Proton Pump Inhibitors

[Developed, October 2000 (formerly a component of Anti-Ulcer Therapy criteria); Revised, December 2001; October 2002, November 2003; December 2005; June 2009; September 2009; September 2011; November 2011]

MEDICAID DRUG USE REVIEW CRITERIA FOR OUTPATIENT USE

Information on indications for use or diagnosis is assumed to be unavailable. All criteria may be applied retrospectively; prospective application is indicated with [*].

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1.* Dosage

Proton pump inhibitors (PPIs) are FDA-approved for managing duodenal and gastric ulcers, erosive esophagitis (EE), gastroesophageal reflux disease (GERD), hypersecretory conditions, and heartburn, preventing nonsteroidal anti-inflammatory drug (NSAID)-induced ulcers, and eradicating Helicobacter pylori (as a component of combination therapy).

Omeprazole/sodium bicarbonate combination therapy is FDA-approved for managing gastric and duodenal ulcer, EE, GERD, and upper gastrointestinal bleed risk reduction in critically ill patients.

Adults
Maximum daily adult doses for PPIs when prescribed as acute and maintenance therapy are summarized in Tables 1 and 2. Dosages exceeding these recommended values will be reviewed.

Table 1
Adult Maximum Daily Acute Dose for Proton Pump Inhibitors
DRUG MAXIMUM DOSE
Monotherapy: dexlansoprazole (Dexilant®) GERD (nonerosive):  30 mg/day
EE:  60 mg/day
Monotherapy: esomeprazole (Nexium®) GERD (nonerosive):  20 mg/day
EE:  40 mg/day
H. pylori eradication:  40 mg/day
hypersecretory conditions:  240 mg/day
Monotherapy: lansoprazole (Prevacid®) duodenal ulcer, GERD (nonerosive):  15 mg/day
EE, gastric ulcer, NSAID-associated gastric ulcer:  30 mg/day
H. pylori eradication:  60 mg/day (in divided doses)
hypersecretory conditions:  180 mg/day
heartburn (OTC*):  15 mg/day
Monotherapy: omeprazole (Prilosec®, generics) duodenal ulcer, EE, GERD (nonerosive):  20 mg/day
gastric ulcer:  40 mg/day
H. pylori eradication:
triple therapy – 40 mg/day in divided doses
dual therapy – 40 mg/day
hypersecretory conditions:  360 mg/day
heartburn (OTC):   20 mg/day
Monotherapy: pantoprazole (Protonix®, generics) EE:  40 mg/day
hypersecretory conditions:  240 mg/day
Monotherapy: rabeprazole (Aciphex®) duodenal ulcer, EE, GERD (nonerosive):  20 mg/day
H. pylori eradication:  40 mg/day
hypersecretory conditions:  120 mg/day (in divided doses)
Combination Therapy: omeprazole/sodium bicarbonate (Zegerid®) duodenal ulcer, EE, GERD (nonerosive):  20 mg/day
gastric ulcer:  40 mg/day
upper GI bleed risk reduction in critically ill (suspension only):  40 mg/day
heartburn (OTC):  20 mg/day
Table 2
Adult Maximum Daily Maintenance Dose for Proton Pump Inhibitors
DRUG MAXIMUM DOSE
dexlansoprazole EE:  30 mg/day
esomeprazole EE:  20 mg/day
risk reduction of NSAID-associated gastric ulcer: 40 mg/day
lansoprazole duodenal ulcer, EE: 15 mg/day
risk reduction of NSAID-associated gastric ulcer: 15 mg/day
hypersecretory conditions: 180 mg/day
omeprazole EE: 20 mg/day
hypersecretory conditions:  360 mg/day
pantoprazole EE: 40 mg/day
hypersecretory conditions:  240 mg/day
rabeprazole hypersecretory conditions: 120 mg/day
EE: 20 mg/day

Pediatrics

Safety and efficacy of dexlansoprazole, pantoprazole, and omeprazole/sodium bicarbonate in patients less than 18 years of age have not been established.

Esomeprazole, lansoprazole, omeprazole, and rabeprazole are FDA-approved for use in pediatric patients; doses are age-dependent. The maximum recommended daily pediatric doses for these PPIs are summarized in Table 3. Dosages exceeding these recommendations will be reviewed.

Table 3
Pediatric Maximum Recommended Doses for Proton Pump Inhibitors
DRUG MAXIMUM DOSE
lansoprazole acute therapy:
1 to 11 years of age:
GERD, EE*: 
> 30 kg - 30 mg/day
< 30 kg - 15 mg/day
> 12 years of age:
EE:  30 mg/day
GERD:  15 mg/day
maintenance dose:
> 12 years of age:
EE:  15 mg/day
omeprazole acute therapy:
> 1 year of age:
EE, GERD:
5 to  < 10 kg - 5 mg /day
10 to 20 kg - 10 mg/day
> 20 kg - 20 mg/day
rabeprazole acute therapy:
> 12 years of age:
GERD:  20 mg/day

Although not FDA-approved due to limited availability of guidelines and well-designed clinical trials, select proton pump inhibitors have been utilized in combination with antibiotic therapy to manage H. pylori in pediatric patients. The 2011 European Society for Pediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) and North American Society for Pediatric Gastroenterology, Hepatology and Nutrition (NASPGHAN) guidelines for H. pylori management in pediatric patients recommend PPI doses of 1-2 mg/kg/day for 10 to 14 days as combination therapy or sequential therapy. Pediatric dosage recommendations for H. pylori management are summarized in Table 4.

Table 4
ESPGHAN/NASPGHAN Pediatric H. pylori Treatment Recommendations
TREATMENT OPTION ORAL DOSAGE
Option 1:  
amoxicillin
clarithromycin
PPI
50 mg/kg/day up to 1 g twice daily
20 mg/kg/day up to 500 mg twice daily
1-2 mg/kg/day
Option 2:  
amoxicillin
metronidazole
PPI
50 mg/kg/day up to 1 g twice daily
20 mg/kg/day up to 500 mg twice daily
1-2 mg/kg/day
Option 3 (sequential therapy*):
PPI
+
amoxicillin
followed by
PPI
+
metronidazole
+  
clarithromycin
1-2 mg/kg/day
50 mg/kg/day up to 1 g twice daily
1-2 mg/kg/day
20 mg/kg/day
20 mg/kg/day up to 500 mg twice daily

*sequential therapy = PPI + amoxicillin x 5 days followed by PPI + metronidazole + clarithromycin x 5 days

2. Duration of Therapy

In the acute setting, 8 weeks of PPI therapy will heal most non-H. pylori duodenal and gastric ulcers.  The prescribing health care provider may continue acute dosage regimens for longer than 8 weeks in patients with hypersecretory disease states, esophagitis, or GERD, as well as those patients with risk factors for gastric ulcer treatment failure such as smoking. PPI acute dosage regimens may also exceed 8 weeks in patients with risk factors for delayed duodenal ulcer healing such as daily ethanol use, large ulcers, signs of upper GI bleeding, and/or a previous history of duodenal ulcer. Patients with refractory ulcers, defined as ulcers that do not respond to up to 12 weeks of anti-ulcer therapy, may also require extended PPI therapy. Treatment regimens at acute dosage levels lasting longer than four months (16 weeks) in patients with a diagnosis of acute duodenal or gastric ulcer will be reviewed.

Esomeprazole, when prescribed for risk reduction of NSAID-associated gastric ulcer, may be administered for up to six months, as controlled studies for this indication do not extend beyond this time period. Similarly, lansoprazole may be administered for up to 8 weeks when prescribed for healing of NSAID-induced gastric ulcers and up to 12 weeks for risk reduction of NSAID-associated gastric ulcers, as controlled studies have not evaluated longer treatment durations.  Treatment regimens for NSAID-associated gastric ulcers extending beyond six months for esomeprazole, 8 weeks for lansoprazole 30 mg, and 12 weeks for lansoprazole 15 mg will be reviewed.

Unless otherwise specified, maintenance therapy, at the recommended daily maintenance dose (Table 2 and Table 3), may be continued indefinitely based on patient need.

PPI treatment duration in adults for H. pylori eradication is summarized in Table 5.  PPI therapy is prescribed for a maximum of 14 days in most patients, as treatment durations exceeding 14 days do not significantly increase eradication rates.  In treatment failures, retreatment with an alternate antibiotic regimen has been beneficial.  In these circumstances, patients may receive PPI therapy for a maximum of 28 days.

Table 5
Proton Pump Inhibitor Recommended Therapy Duration in Adults
for H. pylori Eradication
DRUG RECOMMENDED THERAPY DURATION
esomeprazole with triple therapy: 10 days
lansoprazole with dual therapy: 14 days
with triple therapy: 10-14 days
omeprazole with ulcer present at treatment initiation,
dual or triple therapy: 28 days
without ulcer present at treatment initiation,
dual therapy: 14 days
triple therapy: 10 days
rabeprazole with triple therapy: 7 days

For heartburn management, PPI treatment duration should not exceed 14 days during a 4-month period, unless alternate instructions are provided by a physician.

Pediatric treatment regimens for H. pylori eradication reported in guidelines and clinical trials should be administered for 10 to 14 days. Pediatric sequential therapy for H. pylori eradication is comprised of a PPI plus amoxicillin administered for 5 days, followed by a PPI plus metronidazole plus clarithromycin given for 5 days.

3.* Duplicative Therapy

The combination of two or more proton pump inhibitors is not supported by the current literature. Additional clinical benefit is not realized when multiple proton pump inhibitors are prescribed adjunctively. Therefore, concurrent use of multiple proton pump inhibitors will be reviewed.

4.* Drug-Drug Interactions

Patient profiles will be assessed to identify those drug regimens which may result in clinically significant    drug-drug interactions.

Drug-drug interactions considered clinically relevant for proton pump inhibitors are summarized in Table 6.  Only those drug-drug interactions identified as clinical significance level 1 or contraindicated, or those considered life-threatening which have not yet been classified will be reviewed:

Table 6
Major PPI Drug-Drug Interactions
TARGET DRUG INTERACTING DRUG INTERACTION RECOMMENDATION CLINICAL SIGNIFICANCE*+
PPIs clopidogrel (Plavix®) combined administration may attenuate clopidogrel effects on platelet aggregation, increase  potential risk of secondary acute cardiovascular events following percutaneous coronary intervention or acute coronary syndrome; exact mechanism for  interaction unknown, but PPIs may delay or minimize clopidogrel conversion to its active form by competitively inhibiting CYP2C19 avoid combined use, if possible; H2RAs# other than cimetidine or pantoprazole (has less CYP2C19 inhibitory activity) are suitable alternatives for acid suppressive therapy in patients requiring clopidogrel major (DrugReax)
2-major (CP)
1 (DIF)
PPIs erlotinib (Tarceva®) adjunctive administration may decrease erlotinib absorption and reduce effectiveness as erlotinib solubility, which is pH dependent, is reduced with PPI therapy avoid combination, if possible; if adjunctive therapy necessary, use lowest effective PPI dose, monitor for reduced erlotinib efficacy, and adjust erlotinib dose as needed; may use alternate acid suppressive therapy (e.g., H2RAs, antacids); antacid and erlotinib doses should be separated by several hours   major (DrugReax)
2 (DIF)
PPIs dasatinib (Sprycel®) adjunctive administration for extended duration may result in reduced dasatinib exposure and serum levels as dasatinib dependent on acidic gastric pH for solubility and absorption  combined use not recommended; alternative acid suppressives (e.g., antacids) should be given 2 hours before or 2 hours after dasatinib dose for optimal efficacy major (DrugReax)
2-major (CP)
PPIs select protease inhibitors (e.g., atazanavir, indinavir, nelfinavir) concurrent administration may result in reduced protease inhibitor serum levels and effectiveness and increased potential for resistance, as PPIs may interfere with protease inhibitor solubility and absorption by increasing gastric pH avoid PPI and atazanavir, indinavir, or nelfinavir combinations major (DrugReax)
1-severe: atazanavir, nelfinavir; 2-major: indinavir (CP)
1 (DIF)
PPIs select azole antifungals (e.g., itraconazole, ketoconazole, posaconazole) combined administration may decrease antifungal absorption and effectiveness; itraconazole, ketoconazole, and posaconazole dependent on acidic environment for favorable absorption and PPIs increase gastric pH avoid concurrent administration, if possible; if PPI-antifungal combination necessary, may administer antifungal with acidic beverage (e.g., Coke) to increase absorption; monitor closely for continued antifungal efficacy moderate (DrugReax)
2-major (CP)
2 (DIF)
omeprazole cilostazol (Pletal®) adjunctive use may increase cilostazol serum levels and enhance cilostazol pharmacologic/adverse effects as cilostazol is metabolized by CYP2C19 and omeprazole is potent CYP2C19 inhibitor reduce cilostazol dose by 50% when given concurrently with omeprazole and monitor for enhanced cilostazol pharmacologic/adverse effects moderate (DrugReax)
2-major (CP)
2 (DIF)
PPIs delavirdine combined use for extended treatment duration may result in reduced delavirdine absorption, decreased delavirdine serum levels, and attenuated delavirdine efficacy as delavirdine is dependent on an acidic gastric pH for absorption; separating drug doses may not improve delavirdine absorption as PPIs affect gastric pH for prolonged time period concomitant use not recommended; antacids may be alternative acid suppressive therapy, with  antacid and delavirdine doses separated by at least one hour
 
major (DrugReax)
2-major (CP)
PPIs mycophenolate combined administration may result in decreased mycophenolic acid serum levels and reduced therapeutic efficacy, most likely due to decreased mycophenolate absorption with increased gastric pH avoid combined use, if possible; if adjunctive therapy necessary, closely monitor mycophenolic acid serum levels and adjust mycophenolate doses as necessary major (DrugReax)
2 (DIF)
PPIs rilpivirine (Edurant®) adjunctive administration may promote rilpivirine treatment failure and potential for impaired virologic response and rilpivirine/NNRI† resistance as rilpivirine requires more acidic gastric pH for absorption combined administration contraindicated contraindicated (DrugReax)
1-severe (CP)

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Prepared by: Drug Information Service, The University of Texas Health Science Center at San Antonio, and the College of Pharmacy, The University of Texas at Austin.