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A review of omeprazole use in the treatment of acid-related disorders in children
CLINICAL
THERAPEUTICWVOL.
23, NO. 5,200l
A Review of Omeprazole Use in the Treatment of Acid-Related Disorders in Children Anthony E. Zimmermann, PharmD,’ J. Ken Walters, PharmD,2 Brian G. Katona, PharmD,3 Paul E Souney, RPh, MS,3 and Douglas Levine, MD3 ‘Massachusetts College of Pharmacy/Health Sciences and Baystate Medical Center Springfield, Massachusetts, 2Sheppard and Enoch Pratt Hospital, Towson, Maryland, and 3AstraZeneca Pharmaceuticals LP, Wilmington, Delaware
ABSTRACT Background: Acid peptic disease is a common problem, with a similar prevalence of gastroesophageal reflux disease (GERD) in adults and children. The presentation of GERD in infants and children varies from crying, irritability, or sleep disturbance to feeding difftculties, vomiting, or rumination. Helicobacter pylori (HP)-related diseases and gastric and duodenal ulcers are much more common in adults than in children, who are more likely to have gastritis or duodenitis. However, because HP infection is most likely acquired in childhood, treatment of children with endoscopically documented active HP disease may minimize the potential risk for peptic ulcer or gastric cancer in adulthood, although this is yet to be proved. Objective: Omeprazole has been shown to be effective in the treatment of acid-related diseases. This paper reviews the literature on the use and administration of omeprazole for the treatment of GERD, peptic ulcer disease, HP infection, and other acid-related conditions in children. Methods: Studies were identified through searches of MEDLINE@ and Science Citation Index for the period 1986 to November 2000, and from the reference lists of identified articles. The search terms used included omeprazole, proton pump inhibitor (PPI), children, pediatrics, routes of administration, GERD, HP infection, esophagitis, and administration. In addition, the manufacturer of omeprazole was asked for relevant unpublished information. Results: Marketed and extemporaneous formulations of omeprazole have been administered to children aged 2 months to 18 years for the treatment of erosive esophagitis, gastric ulcer, duodenal ulcer, HP infection, and related conditions at dosages of 5 to 80 mg/d (0.2-3.5 mg/kg/d) for periods ranging from 14 days to 36 months with a low incidence of adverse effects. The initial dose most consistently reported to heal esophagitis and provide relief of symptoms of GERD appears to be 1 mg/kg per day. Accepted for publication
March 5, 2001.
Printed in the USA. Reproduction
660
in whole or part is not permitted
0149.2918/01/$19.00
A.E. ZIMMERMANN ET AL.
Conclusions: In uncontrolled clinical trials and case reports to date, omeprazole has been effective and well tolerated for the acute and chronic treatment of esophageal and peptic ulcer disease in children, particularly those who had failed to respond to previous treatment with histamine,receptor antagonists. Should future longterm, controlled clinical trials in children demonstrate safety and efficacy, this PPI is likely to find a place in the armamentarium of pediatric pharmacotherapy. Key words: children, Helicobacter pyZori, treatment, GERD, esophagitis, proton pump inhibitor. (C/in Thel: 2001;23: 660479)
INTRODUCTION Acid peptic disease is an exceedingly common problem in the western world. The prevalence of gastroesophageal reflux disease (GERD) is similar in the adult and pediatric populations, from 3% to 7% in the former and 8% in the latter.im3 The presentation of GERD in infants and children varies from crying, irritability, or sleep disturbance to feeding difficulties, vomiting, or rumination. In some cases, positional and dietary measures are sufficient to resolve mild cases of GERD in infants.z Gastric and duodenal ulcers are much more common in adults than in children, who are more likely to have gastritis or duodenitis.4 The incidence of Helicobacter pylori (HP)-related diseases is also much lower in children than adults; however, because HP is most likely acquired in childhood, treatment of children with endoscopically documented active HP disease may minimize the potential risk for peptic ulcer or gastric cancer in adulthood, although this is yet to be proved.
Empiric treatment of HP infection is currently not recommended in children. Omeprazole* has been shown to be well tolerated and effective in the treatment of acid-related diseases. In the United States, it is approved for use in adults for acute and maintenance treatment of erosive esophagitis, symptomatic treatment of GERD, acute treatment of gastric and duodenal ulcer, and eradication of HP in patients with active duodenal ulcer.5 The frequency of adverse effects (AEs) is low, with the most common AEs including headache, diarrhea, abdominal pain, and nausea.5 Because omeprazole is metabolized in the liver by cytochrome P450 enzymes, it may increase the elimination or half-life of diazepam, phenytoin, warfarin, and digoxin.5 Omeprazole is approved for pediatric use in the United Kingdom and other European countries6 and is currently under review for pediatric use in the United States. This paper reviews the published literature on the use and administration of omeprazole for the treatment of GERD, peptic ulcer disease, HP infection, and other acid-related conditions in children. Studies were identified through searches of MEDLINE@ and Science Citation Index for the period 1986 to November 2000, and from the reference lists of identified articles. The search terms used included omeprazole, proton pump inhibitor (PPI), children, pediatrics, routes of administration, GERD, HP infection, esophagitis, and administration. In addition, the manufacturer of omeprazole was asked for relevant unpublished information. For the purposes of this paper, the terms refractory and unresponsive are defined as no clinical response or an incomplete *Trademark: Prilosec@ (AstraZeneca cals LP, Wilmington, Delaware).
Pharmaceuti-
661
CLINICAL THERAPEUTICSO
clinical response to previous therapy of between 4 weeks and 12 months in duration, depending on the study design. Healing rates in the reviewed studies were determined based on endoscopic findings before and after treatment. Severity of esophagitis was assessed based on a standard grading system (from 0 = no mucosal abnormalities to 4 = deep peptic ulceration anywhere in the esophagus).
AIDS, organ transplantation, organ failure, and hematologic malignancy. Dosage was calculated based on adult IV dosing information: a 60- to 80-mg/1.73 m2 loading dose was followed by 40 mgU.73 m2 given as a slow bolus over 15 minutes every 12 hours. The children received doses ranging from 36.9 to 139 mg11.73 m2. Kato et al8 assessed the pharmacokinetic parameters of oral omeprazole 0.6 mg/kg in 7 Japanese children whose esophagitis or ulcer disease had been unresponsive to therapy with histamine,-receptor antagonists.
PHARMACOKINETICS Two studies have evaluated the pharmacokinetics of omeprazole in children.7s Based on the findings of these studies, the pharmacokinetic parameters of IV and oral omeprazole do not appear to differ significantly between adults9-‘” and children (Table I). Jacqz-Aigrain et al7 studied the pharmacokinetics of IV omeprazole in I3 critically ill children (age range, 0.3-19 years) who had failed to respond to IV ranitidine and were unable to take omeprazole orally. The patients’ underlying conditions included
Table I. Comparison of the pharmacokinetic in children and adults.
Route of Administration Intravenous Children? mg/l.73 m* Adults,“-I3 mg/kg
Oral, mg/kg Children’ Adultsi
Dose
GASTROESOPHAGEAL REFLUX DISEASE AND ESOPHAGITIS Reflux esophagitis is a chronic relapsing condition. In adults, relapse rates of >80% have been reported within 6 months of the cessation of medical therapy,i4 but no data are available on the relapse rate in children. Published studies on omeprazole for the acute management and maintenance therapy of GERD in children are limited to
profiles of intravenous
AUC, pmol/L.h
and oral omeprazole
Cl, L/h.kg
V, L/kg
b2’ h
47.4 -+ 27.2 0.15 0.53 1.07
14.1 f 15.3 0.99 2.93 c 0.81 8.51 k2.55
0.23 + 0.32 0.45 0.56 + 0.15 0.41 +0.17
0.45 f 0.17 0.49 + 0.27 0.42+0.18
0.86 2 0.88 0.58 0.57 + 0.12 0.81 kO.17
0.6 0.28
5.40 + 1.96 0.84-1.88
0.454
0.31 2 0.09
0.9 f 0.1 0.87 t 0.73
Values are mean + SEM, unless reported otherwise in individual studies. AUC = area under the curve; Cl = clearance;
662
V = volume of distribution;
t,,? = half-life.
A.E. ZiifMERMANN
ET AL.
1 randomized, comparative clinical trial,i5 10 case series,1”25 2 case reports,26.27 and 3 abstracts (Table II).**-30 The largest and most complete are discussed in the following paragraphs. In the prospective comparative trial,i5 32 patients whose reflux esophagitis (confirmed by endoscopy and 24-hour intraesophageal pH monitoring) had not responded to 8 weeks of ranitidine (4 mg/kg BID plus cisapride 0.265 mg/kg TID) were randomized to omeprazole (40 mg/1.73 m*/d) or high-dose ranitidine (20 mg/kg/d in divided doses) for 8 weeks. Twenty-five patients (12 omeprazole, 13 ranitidine) aged between 6 months and 13 years completed the study. Esophageal healing occurred in 9 of 12 (75%) omeprazole-treated patients and 8 of 13 (62%) ranitidine-treated patients; symptom relief was reported in 10 of 12 (83%) omeprazole-treated patients and 9 of 13 (69%) ranitidine-treated patients. These differences were not statistically significant, and the treatments were considered equally efftcacious. In other studies of omeprazole for the treatment of initial or refractory GERD/ esophagitis in children,‘“26 reported endoscopic healing rates ranged from 40% to 100% and symptom relief from 73% to 100%. The dosages used ranged from 0.4 to 3.5 mg/kg per day (5-80 mg/d), and the duration of treatment ranged from 6 weeks to 30 months. In 1 study, l* 153 patients between the ages of 6 and 18 years who had experienced ~3 weeks of continuous epigastric pain underwent endoscopy and received the following diagnoses peptic esophagitis (129 [84%]), peptic ulcer (2 [ 1%I), and HP gastritis (4 [3%]). Eighteen patients (12%) had normal endoscopic findings. In those with esophagitis, 94 (73%) of patients had grade 1 or 2 disease. All patients were ini-
tially treated with ranitidine 4 mgkg BID, with an increase to 4 mg/kg TID after 2 weeks if symptoms were not alleviated. Prokinetic agents were not permitted. If patients were still symptomatic after 4 weeks of the maximum ranitidine regimen, they were switched to omeprazole 20 mg/d, with titration to a maximum of 60 mgld based on response. Ranitidine treatment was successful in 91 of the 129 (71%) children with esophagitis, and omeprazole was successful in 33 of the 38 (87%) children who failed to respond to ranitidine. Hassall et al** studied 5 1 children aged between 1 and 16 years who had esophagitis of grades 2 through 4 (grade 2, 33%; grade 3,43%; grade 4,24%). Twenty-eight had not responded to treatment with prokinetic agents and/or histamine,-receptor antagonists, and 5 had failed to respond to fundoplication. The initial omeprazole dosage of 0.7 mg/kg daily was increased as needed to achieve the therapeutic goal of an esophageal pH ~4.0 for ~6% of the 24-hour monitoring period. The maximum total daily dose was 3.5 mg/kg, with no child receiving >80 mg/d. Forty-nine of 51 (96%) children had esophageal healing on follow-up endoscopy; 3 of 49 (6%) required a second course of therapy. The proportion of children requiring an omeprazole dosage of >1.4 mg/kg per day was higher in those with more severe esophagitis (grade 3 or 4). Healing rates with the various regimens were as follows: 0.7 mg/kg, 23/49 (47%); 1.4 mg/kg, 13/49 (27%); 2.1 mg/kg, 7/49 (14%); 2.8 mg/kg, 4/49 (8%); and 3.5 mg/kg, 2/49 (4%). At the last reported visit (up to 53 weeks of therapy), 26% were asymptomatic, 45% had mild symptoms, 20% had moderate symptoms, and 9% had severe symptoms. No AEs were reported with omeprazole therapy.
Weight ~30 kg, 20 mg Weight >30 kg, 40 mg (0X-2.2 mgkg) 0.5 mg/kg
19 mo-12 y
2-9 y
2.9 k 0.9 mo
22
10
12
De Giacomo et al*’
Alliet et al22
1 mg/kg
6 wk
3mo
8 wk
in 11 (73%)
Healing of esophagitis in 9 (75%): symptom relief in 10 (83%)
Endoscopic healing in 9 (10%) and symptom improvement in 10 (100%)
Symptom resolution or improvement in 22 (100%)
Symptom improvement
3 mo
Cucchiara et al*”
5-20 mg (0.8 mg/kg)
I-16 y
15
in 33 (87%)
Martin et aIt9
Symptom improvement
8 wk
20-60 mg
6-18 y
35
Karjoo and KaneIs
Healing of esophagitis by 6 mo in 9 (60%); 15 (100%) symptom free at 12 mo
5.5-26 mo
1O-60 mg (0.7-3.3 mg/kg)
0.8-17 y
15
Gunasekaran and Hassallt7
Endoscopic healing of esophagitis and maintenance of healing in 3 (100%)
24-30 mo
40 mg healing; 2&40 mg maintenance
healing of esophagitis
Healing of esophagitis in 9 (75%); symptom improvement in 10 (83%)
Endoscopic in 4 (80%)
Outcome
g-15 y
3
Nelis and Westerveld’l
6 wk
of Treatment
Duration
in children.
8 wk
6 mo-13 y
12
Cucchiara et alI5
0.3-0.7 mg/kg
Daily Dose
reflux disease and erosive esophagitis
40 mg/1.73 mz
3-1.8 y
Age
5
No. of Patients
treatment for gastroesophageal
Kato et al*
Author
Table II. Summary of studies of omeprazole
51
88
Hassall et a128
A~ull~
Cucchiara et a130
12
7Y
1
Daizell et a12’
et alz9
4mo
1
Alliet et alz6
Uns~ci~ed
40 mg0.73
1.7-13.4 y
m2
10-80 mg (0.7-3.5 mg/kg)
(0.4 mg/kg)
10 mg
(0.5 mg/kg)
3.5 mg
6 d-17 y
l-16 y
2-17 y
18
Strauss et aP5 0.26-l .3.5 mgn
Weight >20 kg, 40 mg Weight ~20 kg, 20 mg Maintenance, 20 mg (10 mg, weight ~20 kg)
4-19 y
51
Bohmer et a124
Daily Dose
0.5 and 1.0 mg/kg
Age
4 and 5 mo
2
Patients
No. of
She&h et a123
Author
Table II. (Continued)
8 wk
Mean, 4.2 mo
$53 wk
8 wk
6 wk
8-12 wk
9 mo
3 mo
8 and 10 wk
Treatment
Duration of
and
and
Histologic and symptomatic in 12 (100%)
improvement
Endoscopjc improvement in 60 (68%); symptom improvement in 64 (73%)
Endoscopic healing in 49 (96%); symptom relief in 46 (90%)
Endoscopic healing of esophagitis symptom resolution
Endoscopic healing of esophagitis symptom resolution
Endoscopic healing in 6/17 (35%); symptom resolution in 13117 (76%)
Endoscopic healing and symptom improvement in 5 1 (100%); 48 (94%) remained healed; 7 (14%) healed with dose increase
Normaiization of pulmonary function test results and symptom improvement in 2 (100%)
Outcome
F
7
3
g
3
B $
,N
CLINICAL THERAPEUTICS”
Bohmer et alz4 performed endoscopic examinations of 69 intellectually disabled children (IQ <50) between the ages of 4 and 19 years for symptoms that included vomiting, regurgitation, food refusal, hematemesis, and behavioral problems. Fiftytwo (75%) of the children had esophagitis of grades 1 to 4 (grade I,19 [37%]; grade 2, 20 [38%]; grade 3, 6 [12%]; grade 4, 7 [ 13%]). Esophagitis was accompanied by hiatal hernia in 40 (77%) patients, Barrett’s esophagus in 7 (13%), and peptic strictures in 3 (6%). Twenty-one (40%) patients were taking antireflux medications (12, ranitidine 300 mg/d; 9, cisapride), and 5 (10%) had previously undergone Nissen fundoplication. Patients were initially given omeprazole 40 mg/d (body weight <20 kg, 20 mg) for 3 months. If the esophagitis was healed, maintenance therapy consisted of omeprazole 20 mg/d (body weight ~20 kg, 10 mg). If symptoms persisted and endoscopic examination revealed improvement in the esophagitis, omeprazole 40 mg/d was continued for 3 additional months. If the esophagitis was unchanged, omeprazole therapy was increased to 60 mg/d (body weight <20 kg, 40 mg). Endoscopic examination was repeated at 3, 6, and 9 months. After 3 months of omeprazole therapy, 47 of 52 (90%) children with esophagitis were asymptomatic. Of the 5 children with persistent symptoms of esophagitis, endoscopy revealed healing in 2 and improvement in 3, who continued therapy for an additional 3 months. During the maintenance phase of the study, 48 of 5 1 (94%) patients demonstrated healing and remained symptom free at 9-month followup. Seven of 48 (12%) patients experienced a relapse at the maintenance dose but demonstrated healing and remained symptom free when omeprazole 40 mg/d was reinstituted. No AEs were reported.
666
Cucchiara et al*O studied 22 children aged 19 months to 12 years (median age, 6.6 years) with severe reflux esophagitis that was refractory to 8 weeks of combined therapy with ranitidine (8 mg/kg/d) and cisapride (0.6 mg/kg/d). The children were treated with 8 weeks of omeprazole 1 mg/kg per day given as granules dissolved in an acidic vehicle (eg, grapefruit or orange juice), after which symptoms improved or disappeared in all patients. Two months after discontinuation of omeprazole, 16 of 22 (73%) children were symptomatic. No AEs were reported. De Giacomo et a121prospectively evaluated 10 children aged between 2 and 9 years (mean, 6.3 years) who had esophagitis of grades 2 to 4 and symptomatic GERD and were treated with omeprazole for 3 months. Five patients had received previous combination therapy consisting of prokinetic agents plus histamine,-receptor antagonists (n = 3) or antacids (n = 2); the other 5 patients had received no previous treatment. Children weighing ~30 kg received omeprazole 20 mgld and those weighing >30 kg received 40 mg/d (range, 0.8-2.2 mg/kg/d). Symptoms were evaluated weekly, and repeat endoscopy was performed in all patients 2.5 to 3 months into omeprazole therapy. Nine of 10 (90%) patients demonstrated endoscopic healing of esophagitis. One child who initially received omeprazole 20 mg/d ( 1.1 mg/kg) did not show endoscopic improvement, and the dosage was increased to 40 mg/d (2.2 mgkg) for 2 months, with resultant endoscopic healing. Improvement in symptoms was noted in 10 of 10 (100%) patients. After discontinuation of omeprazole, 6 children experienced a return of symptoms requiring additional omeprazole treatment; 3 were maintained on omeprazole therapy, and 3 required surgery for Barrett’s esophagus and recurrent pneumonia.
A.E. ZIMMERMANN ET AL.
Alliet et al22 described the use of omeprazole 0.5 mg/kg per day for 6 weeks in 12 infants (mean age, 2.9 + 0.9 months) with grade 2 esophagitis who had not responded to 3 weeks of treatment with the combination of cimetidine (10 mg/kg TID) plus cisapride (0.265 mg/kg TID) and antacids. Cisapride and antacids were continued during omeprazole therapy. There was a significant decrease in irritability and an improvement in feeding behavior in 10 of 12 (83%) children, with 9 of 12 (75%) achieving complete endoscopic healing of esophagitis. In the 3 infants whose esophagitis did not heal, improvement from grade 2 to 1 and marked improvement in symptoms was seen. Sheikh et al23 reported the effects of omeprazole in 2 infants (aged 4 and 5 months) with persistent wheezing who had been unresponsive to cromolyn, albuterol, inhaled steroids, systemic steroids, ranitidine, and prokinetic agents. Esophageal pH monitoring revealed significant GERD, and the patients were respectively administered omeprazole 0.5 and 1 mg/kg daily. Shortly after omeprazole was begun, the wheezing ceased and all asthma medications were stopped. Pulmonary function test results normalized after 8 and 10 weeks of omeprazole therapy, which was subsequently discontinued. Symptom resolution lasted for 18 months in 1 infant and 36 months in the other.
PEPTIC ULCER DISEASE AND ERADICATION OF HELICOBACTER PYLORI In the pediatric population, the incidence of peptic ulcer disease is low compared with that in adults. Thus, few clinical trials have been performed, most of them small open-label studies. In the past, noncompliance due to AEs and the complexity of reg-
imens for the eradication of HP have resulted in high failure rates; however, the currently recommended shorter courses of better-tolerated combinations of agents3i have increased compliance with similar eradication rates. It must be noted that not all peptic ulcer disease is HP related; 15% to 20% of all duodenal ulcers in children are non-HP related and thus will respond to acid suppression alone.32 There have been 8 complete studies 8,33,34736-38940.41 2 case reports,42343 15 a&racts 35,45-58and 2 letters39,44 published on the use of omeprazole in gastritis, gastric and duodenal ulcers, and dyspepsia in children (Table III). These studies have evaluated symptom relief, healing and eradication of HP, and prevention of recurrence. The largest and most complete of these studies are discussed in subsequent paragraphs. In all the clinical trials, triple therapy (a PPI plus 2 antibiotics) was clinically and statistically superior to dual therapy (a PPI plus an antibiotic). Fifteen HP-positive children aged 9 to 16 years with endoscopically confirmed duodenal ulcers (11) and/or antral gastritis (4) were administered omeprazole, metronidazole, and clarithromycin for 2 weeks in an open-label trial of efficacy in the eradication of HP.33 Endoscopy was performed before treatment and repeated 2 months after completion of therapy. HP infection was eradicated in 14 of 15 (93%) children, and duodenal ulcer healing was achieved in 10 of 11 (9 1%) children. Compliance with the regimen was lOO%, and the combination was well tolerated. Another study34 assessed the efficacy of 2 weeks of combination therapy with omeprazole and amoxicillin ( 10 children) compared with omeprazole, amoxicillin, and clarithromycin (12 children) for the eradication of HP infection. On initial en-
667
CLINICAL THERAPEUTICS@
doscopic examination, 3 children had gastric ulcers, 12 had duodenal ulcers, and 7 had gastritis. Those with active peptic ulcers received an additional 4 weeks of omeprazole (0.6 mg/kg/d, maximum 20 mg/d). All 10 children with active ulcer disease at admission had symptom resolution within several days of starting therapy. At repeat endoscopy 1 month after completion of therapy, HP eradication was achieved in 7 of 10 (70%) children who received dual therapy and 11 of 12 (92%) children who received triple therapy. The overall incidence of AEs was low, possibly because of the children’s difficulty reporting them. AEs consisted of diarrhea in 1 child in the dual-therapy arm and metallic taste, dry mouth, and/or diarrhea in 4 children in the triple-therapy arm. Moshkowitz et al35 treated 35 adolescents with a mean age of 15.9 years (range, 10-19 years) for gastritis (25), duodenitis (4), gastric ulcer (l), and duodenal ulcer (5). All patients received twice-daily doses of omeprazole 20 mg, clarithromycin 250 mg, and either metronidazole or tinidazole 500 mg for 7 days. Patients were divided into 2 groups: those receiving their first anti-HP treatment during this study and those who had not responded to previous bismuth-based therapy. Bacterial cure was achieved in 25 of 35 (71%) patients: 24 of 27 (89%) patients receiving their first course of therapy and 1 of 8 (13%) who had received previous bismuthbased therapy. Casswall et al38 studied the effect of HP eradication in 32 children (mean age, 10.6 years; range, 4.7-17.1 years) with recurrent abdominal pain and gastritis. The children were treated for 1 week with omeprazole 20 mgld (body weight ~20 kg, 10 mg), clarithromycin 7.5 mg/kg BID, and metronidazole 7.5 mg/kg TID. HP infec-
668
tion was cured in 28 of 32 (88%) patients, with recurrent abdominal pain improved or resolved in 25 of 30 (83%) patients. Two children were lost to follow-up before symptoms could be reevaluated. Tiren et a140reported the efficacy of a 2week course of omeprazole, amoxicillin, and clarithromycin for the eradication of HP in 32 children (mean age, 10.5 years) with positive serologic results for HP and long-standing antral gastritis. All patients received omeprazole 0.3 mg/kg BID, amoxicillin 50 mg/kg BID, and clarithromycin 15 mg/kg BID. Endoscopy was performed at study entry and 3 months after completion of the course of therapy. HP eradication was achieved in 24 of 32 patients (75%). Compliance was not assessed. In the largest trial to date, Behrens et a14’ studied 136 children (age range, 3-l 8 years) with chronic abdominal pain who were histologically positive for HP infection. Patients were treated for 2 weeks with either amoxicillin 50 mg/kg per day (maximum, 2 g/d) or amoxicillin and clarithromycin 20 mg/kg per day (maximum, 1 g/d), both plus omeprazole 1 or 2 mg/kg per day. Endoscopic examination and histologic testing were repeated 4 to 6 weeks after the completion of therapy. HP infection was eradicated in 27 of 52 (52%) patients who received dual therapy and 44 of 53 (83%) patients who received triple therapy. The results did not differ by omeprazole dose.
METHODS
OF ADMINISTRATION
Omeprazole is available as a capsule containing enteric-coated, delayed-release granules that should not be chewed or crushed because they are acid labile. Omeprazole is not currently available as a proprietary stable oral liquid. Children un-
A.E. ZIMMERMANN
ET AL.
q
2
32
20
Casswall et a138
Artan and Gelens
3
5-16
Refractory peptic ulcer disease, antral G-cell hyperfunction
HP gastritis
Recurrent abdominal pain, gastritis
Ulcer pain, abdominal pain
Gastric ulcer, duodenal ulcer, gastritis
Gastric ulcer, duodenal ulcer, gastritis
Diagnoses
20 mgld IV (60 mg/l.73 m*) for 14 d, then 20 mg/d PO
0 20 mg (1 dose) A 250 mg QID (4 doses) CBS 150 mg QID (4 doses) M 250 mg QID (4 doses)
0 10-20 mg/d C 7.5 mg/kg BID M 7.5 mg/kg TID
0 20 mg/d A 50 mglkgld C 15 mgkgld
0 0.5-I .O mg/kg/d M 10 mg/kg BID C 7.5 mgkg BID
0 0.5-1.0 mg/kg BID A 25 mg/kg BID C 7.5 mg/kg BID
Treatment
3 mo initially, then 36 mo maintenance
Id
1 wk
2 wk
1 wk
2wk
Duration
l(100)
NA
NA
NA
NA
NA
Ulcer Healing, %
NA = not available; 0 = omeprazole; A = amoxicillin; C = clarithromycin; M = metronidazole: CBS = colloidal bismuth subcitrate.
De Giacomo et a14?
6.5-18
41
Fradkin et a13’
4.7-17.1
NA
34
Oderdg6
NA
Age, y
45
No. of Patients
Oderda36
Author
Table III. (Continued)
(continued)
NA
14 (70)
28 (88)
NA
23 (68)
35 (78)
HP Eradication, %
wGl
z-
g %
B
16
Ashom et a150 NA
NA
Mean, 11
6-16
5-17
Mean, 9.5
I1
12
Age, y
*Doses unknown.
0 = omeprazole; A = amoxicillin; M = metronidazole;
15
Radke et al49
25
12
et a14’
Mounla and ElitsutiE
Gonzalez-Ortiz
32
Czkwianianc
et al46
12
1
Camicer et al4
Cilleruelo et a145
1
No. of Patients
Dyrek et a143
Author
Table III. (Continued)
C = clarithromycin;
Gastritis
Abdominal pain
Gastritis (9)
Abdominal pain, HP infection
Gastritis
Chronic gastritis
Gastritis and sideropenic anemia
Duodenal ulcer
Diagnoses
NA = not available.
O+A* Or: O+A+M* Or: O+M+C*
0 20 mg BID A 50 mg/kg BID C 125-250 mg BID
O+M+C*
0 40 mg/l.73 m2 A 40 mg/kg TID
0 1 mg/kg BID M 20 mg/kg BID C 15 mg/kg BID
O+A*
O+A+C*
0 20 mg BID A 500 mg TID M 250 mg TID
Treatment
(continued)
313 (loo)
1-2 wk
l/4 (25)
12 (80)
11 (92)
12125 (48)
29 (91)
2 (16)
HP Eradication, %
619 (67)
NA
NA
NA
NA
NA
NA
Ulcer Healing, %
l-2 wk
1-2 wk
1 wk
2 wk
2wk
1 wk
2 wk
NA
2 wk 2 wk 8d
Duration
2 Age, y NA
8-14
2
21
5
1
Bontems et a15’
Carvalho et aIs
Illueca et a153
102
16
61
Urruzuno et al56
Maherzi et als6
Schildt et a15*
*Doses unknown.
NA = not available; 0 = omeprazole;
NA
20
Lopez-Brea et als5
A = amoxicillin;
6-18
8-15
NA
5-17.5
20
Logat-Car et a154
Author
No. of Patients
Table III. (Continued)
C = clarithromycin;
Gastritis
Gastritis, duodenal ulcer
Gastritis, peptic ulcer
HP infection
Gastritis, duodenal ulcer
Growth deceleration
Gastritis, peptic ulcer
HP infection
Diagnoses
.O mgAcg/d
M = metronidazole;
O+A*
O+A+M+C*
T = tinidazole.
45 (74)
14 (88)
16 (100)
NA
60 (59)
13 (65)
18 (90)
l(lO0)
4 (80)
21 (78)
HP Eradication, %
NA
NA
NA
NA
NA
NA
Ulcer Healing, %
R = roxithromycin;
2 wk
15 d
NA
NA
10d
NA
1 wk
1 wk
Duration
F = furazolidone;
0 20 mg/d A 50 mg/kg TID C 15 mg/kg BID
O+A+C*
0 10-20 mg BID R 5-10 mg/kg BID T 20 mg/kg BID
A 250 mg TID
0 10 mg/d
A 50 mg/kg/d M 20-30 mg/kg/d F 68 mg/kg/d
0 0.5-l
C 25 mg/kg/d
0 10-20 mg/d A 50 mglkgfd
Treatment
2
&
g ZZ 3
A.E. ZIMMERMANN
ET AL.
able to swallow intact capsules or who require a nonstandard dose of omeprazole have received the drug by a variety of methods 17,28,59-70 as summarized in Table IV. Omeirazole capsules have been open-
kled on applesauce17,28*59 or yogurti7,**; given with fruit juice17,59,69,70; or swallowed immediately with water.** Even when the drug is administered as a semi-
ed and the enteric-coated
frain
granules
Table IV. Methods of administering
sprin-
liquid,
omeprazole
children from
may find it difficult
chewing
the granules.
to reWhen
to children.
Intact granules 1. Open capsule and place granules in a small cup. Flush 6 to 10 granules through a nasogastric tube with 10 to 20 mL water, for a total volume of 120 to 140 mL.65 2. Open capsule and place granules in a bowl containing 30 mL water. Pour one third to one half of the granules in water into a 30-mL syringe with the plunger removed and flush through a nasogastric tube. Repeat until all the granules in water have been administered, then flush with 15 mL water. A total of 45 mL water is required.66 Sodium bicarbonate 1. Simplified omeprazole suspension Empty 1 or 2 omeprazole capsules (20 or 40 mg) into a lo- or 20-mL syringe with the needle in place. Add 10 or 20 mL (depending on which omeprazole dose is used) of 8.4% (mEq/mL) sodium bicarbonate solution. Let stand for >30 minutes, with periodic agitation. The final omeprazole concentration should be 2 mg/mL. Flush through a nasogastric tube with 5 to 10 mL tap water and clamp tube for 1 hour. The total volume administered is 15 or 30 mL, depending on the dose.6’,62 OR: Open five 20-mg omeprazole capsules and empty the granules into a 30- or 60-mL amber vial. Withdraw 50 mL of 8.4% sodium bicarbonate solution from a vial and inject it into the amber vial. Shake well until dissolved. Label this as a 2-mg/mL concentration with an expiration date of 14 days if stored at room temperature or 180 days if refrigerated or frozen. Administer orally or by nasogastric, gastrostomy, or jejunostomy tube.63,64,67,69 2. Place 2 Alka-Seltzer Gold@ (Bayer Corporation, Morristown, New Jersey) tablets into 240 mL water. Open the omeprazole capsule and sprinkle the granules onto the effervescent liquid. Stir until the granules are completely dissolved and administer.59*68 3. Sodium bicarbonate solution can be prepared extemporaneously by placing one half to 1 tsp baking soda (sodium bicarbonate) into 240 mL warm water and used as described above.60
Open capsule and sprinkle granules onto 1 tsp yogurt. Fruit
juice17S9.69.70
Open capsule and add granules to apple, cranberry, grape, grapefruit, orange, pineapple, prune, tomato, or V-8@ juice (Campbell Soup Company, Camden, New Jersey) and give orally. Granules should not be chewed.
Open capsule and sprinkle granules onto 1 tsp applesauce.
673
CLINICAL THERAPEUTICS@
the granules are chewed, their bitter taste may result in noncompliance with subsequent doses. The pharmacodynamics resulting from these alternative methods of omeprazole administration have been reported to be the same as for the intact capsule. 17,28~59 However, the oral bioavailability of omeprazole in nonproprietary formulations may be unpredictable and produce variable degrees of drug exposure. The advantages and disadvantages of these methods of administration in terms of bioequivalance, intragastric pH, and efficacy have been extensively reviewed by Zimmermann et a1.60 We recommend sprinkling the omeprazole granules on applesauce or yogurt or placing them in an acidic fruit juice and swallowing quickly as an effective method of administration in individuals who cannot swallow intact capsules. Phillips et a161 and Lasky et a1(j2 have reported the effectiveness of a simplified omeprazole suspension (SOS) in preventing stress-associated mucosal injury in critically ill adult patients. The sodium bicarbonate in SOS is postulated to work by 2 mechanisms: activation of H+,K+-adenosine triphosphatase translocation in the parieta1 cells and alteration of intragastric pH sufficient to protect omeprazole from acid degradation in the stomach.59 Quercia et a163 have published a procedure for extemporaneously compounding this solution. At a concentration of 2 mg/mL, SOS is reported to be stable for 14 days at room temperature and for 180 days when refrigerated or frozen.63,64 To improve the palatability of omeprazole suspension in children, the contents of 10 omeprazole capsules can be added to Choco-base@ dry powder (Department of Surgery, University of Missouri-Columbia Hospital, Springfield, Missouri), available
674
in an amber bottle. When refrigerated after reconstitution, the powder is stable for 1 year and 38 days (Jeffrey 0. Phillips, personal communication, March 1999). Mohiuddin et a159 assessed the effect on gastric acid suppression of a second type of extemporaneous bicarbonate formulation. Patients were administered either omeprazole 20 mg capsules with water or omeprazole 20 mg granules mixed in 240 mL water containing 2 Alka-Seltzer Gold@ tablets (Bayer Corporation, Morristown, New Jersey) (958 mg sodium bicarbonate, 832 mg citric acid, and 3 12 mg potassium bicarbonate per tablet), which was left to stand for 215 minutes before drinking. The total percentage of time intragastric pH was >4 and the time to intragastric pH <4 were not statistically different between omeprazole administered as an intact capsule and in the formulation containing Alka-Seltzer (68.7 vs 65.1%, respectively, and 327.5 vs 310.5 minutes, respectively).
CONCLUSIONS Marketed and extemporaneous formulations of omeprazole have been administered to children aged 2 months to 18 years at dosages of 5 to 80 mg/d (0.2-3.5 mg/kg/d) for periods of 14 days to 36 months in the treatment of erosive esophagitis, gastric ulcer, duodenal ulcer, HP infection, and associated conditions. The initial dose most consistently reported to heal esophagitis and provide relief of svmntoms of GERD annears to be 1 . I
mgn
II
per
day.
1’,20,2
I.71 372
For children who have difficulty swallowing capsules, opening the capsule and sprinkling the granules on applesauce or dispersing them in fruit juice may be an alternative. However, if the child acciden-
A.E. ZIMMERMANN
ET AL.
tally chews the granules, the bitter taste will be unpalatable. Use of an extemporaneously prepared flavored omeprazole suspension may increase compliance and palatability in pediatric patients. However, the oral bioavailability of omeprazole in nonproprietary formulations may be unpredictable and produce variable degrees of drug exposure. To date, omeprazole has been effective and well tolerated in the acute and chronic treatment of esophageal and peptic ulcer diseases, particularly in children who have not responded to previous histamine,receptor antagonists. Results of a recent study of omeprazole maintenance therapy lasting up to 11 years in adults73 suggest that the drug is safe and effective for longterm acid suppression, with no reported dysplasias or neoplasms. Should future long-term, controlled clinical trials in children demonstrate safety and efficacy, this PPI is likely to find a place in the armamentarium of pediatric pharmacotherapy.
ACKNOWLEDGMENT The opinions and assertions expressed herein are the authors’ and are not to be construed as reflecting the offtcial policy or views of AstraZeneca, LP The authors thank Mark Haythom for his assistance.
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3. Vandenplas Y, Goyvaerts H, Helven R, Sacre L. Gastroesophageal reflux, as measured by 24-hour pH monitoring in 509 healthy infants screened for sudden infant death syndrome. Pediatrics. 1991;88:83& 840. 4. Vandenplas Y. Reflux esophagitis in infants and children: A report from the Working Group on Gastro-oesophageal Reflux Disease of the European Society of Paediatric Gastroenterology and Nutrition. J Pediatr Gastroenterol Nuts: 1994; 18:413-422. 5. Prilosec [package insert]. Wilmington, Del: AstraZeneca LP; 2000. 6. Losec [package insert]. Molndal, Sweden: AstraZeneca LP; 2000. 7. Jacqz-Aigrain E, Bellaich M, Faure C, et al. Pharmacokinetics of intravenous omeprazole in children. Eur J Clin Pharmacol. 1994;47:181-185. 8. Kato S, Ebina K, Fujii K, et al. Effect of omeprazole in the treatment of refractory acid-related diseases in childhood: Endoscopic healing and twenty-four-hour intragastric acidity. J Pediatr. 1996; 128: 415-421. 9. Regardh CG. Pharmacokinetics and metabolism of omeprazole in man. Stand J Gastroenterol Suppl. 1986;118:99-104. 10. Regardh CG, Gabrielsson M, Hoffman KJ, et al. Pharmacokinetics and metabolism of omeprazole in animals and man-an overview. Stand J Gastroenterol Suppl. 1985:108:79-94. 11. Cederberg C, Rohss K, Lundborg L, Olbe L. Effect of once daily intravenous and oral omeprazole on 24-hour intragastric acidity in healthy subjects. Stand J Gastmenterol. 1993;28:179-184.
675
CLINICAL THERAPEUTICS”
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Gastroenterol
Nutr 1997;24:528-532.
22. Alliet P, Raes M, Bruneel E, Gillis P. Omeprazole in infants with cimetidineresistant peptic esophagitis. J Pediatr 1998;132:352-354.
23. Sheikh SI, Stephen TC, Eid NS. The use of omeprazole in infants with gastroesophageal reflux-induced wheezing. Pediatr Asthma Allergy Immunol. 1998; 12:4348. 24. Bohmer CJ, Niezen-de Boer RC, Klinkenberg-Knol EC, Meuwissen SG. Omeprazole: Therapy of choice in intellectually disabled children. Arch Pediatr Adolesc Med. 1998;152:1113-1118. 25. Strauss RS, Calenda KA, Day al Y, Mobassaleh M. Histological esophagitis: Clinical and histological response to omeprazole in children. Dig Dis Sci. 1999;44: 134-139. 26. Alliet P, Raes M, Gillis P, et al. Treatment of refractory ulcerative oesophagitis with omeprazole. Arch Dis Child. 1993;68:526. Letter.
18. Karjoo M, Kane R. Omeprazole treatment of children with peptic esophagitis refractory to ranitidine therapy. Arch Pediatr Adolesc Med. 1995; 149:267-27 1.
27. Dalzell AM, Searle JW, Patrick MK. Treatment of refractory ulcerative oesophagitis with omeprazole. Arch Dis Child. 1992; 67:641-642.
19. Martin PB, Imong SM, Krischer J, et al. The use of omeprazole for resistant oesophagitis in children. Eur J Pediatr Surg.
28. Hassall E, Shepherd R, Radke M, et al. Omeprazole for chronic erosive esophagitis in children: A multicenter study of dose requirement for healing. Gastroenterology. 1997(Suppl);l12:A143. Abstract.
1996:6:195-197.
20. Cucchiara S, Minella R, Campanozzi A, et al. Effects of omeprazole on mechanisms of gastroesophageal reflux in childhood. Dig Dis Sci. 1997;42:293-299. 21. De Giacomo C, Bawa P, Franceschi M, et al. Omeprazole for severe reflux esophagi-
676
29. Abdullah B, Gupta SK, Fitzgerald JF, et al. Long term management of moderate/ severe peptic esophagitis in children/ adolescents. H2 blocker vs proton pump inhibitor. Gustroenterology. 1998;112(Suppl ]):A208 Abstract.
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30. Cucchiara S, Minella R, Frances&i M, et al. Omeprazole versus very high doses of ranitidine in children with refractory gastroesophageal reflux disease. Gastroenternlogy. 1993;104(Suppl l):A59. Abstract. 31. Sherman P, Hassall E, Hunt RH, et al. Canadian Helicobacter Study Group consensus conference on the approach to Helicobacter pylori infection in children and adolescents. Can J Gastroenterol. 1999; 13553-559. 32. Israel DM, Hassall E. Omeprazole and other proton pump inhibitors: Pharmacology, efficacy, and safety, with special reference to use in children. J Pediatr Gastroenterol Nuts: 1998;27:568-579. 33. Dohil R, Israel DM, Hassall E. Effective 2-wk therapy for Helicobacter pylori disease in children. Am J Gastroenterol. 1997;92:244-247.
34. Kato S, Takeyama J, Ebina K, Naganuma H. Omeprazole-based dual and triple regimens for Helicobacter pylori eradication in children. Pediatrics. 1997;lOO: l-5. 35. Moshkowitz M, Reif S, Brill S, et al. Oneweek triple therapy with omeprazole, clarithromycin, and nitroimidazole for Helicobacter pylori infection in children and adolescents. Pediatrics. 1998;102:14. Abstract. 36. Oderda G. Cure of Helicobacter pylori in children. Helicobacte,: 1997;2(Suppl 1): S73-S76. 37. Fradkin A, Yahav Y, Diver-Haber A, et al. The value of anti-Helicobacter pylon’ IgG antibodies in establishing eradication of infection in children. Isr J Med Sci. 1997; 33:87-92.
38. Casswall TH, Alfven G, Drapinski M, et al. One-week treatment with omeprazole, clarithromycin, and metronidazole in chil-
dren with Helicobacter J Pediatr
Gastroenterol
pylori
infection. Nuts. 1998;27:
415-418. 39. Artan R, Gelen T. One-day combined therapy of children with Helicobacter pyloriassociated peptic disease. Dig Dis Sci. 1996;41:798. Letter. 40. Tiren U, Sandstedt B, Finkel Y. Helicobacter pylon’ gastritis in children: Efficacy of 2 weeks of treatment with clarithromycin, amoxicillin, and omeprazole. Acta Paediatl:
1999;88:16&168.
41. Behrens R, Lang T, Keller KM, et al. Dual versus triple therapy of Helicobacter pylori infection: Results of a multicentre trial. Arch Dis Child. 1999;81:68-70. 42. De Giacomo C, Fiocca R, Villani L, et al. Omeprazole treatment of severe peptic disease associated with antral G cell hyperfunction and hyperpepsinogenemia in an infant. J Pediat,: 1990;117:989-993. 43. Dyrek I, Gaida G, Bock H, et al. Bleeding ulcus (duodem) duodenum in a 12-yearold boy as the first symptom of familial Helicobacter pylon’ infection. Monatsschr Kinderheilkd. 1997;145:897-900. J, Badia R, Argemi J. Heligastritis and sideropenic refractory anemia. J Pediatr Gastmenterol Nuts: 1997;25:44 1. Letter.
44. Carnicer cobacter
pylori
45. Cilleruelo ML, Urruzuno P, Martinez MJ, et al. Helicobacter pylori reinfection after eradication in children. Gut. 1997;41 (Suppl l):A70. Abstract. 46. Czkwianianc E, Bak-Romaniszyn L, Lipczyk J, Planeta-Malecka I. Treatment of Helicobacter pylori infection in children: An evaluation of two different therapeutic regimens. Gut. 1997;41(Suppl 3): A21GA211. Abstract.
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47. Gonzalez-Ortiz B, Torres J, Camorlinga M, et al. Two week double vs triple therapy for Helicobacter pylori (Hp) eradication in Mexican children. J Pediatr Gustroenterol Nuts: 1997;25:468. Abstract. 48. Mounla R, Elitsur Y. Triple therapy for children with H. pylori gastritis. Am J Gastroenterol. 1997;92: 1620. Abstract. 49. Radke M, Dahne S, Wutzke KD, Klipstein P Delayed gastric emptying due to H. pylori infection in children and adolescents with recurrent abdominal pain. Gut. 1997; 4l(Suppl l):A65. Abstract. 50. Ashom M, Ruuska T, Kokkonen J. Omeprazole based double- and triple therapy in children with Helicobacter pylori infection. Gastroenterology. 1998;114(Suppl): A60. Abstract. 51. Bontems P, Corvaglia L, Devaster JM, et al. Treatment of Helicobacterpylori in children: Is a proton pump inhibitor necessary? Gut. 1998;43(Suppl2):A71-A72. Abstract. 52. Carvalho AST, Queiroz DMM, Mendes EN, et al. Triple antimicrobial therapy plus H2 receptor antagonist or omeprazole in the eradication of Helicobacter pylori in children with duodenal ulcer. Gut. 1998; 43(Suppl 2):A74. Abstract. 53. Illueca M, Moustafellos E, Chen Y. Helicobacterpylori associated failure to thrive: Case report. Gastroenterology. 1998; 114 (Suppl):Al57. Abstract. 54. Logar-Car G, Gubina M, Ferlan-Marolt V, Avsic-Zupanc T. Roxithromycin, tinidazole and omeprazole: lo-Day eradication treatment for children. Digestion. 1998;59 (Suppl 3):418419. Abstract. 55. Lopez-Brea M, Martinez MJ, Madruga D, et al. Clarithromycin resistance in Helicobacter pylon’ as a marker for treatment
678
failure in a paediatric population. 1998;43(Suppl 2):A75. Abstract.
Gut.
56. Urruzuno P, Cilleruelo ML, Martinez MJ, et al. Randomized study comparing two seven days triple therapy for Helicobacter pylori eradication in children. Gut. 1998; 43(Suppl 2):A71. Abstract. 57. Maherzi A, Oueslati L, Fendri C, et al. Helicobacter pylori and duodenal ulcers in children: Prevalence and therapeutic modalities observed in twenty-two cases. Arch Pediatr: 1998;5:223. Abstract. 58. Schildt J, Radke M, Wutzke KD. 13CUrea breath test-controlled long-term effect of dual eradication therapy (omeprazole and amoxicillin) in children with Helicobacter pylori gastritis. Monatsschr Kinderheilkd. 1998;146:562. Abstract. 59. Mohiuddin MA, Pursnani KG, Katzka DA, et al. Effective gastric acid suppression after oral administration of entericcoated omeprazole granules. Dig Dis Sci. 1997;42:715-719. 60. Zimmermann AE, Walters JK, Katona B, Souney P Alternative methods of proton pump inhibitor administration. Consult Pharm. 1997;12:99&998. 61. Phillips JO, Metzler MH, Palmieri MT, et al. A prospective study of simplified omeprazole suspension for the prophylaxis of stress-related mucosal damage. Crit Care Med. 1996;24: 1793-1800. 62. Lasky MR, Metzler MH, Phillips JO. A prospective study of omeprazole suspension to prevent clinically significant gastrointestinal bleeding from stress ulcers in mechanically ventilated trauma patients. .I Trauma Inj Infect Crit Care. 1998;44:527-533. 63. Quercia RA, Fan C, Liu X, Chow MS. Stability of omeprazole in an extempora-
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neously prepared oral liquid. Am .I Health Syst Pharm. 1997;54: 1833-l 836. 64. Phillips JO, Metzler M, Johnson K. The stability of simplified omeprazole suspension (SOS). Crit Care Med. 1998;26(Suppl): AlO. Abstract. 65. Larson C, Cavuto NJ, Flockhart DA, Weinberg RB. Bioavailability and efficacy of omeprazole given orally and by nasogastric tube. Dig Dis Sci. 1996;41:475-479. 66. Balaban DH, Duckworth CW, Peura DA. Nasogastric omeprazole: Effects on gastric pH in critically ill patients. Am J Gastroenterol. 1997;92:79-83. of omeprazole 67. Kane DL. Administration (Prilosec?) in the atypical patient. Int J Pharm Compounding. 1997; 1: 13. Letter. 68. Pesko LJ. Oral liquid for omeprazole. Drug. 1997;214:48. Letter.
Address Pharmacy,
correspondence Baystate
tzimmermann
Medical
Am
69. Woods DJ, McClintock AD. Omeprazole administration. Ann Pharmacother: 1993; 27:65 I. Letter. 70. Data on tile. Wayne, Pa: Astra Merck Inc; 1997. 71. Hassall E, Israel D, Shepherd R, et al. Omeprazole for healing of severe erosive esophagitis in children. J Pediatr Gastroenterol Nuts: 1998;26:547. Abstract. 72. Andersson T, Hassall E, Lundborg P, et al, for the International Pediatric Omeprazole Pharmacokinetic Group. Pharmacokinetits of orally administered omeprazole in children. Am J Gastroenterol. 2000;95: 3101-3106. 73. Klinkenberg-Knol EC, Nelis F, Dent J, et al. Long-term omeprazole treatment in resistant gastroesophageal reflux disease: Efficacy, safety, and influence on gastric mucosa. Gastroenterology. 2000; 118:661- 669.
to: Anthony E. Zimmermann, PharmD, Department of Center, 759 Chestnut Street, Springfield, MA 01199. E-mail:
@ mcp.edu
679
THERAPEUTICWVOL.
23, NO. 5,200l
A Review of Omeprazole Use in the Treatment of Acid-Related Disorders in Children Anthony E. Zimmermann, PharmD,’ J. Ken Walters, PharmD,2 Brian G. Katona, PharmD,3 Paul E Souney, RPh, MS,3 and Douglas Levine, MD3 ‘Massachusetts College of Pharmacy/Health Sciences and Baystate Medical Center Springfield, Massachusetts, 2Sheppard and Enoch Pratt Hospital, Towson, Maryland, and 3AstraZeneca Pharmaceuticals LP, Wilmington, Delaware
ABSTRACT Background: Acid peptic disease is a common problem, with a similar prevalence of gastroesophageal reflux disease (GERD) in adults and children. The presentation of GERD in infants and children varies from crying, irritability, or sleep disturbance to feeding difftculties, vomiting, or rumination. Helicobacter pylori (HP)-related diseases and gastric and duodenal ulcers are much more common in adults than in children, who are more likely to have gastritis or duodenitis. However, because HP infection is most likely acquired in childhood, treatment of children with endoscopically documented active HP disease may minimize the potential risk for peptic ulcer or gastric cancer in adulthood, although this is yet to be proved. Objective: Omeprazole has been shown to be effective in the treatment of acid-related diseases. This paper reviews the literature on the use and administration of omeprazole for the treatment of GERD, peptic ulcer disease, HP infection, and other acid-related conditions in children. Methods: Studies were identified through searches of MEDLINE@ and Science Citation Index for the period 1986 to November 2000, and from the reference lists of identified articles. The search terms used included omeprazole, proton pump inhibitor (PPI), children, pediatrics, routes of administration, GERD, HP infection, esophagitis, and administration. In addition, the manufacturer of omeprazole was asked for relevant unpublished information. Results: Marketed and extemporaneous formulations of omeprazole have been administered to children aged 2 months to 18 years for the treatment of erosive esophagitis, gastric ulcer, duodenal ulcer, HP infection, and related conditions at dosages of 5 to 80 mg/d (0.2-3.5 mg/kg/d) for periods ranging from 14 days to 36 months with a low incidence of adverse effects. The initial dose most consistently reported to heal esophagitis and provide relief of symptoms of GERD appears to be 1 mg/kg per day. Accepted for publication
March 5, 2001.
Printed in the USA. Reproduction
660
in whole or part is not permitted
0149.2918/01/$19.00
A.E. ZIMMERMANN ET AL.
Conclusions: In uncontrolled clinical trials and case reports to date, omeprazole has been effective and well tolerated for the acute and chronic treatment of esophageal and peptic ulcer disease in children, particularly those who had failed to respond to previous treatment with histamine,receptor antagonists. Should future longterm, controlled clinical trials in children demonstrate safety and efficacy, this PPI is likely to find a place in the armamentarium of pediatric pharmacotherapy. Key words: children, Helicobacter pyZori, treatment, GERD, esophagitis, proton pump inhibitor. (C/in Thel: 2001;23: 660479)
INTRODUCTION Acid peptic disease is an exceedingly common problem in the western world. The prevalence of gastroesophageal reflux disease (GERD) is similar in the adult and pediatric populations, from 3% to 7% in the former and 8% in the latter.im3 The presentation of GERD in infants and children varies from crying, irritability, or sleep disturbance to feeding difficulties, vomiting, or rumination. In some cases, positional and dietary measures are sufficient to resolve mild cases of GERD in infants.z Gastric and duodenal ulcers are much more common in adults than in children, who are more likely to have gastritis or duodenitis.4 The incidence of Helicobacter pylori (HP)-related diseases is also much lower in children than adults; however, because HP is most likely acquired in childhood, treatment of children with endoscopically documented active HP disease may minimize the potential risk for peptic ulcer or gastric cancer in adulthood, although this is yet to be proved.
Empiric treatment of HP infection is currently not recommended in children. Omeprazole* has been shown to be well tolerated and effective in the treatment of acid-related diseases. In the United States, it is approved for use in adults for acute and maintenance treatment of erosive esophagitis, symptomatic treatment of GERD, acute treatment of gastric and duodenal ulcer, and eradication of HP in patients with active duodenal ulcer.5 The frequency of adverse effects (AEs) is low, with the most common AEs including headache, diarrhea, abdominal pain, and nausea.5 Because omeprazole is metabolized in the liver by cytochrome P450 enzymes, it may increase the elimination or half-life of diazepam, phenytoin, warfarin, and digoxin.5 Omeprazole is approved for pediatric use in the United Kingdom and other European countries6 and is currently under review for pediatric use in the United States. This paper reviews the published literature on the use and administration of omeprazole for the treatment of GERD, peptic ulcer disease, HP infection, and other acid-related conditions in children. Studies were identified through searches of MEDLINE@ and Science Citation Index for the period 1986 to November 2000, and from the reference lists of identified articles. The search terms used included omeprazole, proton pump inhibitor (PPI), children, pediatrics, routes of administration, GERD, HP infection, esophagitis, and administration. In addition, the manufacturer of omeprazole was asked for relevant unpublished information. For the purposes of this paper, the terms refractory and unresponsive are defined as no clinical response or an incomplete *Trademark: Prilosec@ (AstraZeneca cals LP, Wilmington, Delaware).
Pharmaceuti-
661
CLINICAL THERAPEUTICSO
clinical response to previous therapy of between 4 weeks and 12 months in duration, depending on the study design. Healing rates in the reviewed studies were determined based on endoscopic findings before and after treatment. Severity of esophagitis was assessed based on a standard grading system (from 0 = no mucosal abnormalities to 4 = deep peptic ulceration anywhere in the esophagus).
AIDS, organ transplantation, organ failure, and hematologic malignancy. Dosage was calculated based on adult IV dosing information: a 60- to 80-mg/1.73 m2 loading dose was followed by 40 mgU.73 m2 given as a slow bolus over 15 minutes every 12 hours. The children received doses ranging from 36.9 to 139 mg11.73 m2. Kato et al8 assessed the pharmacokinetic parameters of oral omeprazole 0.6 mg/kg in 7 Japanese children whose esophagitis or ulcer disease had been unresponsive to therapy with histamine,-receptor antagonists.
PHARMACOKINETICS Two studies have evaluated the pharmacokinetics of omeprazole in children.7s Based on the findings of these studies, the pharmacokinetic parameters of IV and oral omeprazole do not appear to differ significantly between adults9-‘” and children (Table I). Jacqz-Aigrain et al7 studied the pharmacokinetics of IV omeprazole in I3 critically ill children (age range, 0.3-19 years) who had failed to respond to IV ranitidine and were unable to take omeprazole orally. The patients’ underlying conditions included
Table I. Comparison of the pharmacokinetic in children and adults.
Route of Administration Intravenous Children? mg/l.73 m* Adults,“-I3 mg/kg
Oral, mg/kg Children’ Adultsi
Dose
GASTROESOPHAGEAL REFLUX DISEASE AND ESOPHAGITIS Reflux esophagitis is a chronic relapsing condition. In adults, relapse rates of >80% have been reported within 6 months of the cessation of medical therapy,i4 but no data are available on the relapse rate in children. Published studies on omeprazole for the acute management and maintenance therapy of GERD in children are limited to
profiles of intravenous
AUC, pmol/L.h
and oral omeprazole
Cl, L/h.kg
V, L/kg
b2’ h
47.4 -+ 27.2 0.15 0.53 1.07
14.1 f 15.3 0.99 2.93 c 0.81 8.51 k2.55
0.23 + 0.32 0.45 0.56 + 0.15 0.41 +0.17
0.45 f 0.17 0.49 + 0.27 0.42+0.18
0.86 2 0.88 0.58 0.57 + 0.12 0.81 kO.17
0.6 0.28
5.40 + 1.96 0.84-1.88
0.454
0.31 2 0.09
0.9 f 0.1 0.87 t 0.73
Values are mean + SEM, unless reported otherwise in individual studies. AUC = area under the curve; Cl = clearance;
662
V = volume of distribution;
t,,? = half-life.
A.E. ZiifMERMANN
ET AL.
1 randomized, comparative clinical trial,i5 10 case series,1”25 2 case reports,26.27 and 3 abstracts (Table II).**-30 The largest and most complete are discussed in the following paragraphs. In the prospective comparative trial,i5 32 patients whose reflux esophagitis (confirmed by endoscopy and 24-hour intraesophageal pH monitoring) had not responded to 8 weeks of ranitidine (4 mg/kg BID plus cisapride 0.265 mg/kg TID) were randomized to omeprazole (40 mg/1.73 m*/d) or high-dose ranitidine (20 mg/kg/d in divided doses) for 8 weeks. Twenty-five patients (12 omeprazole, 13 ranitidine) aged between 6 months and 13 years completed the study. Esophageal healing occurred in 9 of 12 (75%) omeprazole-treated patients and 8 of 13 (62%) ranitidine-treated patients; symptom relief was reported in 10 of 12 (83%) omeprazole-treated patients and 9 of 13 (69%) ranitidine-treated patients. These differences were not statistically significant, and the treatments were considered equally efftcacious. In other studies of omeprazole for the treatment of initial or refractory GERD/ esophagitis in children,‘“26 reported endoscopic healing rates ranged from 40% to 100% and symptom relief from 73% to 100%. The dosages used ranged from 0.4 to 3.5 mg/kg per day (5-80 mg/d), and the duration of treatment ranged from 6 weeks to 30 months. In 1 study, l* 153 patients between the ages of 6 and 18 years who had experienced ~3 weeks of continuous epigastric pain underwent endoscopy and received the following diagnoses peptic esophagitis (129 [84%]), peptic ulcer (2 [ 1%I), and HP gastritis (4 [3%]). Eighteen patients (12%) had normal endoscopic findings. In those with esophagitis, 94 (73%) of patients had grade 1 or 2 disease. All patients were ini-
tially treated with ranitidine 4 mgkg BID, with an increase to 4 mg/kg TID after 2 weeks if symptoms were not alleviated. Prokinetic agents were not permitted. If patients were still symptomatic after 4 weeks of the maximum ranitidine regimen, they were switched to omeprazole 20 mg/d, with titration to a maximum of 60 mgld based on response. Ranitidine treatment was successful in 91 of the 129 (71%) children with esophagitis, and omeprazole was successful in 33 of the 38 (87%) children who failed to respond to ranitidine. Hassall et al** studied 5 1 children aged between 1 and 16 years who had esophagitis of grades 2 through 4 (grade 2, 33%; grade 3,43%; grade 4,24%). Twenty-eight had not responded to treatment with prokinetic agents and/or histamine,-receptor antagonists, and 5 had failed to respond to fundoplication. The initial omeprazole dosage of 0.7 mg/kg daily was increased as needed to achieve the therapeutic goal of an esophageal pH ~4.0 for ~6% of the 24-hour monitoring period. The maximum total daily dose was 3.5 mg/kg, with no child receiving >80 mg/d. Forty-nine of 51 (96%) children had esophageal healing on follow-up endoscopy; 3 of 49 (6%) required a second course of therapy. The proportion of children requiring an omeprazole dosage of >1.4 mg/kg per day was higher in those with more severe esophagitis (grade 3 or 4). Healing rates with the various regimens were as follows: 0.7 mg/kg, 23/49 (47%); 1.4 mg/kg, 13/49 (27%); 2.1 mg/kg, 7/49 (14%); 2.8 mg/kg, 4/49 (8%); and 3.5 mg/kg, 2/49 (4%). At the last reported visit (up to 53 weeks of therapy), 26% were asymptomatic, 45% had mild symptoms, 20% had moderate symptoms, and 9% had severe symptoms. No AEs were reported with omeprazole therapy.
Weight ~30 kg, 20 mg Weight >30 kg, 40 mg (0X-2.2 mgkg) 0.5 mg/kg
19 mo-12 y
2-9 y
2.9 k 0.9 mo
22
10
12
De Giacomo et al*’
Alliet et al22
1 mg/kg
6 wk
3mo
8 wk
in 11 (73%)
Healing of esophagitis in 9 (75%): symptom relief in 10 (83%)
Endoscopic healing in 9 (10%) and symptom improvement in 10 (100%)
Symptom resolution or improvement in 22 (100%)
Symptom improvement
3 mo
Cucchiara et al*”
5-20 mg (0.8 mg/kg)
I-16 y
15
in 33 (87%)
Martin et aIt9
Symptom improvement
8 wk
20-60 mg
6-18 y
35
Karjoo and KaneIs
Healing of esophagitis by 6 mo in 9 (60%); 15 (100%) symptom free at 12 mo
5.5-26 mo
1O-60 mg (0.7-3.3 mg/kg)
0.8-17 y
15
Gunasekaran and Hassallt7
Endoscopic healing of esophagitis and maintenance of healing in 3 (100%)
24-30 mo
40 mg healing; 2&40 mg maintenance
healing of esophagitis
Healing of esophagitis in 9 (75%); symptom improvement in 10 (83%)
Endoscopic in 4 (80%)
Outcome
g-15 y
3
Nelis and Westerveld’l
6 wk
of Treatment
Duration
in children.
8 wk
6 mo-13 y
12
Cucchiara et alI5
0.3-0.7 mg/kg
Daily Dose
reflux disease and erosive esophagitis
40 mg/1.73 mz
3-1.8 y
Age
5
No. of Patients
treatment for gastroesophageal
Kato et al*
Author
Table II. Summary of studies of omeprazole
51
88
Hassall et a128
A~ull~
Cucchiara et a130
12
7Y
1
Daizell et a12’
et alz9
4mo
1
Alliet et alz6
Uns~ci~ed
40 mg0.73
1.7-13.4 y
m2
10-80 mg (0.7-3.5 mg/kg)
(0.4 mg/kg)
10 mg
(0.5 mg/kg)
3.5 mg
6 d-17 y
l-16 y
2-17 y
18
Strauss et aP5 0.26-l .3.5 mgn
Weight >20 kg, 40 mg Weight ~20 kg, 20 mg Maintenance, 20 mg (10 mg, weight ~20 kg)
4-19 y
51
Bohmer et a124
Daily Dose
0.5 and 1.0 mg/kg
Age
4 and 5 mo
2
Patients
No. of
She&h et a123
Author
Table II. (Continued)
8 wk
Mean, 4.2 mo
$53 wk
8 wk
6 wk
8-12 wk
9 mo
3 mo
8 and 10 wk
Treatment
Duration of
and
and
Histologic and symptomatic in 12 (100%)
improvement
Endoscopjc improvement in 60 (68%); symptom improvement in 64 (73%)
Endoscopic healing in 49 (96%); symptom relief in 46 (90%)
Endoscopic healing of esophagitis symptom resolution
Endoscopic healing of esophagitis symptom resolution
Endoscopic healing in 6/17 (35%); symptom resolution in 13117 (76%)
Endoscopic healing and symptom improvement in 5 1 (100%); 48 (94%) remained healed; 7 (14%) healed with dose increase
Normaiization of pulmonary function test results and symptom improvement in 2 (100%)
Outcome
F
7
3
g
3
B $
,N
CLINICAL THERAPEUTICS”
Bohmer et alz4 performed endoscopic examinations of 69 intellectually disabled children (IQ <50) between the ages of 4 and 19 years for symptoms that included vomiting, regurgitation, food refusal, hematemesis, and behavioral problems. Fiftytwo (75%) of the children had esophagitis of grades 1 to 4 (grade I,19 [37%]; grade 2, 20 [38%]; grade 3, 6 [12%]; grade 4, 7 [ 13%]). Esophagitis was accompanied by hiatal hernia in 40 (77%) patients, Barrett’s esophagus in 7 (13%), and peptic strictures in 3 (6%). Twenty-one (40%) patients were taking antireflux medications (12, ranitidine 300 mg/d; 9, cisapride), and 5 (10%) had previously undergone Nissen fundoplication. Patients were initially given omeprazole 40 mg/d (body weight <20 kg, 20 mg) for 3 months. If the esophagitis was healed, maintenance therapy consisted of omeprazole 20 mg/d (body weight ~20 kg, 10 mg). If symptoms persisted and endoscopic examination revealed improvement in the esophagitis, omeprazole 40 mg/d was continued for 3 additional months. If the esophagitis was unchanged, omeprazole therapy was increased to 60 mg/d (body weight <20 kg, 40 mg). Endoscopic examination was repeated at 3, 6, and 9 months. After 3 months of omeprazole therapy, 47 of 52 (90%) children with esophagitis were asymptomatic. Of the 5 children with persistent symptoms of esophagitis, endoscopy revealed healing in 2 and improvement in 3, who continued therapy for an additional 3 months. During the maintenance phase of the study, 48 of 5 1 (94%) patients demonstrated healing and remained symptom free at 9-month followup. Seven of 48 (12%) patients experienced a relapse at the maintenance dose but demonstrated healing and remained symptom free when omeprazole 40 mg/d was reinstituted. No AEs were reported.
666
Cucchiara et al*O studied 22 children aged 19 months to 12 years (median age, 6.6 years) with severe reflux esophagitis that was refractory to 8 weeks of combined therapy with ranitidine (8 mg/kg/d) and cisapride (0.6 mg/kg/d). The children were treated with 8 weeks of omeprazole 1 mg/kg per day given as granules dissolved in an acidic vehicle (eg, grapefruit or orange juice), after which symptoms improved or disappeared in all patients. Two months after discontinuation of omeprazole, 16 of 22 (73%) children were symptomatic. No AEs were reported. De Giacomo et a121prospectively evaluated 10 children aged between 2 and 9 years (mean, 6.3 years) who had esophagitis of grades 2 to 4 and symptomatic GERD and were treated with omeprazole for 3 months. Five patients had received previous combination therapy consisting of prokinetic agents plus histamine,-receptor antagonists (n = 3) or antacids (n = 2); the other 5 patients had received no previous treatment. Children weighing ~30 kg received omeprazole 20 mgld and those weighing >30 kg received 40 mg/d (range, 0.8-2.2 mg/kg/d). Symptoms were evaluated weekly, and repeat endoscopy was performed in all patients 2.5 to 3 months into omeprazole therapy. Nine of 10 (90%) patients demonstrated endoscopic healing of esophagitis. One child who initially received omeprazole 20 mg/d ( 1.1 mg/kg) did not show endoscopic improvement, and the dosage was increased to 40 mg/d (2.2 mgkg) for 2 months, with resultant endoscopic healing. Improvement in symptoms was noted in 10 of 10 (100%) patients. After discontinuation of omeprazole, 6 children experienced a return of symptoms requiring additional omeprazole treatment; 3 were maintained on omeprazole therapy, and 3 required surgery for Barrett’s esophagus and recurrent pneumonia.
A.E. ZIMMERMANN ET AL.
Alliet et al22 described the use of omeprazole 0.5 mg/kg per day for 6 weeks in 12 infants (mean age, 2.9 + 0.9 months) with grade 2 esophagitis who had not responded to 3 weeks of treatment with the combination of cimetidine (10 mg/kg TID) plus cisapride (0.265 mg/kg TID) and antacids. Cisapride and antacids were continued during omeprazole therapy. There was a significant decrease in irritability and an improvement in feeding behavior in 10 of 12 (83%) children, with 9 of 12 (75%) achieving complete endoscopic healing of esophagitis. In the 3 infants whose esophagitis did not heal, improvement from grade 2 to 1 and marked improvement in symptoms was seen. Sheikh et al23 reported the effects of omeprazole in 2 infants (aged 4 and 5 months) with persistent wheezing who had been unresponsive to cromolyn, albuterol, inhaled steroids, systemic steroids, ranitidine, and prokinetic agents. Esophageal pH monitoring revealed significant GERD, and the patients were respectively administered omeprazole 0.5 and 1 mg/kg daily. Shortly after omeprazole was begun, the wheezing ceased and all asthma medications were stopped. Pulmonary function test results normalized after 8 and 10 weeks of omeprazole therapy, which was subsequently discontinued. Symptom resolution lasted for 18 months in 1 infant and 36 months in the other.
PEPTIC ULCER DISEASE AND ERADICATION OF HELICOBACTER PYLORI In the pediatric population, the incidence of peptic ulcer disease is low compared with that in adults. Thus, few clinical trials have been performed, most of them small open-label studies. In the past, noncompliance due to AEs and the complexity of reg-
imens for the eradication of HP have resulted in high failure rates; however, the currently recommended shorter courses of better-tolerated combinations of agents3i have increased compliance with similar eradication rates. It must be noted that not all peptic ulcer disease is HP related; 15% to 20% of all duodenal ulcers in children are non-HP related and thus will respond to acid suppression alone.32 There have been 8 complete studies 8,33,34736-38940.41 2 case reports,42343 15 a&racts 35,45-58and 2 letters39,44 published on the use of omeprazole in gastritis, gastric and duodenal ulcers, and dyspepsia in children (Table III). These studies have evaluated symptom relief, healing and eradication of HP, and prevention of recurrence. The largest and most complete of these studies are discussed in subsequent paragraphs. In all the clinical trials, triple therapy (a PPI plus 2 antibiotics) was clinically and statistically superior to dual therapy (a PPI plus an antibiotic). Fifteen HP-positive children aged 9 to 16 years with endoscopically confirmed duodenal ulcers (11) and/or antral gastritis (4) were administered omeprazole, metronidazole, and clarithromycin for 2 weeks in an open-label trial of efficacy in the eradication of HP.33 Endoscopy was performed before treatment and repeated 2 months after completion of therapy. HP infection was eradicated in 14 of 15 (93%) children, and duodenal ulcer healing was achieved in 10 of 11 (9 1%) children. Compliance with the regimen was lOO%, and the combination was well tolerated. Another study34 assessed the efficacy of 2 weeks of combination therapy with omeprazole and amoxicillin ( 10 children) compared with omeprazole, amoxicillin, and clarithromycin (12 children) for the eradication of HP infection. On initial en-
667
CLINICAL THERAPEUTICS@
doscopic examination, 3 children had gastric ulcers, 12 had duodenal ulcers, and 7 had gastritis. Those with active peptic ulcers received an additional 4 weeks of omeprazole (0.6 mg/kg/d, maximum 20 mg/d). All 10 children with active ulcer disease at admission had symptom resolution within several days of starting therapy. At repeat endoscopy 1 month after completion of therapy, HP eradication was achieved in 7 of 10 (70%) children who received dual therapy and 11 of 12 (92%) children who received triple therapy. The overall incidence of AEs was low, possibly because of the children’s difficulty reporting them. AEs consisted of diarrhea in 1 child in the dual-therapy arm and metallic taste, dry mouth, and/or diarrhea in 4 children in the triple-therapy arm. Moshkowitz et al35 treated 35 adolescents with a mean age of 15.9 years (range, 10-19 years) for gastritis (25), duodenitis (4), gastric ulcer (l), and duodenal ulcer (5). All patients received twice-daily doses of omeprazole 20 mg, clarithromycin 250 mg, and either metronidazole or tinidazole 500 mg for 7 days. Patients were divided into 2 groups: those receiving their first anti-HP treatment during this study and those who had not responded to previous bismuth-based therapy. Bacterial cure was achieved in 25 of 35 (71%) patients: 24 of 27 (89%) patients receiving their first course of therapy and 1 of 8 (13%) who had received previous bismuthbased therapy. Casswall et al38 studied the effect of HP eradication in 32 children (mean age, 10.6 years; range, 4.7-17.1 years) with recurrent abdominal pain and gastritis. The children were treated for 1 week with omeprazole 20 mgld (body weight ~20 kg, 10 mg), clarithromycin 7.5 mg/kg BID, and metronidazole 7.5 mg/kg TID. HP infec-
668
tion was cured in 28 of 32 (88%) patients, with recurrent abdominal pain improved or resolved in 25 of 30 (83%) patients. Two children were lost to follow-up before symptoms could be reevaluated. Tiren et a140reported the efficacy of a 2week course of omeprazole, amoxicillin, and clarithromycin for the eradication of HP in 32 children (mean age, 10.5 years) with positive serologic results for HP and long-standing antral gastritis. All patients received omeprazole 0.3 mg/kg BID, amoxicillin 50 mg/kg BID, and clarithromycin 15 mg/kg BID. Endoscopy was performed at study entry and 3 months after completion of the course of therapy. HP eradication was achieved in 24 of 32 patients (75%). Compliance was not assessed. In the largest trial to date, Behrens et a14’ studied 136 children (age range, 3-l 8 years) with chronic abdominal pain who were histologically positive for HP infection. Patients were treated for 2 weeks with either amoxicillin 50 mg/kg per day (maximum, 2 g/d) or amoxicillin and clarithromycin 20 mg/kg per day (maximum, 1 g/d), both plus omeprazole 1 or 2 mg/kg per day. Endoscopic examination and histologic testing were repeated 4 to 6 weeks after the completion of therapy. HP infection was eradicated in 27 of 52 (52%) patients who received dual therapy and 44 of 53 (83%) patients who received triple therapy. The results did not differ by omeprazole dose.
METHODS
OF ADMINISTRATION
Omeprazole is available as a capsule containing enteric-coated, delayed-release granules that should not be chewed or crushed because they are acid labile. Omeprazole is not currently available as a proprietary stable oral liquid. Children un-
A.E. ZIMMERMANN
ET AL.
q
2
32
20
Casswall et a138
Artan and Gelens
3
5-16
Refractory peptic ulcer disease, antral G-cell hyperfunction
HP gastritis
Recurrent abdominal pain, gastritis
Ulcer pain, abdominal pain
Gastric ulcer, duodenal ulcer, gastritis
Gastric ulcer, duodenal ulcer, gastritis
Diagnoses
20 mgld IV (60 mg/l.73 m*) for 14 d, then 20 mg/d PO
0 20 mg (1 dose) A 250 mg QID (4 doses) CBS 150 mg QID (4 doses) M 250 mg QID (4 doses)
0 10-20 mg/d C 7.5 mg/kg BID M 7.5 mg/kg TID
0 20 mg/d A 50 mglkgld C 15 mgkgld
0 0.5-I .O mg/kg/d M 10 mg/kg BID C 7.5 mgkg BID
0 0.5-1.0 mg/kg BID A 25 mg/kg BID C 7.5 mg/kg BID
Treatment
3 mo initially, then 36 mo maintenance
Id
1 wk
2 wk
1 wk
2wk
Duration
l(100)
NA
NA
NA
NA
NA
Ulcer Healing, %
NA = not available; 0 = omeprazole; A = amoxicillin; C = clarithromycin; M = metronidazole: CBS = colloidal bismuth subcitrate.
De Giacomo et a14?
6.5-18
41
Fradkin et a13’
4.7-17.1
NA
34
Oderdg6
NA
Age, y
45
No. of Patients
Oderda36
Author
Table III. (Continued)
(continued)
NA
14 (70)
28 (88)
NA
23 (68)
35 (78)
HP Eradication, %
wGl
z-
g %
B
16
Ashom et a150 NA
NA
Mean, 11
6-16
5-17
Mean, 9.5
I1
12
Age, y
*Doses unknown.
0 = omeprazole; A = amoxicillin; M = metronidazole;
15
Radke et al49
25
12
et a14’
Mounla and ElitsutiE
Gonzalez-Ortiz
32
Czkwianianc
et al46
12
1
Camicer et al4
Cilleruelo et a145
1
No. of Patients
Dyrek et a143
Author
Table III. (Continued)
C = clarithromycin;
Gastritis
Abdominal pain
Gastritis (9)
Abdominal pain, HP infection
Gastritis
Chronic gastritis
Gastritis and sideropenic anemia
Duodenal ulcer
Diagnoses
NA = not available.
O+A* Or: O+A+M* Or: O+M+C*
0 20 mg BID A 50 mg/kg BID C 125-250 mg BID
O+M+C*
0 40 mg/l.73 m2 A 40 mg/kg TID
0 1 mg/kg BID M 20 mg/kg BID C 15 mg/kg BID
O+A*
O+A+C*
0 20 mg BID A 500 mg TID M 250 mg TID
Treatment
(continued)
313 (loo)
1-2 wk
l/4 (25)
12 (80)
11 (92)
12125 (48)
29 (91)
2 (16)
HP Eradication, %
619 (67)
NA
NA
NA
NA
NA
NA
Ulcer Healing, %
l-2 wk
1-2 wk
1 wk
2 wk
2wk
1 wk
2 wk
NA
2 wk 2 wk 8d
Duration
2 Age, y NA
8-14
2
21
5
1
Bontems et a15’
Carvalho et aIs
Illueca et a153
102
16
61
Urruzuno et al56
Maherzi et als6
Schildt et a15*
*Doses unknown.
NA = not available; 0 = omeprazole;
NA
20
Lopez-Brea et als5
A = amoxicillin;
6-18
8-15
NA
5-17.5
20
Logat-Car et a154
Author
No. of Patients
Table III. (Continued)
C = clarithromycin;
Gastritis
Gastritis, duodenal ulcer
Gastritis, peptic ulcer
HP infection
Gastritis, duodenal ulcer
Growth deceleration
Gastritis, peptic ulcer
HP infection
Diagnoses
.O mgAcg/d
M = metronidazole;
O+A*
O+A+M+C*
T = tinidazole.
45 (74)
14 (88)
16 (100)
NA
60 (59)
13 (65)
18 (90)
l(lO0)
4 (80)
21 (78)
HP Eradication, %
NA
NA
NA
NA
NA
NA
Ulcer Healing, %
R = roxithromycin;
2 wk
15 d
NA
NA
10d
NA
1 wk
1 wk
Duration
F = furazolidone;
0 20 mg/d A 50 mg/kg TID C 15 mg/kg BID
O+A+C*
0 10-20 mg BID R 5-10 mg/kg BID T 20 mg/kg BID
A 250 mg TID
0 10 mg/d
A 50 mg/kg/d M 20-30 mg/kg/d F 68 mg/kg/d
0 0.5-l
C 25 mg/kg/d
0 10-20 mg/d A 50 mglkgfd
Treatment
2
&
g ZZ 3
A.E. ZIMMERMANN
ET AL.
able to swallow intact capsules or who require a nonstandard dose of omeprazole have received the drug by a variety of methods 17,28,59-70 as summarized in Table IV. Omeirazole capsules have been open-
kled on applesauce17,28*59 or yogurti7,**; given with fruit juice17,59,69,70; or swallowed immediately with water.** Even when the drug is administered as a semi-
ed and the enteric-coated
frain
granules
Table IV. Methods of administering
sprin-
liquid,
omeprazole
children from
may find it difficult
chewing
the granules.
to reWhen
to children.
Intact granules 1. Open capsule and place granules in a small cup. Flush 6 to 10 granules through a nasogastric tube with 10 to 20 mL water, for a total volume of 120 to 140 mL.65 2. Open capsule and place granules in a bowl containing 30 mL water. Pour one third to one half of the granules in water into a 30-mL syringe with the plunger removed and flush through a nasogastric tube. Repeat until all the granules in water have been administered, then flush with 15 mL water. A total of 45 mL water is required.66 Sodium bicarbonate 1. Simplified omeprazole suspension Empty 1 or 2 omeprazole capsules (20 or 40 mg) into a lo- or 20-mL syringe with the needle in place. Add 10 or 20 mL (depending on which omeprazole dose is used) of 8.4% (mEq/mL) sodium bicarbonate solution. Let stand for >30 minutes, with periodic agitation. The final omeprazole concentration should be 2 mg/mL. Flush through a nasogastric tube with 5 to 10 mL tap water and clamp tube for 1 hour. The total volume administered is 15 or 30 mL, depending on the dose.6’,62 OR: Open five 20-mg omeprazole capsules and empty the granules into a 30- or 60-mL amber vial. Withdraw 50 mL of 8.4% sodium bicarbonate solution from a vial and inject it into the amber vial. Shake well until dissolved. Label this as a 2-mg/mL concentration with an expiration date of 14 days if stored at room temperature or 180 days if refrigerated or frozen. Administer orally or by nasogastric, gastrostomy, or jejunostomy tube.63,64,67,69 2. Place 2 Alka-Seltzer Gold@ (Bayer Corporation, Morristown, New Jersey) tablets into 240 mL water. Open the omeprazole capsule and sprinkle the granules onto the effervescent liquid. Stir until the granules are completely dissolved and administer.59*68 3. Sodium bicarbonate solution can be prepared extemporaneously by placing one half to 1 tsp baking soda (sodium bicarbonate) into 240 mL warm water and used as described above.60
Open capsule and sprinkle granules onto 1 tsp yogurt. Fruit
juice17S9.69.70
Open capsule and add granules to apple, cranberry, grape, grapefruit, orange, pineapple, prune, tomato, or V-8@ juice (Campbell Soup Company, Camden, New Jersey) and give orally. Granules should not be chewed.
Open capsule and sprinkle granules onto 1 tsp applesauce.
673
CLINICAL THERAPEUTICS@
the granules are chewed, their bitter taste may result in noncompliance with subsequent doses. The pharmacodynamics resulting from these alternative methods of omeprazole administration have been reported to be the same as for the intact capsule. 17,28~59 However, the oral bioavailability of omeprazole in nonproprietary formulations may be unpredictable and produce variable degrees of drug exposure. The advantages and disadvantages of these methods of administration in terms of bioequivalance, intragastric pH, and efficacy have been extensively reviewed by Zimmermann et a1.60 We recommend sprinkling the omeprazole granules on applesauce or yogurt or placing them in an acidic fruit juice and swallowing quickly as an effective method of administration in individuals who cannot swallow intact capsules. Phillips et a161 and Lasky et a1(j2 have reported the effectiveness of a simplified omeprazole suspension (SOS) in preventing stress-associated mucosal injury in critically ill adult patients. The sodium bicarbonate in SOS is postulated to work by 2 mechanisms: activation of H+,K+-adenosine triphosphatase translocation in the parieta1 cells and alteration of intragastric pH sufficient to protect omeprazole from acid degradation in the stomach.59 Quercia et a163 have published a procedure for extemporaneously compounding this solution. At a concentration of 2 mg/mL, SOS is reported to be stable for 14 days at room temperature and for 180 days when refrigerated or frozen.63,64 To improve the palatability of omeprazole suspension in children, the contents of 10 omeprazole capsules can be added to Choco-base@ dry powder (Department of Surgery, University of Missouri-Columbia Hospital, Springfield, Missouri), available
674
in an amber bottle. When refrigerated after reconstitution, the powder is stable for 1 year and 38 days (Jeffrey 0. Phillips, personal communication, March 1999). Mohiuddin et a159 assessed the effect on gastric acid suppression of a second type of extemporaneous bicarbonate formulation. Patients were administered either omeprazole 20 mg capsules with water or omeprazole 20 mg granules mixed in 240 mL water containing 2 Alka-Seltzer Gold@ tablets (Bayer Corporation, Morristown, New Jersey) (958 mg sodium bicarbonate, 832 mg citric acid, and 3 12 mg potassium bicarbonate per tablet), which was left to stand for 215 minutes before drinking. The total percentage of time intragastric pH was >4 and the time to intragastric pH <4 were not statistically different between omeprazole administered as an intact capsule and in the formulation containing Alka-Seltzer (68.7 vs 65.1%, respectively, and 327.5 vs 310.5 minutes, respectively).
CONCLUSIONS Marketed and extemporaneous formulations of omeprazole have been administered to children aged 2 months to 18 years at dosages of 5 to 80 mg/d (0.2-3.5 mg/kg/d) for periods of 14 days to 36 months in the treatment of erosive esophagitis, gastric ulcer, duodenal ulcer, HP infection, and associated conditions. The initial dose most consistently reported to heal esophagitis and provide relief of svmntoms of GERD annears to be 1 . I
mgn
II
per
day.
1’,20,2
I.71 372
For children who have difficulty swallowing capsules, opening the capsule and sprinkling the granules on applesauce or dispersing them in fruit juice may be an alternative. However, if the child acciden-
A.E. ZIMMERMANN
ET AL.
tally chews the granules, the bitter taste will be unpalatable. Use of an extemporaneously prepared flavored omeprazole suspension may increase compliance and palatability in pediatric patients. However, the oral bioavailability of omeprazole in nonproprietary formulations may be unpredictable and produce variable degrees of drug exposure. To date, omeprazole has been effective and well tolerated in the acute and chronic treatment of esophageal and peptic ulcer diseases, particularly in children who have not responded to previous histamine,receptor antagonists. Results of a recent study of omeprazole maintenance therapy lasting up to 11 years in adults73 suggest that the drug is safe and effective for longterm acid suppression, with no reported dysplasias or neoplasms. Should future long-term, controlled clinical trials in children demonstrate safety and efficacy, this PPI is likely to find a place in the armamentarium of pediatric pharmacotherapy.
ACKNOWLEDGMENT The opinions and assertions expressed herein are the authors’ and are not to be construed as reflecting the offtcial policy or views of AstraZeneca, LP The authors thank Mark Haythom for his assistance.
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to: Anthony E. Zimmermann, PharmD, Department of Center, 759 Chestnut Street, Springfield, MA 01199. E-mail:
@ mcp.edu
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