conroy

Survey of unlicensed and off label drug use in paediatric wards in European countries

Abstract Objective: To determine the extent of use of unlicensed and off label drugs in children in hospital in five European countries. Design: Prospective study of drugs administered to children in general paediatric medical wards over four weeks. Setting: Childrens wards in five hospitals (one each in the United Kingdom, Sweden, Germany, Italy, and the Netherlands). Subjects: Children aged 4 days to 16 years admitted to general paediatric medical wards. Main outcome measure: Proportion of drugs that were used in an unlicensed or off label manner. Results: 2262 drug prescriptions were administered to 624 children in the five hospitals. Almost half of all drug prescriptions (1036; 46%) were either unlicensed or off label. Of these 1036, 872 were off label and 164 were unlicensed. Over half of the patients (421; 67%) received an unlicensed or off label drug prescription. Conclusions: Use of off label or unlicensed drugs to treat children is widespread. This problem is likely to affect children throughout Europe and requires European action. Key messages Many drugs are not tested in children, which means that they are not specifically licensed for use in children Licensed drugs are often prescribed outside the terms of the product license (off label) in relation to age, indication, dose of frequency, route of administration, or formulation Over two thirds (67%) of 624 children admitted to wards in five European hospitals received drugs prescribed in an unlicensed or off label manner 39% of the 2262 drug prescriptions given to children were off label The problem of off label and unlicensed drug prescribing in children is a European problem that requires European action

Unlicensed and Off-Label Drug Use in Children

A significant number of children receive either an unlicensed or an off-label drug during their stay in hospital. Studies throughout Europe have shown that at least one-third of children in hospital and up to 90% of neonates in a neonatal intensive care unit receive such drug prescriptions. The medicines that are most frequently used off-label include analgesics, antibiotics and bronchodilators. The purpose of licensing a drug is to ensure safety, efficacy and quality. If a drug is used in a different manner, one would expect a greater risk of toxicity. Only three studies have commented on the risk of toxicity in relation to unlicensed or off-label drug use. Only one of these three studies prospectively tried to evaluate the risk associated with off-label and unlicensed drug prescription. This study suggested that the percentage of unlicensed and off-label drug use was significantly associated with the risk of an adverse drug reaction. Two studies looking at adverse drug reactions suggest that there is a greater risk of a severe adverse drug reaction occurring in association with the off-label or unlicensed use of drugs. One study found that five out of eight severe adverse drug reactions were associated with the off-label use of a medicine. The other study found that 14 of 19 drug prescriptions associated with 17 severe adverse drug reactions were either unlicensed or off-label. The risk of prescribing off-label and unlicensed drugs in children is not clear from the limited data available.

Interventions to reduce dosing errors in children: a systematic review of the literature.

Children are a particularly challenging group of patients when trying to ensure the safe use of medicines. The increased need for calculations, dilutions and manipulations of paediatric medicines, together with a need to dose on an individual patient basis using age, gestational age, weight and surface area, means that they are more prone to medication errors at each stage of the medicines management process. It is already known that dose calculation errors are the most common type of medication error in neonatal and paediatric patients. Interventions to reduce the risk of dose calculation errors are therefore urgently needed. A systematic literature review was conducted to identify published articles reporting interventions; 28 studies were found to be relevant. The main interventions foundwere computerised physician order entry (CPOE) and computer-aided prescribing. Most CPOE and computer-aided prescribing studies showed some degree of reduction in medication errors, with some claiming no errors occurring after implementation of the intervention. However, one study showed a significant increase in mortality after the implementation of CPOE. Further research is needed to investigate outcomes such as mortality and economics. Unit dose dispensing systems and educational/risk management programmes were also shown to reduce medication errors in children. Although it is suggested that ‘smart’ intravenous pumps can potentially reduce infusion errors in children, there is insufficient information to draw a conclusion because of a lack of research. Most interventions identified were US based, and since medicine management processes are currently different in different countries, there is a need to interpret the information carefully when considering implementing interventions elsewhere.

Interventions to Reduce Dosing Errors in Children

Children are a particularly challenging group of patients when trying to ensure the safe use of medicines. The increased need for calculations, dilutions and manipulations of paediatric medicines, together with a need to dose on an individual patient basis using age, gestational age, weight and surface area, means that they are more prone to medication errors at each stage of the medicines management process. It is already known that dose calculation errors are the most common type of medication error in neonatal and paediatric patients. Interventions to reduce the risk of dose calculation errors are therefore urgently needed. A systematic literature review was conducted to identify published articles reporting interventions; 28 studies were found to be relevant. The main interventions foundwere computerised physician order entry (CPOE) and computer-aided prescribing. Most CPOE and computer-aided prescribing studies showed some degree of reduction in medication errors, with some claiming no errors occurring after implementation of the intervention. However, one study showed a significant increase in mortality after the implementation of CPOE. Further research is needed to investigate outcomes such as mortality and economics. Unit dose dispensing systems and educational/risk management programmes were also shown to reduce medication errors in children. Although it is suggested that ‘smart’ intravenous pumps can potentially reduce infusion errors in children, there is insufficient information to draw a conclusion because of a lack of research. Most interventions identified were US based, and since medicine management processes are currently different in different countries, there is a need to interpret the information carefully when considering implementing interventions elsewhere.

Unlicensed and off-label drug use: issues and recommendations.

Most adult patients would expect to receive only medicines which have been shown to be well tolerated, effective, and of a high quality. The licensing process to which most drugs are subjected gives the best assurance available that these criteria are met. However, every day, children are required to take medicines which are either not licensed, or are being used outside the terms of their license. Consequently, we cannot be sure that they meet the high standards we require for adult patients. This situation exists wherever children are treated across the world, and when they are in hospital or treated at home. The drugs involved are not obscure; they are routinely used drugs, and many are the mainstay of pediatric therapeutics.The terms ‘unlicensed’ and ‘off-label’ should not be taken to imply disapproval, nor incorrect or improper use of drugs, as such prescribing is a vital part of everyday pediatric drug therapy. It is essential because the gold-standard randomized clinical trials supporting adult medicine are often unavailable for children’s treatments. Adequate information is not available to ensure that children have timely access to well tolerated and effective medicines with accurate, scientifically justified prescribing information. Many problems arise from this situation, including the lack of availability of appropriate pediatric drug formulations, poor prescribing information, and increased risk of medication errors and unanticipated adverse drug reactions. This situation is unacceptable.The US has taken the lead to change this situation by providing legislation and incentives to the pharmaceutical industry to perform pediatric clinical trials. Funding has been provided to set up research facilities where trials can be conducted by experienced pediatric investigators using imaginative, innovative, and noninvasive testing methods. The rest of the world should learn from these experiences and follow this lead to ensure that children have the same rights as adults to well tolerated and effective medicines.

Unlicensed and off label analgesic use in paediatric pain management

Background: The management of pain in children has advanced enormously in recent years. Pharmacological treatment of pain is complicated however, by the widespread use of unlicensed and off label medicines in the paediatric population, leading to everyday practical problems. This study aimed to document the incidence and nature of unlicensed and off label analgesic agents in children.

Double checking the administration of medicines: what is the evidence? A systematic review

Objective To evaluate the evidence for double checking the administration of medicines. Design A systematic search of six electronic databases—Embase, Medline, British Nursing Index and Archive, CINAHL, National electronic library for Medicines (NeLM) and PsycINFO—for all articles describing double checking of medication and dose calculation, for either dispensing or administration in both adults and children up to and including October 2010. Results Sixteen articles met the inclusion criteria. There were only three quantitative studies. Only one of these was a randomised controlled clinical trial in a clinical setting. This study showed a statistically significant reduction in the medication error rate from 2.98 (95% CI 2.45 to 3.51) to 2.12 (95% CI 1.69 to 2.55) per 1000 medications administered with double checking. One study reported a reduction in dispensing errors, by a hospital pharmacy, from 9.8 to 6 per year following the introduction of double checking. The majority of the studies were qualitative and involved interviews, focus groups and questionnaires. Conclusion There is insufficient evidence to either support or refute the practice of double checking the administration of medicines. Clinical trials are needed to establish whether double checking medicines are effective in reducing medication errors.

Association between licence status and medication errors

Background and aims Unlicensed and off label drug use in children is common and leads to well-recognised problems. This study aimed to determine whether a relationship exists between medication errors and licence status. Methods Reports of errors in a UK childrens hospital from 2004 to 2006 were analysed in terms of licence status and degree of harm and compared to the incidence of unlicensed and off label drug use in the hospital. Results 20 of 158 (13%) errors were considered to have caused moderate harm and 12 of these involved unlicensed/off label drugs. 138 (87%) caused no or low harm. None caused severe harm. Unlicensed drug usage was significantly more likely to be associated with errors than licensed use in both children and neonates. Conclusion Unlicensed drug use appears to be associated with medication errors in neonates and children. Medication errors causing moderate harm were significantly more likely to be associated with both unlicensed and off label than licensed drugs.

Educational interventions to reduce prescribing errors.

Objective: Little is known about teaching paediatricians to prescribe or about assessing their competency. This study aimed to identify educational interventions to reduce dose calculation errors. Design: Literature review, a questionnaire survey of paediatric healthcare professionals, observation and interviews were performed. Results: Literature review identified one paper describing an in-service test for medical trainees. 319/559 questionnaires were returned (57%). 34 mentioned educational interventions, 15 centres provided further information on teaching and assessment methods and 13 provided presentations, usually at doctors’ induction. Many interventions had a similar format, including describing differences from adult prescribing, common errors and how to calculate doses. Paediatric clinical pharmacists play a significant role in delivering training and competency assessment. Conclusion: Teaching of paediatric prescribing takes place mostly in the format of lectures during doctors’ induction. Few centres assess competency and no validated tool exists. There has been little evaluation of the impact of teaching on competency to prescribe.

How do we ensure safe prescribing for children

Between January 2005 and June 2006 almost 10 000 medication safety incidents related to prescribing were reported to the UK National Patient Safety Agency, and over 80% of these occurred in hospitals.1 Children aged up to 4 years were involved in more than 10% of all incidents where age was stated, higher than the proportion of bed days they account for. This is likely to be an underestimate as it relies on a voluntary reporting scheme. However, the reluctance to report errors in the NHS is gradually changing as it is increasingly recognised that systems, not individuals, are usually to blame. There has recently been debate in the medical press about the competency of medical professionals to prescribe. Aronson et al 2 highlighted the fact that medical students and junior doctors may be unprepared for prescribing drugs when they qualify. Subsequent intense discussion led to a review by the General Medical Council (GMC) Education Committee of UK teaching and assessment of prescribing. This has prompted plans for research into the prevalence and causes of prescribing errors and recommendations about educational or ethical interventions to reduce them (see http://www.gmc-uk.org/education/documents/pap\_prescribingITT\_v1.0.pdf). A core curriculum for teaching safe and effective prescribing in UK medical schools has been described.3 This mentions children in two sections: However, further detail is not provided in either section. Children are not small adults when it comes to either drug development or prescribing. The availability of information to support paediatric prescribing practice has improved in recent years with moves from the use of a plethora of paediatric formularies and dose guides based on local practice, to the …