Pediatric

Pharmacotherapy
A Monthly Newsletter for Health Care Professionals
Children’s Medical Center at the University of Virginia
Volume 5 Number 4 April 1999

Using Proton Pump Inhibitors in Children

Marcia L. Buck, Pharm.D., FCCP

P roton pump inhibitors (PPIs) offer a

distinctly different mechanism for reducing
gastric acidity than H2 blockers or
from 5 to 26 months (average 12 months).
Dosages were titrated based on the results of 24-
hour intraesophageal pH studies and
anticholinergics. These agents, omeprazole and symptomatic improvement. The effective dose
lansoprazole, have been found to be successful in ranged from 0.7 to 3.3 mg/kg/day, with a mean
the treatment of gastric and duodenal ulcers, of 2 mg/kg/day. At the 4-6 month follow-up, all
including those related to Helicobacter pylori patients had healing of erosions and experienced
infection, gastroesophageal reflux disease improvement in clinical symptoms.
(GERD), and chronic hypersecretory conditions
such as Zollinger-Ellison syndrome.1-4 That same year, Cucchiara et al7 conducted a
randomized, controlled trial in 32 children (aged
Mechanism of Action 6 months to 13 years) comparing omeprazole to
Omeprazole and lansoprazole act by inhibiting ranitidine for refractory esophagitis. Patients
parietal cell H+/K+ ATPase, the “proton pump.” received either omeprazole 40 mg/1.73m2 given
The PPIs are both prodrugs, which once released once daily or ranitidine 10 mg/kg given twice
from their granular coating, are converted in an daily for 8 weeks. Symptomatic improvement
acidic environment to the active sulfenamide occurred in 83% of children given omeprazole
form. The active drug then forms a covalent and 69% of children given ranitidine.
bond to cysteine residues of actively secreting Esophageal healing, as determined by
proton pumps. As a result of this irreversible endoscopy, was noted in 75% of the children in
bond, the inhibition of gastric acid production is the omeprazole group and 62% of the children
nearly complete and lasts until new pumps are receiving ranitidine. None of the differences
synthesized. Because the PPIs act at the final were statistically significant. The authors
point of gastric acid production, they are concluded that omeprazole was as effective as
effective regardless of the source of stimulus: ranitidine in treating GERD in children.
histamine, gastrin, or acetylcholine.1-3
A number of subsequent studies have added
Indications support for the role of omeprazole in infants and
The PPIs are currently approved by the Food and children with GERD.9-15 Many of these studies
Drug Administration for the treatment of gastric have included children with neurologic
and duodenal ulcers, GERD, and hypersecretory impairment who have difficulties with
conditions in adults.4 swallowing and severe reflux disease. In these
patients, long-term use of omeprazole appears to
Use in Children offer a useful alternative to antireflux surgery.
Despite their indication for adults and the lack of
pediatric dosage formulations, PPIs have gained Although peptic ulcer disease is much less
wide-spread use in the treatment of gastric acid common in children than GERD, there have been
disorders in children.2,5-21 Several groups have reports of using PPIs to heal ulcers and to
examined the efficacy of omeprazole in the eradicate H. pylori.16-20 Kato and colleagues17
treatment of GERD in infants and children.6-15 In studied 22 children (aged 8 to 16 years) with
1993, Gunasekarn and Hassall6 reported their gastric and duodenal ulcers who were given
experience using omeprazole to treat 15 children omeprazole as part of a multidrug regimen to
(ages 10 months to 17 years) with grade 3 or 4 eradicate H. pylori. Patients received either a
GERD. Therapy was initiated with doses of 10 dual drug regimen of omeprazole 0.6 mg/kg with
or 20 mg per day. Patients remained on therapy amoxicillin 30 mg/kg given twice daily for 2
weeks or a three drug regimen including the first data suggest a more rapid clearance of
two agents plus clarithromycin 15 mg/kg twice omeprazole in children compared to adults.2
daily. In children with active ulcers, omeprazole
was continued for an additional 4 weeks. Half-life is not correlated to duration of action.
Comparisons of endoscopic biopsy results from Duration of gastric acid suppression is better
the time of initiation to completion revealed estimated by the length of time that the drugs
healing of all ulcers. H. pylori was eradicated in bind to the parietal H+/K+ ATPase enzyme. For
70% of the children on the dual regimen and both agents, the duration of action in adults is
92% on the triple regimen. greater than 24 hours, allowing once daily dosing
in most patients.2,4
In the past year, several other groups have
replicated the success demonstrated in Kato’s Elimination half-life is increased for both drugs
study using triple drug regimens for a one-week in patients with hepatic dysfunction. There is a
period.18-20 Researchers from both Sweden and greater effect on lansoprazole, with area under
Israel have found a one-week course of the curve values increasing by 500% in some
omeprazole, clarithromycin, and metronidazole patients. It is recommended that the dose of
to be 85-90% effective in eradicating H. pylori in lansoprazole be reduced in patients with
children.18-19 Kato’s group has also published significant hepatic disease. No dosage
their results demonstrating the efficacy of adjustments are necessary for either agent in
lansoprazole as an alternative to omeprazole.20 patients with renal impairment.4

PPIs have been used in children to treat Barrett’s Drug Interactions

esophagus, hyperpepsinogenemia type I with PPIs have the potential for a number of drug
antral G cell hyperfunction (pseudo Zollinger- interactions. Because of their effect on gastric
Ellison syndrome), and complications resulting acidity, PPIs can reduce the bioavailability of
from gastrocystoplasty. These agents have also drugs that require a low pH for absorption, such
been used to reduce gastric residual volume and as ampicillin, cyanocobalamin, digoxin, iron, or
increase pH prior to surgery, and to improve fat ketoconazole. Sucralfate decreases the
absorption in children with cystic fibrosis.2,5,21 absorption of omeprazole and lansoprazole;
administration of these agents should be
Pharmacokinetics and Pharmacodynamics separated by at least 30 minutes.4
Both omeprazole and lansoprazole are degraded
in an acidic medium. If given alone, the active The metabolism of omeprazole and lansoprazole
drug would be degraded in the stomach before by cytochrome P450 enzymes is another
reaching the site of activity. As a result, both potential source of drug interactions.
drugs are produced as capsules which contain Omeprazole is involved with more drug
enteric-coated granules.2 Absorption of the drug interactions because of its greater activity at
is rapid once the granules enter the small CYP2C19. It inhibits the metabolism of
intestine. Absolute bioavailability of clarithromycin, benzodiazepines, phenytoin, and
lansoprazole is 80%. The bioavailability of warfarin. The clinical significance of these
omeprazole is only 30 to 40% with initial doses, reactions is highly variable among patients.
but increases with continued administration. Lansoprazole inhibits the metabolism of
Both drugs are more than 95% protein bound.4 theophylline. Patients receiving any of these
combinations should be closely monitored for
Both drugs are metabolized by hepatic signs of drug accumulation.
cytochrome P450 enzymes. Omeprazole is
metabolized by CYP2C19, while lansoprazole is The drug interaction between omeprazole and
metabolized by CYP3A4/5 and CYP2C19 clarithromycin is unique. Each drug inhibits the
enzymes. Both drugs form inactive metabolites. metabolism of the other, resulting in increased
Approximately 77% of an omeprazole dose is serum concentrations of both agents. The result
eliminated unchanged in the urine, compared to of this interaction may actually be beneficial to
33% of a lansoprazole dose. The elimination the patient during short-term therapy. The
half-life of omeprazole ranges from 0.5 to 3.5 success of multidrug regimens to eradicate H.
hours in adults. Lansoprazole has an average pylori may be due to the higher concentrations of
half-life of 1.7 hours in adults.4 There are no the drugs achieved when given together.3,4
pharmacokinetic studies of these agents in
children published at this time, but unpublished Adverse Effects
In general, PPIs are well tolerated. The most Lansoprazole is available in 15 and 30 mg
frequently reported adverse effects during capsules (Prevacid ; TAP Pharm.) In adults, the
clinical trials in adults and children were diarrhea starting dose for duodenal ulcers is 15 mg once
(3-4% of patients), abdominal pain (1-4%), daily; for gastric ulcers or erosive esophagitis,
nausea (1-2%), headache (1-9%), dizziness (1- the dose is 30 mg once daily. For duodenal
2%), and rash (1%).4 The incidence of these ulcers associated with H. pylori, the regimen for
adverse effects has not been significantly adults is 30 mg lansoprazole plus 500 mg
different between omeprazole and lansoprazole clarithromycin and 1 gram amoxicillin twice
in trials conducted to date.22 daily for 2 weeks. 4

Omeprazole has been associated with rare cases There are limited data in children using
of pancreatitis, agranulocytosis, and toxic lansoprazole. In the study by Kato and
epidermal necrolysis. Some of these cases have coworkers, a lansoprazole dose of 0.75 mg/kg
been fatal.4 There have also been reports of was given twice daily for 1 week as part of a
interstitial nephritis and optic neuritis with PPI triple drug therapy for eradicating H. pylori.
use.1 All of these severe reactions appear to be
idiosyncratic, with no relation to dose. Omeprazole and lansoprazole are formulated in
capsules containing enteric-coated granules. The
Laboratory values may be affected by PPI use. gelatin capsule dissolves in the stomach,
Both omeprazole and lansoprazole have been releasing the granules. The polymer coating of
associated with transient elevations in liver the granules has been designed to dissolve only
function studies. A decrease in hemoglobin and at a pH greater than 6, so dissolution occurs in
hematocrit levels has also been reported, but the duodenum. In patients unable to swallow the
appears to occur more frequently in patients capsules or in those for whom less than a full
treated with lansoprazole.22 capsule is needed, the capsules may be opened
and the granules mixed with a slightly acidic
Concerns for the development of carcinoid substance, such as applesauce, yogurt, or apple,
changes in gastric cells with long-term PPI use orange, or cranberry juice. The use of an acidic
have not been substantiated. It should be noted, substance preserves the enteric coating of the
however, that hypergastrinemia, histiologic granules, allowing them to remain intact until
changes in gastric cells (hyperplasia, they reach the small intestine.2,5
pseudohypertrophy, and fundic gland cysts), and
gastric polyps have all been described in Administering the granules provides a similar
children, as well as adults, receiving PPIs.2 bioavailability to intact capsules. The primary
drawback of this method is the temptation for the
Dosing Recommendations patient to chew on the granules. Biting down on
Both omeprazole and lansoprazole are produced the granules not only releases a very bitter taste,
as delayed release solid oral dosage forms. but also destroys the protective coating which
Omeprazole is available in 10 and 20 mg prevents the contents from being exposed to
capsules (Prilosec ; Astra). For the treatment of gastric acid. In addition, patients receiving PPIs
GERD or duodenal ulcers, the recommended through feeding tubes may find the drug-juice
dose for adults is 20 mg daily. For gastric ulcers, slurry clogs the tube.
the dose should be increased to 40 mg daily. For
eradication of H. pylori, the regimen for adults is Several authors have attempted to avoid this
20 mg omeprazole with 500 mg clarithromycin issue by administering sodium bicarbonate along
and 1 gram amoxicillin twice daily for 10 days. 4 with the drug to buffer the stomach. In theory,
this method protects the drug from being
In case reports and clinical trials, children older activated in the stomach, and allows it to pass
than 3 years of age have typically been treated into the duodenum for absorption.2 Phillips and
with adult doses. Most papers report the use of colleagues have described a method for
20 mg in children less than 10 years or 30 kg and preparing an omeprazole suspension using
40 mg in older, larger children. Some studies sodium bicarbonate and flavored with root beer
have titrated by patient weight, with regimens for children.23 Quercia and coworkers have also
ranging from 0.2 to 3.5 mg/kg/day. It has been published their method for creating an
suggested by dose-ranging studies that an extemporaneous omeprazole liquid.24 These
optimal starting dose is 0.7 mg/kg/day.2,6 formulations are useful alternatives for children
who have not been able to swallow the granules
with juice. Newer formulations that utilize 19. Casswall TH, et al. One-week treatment with omeprazole,
clarithromycin, and metronidazole in children with
micropellets of drug that more readily mix with
Helicobacter pylori infection. J Pediatr Gastroenterol Nutr
liquids is under investigation. 1998;27:415-8.
20. Kato S, et al. Safety and efficacy of one-week triple
Summary therapy for eradicating Helicobacter pylori in children.
PPIs are highly effective therapies for ulcers, Helicobacter 1998;3:278-82.
21. De Giacomo C, et al. Omeprazole treatment of severe
GERD, or hypersecretory diseases. They peptic disease associated with antral G cell hyperfunction
provide a high level of gastric acid inhibition and hyperpepsinogenemia I in an infant. J Pediatr
with relatively few adverse effects. The primary 1990;117:989-93.
limitation of this therapeutic class is the lack of a 22. Freston JW, et al. Safety profile of lansoprazole: the US
clinical trial experience. Drug Safety 1999;20:195-205.
titratable dosage formulation for children. 23. Phillips J, et al. A prospective study of simplified
omeprazole suspension for the prophylaxis of stress-related
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inhibitors: pharmacology, efficacy, and safety, with special
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1998;27:568-79. The following actions were taken by the
3. Langtry HD, et al. Lansoprazole: an update of its
pharmacological properties and clinical efficacy in the
Pharmacy and Therapeutics Committee at their
management of acid-related disorders. Drugs 1997;54:473- meeting on 3/26/99:
500.
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These agents are designed to provide more
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the treatment of refractory reflux oesophagitis. Arch Dis adverse effects on gastric mucosa. Celecoxib is
Child 1993;69:655-9. restricted to the Rheumatology service.
8. Nelis GF, et al. Treatment of resistant reflux oesophagitis
in children with omeprazole. Eur J Gastroenterol Hepatol
2. An extended-release formulation of niacin
1990;2:215-7. (Niaspan ) was also added to the formulary.
9. Karjoo M, et al. Omeprazole treatment of children with 3. Tretinoin Microsphere Gel (Retin-A Micro )
peptic esophagitis refractory to ranitidine therapy. Arch was added to the formulary for the treatment of
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10. Martin PB, et al. The use of omeprazole for resistant severe acne and other dermatologic conditions.
oesophagitis in children. Eur J Pediatr Surg 1996;6:195-7. 4. The following nonsteroidal anti-inflammatory
11. Kato S, et al. Effect on omeprazole in the treatment of agents were removed from the formulary:
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healing and twenty-four-hour intragastric acidity. J Pediatr
1996;128:415-21.
12. De Giacomo C, et al. Omeprazole for severe reflux Contributing Editor: Marcia L. Buck, Pharm.D.
esophagitis in children. J Pediatr Gastroenterol Nutr Editorial Board: Anne E. Hendrick, Pharm.D.
1997;24:528-32. Michelle W. McCarthy, Pharm.D.
13. Hassall E, et al. Omeprazole for chronic erosive
esophagitis in children: a multicenter study of dose Douglas S. Paige, R.Ph.
requirement for healing. Gastroenterology 1997;112 If you have any comments or would like to be on
(suppl):A425. Abstract. our mailing list, please contact us at Box 274-11,
14. Alliet P, et al. Omeprazole in infants with cimetidine- UVA Medical Center, Charlottesville, VA 22908
resistant peptic esophagitis. J Pediatr 1998;132:352-4.
15. Bohmer CJ, et al. Omeprazole: therapy of choice in
or by phone (804) 982-0921, fax (804) 982-
intellectually disabled children. Arch Pediatr Adolesc Med 1682, or e-mail to mlb3u@virginia.edu.
1998;152:1113-8.
16. Dohil R, et al. Effective 2-wk therapy for Helicobacter
pylori disease in children. Am J Gastroenterol 1997;92:244-
7.
17. Kato S, et al. Omeprazole-based dual and triple regimens
for Helicobacter pylori eradication in children. Pediatrics
1997;100:e3.
18. Moshkowitz M, et al. One-week triple therapy with
omeprazole, clarithromycin, and nitroimidazole for
Helicobacter pylori infection in children and adolescents.
Pediatrics 1998;102:e14.