Proton Pump Inhibitors

Revised March 2015; June 2013; November 2011; September 2011; September 20009; June 2009; December 2005; November 2003; October 2002. Developed December 2001.

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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.

Esomeprazole combined with naproxen is FDA-approved for use in osteoarthritis (OA), rheumatoid arthritis (RA), or ankylosing spondylitis (AS) in adult patients at greater risk for developing NSAID-induced gastric ulcers.

Adults
Maximum daily adult doses for PPIs when prescribed as acute and maintenance therapy, as well as components of combination treatments, 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 Name Maximum Recommended Dosage
Monotherapy
Dexlansoprazole (Dexilant®) EE 60 mg/day
GERD (nonerosive) 30 mg/day
Esomeprazole (Nexium®, generics) EE 40 mg/day
GERD (nonerosive) 20 mg/day
H. pylori eradication 40 mg/day
Heartburn 20 mg/day
Hypersecretory conditions 240 mg/day
lansoprazole (Prevacid®, generics) Duodenal ulcer, GERD (nonerosive) 15 mg/day
EE, gastric ulcer, NSAID-associated gastric ulcer 30 mg/day
Heartburn (OTC*) 15 mg/day
H. pylori eradication 90 mg/day (in divided doses)
Hypersecretory conditions 180 mg/day
Omeprazole (Prilosec®, generics) Duodenal ulcer, EE, GERD (nonerosive) 20 mg/day
Gastric ulcer 40 mg/day
Heartburn (OTC) 20 mg/day
H. pylori eradication Triple therapy:
40 mg/day in divided doses
Dual therapy:
40 mg/day
Hypersecretory conditions 360 mg/day
Pantoprazole (Protonix®, generics) EE 40 mg/day
Hypersecretory conditions 240 mg/day
Rabeprazole (Aciphex®, generics) 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®, generics)
Duodenal ulcer, EE, GERD (nonerosive) 20 mg/day
Gastric ulcer 40 mg/day
Heartburn (OTC) 20 mg/day
Upper GI bleed risk reduction in critically ill (suspension only) 40 mg/day
Table 2
Adult Maximum Daily Maintenance Dose for Proton Pump Inhibitors
DRUG MAXIMUM DOSE
Monotherapy
Dexlansoprazole EE 30 mg/day
Esomeprazole EE 20 mg/day
Hypersecretory conditions:  240 mg/day
Risk reduction of NSAID-associated gastric ulcer:  40 mg/day
Lansoprazole Duodenal ulcer, EE 15 mg/day
Hypersecretory conditions 180 mg/day
Risk reduction of NSAID-associated gastric ulcer 15 mg/day
Omeprazole EE 20 mg/day
Hypersecretory conditions 360 mg/day
Pantoprazole EE 40 mg/day
hypersecretory conditions 240 mg/day
Rabeprazole EE 20 mg/day
hypersecretory conditions 120 mg/day (in divided doses)
Combination Therapy
Esomeprazole/naproxen (Vimovo®) prevention of NSAID-associated gastric ulcer in patients with OA, RA, AS 40 mg/1000 mg per day

Pediatrics

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

Esomeprazole, lansoprazole, omeprazole, pantoprazole, 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 Name Maximum Recommended Dosage
Esomeprazole Acute therapy
1 to 11 months of age EE due to only acid-mediated GERD 3 kg to 5 kg: 2.5 mg once daily
5 kg to 7.5 kg:  5 mg once daily
7.5 kg to 12 kg: 10 mg once daily
1 to 11 years of age EE 20 kg:  20 mg/day
< 20 kg:  10 mg/day
GERD 10 mg/day
12 to 17 years of age EE 40 mg/day
GERD 20 mg/day
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
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
Pantoprazole Acute therapy
≥  5 years of age EE 15 kg to < 40 kg: 20 mg/day
≥ 40 kg:  40 mg/day
Rabeprazole Acute therapy
1 to 11 years of age GERD < 15 kg: 5 mg once daily+
15 kg: 10 mg once daily
≥ 12 years of age GERD 20 mg once daily

*dose increased to 30 mg twice daily in some children who remained symptomatic after 2 weeks of therapy at lower doses
+may increase to 10 mg daily in those with inadequate response to 5 mg dose

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 50 mg/kg/day up to 1 g twice daily
Clarithromycin 20 mg/kg/day up to 500 mg twice daily
PPI 1-2 mg/kg/day
Option 2 Amoxicillin 50 mg/kg/day up to 1 g twice daily
Metronidazole 20 mg/kg/day up to 500 mg twice daily
PPI 1-2 mg/kg/day
Option 3
(sequential therapy*)
PPI 1-2 mg/kg/day
+ amoxicillin 50 mg/kg/day up to 1 g twice daily
followed by
PPI 1-2 mg/kg/day
+ metronidazole 20 mg/kg/day
+ clarithromycin 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

Dosage in Renal Impairment

Dosage adjustments are not necessary when PPIs are prescribed as monotherapy to patients with renal impairment. Omeprazole/sodium bicarbonate therapy also does not require dosage adjustments in renally impaired patients.  However, the esomeprazole/naproxen combination is not recommended for use in patients with a creatinine clearance below 30 ml/min due to the potential for naproxen and metabolite accumulation and increased risk for adverse events.

2.   Duration of Therapy
PPI acute treatment durations for both adult and pediatric patients based on FDA-approved indications are summarized in Table 5. 

 

Table 5
PPI Acute Duration of Therapy for Adult and Pediatric Patients

Drug Maximum Recommended Treatment Duration
(based on FDA-approved indication)
Adults:  Monotherapy
Dexlansoprazole EE 8 weeks
GERD 4 weeks
Esomeprazole EE 8 weeks^
GERD 4 weeks+
Heartburn 14 days*
Lansoprazole duodenal ulcer 4 weeks
EE 8 weeks#
Gastric ulcer, GERD 8 weeks
Heartburn 14 days*
NSAID-associated gastric ulcer (without prior gastric ulcer) 8 weeks
NSAID-associated gastric ulcer (with prior gastric ulcer) 12 weeks
Omeprazole duodenal ulcer 4 weeks+
EE 8 weeks#
Gastric ulcer 8 weeks
GERD 4 weeks
Heartburn 14 days*
Pantoprazole EE 8 weeks#
Rabeprazole Duodenal ulcer 4 weeks+
EE 8 weeks#
GERD 4 weeks+
Adults:  Combination Therapy
Omeprazole/Sodium bicarbonate Duodenal ulcer 4 weeks+
EE 8 weeks#
Gastric ulcer 8 weeks
GERD (nonerosive) 4 weeks
Heartburn 14 days*
Upper GI bleed risk reduction in critically ill 14 days~
Pediatrics:  Monotherapy
Esomeprazole 1 to 11 months of age EE due to acid-mediated GERD 6 weeks
1 to 11 years of age EE healing, symptomatic GERD 8 weeks
12 to 17 years of age EE healing 8 weeks
Symptomatic GERD 4 weeks
Lansoprazole 1 to 11 years of age EE, GERD 12 weeks
12 to 17 years of age EE, GERD 8 weeks
Pantoprazole ≥ 5 years of age EE 8 weeks
Rabeprazole 1 to 11 years of age GERD 12 weeks
12 to 17 years of age GERD 8 weeks

^may consider an additional 4- to 8-week treatment course in patients who do not heal with initial treatment
+may consider an additional 4-week treatment course in patients who do not heal with initial treatment
#may consider an additional 8-week treatment course in patients with incomplete healing or EE recurrence after initial treatment
* PPI treatment duration should not exceed 14 days during a 4-month period, unless alternate instructions are provided by a physician
~ Treatment longer than 14 days has not been studied in critically ill patients

In the acute setting in both adult and pediatric patients older than 11 months of age, 8 weeks of PPI therapy will treat EE and 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.  Treatment regimens for NSAID-associated gastric ulcers extending beyond designated treatment times for esomeprazole and lansoprazole will be reviewed.

Unless otherwise specified, maintenance therapy, at the recommended daily maintenance dose (Tables 2 and 3), may be continued indefinitely based on patient need.  Omeprazole treatment for EE and GERD in pediatric patients may continue indefinitely.

PPI treatment duration in adults for H. pylori eradication is summarized in Table 6.  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 6
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

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 PPIs is not supported by the current literature.  Additional clinical benefit is not realized when multiple PPIs are prescribed adjunctively.  Therefore, concurrent use of multiple PPIs 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 PPIs are summarized in Table 7.  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 7
Major PPI Drug-Drug Interactions

Target Drug Interacting Drug Interaction Recommendation Clinical Significance*+
Esomeprazole, Omeprazole citalopram (Celexa®) adjunctive use may increase citalopram serum levels and enhance citalopram, pharmacologic/adverse effects (including QT interval prolongation) as citalopram is metabolized by CYP2C19 and esomeprazole and omeprazole are CYP2C19 inhibitors citalopram dose should not exceed 20 mg/day if this drug combination is utilized; monitor for enhanced citalopram pharmacologic/adverse effects major (DrugReax)
2-major (CP)
4 (DIF)
Esomeprazole, Omeprazole cilostazol (Pletal®) adjunctive use may increase cilostazol serum levels and enhance cilostazol pharmacologic/adverse effects as cilostazol is metabolized by CYP2C19 as esomeprazole and omeprazole are CYP2C19 inhibitors 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 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)
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 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 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)
PPIs other agents with solubility affected by changes in gastric pH (e.g., bosutinib, ponatinib, vismodegib           ) concomitant administration may result in reduced bioavailability and activity of agents requiring low gastric pH for solubility as PPIs increase gastric pH avoid combination, if possible; if adjunctive therapy necessary, use lowest effective PPI dose, monitor for reduced efficacy of agents requiring low gastric pH for solubility, and adjust dose as needed; may use alternate acid suppressive therapy (e.g., H2RAs, antacids); antacid and doses for agents with solubility issues should be separated by several hours  major (DrugReax)

 

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