Off-label Drug Use in Hospitalized Children: A Systematic Review_Chinese Journal of Evidence-Based Medicine

Authors：

ZHANG Lingli ^1,2 ,  LI Youping ¹ , LIANG Yi ^2,3 , ZENG Linan ² , LIU Yi ^2,3 , CHEN Min ^2,3

1. Chinese Evidence-Based Medicine Center, West China Hospital, Sichuan University, Chengdu 610041, China;2. Department of Pharmacy, West China Second University Hospital, Sichuan University, Chengdu 610041, China;3. West China School of Pharmacy, Sichuan University, Chengdu 610041, China;

Corresponding author：

LI Youping, Email: yzmylab@hotmial.com

Keywords：

Hospitalized children; Off label; Systematic review

DOI：

10.7507/1672-2531.20120030

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Objective 　To assess the global situation of off-label drug use in hospitalized children.
Methods 　The databases such as PubMed, EMbase, CBM, CNKI and VIP were searched to collect studies on off-label drug use in hospitalized children at age of 0 to 18 years old. The publication language was limited to English and Chinese. The quality assessment was based on Crombie Criteria for cross-sectional studies. The incidence of off-label drug use was described in different wards and age groups, and the proportion of different off-label used drugs was analyzed.
Results　 The total 29 cross-sectional studies were included, involving 8 560 children and 41 655 prescriptions. a) Median (IQR) of off-label use incidence: Neonatal ICU 52.5% (23.0% to 44.8%), Pediatric ICU 43.5% (34.5% to 60%), General pediatric ward 35.5% (23.8% to 43.3%), Pediatric surgical ward 27.5% (23.0% to 44.8%); b) The results of off-label incidence in different age groups were inconsistent among different studies; and c) The off-label drug use for “no pediatric information” had the largest proportion, followed by dose and age.
Conclusion 　a) Off-label drug use exists widely around the world, but the incidence varies a lot in different countries and different types of wards; b) The incidence of off-label drug use may be higher in ICU than in non-ICU, and higher in the neonatal ward than the pediatric ward; c) The off-label drug use for no pediatric information is the commonest type, and further clinical studies should focus on areas in which high quality evidence is totally absent; and d) The multi-center studies with unified design on off-label drug use in hospitalized children in China are urgently needed to provide evidence for policy-making.

Citation： ZHANG Lingli,LI Youping,LIANG Yi,ZENG Linan,LIU Yi,CHEN Min. Off-label Drug Use in Hospitalized Children: A Systematic Review. Chinese Journal of Evidence-Based Medicine, 2012, 12(2): 176-187. doi: 10.7507/1672-2531.20120030 Copy

1.	NLM (2010), MeSH NLM Controlled Vocabulary. [2011-09-13] Aavailable from: http://www.ncbi.nlm.nih.gov/mesh/68056687.
2.	International Conference on Harmonisation; guidance on E11 clinical investigation of medicinal products in the pediatric population; availability. Notice. Federal Register, 2000, 78493-4.
3.	Crombie I. The pocket guide to critical appraisal London: BMJ Publishing Group; 1996.
4.	Landis JR, Koch GG. The measurement of observer agreement for categorical data. Biometrics, 1977, 33(1): 159-174.
5.	Van den Berg H, Tak N. Licensing and labeling of drugs in a pediatric oncology ward. Br J Clin Pharmacol, 2011, 72(3): 474-481.
6.	‘t Jong GW, van der Linden PD, Bakker EM, et al. Unlicensed and off-label drug use in a paediatric ward of a general hospital in the Netherlands. Eur J Clin Pharmacol, 2002, 58(4): 293-297.
7.	‘t Jong GW, Vulto AG, de Hoog M, et al. A survey of the use of off-label and unlicensed drugs in a Dutch children’s hospital. Pediatrics, 2001, 108(5): 1089-1093.
8.	Dessì A, Salemi C, Fanos V, et al. Drug treatments in a neonatal setting:focus on the off-label use in the first month of life. Pharm World Sci, 2010, 32(2): 120-124.
9.	Dell'Aera M, Gasbarro AR, Padovano M, et al. Unlicensed and off-label use of medicines at a neonatology clinic in Italy. Pharm World Sci, 2007, 29(4): 361-367.
10.	Pandolfini C, Impicciatore P, Provasi D, et al. Off-label use of drugs in Italy: a prospective, observational and multicentre study. Acta Paediatrica, 2002, 91(3): 339-347.
11.	Conroy S, McIntyre J, Choonara I. Unlicensed and off-label drug use in neonates. Arch Dis Child Fetal Neonatal Ed, 1999, 80(2): F142-F145.
12.	Turner S, Longworth A, Nunn AJ, et al. Unlicensed and off-label drug use in paediatric wards: prospective study. BMJ, 1998, 316(7128): 343-345.
13.	Nguyen KA, Claris O, Kassai B, et al. Unlicensed and off-label drug use in a neonatal unit in France. Acta Paediatr, 2011, 100(4): 615-617.
14.	Neubert A, Dormann H, Weiss J. The Impact of Unlicensed and Off-Label Drug Use on Adverse Drug Reactions in Paediatric Patients. Drug Safety, 2004, 27(13): 1059-1067.
15.	Di Paolo ER, Stoetter H, Cotting J, et al. Unlicensed and off-label drug use in a Swiss paediatric university hospital. Swiss Med Wkly, 2006, 136(13-14): 218-222.
16.	Lindell-Osuagwu L, Korhonen MJ, Saano S, et al. Off-label and unlicensed drug prescribing in three paediatric wards in Finland and review of the international literature. J Clin Pharm Ther, 2009, 34(3): 277-287.
17.	Craig JS, Henderson CR, Magee FA. The extent of unlicensed and off-label drug use in the paediatric ward of a district general hospital in Northern Ireland. Ir Med J, 2001, 94(8): 237-240.
18.	Conroy S, Choonara I, Impicciatore P, et al. Survey of unlicensed and off label drug use in paediatric wards in European countries. European Network for Drug Investigation in Children. BMJ, 2000, 320(7227): 79-82.
19.	Lass J, Kaar R, Jogi K, et al. Drug utilisation pattern and off-label use of medicines in Estonian neonatal units. Eur J Clin Pharmacol, 2011, 67(12): 1263-1271.
20.	Payares MC, Pedrosa MJ, Salvador A, et al. Off-label use of medications in the paediatric and neonatal intensive care units. British Journal of Clinical Pharmacology, 2010, 70(2): 286-287.
21.	Prandstetter C, Tamesberger M, Wagner O. Medical prescriptions to premature and newborn infants in an Austrian neonatal intensive care unit. Klin Padiatr, 2009, 221(5): 312-317.
22.	Annicq A, Robeyst A, Segers N. Unlicensed and off-label use of medication at the department of paediatrics in the university hospital UZ Ghent. 2008, Tijdschrift voor Geneeskunde, 2008, 64(13): 677-688.
23.	Eiland LS, Knight P. Evaluating the off-label use of medications in children. Am J Health Syst Pharm, 2006, 63(11): 1062-1065.
24.	Doherty DR, Pascuet E, Ni A, et al. Off-label drug use in pediatric anesthesia and intensive care according to official and pediatric reference formularies. Can J Anaesth, 2010, (12): 1078-1088.
25.	O'Donnell CP, Stone RJ, Morley CJ. Unlicensed and off-label drug use in an Australian neonatal intensive care unit. Pediatrics, 2002, 110(5): e52.
26.	Barr J, Brenner-Zada G, Heiman E, et al. Unlicensed and off-label medication use in a neonatal intensive care unit: a prospective study. Am J Perinatol, 2002, 19(2): 67-72.
27.	Santos DB, Clavenna A, Bonati M, et al. Off-label and unlicensed drug utilization in hospitalized children in Fortaleza, Brazil. Eur J Clin Pharmacol, 2008, 64(11): 1111-1118.
28.	Carvalho PR, Carvalho CG, Alievi PT, et al. Prescription of drugs not appropriate for children in a Pediatric Intensive Care Unit. J Pediatr (Rio J), 2003, 79(5): 397-402.
29.	曾雪花, 周炳丰. 住院儿科药品说明书之外用药的调查分析. 中国医药导报, 2011, 8(6): 113-114.
30.	Bajcetic M, Jelisavcic M, Mitrovic J, et al. Off label and unlicensed drugs use in paediatric cardiology. Eur J Clin Pharmacol, 2005, 61(10): 775-779.
31.	Khdour MR, Hallak HO, Alayasa KS, et al. Extent and nature of unlicensed and off-label medicine use in hospitalised children in Palestine. Int J Clin Pharm, 2011, 33(4): 650-655.
32.	Bavdekar SB, Sadawarte PA, Gogtay NJ, et al. Off-label drug use in a Pediatric Intensive Care Unit. Indian J Pediatr, 2009, 76(11): 1113-1118.
33.	Jain SS, Bavdekar SB, Gogtay NJ, et al. Off-label drug use in children. Indian J Pediatr, 2008, 75(11): 1133-1136.
34.	Pandolfini C, Bonati M. A literature review on off-label drug use in children. Eur J Pediatr, 2005, 164(9): 552-558.
35.	Cuzzolin L, Atzei A, Fanos V. Off-label and unlicensed prescribing for new borns and children in different setting: a review of the literature and a consideration about drug safety. Expert Opin Drug Saf, 2006, 5(5): 703-718.

1. NLM (2010), MeSH NLM Controlled Vocabulary. [2011-09-13] Aavailable from: http://www.ncbi.nlm.nih.gov/mesh/68056687.
2. International Conference on Harmonisation; guidance on E11 clinical investigation of medicinal products in the pediatric population; availability. Notice. Federal Register, 2000, 78493-4.
3. Crombie I. The pocket guide to critical appraisal London: BMJ Publishing Group; 1996.
4. Landis JR, Koch GG. The measurement of observer agreement for categorical data. Biometrics, 1977, 33(1): 159-174.
5. Van den Berg H, Tak N. Licensing and labeling of drugs in a pediatric oncology ward. Br J Clin Pharmacol, 2011, 72(3): 474-481.
6. ‘t Jong GW, van der Linden PD, Bakker EM, et al. Unlicensed and off-label drug use in a paediatric ward of a general hospital in the Netherlands. Eur J Clin Pharmacol, 2002, 58(4): 293-297.
7. ‘t Jong GW, Vulto AG, de Hoog M, et al. A survey of the use of off-label and unlicensed drugs in a Dutch children’s hospital. Pediatrics, 2001, 108(5): 1089-1093.
8. Dessì A, Salemi C, Fanos V, et al. Drug treatments in a neonatal setting:focus on the off-label use in the first month of life. Pharm World Sci, 2010, 32(2): 120-124.
9. Dell'Aera M, Gasbarro AR, Padovano M, et al. Unlicensed and off-label use of medicines at a neonatology clinic in Italy. Pharm World Sci, 2007, 29(4): 361-367.
10. Pandolfini C, Impicciatore P, Provasi D, et al. Off-label use of drugs in Italy: a prospective, observational and multicentre study. Acta Paediatrica, 2002, 91(3): 339-347.
11. Conroy S, McIntyre J, Choonara I. Unlicensed and off-label drug use in neonates. Arch Dis Child Fetal Neonatal Ed, 1999, 80(2): F142-F145.
12. Turner S, Longworth A, Nunn AJ, et al. Unlicensed and off-label drug use in paediatric wards: prospective study. BMJ, 1998, 316(7128): 343-345.
13. Nguyen KA, Claris O, Kassai B, et al. Unlicensed and off-label drug use in a neonatal unit in France. Acta Paediatr, 2011, 100(4): 615-617.
14. Neubert A, Dormann H, Weiss J. The Impact of Unlicensed and Off-Label Drug Use on Adverse Drug Reactions in Paediatric Patients. Drug Safety, 2004, 27(13): 1059-1067.
15. Di Paolo ER, Stoetter H, Cotting J, et al. Unlicensed and off-label drug use in a Swiss paediatric university hospital. Swiss Med Wkly, 2006, 136(13-14): 218-222.
16. Lindell-Osuagwu L, Korhonen MJ, Saano S, et al. Off-label and unlicensed drug prescribing in three paediatric wards in Finland and review of the international literature. J Clin Pharm Ther, 2009, 34(3): 277-287.
17. Craig JS, Henderson CR, Magee FA. The extent of unlicensed and off-label drug use in the paediatric ward of a district general hospital in Northern Ireland. Ir Med J, 2001, 94(8): 237-240.
18. Conroy S, Choonara I, Impicciatore P, et al. Survey of unlicensed and off label drug use in paediatric wards in European countries. European Network for Drug Investigation in Children. BMJ, 2000, 320(7227): 79-82.
19. Lass J, Kaar R, Jogi K, et al. Drug utilisation pattern and off-label use of medicines in Estonian neonatal units. Eur J Clin Pharmacol, 2011, 67(12): 1263-1271.
20. Payares MC, Pedrosa MJ, Salvador A, et al. Off-label use of medications in the paediatric and neonatal intensive care units. British Journal of Clinical Pharmacology, 2010, 70(2): 286-287.
21. Prandstetter C, Tamesberger M, Wagner O. Medical prescriptions to premature and newborn infants in an Austrian neonatal intensive care unit. Klin Padiatr, 2009, 221(5): 312-317.
22. Annicq A, Robeyst A, Segers N. Unlicensed and off-label use of medication at the department of paediatrics in the university hospital UZ Ghent. 2008, Tijdschrift voor Geneeskunde, 2008, 64(13): 677-688.
23. Eiland LS, Knight P. Evaluating the off-label use of medications in children. Am J Health Syst Pharm, 2006, 63(11): 1062-1065.
24. Doherty DR, Pascuet E, Ni A, et al. Off-label drug use in pediatric anesthesia and intensive care according to official and pediatric reference formularies. Can J Anaesth, 2010, (12): 1078-1088.
25. O'Donnell CP, Stone RJ, Morley CJ. Unlicensed and off-label drug use in an Australian neonatal intensive care unit. Pediatrics, 2002, 110(5): e52.
26. Barr J, Brenner-Zada G, Heiman E, et al. Unlicensed and off-label medication use in a neonatal intensive care unit: a prospective study. Am J Perinatol, 2002, 19(2): 67-72.
27. Santos DB, Clavenna A, Bonati M, et al. Off-label and unlicensed drug utilization in hospitalized children in Fortaleza, Brazil. Eur J Clin Pharmacol, 2008, 64(11): 1111-1118.
28. Carvalho PR, Carvalho CG, Alievi PT, et al. Prescription of drugs not appropriate for children in a Pediatric Intensive Care Unit. J Pediatr (Rio J), 2003, 79(5): 397-402.
29. 曾雪花, 周炳丰. 住院儿科药品说明书之外用药的调查分析. 中国医药导报, 2011, 8(6): 113-114.
30. Bajcetic M, Jelisavcic M, Mitrovic J, et al. Off label and unlicensed drugs use in paediatric cardiology. Eur J Clin Pharmacol, 2005, 61(10): 775-779.
31. Khdour MR, Hallak HO, Alayasa KS, et al. Extent and nature of unlicensed and off-label medicine use in hospitalised children in Palestine. Int J Clin Pharm, 2011, 33(4): 650-655.
32. Bavdekar SB, Sadawarte PA, Gogtay NJ, et al. Off-label drug use in a Pediatric Intensive Care Unit. Indian J Pediatr, 2009, 76(11): 1113-1118.
33. Jain SS, Bavdekar SB, Gogtay NJ, et al. Off-label drug use in children. Indian J Pediatr, 2008, 75(11): 1133-1136.
34. Pandolfini C, Bonati M. A literature review on off-label drug use in children. Eur J Pediatr, 2005, 164(9): 552-558.
35. Cuzzolin L, Atzei A, Fanos V. Off-label and unlicensed prescribing for new borns and children in different setting: a review of the literature and a consideration about drug safety. Expert Opin Drug Saf, 2006, 5(5): 703-718.

Chinese Journal of Evidence-Based Medicine

Off-label Drug Use in Hospitalized Children: A Systematic Review

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