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Purpose: Historically, somatropin has been used for conditions related with ageing, but since the marketing of recombinant human growth hormone (rhGH), increasing promotional pressure has prompted aesthetic uses, despite lack of evidences about its efficacy and safety for those purposes.Methods: A routine analysis of the Pharmacovigilance Center of São Paulo (Brazil) showed reports of suspected adverse reactions in young adults and mature patients receiving rhGH. After presuming an off-label use of this expensive product, a drug utilisation study within the pharmacovigilance database has been carried out.Results: The analysis showed a bimodal age distribution of the rhGH reports. Up to 17.1% of the 1289 reports (n = 220) involved patients aged ≥ 20 years taking rhGH for off-label uses.Conclusions: This information was the basis to design interventions in order to reduce inappropriate utilisation of this expensive product. Analyses of how medicines are being used through pharmacovigilance databases are a way to identify its irrational utilisation, thus facilitating preventive actions to improve how medicines are used and reducing avoidable adverse effects. [ABSTRACT FROM AUTHOR]

Purpose: The aim of this review is to assess the extent of the use of off-label and/or unlicenced drugs among hospitalised children. Methods: A systematic search was made in MEDLINE-PubMED for papers published from 1994 to 2012, addressing the prescription of off-label and/or unlicenced drugs for the paediatric population in hospital care. Results: Of the 829 studies retrieved, 34 met the inclusion criteria. Prescriptions ranged from 12.2 to 70.6 % for off-label and from 0.2 to 47.9 % for unlicensed drugs. The percentage of children who received at least one off-label and/or unlicensed drug ranged from 42.0 to 100 %, with newborns being the population that received most of such drugs. Off-label prescriptions were essential for dose modification (7.1-73.1 %) and unlicensed prescriptions for formulation modification purposes (3.6-100 %). Conclusions: These findings show that: (i) off-label and/or an unlicensed prescribing is widespread among the hospitalised paediatric population worldwide, (ii) there is no consensus on a definition of off-label and/or unlicensed drugs and (iii) preterm newborns receive most off-label and/or unlicensed drugs. By shedding new light on off-label and/or unlicensed drug prescribing, these findings will hopefully contribute to generating new, more effective knowledge about the paediatric population's need for quality drugs that are both safe and efficacious. [ABSTRACT FROM AUTHOR]

Purpose: This nationwide study is aimed at describing to what extent the European Paediatric Regulation has met therapeutic needs in children. Methods: Data for each drug substance in defined daily doses (DDD) were extracted from the national Danish data base. We evaluated if drug substances were used off-label and whether they had a paediatric investigation plan (PIP). This study did not include drug prescriptions for individual paediatric patients; thus, it was not possible to make use of all off-label categories previously used. Additionally, paediatric standard assortments (SA) were compared to the European survey on paediatric medicinal products. Results: Thirteen percent of the 100 most used drug substances were determined as being used off-label, four of which had a PIP and one had a full waiver. Only one of the three drug substances used off-label most often, accounting for 85 % of such use, had a PIP. Neonates were included in one-third of PIPs and adolescents in 15. Nineteen out of 21 PIPs had a waiver and 14 PIPs were deferred. In line with the European survey, carbapenems, corticosteroids and proton pump inhibitors were frequent found in SAs. Conclusion: PIPs only cover a small proportion of the drugs found to be used off-label in this study. Despite waivers granted, drug substances were used nonetheless. Unmet regulatory needs are still considerable in some therapeutic areas in neonates as well as in children. [ABSTRACT FROM AUTHOR]

Purpose: The aim of this study was to determine the prevalence and pattern of unlicensed and off-label drugs prescribed to hospitalized children at the Department of Paediatrics, University Hospital Rijeka, Croatia. Methods: A prospective cross-sectional study was performed on 1 day each month during a 12 month period and included all hospitalized children and adolescents. Results: A total of 1,643 prescriptions for 198 different drugs were prescribed to 531 out of 691 (77%) hospitalized patients. Forty-six percent of the different drugs were prescribed in an unlicensed or off-label manner. Of all drug prescriptions, 25% were either unlicensed or off-label. Forty-eight percent of the patients received either an unlicensed or off-label drug. The most frequently prescribed off-label drugs were proton pump inhibitors. Conclusion: Unlicensed and off-label drug use is common. It is not illegal and may be clinically appropriate but is associated with a number of clinical, safety, and ethical issues. Regulatory authorities should use existing clinical evidence on the use of off-label and unlicensed drugs in decision making. Marketing authorization holders and national regulatory authorities should monitor for any safety concerns associated with unlicensed and off-label drug use and take appropriate measures as well as identify research priorities and mandate clinical studies to resolve important questions. [ABSTRACT FROM AUTHOR]

Background: Off-label use is the practice of prescribing a drug outside the terms of its official labeling. Worldwide, about 20% of the commonly prescribed medications are off-label, and the percentage increases in specific patient populations, such as children, pregnant women, and cancer patients. Off-label use is particularly widespread in oncology for many reasons, including the wide variety of cancer subtypes, the difficulties involved in performing clinical trials, the rapid diffusion of preliminary results, and delays in the approval of new drugs by regulatory organizations/agencies. Objective: The aim of this article is to describe the use of off-label drugs in oncology, with an emphasis on the role of the world's leading regulatory agencies and an assessment of current Italian legislation. Conclusion: Off-label drug utilization is essential in oncology when based on evidence. However, off-label drugs must be prescribed in accordance with existing national laws and only when the potential benefit outweighs the potential toxic effects. [ABSTRACT FROM AUTHOR]

This study aims to describe the drug use on a Neonatal Intensive Care Unit (NICU) at a University Children’s Hospital in Germany, to investigate the licensing status of the drugs used and to conclude critical areas in neonatal intensive care to support prioritisation of future research. An 11-month, prospective cohort study was conducted on the NICU at the University Children’s Hospital Erlangen, Germany. All products prescribed during the study period were analysed whether or not the SPC contains information on term and preterm neonates. A total of 183 patients (102 male) with a mean gestational age of 33.6 weeks (minimum = 24, maximum = 42) were included. The mean length of hospitalisation was 19.4 days (minimum = 2, maximum = 167). On average, patients received 11.1 drugs (minimum = 0, maximum = 46). The majority of prescriptions were accounted for by antibiotics ( n = 515), which were received by 90% of all patients, followed by CNS drugs ( n = 448) and respiratory drugs ( n = 306). Of all the different drugs prescribed ( n = 102) only 38% had information regarding their use in patients aged less than 1 month in their SPC. Analgesics and cardiovascular drugs were prescribed frequently, but without having information for use in neonates. Seventy percent of all patients and 100% of very preterm infants received at least one of these drugs. Treatment strategies on a preterm intensive care unit are complex and little information is available for the drugs used. Analgesics and cardiovascular drugs are of major concern. Efforts will have to be made to conduct well-designed and powered studies in this vulnerable population. [ABSTRACT FROM AUTHOR]

In some cases of drug therapy, the available evidence might be sufficient to extend the indications to children without further clinical studies. We reviewed the available evidence for one of the categories of drugs most frequently used off-label in children: proton pump inhibitors (PPIs) used for the treatment of gastroesophageal reflux disease (GERD). A classification of the appropriateness of off-label use of PPIs in children with GERD was also performed. Of the five PPIs evaluated, only omeprazole has a paediatric indication in Europe. Overall, 19 clinical trials were retrieved and evaluated on the basis of pharmacokinetics, efficacy and safety data. The off-label use of omeprazole, esomeprazole and lansoprazole in children was evaluated as appropriate given the consistent available evidence retrieved in literature. This study demonstrates the existence of a large body of clinical evidence on the use of PPIs in children. Regulatory agencies and ethical committees should cope with this issue for ethical reasons to avoid unnecessary trial replication. [ABSTRACT FROM AUTHOR]

To investigate the use of drugs, the extent and pattern of unlicensed and off-label use, and the potential relationship between off-label drug use and adverse drug reactions in northeastern Brazil. A follow-up study of drug utilization in a general ward of a pediatric reference hospital, involving patients hospitalized for more than 24 h. Prescriptions and medical records were reviewed daily from August to December 2001. Drug licensing status of all prescriptions given to these patients was determined. A total of 272 patients were admitted during the study, 265 (97.4%) of whom received one or more drugs. The median number of drugs/patient was 6 (1–18), and the most frequent diagnosis was pneumonia (29.4% of patients). The therapeutic class most prescribed was anti-infectives for systemic use (68.8% of all children). In all, 82.6% of children received at least one unlicensed or off-label drug, and 17% received both an unlicensed and an off-label drug. Dose/frequency was the most common form of off-label drug use. Off-label drug use was significantly associated with adverse drug reactions (relative risk 2.44; 95% CI 2.12, 2.89). Although off-label drug use is a complex issue and is not synonymous with inappropriate drug use, a high rate of unlicensed/off-label drug use was found and was also associated with an increased risk of adverse drug reactions. More efforts are needed to increase rational drug use in children. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Objectives: In the light of the undesired effects that unlicensed and off-label drug use might have, it is necessary to study the determinants affecting the prescribing of such drugs. Prescription of drugs to children younger than the minimum licensed age may carry the highest risk of adverse reactions. To obtain insight into the factors that affect prescription of drugs to children below the minimum licensed age, we conducted a population-based case-control study. Methods: The case-control study was nested in a cohort of 13,426 children aged 0–16 years, who were registered in the Integrated Primary Care Information (IPCI) project, a longitudinal observational general practitioners' database in the Netherlands. "Cases" were children who received a drug prescription for which they were below the minimum licensed age. To each case we matched up to four controls based on GP practice and patient age. As potential risk factors we evaluated the use of health care resources, and acute and chronic morbidity. Results: We identified 447 cases who were matched to 1355 controls. The cases consulted their GPs significantly more often during the preceding half year, had more drug prescriptions, and had more specialist referrals than the controls. Respiratory diseases were the most important determinants for the prescription of drugs to children below the minimum licensed age. In adolescents, migraine and other headaches were the most important reasons. Conclusions: This study showed that children suffering from respiratory disease or migraine have the highest risk of receiving a drug prescription for which the patient is below the minimum licensed age. Regulatory authorities and the pharmaceutical industry should be stimulated to improve the evaluation of drug efficacy and safety in children. [ABSTRACT FROM AUTHOR]

Objective: To determine the extent of unlicensed and off-label antidotes among medicines recommended by the International Programme on Chemical Safety (IPCS) for children. Materials and methods: We considered 77 antidotes from the "IPCS List of antidotes and other useful agents in the treatment of human poisoning" (1996 version). Primary reference sources used were the Physicians' Desk Reference (PDR) and package inserts. Antidotes were assessed for off-label (outside of the term of product license) and unlicensed use in children. Results: Our data show that only 31 (40.3%) of 77 recommended antidotes correspond to the demands of licensing systems for use in children. The rest (46 or 59.7%) are either off-label (32 or 41.5%) or unlicensed (14 or 18.2%). Five antidotes are off-label for two reasons; thus the total number of off-label use (37) is greater than the number of such drugs (32). Inappropriate age is the main reason for use outside the stipulations of the product license (24 of 77 antidotes or 31.2%), whereas different indication and route occur in 11 (14.3%) and 2 (2.6%) antidotes, respectively. The 14 unlicensed antidotes have been used only in animal experiments or in a small number of patients in certain poison centres. Conclusions: Sixty percent of antidotes and other useful agents in the poison treatment of children do not correspond to the demands of licensing systems. Drugs used in the treatment of poisoned children, as well as adults, must be evaluated scientifically. [ABSTRACT FROM AUTHOR]