Eur J Clin Pharmacol DOI 10.1007/s00228-014-1768-9

REVIEW ARTICLE

Use of off-label and unlicenced drugs in hospitalised paediatric patients: a systematic review Joana Magalhães & António Teixeira Rodrigues & Fátima Roque & Adolfo Figueiras & Amílcar Falcão & Maria Teresa Herdeiro

Received: 29 July 2014 / Accepted: 6 October 2014 # Springer-Verlag Berlin Heidelberg 2014

Abstract Purpose The aim of this review is to assess the extent of the use of off-label and/or unlicenced drugs among hospitalised children. Methods A systematic search was made in MEDLINEPubMED for papers published from 1994 to 2012, addressing the prescription of off-label and/or unlicenced drugs for the paediatric population in hospital care. Results Of the 829 studies retrieved, 34 met the inclusion criteria. Prescriptions ranged from 12.2 to 70.6 % for offlabel and from 0.2 to 47.9 % for unlicensed drugs. The J. Magalhães : A. T. Rodrigues : F. Roque : M. T. Herdeiro Centre for Cell Biology, University of Aveiro (CBC/UA), Aveiro, Portugal J. Magalhães : A. T. Rodrigues : A. Falcão Faculty of Pharmacy, Health Sciences Campus, University of Coimbra, Coimbra, Portugal F. Roque Research Unit for Inland Development, Polytechnic Institute of Guarda(UDI/IPG), Guarda, Portugal A. Figueiras University of Santiago de Compostela, Santiago de Compostela, Spain A. Figueiras Consortium for Biomedical Research in Epidemiology & Public Health (CIBER en Epidemiología y Salud Pública—CIBERESP), Madrid, Spain A. Falcão Centre for Neuroscience and Cell Biology, University of Coimbra (CNC/UC), Coimbra, Portugal M. T. Herdeiro (*) CESPU, Instituto de Investigação e Formação Avançada em Ciências e Tecnologias da Saúde, Rua Central de Gandra, 1317, 4585-116 Gandra, PRD, Portugal e-mail: [email protected]

percentage of children who received at least one off-label and/or unlicensed drug ranged from 42.0 to 100 %, with newborns being the population that received most of such drugs. Off-label prescriptions were essential for dose modification (7.1–73.1 %) and unlicensed prescriptions for formulation modification purposes (3.6–100 %). Conclusions These findings show that: (i) off-label and/or an unlicensed prescribing is widespread among the hospitalised paediatric population worldwide, (ii) there is no consensus on a definition of off-label and/or unlicensed drugs and (iii) preterm newborns receive most off-label and/or unlicensed drugs. By shedding new light on off-label and/or unlicensed drug prescribing, these findings will hopefully contribute to generating new, more effective knowledge about the paediatric population’s need for quality drugs that are both safe and efficacious. Keywords Paediatric . Unlicensed . Off-label . Drug . Hospital care

Introduction In general, when a drug is marketed, its efficacy and safety are evaluated by conducting clinical trials on highly selected populations from which the paediatric population has been systematically not sufficiently represented [1–4]. In clinical practice, however, untested drugs have to be administered to a paediatric population in spite of any problems that may entail in the form of: (i) a lack of information about proper dosages, thus leading to an increased risk of adverse reactions that may endanger life; (ii) ineffective treatments; (iii) use of magistral and officinal preparations with no information on stability testing; and (iv) administration of excipients which are included in the prescribed drug formulation and are potentially harmful to this population [1, 5].

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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 newborns [2, 6, 7]. Aware of this, the European Union regulatory authorities issued a new paediatric regulation, i.e. Regulation (EC) No. 1901/2006 of the European Parliament and of the Council of 12 December 2006, which came into force on 26 January 2007 and laid down rules on the development of drugs for human use, in order to meet the therapeutic needs of the paediatric population without subjecting children to unnecessary clinical trials [1, 8, 9]. Despite the above regulation, the use of off-label and/or unlicensed drugs in children inevitably remains an option, and the extent of adverse drug reactions (ADRs) linked to the use of these drugs has been assessed in a number of countries [10–16]. Although previous studies have addressed this problem, we were unable to locate any systematic reviews that evaluated the degree to which off-label and/or unlicensed drugs were prescribed in hospital care. Accordingly, this review aimed to analyse and evaluate the results of papers that focused on assessing the extent of the use of off-label and/or unlicensed prescriptions for paediatric patients in hospital care and thereby provide an overview of the respective reasons given for off-label and/or unlicensed prescribing.

Material and methods Search strategy/search methods for identification of studies A search was made of papers published in the scientific MEDLINE-PubMED database from January 1994 to December 2013. The 19-year period immediately preceding the review was set as the time limit for our search because the topic is a relatively new one and the earliest paper located which was of relevance to our review dated from 1994. To update our results, we conducted a further search from January to February 2014 to include any papers that had been subsequently submitted to the database. The search strategy included the following search terms and equivalents: (child* OR new-born* OR new born* OR newborn* OR infant* OR paediatric* OR pediatric* OR adolescent* OR neonate*) and (off-label* OR off label* OR unlicensed*) and (drug OR off-patent* OR off patent). The study selection criteria required papers to be published in English, Portuguese, or Spanish, with those in other languages being excluded from the review.

Study inclusion criteria To be considered eligible for review, studies were required to: (i) state that their main aim was to assess drug prescription status or ascertain the extent of off-label and/or unlicensed prescriptions in the paediatric population, (ii) use quantitative methodology; (iii) focus on hospital care; (iv) report that data was collected from all patients, a randomised sample or consecutive patients admitted during the study period; and (v) confirm that all drugs prescribed or administered during the study period were assessed for licenced, off-label or/and unlicensed status.

Data extraction To summarise the methodological characteristics of the studies selected and the sample characteristics, Table 1 was drawn up showing the following parameters: author (year of publication), country, setting, study design, study period, criteria used to classify prescriptions as off-label and/or unlicensed, sample size (number of patients) and age of patients included. The age range of the paediatric population was classified in accordance with the definition issued by the International Conference Harmonisation (ICH) [17], namely preterm and term newborn infants (0 to 27 days), infants and toddlers (28 days to 23 months), children (2 to 11 years) and adolescents (12 to 18 years). Studies which reported data from different paediatric care units were considered for review purposes, with the data in such cases being pooled and shown as a single figure. To indicate the extent of off-label and unlicensed prescriptions, the following breakdown was provided in Table 2: total number of prescriptions (n), number of different drugs prescribed (n), number and percentage of licenced prescriptions (n/%), number and percentage of off-label prescriptions (n/%), number and percentage of unlicensed prescriptions (n/%) and number and percentage of children who received off-label and/or unlicensed drugs (n/%). For data extraction purposes, any drug prescribed in accordance with the terms of the marketing authorisation was deemed to be licenced. The following tables were also drawn up: Table 3 shows the distribution of off-label and/or unlicensed prescriptions according to patients’ age and Table 4 gives a breakdown by category. Depending on the authors, the definition of off-label and/or unlicensed prescriptions differed, and the tables thus describe all the categories considered by the authors in their respective studies. With respect to the pertinent drug marketing authorisation, the categories for drugs prescribed on an off-label basis were classified as: (i) different route of administration, (ii) different dose, (iii) outside age range, (iv) different indication, (v) different formulation and (vi) different frequency. Categories other than these were grouped under a separate column.

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contraindicated drugs and (viii) drugs with no information on use among children. Lastly, data on prescribed off-label and/or unlicensed drugs were processed, pooled and categorised according to the Anatomical Therapeutic Chemical (ATC) classification system [18] (Table 5).

In the case of unlicensed drug prescriptions, the categories were as follows: (i) special formulation, (ii) modification of licenced drugs, (iii) new drugs under special manufacturing licence, (iv) drugs prepared from raw materials and chemicals used as drugs, (v) imported drugs not licenced, (vi) drugs available only for patients taking part in trials, (vii)

Table 1 Characteristics of the 33 studies selected, exclusion criteria and off-label and unlicenced drug classification Author

Year of Country Setting publication

Study Study design period

months months months months months months

Classification criteria

Patient Patients’ age sample (n)

Off-label

Unlicenced

1,2,3,4,5 1,2,3,4 1,2,3,4,6,7 1,2,3,4,6,7 1,2,3,4,6,7 1,2,3,4,6,7

a,b,c,d,e,f a,b,c a,b,c,d,e,f a,g a,d,e,f a,c

609 70 624 237 1461 105

0–20 0–27 0–16 0–17 0–18 0–27

years days years years years days

a,g – g f,g a,g a,f,g – a,b,e

293 97 54 48 544 60 403 34

0–17 0–27 0–13 0–27 0–18 0–14 0–18 0–27

years days years days years years years days

600 272 141 300 183 462 38 228 65 387

0–12 years 0–16 years 0–18 years 28 days–12 years 0–27 days 0–14 years 0–27 days – 0–27 days 0–18 years

Turner et al. [19] Conroy et al. [20] Conroy et al. [21] ’t Jong et al. [22] Pandolfini et al. [23] Barr et al. [24]

1998 1999 2000 2001 2002 2002

GBR GBR GBR NLD ITA ISR

W ICU W H W ICU

PS PS PS PS PS PS

4 4 1 1 3 4

’t Jong et al. [25] O’Donnell et al. [26] Carvalho et al. [27] López Martínez et al. [28] Bajcetic et al.[29] Di Paolo et al. [30] Eiland et al. [31] Dell’Aera et al. [32] Jain et al. [33]

2002 2002 2003 2005 2005 2006 2006 2007 2008

NLD AUS BRA ESP SRB SWZ USA ITA IND

W ICU ICU ICU W W H ICU W

PS PS – PS PS PS PS PS PS

5 months 2.5 months 2 months 3 months 25 months 6 months 6 months 2 months 2 months

1,2,3,4,5,6,7,8 – 1,2,3,4,6,7 1,2,3,4,6 1,3,4 1,2,3,4,5,6,8 2,3 1,3,4,6,8 1,2,3,4,6

Santos et al. [34] Lindell-Osuagwu et al. [35] Bavdekar et al. [36] Neubert et al. [37] Morales-Carpi et al.[38] Dessì et al. [39] Doherty et al. [40] Nguyen et al. [41] Khdour et al. [42]

2008 2009 2009 2010 2010 2010 2010 2011 2011

BRA FIN IND GER ESP ITA CAN FRA PLE

W W ICU ICU ER ICU ICU ICU ICU/W

PS PS PS PS PS PS RS PS PS

5 months 0.5 months 7 months 11 months 14 months 1 months 1 months 4 months 1 months

1,3,4,6,7,8 1,2,3,4,5 1,3,6,4 8 1,2,3,4,6,8 1,2,3,4,6,8 1,3,4,5,7,8 1,2,3,4,6,7 1,3,4,6,8

– a,g a,b,d,f – d,f – a,f – a,b,d,e,f a,b,d,f

Van den Berg et al. [43] Lass et al. [44] Ferreira et al. [45] Oguz et al.[46] Dos Santos et al. [47] Palčevski et al. [48] Kimland et al. [49] Carvalho et al. [50]

2011 2011 2012 2012 2012 2012 2012 2012

NLD EST BRA TUR BRA CRO SWE BRA

W H ICU ICU H ICU H ICU

– PS – PS PS PS – PS

0.5 months 12 months 9 months 24 h 3 months 12 months 96 h 1.5 months

1,2,3,4,5,6,7,8 3 1,2,3,4,6,8 1,2,4,5,6,8 1,2,3,4,6,7 2,3,4,5 3,4,5,8 1,2,3,4,6,7

a,g e,d a,e,g a,f,g e,g e,g a,e,g f,g

39 490 73 464 342 691 2947 129

0–17 years 0–27 days 0–16 years 0–27days 0–14 years 0–19 years 0–18 years 0–27 days

Ballard et al. [51] Maltz et al. [52]

2012 2013

AUS USA

W ICU

RS RS

3 months 3 months

1,2,3,4,6,8 3

– –

300 82

0–12 years 0–18 years

Country: GBR UK, NLD The Netherlands, ITA Italy, ISR Israel, AUS Australia, BRA Brazil, ESP Spain, SRB Serbia, SWZ Switzerland, USA United States of America, IND India, FIN Finland, GER Germany, CAN Canada, FRA France, PLE Palestine, EST Estonia, TUR Turkey, CRO Croatia, SWE Sweden; setting: W ward, ICU intensive care unit, H hospital, ER emergency room; study design: PS prospective study, RS retrospective study; off-label: 1 dose, 2 indication, 3 age, 4 route of administration, 5 contraindication, 6 frequency, 7 formulation, 8 other; Unlicenced: a modifications to licenced drugs/ extemporaneous preparations/changes in the pharmaceutical form of the drug, b drugs that are licenced but the particular formulation is manufactured under special licence, c new drug available under a special manufacturing licence, d use of chemicals as drugs/drugs made from raw materials, e drugs used before a licence has been granted/no marketing authorisation, f imported drugs, g other

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Results

Characteristics of selected studies

Selection of papers/search results

The general characteristics of the selected papers are summarised in Table 1. All 34 studies included in this review were undertaken at different hospital departments. Although two studies met the above inclusion criteria, their qualitative data could not be incorporated and they were therefore not included for review purposes [53, 54].

The search strategy identified a total of 881 papers eligible for inclusion. Following screening, 228 papers were retrieved and assessed as eligible for perusal of the full text, resulting in 34 studies [19–52] being included in the review (Fig. 1).

Table 2 Total drug prescriptions and extent of licenced, off-label and unlicenced prescriptions Author

Prescriptions Number of Licenced Off-label Unlicenced Children receiving off-label (n) different drugs (n) prescriptions (%) prescriptions (%) prescriptions (%) and/or unlicenced drugs (%)

Turner et al. [19] Conroy et al. [20] Conroy et al. [21] ’t Jong et al. [22] Pandolfini et al. [23] Barr et al. [24] ’t Jong et al. [25] O’Donnell et al. [26]

2013 455 2262 2139 4255 525 1017 1442

– – – 189 231 – 114 69

74.9 35.4 54.2 33.9 40.1 – 28.4 42.2

18.2 54.7 38.5 18.2 59.7 63.0 43.6 47.2

6.9 9.9 7.3 47.9 0.2 16.6 28.0 10.5

42.0 90.0 67.5 90.1 89.2 93.3 91.8 80.4

Carvalho et al. [27] López Martínez et al. [28] Bajcetic et al. [29] Di Paolo et al. [30] Eiland et al. [31] Dell’Aera et al. [32] Jain et al. [33] Santos et al. [34] Lindell-Osuagwu et al. [35] Bavdekar et al. [36]

747 236 2037 483 1383 176 2064 1450 629 2237

– 48 102 204 – 61 – 120 –

45.8 36.9 41.2 51.1 – 37.5 – – 51.0

42.3 49.6 47.2 25.3 30.9 50.5 50.6 37.4 35.9

11.9 13.5 11.6 23.6 – 11.9 – 5.5 13.0

100 – 76,1 100 – – 90.5 82.6 75.9

1978 667 88 2593 265 917 268 1981

– 102 161 23 – 24 66 – 105

– – 49.3 46.6 – 54.0 57.8 – 113.2

70.6 34.3a 50.7 47.7 12.2 29.4 35.3 43.0 65.0



Neubert et al. [37] Morales-Carpi et al. [38] Dessì et al. [39] Doherty et al. [40] Nguyen et al. [41] Khdour et al. [42] Van den Berg et al. [43] Lass et al. [44]

96.7 70.0 67.9 – 66.7 70.8 51.4 87.2 98.3

Ferreira et al. [45] Oguz et al. [46] Dos Santos et al. [47] Palčevski et al. [48] Kimland et al. [49] Carvalho et al. [50] Ballard et al. [51] Maltz et al. [52] Median (%)

1054 1315 2026 1643 11,294 318 887 1090

– 93 – 198 948 57 106 –

62.5 – 49.3 74.6 84.3 – – 64.0

23.4 47.6a 38.9 13.3 34.3 35.2 31.9 36.0 39.0

a

The results of off-label and unlicenced prescription are presented as one

– 5.7 – 16.6 7.1 28.0 21.8 12.6 11.8 11.9 4.6 – – – 13.0

86.0 – 95.3 47.8 – 78.7 57.3 94.0 90.0

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49–52]. In addition, the exclusion criteria also ruled out oxygen therapy [19–23, 25–27, 29, 30, 33, 36, 37, 39, 41, 44–47, 49–52], drugs used in clinical trials [21, 26, 35, 41, 42] and parenteral nutrition [22, 25–27, 37, 41, 44–47, 50, 51]. In terms of the age of patients included in the studies, the population was very heterogeneous, mainly comprising newborns (n=11) [20, 24, 26, 28, 32, 37, 39, 41, 44, 46, 50]. Two papers that included patients over 18 years old were not excluded because the patients concerned had been followed up by the hospital care unit from an early age [19, 48].

The study setting in the majority of cases was a hospital ward (n=11) [19, 21, 23, 25, 29, 30, 33–35, 43, 51] or intensive care unit (n = 16) [20, 24, 26–28, 32, 36, 37, 39–41, 45, 46, 48, 50, 52]. The studies were conducted in 18 countries spread across four continents, principally Europe (55.9 %) [19–23, 25, 28–30, 32, 35, 37–39, 41, 43, 44, 48, 49], followed by America (23.5 %) [27, 31, 34, 40, 45, 47, 50, 52], Asia (11.8 %) [24, 33, 36, 42, 46] and Oceania (5.9 %) [26, 51]. The country with most studies was Brazil (14.7 %) [27, 34, 45, 47, 50]. Seven studies omitted to define their exclusion criteria [28, 31, 32, 34, 40, 43, 48] and one study drew none identification of classification criteria [26]. The main drugs excluded from evaluation by the papers were from ATC group (B), blood and blood-forming organs, e.g. solutions affecting the electrolyte balance (flushes of sodium chloride 0.9 %, standard intravenous replacement solutions and saline rehydration solutions) [19–27, 30, 33, 35–37, 41, 42, 44–46, 52] and blood products (heparin, plasma derivatives and blood transfusions) [19–25, 27, 29, 30, 33, 35, 36, 39, 42, 44–47,

Off-label and unlicensed prescriptions All studies assessed the extent of off-label prescriptions [19–52] and two papers reported off-label and unlicensed data as combined [37, 46]; the extent of unlicensed prescribing was not assessed by seven studies [31, 33, 36, 38, 40, 51, 52] (Table 2).

Table 3 Distribution of off-label prescriptions by age of population Author

Newborns (0–27 days)

Preterm

Infants (28 days–23 months)

Children (2–11 years)

Adolescents (12–18 years)

Term

TP (n)

OF (%)

UNL TP (%) (n)

OF (%)

UNL TP (%) (n)

OF (%)

UNL (%)

TP (n)

OF (%)

UNL (%)

TP (n)

OF (%)

UNL (%)

Pandolfini et al. [23] ’t Jong et al. [25] Carvalho et al. [27] Bajcetic et al. [29] Di Paolo et al. [30]

– – – – –

– – – – –

– – – – –

– 343 – 25 94

– 51.3 – 64.0 27.6

– 37.3 – 0 19,1

– 304 432 847 166

– 40.8 40.0 45.8 18.7

– 28.9 12.7 5.3 33.1

– 272 254 578 182

58.0 43.0 45.7 55.5 26.9

15.8 10.2 16.8 19.8

– 98 61 587 41

66.0 26.5 44.3 40.2 39.0

26.5 13.1 16.0 12.2

Dell’Aera et al.[32] Jain et al.[33] Lindell-Osuagwu et al.[35] Bavdekar et al.[36] Neubert et al. [37] Dessì et al. [39] Van den Berg et al. [43] Lass et al. [44] Ferreira et al. [45] Palčevski et al. [48] Kimland et al. [49] Carvalho et al. [50] Median (%)

109 – – – 1407 37 – 1339 – – – 134

48.6 – – – 33.3a 43.2 – 68.6 – – – 35.1 45.9

14.7 – – –

67 – 54 – 571 51 42 642 – 80 1875 184

53.7 – 27.8 – 36.6a 51.0 50.5 57.5 – 23.8 38.9 35.3 50.5

7.5 – 16.7 –

– 507 245 1098 – – – – – 526 2644 –

– 51.3 31.0 72.4 – – – – – 16.2 38.6 – 40.0

– – 25.3 – – – – – – 12.7 4.9 – 12.7

– 1557 241 1139 – – 128 – – 645 3800 –

– 50.4 42.7 68.8 – – 39.8 – 16.7 16.2 36.3 – 42.9

– – 4.1 – – – 28.1 – 60.0 10.5 3.4 – 15.8

– – 89 – – – 98 – – 392 2975 –

– – 36.0 – – – 39.8 – 0 3.3 25.2 – 37.5

– – 1.1 – – – 35.7 – 40.0 12.0 3.9 – 13.1

10.8 – 23.2 – – – 14.7

1.9 31.0 19.0 – 16.3 7.4 16.3

TP total prescriptions, OF off-label prescriptions, UNL unlicenced prescriptions a

The results of off-label and unlicenced prescription are presented as one

31.5 16.8 24.6 – 12.4

20.0 23.1 54.6 –

– 30.3 45.7 – – 54.8 – 7.1 12.3 7.7 –

0.5

6.7 0.3 0.2

3.0 –

0 4.9

– 3.4 – –

34.1

1.4 – 16.7 – 20.5 –

Pandolfini et al. [23] Barr et al. [24] ’t Jong et al. [25]

Carvalho et al. [27] López Martínez et al. [28] Bajcetic et al. [29] Di Paolo et al. [30]

Eiland et al. [31] Dell’Aera et al. [32] Jain et al. [33] Santos et al. [34]

Lindell-Osuagwu et al. [35] Bavdekar et al. [36] Morales-Carpi et al. [38] Dessì et al. [39] Doherty et al. [40]a Nguyen et al. [41] Oguz et al. [46]

67.3 67.7 –



34.6 4.7 47.6 – 66.7 –

45.4 18.0

5.0 16.2

8.9 6.9 36.3

1.8

59.1 25.3 17.7

’t Jong et al. [22]

24.3 73.1 –

4.6 9.6 9.4

Age (%)

Turner et al. [19] Conroy et al. [20] Conroy et al. [21]

Dose (%)

Route of admin. (%)

Off-label Reasons Authors

Table 4 Off-label and unlicenced prescription categories

8.4 32.7 – – 5.1 –

19.0

– 25.6 – 21.4 – – –

– – – 2.8 0 –

– 1.1 13.6 –

– –

– 24.3 7.1 1.6 – 33.3

38.5

– 44.9 – –

– 54.1

– –

11.9 – –

– – –

14.0 –



– – –

– Indication/contraindication: 4.9 Dose/frequency: 18.0 – Age/route: 3.4 – Age/weight: 19.9 Dose/frequency: 44.6 Dose/frequency/ weight: 22.1 – Dose/frequency: 38.2 – – – Indication/contraindication: 8.1 Dose/frequency: 13.5

Contraindication: 0.5 – Dose/frequency: 60.7 Dose/indication: 4.4 Dose/frequency: 21.8 Dose/frequency/ indication: 5.1 Dose/frequency/route: 4.4 Dose/frequency/age: 23.1 Dose/frequency/ age/route: 0.8 – – Contraindication: 1.1 Dose/frequency: 56.0 – –

Lack of paediatric Other licence/information (%)

10.5

Frequency of administration (%) – –

2.2

– – – –

– –

– –

68.5 – 22.3 –

5.0 –

5.0 – 0.7



– – 29.9

Formulation (%)

2.5 59.8

12.4 30.2 5.6

1.5

27.2 27.3 9.7

Indication (%)

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72.0 – 3.6 100 20.5 59.4

17.5 – 32.9

– – 20.4

– – 40.0

– – 62.2

11.5 40.0 – – –

– – 12.9

– – –

20.7 Drug made from raw materials/ chemical used as drug (%) 12.9 – – – –

53.8 6.3 30.0

20.6 5.4 –

– – –

– 8.3 8.3

10.5 – 1.2

5.8 – – – 40.6

– – 0.7

– – –

0.7 – – – –

– – 1.4

– – –

– – 2.1 0.7 –

3.9 13.8 28.8 Imported drug Drug available only Contraindicated not licenced to patients taking drug (%) (%) part in trial (%)

10.5 – –

– – 23.6

– 58.8 –

– – 23.6 12.9 –

– – Dose/frequency: 41.0 Age/ weight: 33.2 18.0 No information on use in children (%)

a Authors report results comparing with four compendium, one Canadian, one French and two Contemporary Pediatric References (this two have results aggregated). This table presented the results considering Contemporary Pediatric References

22.3 46.7 74.2 66.0 59.4

46.8 13.3 – 20.4 –

Turner et al. [19] Conroy et al. [20] ’t Jong et al. [22] ’t Jong et al. [25] López Martínez et al. [28] Di Paolo et al. [30] Santos et al. [34] Lindell-Osuagwu et al. [35] Dessì et al. [39] Oguz et al. [46] Median (%)

30.7 55.4 –

24.3 24.6 Modification New drug under (%) special manufacturing licence (%)

16.1 11.6 –

4.6 Special formulation (%)

2.8

8.5

Median (%) Unlicenced Reasons Authors

Dos Santos et al. [47] Carvalho et al. [50] Ballard et al. [51]

Table 4 (continued)

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The off-label prescription data revealed a high degree of use, rising as high as 70.6 % in one study [35], with a median of 39.0 %, and the use of unlicensed prescriptions rose to 47.9 % [22], with median of 13.0 %. Two papers reported that the percentage of children who had received at least one offlabel and/or unlicensed drug was 100 % [27, 30], with a median of 90.0 %. Off-label and unlicensed prescriptions by age of population A total of 17 papers assessed off-label and/or unlicensed prescriptions by reference to patients’ age range [23, 25, 27, 29, 30, 32, 33, 35–37, 39, 43–45, 48–50]. One of these studies reported the off-label and unlicensed data as combined [37] (Table 3). Analysis of off-label and/or unlicensed drugs by age showed that term newborns received the highest percentage of off-label and unlicensed drugs, with a median use of 50.5 and 16.3 %, respectively. Off-label and unlicensed prescription categories As regards the reasons for off-label and/or unlicensed prescribing, 25 studies reported data on off-label prescription categories [19–25, 27–36, 38–41, 46, 47, 50, 51] and ten reported data on unlicensed prescription categories [19, 20, 22, 25, 28, 30, 34, 35, 39, 46] (Table 4). The main reasons cited for off-label prescribing were lack of a paediatric licence or information (median use 28.8 %), use of drugs outside the age range permitted under the marketing authorisation (median use 24.6 %) and use of drugs outside the established dose range (median use 24.3 %). The main reasons identified for unlicensed drug use were modification of licenced drugs (median use 59.4 %), followed by the use of new drugs under a special manufacturing licence (median use 40.0 %). Off-label and unlicenced prescriptions according to the ATC classification A total of 21 studies analysed off-label and/or unlicenced drugs according to the ATC classification [19–21, 23, 24, 26, 28–32, 34–38, 40, 42, 45, 47, 52]; of these, six did not break down the prescriptions into off-label and unlicenced but showed the data as combined [19, 20, 26, 28, 32, 37]. The most prescribed off-label ATC groups were cardiovascular system preparations (C), rising to 43.5 % in one study [29], and anti-infectives for systemic use (J), 39.6 % [29]. In the case of the preparations for alimentary tract and metabolism (A), respiratory system (R) and nervous system, off-label and/or unlicenced prescriptions reached figures of 31.5, 25.2 and 22.6 %, respectively [21, 36, 47].

Discussion This systematic review’s major finding is evidence of a high degree of off-label and/or unlicenced drug use among hospitalised paediatric patients. The percentage of off-label and/or unlicenced drugs was highest in hospital wards, while the most prescribed drugs were for alimentary tract and metabolism, e.g. antiemetics. Methodology was observed to vary among authors, and there was no consensus on a common definition of off-label and unlicenced drugs. Most of the papers included in this systematic review assumed that the use of drugs under offlabel conditions occurred when prescriptions were taken outside the terms of the marketing authorisation, i.e. where there was a difference in age, route of administration, frequency, dose or indication. However, other factors, such as the presence of a different formulation or contraindication, were regarded as off-label or unlicenced by different authors. Only 12 papers [19, 20, 28, 30, 32, 33, 35, 38, 39, 46, 49, 51] accepted the definition of off-label and/or unlicenced drugs proposed by Turner et al. [19]. Unlike the latter [19], some authors viewed contraindicated drugs for paediatric use as unlicenced [22, 27, 34, 43, 47, 48] and drugs with a formulation other than that which had been approved as offlabel [21–25, 27, 34, 40, 41, 43, 47, 50]. This underscores the fact that the definition of off-label and unlicenced drugs is of real interest, particularly in the case of the paediatric population, when it comes to ensuring correct use of terminology, facilitating comprehension among the scientific community as a whole and enabling comparisons between different studies and different countries [55]. Our study’s major limitation is the lack of consensus on the definition of off-label and/or unlicenced drugs, something that, as other studies have shown [7, 35], renders direct comparison of results difficult. This in turn reveals the need to conduct an international study with common evaluation criteria, as suggested by Pandolfini et al. and LindellOsuagwu et al. [7, 35] and to arrive at a common definition of off-label and unlicenced drugs, which should then be made statutory [55]. Another reason why direct comparison of results between studies is difficult lies in the fact that prescribing habits tend to vary not only among the countries where the studies were performed but also among the physicians themselves. Taking the percentage of off-label prescriptions together with that of unlicenced prescriptions gave an overall picture of the situation and, according to our review, revealed that the prescription of off-label and/or unlicenced drugs was both common and widespread [2, 7, 35]. In general, the prescription of off-label and unlicenced drugs was, as reported by Lindell-Osuagwu et al. [35], highest in wards and intensive care units since the majority of hospitalised paediatric patients received at least one drug under off-label and/or unlicenced

6.6 28.5 6.4 4.6 15.9 8.4 24.0 13.6 6.0 0.6 – 31.5 5.4 6.6

Di Paolo et al. [30] Eiland et al. [31] Dell’Aera et al. [32] Santos et al. [34] Lindell-Osuagwu et al. [35] Bavdekar et al. [36] Neubert et al. [37] Morales-Carpi et al. [38] Doherty et al. [40] Khodour et al. [42] Ferreira et al. [45] Dos Santos et al. [47] Maltz et al. [52] Median (%)

C

– – – 21.0 0.8 – 19.4

– 26.8 –

– –

17.8

– – –

– – – 4.2 – 4.9 31.2 – 6.0 – – – – 3.5

5.7 19.0 – – – – 6.0 1.0

– – – – – – 11.9

– – –

– –

11.9

– – –

– 3.0 – 2.6 – 27.6 27.5 – 9.0 4.0 – – 30.3 6.5

2.6 – 3.8 – – 6.6 27.5 43.5

UNL OF UNL OF (%) (%) (%) (%)

B

J

– – – – – – 19.3

– – –

19.3 –

38.1

– – 6.9

– – – – – 0.2 – – – – – – – 0.1

– – – – – – – 0

– – – – – – – – – – 0.0

– –

– 0

– – –



– 1.4 22.7 18.0 1.8 19.8 75.7 8.3 7.0 24.4 25.0 18.7 3.6 8.9

– 27.1 4.2 4.2 9.4 – 30.9 39.6

UNL OF UNL OF (%) (%) (%) (%)

D

H

M

– – – – 0.0 – 0.4

– – –

– –

0.8

– – –



– – – – – 4.4 – – – – – – – 2.2

4.5 – – – – – – 0

– – – – – – – – – – 0.0

– –

– 0

– – –

– 5.1 – – 3.1 1.2 3.2 – 0 8.0 – – – 4.1

– – – – – 4.0 5.1

– – – – – – 1.0

– – –

– –

0.8

– – 1.1



– – – – – 0.4 11.5 16.6 15.0 – – 2.4 3.1 3.1

– – – – – – – 3.0

UNL OF UNL OF UNL OF (%) (%) (%) (%) (%) (%)

G

– – – – 0.8 – 4.8

– – –

4.8 –

– 11.9

– – –



20.5 3.5 5.5 3.5 14.6 22.6 66.0 23.1 10.0 8.3 33.0 12.2 20.5 12.2

14.0 10.6 10.3 15.2 1.5 22.9 4.7 4.4

UNL OF (%) (%)

N

– – – – 83.3 – 50.1

– – –

– –

18.6

– – –

– 11.7 – 1.7 – 19.7 45.9 31.4 7.0 9.6 – – – 11.7

11.7 – 25.2 13.3 – 19.2 26.2 1.9

UNL OF (%) (%)

R

S

– – – – – – 35.1

– – –

– –

0

– – 70.1

Other

– – – – – – 14.6

– 14.6 –

– –



– – –

– 0.7 – – – – – – – – – – – 0.7

– – – – – – – –

– – – – – – – – – – –

– –

– –

– – –

– – 5.5 – – 0.7 – – – – – – – 0.7

– – – – – – 0.7 –

– – – – – – – – – – –

– –



– – –

UNL OF UNL OF UNL (%) (%) (%) (%) (%)

L

ATC Anatomical Therapeutic Chemical, A alimentary tract and metabolism, B blood and blood-forming organs, C cardiovascular system, D dermatologicals, J anti-infectives for systemic use, G genitourinary system and sex hormones, H systemic hormonal preparations excluding sex hormones and insulins, M musculo-skeletal system, N nervous system, R respiratory system, S sensory organs, L antineoplastic and immunomodulating agents, TP total prescriptions, OF off-label prescriptions, UNL unlicenced prescriptions

– 4.2 – – 40.7 – 3.5 – – 2.5 – – – 4.2

– 2.5 – – – – 0 –

UNL OF (%) (%)

The total number of off-label prescriptions may be higher than the total number of prescriptions because a prescription can be off-label for more than one category

10.7 – – 2.0 10.6 – 0.0 1.5

OF (%)

A

Turner et al. [19] Conroy et al. [20] Conroy et al.[21] Pandolfini et al. [23] Barr et al. [24] O’Donnell et al.[26] López Martínez et al. [28] Bajcetic et al. [29]

ATC group

Table 5 Off–label and unlicenced prescriptions according to ATC classification group

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Eur J Clin Pharmacol Fig. 1 Flow diagram showing study extraction and selection

863 papers idenfied by MEDLINE database search (January 1994 – December 2013)

88 papers idenfied by addional MEDLINE database search (January 2014 – February)

875 papers aer duplicates removed 630 papers excluded: - guidelines, editorials and commentaries (n=306) 875 papers screened

- original research but not focused on the use of off-label and/or unlicensed drugs (n=268) - case-report studies of drug safety and efficacy (n=56) 211 papers excluded:

245 full-text papers assessed for eligibility

-failure to focus on off-label and/or unlicensed prescripons in paediatric paents (n=51) - failure to use quantave methodology (n=29) - failure to focus on off-label and unlicensed paediatric prescribing in hospital care (n= 24) - failure to assess status of all drugs prescribed (n=87) - focus on paediatric adverse drug reacons (n=18) - quality assessment (2)

34 papers included in systemac review

conditions [2, 35]. Analysis by age of the study population indicated that the prescription of off-label and/or unlicenced drugs was highest among the younger patients, with newborns registering the highest percentage of off-label and/or unlicenced drug use [2, 7, 20, 56]. The majority of studies reported that the causes of off-label drug prescribing lay in changes in the respective market authorisations in terms of dose, age, indication, dosage form, frequency of administration and in the lack of a paediatric licence or information [19–25, 27–36, 38–41, 46, 47, 50, 51]. Indeed, the main reason for off-label prescriptions was the lack of a paediatric licence or information. The absence of studies on the quality, safety and efficacy of drugs administered to children meant that there was a lack of information on recommendations for drugs used in the paediatric population, and as drug efficacy, quality and safety studied for the adult

population is generally assumed to be the same as that for the paediatric population, this resulted in these same drugs being administered to paediatric patients [57]. As already reported by Pandolfini et al. and LindellOsuagwu et al. [7, 35], another reason observed for off-label prescribing to paediatric patients was drugs being given outside the dose and age range of the marketing authorisation. This may be due to the fact that a drug, albeit licenced for use in paediatric patients, can nevertheless be administered in different doses and given to different age groups of the paediatric population with differences in physiological and metabolic development. The main cause cited for the prescription of unlicenced drugs was modification of licenced drugs. This finding reinforces the need for an adequate pharmaceutical form of medicinal products for the paediatric population since formulations suitable for the paediatric population are often

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unavailable, and therefore, licenced drugs have to be modified into extemporaneous preparations with unknown pharmacokinetic characteristics [2, 56, 57]. It was, however, possible to establish that the ATC groups which were most prescribed on an off-label and/or unlicenced basis were systemic hormonal preparations, excluding sex hormones and insulins (H), with some studies specifically identifying betamethasone and beclomethasone [21, 23] and dexamethasone [36, 42], i.e. the active substances in this group. Medications for the alimentary tract and metabolism (A) and respiratory system (R) were also frequently prescribed off-label and/or unlicenced. In the case of the respiratory system, anticholinergic and β2 adrenoreceptors agonists are drugs to treat associated diseases, and our findings show that off-label and/or unlicenced prescriptions included items such as ipratropium bromide [19, 21, 31, 42] and salbutamol [19, 21, 23, 25, 42]. Some authors [58–60] reported that drugs used for the respiratory system were widely administered and that a high percentage of such drugs were prescribed off-label, accounting for 20 % of all prescriptions. With respect to the alimentary tract and metabolism group (A), prescriptions of antiemetics, such as ondansetron [30], were prescribed off-label and/or unlicenced. Our data confirm findings which show that antiemetics display a high rate of off-label prescriptions [61]. Some studies included in this systematic review reported that antibiotics, such as amikacin [29, 32, 36, 42], amoxicillin [21, 23, 25, 29, 38] and ceftriaxone [34, 36, 42], were also prescribed off-label and/or unlicenced, thus confirming previous reports that antibiotics are the most prescribed off-label and/or unlicenced drug subgroups [2, 56, 62, 63]. Analysis of studies [47–51] undertaken after the paediatric regulation came into force showed that, while there was still a high percentage of off-label and/or unlicenced prescriptions, the number of such prescriptions was slightly lower than that reported by studies performed before 2007. Even so, these results cannot be used to assess the impact of the paediatric regulation because only two studies [48, 49] conducted after 2007 were undertaken in European countries. However, there was one study [9] performed after 10 years of European Medicines Agency (EMA) activity, which reported that the number of well-studied paediatric drugs increased, thereby creating relevant paediatric data and showing that the lack of drugs in specific sectors may be overcome. According to the EMA, the proportion of paediatric trials which form part of an agreed Paediatric Investigation Plan rose to 23 % in 2012 [64]. Despite statutory and regulatory changes, there is still a lack of alternative drugs with marketing authorisation for use in paediatric populations, meaning that off-label and unlicenced drugs continue to be prescribed in medical practice [65] and that new studies are thus called for to ascertain the current extent of off-label and/or unlicenced prescriptions. A further problem associated with the use off-label and/or unlicenced drugs is the occurrence of ADRs. Some studies

[10, 14–16, 34, 66, 67] report that a very high percentage of ADRs in the paediatric population is associated with off-label and/or unlicenced prescriptions or that children who are administered off-label and/or unlicenced drugs have an increased risk of developing ADRs. In addition, some studies have estimated that the risk of ADRs linked to the use of offlabel and/or unlicenced drugs in the paediatric population is three times higher than that observed for the adult population [68, 69]. Moreover, off-label and/or unlicenced drug prescriptions are not only a hospital but also a primary care problem, which highlights the need for further in-depth research into the use of off-label and/or unlicenced drugs in primary care and the association between such use and the occurrence of ADRs. Despite the entry into force of the paediatric regulation, the high prevalence of off-label and/or unlicenced drugs reveals the need to conduct clinical trials in the paediatric population, as recommended by the EMA, and to complement these with ADR studies. Hence, by shedding new light on off-label and/or unlicenced prescriptions, these findings will hopefully contribute to generating new and more effective knowledge about the needs of the paediatric population and continuing the incentives of the EMA with the application of the paediatric regulation, will result in an enhanced body of evidence on drug efficacy and safety for the paediatric population and will predictably serve to reduce off-label and/or unlicenced drug use.

Acknowledgements Author FR wish to thank to UDI/IPG and to the Foundation for Science and Technology (FCT) [Pest-OE/EGE/UI4056/ 2014], and author AF to the Health Research Fund (Fondo de Investigación Sanitaria) [PI12/02414 y PI081239]. Funding None Conflict of interest None

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Use of off-label and unlicenced drugs in hospitalised paediatric patients: a systematic review.

The aim of this review is to assess the extent of the use of off-label and/or unlicenced drugs among hospitalised children...
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