A study of off-label and unlicensed medicines use in neonatal units

Despite all efforts to improve the on-label use of licensed medicines for neonates, there is still high percentage and demands of off-label and unlicensed medicines use in neonatal therapy. Therefore, the general objective of this survey is to provide a description of off-label and unlicensed medicines use within the neonatal therapeutic areas in a Department of Neonatology, University Clinic for Gynecology and Obstetrics, in Skopje, Republic of Macedonia. All analyzed prescriptions were given in accordance with the Evidence Based Guidelines applied in the Department. During the three months’ period in 2015, there were given 1595 prescriptions, comprising 3.99 prescriptions per newborn during the hospital stay. Out of them, 532 (33.3%) were on-label medicine uses, 1052 (66%) were off-label medicines, and 11 prescriptions (0.7%) were unlicensed medicines. The results from this study show the high level of off-label medicine use in neonatal therapy. These results present only the “top of the iceberg” and require more comprehensive analysis that will gradually evolve in a National Guideline on off-label use areas in pediatric medicine, especially for critically ill newborns who are prescribed much more life-saving medicines.


Introduction
The practice of off-label prescribing and use is a complex issue with advantages and weaknesses. It refer to prescription of a registered medicine for a use that is not included in the Summary of Product Characteristics (SPC), not listed in the product information, the uses outside the terms of their product license (approval) disclaimed in the SPC (Kimland et al., 2007). This practice is a real challenge for any prescriber since, as acknowledge, the product information will not include advice about off-label use and the medicines companies are unable to promote these practices.
The detailed description of this category of medicines is presented in Table 1, although the more frequent categories are off-label use out of: age, indication, dose/frequency and route of administration. Unlicensed or unregistered medicine use, is the use of a medicine or dosage form of a medicine that has not been evaluated nor approved by the regulatory authorities. These include medicines whose formulation is modified, those that are imported before a li-Elizabeta Zisovska, Blerina Koshi, Renata Slaveska-Raichki cense has been granted; those that are chemicals used for therapeutic purposes, new drugs/formulations produced under a "special" manufacturing license or drugs that have license in other countries but not in the certain (Pandolfini & Bonati 2005;Cuzzolin et al., 2006).
The principal reason of off-label medicine use is to respond to unmet needs of patients in valid situations when this use is clinically appropriate or essential. There is no legal obstacle to prescribing off-label however, the prescriber should be able to justify and support off-label prescribing decision and feel competent in using such medicines. Actually, in practice, this approach is not different from what should ideally be done for the rational prescribing of any medicine.
Consequently it is a common practice in paediatric pharmacotherapy, since the labelling information about appropriate use of medicines in this population group is lacking. On the other hand, pharmaceutical researches are reluctant to enrol children in clinical trials, often based on liability fears (Dresser & Frader 2009). Especially, neonatologists have almost no choice but to prescribe off-label or unlicensed drugs because their patients are rarely entered into trials of new medications (Palčevski et al., 2012).
While off-label medicines use is not illegal, and may sometimes be the only appropriate, it is associated with important clinical and ethical concerns which need to be considered when assessing overall benefits and risks (Bavdekar & Gogtay 2005;Gazarian et al., 2006).
The health outcomes of unapproved medicines use in the neonatal population are not systematically evaluated, which compounds the original problem by even further limiting the evidence base for future treatment decisions. This is particularly true for safety outcomes, with gross under-reporting of adverse drug reactions, which may be even more pronounced for unapproved vs. approved uses of medicines. However, there is now accumulating evi-dence of resulting harm, with increased incidence and seriousness of adverse drug reactions associated with offlabel and unlicensed medicines use in neonates (Ufer et al., 2004;Miller et al., 2007). Even the so-called Pediatric Regulation (Regulation No 1901, whose one of the key objectives is to reduce the off-label use of medicines in the pediatric population, cannot entirely solve this problem and the practice of off-label use will remain an issue (European Commission, 2013).
Therefore, the aim of this study was to investigate, analyze and present the extent and manner of use of medicines that are either outside the terms of their product license (off-label), or are unlicensed within the neonatal therapeutic areas.

Materials and methods
The setting for this research was at the Department of Neonatology within the University Clinic for Gynecology and Obstetrics, in Skopje, Republic of Macedonia. This Clinic is a tertiary level hospital care with approximately 6000 deliveries per year. The Department of Neonatology itself consists of three Units: classical Intensive Care Unit (ICU) which contains 22 intensive beds; Transitional Care Unit (TCU), containing 15 beds for full term or near term newborns that require close monitoring or therapy, but not intensive care; and Routine Care Unit (RCU) for healthy full term newborns, which are rooming in with their mothers during the whole hospital stay until discharge.
This study was designed as a pilot cohort study, prospectively conducted during the period of three months in 2014 (beginning of March -end of June) and involving 400 admitted neonates to the three units of the Department of Neonatology. The sample of patients for the study included: a) 200 successively admitted neonates to

Contraindication
Medicine use when there is a specific contraindication to neonatal period stated in the SPC

Route of administration
Medicine administered by a route not approved according to the SPC

Dose/frequency
Medicine dose /frequency not stated in SPC the ICU, 152 of them were preterm neonates and 48 full term ill neonates; b) 100 full term neonates successively admitted to the TCU; c) 100 successively born, full term healthy neonates, rooming in with their mothers in RCU. Patients were categorized based on their gestational age to preterm (<37 weeks) and full-term (≥37 weeks) newborns.
Since there were no human beings involved directly in the study (only the medication charts were analyzed, and the treatment was based on the nationally approved Clinical Guidelines), and none of the information used in the research contained any references to patient identity, it was considered ethically appropriate without official Ethical Committee approval.
A data collection form was designed and used for further analysis. The data were imported and analyzed in a database (Microsoft Access, 2000). The information about all drug prescriptions were derived out from the clinical records of the admitted patients in the Department of Neonatology, and transferred to the database. Details recorded included: patient's birth number, date of birth, weight, gestational age and diagnosis, indication for drug use, medicines administered, date and route of administration, dose and frequency.
Firstly, all prescribed medicines were analyzed with regard to their license status (licensed or unlicensed) then the licensed medicines were classified in accordance to onlabel or off-label uses.

Results and discussion
In the cohort group as whole, 1595 prescriptions were given according to the medical condition and indication in accordance with the Macedonian Evidence based Guidelines applied in the Department of Neonatology (Ministry of Health, n.d.), which comprised 3.99 prescriptions per newborn during the hospital stay. Out of them, 33.3% were on-label medicine uses, 66% were offlabel medicines, and 0.7% of prescriptions were unlicensed medicines (Table 2). The further analysis showed 2.63 prescriptions of offlabel medicines/newborn, 0.03 prescriptions of unlicensed medicines/newborn, and 1.33 prescriptions/newborn for licensed, on-label medicines, appropriate from each point of view (Fig. 1).
The results were more specific regarding the severity of the medical conditions of the admitted newborns, when presented in details for each Unit. In the neonatal ICU, there were in total 6.54 prescriptions/newborn. The research came up with different results for premature neonates and full term neonates (7.31 and 4.1 respectively). The detailed analysis showed 1.39 prescriptions/neonate on-label medicines (premature neonate 1.4 and full term 1.33); 5.1 prescriptions/neonate off-label medicines (5.8 premature and 2.75/full term ill newborns), and 0.055/neonate unlicensed medicines (0.06/premature and 0.021/full term ill neonate) (Fig. 1). Out of them, 21.3% were licensed on-label medicines, 77.9% were licensed off-label medicines, and 0.8% were unlicensed medicines (Table 3).
In both units, TCU and RCU, where near term or full term neonate are admitted (not severely ill or healthy) the distribution of the prescriptions was completely different. From the medical history, the following data was retrieved: in total, there were 1.8 prescriptions/newborn in TCU; more precisely, there were 1.5 prescriptions/neonate on-label medicines; 0.3 prescriptions/neonate off-label medicines, and no unlicensed medicines (Fig. 1). Out of them, 84.1% were licensed on-label medicines, 15.9% were licensed off-label medicines. In addition, in the other Unit, the RCU, there were 1.06 prescriptions/neonate onlabel medicines, 0.04 prescriptions/neonate off-label, and no unlicensed medicines. Presented in proportions, 96.4 % were on-label and only 3.6% were off-label because of different terms of inappropriateness (Table 4).
The most frequently prescribed off-label drug at the Department of Neonatology was imipenem and five most frequently prescribed off-label drugs of all prescriptions are presented in Table 5.
To the best of our knowledge, this is the first study evaluating off-label and unlicensed drug uses in newborns in the country and in the region of South Eastern European Countries. This Clinic is a tertiary level of care hospital, where all high-risk pregnant women are transferred as "transport in utero" for further care and delivery, and thus mostly of the newborns are admitted to the NICU or TCU.
Majority of them are very preterm, or critically ill, requiring intensive care and multidrug treatment, clearly presented in Figure 1.
There was statistically significant difference in the results of off-label drug use between the premature newborns admitted in the NICU and all other groups, as follows: p<0.05 for the difference between premature newborns in NICU and full term newborns in NICU and p<0.01 between the premature newborns in NICU and all other newborns in TCU and RCU.
The results presented in our paper show differences when compared to some of the other studies (Table 6). In  Unlicensed 0 0 0 0 All medicines 176 100 110 100 P 4 -prescriptions for neonates in TCU; P 5 -prescriptions for full term neonates in RCU, rooming in with their mothers; ne nnumber of neonates; ftne n-number of full term neonates. these studies, off-label drug use varies between 7-65% and unlicensed use between 4.4-28%, which is not surprising due to the variability the study design, inconsistency between the settings, in terms of the severity of diseases and indications among the patients (maternity hospital vs. pediatric hospital care), category of Unit (NICU vs. Ordinary Unit), etc. Moreover, the definitions of offlabel and unlicensed use vary between different surveys, therefore the comparison of the results of these studies is not directly possible. Higher off-label and unlicensed prescription rates has been found in settings offering more sophisticated care, or in which the patients present more complex disease processes (Czarniak et al., 2015). In an international literature review (Lindell-Osuagwu et al., 2009) it was noted that 88-90% of infants in NICU-s receive off-label or unlicensed drugs. The results of our study confirm these findings, with a significant higher rate of off-label prescriptions found in NICU compared to TCU and RCU.
Compared to other studies, there is variability between the results of off-label and unlicensed prescription in NI-CU-s, with higher proportion of off-label prescriptions, but lower unlicensed prescriptions found in our study compared to those conducted in England (Conroy et al.,1999), Australia (O'Donnell et al., 2002), Italy (Dell'Aera et al., 2007), Ireland (Kieran et al., 2014) and Portugal (Silva et al., 2015). On the other hand, in a France study (Nguyen et al., 2011) involving neonatal units without intensive care, the rate of off-label prescriptions was 29.4%, which is pretty much higher compared to our study (in TCU and RCU). With regards to unlicensed prescriptions, they comprised 16.6% of total prescriptions, whereas there were no unlicensed prescriptions in our study (in TCU and RCU).
In a previous study conducted in similar neonatal units (NICU and intermediate-level wards of neonatal care) (Lass et al., 2011), the rate of off-label prescriptions was almost the same (65%), but compared to our study, the extent of unlicensed prescriptions was totally different, with 22% of all prescriptions being unlicensed.
The small number of unlicensed medicines use found in our study was probably due to the tide regulation about unlicensed medicine use in our country.
Direct comparison of different study results for drug utilization is often not possible, as well, due to the lack of uniform methods, for example, which drugs are to be included in the study. In a German study (Neubert et al., 2010), the median number of prescriptions per newborn was 11.1, which is almost twofold higher rate compared to our results for the drug prescriptions in the NICU. High amount of drugs use was also reported in recent studies conducted in Finland (Lindell-Osuagwu et al. 2014), 9 prescriptions/newborn andSpain (Blanco-Reina et al. 2016), 8.3 prescription/newborn. Whilst, in some other studies the drug utilization was smaller, with a median number of 5.5 prescriptions/newborn in Italy (Dell'Aera et al., 2007) and4 prescriptions/newborn in Ireland (Kieran et al., 2014).
With regards to the most frequently prescribed offlabel medicines, indomethacin and furosemide were prescribed off-label for different indications (indomethacin for patent ductus arteriosus and furosemide for chronic lung disease), gentamicin was regarded as off-label for dose and/or frequency, diazepam formulation for intravenous use was used for different route of administration  (Silva et al., 2015) Elizabeta Zisovska, Blerina Koshi, Renata Slaveska-Raichki (rectally in the case of neonatal seizures) while imipenem was used out of age range (it is licensed for use in infants above 3 months of age). All off-label and unlicensed medicines were administered according to the current Guidelines, evidencebased and regularly updated but, the level of evidence for majority of the recommendations was not very high. These data further confirm the findings of previous researchers in the field, that there is a lack of knowledge about the efficacy and safety in neonatal therapy. In general, off label use pattern in the one hand attempts to provide appropriate dosage form for patient but on the other hand runs the risk of errors in compounding, dispensing or administration. The bioavailability of such adjusted medicine is unpredictable and there may be no compatibility and/or stability data available.
The specific difficulties for the therapy are in close link to the diagnostic dilemmas for newborns, and the appropriateness of the level of care. Important point for discussion is the cross-matching between the Guidelines and availability of licensed and on-label medicines (Guyatt et al., 1999;Ansani et al., 2006;Glasziou et al., 2007).

Conclusions
The results presented above present only the "top of the iceberg" but there is a lot of work that has to be done in the near future. Nowadays, a growing and stronger demand is observed in off-label medicines, they will be in continuum prescribed within the neonatal therapy and this practice will not be excluded from the evidence based Guidelines. In fact, the majority of off label uses have made substantial progress in treating newborns, especially those critically ill and premature ones. However, the evidence for their efficacy and safety is not on high level, and information on adverse effects is lacking. All these facts require further work and research in this area. This particular study has additionally initiated in depth analysis of the type of pharmaceutical formulations, unlicensed reformulation before administration which were mostly used, pharmacological groups, license status, indications, etc., and the results are intended to be published later as continuum on this topic. Despite the considerable off-label medicines use there is little guidance for prescribers in neonatology Improving drug information for physicians but also for the public is one of the crucial activities in the field of neonatal pharmacotherapy. It could be only achieved by identification of real needs within the neonatal treatment, intensive and systematic research agenda and by providing a National Guideline on off-label use areas in pediatric medicine, which in turn should result in more useful new knowledge to facilitate future treatment decisions.