Incidence of unlicensed and off-label medication prescriptions at the Department of Paediatrics: what has changed after seven years?

Many common drugs have not been registered for use in children. Therefore, they are sometimes prescribed as unlicensed or off-label. This study, performed at the Department of Paediatrics, University Hospital Olomouc, Czech Republic, evaluated off-label and unlicensed prescriptions. A similar study, conducted in 2013 by the same authors (P. Matalová – maiden name P. Langerová), showed that the number of off-label and unlicensed prescriptions was relatively low, compared to other studies. The goal of this study was to compare the frequency of off-label and unlicensed drug prescriptions, and to assess whether these prescriptions have declined. The study evaluated the incidence of unlicensed and off-label prescriptions at the of Paediatrics, University Hospital Olomouc during a period of six months. A total of 10,710 prescriptions for 5,243 children were processed. months was performed to ascertain the development in prescribing practice. In the 2019 study, the total number of prescriptions and patients was higher (18.8% and 22.2%, respectively) as was the number of off-label and unlicensed prescriptions (11.1% and 1.7%, respectively).


Introduction
A broad spectrum of drugs has not been registered for use in children or their prescription for children is limited because of age. Sometimes, medicines have to be prescribed as unlicensed (drugs unregistered for children) or off-label. Off-label use refers to prescribing a drug outside the terms of the product licence, for example in an indication, age group, dose or route different from that which is approved by the regulatory authority [1].
In the last twenty years, there has been increased awareness of the lack of medicines documented for use in children. Regulatory actions have been taken to improve the situation by proposing requirements to the pharmaceutical industry to develop new products also suitable for children [2,3]. The European Union regulatory authorities issued a paediatric regulation, namely the Regulation (EC) No. 1901/2006 of the European Parliament and the Council of 12 December 2006 which came into force in January 2007. This regulation requires clinical trials to be conducted in the paediatric population as well, particularly if children may bene t from a new drug. The regulation permits pharmaceutical companies to modify the Summary of Product Characteristics (SPC) by data acquired from new paediatric trials [4,5]. In spite of these activities, progress has been slow and paediatricians still have to prescribe drugs without scienti c and legal support.
During the rst decade of life, changes in pharmacokinetics are dynamic and can be non-linear and discordant, making standardized dosing inadequate. During rapid phases of growth/development, drug disposition and response may be altered [6]. Moreover, the safety of patients as well as the therapeutic effect of drugs depend on the experience of the clinician and are not scienti cally approved. The use of off-label and unlicensed drugs is widespread and common to all settings, both in primary and hospital care. In addition, off-label and/or unlicensed drugs are frequently prescribed for the youngest and most vulnerable children [7].
The present study evaluates the incidence of off-label and unlicensed prescriptions of proprietary medicinal products in outpatients at the Department of Paediatrics, University Hospital Olomouc, Czech Republic, during a period of six months (January to June 2019), and also includes patients discharged from hospitalization. For the purpose of this study, unlicensed drugs were those not registered for children at all, and drugs prescribed for children younger than those for whom the drug is registered were evaluated as off-label. The goal was to highlight the need for clinical trials in paediatrics and to determine in which drugs the demand for also being registered for younger children is highest.

Methods
Study design and setting, study population Patients between 0 and 15 years of age attending the outpatient department of the University Hospital in Olomouc from 1 January to 30 June 2019 were included in the study. A total of 10,710 prescriptions for 5,243 children were evaluated. Patients who reached 15 years of age in the follow-up period were included in this study; those older than 15 years were not enrolled. The following characteristics were recorded for each patient: age, sex, and the number of prescriptions. In addition, the incidence of unlicensed and off-label prescriptions and the most commonly prescribed drugs were recorded.

Data processing
According to the Summary of Product Characteristics (available at www.sukl.cz for each registered drug in the Czech Republic), all drugs prescribed in contradiction with the licence information for age were considered off-label. In this study, it meant a drug prescribed for a child younger than the age for which the drug was registered. All drugs that were not registered for children at all were considered unlicensed.

Statistical analysis
All statistical analyses were performed using the R software, version 3.6.3. Frequencies and percentages were used to describe the characteristics of the sample. The differences in proportions were compared with the test of proportions (z-test). The signi cance level was set at the level of p < 0.05 for all statistical signi cance testing.

Results
The study included 5,243 children under the age of 15 years. A total of 10,710 drugs were prescribed during the six-month follow-up period. The descriptive characteristics of the study cohort are presented in Table 1. Of all prescriptions, unlicensed and off-label prescriptions accounted for 1.7% and 11.1%, respectively. A slight majority (55.5%) of the patients were six years of age or older. The percentage of male patients was signi cantly higher than that of females (56.5% vs. 43.5%, p < 0.001). The number of prescriptions was signi cantly higher in males as well (57.8% vs. 42.2%, p < 0.001).  The proportion of unlicensed medications prescribed in school age children was signi cantly higher than in any other age group (p < 0.001).
The highest proportion of off-label prescriptions was found in infants, 19.6% (95% CI: 16.6-22.9). On the contrary, the lowest incidence of offlabel medications was observed in school age children (4.5%, 95% CI: 3.8-5.3). In the other age groups, approximately 13% of the prescriptions were off-label drugs. The distribution of unlicensed and off-label prescriptions in different age categories is presented in Table 2.
The drugs most commonly prescribed as off-label and unlicensed are presented in Tables 3 and 4. The most commonly prescribed unlicensed drugs were ramipril and aescin alpha; among off-label drugs, desloratadine and bronchodilators were prescribed most frequently.   [9,10]. One of the reasons is that many studies were performed in neonatal intensive care units [11,12,13,14] or emergency departments [15] where the proportion of off-label prescriptions seems to be the highest.
Another reason may be the ambiguity in the de nition of off-label and unlicensed drugs [9] We evaluated prescriptions of proprietary medicinal products from specialized outpatient departments where the number of prescriptions is the highest. Proprietary medicinal products were chosen because of their availability and their being most likely to be registered for children.

Conclusion
In our previous study, performed from January to June 2012, 8,559 prescriptions for 4,282 children were processed. Off-label and unlicensed prescriptions were found in 9.01% and 1.26% of all prescriptions, respectively. Unlicensed prescriptions were signi cantly more common in boys (1.5%) than in girls (1.0%). Seven years later, the same study in the same months was performed to ascertain the development in prescribing practice. In the 2019 study, the total number of prescriptions and patients was higher (18.8% and 22.2%, respectively) as was the number of off-label and unlicensed prescriptions (11.1% and 1.7%, respectively).
In other words, the number of off-label and unlicensed prescriptions indicates a gap in registration processes and should provide a clue as to which drugs are candidates for having their SPCs changed. Despite numerous initiatives aimed at promoting rational medicine use in children, the prevalence of off-label prescription in outpatient paediatric practice remains high.