Off-label use of medicines in children: can available evidence avoid useless paediatric trials? The case of proton pump inhibitors for the treatment of gastroesophageal reflux disease.
OBJECTIVE
In some cases of drug therapy, the available evidence might be sufficient to extend the indications to children without further clinical studies.


METHODS
We reviewed the available evidence for one of the categories of drugs most frequently used off-label in children: proton pump inhibitors (PPIs) used for the treatment of gastroesophageal reflux disease (GERD). A classification of the appropriateness of off-label use of PPIs in children with GERD was also performed.


RESULTS
Of the five PPIs evaluated, only omeprazole has a paediatric indication in Europe. Overall, 19 clinical trials were retrieved and evaluated on the basis of pharmacokinetics, efficacy and safety data. The off-label use of omeprazole, esomeprazole and lansoprazole in children was evaluated as appropriate given the consistent available evidence retrieved in literature.


CONCLUSIONS
This study demonstrates the existence of a large body of clinical evidence on the use of PPIs in children. Regulatory agencies and ethical committees should cope with this issue for ethical reasons to avoid unnecessary trial replication.
Tafuri
Giovanni
G
Utrecht Institute for Pharmaceutical Sciences, Utrecht University, P.O. Box 80 082, 3508 TB, Utrecht, The Netherlands.
Trotta
Francesco
F
Leufkens
Hubert G M
HG
Martini
Nello
N
Sagliocca
Luciano
L
Traversa
Giuseppe
G
D053799:2-Pyridinylmethylsulfinylbenzimidazoles / Q000493:pharmacokinetics / Q000627:therapeutic use; D002648:Child; D002986:Clinical Trials as Topic; D016206:Databases, Bibliographic; D004305:Dose-Response Relationship, Drug; D004333:Drug Administration Routes; D004334:Drug Administration Schedule; D017723:Drug Utilization Review; D064098:Esomeprazole; D005062:European Union; D005764:Gastroesophageal Reflux / Q000188:drug therapy*; D006077:Government Agencies / Q000331:legislation & jurisprudence / Q000592:standards; D006801:Humans; D007536:Isomerism; D064747:Lansoprazole; D015337:Multicenter Studies as Topic; D009853:Omeprazole / Q000493:pharmacokinetics / Q000627:therapeutic use; D010372:Pediatrics; D054328:Proton Pump Inhibitors / Q000493:pharmacokinetics / Q000627:therapeutic use*; D014481:United States; D014486:United States Food and Drug Administration / Q000331:legislation & jurisprudence / Q000592:standards
D053799:2-Pyridinylmethylsulfinylbenzimidazoles; D054328:Proton Pump Inhibitors; D064747:Lansoprazole; D009853:Omeprazole; D064098:Esomeprazole
Pediatrics. 2007 Nov;120(5):946-9
17974730
N Engl J Med. 2009 Apr 9;360(15):1557-66
19357413
J Pediatr. 2003 Aug;143(2):219-23
12970637
Dig Liver Dis. 2000 Nov;32(8):660-6
11142573
J Pediatr Gastroenterol Nutr. 2002;35 Suppl 4:S308-18
12607791
J Pediatr Gastroenterol Nutr. 2007 Oct;45(4):421-7
18030207
BMJ. 2000 Jan 8;320(7227):79-82
10625257
Eur J Clin Pharmacol. 2007 Jan;63(1):81-5
17124577
Clin Ther. 2006 Nov;28(11):1868-76
17213007
J Pediatr Gastroenterol Nutr. 2007 Nov;45(5):530-7
18030229
Pediatrics. 2006 May;117(5):e817-20
16651285
J Pediatr. 1998 Feb;132(2):352-4
9506656
J Pediatr Gastroenterol Nutr. 2007 Jan;44(1):41-4
17204951
J Pediatr Gastroenterol Nutr. 2007 Nov;45(5):520-9
18030228
J Pediatr Gastroenterol Nutr. 2006 Apr;42(4):384-91
16641576
Lancet. 2004 Aug 28-Sep 3;364(9436):803-11
15337409
Clin Ther. 2006 Mar;28(3):419-27
16750456
Aliment Pharmacol Ther. 2001 Sep;15(9):1397-402
11552911
J Pediatr. 2000 Dec;137(6):800-7
11113836
J Pediatr Gastroenterol Nutr. 2005 Mar;40(3):319-27
15735486
J Pediatr Gastroenterol Nutr. 2003 Feb;36(2):261-5
12548064
J Pediatr Gastroenterol Nutr. 2007 Jul;45(1):50-5
17592364
Dig Liver Dis. 2003 Oct;35(10):738-46
14620626
Eur J Clin Pharmacol. 2008 Feb;64(2):201-5
17972069
Arch Dis Child. 1993 Dec;69(6):655-9
8285777
J Pediatr Gastroenterol Nutr. 2007 Jan;44(1):35-40
17204950
J Pediatr Gastroenterol Nutr. 2002;35 Suppl 4:S327-35
12607793
J Pediatr Gastroenterol Nutr. 2001;32 Suppl 2:S1-31
11525610
JAMA. 2008 Apr 23;299(16):1949-51
18430914
J Pediatr Gastroenterol Nutr. 2002 Aug;35(2):113-8
12187284
Eur J Clin Pharmacol. 2009 Feb;65(2):209-16
18797857
J Pediatr. 2007 Mar;150(3):262-7, 267.e1
17307542
BMJ. 2007 Dec 15;335(7632):1221-2
18079516
Clin Ther. 2007 Sep;29(9):2082-92
18035206