British Journal of Clinical

Pharmacology

Adverse effects reported in the use of gastroesophageal reflux disease treatments in children: a 10 years literature review

Shlomi Cohen,1,2,3 Mirjam Bueno de Mesquita1,2 & Francis B. Mimouni2,3,4

1The Pediatric Gastroenterology unit, 2Department of Pediatrics, ’Dana-Dwek’ Children’s Hospital, Tel Aviv Medical Center and, the 3Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel and

4Division of Neonatology, Shaare Zedek Medical Center, Jerusalem, Israel

DOI:10.1111/bcp.12619

Correspondence

Dr Shlomi Cohen, MD, Pediatric Gastroenterology Unit, ’Dana-Dwek’

Children’s Hospital, Tel Aviv Medical Center, 6 Weizman Street, Tel Aviv, 64239,

Israel.

Tel.: + 972 3 697 4515

Fax: + 972 3 697 4181

E-mail: shlomico@tlvmc.gov.il

----------------------------------------------------

Keywords

antacids, children, gastroesophageal reflux disease, histamine H2 receptor antagonists, metoclopramide,

prokinetics, proton pump inhibitors

----------------------------------------------------

Received

14 October 2014

Accepted

26 February 2015

Accepted Article

Published Online

5 March 2015

Introduction

Gastroesophageal reflux (GER) is commonly observed in children, particularly during the first year of life. Up to 65% of infants regurgitate stomach contents at least once a day at the age of 3–6 months [1]. Most cases resolve spontaneously, with complete resolution in 95% of babies by 1 year of age [1]. The efficacy of anti-GER medications in reducing GER symptoms is debatable and there is mount- ing evidence that these medications are not without adverse effects (AEs). Thus, pharmacological therapy is mostly reserved for symptomatic infants diagnosed with

complicated GER, or GER disease (GERD), usually as defined in a recent consensus statement [2].

The purpose of the present article was to review re- ported AEs of pharmacological agents commonly used in the treatment of paediatric GERD.

Search strategy

We conducted the present review using the electronic jour- nal database Pubmed and Cochrane database systematic reviews, using the latest 10-year period (1 January 2003 to

S. Cohen et al.

31 December 2012). Our search strategy included the fol- lowing keywords: omeprazole, esomeprazole, lansoprazole, pantoprazole, ranitidine, cimetidine, famotidine, nizatidine, domperidone, metoclopramide, betanechol, erythromycin, baclofen and alginate. For each search and for each pharmacological agent we used the term: ’AND GERD’ in order to retrieve only the side effects of these agents when used to treat GERD (and no other therapeutic indication). In order to limit our search to articles related to the paediatric population, we used Pubmed’s own filter of: ’child: birth– 18 years’, ’humans only’, published in English. We also scrutinized the citations of the retrieved articles for any references not identified by our search. All full articles were reviewed and included only randomized controlled trials retrieved from our Pubmed search, or from our search of the references found in the articles. All AEs reported were recorded by drug and by article, without exception. Below is a summary of our search, on a drug-by-drug basis.

Results

Proton pump inhibitors (PPIs)

PPIs are the most frequently prescribed medications for the treatment of adults and children with GERD. Their effectiveness for the treatment of peptic conditions in the paediatric population is well established [3]. The effectiveness of PPIs relates to their structure, which must undergo acidic activation within the parietal cell to allow the PPI to be ionized and form covalent disulfide bonds with cysteine residues of the H+-K+-adenosine triphosphatase (H+-K+-ATPase). Once the PPI binds to the proton pump, the pump is inactivated [3]. Table 1 shows the results of the search, in terms of the number of publications identified and selected, and the cumula- tive patient number.

Esomeprazole Esomeprazole is the s-isomer of omeprazole, with less first-pass metabolism than omeprazole, resulting in higher bioavailability; this provides more effective and longer lasting inhibition of gastric acid secretion over the 24-h period [4].

A total of 69 articles on esomeprazole were retrieved. Only 12 were found to be relevant, in that they addressed a paediatric population treated for GERD [5–16]. All other

Table 1

Proton pump inhibitors

articles were excluded because of mislabelling (dealing with an adult population), because the indication for ther- apy was not GERD, because they were not original articles (reviews mostly) or because they did not report AEs.

The cumulative sample size of all these studies was 764 paediatric patients, ranging in age from 0 to 17 years (five studies dealt with patients <1 year).The studies were difficult to combine as the doses used ranged from 0.5 mg kg–1 to 1 mg kg–1, or were empirically 5, 10, 20 or 40 mg per dose (depending on the weight of the pa- tients), and because of patients’ heterogeneity (outpa- tients or inpatients). The proportion having at least one AE was 266/764 (34.8%). However, these AEs were usu- ally mild, and included: diarrhoea in 25 (3.2%); abdominal pain in 21 (2.7%); fever in 17 (2.2%); eczema in one (0.1%); nausea, vomiting or regurgitation in 31 (4%); pharyngitis in 17 (2.2%); irritability in three (0.4%); flatulence in one (0.1%); somnolence in three (0.4%); constipation in six (0.8%); arthralgia in three (0.4%); and headache, the most commonly reported AE, in 34 patients (4.4%). In one study of 57 patients who received esomeprazole paren- terally, six patients (10%) suffered from catheter-related infection [6]. The proportion of serious AEs reported in these series (and which included the six patients with catheter-related infection) was 7/764 (0.9%).

Omeprazole A total of 133 articles on omeprazole were retrieved but only 10 were relevant [17–26]. The cumulative sample size of these studies was 318 paediatric patients, ranging in age from 0 to 16 years (four studies dealt with patients <1 year). The doses used ranged from 0.25 mg kg–1 to 3.5 mg kg–1, or were empirically 20 mg per dose (in one study), and patients were outpatients or inpatients. The proportion having at least one AE was 108/318 (34%). However, this percentage could not be firmly established as the reporting of AEs was not consistent from one study to the next. For instance, in one study [18], 43 out of 46 children aged 1–16 years and receiving doses of 0.7–35 mg kg–1 day–1 were reported as having at least one AE, while in another study [17], none of the 35 children aged 1–181 months were reported as having at least one AE. Overall, the AEs reported were usually mild: abdominal pain in two (0.6%); eczema in one (0.3%); nausea, vomiting or regurgitation in 31 (9.7%); pharyngitis in 17 (5.3%); irritability in three (0.9%);

flatulence in one (0.3%); somnolence in three (0.9%); constipation in six (1.9%); arthralgia in three (0.9%); and headache in one patient (0.3%).

Lansoprazole Fifty-four articles on lansoprazole were retrieved from the search but only nine were found to be relevant [27–35]. The cumulative sample size of the nine studies was 620 paediatric patients, ranging in age from 0 to 18 years (three studies dealt with patients <1 year). The doses used ranged from 0.3 mg kg–1 to 2 mg kg–1, or were empirically 15, 30 or 60 mg per dose, depending on the weight of the patients (outpatients or inpatients). The proportion having at least one AE was 271/620 (43.7%). Serious AEs were reported in 14 (2.3%) patients. Ten children had asthma exacerbations [27], and four had pneumonia that was diagnosed as serious by the authors [31]. Overall, the AEs were usually mild and included upper respiratory tract infection (URTI) in 93 (15%); pharyngeal pain in 77 (12%); sinusitis in 16 (2.6%); otitis media in 12 (1.9%); bronchitis in 10 (1.6%); asthma exacerbation in 10 (1.6%); abdominal pain in nine (1.5%); pneumonia in nine (1.5%); headache in seven (1.1%); pharyngitis in six (1%); nausea, vomiting or regurgitation in six (1%); diarrhoea in three (0.5%); dizziness in three (0.5%); liver enzyme elevation in two (0.3%); flushing in two (0.3%); and anorexia, anaemia, chest tightness, hair loss or constipation in one (0.2%).

Pantoprazole Thirty-four articles on pantoprazole were retrieved but only six were found to be relevant [36–41]. The cumulative sample size was 340 ambulatory patients, ranging in age from 0 to 16 years (four studies dealt with patients <1 year). The doses used ranged from 0.3 mg kg–1 to 1.5 mg kg–1, or were empirically 40 mg per dose, depending on the weight of the patients. The proportion having at least one AE was 135/340 (40%). This was probably an underestimate of the real number because one large study of 128 children [41] did not report AEs. For all the other studies combined, the average proportion of patients having AEs was 63.7%, ranging from 44% (n = 43) and 100% (n = 1). Only one serious AE was reported (one case report of acute pancreatitis) [36]. All other reported AEs were mild and included fever in 23 (17%); abdominal pain in 13 (10%); diarrhoea or gastroenteritis in 26 (19%); headache in 12 (9%); nausea, vomiting or regurgitation in 20 (15%); pharyngeal pain or pharyngitis in seven (5%); eczema or rash in 12 (9%); viral infection in six (4.5%); constipation in five (4%); URTI in 74 (55%); anaemia in four (3%); and tooth discoloration in two patients (1.5%). Overall, there were 11 cases of accidental injuries (8%).

Rabeprazole Rabeprazole has a greater antisecretory potency relative to equivalent doses of the above- mentioned PPIs [42]. We retrieved 39 articles on

Gastroesophageal reflux disease in children

rabeprazole but only two were paediatric RCTs and were retained for analysis [43, 44]. The cumulative sample size was 52 outpatients, ranging from 1 to 16 years of age; doses used ranged from 0.14 mg kg–1 to 1 mg kg–1, or were empirically 10 mg or 20 mg per dose, depending on the weight of the patients. The proportion having at least one AE was 32/52 (61.5%). However, these AEs were usually mild, and included: diarrhoea in three (5.7%); abdominal pain in three (5.7%); fever in two (3.8%); pharyngitis and pharyngolaryngeal pain in three (5.7%); headache in four (7.7%); cough in three (5.7%); and asthma exacerbation in two (3.8%). The following AEs were each reported once (1.9%): URTI, proteinuria, dysmenorrhoea, fatigue, periorbital oedema, increase in urine output, mild hypergastrinaemia, increase in blood uric acid, heart murmur, chills, toothache and pancreatitis; the most common AE reported was nausea, vomiting or regurgitation, in seven patients (13.4%). Serious AEs were reported in only one individual (1.9%), who was diagnosed as having moderate viral gastritis on Day 4, severe intestinal volvulus on Day 7 and moderate hepatitis on day 19 (all of which we considered as unlikely to be related to the study drug) [44].

H2 receptor antagonists (H2RAs)

H2RAs act by reducing histamine-induced gastric acid secretion and pepsin output. They are well absorbed from the gastrointestinal tract but, due to high first-pass metabolism, the bioavailability of oral doses is only 50%. Intravenous dosing provides better bioavailability [45]. Table 2 shows the results of the search in terms of the number of publications identified and selected, and the cumulative patient number.

Ranitidine Ranitidine is the most commonly used H2RA. Twenty-eight articles on ranitidine were retrieved but only four were found to be relevant [17,24,46, 47]. The cumulative sample size was 245 patients, ranging in age from 0 to 15 years (two studies dealt with patients <1 year), with doses used ranging from 2 mg kg–1 to 15 mg kg–1, or empirically 45 mg per dose, depending on the weight of the patients (outpatients in three studies and inpatients in one). The proportion having at least one AE was 58/245 (23.7%) but this percentage could not be

Table 2

H2 receptor antagonists

	Ranitidine	Cimetidine	Famotidine	Nizatidine
Number of	28	0	7	3
articles identified
Number of	4	0	0	1
paediatric articles
Sample size	245	0	0	210
Placebo- controlled studies	17	0	0	210

firmly established as in one large study of 91 children [24] the proportion having at least one AE was 59%, while in another large study of 102 patients the proportion was 4% [46]. There were no serious AEs reported in any of the studies. All other reported AEs were mild, and included abdominal pain in one (1.7%); diarrhoea or gastroenteritis in 43 (74%); headache in two (3.4%); somnolence in one (1.7%); and pneumonia in 11 (19%).

Canani et al. [24] reported on 186 subjects, aged 4–36 months, consisting of 95 controls and 91 patients with GERD. The GERD patients were treated with ranitidine (10 mg kg–1) or omeprazole (1 mg kg–1) for 4 months. The rates of pneumonia and gastroenteritis were signifi- cantly higher in the patients receiving either of the drugs (12% vs. 2%, and 47% vs. 20%, respectively). The study was not placebo controlled or randomized.

Cimetidine Cimetidine is rarely used clinically as there are concerns about its effect on cytochrome P450 and consequent multiple drug interactions, as well as interference with vitamin D metabolism and endocrine function [48]. We could not find any prospective studies of paediatric patients with GERD exposed to cimetidine reporting AEs.

Famotidine Famotidine is an alternative H2RA; it is not licensed for use in children in the UK but is licensed in the US. Seven articles on famotidine were retrieved but only one dealt with paediatric patients with GERD; the focus of this article [49] was on the pharmacokinetics of famotidine and AEs were not reported systematically.

Nizatidine Nizatidine is a competitive, reversible, H2RA. It has a much lower drug interaction potential than cimetidine and a lower risk of drug-associated pancreatitis than either cimetidine or ranitidine [50]. Three articles were retrieved in our search but only one [51] dealt with ambulatory paediatric patients (n = 210), ranging from 0 to 18 years of age. The dose used was 2.5–5 mg kg–1 day–1. The proportion having at least one AE was 115/210 (54.7%). A total of 292 AEs occurred in these 115 patients. Four (1.4%) serious AEs were reported, of which only one (worsening sickle cell anaemia) was considered as possibly related to the to the study drug. The other AEs were considered as mild or moderate, and included fever in

Table 3

Prokinetics

12/292 (4%), diarrhoea in nine (3%), pharyngitis in 12 (4%), cough or URTI in 40 (14%), vomiting in nine (3%), somnolence in one (0.3%) and eczema in one (0.3%).

Prokinetics Table 3 shows the results of the search in terms of the number of publications identified and selected, and the cumulative patient number.

Metoclopramide Metoclopramide blocks dopamine and serotonin receptors, and has sympathomimetic activity. Twenty-eight articles on metoclopramide were retrieved but only two were relevant [52, 53]. They were both single case reports of dystonia (n = 1) and galactorrhoea (n = 1) and therefore were excluded from analysis. As a result of our search method (using a recent 10–year period), we did not any find recent studies of this relatively ’old’ drug. However, we were able to retrieve a systematic study of metoclopramide for the treatment of GERD in infants [54], published in 2006. Briefly, AEs were reported in only four of 12 studies. The AEs that were reported consisted of dystonic reactions, oculogyric crisis, irritability, drowsiness, emesis and apnoea, present in 9–15% of the patients [54–56].

Betanechol Bethanechol is a muscarinic receptor agonist that has been shown to increase the tone of the lower oesophageal sphincter. No paediatric studies on this molecule were reported in the 10-year study period.

Domperidone Domperidone is a prokinetic agent [57], through its action as a peripheral dopamine-2 receptor antagonist, but, unlike metoclopramide, it does not readily cross the blood–brain barrier and reports of AEs on the central nervous system are rare. Fifteen articles on domperidone were retrieved but only four were found to be relevant [58–61]. The cumulative sample size was 120 patients, ambulatory and hospitalized, ranging in age from 0 to 12 months, with the doses used ranging from 0.5 mg kg–1 day–1 to 1.8 mg kg–1 day–1. None of the four studies systematically addressed AEs, focusing only on whether or not domperidone prolonged the QT interval on the electrocardiogram. Two of the studies reported no change in the QT interval (n = 43 and 45, respectively), while the other two reported an increase in the QT interval (n = 31 and n = 1, respectively).

Erythromycin Erythromycin is a macrolide antibiotic that increases gastrointestinal motility by acting as a motilin receptor agonist [62]. Eight articles on erythromycin were retrieved but none was relevant, in that they were either reviews or did not deal with paediatric subjects.

Cisapride Cisapride is a prokinetic agent but, as of 14 July 2000, it has been withdrawn from the market because of at least 341 reports of heart rhythm abnormalities, including 80 deaths [63].

Baclofen Gamma-amino-butyric acid (GABA) plays an inhibitory role in the transient lower oesophageal sphincter relaxation reflex mediated via GABA(B) receptors. We retrieved seven articles on the use of baclofen but only two were relevant [64, 65], with a cumulative sample size of 38 paediatric patients, aged 0.2–17.4 years. Doses ranged from 0.5 mg kg–1 day–1 to 0.7 mg kg–1 day–1. No AEs were reported.

Thickening agents (Alginate)

Alginate contains sodium and magnesium alginate; it acts as a feed thickener by increasing the viscosity of feeds and, together with sodium/potassium bicarbonate in the presence of gastric acid, forms a ’foam raft’ to neu- tralize gastric acid (providing symptomatic relief) and to reduce oesophageal irritation [66]. We retrieved 20 arti- cles on the use of alginate but only two were found to be relevant [67, 68]. The cumulative sample size was 73 preterm infants, ranging in age from 0 to 30 days, with doses ranging from 0.25 ml kg–1 dose–1 to 1.0 ml kg–1 dose–1. No AEs were reported.

Discussion

Many studies have shown that H2RAs and PPIs are effective in suppressing gastric acid production and relieving oesophagitis in children. The current review has allowed us to determine the relative safety of anti-GERD drug ther- apy in children. Out of the list of AEs reported for the vari- ous drugs considered, it is not always clear which were truly related to the drug, as opposed to the disease itself or a randomly acquired illness. For instance, it is difficult, in a patient with GERD, to determine whether an episode of vomiting, regurgitation or abdominal pain is related to the drug used for GERD, or to GERD. It has been reported that in ill patients with a compromised immune system, the use of acid suppression, which is likely to decrease the natural immune barrier of gastric acidity, has been asso- ciated with an increased rate of nosocomial sepsis [69]. Within this context, it is not possible, for instance, to determine whether or not the use of esomeprazole was a contributory factor in the six reported cases of catheter- related sepsis in the study by Sandström [6]. It is also difficult, in a patient with GERD, to determine whether

Gastroesophageal reflux disease in children

pharyngeal pain or pneumonia is related to GERD (directly or indirectly) or to lansoprazole [31].

However, the most used H2RA, ranitidine, is well known for its ability to lead to tachyphylaxis, which seri- ously restricts its long-term (more than a few weeks) use [70]. PPIs do not appear to lead to tachyphylaxis and might be more appropriate for long-term therapy. A major limitation of acid-suppressant therapy is that it has little efficacy over placebo in reducing symptoms such as irritability [71]. From our search, it appears that AEs have been reported in at least 23% of patients treated with H2ARs and 34% of those treated with PPIs. Headaches, diarrhoea and nausea have been reported routinely in trials of H2RAs and PPIs, and constipation can be added to this list in patients treated with PPIs. These numbers might greatly underestimate the true incidence of AEs as some of them, such as headaches or nausea, are relatively subjective and cannot be reliably estimated in non-verbal infants. Moreover, as our review was focused on 10 recent years of literature, we may have missed other AEs, published in earlier studies and not reported in recent reviews (that were retrieved and analysed). There is increasing evidence that acid suppression may place susceptible infants and children, particularly those with defective immune systems or with indwelling catheters, at risk for the development of lower respiratory tract infections, gastroenteritis and candidaemia, and in premature infants may increase the risk of necrotizing enterocolitis and nosocomial infections. One report not included in our analysis was a retrospective study of 274 very low birth weight infants who were (n = 91) or were not (n = 183) exposed to ranitidine during their hospitalization [72]. The authors reported that the risks of necrotizing enterocolitis, nosocomial infection and mortality were significantly higher in the exposed infants (odds ratio 6.6, 95% confidence interval 1.7–25; odds ratio 5.5, 95% confidence interval 2.9–10.4; mortality rate 9.9% vs. 1.6%, respectively; P = 0.003). This paper is both provoc- ative and concerning, but its nonprospective, noncon- trolled and nonblinded design limits its significance as ranitidine exposure may have been associated in a non- causal manner with the above-mentioned complications. Nevertheless, one should carefully weigh the use of acid- suppressing agents to ameliorate GERD symptoms against the inherent risks of the medications.

A meta-analysis of metoclopramide in children youn- ger than 2 years with GERD confirmed a decrease in GERD symptoms [73]. However, this efficacy comes at the cost of significant AEs that include drowsiness, restlessness and extrapyramidal reactions in 10–20% of patients from our search and up to 34% of patients reported in older studies [73]. Therefore, we support the most recent state- ment in the American Academy of Pediatrics clinical re- port on GER, suggesting that: ’there is insufficient evidence to support the routine use of any prokinetic agent for the treatment of GERD in infants or older

S. Cohen et al.

children’ [74]. At this time, thickening agents have not been studied adequately in the paediatric population, both in terms of efficacy and AEs, so their routine use cannot be recommended as independent agents [70].

The weaknesses of the research carried out in the field of GERD therapy so far include a relatively low number of drug trials conducted in the paediatric age group, as com- pared with the much larger number of adult studies; and combined sample sizes that were too small in nearly all the included articles, for all medications, that we studied. Finally, the reporting quality of many of the studies retrieved in our search was very poor, which may have significantly affected the results, a phenomenon almost universally described when dealing with AE reporting [75].

Thus, our recommendations are that the primum non nocere (’first, do no harm’) rule should also apply to pae- diatric GERD. We suggest that the use of GERD medica- tions should be used only after nonpharmacological measures have been taken with incomplete success, to infants and children with significant symptoms, and that the use of such medications in ’happy spitter’ infants should be avoided. The use of the minimum number of acid-suppressant medicines, at the lowest dose, for the shortest period should enable physicians to minimize the rate and the severity of AEs [76]. Continual vigilance by prescribers and the reporting of AEs should be per- formed in order to improve knowledge and reduce the number of AEs that occur.

REFERENCES

1Hegar B, Dewanti NR, Kadim M, Alatas S, Firmansyah A, Vandenplas Y. Natural evolution of regurgitation in healthy infants. Acta Paediatr 2009; 98: 1189–93.

2Sherman PM, Hassall E, Fagundes-Neto U, Gold BD, Kato S, Koletzko S, Orenstein S, Rudolph C, Vakil N, Vandenplas Y. A global, evidence-based consensus on the definition of gastroesphageal reflux disease in the pediatric population. Am J Gastroenterol 2009; 104: 1278–95.

3Ward RM, Kearns GL. Proton pump inhibitors in pediatrics: mechanism of action, pharmacokinetics, pharmacogenetics, and pharmacodynamics. Paediatr Drugs 2013; 15: 119–31.

4Lind T, Rydberg L, Kyleback A, Jonsson A, Andersson T, Hasselgren G, Holmberg J, Röhss K. Esomeprazole provides improved acid control vs. omeprazole inpatients with symptoms of gastro-oesophageal reflux disease. Aliment Pharmacol Ther 2000; 14: 861–7.

5Davidson G, Wenzl TG, Thomson M, Omari T, Barker P, Lundborg P, Illueca M. Efficacy and safety of once-daily esomeprazole for the treatment of gastroesophageal reflux disease in neonatal patients. J Pediatr 2013; 163: 692–8.e1-2.

6Sandström M, Davidson G, Tolia V, Sullivan JE, Långström G, Lundborg P, Brown K. Phase I, multicenter, randomized, open-label study evaluating the pharmacokinetics and safety profile of repeated once-daily doses of intravenous

esomeprazole in children 0 to 17 years of age. Clin Ther 2012; 34: 1828–38.

7Winter H, Gunasekaran T, Tolia V, Gottrand F, Barker PN, Illueca M. Esomeprazole for the treatment of GERD in infants ages 1–11 months. J Pediatr Gastroenterol Nutr 2012; 55: 14–20.

8Tolia V, Gilger MA, Barker PN, Illueca M. Healing of erosive esophagitis and improvement of symptoms of gastroesophageal reflux disease after esomeprazole treatment in children 12 to 36 months old. J Pediatr Gastroenterol Nutr 2010; 51: 593–8.

9Tolia V, Youssef NN, Gilger MA, Traxler B, Illueca M. Esomeprazole for the treatment of erosive esophagitis in children: an international, multicenter, randomized, parallel-group, double-blind (for dose) study. BMC Pediatr 2010; 10: 41.

10Omari T, LundborgP, Sandström M, Bondarov P, Fjellman M, Haslam R, Davidson G. Pharmacodynamics and systemic exposure of esomeprazole in preterm infants and term neonates with gastroesophageal reflux disease. J Pediatr 2009; 155: 222–8.

11Gilger MA, Tolia V, Vandenplas Y, Youssef NN, Traxler B, Illueca M. Safety and tolerability of esomeprazole in children with gastroesophageal reflux disease. J Pediatr Gastroenterol Nutr 2008; 46: 524–33.

12Omari T, Davidson G, Bondarov P, Nauclér E, Nilsson C, Lundborg P. Pharmacokinetics and acid-suppressive effects of esomeprazole in infants 1–24 months old with symptoms of gastroesophageal reflux disease. J Pediatr Gastroenterol Nutr 2007; 45: 530–7.

13Gold BD, Gunasekaran T, Tolia V, Wetzler G, Conter H, Traxler B, Illueca M. Safety and symptom improvement with esomeprazole in adolescents with gastroesophageal reflux disease. J Pediatr Gastroenterol Nutr 2007; 45: 520–9.

14Baldassarre E, Sagaon MM, Ferrarini A, Bianchetti MG. Severe systemic adverse reaction to proton pump inhibitors in an infant. Pediatr Pulmonol 2007; 42: 563–4.

15Zhao J, Li J, Hamer-Maansson JE, Andersson T, Fulmer R, Illueca M, Lundborg P. Pharmacokinetic properties of esomeprazole in children aged 1 to 11 years with symptoms of gastroesophageal reflux disease: a randomized, open- label study. Clin Ther 2006; 28: 1868–76.

16Li J, Zhao J, Hamer-Maansson JE, Andersson T, Fulmer R, Illueca M, Lundborg P. Pharmacokinetic properties of esomeprazole in adolescent patients aged 12 to 17 years with symptoms of gastroesophageal reflux disease: a randomized, open-label study. Clin Ther 2006; 28: 419–27.

17Ummarino D, Miele E, Masi P, Tramontano A, Staiano A, Vandenplas Y. Impact of antisecretory treatment on respiratory symptoms of gastroesophageal reflux disease in children. Dis Esophagus 2012; 25: 671–7.

18Hassall E, Shepherd R, Koletzko S, Radke M, Henderson C, Lundborg P. Long-term maintenance treatment with omeprazole in children with healed erosive oesophagitis: a prospective study. Aliment Pharmacol Ther 2012; 35: 368–79.

19Tuleu C, Arenas-Lopez S, Robinson C, McCarthy D, Paget RI, Tibby S, Taylor KM. ’Poppy seeds’ in stomach aspirates: is

oral omeprazole extemporaneous dispersion bioavailable? Eur J Pediatr 2008; 167: 823–5.

20Bishop J, Furman M, Thomson M. Omeprazole for gastroesophageal reflux disease in the first 2 years of life: a dose-finding study with dual-channel pH monitoring. J Pediatr Gastroenterol Nutr 2007; 45: 50–5.

21Baldassarre E, Sagaon MM, Ferrarini A. Severe systemic adverse reaction to proton pump inhibitors in an infant. Pediatr Pulmonol 2007; 42: 563–4.

22Boccia G, Manguso F, Miele E, Buonavolontà R, Staiano A. Maintenance therapy for erosive esophagitis in children after healing by omeprazole: is it advisable? Am J Gastroenterol 2007; 102: 1291–7.

23Omari TI, Haslam RR, Lundborg P, Davidson GP. Effect of omeprazole on acid gastroesophageal reflux and gastric acidity in preterm infants with pathological acid reflux. J Pediatr Gastroenterol Nutr 2007; 44: 41–4.

24Canani RB, Cirillo P, Roggero P, Romano C, Malamisura B, Terrin G, Passariello A, Manguso F, Morelli L, Guarino A; Working Group on Intestinal Infections of the Italian Society of Pediatric Gastroenterology, Hepatology and Nutrition (SIGENP). Therapy with gastric acidity inhibitors increases the risk of acute gastroenteritis and community- acquired pneumonia in children. Pediatrics 2006; 117: e817–20.

25Orel R, Brecelj J, Homan M, Heuschkel R. Treatment of oesophageal bile reflux in children: the results of a prospective study with omeprazole. J Pediatr Gastroenterol Nutr 2006; 42: 376–83.

26Størdal K, Johannesdottir GB, Bentsen BS, Knudsen PK, Carlsen KC, Closs O, Handeland M, Holm HK, Sandvik L. Acid suppression does not change respiratory symptoms in children with asthma and gastro- oesophageal reflux disease.Arch Dis Child 2005; 90: 956–60.

27Holbrook JT, Wise RA, Gold BD, Blake K, Brown ED, Castro M, Dozor AJ, Lima JJ, Mastronarde JG, Sockrider MM, Teague WG. Writing Committee for the American Lung Association Asthma Clinical Research Centers. Lansoprazole for children with poorly controlled asthma: a randomized controlled trial. JAMA 2012; 307: 373–81.

28Kukulka M, Wu J, Perez MC J. Pharmacokinetics and safety of dexlansoprazole MR in adolescents with symptomatic GERD. J Pediatr Gastroenterol Nutr 2012; 54: 41–7.

29Eren M, Yıldırım SH, Sivrikoz IA. Safety profile of six months lansoprozole treatment in children. Indian J Gastroenterol 2010; 29: 247–8.

30Lee JH, Kim MJ, Lee JS, Choe YH. The effects of three alternative treatment strategies after 8 weeks of proton pump inhibitor therapy for GERD in children. Arch Dis Child 2011; 96: 9–13.

31Orenstein SR, Hassall E, Furmaga-Jablonska W, Atkinson S, Raanan M. Multicenter, double-blind, randomized, placebo- controlled trial assessing the efficacy and safety of proton pump inhibitor lansoprazole in infants with symptoms of gastroesophageal reflux disease. J Pediatr 2009; 154: 514–20.

Gastroesophageal reflux disease in children

32Springer M, Atkinson S, North J, Raanan M. Safety and pharmacodynamics of lansoprazole in patients with gastroesophageal reflux disease aged <1 year. Paediatr Drugs 2008; 10: 255–63.

33Khoshoo V, Dhume P. Clinical response to 2 dosing regimens of lansoprazole in infants with gastroesophageal reflux. J Pediatr Gastroenterol Nutr 2008; 46: 352–4.

34Heyman MB, Zhang W, Huang B, Chiu YL, Amer F, Winter HS. Pharmacokinetics and pharmacodynamics of lansoprazole in children 13 to 24 months old with gastroesophageal reflux disease. J Pediatr Gastroenterol Nutr 2007; 44: 35–40.

35Fiedorek S, Tolia V, Gold BD, Huang B, Stolle J, Lee C, Gremse

D.Efficacy and safety of lansoprazole in adolescents with symptomatic erosive and non-erosive gastroesophageal reflux disease. J Pediatr Gastroenterol Nutr 2005; 40:

319–27.

36Das S, Ganguly A, Ghosh A, Mondal S, Dey JK, Saha I. Oral pantoprazole-induced acute pancreatitis in an 11-year-old child. Ther Drug Monit 2012; 34: 242–4.

37Tammara BK, Sullivan JE, Adcock KG, Kierkus J, Giblin J, Rath N, Meng X, Maguire MK, Comer GM, Ward RM. Randomized, open-label, multicentre pharmacokinetic studies of two dose levels of pantoprazole granules in infants and children aged 1 month through <6 years with gastro-oesophageal reflux disease. Clin Pharmacokinet 2011; 50: 541–50.

38Ward RM, Kearns GL, Tammara B, Bishop P, O’Gorman MA, James LP, Katz MH, Maguire MK, Rath N, Meng X, Comer GM.

Amulticenter, randomized, open-label, pharmacokinetics and safety study of pantoprazole tablets in children and adolescents aged 6 through 16 years with gastroesophageal reflux disease. J Clin Pharmacol 2011; 51: 876–87.

39Kierkus J, Furmaga-Jablonska W, Sullivan JE, David ES, Stewart DL, Rath N, Fu C, Wang W, Maguire MK, Comer GM. Pharmacodynamics and safety of pantoprazole in neonates, preterm infants, and infants aged 1 through 11 months with a clinical diagnosis of gastroesophageal reflux disease. Dig Dis Sci 2011; 56: 425–34.

40Baker R, Tsou VM, Tung J, Baker SS, Li H, Wang W, Rath N, Maguire MK, Comer GM. Clinical results from a randomized, double-blind, dose-ranging study of pantoprazole in children aged 1 through 5 years with symptomatic histologic or erosive esophagitis. Clin Pediatr (Phila) 2010;

49:852–65.

41Winter H, Kum-Nji P, Mahomedy SH, Kierkus J, Hinz M, Li H, Maguire MK, Comer GM. Efficacy and safety of pantoprazole delayed-release granules for oral suspension in a placebo- controlled treatment-withdrawal study in infants 1–11 months old with symptomatic GERD. J Pediatr Gastroenterol Nutr 2010; 50: 609–18.

42Tolman KG, Taubel J, Warrington S, Chiu YL, Pilmer BL, Pan WJ. Comparison of the effects of single and repeated oral doses of lansoprazole and rabeprazole on ambulatory 24-hour intragastric pH in healthy volunteers. Clin Drug Invest 2006; 26: 21–8.

43James L, Walson P, Lomax K, Kao R, Varughese S, Reyes J. Study 119 Pediatric Trial Investigators. Pharmacokinetics

S. Cohen et al.

and tolerability of rabeprazole sodium in subjects aged 12 to 16 years with gastroesophageal reflux disease: an open- label, single- and multiple-dose study. Clin Ther 2007 29:

2082–92.

44Zannikos PN, Doose DR, Leitz GJ, Rusch S, Gonzalez MD, Solanki B, Haddad I, Mulberg AE. Pharmacokinetics and tolerability of rabeprazole in children 1 to 11 years old with gastroesophageal reflux disease. J Pediatr Gastroenterol Nutr 2011; 52: 691–701.

45Joint publication of the British Medical Association, the Royal Pharmaceutical Society of Great Britain, the Royal College of Paediatrics and Child Health, and the Neonatal and Paediatric Pharmacists Group. British National Formulary for Children.

Section 1.1.2. London: BMJ Group, 2007: 53.

46Wheatley E, Kennedy KA. Cross-over trial of treatment for bradycardia attributed to gastroesophageal reflux in preterm infants. J Pediatr 2009; 155: 516–21.

47Ameen VZ, Pobiner BF, Giguere GC, Carter EG. Ranitidine (Zantac) syrup versus ranitidine effervescent tablets (Zantac EFFERdose) in children: a single-center taste preference study. Paediatr Drugs 2006; 8: 265–70.

48Cucchiara S, Franco MT, Terrin G, Spadaro R, di Nardo G, Iula V. Role of drug therapy in the treatment of gastro-oesophageal reflux disorder in children. Paediatr Drugs 2000; 2: 263–72.

49Wenning LA, Murphy MG, James LP, Blumer JL, Marshall JD, Baier J, Scheimann AO, Panebianco DL, Zhong L, Eisenhandler R, Yeh KC, Kearns GL. Pharmacokinetics of famotidine in infants. Clin Pharmacokinet 2005; 44: 395–406.

50Furuta S, Kamada E, Suzuki T, Sugimoto T, Kawabata Y, Shinozaki Y, Sano H. Inhibition of drug metabolism in human liver microsomes by nizatidine, cimetidine and omeprazole. Xenobiotica 2001; 31: 1–10.

51Orenstein SR, Gremse DA, Pantaleon CD, Kling DF, Rotenberg KS. Nizatidine for the treatment of pediatric gastroesophageal reflux symptoms: an open-label, multiple-dose, randomized, multicenter clinical trial in 210 children. Clin Ther 2005; 27: 472–83.

52Eras Z, Oğuz SS, Dilmen U. Is metoclopramide safe for the premature infant? Eur Rev Med Pharmacol Sci 2013; 17: 1655–7.

53Paturi B, Ryan RM, Michienzi KA, Lakshminrusimha S. Galactorrhea with metoclopramide use in the neonatal unit. J Perinatol 2009; 29: 391–2.

54Hibbs AM, Lorch SA.Metoclopramide for the treatment of gastroesophageal reflux disease in infants: a systematic review. Pediatrics 2006; 118: 746–52.

55Leung AKC, Lai PCW. Use of metoclopramide for the treatment of gastroesophageal reflux in infants and children. Curr Ther Res Clin Exp 1984; 36: 911–5.

56Hyams JS, Leichtner AM, Zamett LO, Walters JK. Effect of metoclopramide on prolonged intraesophageal pH testing in infants with gastroesophageal reflux. J Pediatr Gastroenterol Nutr 1986; 5: 716–20.

57Glassman M, George D, Grill B. Gastroesophageal reflux in children. Clinical manifestations, diagnosis and therapy. Gastroenterol Clin North Am 1995; 24: 71–98.

58Vieira MC, Miyague NI, Van Steen K, Salvatore S, Vandenplas Y. Effects of domperidone on QTc interval in infants. Acta Paediatr 2012; 101: 494–6.

59Günlemez A, Babaoğlu A, Arisoy AE, Türker G, Gökalp AS. Effect of domperidone on the QTc interval in premature infants. J Perinatol 2010; 30: 50–3.

60Djeddi D, Kongolo G, Lefaix C, Mounard J, Léké A. Effect of domperidone on QT interval in neonates. J Pediatr 2008; 153: 663–6.

61Rocha CM, Barbosa MM. QT interval prolongation associated with the oral use of domperidone in an infant. Pediatr Cardiol 2005; 26: 720–3.

62Peeters TL. Erythromycin and other macrolides as prokinetic agents. Gastroenterology 1993; 105: 1886–99.

63Wysowski DK, Corken A, Gallo-Torres H, Talarico L, Rodriguez EM. Postmarketing reports of QT prolongation and ventricular arrhythmia in association with cisapride and Food and Drug Administration regulatory actions. Am J Gastroenterol 2001; 96: 1698–703.

64Omari TI, Benninga MA, Sansom L, Butler RN, Dent J, Davidson GP. Effect of baclofen on esophagogastric motility and gastroesophageal reflux in children with gastroesophageal reflux disease: a randomized controlled trial. J Pediatr 2006; 149: 468–74.

65Kawai M, Kawahara H, Hirayama S, Yoshimura N, Ida S. Effect of baclofen on emesis and 24-hour esophageal pH in neurologically impaired children with gastroesophageal reflux disease. J Pediatr Gastroenterol Nutr 2004; 38: 317–23.

66Mandel KG, Daggy BP, Brodie DA. Review article alginate- raft formulations in the treatment of heartburn and acid reflux. Aliment Pharmacol Ther 2000; 14: 669–90.

67Corvaglia L, Aceti A, Mariani E, De Giorgi M, Capretti MG, Faldella G. The efficacy of sodium alginate (Gaviscon) for the treatment of gastro-oesophageal reflux in preterm infants. Aliment Pharmacol Ther 2011; 33: 466–70.

68Atasay B, Erdeve O, Arsan S, Türmen T. Effect of sodium alginate on acid gastroesophageal reflux disease in preterm infants: a pilot study. J Clin Pharmacol 2010; 50: 1267–72.

69Pasqualotto AC, Nedel WL, Machado TS, Severo LC. A comparative study of risk factors and outcome among outpatient-acquired and nosocomial candidaemia. J Hosp Infect 2005; 60: 129–34.

70Lightdale JR, Gremse DA. American Academy of Pediatrics Section on Gastroenterology, Hepatology, and Nutrition. Gastroesophageal reflux: management guidance for the pediatrician. Pediatrics 2013; 131: e1684–95.

71Moore DJ, Tao BS, Lines DR, Hirte C, Heddle ML, Davidson GP. Double-blind placebo-controlled trial of omeprazole in irritable infants with gastroesophageal reflux. J Pediatr 2003; 143: 219–23.

72Terrin G, Passariello A, De Curtis M, Manguso F, Salvia G, Lega L, Messina F, Paludetto R, Canani RB. Ranitidine is associated with infections, necrotizing enterocolitis, and fatal outcome in newborns. Pediatrics 2012; 129: e40–5.

73Craig WR, Hanlon-Dearman A, Sinclair C, Taback S, Moffatt M. Metoclopramide, thickened feedings, and positioning for gastro-oesophageal reflux in children under two years. Cochrane Database Syst Rev 2004; (4): CD003502.

74Vandenplas Y, Rudolph CD, Di Lorenzo C, Hassall E, Liptak G, Mazur L, Sondheimer J, Staiano A, Thomson M, Veereman- Wauters G, Wenzl TG. Pediatric gastroesophageal reflux clinical practice guidelines: joint recommendations of the North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition (NASPGHAN) and the European Society for Pediatric Gastroenterology, Hepatology, and Nutrition (ESPGHAN). J Pediatr Gastroenterol Nutr 2009; 49: 498–547.

Gastroesophageal reflux disease in children

75Smyth RM, Gargon E, Kirkham J, Cresswell L, Golder S, Smyth R, Williamson P. Adverse drug reactions in children – a systematic review. PLoS One 2012; 7: e24061.

76Bellis JR, Kirkham JJ, Thiesen S, Conroy EJ, Bracken LE, Mannix HL, Bird KA, Duncan JC, Peak M, Turner MA, Smyth RL, Nunn AJ, Pirmohamed M. Adverse drug reactions and off-label and unlicensed medicines in children: a nested case-control study of inpatients in a pediatric hospital. BMC Med 2013; 11: 238