Off-Label Drug Use in Outpatient 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

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@hotmail.com

Keywords：

Outpatient children; Off-label; Systematic review; Drug safety

DOI：

10.7507/1672-2531.20120050

Video：

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Objective　 To assess the global situation of off-label drug use in outpatient children.
Methods　 A search was conducted in PubMed, EMbase, CBM, CNKI and VIP for collecting studies on off-label drug use in outpatient children aged 0 to 18 years, and the publication language was limited to English and Chinese. The quality assessment was based on Crombie Criteria for cross-sectional studies, and the descriptive analysis was performed to analyze the incidence of off-label drug use at all levels of medical institutes and different age groups, the common types of off-label used drugs, and the constitution ratio of off-label use drugs.
Results　 A total of 20 cross-sectional studies were included, involving 1 933 760 children and 5 262 573 prescriptions. The results of descriptive analysis showed: a) The incidence of off-label drug use in outpatient children in primary care and tertiary care institutes were 19.5% (IQR 13.5%, 24.5%) and 26.0% (IQR 24.0%, 35.0%), respectively; b) The primary studies reported that neonate, infant and adolescent had the highest incidence of off-label drug use, while the other children had the lowest incidence; c) Drugs for respiratory system, anti-infection, sensory organs, and dermatosis were listed as the top 5 frequently used off-label drugs by more than half of the studies; d) The studies with issue of “lack of instruction for children” showed it was exactly the type with highest incidence of off-label use, while other studies without that issue showed the highest incidence was over aged off-label use.
Conclusion　 a) Off-label drug use is common in outpatient children. The incidence of off-label drug use may be higher in tertiary care institutes than primary care institutes, and it is higher in neonate, infant and adolescent rather than other age groups of children; b) Incidence of off-label use may be higher in inpatient children than outpatient ones; c) Drugs for respiratory system, anti-infection, sensory organs, and dermatosis were most common types of off-label use; and d) Off-label use due to both “lack of instruction for children” and “over aged use” is more common. So it suggests that further studies trials should focus on fields in which clinical trials of drugs are totally absent.

Citation： ZHANG Lingli,LI Youping,LIANG Yi,ZENG Linan,LIU Yi. Off-Label Drug Use in Outpatient Children: A Systematic Review. Chinese Journal of Evidence-Based Medicine, 2012, 12(3): 305-313. doi: 10.7507/1672-2531.20120050 Copy

1.	NLM (2010), MeSH NLM Controlled Vocabulary. [2011-09-13] Aavailable from: http://www.ncbi.nlm.nih.gov/mesh/68056687.
2.	张伶俐, 李幼平. 基于风险与责任, 促进中国儿童合理用药的思考. 中国循证医学杂志, 2011, 11(9): 983-984.
3.	张伶俐, 李幼平, 梁毅, 等. 全球住院儿童超说明书用药现状的系统评价. 中国循证医学杂志, 2012, (2): 176-187.
4.	张伶俐, 李幼平, 胡蝶, 等. 四川大学华西第二医院2010年住院患儿超说明书用药情况调查. 中国循证医学杂志, 2012, (2): 161-167.
5.	International Conference on Harmonisation; guidance on E11 clinical investigation of medicinal products in the pediatric population; availability. Notice. Federal Register, 2000, 78493-78494.
6.	Crombie I: The pocket guide to critical appraisal London: BMJ Publishing Group, 1996.
7.	Landis JR, Koch GG. The measurement of observer agreement for categorical data. Biometrics, 1977, 33(1): 159-174.
8.	WHO. ATC. [2012-02-01] Available from: http: //www.whocc.no/atc/structure_and principles/.
9.	Schirm E, Tobi H, de Jong-van den Berg LTW. Risk Factors for Unlicensed and Off-Label Drug Use in Children Outside the Hospital. Pediatrics, 2003, 111(2): 291-295.
10.	Schirm E, Tobi H, de Jong-van den Berg LTW. Unlicensed and off label drug use by children in the community: cross sectional study. BMJ, 2002, 324(7349): 1312-1313.
11.	W `t Jong G, Eland IA, Sturkenboom MCJM, et al. Unlicensed and off label prescription of drugs to children: population based cohort study. BMJ, 2002, 324(7349): 1313-1314.
12.	Dick A, Keady S, Mohamed F, et al. Use of unlicensed and off-label medications in paediatric gastroenterology with a review of the commonly used formularies in the UK. Aliment Pharmacol Ther, 2003, 17(4): 571-575.
13.	McIntyre J, Conroy S, Avery A, et al. Unlicensed and off label prescribing of drugs in general practice. Arch Dis Child, 2000, 83(6): 498-501.
14.	Horen B, Montastruc J, Lapeyre-Mestre M, et al. Adverse drug reactions and off-label drug use in paediatric outpatients. Br J Clin Pharmacol, 2002, 54(6): 665-670.
15.	Chalumeau M, Treluyer JM, Salanave B, et al. Off label and unlicensed drug use among French office based paediatricians. Arch Dis Child, 2000, 83(6): 502-505.
16.	Olsson L, Kimland E, Pettersson S, et al. Paediatric drug use with focus on off-label prescriptions in Swedish outpatient care – a nationwide study. Acta Paediatrica, 2011, 100(9): 1272-1275.
17.	Ufer M, Rane M, Karlsson A, et al. Widespread off-label prescribing of topical but not systemic drugs for 350, 000 paediatric outpatients in Stockholm. Eur J Clin Pharmacol, 2003, 58(11): 779-783.
18.	Moral es-Carpi C, Estañ L, Rubio E, et al. Drug utilization and off-label drug use among Spanish emergency room paediatric patients. Eur J Clin Pharmacol, 2010, 66(3): 315-320.
19.	Pandolfini C, Campi R, Clavenna A, et al. Italian paediatricians and off-label prescriptions: Loyal to regulatory or guideline standards? Acta Pædiatrica, 2005, 94(6): 753-757.
20.	Lass J, Irs A, Pisarev H, et al. Off label use of prescription medicine s in children in outpatient setting in Estonia is common. Pharmacoepidemiology & Drug Safety, 2011, 20(5): 474-481.
21.	Bücheler R, Schwab M, Mörike K, et al. Off label prescribing to children in primary care in Germany: retrospective cohort study. BMJ, 2002, 324(7349): 1311-1312.
22.	Sturkenboom M, Felisi M, Manfredi C, et al. Paediatric status and off-label use of drugs in children in Italy, United Kingdom and the Netherlands. Pharmaceuticals Policy and Law, 2009, 11(1-2): 51–59.
23.	Lifshitz M, Gavrilov V, Grossman V, et al. Unapproved Prescription Practices in Primary Pediatric Clinics in Israel: A Prospective Analysis. Current Therapeutic research, 2002, 63(12): 830-837.
24.	Gavrilov V, Lifshitz M, Levy J, et al. Unlicensed and Off-Label Medication Use in a General Pediatrics Ambulatory Hospital Unit in Israel. Isr Med Assoc J, 2000, 2(8): 595-597.
25.	Phan H, Leder M, Fishley M, et al. Off-Label and Unlicensed Medication Use and Associated Adverse Drug Events in a Pediatric Emergency Department. Pediatric Emergency Care, 2010, 26(6): 424-430.
26.	王海滢, 刘芳. 北京大学第三医院儿科门诊超说明书用药调查与分析.中国医院用药评价与分析, 2011, 11(2): 184-186.
27.	张伶俐, 李幼平, 黄亮, 等. 四川大学华西第二医院儿科门诊处方超药品说明书用药情况调查. 中国循证医学杂志, 2011, 11(10): 1120-1124.
28.	薛丽萍, 汪琪. 儿科超说明书用药的调查分析.中国药房, 2008, 19(4): 315-31.
29.	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.
30.	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.
31.	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.
32.	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.
33.	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.
34.	Jain SS, Bavdekar SB, Gogtay NJ, et al. Off-label drug use in children. Indian J Pediatr, 2008, 75(11): 1133-1136.
35.	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.
36.	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.
37.	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.
38.	Pandolfini C, Bonati M. A literature review on off-label drug use in children. Eur J Pediatr, 2005, 164(9): 552-558.
39.	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.
40.	‘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.
41.	Allergy&AsthmaNetwork. [2012-02-01] http: //www.aanma.org/faqs/welcome-to-precious-breathers/respiratory-diseases/.
42.	WHO. [2012-02-10] http: //www.who.int/infectious-disease-report/pages/textonly.html.

1. NLM (2010), MeSH NLM Controlled Vocabulary. [2011-09-13] Aavailable from: http://www.ncbi.nlm.nih.gov/mesh/68056687.
2. 张伶俐, 李幼平. 基于风险与责任, 促进中国儿童合理用药的思考. 中国循证医学杂志, 2011, 11(9): 983-984.
3. 张伶俐, 李幼平, 梁毅, 等. 全球住院儿童超说明书用药现状的系统评价. 中国循证医学杂志, 2012, (2): 176-187.
4. 张伶俐, 李幼平, 胡蝶, 等. 四川大学华西第二医院2010年住院患儿超说明书用药情况调查. 中国循证医学杂志, 2012, (2): 161-167.
5. International Conference on Harmonisation; guidance on E11 clinical investigation of medicinal products in the pediatric population; availability. Notice. Federal Register, 2000, 78493-78494.
6. Crombie I: The pocket guide to critical appraisal London: BMJ Publishing Group, 1996.
7. Landis JR, Koch GG. The measurement of observer agreement for categorical data. Biometrics, 1977, 33(1): 159-174.
8. WHO. ATC. [2012-02-01] Available from: http: //www.whocc.no/atc/structure_and principles/.
9. Schirm E, Tobi H, de Jong-van den Berg LTW. Risk Factors for Unlicensed and Off-Label Drug Use in Children Outside the Hospital. Pediatrics, 2003, 111(2): 291-295.
10. Schirm E, Tobi H, de Jong-van den Berg LTW. Unlicensed and off label drug use by children in the community: cross sectional study. BMJ, 2002, 324(7349): 1312-1313.
11. W `t Jong G, Eland IA, Sturkenboom MCJM, et al. Unlicensed and off label prescription of drugs to children: population based cohort study. BMJ, 2002, 324(7349): 1313-1314.
12. Dick A, Keady S, Mohamed F, et al. Use of unlicensed and off-label medications in paediatric gastroenterology with a review of the commonly used formularies in the UK. Aliment Pharmacol Ther, 2003, 17(4): 571-575.
13. McIntyre J, Conroy S, Avery A, et al. Unlicensed and off label prescribing of drugs in general practice. Arch Dis Child, 2000, 83(6): 498-501.
14. Horen B, Montastruc J, Lapeyre-Mestre M, et al. Adverse drug reactions and off-label drug use in paediatric outpatients. Br J Clin Pharmacol, 2002, 54(6): 665-670.
15. Chalumeau M, Treluyer JM, Salanave B, et al. Off label and unlicensed drug use among French office based paediatricians. Arch Dis Child, 2000, 83(6): 502-505.
16. Olsson L, Kimland E, Pettersson S, et al. Paediatric drug use with focus on off-label prescriptions in Swedish outpatient care – a nationwide study. Acta Paediatrica, 2011, 100(9): 1272-1275.
17. Ufer M, Rane M, Karlsson A, et al. Widespread off-label prescribing of topical but not systemic drugs for 350, 000 paediatric outpatients in Stockholm. Eur J Clin Pharmacol, 2003, 58(11): 779-783.
18. Moral es-Carpi C, Estañ L, Rubio E, et al. Drug utilization and off-label drug use among Spanish emergency room paediatric patients. Eur J Clin Pharmacol, 2010, 66(3): 315-320.
19. Pandolfini C, Campi R, Clavenna A, et al. Italian paediatricians and off-label prescriptions: Loyal to regulatory or guideline standards? Acta Pædiatrica, 2005, 94(6): 753-757.
20. Lass J, Irs A, Pisarev H, et al. Off label use of prescription medicine s in children in outpatient setting in Estonia is common. Pharmacoepidemiology & Drug Safety, 2011, 20(5): 474-481.
21. Bücheler R, Schwab M, Mörike K, et al. Off label prescribing to children in primary care in Germany: retrospective cohort study. BMJ, 2002, 324(7349): 1311-1312.
22. Sturkenboom M, Felisi M, Manfredi C, et al. Paediatric status and off-label use of drugs in children in Italy, United Kingdom and the Netherlands. Pharmaceuticals Policy and Law, 2009, 11(1-2): 51–59.
23. Lifshitz M, Gavrilov V, Grossman V, et al. Unapproved Prescription Practices in Primary Pediatric Clinics in Israel: A Prospective Analysis. Current Therapeutic research, 2002, 63(12): 830-837.
24. Gavrilov V, Lifshitz M, Levy J, et al. Unlicensed and Off-Label Medication Use in a General Pediatrics Ambulatory Hospital Unit in Israel. Isr Med Assoc J, 2000, 2(8): 595-597.
25. Phan H, Leder M, Fishley M, et al. Off-Label and Unlicensed Medication Use and Associated Adverse Drug Events in a Pediatric Emergency Department. Pediatric Emergency Care, 2010, 26(6): 424-430.
26. 王海滢, 刘芳. 北京大学第三医院儿科门诊超说明书用药调查与分析.中国医院用药评价与分析, 2011, 11(2): 184-186.
27. 张伶俐, 李幼平, 黄亮, 等. 四川大学华西第二医院儿科门诊处方超药品说明书用药情况调查. 中国循证医学杂志, 2011, 11(10): 1120-1124.
28. 薛丽萍, 汪琪. 儿科超说明书用药的调查分析.中国药房, 2008, 19(4): 315-31.
29. 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.
30. 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.
31. 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.
32. 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.
33. 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.
34. Jain SS, Bavdekar SB, Gogtay NJ, et al. Off-label drug use in children. Indian J Pediatr, 2008, 75(11): 1133-1136.
35. 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.
36. 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.
37. 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.
38. Pandolfini C, Bonati M. A literature review on off-label drug use in children. Eur J Pediatr, 2005, 164(9): 552-558.
39. 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.
40. ‘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.
41. Allergy&AsthmaNetwork. [2012-02-01] http: //www.aanma.org/faqs/welcome-to-precious-breathers/respiratory-diseases/.
42. WHO. [2012-02-10] http: //www.who.int/infectious-disease-report/pages/textonly.html.

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