See “US Perspective on Off-label Use in Pediatrics” by Karesh and Mulberg on page 113.
The improvement of children's access to necessary medicines as well as improved legal and scientific conditions for the use of medicines in pediatrics has been a subject of interest for many years. There have been several recent and valuable regulatory initiatives in the European Union to promote the availability of medicines specifically developed for children and to increase the number of medicines that are correctly evaluated in children and include recommendations for use in children in their officially approved conditions of use (1–4). Nevertheless, off-label use of medicines in children is still a relevant issue. New legislation on compassionate and off-label use of medicines has recently been adopted in Spain (5). The purpose of this national law is to facilitate access to necessary medicines by decreasing administrative burdens and delays, as well as to clarify the legality of off-label use, establishing principles such as physician and institutional responsibilities and the need for documented oral consent from the patient (or their parents).
The aim of the present study is to describe the medicines prescribed to children attending our pediatric gastroenterology outpatient clinic and to outline the magnitude and characteristics of off-label drug use, identifying the medicines most commonly prescribed off-label. Additionally, the identification of possible actions to improve the quality of medical prescription has been considered.
An observational, transversal, and descriptive drug use study was carried out in the pediatric gastroenterology outpatient clinic of a tertiary care university hospital, which incorporated pediatric care only 3 years ago and still has no pediatric surgery. All of the patients attended in the pediatric gastroenterology outpatient clinic from January 1, 2010 to October 31, 2010 were retrospectively reviewed using a structured questionnaire and the following information was collected for each patient from his or her medical records: date of birth; weight; diagnoses; and prescription details such as indication, dose, dose frequency, and route of administration.
Medicines prescribed to children of up to 16 years were registered and assessed and their conditions of use were analyzed by comparing them with the authorized conditions set out in the official information of the Spanish Agency for Medicines and Health Products (AEMPS). Official (SPC) was obtained from the AEMPS online Medicines Information Center (CIMA), accessible at the AEMPS Web page (6).
For some extremely old medicines, with no available official SPC, such as bismuth citrate, published recommendations of use by European or national scientific societies and expert groups were taken as the authorized conditions of use.
We considered off-label use to be the use of a drug at an indication, dosage, frequency, or route of administration different from those specified in the SPC or in children outside the authorized age group. We also considered as off-label the use of a medicine with no specific information on pediatric use in its SPC.
The study was conducted in line with national regulations and international ethics recommendations on biomedical investigation and was approved by the Research Ethics Committee of Puerta de Hierro Majadahonda University Hospital.
Data were entered into a relational database (Microsoft Excel, Microsoft, Redmond, WA). A descriptive analysis of continuous variables was performed using mean, standard deviation, median, and range. The statistical analysis was performed with the Microsoft Office Excel Professional Edition 2003 package.
A total of 695 children (367 boys and 328 girls; average age 4.3 ± 4.4 [22 days–15.6 years]) were included in the study. Patients were placed into 3 age groups, namely, infants (younger than 2 years) 48.2%, children (between 2 and 10 years) 39.7%, and adolescents (11 years or older) 12.1%. Of these, 207 children (29.8%) had received prescriptions (Table 1).
The probability of receiving a medical prescription increases with age. The percentage of patients who received medicine ranges from 18.5% in infants or 36.6% in children to 52.4% in adolescents (Fig. 1A).
The most common diagnoses in the total infant population were cow's-milk protein allergy (161 cases), gastroesophageal reflux disease (63 cases), failure to thrive (58 cases), and celiac disease (19 cases). In the children group, common diagnoses were constipation (62 cases), nonspecific abdominal pain (56 cases), celiac disease (52 cases), and nonspecific diarrhea (25 cases). For the adolescent group, diagnoses were nonspecific abdominal pain (30 cases), Helicobacter pylori infection (22 cases), celiac disease (10 cases), failure to thrive (8 cases), and constipation (6 cases).
A total of 331 drug prescriptions involving 39 different active substances were analyzed (Table 2). The most frequent active substances were polyethylene glycol (76; 23.9%), ranitidine (47; 12.2%), esomeprazole (30; 9.1%), amoxicillin (24; 7.3%), clarithromycin (23; 6.9%), metronidazole (23; 6.9%), domperidone (20; 6.0%), omeprazole (16; 5.4%), and lansoprazole (15; 4.5%). The majority of medicines were administered orally (97.8%), with 1.2% by parenteral route, 0.6% by rectal route, and 0.4% by topical application.
Of the 331 prescriptions recorded, 110 (33.2%) were off-label. The most representative pharmacotherapeutic groups involved in off-label use were antiacid (100% off-label use), anti-H2 (78.2%), proton pump inhibitors (58.0%), antibiotics (16.4%), and laxatives (14.3%). It is worth noting that there are some therapeutic groups (immunosuppressive agents, antiemetics), with extremely infrequent use (<5 prescriptions), but they were used as off-label in all of the cases. Table 3 identifies all of the active substances with any off-label prescription (by age group).
The main reason for considering off-label use was that the age range was not covered by the SPC either by not being directly included in the indication wording or indirectly through the inclusion of specific age-adpated posology recommendations. The remaining off-label uses (17.3%) were related to the use of higher or lower than recommended doses (Table 4). It is noteworthy that most of these situations are detected in the group of adolescent patients, in whom clinical practice should sometimes overrule the established in the SPC according to the calculation of the dose depending on weight or age.
Of a total of 207 children that received medicines, 47.3% received off-label drugs, with 89.8% of these receiving 1 off-label drug, 8.2% receiving 2 off-label drugs, and 2.0% receiving 3 off-label drugs. With regards to the analysis of off-label use according to age group, the most elevated percentage was that of the infant group (in which 85.5% received at least 1 off-label medicine) versus 28.7% and 36.4% for the children and adolescent groups, respectively. (Fig. 1B)
With regard to obtaining parental informed consent in the case of off-label use, no documentation was found in medical records. Therefore, it was not possible to verify obtaining an oral parental informed consent, a practice that is now mandatory according to the recent Spanish law on off-label use of medicines.
The use of off-label drugs in children has been extensively documented in different settings and countries (7–16). With regard to use in pediatric gastroenterology, Dick et al (16) analyzed the conditions of use of medicines in 2002 in the United Kingdom and found that 37.4% of 777 prescriptions were administered off-label, 26.7% of the cases due to a different indication, and 10.7% due to unauthorized age. The 5 most common clinical diagnoses were gastroesophageal reflux, constipation, inflammatory bowel disease, H pylori infection, and intestinal malabsorption. The off-label drugs most frequently prescribed were domperidone (19.6%), ranitidine (17.2%), omeprazole (12.8%), azathioprine (10.3%), tacrolimus (8.3%), metronidazole (7.2%), mesalazine (5.2%), and polyethylene glycol (3.8%).
In our study, we analyze off-label use in relation to age and, as was expected, we found that off-label use accounted for 33.2% of all the prescriptions with a higher percentage at early ages. In children younger than 2 years, up to 85.5% of the prescriptions were off-label. In comparison with the study carried out by Dick et al (16), our study shows an increase in the off-label use of polyethylene glycol and proton pump inhibitors. These differences are probably not related to differences between the 2 units, but rather to the increase in use of these medicines as a consequence of pediatric therapeutic protocols and scientific evidence that have been developed during the time elapsed between both studies.
It has been widely reported that information available for children in the SPC is inadequate, incomplete, and shows inconsistencies in many cases (17,18). There is usually no dosage recommendation according to weight, body surface, or age range, although it is widely recognized that extrapolation of pediatric dosages from the adult population is not always appropriate due to specific pharmacokinetics and pharmacodynamics in children (13,17). It is not infrequent to find that the widely accepted therapeutic recommendations or practice guidelines in children are not in accordance with the formally approved conditions of use in the SPC, even in cases in which good supporting scientific evidence is available.
Another aspect that has been studied with respect to the use of off-label medicines is its safety because it is possible that adverse reactions are more frequent or severe than those related to medicines prescribed in line with the SPC. Off-label use implies that there are no adequately stated recommendations on dosage and other conditions for use. This could lead to medication errors, including dosage errors that are the cause of adverse reactions in children. Errors in drug administration were studied by Conroy (19) using a series of 158 errors occurring between 2004 and 2006, and it was concluded that mistakes were more common when prescribing off-label drugs or unlicensed drugs (not commercially available, such as magistral formulas that are sometimes required by pediatricians). A recent study carried out in Denmark (20) analyzed spontaneous reporting of adverse reactions in children from birth to 17 years during a 10-year period (1998–2007). Seventeen percent of adverse reactions were associated with off-label use and of these, 60% were severe. The populations most affected by these reactions were teenagers, particularly in the use of oral contraceptives and drugs for the treatment of severe acne. In contrast, Phan et al (15) found there was a rate of reported adverse reactions related to off-label use lower than the rate reported with approved uses. They had reviewed the medical records of all of the patients of 18 years or younger admitted to pediatric emergency department during a 5-month period. A total of 2191 patients with 6675 medications were revised and they found only 40 reported adverse reactions (0.6%). Only 12.5% were due to off-label drug use, which is half of those expected according to the frequency of off-label use. Nevertheless, underreporting appears to be an issue in the present study and we agree with other authors (19,20) in concluding that it is necessary to improve pharmacovigilance, monitoring, and documentation of adverse effects associated with off-label drug use. To change this situation and meet the therapeutic needs of a population that is still in inferiority with respect to drug use, the performance of clinical trials and safety studies in children should be encouraged by all of the agents involved (eg, pediatricians, parents, research ethics committees, health authorities, financing bodies). In addition, health authorities should ensure that the SPC of all of the authorized medicines are amended with regard to the scientific evidence available at any given time.
The situation of the regulatory approval of pediatric use of medicines began to change in Europe a few years ago. In the same way as previous experience in the United States, the European Union issued pediatric regulation in 2007 with the objective of ensuring both high-quality research in the development of medicines for children and the availability of high-quality information about medicines used in children (1). At the same time, International Networks of Excellence, such us Task-force in Europe for Drug Development for the Young, comprising >300 pediatric experts from 11 countries, including Spain, have informed and advised the European Medicines Agencies Network on pediatric drug use, and important cooperative work has been carried out so as to identify unmet therapeutic needs in children (21). Therapeutic research in children has been specifically supported at both European and national level, and new research projects have been generated in Europe through Task-force in Europe for Drug Development for the Young and other interested parties. At the national level, several different initiatives have been started. One example is the Committee for Medicinal Products of the Spanish Pediatrics Association, a working group that has the aim adjusting the use of drugs in children in our country (21).
As a result of new pediatric legislation, an exhaustive task reviewing pediatric evidence on use of medicines is presently being carried out by pharmaceutical companies and the European Medicines Agencies and recently, several new revised pan-European–approved conditions of use in children have been issued by the official European Medicines Agencies Network (4). Although this is an extremely positive achievement, the agreed wordings appear to be too factual and are lacking true endorsement of new indications. The example of omeprazole is shown in Table 5. In addition, there is some delay in the implementation of agreed changes into the official SPCs available in the different European Union countries and, more important, there are many pediatric conditions, which still lack scientific evidence on medicine use or need the development of new pharmaceutical formulations suitable for children. One such example is the nonavailability of a nonalcoholic commercial formulation of ranitidine.
At the same time, a new regulation has been issued in Spain (5) with the aim of facilitating off-label use of medicines when they are well supported by pediatric evidence or established in practice guidelines, as well as clarifying the responsibilities in off-label use. Regulation establishes that in these situations, the physician should register off-label use in the medical record of the patient together with justification for its use, as well as informing parents about the benefits and potential risks arising from off-label use and obtaining their oral consent. It would be good practice for the physician to register in the patient's medical record that oral informed consent has been obtained, but this procedure has not yet been implemented in present practice. In our study, no documentation of an informed consent could be found in medical records nor was any reference made to the justification of off-label use. It is our belief that the oral informed consent was not obtained in most cases and it is likely that the pediatrician was not even aware that he/she was prescribing a drug not approved for children.
Presently, there are 2 realities concerning the off-label use of drugs in pediatrics. On the one hand, there is an increasing awareness about how undesirable off-label use of medicines in children is and there are many initiatives to foster pediatric clinical trials as well as encourage Pharmaceutical Companies and Medicines Agencies to work together to face this challenge in children's health care. On the other hand, a great percentage of pediatricians continue to prescribe medicines without knowing whether the dose is adjusted to the approved SPC, and even whether the drug is formally indicated in children or in certain age groups. It is obvious that if the doctor does not know it is off-label use, then the family is also not informed. Sometimes off-label use is supported by well-accepted recommendations or therapeutic protocols. Meanwhile, there is a question that remains unanswered. Does off-label use really pose a risk for children? Or perhaps the question should be whether official SPC are really updated or do they fulfill their basic purpose of informing physicians about the use of a medicine with a positive benefit risk ratio?
In any case, the present responsibility for prescribing an off-label drug belongs exclusively to the pediatrician, and therefore, clinical practice guidelines are of utmost importance as they could establish the use of medicines based on both the approved conditions and the best available evidence even in off-label use.
Given this situation, several new initiatives have been implemented in our hospital. First, the need to inform pediatricians about whether the use is approved or not so as to ensure that, whenever possible, the approved medicine is used. Second, to always reflect off-label use of medicines in the clinical history, and to inform parents of such use. Third, the decision was made to identify common off-label use still not supported by guidelines and scientific evidence and to prospectively collect follow-up efficacy and safety data so as to provide evidence and support for future formal endorsement of pediatric use.
We think that description of off-label use and identification and implementation of similar measures of those taken at our hospital could be of value also for other pediatric centers.
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4. Heads of Medicines Agencies. List of active substances and agreed SPC wordings—EU work sharing procedure in the assessment of paediatric data. http://www.hma.eu/99.html
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