International Journal of Clinical Pharmacy

, Volume 34, Issue 1, pp 136–141 | Cite as

Off-label and unlicensed drug use in neonatal intensive care units in Turkey: the old-inn study

Research Article


Background Recently several developed countries have improved the safety and efficacy of drugs used in infants and pediatric patients. Most drugs administered to adults have licensed approvals outlining indications, doses, and the recommended route of administration. However, many drugs that are given to children are unlicensed or used off-label. Objectives To assess the extent and nature of unregistered and off-label drug use in neonatal intensive care units (NICUs) in Turkey, and to explore awareness and views of the general public on the unlicensed use of medicine in preterm and term infants in developing countries. Study Design A prospective observational study of a dynamic cohort of 464 neonates from 17 NICUs in Turkey. All medications administered to neonates who were hospitalized and admitted to the NICU over a 24-h period were recorded. The prescriptions were analyzed to determine whether the medicines were used in a licensed or unlicensed manner. Results In total, 1,315 prescriptions comprising 93 different medicines were written. We found that 62.3% of the drugs prescribed to the neonates over the 24-h period were unlicensed or off-labeled. Conclusions The present study indicates that unlicensed and off-label medicines are frequently used in preterm and term infants in Turkish NICUs. This finding is consistent and reported in other countries. We believe that the needs of the neonatal population must be a priority and access to safe and appropriate medicines requires urgent attention.


Neonates Off-label drug Turkey Unlicensed drug 

Impact of finding on practice statements

  • The Medicines Control Agencies should ensure that neonates receive drugs that are as carefully evaluated for efficacy, safety, and quality as the drugs given to adults.

  • The pharmaceutical industry should provide drugs that are appropriate for use in neonates as well as in adults.

  • Healthcare staff caring for children, the industry, and the government should combine their efforts to avoid off-label and unlicensed drug use in neonates.


Recently several developed countries have increased the safety and efficacy of drug use in infants and pediatric patients. However, in developing countries, differing ethical, financial, and legal issues have hampered efforts to ensure the prescription of safe and effective drugs for pediatric patients. It is of paramount importance that all interventions are individualized to the needs of a given country or given region within a country, because one solution will not meet all the differing needs. Thus, the importance of a country-specific assessment cannot be overemphasized.

The neonatal death rate in Turkey decreased significantly, from 29.2% in 1998 to 13% in 2008, as a result of the increase in healthcare providers, standardized and coordinated healthcare services, and quality of care in neonatology advanced in last 10 years [1]. However, further improvements in patient safety and treatment efficacy must be made. Safe and effective treatment for newborns is possible when the indication is accurate and the medication is licensed and the proper route of administration is used [2].

In Turkey, drugs are required to be licensed by the Ministry of Health. This is essential to ensure drug safety, efficacy, and quality. Most drugs that are administered to adults have licensed approvals, outlining the indications for which they may be used, appropriate doses, and the recommended route of administration. However, several drugs administered to children are unlicensed. Furthermore, many licensed drugs are prescribed to children outside of their approved terms of use (i.e., off-label).

Despite considerable concern over the use of unlicensed and off-label drugs in newborns and children, little information is available on the extent to which these types of treatment are used. Published data from pediatric intensive care units (PICU) and neonatal intensive care units (NICU) are scarce and do not provide a clear picture, because of methodological bias.

The objective of the off-label drugs in neonatology (OLD-INN) study was to assess the extent and nature of unregistered and off-label drug use in Turkey, based on data collected from 17 NICU wards.


We conducted a prospective observational study of all prescriptions for a dynamic cohort of infants in 17 NICUs in Turkey. All medications administered to neonates who were hospitalized and admitted to the NICU during a 24-h period were recorded by volunteers in the 17 wards in December 2010. Data included the patient’s initials, date of prescription, ward, date of birth, weight, and medication (dosage form, dose and frequency of administration, route of administration, and special instructions). Standard intravenous replacement solutions, sodium chloride 0.9% infusions, total parenteral nutrition, blood products (except albumin), and oxygen were not recorded. The indication for drug use was discussed with the responsible physician in each ward.

All prescriptions were analyzed to determine whether the medication was used in a licensed or unlicensed manner. Unlicensed medicines were subdivided into two classes: (1) Medication prepared or modified by neonatal nurses (e.g., an adult tablet is crushed and reconstituted in a solution) or by the hospital pharmacy (e.g., batch or extemporaneous preparations) and (2) Medication imported from a foreign country.

Licensed medication was further classified into two classes: (1) Medication used in an off-label manner with no information concerning its use in neonates. (2) Medication licensed for infant use, but off label for the (a) indication and contra-indication, (b) dose and frequency of administration, or (c) route of administration.

All data forms were sent to the Zekai Tahir Burak Maternity Teaching Hospital NICU, the lead unit in the study. All parts of the medicine’s monograph or package insert were screened using the Rx Media Pharma 10.0.0 interactive program for information regarding pediatric use [3] in Turkey and for an international review all prescriptions were searched in pediatric dosage handbook [4]. The study was approved by the local ethics committee (20 December 2010/21).

Data were collected in a database and summarized using standard descriptive methods.


We enrolled 464 neonates from the 17 participating NICUs in the OLD-INN study. The median gestational age was 32.5 ± 4.7 weeks, the median actual weight was 2,081 ± 951 g, and 24.6% of the subjects were term infants.

In total, 1,315 prescriptions were written, comprising 93 different medicines. The number of prescriptions per patient ranged from 1 to 11 and the median was three prescriptions (Table 1). The 10 most frequently administered drugs were ampicillin (8.2%), multi-vitamins (6.3%), amikacin (5.4%), meropenem (4.9%), vancomycin (4.8%), netilmicin (4.2%), nystatin (4.1%), caffeine citrate (3.5%), theophylline (3.4%), and penicillin G (2.6%). The drugs prescribed during the study were classified into eight groups. The classification of the drugs and the number of prescriptions in each group are shown in Fig. 1. The ratio of licensed drugs to unlicensed drugs according to the each drug group was summarized in Fig. 2 and the off label use of licensed drugs according to the groups was demonsrated in Fig. 3.
Table 1

Summary of data collected from the participating NICU wards

NICU ward

Number of patients

Total number of prescriptions

Number of prescriptions for each infant (min–max; median)




1–9; 3




1–1; .2




1–3; 2




2–7; 4




2–8; 2




1–6; 3




1–3; 2




1–5; 2.5




1–4; 2




1–9; 4




1–6; 3




1–4; 2




1–4; 2




1–5; 2




1–6; 3




1–9; 3




1–7; 3.5

Fig. 1

Drug classification groups and number of prescriptions and different medicines prescribed in each group

Fig. 2

Ratio of licensed drugs to unlicensed drugs

Fig. 3

The distribution of licensed medicine according groups

The present multi-centered study conducted in NICU wards in Turkey showed that 62.3% of the drugs prescribed to the 464 neonates enrolled in the study were unlicensed or used off-label according to national database and 47.6% of them were unlicensed or off-label according to pediatric dosage handbook [4]. The most common reason given for unlicensed or off-label drug use was the lack of information specifically for neonates (50.1, 33.3% national and international consecutively). Other off-label uses were related to dose and frequency of administration (13.5%), and indications and contraindications (8.1%). Unlicensed drugs accounted for 28.8% of the prescriptions and uses were related to modification of adult tablet forms (20.5%) and imported medicines (8.3%). 9.5% of them were unlicensed and 12.4% have extemporaneous preparations according to pediatric dosage handbook [4].


Several studies have described categories of unlicensed drugs used in infants [4, 5, 6, 7, 8]. Hsien et al. [9] demonstrated that 61% of pediatric patients in Germany received an off-label drug at least once in their life. There are several studies showed that at least one off-label drug administration in pediatric patient group was 50% [10, 11]. In a meta-analysis it has been shown that the neonates most often exposed to off-label or unlicensed drugs when compared to other pediatric age group. Such as in NICUs off label drug exposure is 80–97% however in PICUs 36–92%. Furthermore it has been reported that in NICUs only 37.5% of medications were used as it is recommended in product license and 75.3% of medication are off-labeled or unlicensed [12]. Similarly, our study found that the incidence of unlicensed and off-labeled medicine used in Turkish NICUs was 62.3% of NICU prescriptions. In this study unlicensed and off-labeled drug use percentage was found slightly lower than the previous studies published. We thought that this slight difference should be due to the methodology of this study because we recorded the prescriptions only for 24 h however in previous studies this period varied 5–13 weeks long [13, 14, 15, 16]. Furthermore when we reviewed the prescriptions in an international source in pediatric dosage handbook [4] the percentage of unlicensed and off-label drug use decreased to 47.6%. We considered that the number of medicines which are not commercially available (8.3%) and that do not have pediatric formulation caused this difference.

468 neonates from different NICU wards were subjected to this study and to our knowledge this is the largest study in the literature since the number of subjects varies to 40–105 neonates in previous studies [9, 10, 11, 12, 13, 14, 15, 16]. Furthermore we considered that this study underlined the differences between the NICU wards that collaborated to the study. There are a few studies published from Turkey that subjected the unlicensed or off label drug use in adults especially who suffered from cancer or eye diseases but this is the first study which explores the unlicensed and off label drug use in neonates in Turkey [17, 18, 19].

Use of a medicine may be classified as off-label for several reasons, including dose and frequency, indication/contraindication, and route of administration [20, 21]. Medication delivered at a dose other than that recommended in the product license (PL) or marketing authorization (MA) has been reported. For example, doses of aminoglycosides amikacin higher than those recommended by the PL are used in NICUs [22]. Drugs such as ibuprofen and erythromycin are used for indications other than those recommended by the PL or MA [23]. In this study most common reason of off label drug prescription was the lack of information (50.1%), the others were dose and frequency of administration (13.5%), and indications and contraindications respectively (8.1%). Similar to our findings Avenel and Barr also demonstrated that the most common reason for off label drug use was the lack of information [14, 15].

Modification of a licensed product renders it unlicensed [20, 21]. For example, no registered pediatric preparation of furosemide or propranolol is available in Turkey; thus, the adult tablet is crushed and reconstituted in a solution, a portion of which is administered to the neonate. As in other European countries, suspensions made from adult tablets are prepared in hospital pharmacies in Turkey [14, 15, 16, 21]. These suspensions are not physically or chemically stable, usually do not taste good, are not hygienic, and often exceed the daily fluid allowance of newborns, and, as a result, they are unreliable [9, 10, 11, 12, 13, 14, 15, 16, 24]. In this study we reported that 28.8% of the drugs used are unlicensed in newborn patient group, in the literature this number differs in 10–34% [14, 15, 16]. A large proportion of unlicensed medicines are in-house preparations in Turkey because suitable commercial pediatric drug formulations are not available, and even these formulations are not controlled or supervised by the institution.

It is often necessary to use unlicensed or off-label medicines that have not been tested in clinical trials for the indications, doses, age, or route of administration for which they are used in neonates [4, 24]. The pharmaceutical industry lists a number of reasons for not testing medication in neonatal patients such as difficulties in studying drugs in neonates, recruitment problems, ethical issues, and consent issues. However, the truth is that neonatal clinical trials are time-consuming and expensive to perform, and unless the product has a large guaranteed neonatal market, the financial rewards of the work are limited [24, 25]. Without a legal obligation requiring the pharmaceutical industry to conduct appropriate studies, and/or financial incentives to do so, such studies are unlikely to be conducted. Studies of medicine licensed in developed countries show that most of the medications used in neonates have not been tested and subsequently licensed for this population [26, 27]. These findings are not indicative of poor medical or pharmacy practice; unlicensed and off-label drugs are used when no alternative exists. Legislation in Turkey, similar to that in the United States and the United Kingdom, makes provisions for doctors to prescribe, pharmacists to dispense, and nurses to administer unlicensed and off-label medicines [28]. A physician could be sued for malpractice if he or she denied a patient the best potential treatment only because it was unlicensed or off-label. Moreover, professional bodies advise that it is generally not necessary to obtain consent from parents/caregivers or child patients to prescribe or administer unlicensed and off-label medicine any more than consent is necessary for other prescribed medication. All manufactured and marketed medicine is licensed by the Ministry of Health in Turkey; this licensing system was designed to ensure that the medication is tested for efficacy, safety, and quality [28]. In Turkey, it is the physician’s responsibility to fully inform the patient of the warnings stated in the MA [29]. Thus, according to the law, the prescriber is responsible for an adverse reaction to an off-label or unlicensed drug if the parents were not fully informed [2]. In 2006, the Ministry of Health distributed a circular warning against the use of medicine for indications not stated in the MA [30]. According to the circular, unlicensed and off-label medicine could be used only if clear evidence of its safety and efficacy was available and if a standard dosage for the indication had been determined in clinical trials. Furthermore, the circular stated that the Ministry of Health should be informed and permission obtained for other uses of off-label or unlicensed medicines [31]. The current situation is far from ideal, particularly in regard to drugs administered to neonates.


The results of the present study show that unlicensed and off-label medicines are frequently used in preterm and term infants in Turkish NICUs. The present study is the largest reported investigation to focus on unlicensed and off-label drug use in Turkish NICUs, and our findings indicate that the needs of the neonatal population must be a priority and that access to safe and appropriate medication requires immediate attention.

In conclusion, we want to urge neonatal societies, medical associations, pharmaceutical companies, and other non-government organizations to establish committees to monitor unlicensed and off-label drug administration and demand for finding a solution to this problem from government.



Special thanks to Esra Arun Ozer from Tepecik Training and Research Hospital, Güner Karatekin from Zeynep Kamil Maternity and Children’s Education and Training Hospital, Nurullah Okumus from Dr. Sami Ulus Maternity and Children’s Hospital, Nihal Demirel from Etlik Zubeyde Hanım Maternity and Children’s Education and Training Hospital, Seyhan Erişir Oygucu from Diyarbakır Children’s Hospital, Gokhan Buyukkale from Sanlıurfa Children’s Hospital, Murat Saygili from Urfa Maternity Hospital, Sevim Ünal from Ankara Children’s Hematology and Oncology Research Hospital,Neonatology Department, Erdal Peker from Yuzuncu Yil University School of Medicine, Department of Pediatrics, Division of Neonatology, Bilge Tanyeri from Gaziantep Children’s Hospital, Sinan Uslu from Sisli Etfal Children’s Hospital, Ahmet Karadag from İnonu University, School of Medicine Turgut Ozal Medical Center, Department of Pediatrics, Division of Neonatology, Rahmi Örs from Selcuk University, School of Medicine Meram Medical Center, Department of Pediatrics, Division of Neonatology, Esat Köklü from Trabzon Maternal and Child Health State Hospital, Hasan Kahveci from Nenehatun Maternity State Hospital, Yaşar Bildirici from Eskişehir Maternal Child Health State Hospital for their collaboration to the study, sharing information and kind support.



Conflicts of interest

All authors declare that they have no conflict of interest.


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Copyright information

© Springer Science+Business Media B.V. 2012

Authors and Affiliations

  1. 1.Neonatal Intensive Care UnitZekai Tahir Burak Maternity Teaching HospitalCebeci, AnkaraTurkey

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