Off-label and unlicensed drug prescribing in three paediatric wards in Finland and review of the international literature
L. Lindell-Osuagwu, Department of Social Pharmacy, University of Kuopio, PO Box 1627, FI-70211 Kuopio, Finland. Tel.: +358 17 162510; fax: +358 17 162515; e-mail: Leena.Lindell-Osuagwu@uku.fi
Objectives: In paediatric pharmacotherapy, many drugs are prescribed to be given in ways and for conditions not approved in the marketing authorization (MA). Thus, off-label prescribing of drugs with no MA is widespread in paediatric wards. However, drug MA status and clinical practices differ across countries. In this prospective study, we studied the prescribing of off-label and unlicensed drugs in three paediatric wards in a tertiary hospital in Finland. Furthermore, we reviewed previous published studies to provide an up-to-date international perspective on prescribing of off-label and unlicensed drugs for hospitalized children.
Methods: During a 2-week period, prescriptions for patients under 18 years of age (median age 1·6 years) in three wards; neonatal intensive care unit (NICU), general paediatric ward and paediatric surgical ward were recorded daily and drug-licensing status of all prescriptions was determined according to the approved summary of product characteristics. Published studies were retrieved through electronic searches, including MEDLINE (PubMed).
Results: Of the 141 children, 108 received 629 prescriptions. Of the 108 children with a prescription, 82 (76%) had at least one off-label or unlicensed drug prescribed; 79% in the NICU, 63% in the general ward and 91% in the surgical ward (P = 0·014). Of the 108 children with a prescription, 26 (24%) received prescriptions for licensed drugs, 71 (66%) received prescriptions off-label and 36 (33%) for unlicensed drugs. Of all 629 prescriptions, 321 (51%) were for licensed drugs, 226 (36%) for off-label and 82 (13%) for unlicensed drugs. International studies showed similar extents of off-label and unlicensed-drug prescribing.
Conclusion: This study indicates that the use of off-label and unlicensed drugs is widespread in all the different paediatric wards surveyed and was as extensive as those reported for other countries.
The regulatory system for drug licensing and clinical trials generally ensure high quality, safety and efficacy of marketed medicinal products. Unfortunately, usually clinical drug trials are conducted mainly in adults; hence physicians must often prescribe drugs for children to be given in ways and for conditions not approved in the marketing authorization (MA), and for which clinical trial evidence of safety and efficacy is sparse. Of all the active substances licensed by the European Agency for the Evaluation of Medicinal Products (EMEA) during October 1995 to September 2005, only 33% were licensed for use in children, 23% in infants and 9% in newborns (1). As a consequence, the use of drugs outside the terms of the MA (off-label use) and the use of drugs with no MA (unlicensed use) is widespread in paediatric pharmacotherapy (2–9). This is a concern because adverse drug reactions in children may be more common with unlicensed and off-label treatment than with drugs licensed for paediatric use, and the practice may result in either over- or underdosing of drugs in different age groups (10–12). The new Regulation (1901/2006/EC) of the European Parliament and Council on medicinal products for paediatric use came into force in January 2007 (13). This Regulation requires clinical trials to be done also in the paediatric population, especially, if children are likely to benefit from a new drug. The regulation also allows pharmaceutical companies to update the summary of the product characteristics (SPC) of authorized drugs used off-label on children by submitting, to the regulatory authorities, accumulated data on safety or efficacy in this age group, and undertaking new paediatric trials.
Prescribing of drugs for off-label and unlicensed use has been described in studies from North and South America, Australia, the Middle East and Europe (9). These studies show that the situation varies across countries because of the differences in authorization status of medicinal products and clinical practice. We initiated the present study to assess the prescribing of unlicensed drugs and of drugs off-label for children in Kuopio University Hospital (KUH), Finland. The new Regulation (1901/2006/EC) of the European Parliament and Council on medicinal products for paediatric use obliges the Member States, including Finland, to collect available data on use of medicinal products in the paediatric population (13). Thus, this study provides valuable information on current practice in Finland and reviews international studies of such prescribing for hospitalized children.
Review of the international literature
Reports of prescribing of drugs off-label and of unlicensed drugs for hospitalized children were retrieved through electronic searches of Medline (PubMed) and International Pharmaceutical Abstracts (IPA), using list of keywords representing pharmaceutical preparations, paediatric population, different hospital departments, and off-label and unlicensed drug prescribing (Appendix 1). The search included reports published in English between the years 1990 and 2007.
Twenty-four studies, from 12 different countries, mostly European (n = 8), were identified for inclusion in this review. The study periods ranged from 4 weeks to 2 years. Most of the studies were prospective (n = 19) and more than half included at least 100 children. The studies report the frequency of prescribing off-label and unlicensed drugs for children in neonatal intensive care units (NICUs), paediatric intensive care units (PICUs), medium-care units (MCUs), surgical intensive care units (SICUs), paediatric general and acute care/emergency department, cardiology, gastroenterology, oncology, psychiatry, isolation and surgical wards. Some studies focused on neonates or infants (n = 4) (3, 14–16), paediatric pain management (6) or adverse drug reactions associated with off-label and unlicensed drug use (10, 17).
The number of patients studied ranged from 34 to 355 409 and their age from less than 1 day to 18 years (Table 1). The number of prescriptions or prescription and drug episodes studied ranged from 176 to 4455. In two studies, the number of prescriptions was not indicated.
Table 1. Summary of studies reporting of prescribing of OL and/or UL drugs for hospitalized children in chronological order
|USa||McKinzie et al. (42)||R|
|Paediatric emergency department||359||<18 years||–||–||–||43% OL|
|UK||Turner et al. (2)||P|
|Surgical and medical paediatric wards||609||4 days to 20 years||2013||18%||7%||36%|
|UK||Conroy et al. (3)||P|
|UK||Turner et al. (10)||P|
|Surgical, medical, neonatal surgical, cardiac ICU, PICU||1046||1 day to 18 years||4455||35% OL or UL||48%|
|Surgical and general paediatric wards||200||49 days to 18 years||735 drug episodes||16% OL or UL||36%|
|UK, Sweden, Italy, Germany, Netherlands||Conroy et al. (4)||P|
|Paediatric wards in 5 hospitals||624||4 days to 16 years||2262||39%||7%||67%|
|Israel||Gavrilov et al. (44)||R|
|Paediatric ambulatory service||132||1 month to 18 years||222||26%||8%||42%|
|UK||Conroy and Peden (6)||P|
|Acute medical and acute surgical ward||–|| ||715 prescription episodes||33%||0%||–|
|Netherlands||‘t Jong et al. (22)||P|
|MCU, NICU, SICU, PICU||237||0−17 years||2139||18%||48%||92%|
|Israel||Barr et al. (14)||P|
|Australia||O’Donnell et al. (15)||P|
|Italyb||Pandolfini et al. (19)||P|
|9 general paediatric wards in different hospitals||1461||1 month to 14 years||4265||60%||0·2%||89% OL|
|Netherlandsc||‘t Jong et al. (20)||P|
|Paediatric ward and neonatology unit||293||0 day to 16·7 years||1017||44%||28%||92%|
|Brazild||Carvalho et al. (35)||P|
|PICU||51||1 month to 13 years||747||50%||11%||100% OL 88% UL|
|UK||Conroy et al. (23)||P|
|Paediatric oncology patients||51||7 months to 16 years||569 prescription episodes||26%||19%||100%|
|UK||Dick et al. (45)||R|
|Paediatric gastroenterology unit||308||20 days to 17 years||777||37%||12%||–|
|Israel||Gavrilov et al. (28)||R + P|
3 + 4 months
|2 PICUs||158||6 days to 18 years||874||40%||41%||83%|
|Germany||Neubert et al. (17)||P|
|Paediatric isolation ward||178||5 days to 17 years||740||26%||0·4%||52%|
|Francee||Serreau et al. (46)||P|
|Child and adolescent psychiatry department||162||3−15 years||295||25%||23%||–|
|Serbia and Montenegro||Bajcetic et al. (24)||P > 2 years||Paediatric cardiology department||544||4 hours to 18 years||2037||47%||11%||76%|
|USa||Eiland and Knight (47)||P|
|Paediatric general ward||403||3 days to 18 years||1383||31%||–||–|
|Switzerland||Di Paolo et al. (21)||P|
|Neonatal, PICU, intermediate care, medical and surgical ward||60||0−13·7 years||483||25%||24%||100%|
|Italy||Dell’Aera et al. (16)||P|
|USf||Shah et al. (48)||R|
|31 hospitals||355 409||≤18 years||–||–||–||79% OL|
The definition of off-label drug use and unlicensed drug varied between different studies. Therefore, the results are not directly comparable but give an overall picture of the issue. The most common (15/24) definitions, as used by Turner et al. (2, 10, 18), describe off-label use as the use of drugs outside the terms of the MA, with regard to dose, age-group, route of administration, different indication or contraindication in children. Unlicensed drugs are defined as modified formulations including extemporaneous preparations, drugs or formulations with ‘specials’ manufacturing licence, and imported drugs and chemicals used as drugs. In addition, three reports used very similar classifications.
The national medicine compendia (British Pharmaceutical Industry’s Data Sheet Compendium, Physician’s Desk Reference, Australian Prescription Products Guide, Swedish Physician’s Desk reference, Rote Liste, Informatore Farmaceutico, Repertorium and Farmacotherapeutisch Kompas, Israel Drug Compendium, National French compendium Vidal, Yugoslav National Formulary, Swiss Drug Compendium) were the primary sources of information, followed by package inserts and manufacturers. Manufacturers were contacted mainly if the information was ambiguous or to confirm the licensing status. In seven studies, a secondary or additional source of information was the British National Formulary.
The proportion of children with at least one prescription for off-label use or unlicensed drug ranged from 36 to 100% in 19 studies (Table 1). Four studies reported the proportion of children with a prescription for off-label use (range 43−93%). In four studies, the proportion of children receiving prescriptions for off-label use or unlicensed drug was not reported.
The proportion of prescriptions for off-label use ranged from 18 to 60% (20 studies) (Table 1). The proportion of prescriptions for unlicensed drugs ranged from 0 to 48% (19 studies). Two studies reported the proportion of prescriptions for off-label use combined with the proportion of prescriptions for unlicensed drugs (16% and 35%).
The most frequent reason (in 12 studies) for off-label prescriptions was deviation from dosage recommendation followed by deviation from approved age range. The most frequent reason (in 15 studies) for prescriptions of unlicensed drugs was modification of licensed drugs.
Thirteen studies, reported that the age-group most commonly receiving prescriptions for off-label use was adolescents (in two studies 66% and 69·7%) (17, 19). Similarly, the age-groups most commonly receiving unlicensed drugs were neonates, infants and children less than 2-year old (20, 21).
Eight studies included NICUs or other neonatal wards (3, 10, 14–16, 20–22). The proportion of infants who received either prescription for off-label use or unlicensed drugs ranged from 80 to 93% in four NICUs (3, 14–16). In addition, ‘t Jong et al. (2001) reported that infants and newborns in NICU had high use of home-label prescriptions (41%). Similarly, in year 2002, ‘t Jong et al. reported that the number of patients receiving one or more unlicensed or off-label drug prescriptions was higher in newborns and small infants (98% compared with 88% in all children). Bajcetic et al. reported that in paediatric cardiology department the neonates received the largest proportion of off-label drugs, and Di Paolo et al. reported that infants and toddlers (1–23 months) received more unlicensed drugs (33%) than other groups.
In studies mainly from intensive care units (n = 9), the proportion of children receiving either prescription for off-label use or unlicensed drugs is high (range 80–100%). Similarly, all children with malignancies and 76% of cardiologic patients received at least one prescription for off-label use or unlicensed drug (23, 24).
The most common single drug prescribed off-label was salbutamol (in seven studies). For unlicensed drugs, the variation among studies was wide. Caffeine was mentioned in three studies among the commonest unlicensed drugs.
Materials and methods
We reviewed prospectively the prescriptions for patients aged below 18 years admitted to three children’s wards; NICU, general paediatric ward and paediatric surgical ward of KUH. The data were collected during a 2-week period in each of the wards between 16 April and 25 May 2001. KUH is one of the five University Hospitals in Finland. In 2001, KUH provided tertiary level treatment for a population of 860 000 inhabitants with 183 000 children aged below 18 years (25).
From the patient records at the wards, we recorded each patient’s age, gender, date of birth, weight and diagnoses. For each drug prescribed, indication for use, dose, frequency, intended route of administration and dosage form were recorded. We did not include cytostatics, standard intravenous replacement solutions, flushes of 0·9% sodium chloride or heparin, blood products, oxygen, nutritional and technical products, basic creams and ointments, or drugs in clinical trials. Drugs were classified according to the World Health Organization’s Anatomical Therapeutic Chemical (ATC) classification system (26). We classified all drugs prescribed in terms of their drug-licensing status, i.e. licensed, off-label and unlicensed, using a previously described classification system (2, 18) and according to the approved SPC texts in the Finnish drug formulary, Pharmaca Fennica (27).
To ensure the validity of the study, we did a parallel classification of the drug-licensing status. Two different pharmacists completed the classification independently. There were no differences in these two parallel classifications of off-label and unlicensed and licensed drug classes. Moreover, to test the reliability of the study parallel data with 15 patients, who received 120 prescriptions, were collected. The differences between the two data collections were slight and not significant; i.e. two different persons were able to collect the same information.
A total of 141 children; 37 in the NICU, 65 in the general paediatric ward and 39 in the children’s surgical ward were treated in KUH during the 2-week study period (Table 2). The children’s median age was 1·6 years and 75 (53%) children were below 2 years of age.
Table 2. Number of children with different types of prescriptions in the three paediatric wards studied
|Neonatal intensive care unit||37 (26)||6 (23)||20 (28)||15 (42)||28 (26)|
|General ward||65 (46)||17 (65)||20 (28)||16 (44)||46 (43)|
|Surgical ward||39 (28)||3 (12)||31 (44)||5 (14)||34 (31)|
|Total||141 (100)||26 (100)||71 (100)||36 (100)||108 (100)|
The study population was considered as a representative sample of the patients in the three paediatric wards of KUH. The diagnoses of children in the study population were typical illnesses and conditions treated in the three wards. The children in the NICU were mainly (23/37) ex-preterm or preterm infants who had problems because of their prematurity (74/91 of recorded the diagnoses). In the NICU, many children had respiratory distress syndrome, which is typical for preterm infants. In the general ward, the most common diagnoses were respiratory diseases and infections (30/109 of the recorded diagnoses); and in the surgical ward, most of the children (25/39 of the patients) had surgical procedures under general or regional anaesthesia. The median of the follow-up-time per child was 3 days (range 0–12 days).
Data were analysed with the Statistical Package for Social Sciences (spss software version 11.5 for Windows; SPSS Inc, Chicago, IL, USA). The differences in proportions between the three wards were compared with Pearson’s chi-squared test and those in continuous variables with the Kruskal–Wallis test. A P-value of 0·05 or less was considered significant. This study was approved by the hospital’s medical administrator.
One hundred and eight of the 141 children, 28/37 in the NICU, 46/65 in the general and 34/39 in the surgical ward received at least one prescription (Table 2). A total of 629 prescriptions, 155 in the NICU, 152 in the general ward and 322 in the paediatric surgical ward were provided. The mean number of prescriptions per child was less, 4·2 ± 4·4 (range: 0–19) in the NICU and 2·3 ± 2·5 (range 0–11) in the general, than in the surgical ward, 8·3 ± 6·4 (range 0–23) prescriptions (P = 0·002 compared with NICU and P = 0·001 compared with general ward).
Of the 108 children with a prescription, 82 (76%) children, 79% in the NICU, 63% in the general ward and 91% in the surgical ward (P = 0·014), were prescribed at least one drug for off-label use or unlicensed drug. Seventy-one (66%) children received prescriptions for off-label use, 36 (33%) for unlicensed drugs and 25 (23%) got both types of prescriptions. Of all prescriptions (n = 629), 51% were for licensed drugs, 36% for off-label use and 13% for unlicensed drugs (Table 3).
Table 3. Off-label prescriptions and prescriptions for unlicensed drugs in the different paediatric age groups
|New-born infants (0–27 days)||28 (20)||30 (9)||15 (7)||9 (11)||54 (9)|
|Infants and toddlers (28 days to 23 months)||47 (33)||107 (33)||76 (34)||62 (76)||245 (40)|
|Children (2–11 years)||53 (38)||128 (40)||103 (45)||10 (12)||241 (38)|
|Adolescents (12–17 years)||13 (9)||56 (18)||32 (14)||1 (1)||89 (14)|
|Total||141 (100)||321 (51)||226 (36)||82 (13)||629 (100)|
The number of off-label prescriptions per child with a prescription ranged from 0 to 17 (median 1). The number of unlicensed drug prescriptions per child with a prescription ranged from 0 to 6 (median 0). Of the children with an off-label prescription, 36 (51%) and of those with prescriptions for unlicensed drugs 26 (72%) were below 2 years (Table 3).
The classification of off-label prescriptions (n = 226) are shown in Table 4. Most of the off-label prescriptions, 161 (71%) were given in the surgical ward, while 36 (16%) of the prescriptions were provided in the NICU and 29 (13%) in the general ward. The classes of prescribed unlicensed drugs are shown in Table 5. Most of the prescriptions for unlicensed drugs, 58 (71%) were given in the NICU, 19 (23%) in the general and five (6%) in the surgical ward.
Table 4. Off-label classes
|No directions for use in children or mention of children in the SPC||87 (38)|
|Administration by an alternative route||77 (34)|
|Outside dosage recommendations (dose, frequency, weight) ||50 (22)|
|Prescribed for off-label indication||43 (19)|
|Outside approved age range||28 (12)|
|Formulation not approved for use in children||5 (2)|
|Not recommended for use in children||1 (<1)|
Table 5. Classes of unlicensed drugs
|Special licence for non-licensed drug (includes products released for consumption in individual cases for special therapeutic reasons)||51 (62)|
|Drugs prepared by the hospital pharmacy||27 (33)|
|Modification of licensed drug||3 (4)|
|Marketing authorization expired||1 (1)|
Of all prescriptions in the NICU, 23% were for licensed drugs prescribed off-label and 37% for unlicensed drugs, in the general ward 19% and 13%, and in the surgical ward 50% and 2%, respectively (P < 0·001).
The 20 most commonly prescribed drugs include over half (56%) of all prescribed drugs (Table 6). Only five drugs among the top 20 were prescribed according to the SPC and formulation had not been modified for use in children. According the ATC classification, the most commonly prescribed drugs in the NICU were drugs for alimentary tract and metabolic diseases and anti-infective drugs for systemic use, in the general ward anti-infective drugs for systemic use and drugs for diseases of the respiratory system, and in the surgical ward, drugs that affect the nervous system and anti-infective drugs for systemic use were the most commonly prescribed drugs.
Table 6. 20 most frequently prescribed drugs (% of total 629) in the three children’s wards
|Midazolam (only in surgical ward)||32 (5)||56||–|
|Oxycodone (only in surgical ward)||22 (4)||100||–|
|Ergocalciferol (vitamin D2)||20 (3)||20||–|
|Ferrous sulphate||18 (3)||0||89|
|Ketaminea (only in surgical ward)||18 (3)||100||–|
|Benzylpenicillin (Penicillin G)||15 (2)||20||–|
|Neostigmine (combined preparation)||13 (2)||0||–|
|Mineral substances (only in NICU)||12 (2)||b||100|
|Ascorbic acid (vitamin C) (only in NICU)||11 (2)||b||100|
|Combined vitamin preparations (only in NICU)||11 (2)||b||100|
Our findings show that prescribing unlicensed drugs for children is as common in Finland as in other countries. The proportion of children who received either an unlicensed or an off-label prescription or both in KUH was 76%, which is somewhat smaller than that (80–90%) described, in previous studies (3, 5, 15, 28). This could be explained by the differences in the study populations, with the previous study populations being mainly from PICUs. This study indicates that there may be significant differences across different types of paediatric wards.
Drugs used during the perioperative period explain why children in the surgical ward most commonly received off-label prescriptions. One example of a drug prescribed off-label and used for pain in children in the surgical ward was oxycodone, a substance which has been in clinical use for 90 years and which is the most commonly used opioid for acute pain in Finland both in adults and in children (29, 30). However, in the SPC of oxycodone there are no directions for use in children (27). Until the incentives of the Regulation (1901/2006/EC) of the European Parliament and Council came into force in January 2007 (13), expanding the MA for an old product or developing a new formulation solely for a small population, such as children, was not profitable for the manufacturers. Now, a paediatric use marketing authorization entitles a manufacturer to 10-year data protection and exclusivity for a new paediatric formulation of an old drug. The lack of a suitable paediatric formulation was the reason why oxycodone, ketamine and midazolam, were prescribed for administration by the alternative buccal route. Published clinical studies provide information on paediatric pharmacokinetics of oxycodone and midazolam administered by different routes, including buccal and oral delivery (31–33). By using these more child-friendly administration routes, intramuscular administration, which is one of the most frightening scenarios for hospitalized children, could be avoided.
Children in the NICU received the largest number of prescriptions for unlicensed drugs, again reflecting lack of suitable formulations for neonates and infants. The overall proportion of prescriptions for unlicensed drugs (13%) in our study was similar to that described by others (10–12%) in PICUs in France, Australia, Brazil and Italy (15, 16, 34, 35). Prescribing unlicensed drugs may be essential and does not necessarily imply poor medical practice. When there was no alternative, many prescriptions in this study were prepared by the hospital pharmacy or used a modification of a licensed product. The sales of such drugs may be insufficient for industrial production. In our study, an example was an ascorbic acid drop, which is no longer marketed by pharmaceutical companies in Finland.
Similar to other studies (3, 15, 34, 36), the age-group of children with the greatest demand was the lower than 2-year-old group. If the SPC of a drug includes an age restriction, it is usually a statement to the effect that information on appropriate use for the youngest potential users is lacking. An overdose increases the risk of adverse drug reactions, whereas an underdose may not be therapeutically useful, e.g. suboptimal doses of antibiotics do not cure infections and may select out resistant microbes.
Implementing paediatric clinical trials is time-consuming and expensive. To increase the availability of suitable, licensed drugs for children in Europe, some legislative measures have been taken. First, the EU directive (2001/20/EC) concerns clinical trials in children and defines how to protect them in trials (37). Second, in 1997, the EMEA published ‘Note for Guidance on Clinical Investigation of Medicinal Products in the Paediatric Population’. This gives directions for testing drugs in children and has been in force since January 2001 (38). Third, a European legislative initiative called ‘Better Medicines for Children’ has been under way since the late 1990s (39), and led to a legislative process that is currently being finalized. The regulation includes, among other things, a 6-month extension for the SPC as an incentive to the pharmaceutical industry (13). The 6-month extension is the same as that provided in the USA since 1997 (40).
In our study, among the top 20 prescribed drugs, five are listed in the EMEA priority list (41), which identifies off-patent products for which paediatric studies are required.
The results of this study, in support of those of earlier studies, indicate that prescribing of off-label and unlicensed drugs is common not only in high dependency units but also in normal inpatient care. In our population, it was most common in the treatment of paediatric surgical patients. Therefore, to avoid exposing children to unnecessary risks and to avoid depriving them of potentially effective pharmacotherapy, both enforcement of legislation and continued incentives are needed to encourage the development of paediatric medicines.
The collaboration of Bachelor in Pharmacy, Sirkka Lampinen, and the personnel in three children’s wards, NICU, general and surgical wards of Kuopio University Hospital, Finland is gratefully acknowledged.
PubMed search profile.
|#29||Search #16 NOT #28 (all other reports, ‘exlution’ of hospitals)||135|
|#28||Search #16 AND #27 (inclusion of hospitals)||188|
|#27||Search ‘Hospitals’[Mesh] OR hospital OR hospitals OR hospitali* OR ‘Hospital Departments’[Mesh] OR ward* OR ‘Patient Care’[Mesh] OR clinic OR clinics OR clinical* OR ‘Hospital Units’[Mesh]||3081441|
|#16||Search #11 OR #14 OR #15 (hospitals, 188 + non-hospitals, 135 = 323)||323|
|#15||Search #7 AND #12 AND (child* OR infant* OR newborn* OR neonate* OR adolesc*) Limits: Publication Date from 1990 to 2007, English||28|
|#14||Search #7 AND #12 Limits: Publication Date from 1990 to 2007, English, All Child: 0–18 years||27|
|#13||Search #7 AND #12||86|
|#12||Search pharmaceutical* AND preparation*||46118|
|#11||Search #9 OR #10||323|
|#10||Search #6 AND #7 AND (child* OR infant* OR newborn* OR neonate* OR adolesc*) Limits: Publication Date from 1990 to 2007, English||323|
|#9||Search #6 AND #7 Limits: Publication Date from 1990 to 2007, English, All Child: 0–18 years||277|
|#8||Search #6 AND #7||1741|
|#7||Search offlabel OR ‘off label’ OR off-label OR unlicen* OR un-licen* OR nonlicen* OR non-licen* OR unregister* OR un-register* OR nonregister* OR non-register* OR unauthori* OR un-authori* OR nonauthor* OR non-author* OR (outside AND (authori* OR label* OR licen*))||5239|
|#6||Search ‘Pharmaceutical Preparations’[Mesh] OR drug OR drugs OR medicines||3513162|
International Pharmaceutical Abstracts (IPA) database query:
(offlabel OR off label OR off-label OR unlicen* OR un-licen* OR
nonlicen* OR non-licen* OR unregister* OR un-register* OR nonregister* OR
non-register* OR unauthori* OR un-authori* OR nonauthor* OR non-author* OR
(outside AND (authori* OR label* OR licen*)))
(toddler* or child* OR infant* OR newborn* OR neonate* OR adolesc* OR pediatr* OR paediatr*)