Imti Choonara

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

Adverse drug reactions to unlicensed and off‐label drugs on paediatric wards: a prospective study

To determine the incidence of adverse drug reactions (ADRs) to unlicensed and off‐label drugs used in paediatric inpatients, we carried out prospective surveillance on five different paediatric wards in a regional childrens hospital for 13 wk. Comparison of the use of each drug with its summary of product characteristics was made to determine whether the drug was used in an unlicensed or off‐label manner. The presence of an ADR was determined using previously defined criteria. In total, 4455 courses of drugs were administered to 936 patients in 1046 admissions. In 507 (48%) of the 1046 admissions, patients received one or more unlicensed or off‐label drugs. ADRs occurred in 116 (11%) of the 1046 patient admissions. ADRs were associated with 112 (3.9%) of the 2881 licensed drug prescriptions and 95 (6%) of the 1574 unlicensed or off‐label drug prescriptions. Use of drugs in an off‐label or unlicensed manner to treat children is widespread. ADRs are a significant problem following unlicensed or off‐label drug prescriptions. □Adverse drug reactions, children, off‐label, unlicensed

Safety and efficacy of buccal midazolam versus rectal diazepam for emergency treatment of seizures in children: a randomised controlled trial

BACKGROUND Rectal diazepam and buccal midazolam are used for emergency treatment of acute febrile and afebrile (epileptic) seizures in children. We aimed to compare the safety and efficacy of these drugs. METHODS A multicentre, randomised controlled trial was undertaken to compare buccal midazolam with rectal diazepam for emergency-room treatment of children aged 6 months and older presenting to hospital with active seizures and without intravenous access. The dose varied according to age from 2.5 to 10 mg. The primary endpoint was therapeutic success: cessation of seizures within 10 min and for at least 1 hour, without respiratory depression requiring intervention. Analysis was per protocol. FINDINGS Consent was obtained for 219 separate episodes involving 177 patients, who had a median age of 3 years (IQR 1-5) at initial episode. Therapeutic success was 56% (61 of 109) for buccal midazolam and 27% (30 of 110) for rectal diazepam (percentage difference 29%, 95% CI 16-41). Analysing only initial episodes revealed a similar result. The rate of respiratory depression did not differ between groups. When centre, age, known diagnosis of epilepsy, use of antiepileptic drugs, prior treatment, and length of seizure before treatment were adjusted for with logistic regression, buccal midazolam was more effective than rectal diazepam. INTERPRETATION Buccal midazolam was more effective than rectal diazepam for children presenting to hospital with acute seizures and was not associated with an increased incidence of respiratory depression.

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.

The treatment of convulsive status epilepticus in children

There is currently little agreement between hospital protocols when treating convulsive status epilepticus in children, and a working party has been set up to produce a national evidence based guideline for treating this condition. This four step guideline is presented in this paper. Its effectiveness will be highlighted and its use audited in a number of centres.

Substandard and counterfeit medicines: a systematic review of the literature

Objective To explore the evidence available of poor-quality (counterfeit and substandard) medicines in the literature. Design Systematic review. Data sources Databases used were EMBASE, MEDLINE, PubMed and the International Pharmaceutical Abstracts, including articles published till January 2013. Eligibility criteria Prevalence studies containing original data. WHO definitions (1992) used for counterfeit and substandard medicines. Study appraisal and synthesis Two reviewers independently scored study methodology against recommendations from the MEDQUARG Checklist. Studies were classified according to the World Bank classification of countries by income. Data extraction Data extracted: place of study; type of drugs sampled; sample size; percentage of substandard/counterfeit medicines; formulations included; origin of the drugs; chemical analysis and stated issues of counterfeit/substandard medicines. Results 44 prevalence studies were identified, 15 had good methodological quality. They were conducted in 25 different countries; the majority were in low-income countries (11) and/or lower middle-income countries (10). The median prevalence of substandard/counterfeit medicines was 28.5% (range 11–48%). Only two studies differentiated between substandard and counterfeit medicines. Prevalence data were limited to antimicrobial drugs (all 15 studies). 13 studies involved antimalarials, 6 antibiotics and 2 other medications. The majority of studies (93%) contained samples with inadequate amounts of active ingredients. The prevalence of substandard/counterfeit antimicrobials was significantly higher when purchased from unlicensed outlets (p<0.000; 95% CI 0.21 to 0.32). No individual data about the prevalence in upper middle-income countries and high-income countries were available. Limitations Studies with strong methodology were few. The majority did not differentiate between substandard and counterfeit medicines. Most studies assessed only a single therapeutic class of antimicrobials. Conclusions The prevalence of poor-quality antimicrobial medicines is widespread throughout Africa and Asia in lower income countries and lower middle-income countries . The main problem identified was inadequate amounts of the active ingredients.

Surveillance for fatal suspected adverse drug reactions in the UK

Aim: To determine the nature and number of suspected adverse drug reactions (ADRs) associated with fatal outcomes in children reported through the yellow card scheme. Methods: All reports of suspected ADRs with a fatal outcome in children received by the UK Committee on Safety of Medicines through its Yellow Card Scheme from 1964 until December 2000 were reviewed. Reports associated with vaccines and overdose were excluded. The medicine, date of the report, diagnosis, ADR, and the age of the child were analysed. No formal causality assessment was performed. Results: There were 331 deaths with 390 suspected medicines reported for children aged 16 years or less. Medicines most frequently mentioned were anticonvulsants (65 deaths), cytotoxics (34 deaths), anaesthetic agents (30 deaths), and antibiotics (29 deaths). The individual drug most frequently mentioned was sodium valproate (31 deaths). The nature of the reported ADRs were diverse, with hepatic failure the most frequent. In the past decade, there has been an increase in both the total number of suspected ADRs reported in children and the number of reports with a fatal outcome. Conclusions: A wide range of suspected ADRs are associated with fatalities in children. Anticonvulsants were associated with the greatest number of reports of fatalities and hepatotoxicity in particular.

A prospective study of the adverse effects of midazolam on withdrawal in critically ill children

Fifty‐three critically ill infants and children received midazolam as sedation in a regional intensive care unit. Assessment of the level of sedation was carried out at regular intervals on withdrawal of midazolam. Forty‐nine patients were fully alert within 4 h of midazolam being stopped. Four patients took from 6 h to 1 week to become fully alert. Four patients had abnormal behaviour highly suggestive of midazolam withdrawal. The onset of abnormal behaviour was within 12 h of discontinuation of midazolam. The duration of the abnormal behaviour ranged from 3 h to 1 week. One child had a paradoxical reaction to midazolam. The overall incidence of adverse effects to midazolam in the patients studied was 17%. No adverse effects were observed in infants; all adverse effects were observed in children. We have shown that it is possible to prospectively study the toxicity of sedatives in critically ill infants and children.

Adverse drug reactions in a paediatric intensive care unit

Adverse drug reactions (ADRs) were prospectively studied in critically ill infants and children. Seventy–six ADRs were reported in 63 patients out of a study group of 899 patients. The majority of the ADRs were mild (49), although 19 were of moderate severity and 8 were severe. Thirty–five ADRs required treatment or alteration in treatment. Midazolam, morphine, salbutamol, vecuronium, hydrocortisone and theophylline were the drugs most likely to cause an ADR. One–third of the ADRs were due to drugs used outside their product licence. The majority of the ADRs were reported by nurses (36) and pharmacists (30). We believe that it is possible to prospectively study drug toxicity in critically ill infants and children.

Melatonin for sleep problems in children with neurodevelopmental disorders: randomised double masked placebo controlled trial.

Objective To assess the effectiveness and safety of melatonin in treating severe sleep problems in children with neurodevelopmental disorders. Design 12 week double masked randomised placebo controlled phase III trial. Setting 19 hospitals across England and Wales. Participants 146 children aged 3 years to 15 years 8 months were randomised. They had a range of neurological and developmental disorders and a severe sleep problem that had not responded to a standardised sleep behaviour advice booklet provided to parents four to six weeks before randomisation. A sleep problem was defined as the child not falling asleep within one hour of lights out or having less than six hours’ continuous sleep. Interventions Immediate release melatonin or matching placebo capsules administered 45 minutes before the child’s bedtime for a period of 12 weeks. All children started with a 0.5 mg capsule, which was increased through 2 mg, 6 mg, and 12 mg depending on their response to treatment. Main outcome measures Total sleep time at night after 12 weeks adjusted for baseline recorded in sleep diaries completed by the parent. Secondary outcomes included sleep onset latency, assessments of child behaviour, family functioning, and adverse events. Sleep was measured with diaries and actigraphy. Results Melatonin increased total sleep time by 22.4 minutes (95% confidence interval 0.5 to 44.3 minutes) measured by sleep diaries (n=110) and 13.3 (−15.5 to 42.2) measured by actigraphy (n=59). Melatonin reduced sleep onset latency measured by sleep diaries (−37.5 minutes, −55.3 to −19.7 minutes) and actigraphy (−45.3 minutes, −68.8 to −21.9 minutes) and was most effective for children with the longest sleep latency (P=0.009). Melatonin was associated with earlier waking times than placebo (29.9 minutes, 13.6 to 46.3 minutes). Child behaviour and family functioning outcomes showed some improvement and favoured use of melatonin. Adverse events were mild and similar between the two groups. Conclusions Children gained little additional sleep on melatonin; though they fell asleep significantly faster, waking times became earlier. Child behaviour and family functioning outcomes did not significantly improve. Melatonin was tolerable over this three month period. Comparisons with slow release melatonin preparations or melatonin analogues are required. Trial registration ISRCT No 05534585.