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  • CLASSES

    Proton Pump Inhibitors/PPIs

    DEA CLASS

    Rx

    DESCRIPTION

    Oral and IV gastric proton-pump inhibitor (PPI)
    Used for erosive esophagitis, GERD, Zollinger-Ellison syndrome, duodenal and gastric ulcers, H. pylori eradication with antibiotics, and stress ulcer prophylaxis
    Lowest propensity of PPIs for CYP-based drug interactions

    COMMON BRAND NAMES

    Protonix

    HOW SUPPLIED

    Pantoprazole Sodium/Protonix Intravenous Inj Pwd F/Sol: 40mg
    Pantoprazole Sodium/Protonix Oral Tab DR: 20mg, 40mg
    Protonix Oral Gran F/Recon: 40mg

    DOSAGE & INDICATIONS

    For the treatment of erosive esophagitis (erosive GERD).
    Oral dosage
    Adults

    40 mg PO once daily for up to 8 weeks. For patients who have not healed after 8 weeks of treatment, an additional 8-week course may be considered. Therapy duration during clinical trials was 12 months or less. In a maintenance therapy trial, 20 mg PO once daily was also effective in reducing daytime or evening episodes of heartburn. Higher oral doses of 80 mg/day (up to 120 mg/day) have been administered safely to patients with esophagitis in published clinical trials. For maintenance of healing, continue 40 mg PO once daily; periodically reassess the need for continued PPI therapy.

    Children and Adolescents 5 years and older weighing 40 kg or more

    40 mg PO once daily for up to 8 weeks. Safety beyond 8 weeks has not been established.

    Children and Adolescents 5 years and older weighing 15 to 39 kg

    20 mg PO once daily for up to 8 weeks. Safety beyond 8 weeks has not been established.

    Children younger than 5 years† or weighing less than 15 kg

    0.6 to 1.2 mg/kg/day PO (as oral suspension) is a suggested dose from pharmacokinetic data and pediatric reviews; the higher dose is usually prescribed for erosive disease. Doses as low as 0.3 mg/kg/day PO have been studied for symptom reduction of GERD. Some studies for high dosing in erosive esophagitis have allowed for dosing of 15 mg/day PO for patients aged 1 year, and 20 mg/day PO for children aged 2 to 5 years.

    Infants† 1 month and older

    1.2 mg/kg/day PO (as oral suspension) is the suggested dose; limited data are available. In 1 study, 1.2 mg/kg/day PO was administered to infants aged 1 to 11 months (mean age 5.1 months, n = 128) with GERD symptoms after 2 weeks of conservative treatment. GERD symptom scores decreased significantly from baseline during pantoprazole therapy (p < 0.001); treatment was well tolerated with no difference in withdrawal rates or mild-to-moderate adverse events between pantoprazole and placebo groups. PPIs should not be prescribed as first line therapy for symptomatic GERD in otherwise healthy infants (aged 1 to 11 months); treatment should instead be reserved for use in infants with acid reflux disease diagnosed by endoscopy (e.g., erosive esophagitis) and nonpharmacologic measures such as diet modification and positioning strategies are recommended.

    Neonates†

    Safety and efficacy have not been established. Data are limited. 0.6 to 1.2 mg/kg/day PO (as oral suspension) is a suggested dose range from pharmacokinetic data and pediatric reviews. Average doses were 1.25 mg/day PO (at roughly 0.6 mg/kg/day), and 2.5 mg/day PO (at roughly 1.2 mg/kg/day).

    Intravenous dosage
    Adults

    40 mg IV infused once daily for 7 to 10 days. The IV formulation is indicated as an alternative to oral therapy for short-term treatment (7 to 10 days). This dose does not raise gastric pH levels sufficiently to treat life-threatening upper GI bleeds. Switch to oral therapy when feasible.

    For the treatment of pathological hypersecretion associated with Zollinger-Ellison syndrome or other hypersecretory syndromes.
    Oral dosage
    Adults

    Initially, 40 mg PO twice daily. Adjust dosage to attain clinical goals. Doses up to 240 mg/day have been administered. Some patients have been treated for more than 2 years.

    Intravenous dosage
    Adults

    Initially, 80 mg IV infused every 12 hours. Approximately 80% of patients may require dosage increase to 80 mg IV every 8 hours. Maximum dosage is 240 mg/day IV, given in divided doses every 8—12 hours. Total daily IV doses of 160—240 mg effectively controlled gastric acid output within 1 hour and maintained acid control for up to 7 days. Safe and effective use of IV pantoprazole beyond 10 days has not been established; switch to oral dosage when feasible.

    For the short-term treatment of frequent dyspepsia† or pyrosis (heartburn)† that occurs >= 2 times per week.
    Oral dosage
    Adults

    20—40 mg PO once daily for up to 14 days. Full relief may take 1—4 days. Reassess if frequent heartburn returns soon after the 14-day treatment regimen.

    For the treatment of non-erosive gastroesophageal reflux disease (GERD)†.
    Oral dosage
    Adults

    20 mg PO once daily for up to 4 weeks. Per clinical practice guidelines, initiate empiric therapy based on a presumptive diagnosis of GERD in the setting of typical symptoms of heartburn and regurgitation. For patients with partial response to once daily therapy, consider pantoprazole 20 mg PO twice daily, or consider a one-time switch to a different PPI. Refer non-responders for further evaluation. Consider maintenance therapy for patients who continue to have symptoms after PPI discontinuation; the lowest effective dose, including on demand or intermittent therapy should be used with regular assessment of the need for continued PPI therapy. Alternatively, step-down maintenance therapy to an H2 blocker is acceptable.

    Children and Adolescents 5 years and older weighing 40 kg or more

    40 mg PO once daily for up to 8 weeks. Safety beyond 8 weeks has not been established.

    Children and Adolescents 5 years and older weighing 15 to 39 kg

    20 mg PO once daily for up to 8 weeks. Safety beyond 8 weeks has not been established.

    Children younger than 5 years† or weighing less than 15 kg

    0.6 to 1.2 mg/kg/day PO (as oral suspension) is a suggested dose from pharmacokinetic data and pediatric reviews; the higher dose is usually prescribed for erosive disease. Doses as low as 0.3 mg/kg/day PO have been studied for symptom reduction of GERD. Some studies for high dosing in erosive esophagitis have allowed for dosing of 15 mg/day PO for patients aged 1 year, and 20 mg/day PO for children aged 2 to 5 years.

    Infants 1 month and older†

    1.2 mg/kg/day PO (as oral suspension) is the suggested dose; limited data are available. In 1 study, 1.2 mg/kg/day PO was administered to infants aged 1 to 11 months (mean age 5.1 months, n = 128) with GERD symptoms after 2 weeks of conservative treatment. GERD symptom scores decreased significantly from baseline during pantoprazole therapy (p < 0.001); treatment was well tolerated with no difference in withdrawal rates or mild-to-moderate adverse events between pantoprazole and placebo groups. PPIs should not be prescribed as first line therapy for symptomatic GERD in otherwise healthy infants (aged 1 to 11 months); treatment should instead be reserved for use in infants with acid reflux disease diagnosed by endoscopy (e.g., erosive esophagitis) and nonpharmacologic measures such as diet modification and positioning strategies are recommended.

    Neonates†

    Safety and efficacy have not been established. Data are limited. 0.6 to 1.2 mg/kg/day PO (as oral suspension) is a suggested dose range from pharmacokinetic data and pediatric reviews. Average doses were 1.25 mg/day PO (at roughly 0.6 mg/kg/day), and 2.5 mg/day PO (at roughly 1.2 mg/kg/day).

    For the healing of duodenal ulcer†.
    Oral dosage
    Adults

    40 mg PO once daily after the morning meal for 2 to 4 weeks. NOTE: The safe and effective use of pantoprazole for long-term maintenance therapy (e.g., more than 16 weeks) for duodenal ulcer disease has not been established.

    For the healing of gastric ulcer†.
    Oral dosage
    Adults

    40 mg PO once daily, until healing and symptom relief occurs (e.g., for 2 to 8 weeks), has been evaluated in clinical trials. Healing of gastric ulcers with proton pump inhibitors generally takes longer than duodenal ulcers and may require 4 to 8 weeks of therapy. The safe and effective use of pantoprazole for long-term maintenance therapy (e.g., more than 16 weeks) of gastric ulcer disease has not been established.

    For Helicobacter pylori (H. pylori) eradication†.
    As part of initial clarithromycin-based therapy in adults without previous macrolide exposure in regions where clarithromycin resistance is less than 15%.
    Oral dosage
    Adults

    40 or 80 mg PO twice daily in combination with clarithromycin and either amoxicillin or metronidazole for 14 days.

    As part of initial clarithromycin-based therapy in adults with or without potential macrolide exposure or resistance.
    Oral dosage
    Adults

    40 mg PO twice daily as part of a combination therapy as a first-line treatment option. Quadruple therapy includes a proton pump inhibitor (PPI) in combination with clarithromycin, amoxicillin, and metronidazole for 10 to 14 days. Hybrid therapy includes amoxicillin plus PPI for 7 days followed by PPI in combination with clarithromycin, amoxicillin, and metronidazole for 7 days. Sequential therapy includes PPI and amoxicillin for 5 to 7 days followed by PPI in combination with clarithromycin and metronidazole for 5 to 7 days.

    As part of salvage clarithromycin-based therapy in adults who failed initial bismuth quadruple therapy.
    Oral dosage
    Adults

    40 mg PO twice daily in combination with clarithromycin, amoxicillin, and metronidazole for 10 to 14 days. For patients with a penicillin allergy, a PPI is recommended in combination with clarithromycin and metronidazole for 14 days.

    In combination with amoxicillin and metronidazole in pediatric patients.
    Oral dosage
    Children and Adolescents weighing 35 kg or more

    40 mg PO twice daily in combination with amoxicillin and metronidazole for 14 days. Triple therapy with standard-dose amoxicillin, metronidazole, and a proton pump inhibitor (PPI) is a first-line treatment option for patients infected with H. pylori strains with known susceptibility to metronidazole and resistance to clarithromycin. Triple therapy with high-dose amoxicillin, metronidazole, and a PPI is a first-line treatment option for patients infected with H. pylori strains with dual resistance to clarithromycin and metronidazole or strains with unknown susceptibility.

    Children and Adolescents weighing 25 to 34 kg

    30 mg PO twice daily in combination with amoxicillin and metronidazole for 14 days. Triple therapy with standard-dose amoxicillin, metronidazole, and a proton pump inhibitor (PPI) is a first-line treatment option for patients infected with H. pylori strains with known susceptibility to metronidazole and resistance to clarithromycin. Triple therapy with high-dose amoxicillin, metronidazole, and a PPI is a first-line treatment option for patients infected with H. pylori strains with dual resistance to clarithromycin and metronidazole or strains with unknown susceptibility.

    Children weighing 15 to 24 kg

    20 mg PO twice daily in combination with amoxicillin and metronidazole for 14 days. Triple therapy with standard-dose amoxicillin, metronidazole, and a proton pump inhibitor (PPI) is a first-line treatment option for patients infected with H. pylori strains with known susceptibility to metronidazole and resistance to clarithromycin. Triple therapy with high-dose amoxicillin, metronidazole, and a PPI is a first-line treatment option for patients infected with H. pylori strains with dual resistance to clarithromycin and metronidazole or strains with unknown susceptibility.

    In combination with amoxicillin and clarithromycin in pediatric patients.
    Oral dosage
    Children and Adolescents weighing 35 kg or more

    40 mg PO twice daily in combination with amoxicillin and clarithromycin for 14 days. Triple therapy with standard-dose amoxicillin, clarithromycin, and a proton pump inhibitor is a first-line treatment option for patients infected with fully susceptible H. pylori strains or strains susceptible to clarithromycin but resistant to metronidazole. In cases of penicillin allergy, use metronidazole in place of amoxicillin for patients infected with fully susceptible strains.

    Children and Adolescents weighing 25 to 34 kg

    30 mg PO twice daily in combination with amoxicillin and clarithromycin for 14 days. Triple therapy with standard-dose amoxicillin, clarithromycin, and a proton pump inhibitor is a first-line treatment option for patients infected with fully susceptible H. pylori strains or strains susceptible to clarithromycin but resistant to metronidazole. In cases of penicillin allergy, use metronidazole in place of amoxicillin for patients infected with fully susceptible strains.

    Children weighing 15 to 24 kg

    20 mg PO twice daily in combination with amoxicillin and clarithromycin for 14 days. Triple therapy with standard-dose amoxicillin, clarithromycin, and a proton pump inhibitor is a first-line treatment option for patients infected with fully susceptible H. pylori strains or strains susceptible to clarithromycin but resistant to metronidazole. In cases of penicillin allergy, use metronidazole in place of amoxicillin for patients infected with fully susceptible strains.

    As part of a sequential therapy regimen in pediatric patients.
    Oral dosage
    Children and Adolescents weighing 35 kg or more

    40 mg PO twice daily for 10 days. Use in combination with amoxicillin for days 1 through 5, and then clarithromycin and metronidazole for days 6 through 10. Sequential therapy is a first-line treatment option for patients infected with fully susceptible H. pylori strains. Sequential therapy is not recommended if susceptibility testing is unavailable.

    Children and Adolescents weighing 25 to 34 kg

    30 mg PO twice daily for 10 days. Use in combination with amoxicillin for days 1 through 5, and then clarithromycin and metronidazole for days 6 through 10. Sequential therapy is a first-line treatment option for patients infected with fully susceptible H. pylori strains. Sequential therapy is not recommended if susceptibility testing is unavailable.

    Children weighing 15 to 24 kg

    20 mg PO twice daily for 10 days. Use in combination with amoxicillin for days 1 through 5, and then clarithromycin and metronidazole for days 6 through 10. Sequential therapy is a first-line treatment option for patients infected with fully susceptible H. pylori strains. Sequential therapy is not recommended if susceptibility testing is unavailable.

    As part of a quadruple therapy regimen in pediatric patients.
    Oral dosage
    Children and Adolescents weighing 35 kg or more

    40 mg PO twice daily in combination with amoxicillin, metronidazole, and clarithromycin for 14 days. Concomitant quadruple therapy with amoxicillin, metronidazole, clarithromycin, and a proton pump inhibitor is a first-line treatment option for patients infected with H. pylori strains with dual resistance to clarithromycin and metronidazole or strains with unknown susceptibility

    Children and Adolescents weighing 25 to 34 kg

    30 mg PO twice daily in combination with amoxicillin, metronidazole, and clarithromycin for 14 days. Concomitant quadruple therapy with amoxicillin, metronidazole, clarithromycin, and a proton pump inhibitor is a first-line treatment option for patients infected with H. pylori strains with dual resistance to clarithromycin and metronidazole or strains with unknown susceptibility.

    Children weighing 15 to 24 kg

    20 mg PO twice daily in combination with amoxicillin, metronidazole, and clarithromycin for 14 days. Concomitant quadruple therapy with amoxicillin, metronidazole, clarithromycin, and a proton pump inhibitor is a first-line treatment option for patients infected with H. pylori strains with dual resistance to clarithromycin and metronidazole or strains with unknown susceptibility.

    As part of levofloxacin-based initial therapy in adults.
    Oral dosage
    Adults

    40 or 80 mg PO twice daily as part of combination therapy as a first-line treatment option. Triple therapy includes pantoprazole 40 mg PO twice daily in combination with levofloxacin and amoxicillin for 10 to 14 days. Sequential therapy includes pantoprazole 40 or 80 mg PO twice daily in combination with amoxicillin for 5 to 7 days followed by pantoprazole 40 mg PO twice daily in combination with levofloxacin and a nitroimidazole for 5 to 7 days. Quadruple therapy includes pantoprazole 80 mg PO once daily in combination with levofloxacin, nitazoxanide, and doxycycline for 7 to 10 days.

    As part of levofloxacin-based salvage therapy in adults.
    Oral dosage
    Adults

    40 mg PO twice daily in combination with levofloxacin and amoxicillin for 14 days. Guidelines recommend this triple therapy in patients who have failed clarithromycin-triple or bismuth-quadruple initial therapies and without previous quinolone exposure. Levofloxacin in combination with metronidazole and a PPI for 14 days could be considered for patients with a penicillin allergy who have failed prior bismuth quadruple therapy.

    As part of bismuth-based initial therapy in adults.
    Oral dosage
    Adults

    40 mg PO twice daily in combination with bismuth subcitrate or subsalicylate, metronidazole, and tetracycline for 10 to 14 days is recommended as a first-line treatment option, particularly in patients with any previous macrolide exposure or a penicillin allergy.

    As part of rifabutin-based salvage therapy in adults.
    Oral dosage
    Adults

    40 mg PO twice daily in combination with rifabutin and amoxicillin for 10 days.

    As part of high-dose dual salvage therapy in adults.
    Oral dosage
    Adults

    40 or 80 mg PO 3 or 4 times daily in combination with high-dose amoxicillin for 14 days. A high-dose proton pump inhibitor in combination with metronidazole may be considered in patients with prior quinolone exposure and a penicillin allergy who have failed initial bismuth quadruple therapy.

    As part of bismuth-based quadruple salvage therapy in adults.
    Oral dosage
    Adults

    40 mg PO twice daily in combination with bismuth subcitrate or subsalicylate, tetracycline, and metronidazole for 14 days is recommended particularly in patients failing clarithromycin triple therapy. A subsequent repeat course of bismuth quadruple therapy may be considered after failed prior bismuth quadruple therapy.

    For NSAID-induced ulcer prophylaxis†.
    Oral dosage
    Adults

    40 mg PO once daily has been studied. Patients (receiving chronic NSAID therapy for rheumatoid conditions) had either normal GI mucosa or endoscopically confirmed mucosal changes or ulcers (Lanza classification grade 0, 1, or 2) at baseline. Patients were randomized to either pantoprazole 40 mg PO once daily or placebo. The primary end point of the study was the incidence of gastric or duodenal ulcers after 4 and 12 weeks of treatment. In patients with normal GI mucosa (Lanza grade 0) at baseline, 82% (CI, 70%—94%) of those receiving pantoprazole were in remission vs. 55% (CI, 33%—77%) with placebo at 12 weeks, a statistically significant difference. In all patients (Lanza grade 0, 1, and 2) with GI lesions at baseline, remission was achieved in 72% of those receiving pantoprazole vs. 59% of the placebo group.

    For stress gastritis prophylaxis† in critically-ill patients.
    Intravenous dosage
    Adults

    40 mg IV once daily; some studies suggest more frequent dosing may be more effective.[55365] [55367] [55651] The optimal dose and duration of treatment has not been established. A usual dose of 40 mg/day led to an upper GI bleed in 3 of 95 mechanically ventilated patients in 1 retrospective study; thus, higher pantoprazole doses (e.g., increased doses and more frequent intervals of dosing) may be needed to prevent stress ulceration.[55363] [55366] In another study, after 2 days of pantoprazole, the mean time that gastric aspirates were pH of 4 or higher was 67.5% +/- 34.4% with 40 mg/day and was 85.7% +/- 21.5% with 80 mg every 8 hours.[55367] For those patients with risk factors qualifying them for stress ulcer prophylaxis, the H2 antagonists, cytoprotective agents, and some PPIs are adequate choices. Optimum duration is unclear, but it is reasonable to provide therapy while risk factors are present, the patient is in a critical care unit, or for at least 1 week after onset of critical illness.[55364] [55365]

    Infants, Children, and Adolescents

    Data are limited; optimal dosing and safety have not been established. 40 mg/1.73 m2/day IV infusion once daily was the initial dose used in patients older than 1 month in a small pharmacokinetic/pharmacodynamic study (n = 20; age range: 10 days to 16.4 years). The initial dosage regimen was extrapolated from the recommended adult dose scaled to body surface area. The median effective dose for all patients was 41.8 mg/1.73 m2/day (range: 19.9 to 80 mg) or approximately 1.1 mg/kg/day (range: 0.5 to 2 mg/kg/day). Max: 80 mg/1.73 m2/day (approximately 2 mg/kg/day) was allowed for patients with inadequate gastric acid suppression. The authors concluded the data best predicted suggested dosing for pediatric patients aged 1 month to 5 years. More studies are needed to confirm optimal dosing regimens. Very few adolescents were included in the study sample.[54684]

    Neonates

    Data are very limited in neonates; optimal dosing and safety have not been established. 20 mg/1.73 m2/day IV infusion once daily (approximately 0.5 mg/kg/day) was the initial neonatal dose used in a small pharmacokinetic/pharmacodynamic study (n = 20; age range: 10 days to 16.4 years). The initial dosage regimen was extrapolated from the recommended adult dose scaled to body surface area. The median effective dose for all patients was 41.8 mg/1.73 m2/day (range: 19.9 to 80 mg) or approximately 1.1 mg/kg/day (range: 0.5 to 2 mg/kg/day). Max: 80 mg/1.73 m2/day (approximately 2 mg/kg/day) was allowed for patients with inadequate gastric acid suppression. The authors concluded the data best predicted suggested dosing for pediatric patients aged 1 month to 5 years. More studies are needed to confirm optimal dosing regimens. Very few neonates were included in the study sample.[54684]

    Oral dosage
    Adults

    40 mg PO once daily; some studies suggest more frequent dosing may be more effective.[55365] [55367] [55651] The optimal dose and duration of treatment has not been established. A usual dose of 40 mg/day led to an upper GI bleed in 3 of 95 mechanically ventilated patients in 1 retrospective study; thus, higher pantoprazole doses (e.g., increased doses and more frequent intervals of dosing) may be needed to prevent stress ulceration.[55363] [55366] In another study, after 2 days of pantoprazole, the mean time that gastric aspirates were pH of 4 or higher was 67.5% +/- 34.4% with 40 mg/day and was 85.7% +/- 21.5% with 80 mg every 8 hours.[55367] For those patients with risk factors qualifying them for stress ulcer prophylaxis, the H2 antagonists, cytoprotective agents, and some PPIs are adequate choices. Optimum duration is unclear, but it is reasonable to provide therapy while risk factors are present, the patient is in a critical care unit, or for at least 1 week after onset of critical illness.[55364] [55365]

    For the treatment of eosinophilic esophagitis (EoE)†.
    Oral dosage
    Adults

    A dosage range of 20 to 40 mg PO twice daily 30 to 60 minutes before meals has been suggested; treat for up to 8 weeks and continue until the time of the follow-up endoscopy and biopsy. The guidelines support the use of PPI therapy for EoE based on reports of reductions in histologic features of disease from 42% in observational studies.

    For upper GI rebleeding prophylaxis after therapeutic endoscopy†.
    Intravenous dosage (continuous IV infusion regimen)
    Adults

    80 mg IV bolus infusion over 30 minutes, followed by 8 mg/hour continuous infusion for 72 hours is recommended after successful endoscopic hemostasis in patients with active bleeding, a non-bleeding visible vessel, or an adherent clot. Patients with ulcers that have flat pigmented spots or clean bases upon endoscopy can instead receive standard, once daily, oral PPI therapy. Pre-endoscopic IV PPI therapy, may be considered to downstage the endoscopic lesion. If endoscopic therapy is to be delayed or cannot be performed, IV PPI therapy is recommended to reduce further bleeding. Patients with an underlying etiology for which a PPI may be beneficial (e.g., peptic ulcers, erosions) should be discharged with a prescription for standard, once daily, oral PPI therapy; otherwise, discontinue the PPI before discharge.

    †Indicates off-label use

    MAXIMUM DOSAGE

    Adults

    80 mg/day PO/IV for most indications; up to 160 mg/day PO has been used off-label for H. pylori eradication; up to 240 mg/day PO/IV for Zollinger-Ellison syndrome.

    Geriatric

    80 mg/day PO/IV for most indications; up to 160 mg/day PO has been used off-label for H. pylori eradication; up to 240 mg/day PO/IV for Zollinger-Ellison syndrome.

    Adolescents

    weight 40 kg or more: 40 mg/day PO is FDA-approved maximum; however, up to 80 mg/day PO has been used off-label for H. pylori eradication; limited data available for off-label IV use.
    weight less than 40 kg: 20 mg/day PO is FDA-approved maximum; however, up to 2.5 mg/kg/day (Max: 80 mg/day) PO has been used off-label for H. pylori eradication; limited data available for off-label IV use.

    Children

    5 to 12 years and weight 40 kg or more: 40 mg/day PO is FDA-approved maximum; however, up to 80 mg/day PO has been used off-label for H. pylori eradication; limited data available for off-label IV use.
    5 to 12 years and weight 15 to 39 kg: 20 mg/day PO is FDA-approved maximum; however, up to 2.5 mg/kg/day (Max: 80 mg/day) PO has been used off-label for H. pylori eradication; limited data available for off-label IV use.
    1 to 4 years or weight less than 15 kg: up to 2.5 mg/kg/day PO has been used off-label; limited data available for off-label IV use.

    Infants

    1.2 mg/kg/day PO off-label; limited data available for off-label IV use.

    Neonates

    1.2 mg/kg/day PO suggested by limited off-label data; very limited data available for off-label IV use.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    No dosage adjustment is necessary. Use pantoprazole with caution in patients with severe hepatic disease or impairment; sufficient data are lacking in this subgroup.

    Renal Impairment

    No dosage adjustment is necessary.
     
    Intermittent hemodialysis
    No dosage adjustment is necessary. Pantoprazole is not removed by hemodialysis.

    ADMINISTRATION

    Oral Administration
    Oral Solid Formulations

    Delayed release tablets: According to the manufacturer, administer without regard to meals , however guidelines suggest to administer PPIs on an empty stomach, 30—60 minutes before meals. Swallow whole. Do not chew, crush, or split. If patient is unable to swallow a 40-mg tablet, then two 20-mg tablets may be prescribed.

    Oral Liquid Formulations

    Delayed release oral suspension granules:
    Do not divide the suspension packet to obtain a smaller dosage.
    Patients should not crush or chew the granules.
    The granules may be sprinkled on 5 ml (one teaspoonful) of cool applesauce; administer within 10 minutes. Alternatively, granules may be mixed in a small cup with 5 ml (one teaspoonful) of apple juice; stir for 5 seconds and administer, then rinse the container with additional apple juice and administer, to assure delivery of the full dose. Do not prepare using any other liquids or foods, including water.
    Nasogastric (NG) tube administration: Empty the contents of one packet or oral suspension granules into the barrel of a 60 ml (2 ounce) catheter tip syringe (with the plunger removed) that is connected to a 16 French (or larger) nasogastric tube. Add 10 ml of apple juice and gently tap and/or shake the barrel of the syringe to help empty the syringe into the tube. Add an additional 10 ml of apple juice and gently tap and/or shake the barrel of the syringe to rinse the syringe and the nasogastric tube. Rinse with additional apple juice at least twice or until the syringe is clear of granules.

    Extemporaneous Compounding-Oral

    Extemporaneous 2 mg/ml Pantoprazole Oral Suspension Preparation:
    NOTE: The extemporaneous preparation of pantoprazole oral suspension is not approved by the FDA.
     
    A compounded oral suspension may be made with pantoprazole tablets, sterile water for irrigation USP, and sodium bicarbonate powder.
    Count out 20 of the Protonix 40-mg oral tablets.
    Remove the Protonix imprint from all of the tablets by gently rubbing the tablets on a paper towel dampened with ethanol. Let the tablets air dry.
    Crush and triturate the tablets in a mortar and reduce to a coarse powder.
    Transfer crushed tablets to a 600 ml beaker, and add 340 ml sterile water irrigation, USP.
    Place beaker on a magnetic stirrer.
    While stirring, add 16.8 g of sodium bicarbonate powder and stir for about 20 minutes until the tablet remnants have disintegrated and coating has dissolved.
    While stirring, add another 16.8 g of sodium bicarbonate powder and stir for about 5 minutes until powder has dissolved.
    Add enough sterile water for irrigation USP to bring the final volume to 400 ml. Mix well.
    Final concentration of suspension: pantoprazole 2 mg/ml.
    Transfer to amber-colored bottle.
    Shake well prior to each use.
    For accurate dosing, measure dosage using an oral syringe or other calibrated device.
    Storage: Suspension is stable for 62 days when stored under refrigeration at 35.6—46.4 degrees F (2—8 degrees C) and protected from light. Label with "shake well".

    Injectable Administration

    Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit.
    Pantoprazole injection is for intravenous use only; do not administer intramuscularly or by subcutaneous injection.

    Intravenous Administration

    Administer pantoprazole IV either through a dedicated IV line or a Y-site. When administered via a Y-site, immediately stop use if a precipitation or discoloration occurs.
    Pantoprazole is incompatible with midazolam during Y-site coadministration and pantoprazole may be incompatible with IV solutions containing zinc salts.
    Do not use spiked IV system adaptors with Protonix IV vials as glass vial breakage may occur.
     
    Slow IV Push:
    Dilute each 40-mg vial with 10 ml NS. Each vial will have a final concentration of 4 mg/ml.
    Flush the IV line with D5W, NS, or LR before and after each dose.
    Infuse slowly over at least 2 minutes. Do not give by fast IV push.
    Do not administer with other IV fluids or medications.
    Storage of reconstituted vials: According to the manufacturer, the 4 mg/ml diluted vial may be stored for up to 24 hours at room temperature prior to administration. Reconstituted vials do not require protection from light. Do not freeze. One study concluded that the 4 mg/ml reconstituted solution is stable in polypropylene syringes for at least 96 hours when stored under refrigeration (3—5 degrees C) or at room temperature (23—25 degrees C). To minimize the potential for solution discoloration, refrigerate if stored beyond 48 hours.
     
    Intermittent IV Infusion:
    Dilute each 40 mg vial with 10 ml NS.
    Prior to infusion, the reconstituted vial should be further admixed with 100 ml (for one vial) or 80 ml (for 2 vials) of D5W, NS, or LR to a final infusion concentration of approximately 0.4 mg/ml or 0.8 mg/ml, respectively.
    Flush the IV line with D5W, NS, or LR before and after each dose.
    Infuse over approximately 15 minutes, not to exceed a rate of 7 ml/min.
    Do not administer with other IV fluids or medications.
    Storage of IV infusions: The IV infusion (0.4 mg/ml or 0.8 mg/ml) may be stored at room temperature and must be used within 24 hours from the time of initial reconstitution.
     
    Continuous intravenous infusion:
    NOTE: Pantoprazole is not approved by the FDA to be administered by continuous IV infusion, but is under FDA review. Several adult consensus guidelines recommend a pantoprazole 80 mg IV infusion bolus, followed by 8 mg/h continuous infusion in the treatment of select indications.
    Dilute each 40-mg vial with 10 ml NS. Each vial will have a final concentration of 4 mg/ml.
    Prior to infusion, two reconstituted vials (80 mg/20 ml total) should be further admixed with 80 ml of NS, to a final pantoprazole infusion concentration of approximately 0.8 mg/ml.
    For the 80 mg IV bolus, give as an IV infusion over a period of 30 minutes.
    Follow the IV bolus with the continuous infusion.
    For continuous infusion, give the 80 mg/100 ml NS the reconstituted solution (80 mg diluted in 100 ml NS injection) should be given as an IV infusion at a rate of 8 mg/h (i.e., 10 ml/hr); change infusion bag as needed to provide continuous infusion for the duration of treatment.
    Storage of IV infusions: The IV infusion (0.8 mg/ml) may be stored at room temperature and must be used within 24 hours from the time of initial reconstitution.

    STORAGE

    Protonix:
    - Store between 68 to 77 degrees F, excursions permitted 59 to 86 degrees F

    CONTRAINDICATIONS / PRECAUTIONS

    Proton pump inhibitors (PPIs) hypersensitivity

    Oral pantoprazole is contraindicated in patients with known hypersensitivity to pantoprazole or other substituted benzimidazoles such as omeprazole or lansoprazole (i.e., known proton pump inhibitors (PPIs) hypersensitivity). Intravenous pantoprazole is contraindicated in patients with known pantoprazole hypersensitivity ; however, the same warnings regarding PPI cross-sensitivity apply clinically. There has been evidence of PPI cross-sensitivity in some sensitive individuals in literature reports. Although rare, occasionally such reactions can be serious (i.e., result in anaphylaxis, angioedema, or acute interstitial nephritis).

    Hepatic disease

    Use pantoprazole with caution in patients with severe hepatic disease or impairment; sufficient data are lacking in this subgroup. Data are scant in patients with severe hepatic impairment; the manufacturer reports modest accumulation (<= 21%) of pantoprazole during once daily dosing in these patients. However, that manufacturer recommends that no dosage adjustment is needed in patients with hepatic impairment.

    Gastric cancer, new primary malignancy

    Gastric polyps/fundic gland polyps have been reported during postmarketing surveillance. Patients are usually asymptomatic and fundic gland polyps are identified incidentally on endoscopy. The risk of fundic gland polyps increases with long term proton pump inhibitor (PPI) use, especially beyond one year. Use the shortest duration of PPI therapy appropriate to treat specific condition. Symptomatic response to therapy with pantoprazole does not preclude the presence of gastric cancer or other malignancy. In addition, maintenance of healing of erosive esophagitis and reduction of GERD episodes may require prolonged administration of pantoprazole. In long-term rodent studies, pantoprazole was associated with new primary malignancy and caused rare types of gastrointestinal tumors. The clinical significance of these findings in humans is uncertain.

    Diarrhea, pseudomembranous colitis

    The use of gastric acid suppressive therapy, such as PPIs, may increase the risk of enteric infection by encouraging the growth of gut microflora and increasing susceptibility to organisms including Salmonella, Campylobacter jejuni, Escherichia coli, Clostridium difficile, Vibrio cholerae, and Listeria. A systematic review examined the relationship between PPI use and susceptibility to enteric infections and found enhanced susceptibility for Salmonella infections (adjusted RR range: 4.2—8.3 in 2 studies), Campylobacter (RR 3.5—11.7 in 4 studies) and C. difficile infections (RR 1.2—5.0 in 17 out of 27 studies). In particular, PPI use has been linked to an increased risk of Clostridium difficile–associated diarrhea (CDAD). A diagnosis of CDAD should be considered for patients taking PPIs who develop diarrhea that does not improve. Advise patients to seek immediate care from a healthcare professional if they experience watery stool that does not go away, abdominal pain, and fever while taking PPIs. Patients should use the lowest dose and shortest duration of PPI therapy appropriate to the condition being treated. The PPIs, including pantoprazole, are recommended for use in combination with certain antibiotics to eradicate Helicobacter pylori. Pseudomembranous colitis has been reported with nearly all antibacterial agents and may range in severity from mild to life-threatening. Therefore, it is important to consider this diagnosis in patients who present with diarrhea subsequent to the administration of antibacterial agents in combination with PPIs.

    Vitamin B12 deficiency

    Daily treatment with gastric acid-suppressing medication such as pantoprazole over a long period of time (e.g., generally >= 2—3 years) may lead to malabsorption of cyanocobalamin and vitamin B12 deficiency. Cases of cyanocobalamin deficiency occurring with acid-suppression therapy have been reported in the literature. One large case-controlled study compared patients with and without an incident diagnosis of vitamin B12 deficiency. A correlation was demonstrated between vitamin B12 deficiency and gastric acid-suppression therapy of > 2 years duration [i.e., proton pump inhibitor (PPI), H2-receptor antagonist]. In addition, a dose-dependant relationship was evident, as larger daily PPI pill counts were more strongly associated with vitamin B12 deficiency. The possibility of cyanocobalamin deficiency should, therefore, be considered if clinical symptoms are observed.

    Zinc deficiency

    The intravenous formulation of pantoprazole contains edetate disodium (the salt form of EDTA), a potent chelator of metal ions including zinc. Clinicians should consider zinc supplementation in patients treated with intravenous pantoprazole who are prone to zinc deficiency. Caution should be used when other EDTA containing products are also co-administered intravenously.

    Bone fractures, osteopenia, osteoporosis

    Use proton pump inhibitors (PPIs) in patients with or who have risk factors for osteoporosis or osteopenia cautiously. PPIs have been associated with a possible increased risk of bone fractures of the hip, wrist, and spine. Epidemiological studies have reported an increased risk of fractures with the use of PPIs; the studies compared claims data of patients treated with PPIs versus individuals who were not using PPIs. The risk of fracture was increased in patients who received high-dose (defined as multiple daily doses or doses greater than those recommended in non-prescription use), and long-term PPI therapy (a year or longer); fractures were primarily observed in adult patients 50 years of age and older. Pre-approval randomized clinical trials (RCTs) of PPIs have not found an increased risk of fractures of the hip, wrist, or spine; however, these RCTs were of shorter study duration (generally 6 months or less). When prescribing PPIs, consider whether a lower dose or shorter duration of therapy would adequately treat the patient's condition. In patients with or at risk for osteopenia or osteoporosis, manage their bone status according to current clinical practice, and ensure adequate vitamin D and calcium supplementation.

    Hypomagnesemia, long QT syndrome

    Daily treatment with a gastric acid-suppressing medication over a long period of time (e.g., 3 months to > 1 year) may lead to hypomagnesemia; cases have been reported in patients taking pantoprazole. Generally, hypomagnesemia is corrected with magnesium supplementation; however, in cases where hypomagnesemia is observed during PPI administration, discontinuation of the PPI may also be necessary. Low serum magnesium may lead to serious adverse events such as muscle spasm (tetany), seizures, and irregular heartbeat (arrhythmias). Use PPIs with caution and, if possible, avoid long-term (> 14 days) use in patients with congenital long QT syndrome, as they may be at higher risk for arrhythmias. In pediatric patients, irregular heartbeat may cause fatigue, upset stomach, dizziness, and lightheadedness. For patients expected to be on PPI therapy for a prolonged period of time, it is prudent for clinicians to obtain serum magnesium concentrations prior to initiating PPI therapy as well as throughout treatment. Patients on concomitant medications such as digoxin or diuretics (see Interactions) may also require periodic monitoring of serum magnesium.

    Rebound acid hypersecretion

    Studies suggest that long-term PPI therapy is associated with a temporal increase in gastric acid secretion shortly following treatment discontinuation. A similar and well established response has been noted after withdrawal of H2 blockers. Profound gastric acid suppression during PPI therapy leads to a drug-induced reflex hypergastrinemia and subsequent rebound acid hypersecretion. In this hypersecretory state, enterochromaffin-like cell hypertrophy also results in a temporal increase in serum chromogranin A (CgA) levels. It is unclear, however, if this hypersecretory reflex results in clinically significant effects in patients on or attempting to discontinue PPI therapy. A clinically significant effect may lead to gastric acid-related symptoms upon PPI withdrawal and possible therapy dependence. Studies in healthy subjects (H. pylori negative) as well as GERD patients, present conflicting data regarding whether PPI therapy beyond 8-weeks is associated with rebound acid hypersecretion and associated dyspeptic symptoms shortly following PPI cessation. Until more consistent study results shed light on this possible effect, it is prudent to follow current treatment guidelines employing the lowest effective dose, for the shortest duration of time in symptomatic patients. For patients requiring maintenance therapy, consider on demand or intermittent PPI therapy, step down therapy to an H2 blocker, and regularly assess the need for continued gastric suppressive therapy.

    Pregnancy

    There are no adequate and well-controlled studies of pantoprazole in pregnant women. Although data from published observational studies in humans failed to demonstrate an association of adverse pregnancy-related outcomes and pantoprazole use, methodological limitations of these observational studies cannot definitely establish or exclude any drug-associated risk during pregnancy. Animal reproductive studies have been conducted in rats and rabbits using doses up to 88 and 16 times, respectively, that of humans based on body surface area; there was no evidence of fetal harm. It is not known if pantoprazole crosses the human placenta, although another PPI with a similar molecular weight, omeprazole, is known to cross the human placenta. In one study, pregnancy outcomes were reported with exposure to omeprazole (n = 295), lansoprazole (n = 62), and pantoprazole (n = 53). Compared to non-exposed control groups, there was no difference in the rate of major malformations with the use of pantoprazole (RR 0.55, 95% CI 0.8 to 3.95). However, there is a possibility that the true risk of malformation was missed due to study design and/or sample size. In another study, there was no significant increase in major birth defects during analysis of first trimester exposure to pantoprazole in 549 live births. In addition, a meta-analysis that compared 1,530 pregnant women exposed to PPIs in at least the first trimester with 133,410 unexposed pregnant women showed no significant increases in risk for congenital malformations or spontaneous abortion with exposure to PPIs (for major malformations OR = 1.12 [95% CI 0.86 to 1.45] and for spontaneous abortions OR = 1.29 [95% CI 0.84 to 1.97]). Pantoprazole likely represents a low risk in pregnancy, but should be used during pregnancy only when clearly needed. In 2009, a population-based observational cohort study explored a possible link between gastric acid suppressive therapy (e.g., proton pump inhibitors) during pregnancy and a diagnosis of allergic disease or a prescription for asthma or allergy medications in the exposed child. Among the cohort (n = 585,716), 1% of children exposed to gastric acid suppressive drugs in pregnancy received a diagnosis of allergic diease. For developing allergy or asthma, an increased OR of 1.43 and 1.51, respectively, were observed regardless of drug used, time of exposure during pregnancy, and maternal history of disease. Proposed possible mechanisms for a link include: (1) exposure to increased amounts of allergens could cause sensitization to digestion-labile antigens in the fetus; (2) the maternal Th2 cytokine pattern could promote an allergy prone phenotype in the fetus; (3) maternal allergen specific immunoglobulin could cross the placenta and sensitize fetal immune cells to food and airborne allergens. Study limitations were present and confirmation of results are necessary before further conclusions can be drawn from this data. Risk versus benefit should be considered prior to use.

    Breast-feeding

    According to the manufacturer, pantoprazole and its metabolites are excreted in the milk of rats. Pantoprazole excretion in human milk has also been detected, but the clinical relevance of this finding is unknown. Because of the potential for tumorigenicity and carcinogenicity found in animal studies, the manufacturer suggests that a decision should be made whether to discontinue nursing or pantoprazole, taking into account the benefit of the drug to the mother. In one study, a partially breast-feeding mother was 10 months postpartum and received a single 40 mg dose of oral pantoprazole. Although small quantities of the drug were present in breast milk at 2 and 4 hours after the dose (36 mcg/L and 24 mcg/L, respectively), the drug was undetectable in expressed milk 6, 8, and 24 hours after the dose. Using the above case, authors estimated that a fully breast fed infant would receive 0.14% of the maternal weight-adjusted dosage. Because of limited human data and the potential for serious adverse reactions from pantoprazole in the breast-fed infant (including suppression of gastric acid secretion), pantoprazole should be used with caution in breast-feeding women. Alternative therapies for consideration include antacids and H2 blockers.

    Infants, neonates

    The safety and efficacy of pantoprazole have not been conclusively demonstrated in neonates or infants < 1 year of age; more data are needed. The lack of commercial availability of age-appropriate oral dose forms may limit the use of pantoprazole orally in pediatric patients < 5 years of age.

    Laboratory test interference

    Administration of pantoprazole may result in laboratory test interference, specifically serum chromogranin A (CgA) tests for neuroendocrine tumors, urine tests for tetrahydrocannabinol (THC), secretin stimulation tests, and diagnostic tests for Helicobacter pylori. Gastric acid suppression may increase serum CgA. Increased CgA concentrations may cause false positive results in diagnostic investigations for neuroendocrine tumors. To prevent this interference, temporarily stop pantoprazole at least 14 days before assessing CgA concentrations and consider repeating the test if initial concentrations are high. If serial tests are performed, ensure the same commercial laboratory is used as reference ranges may vary. Reports have suggested use of proton pump inhibitors (PPIs) may cause false positive urine screening tests for THC. If a PPI-induced false positive urine screen is suspected, confirm the positive results using an alternative testing method. PPIs may also cause a hyper-response in gastrin secretion to the secretin stimulation test, falsely suggesting gastrinoma. Health care providers are advised to temporarily stop pantoprazole at least 14 days prior to performing a secretin stimulation test to allow gastrin concentrations to return to baseline. Preparations that combine PPIs with antimicrobials and bismuth are known to suppress H. pylori; thus, ingestion of these preparations within 4 weeks of performing diagnostic tests for H. pylori may lead to false negative results. At a minimum, instruct the patient to avoid the use of pantoprazole in the 1 to 2 weeks prior to the test and the use of antimicrobials and bismuth preparations in the 4 weeks prior to the test.

    Systemic lupus erythematosus (SLE)

    Use with caution in patients with a history of systemic lupus erythematosus (SLE) as pantoprazole has been reported to activate or exacerbate SLE.

    Geriatric

    According to the Beers Criteria, proton pump inhibitors (PPIs) are considered potentially inappropriate medications (PIMs) for use in geriatric patients due to the risk of Clostridium difficile infection and bone loss/fractures. Avoid use for more than 8 weeks except for high-risk patients (e.g., oral corticosteroids or chronic NSAID use), erosive esophagitis, Barrett's esophagitis, pathological hypersecretory condition, or need for maintenance treatment (e.g., due to failure of drug discontinuation trial or inadequate response to H-2 blockers).[63923] The federal Omnibus Budget Reconciliation Act (OBRA) regulates medication use in residents of long-term care facilities (LTCFs); the indication for PPI use should be based on clinical symptoms and/or endoscopic findings. During the use of PPIs to treat or prevent NSAID-induced gastritis or esophagitis, there should be documentation that analgesics with less GI toxicity than NSAIDs have been tried or were not indicated. If a PPI is used for longer than 12 weeks, the clinical rationale and documentation for continued use should support an underlying chronic disease (e.g., GERD) or risk factors (e.g., chronic NSAID use). Monitor for adverse events, including an increased risk of Clostridium difficile colitis.[60742]

    ADVERSE REACTIONS

    Severe

    GI bleeding / Delayed / 0-1.0
    cholecystitis / Delayed / 0-1.0
    seizures / Delayed / 0-1.0
    myocardial infarction / Delayed / 0-1.0
    arrhythmia exacerbation / Early / 0-1.0
    atrial fibrillation / Early / 0-1.0
    heart failure / Delayed / 0-1.0
    thrombosis / Delayed / 0-1.0
    atrial flutter / Early / 0-1.0
    pancreatitis / Delayed / Incidence not known
    hepatic failure / Delayed / Incidence not known
    agranulocytosis / Delayed / Incidence not known
    pancytopenia / Delayed / Incidence not known
    anaphylactoid reactions / Rapid / Incidence not known
    toxic epidermal necrolysis / Delayed / Incidence not known
    angioedema / Rapid / Incidence not known
    anaphylactic shock / Rapid / Incidence not known
    erythema multiforme / Delayed / Incidence not known
    Stevens-Johnson syndrome / Delayed / Incidence not known
    interstitial nephritis / Delayed / Incidence not known
    lupus-like symptoms / Delayed / Incidence not known
    rhabdomyolysis / Delayed / Incidence not known
    bone fractures / Delayed / Incidence not known

    Moderate

    constipation / Delayed / 0-4.0
    elevated hepatic enzymes / Delayed / 0-4.0
    edema / Delayed / 0-4.0
    hypertriglyceridemia / Delayed / 0-4.0
    hepatitis / Delayed / 0-2.0
    leukopenia / Delayed / 0-2.0
    thrombocytopenia / Delayed / 0-2.0
    depression / Delayed / 0-2.0
    cholelithiasis / Delayed / 0-1.0
    hyperbilirubinemia / Delayed / 0-1.0
    anemia / Delayed / 0-1.0
    eosinophilia / Delayed / 0-1.0
    palpitations / Early / 0-1.0
    sinus tachycardia / Rapid / 0-1.0
    bleeding / Early / 0-1.0
    peripheral vasodilation / Rapid / 0-1.0
    angina / Early / 0-1.0
    hypotension / Rapid / 0-1.0
    migraine / Early / 0-1.0
    hypertension / Early / 0-1.0
    jaundice / Delayed / Incidence not known
    pernicious anemia / Delayed / Incidence not known
    vitamin B12 deficiency / Delayed / Incidence not known
    blurred vision / Early / Incidence not known
    confusion / Early / Incidence not known
    hallucinations / Early / Incidence not known
    phlebitis / Rapid / Incidence not known
    hypomagnesemia / Delayed / Incidence not known
    hyponatremia / Delayed / Incidence not known
    pseudomembranous colitis / Delayed / Incidence not known

    Mild

    headache / Early / 1.0-12.2
    nausea / Early / 1.0-7.0
    abdominal pain / Early / 1.0-6.2
    flatulence / Early / 0-4.0
    dizziness / Early / 0-4.0
    vertigo / Early / 0-4.0
    urticaria / Rapid / 0-4.0
    myalgia / Early / 0-4.0
    arthralgia / Delayed / 0-4.0
    xerostomia / Early / 0-2.0
    fever / Early / 0-2.0
    photosensitivity / Delayed / 0-2.0
    pruritus / Rapid / 0-2.0
    ecchymosis / Delayed / 0-1.0
    leukocytosis / Delayed / 0-1.0
    syncope / Early / 0-1.0
    dyspepsia / Early / 1.0
    vomiting / Early / 4.0
    infection / Delayed / 4.0
    rhinitis / Early / 1.0
    insomnia / Early / 1.0
    injection site reaction / Rapid / 1.0
    rash / Early / 2.0
    diarrhea / Early / 4.0
    gastric polyps / Delayed / Incidence not known
    weight loss / Delayed / Incidence not known
    weight gain / Delayed / Incidence not known
    dysgeusia / Early / Incidence not known
    asthenia / Delayed / Incidence not known
    fatigue / Early / Incidence not known
    drowsiness / Early / Incidence not known
    malaise / Early / Incidence not known
    tinnitus / Delayed / Incidence not known

    DRUG INTERACTIONS

    Acalabrutinib: (Major) Avoid the concomitant use of acalabrutinib and proton pump inhibitors (PPI), such as pantoprazole; decreased acalabrutinib exposure may occur resulting in decreased acalabrutinib effectiveness. Consider using an antacid or H2-blocker if acid suppression therapy is needed. Separate the administration of acalabrutinib and antacids by at least 2 hours; give acalabrutinib 2 hours before a H2-blocker. Acalabrutinib solubility decreases with increasing pH values. The AUC of acalabrutinib was decreased by 43% when acalabrutinib was coadministered with another PPI for 5 days.
    Alendronate: (Moderate) Proton pump inhibitors (PPIs) are widely used and are frequently coadministered in users of oral bisphosphonates. A national register-based, open cohort study of 38,088 elderly patients suggests that those who use proton pump inhibitors in conjunction with alendronate have a dose-dependent loss of protection against hip fracture. While causality was not investigated, the dose-response relationship noted during the study suggested that PPIs may reduce oral alendronate efficacy, perhaps through an effect on absorption or other mechanism, and therefore PPIs may not be optimal agents to control gastrointestinal complaints. It is not yet clear if all bisphosphonates would exhibit a loss of efficacy when PPIs are coadministered, but the results suggest that the interaction may occur across the class.
    Alendronate; Cholecalciferol: (Moderate) Proton pump inhibitors (PPIs) are widely used and are frequently coadministered in users of oral bisphosphonates. A national register-based, open cohort study of 38,088 elderly patients suggests that those who use proton pump inhibitors in conjunction with alendronate have a dose-dependent loss of protection against hip fracture. While causality was not investigated, the dose-response relationship noted during the study suggested that PPIs may reduce oral alendronate efficacy, perhaps through an effect on absorption or other mechanism, and therefore PPIs may not be optimal agents to control gastrointestinal complaints. It is not yet clear if all bisphosphonates would exhibit a loss of efficacy when PPIs are coadministered, but the results suggest that the interaction may occur across the class.
    Aliskiren; Amlodipine; Hydrochlorothiazide, HCTZ: (Moderate) Proton pump inhibitors have been associated with hypomagnesemia. Hypomagnesemia occurs with thiazide diuretics (chlorothiazide, hydrochlorothiazide, indapamide, and metolazone). Low serum magnesium may lead to serious adverse events such as muscle spasm, seizures, and arrhythmias. Therefore, clinicians should monitor serum magnesium concentrations periodically in patients taking a PPI and diuretics concomitantly. Patients who develop hypomagnesemia may require PPI discontinuation in addition to magnesium replacement.
    Aliskiren; Hydrochlorothiazide, HCTZ: (Moderate) Proton pump inhibitors have been associated with hypomagnesemia. Hypomagnesemia occurs with thiazide diuretics (chlorothiazide, hydrochlorothiazide, indapamide, and metolazone). Low serum magnesium may lead to serious adverse events such as muscle spasm, seizures, and arrhythmias. Therefore, clinicians should monitor serum magnesium concentrations periodically in patients taking a PPI and diuretics concomitantly. Patients who develop hypomagnesemia may require PPI discontinuation in addition to magnesium replacement.
    Amiloride; Hydrochlorothiazide, HCTZ: (Moderate) Proton pump inhibitors have been associated with hypomagnesemia. Hypomagnesemia occurs with thiazide diuretics (chlorothiazide, hydrochlorothiazide, indapamide, and metolazone). Low serum magnesium may lead to serious adverse events such as muscle spasm, seizures, and arrhythmias. Therefore, clinicians should monitor serum magnesium concentrations periodically in patients taking a PPI and diuretics concomitantly. Patients who develop hypomagnesemia may require PPI discontinuation in addition to magnesium replacement.
    Amlodipine; Hydrochlorothiazide, HCTZ; Olmesartan: (Moderate) Proton pump inhibitors have been associated with hypomagnesemia. Hypomagnesemia occurs with thiazide diuretics (chlorothiazide, hydrochlorothiazide, indapamide, and metolazone). Low serum magnesium may lead to serious adverse events such as muscle spasm, seizures, and arrhythmias. Therefore, clinicians should monitor serum magnesium concentrations periodically in patients taking a PPI and diuretics concomitantly. Patients who develop hypomagnesemia may require PPI discontinuation in addition to magnesium replacement.
    Amlodipine; Hydrochlorothiazide, HCTZ; Valsartan: (Moderate) Proton pump inhibitors have been associated with hypomagnesemia. Hypomagnesemia occurs with thiazide diuretics (chlorothiazide, hydrochlorothiazide, indapamide, and metolazone). Low serum magnesium may lead to serious adverse events such as muscle spasm, seizures, and arrhythmias. Therefore, clinicians should monitor serum magnesium concentrations periodically in patients taking a PPI and diuretics concomitantly. Patients who develop hypomagnesemia may require PPI discontinuation in addition to magnesium replacement.
    Amphetamine: (Moderate) The use of proton pump inhibitors (PPIs) with amphetamine and/or dextroamphetamine therapy may change the onset of action of these amphetamines due to the increase in gastric pH. The time to maximum concentration (Tmax) of amphetamines is decreased compared to when administered alone, thus increasing amphetamine concentrations and exposure, which may be of particular significance with extended-release dosage forms. Monitor clinical response and adjust if needed. Some extended-release dosage forms of amphetamine or dextroamphetamine salts should not be given with PPIs. The concomitant use of PPIs with some extended-release dosage forms may result in amphetamine dose-dumping.
    Amphetamine; Dextroamphetamine Salts: (Moderate) The use of proton pump inhibitors (PPIs) with amphetamine and/or dextroamphetamine therapy may change the onset of action of these amphetamines due to the increase in gastric pH. The time to maximum concentration (Tmax) of amphetamines is decreased compared to when administered alone, thus increasing amphetamine concentrations and exposure, which may be of particular significance with extended-release dosage forms. Monitor clinical response and adjust if needed. Some extended-release dosage forms of amphetamine or dextroamphetamine salts should not be given with PPIs. The concomitant use of PPIs with some extended-release dosage forms may result in amphetamine dose-dumping.
    Amphetamine; Dextroamphetamine: (Moderate) The use of proton pump inhibitors (PPIs) with amphetamine and/or dextroamphetamine therapy may change the onset of action of these amphetamines due to the increase in gastric pH. The time to maximum concentration (Tmax) of amphetamines is decreased compared to when administered alone, thus increasing amphetamine concentrations and exposure, which may be of particular significance with extended-release dosage forms. Monitor clinical response and adjust if needed. Some extended-release dosage forms of amphetamine or dextroamphetamine salts should not be given with PPIs. The concomitant use of PPIs with some extended-release dosage forms may result in amphetamine dose-dumping.
    Ampicillin: (Major) Proton pump inhibitors (PPIs) have long-lasting effects on the secretion of gastric acid. For enteral ampicillin, whose bioavailability is influenced by gastric pH, the concomitant administration of PPIs can exert a significant effect on ampicillin absorption.
    Ampicillin; Sulbactam: (Major) Proton pump inhibitors (PPIs) have long-lasting effects on the secretion of gastric acid. For enteral ampicillin, whose bioavailability is influenced by gastric pH, the concomitant administration of PPIs can exert a significant effect on ampicillin absorption.
    Anticholinergics: (Moderate) The American College of Gastroenterology states that the effectiveness of proton pump inhibitors (PPIs) may be theoretically decreased if given with other antisecretory agents (e.g., anticholinergics). Proton pump inhibitors (PPIs) inhibit only actively secreting H+-pumps.
    Atazanavir: (Severe) Coadministration of proton pump inhibitors (PPIs) with atazanavir in treatment-experienced patients is contraindicated. PPIs can be used with atazanavir in treatment-naive patients under specific administration restrictions. In treatment-naive patients >= 40 kg, the PPI dose should not exceed the equivalent of omeprazole 20 mg/day, and the PPI must be administered 12 hours before atazanavir and ritonavir; use the dosage regimen of atazanavir 300 mg boosted with ritonavir 100 mg given once daily with food. While data are insufficient to recommend atazanavir dosing in children < 40 kg receiving concomitant PPIs, the same recommendations regarding timing and maximum doses of concomitant PPIs should be followed. Closely monitor patients for antiretroviral therapeutic failure and resistance development during treatment with a PPI. A randomized, open-label, multiple-dose drug interaction study of atazanavir (300 mg) with ritonavir (100 mg) coadministered with omeprazole 40 mg found a reduction in atazanavir AUC and Cmin of 76% and 78%, respectively. Additionally, after multiple doses of omeprazole (40 mg/day) and atazanavir (400 mg/day, 2 hours after omeprazole) without ritonavir, the AUC of atazanavir was decreased by 94%, Cmax by 96%, and Cmin by 95%.
    Atazanavir; Cobicistat: (Severe) Coadministration of proton pump inhibitors (PPIs) with atazanavir in treatment-experienced patients is contraindicated. PPIs can be used with atazanavir in treatment-naive patients under specific administration restrictions. In treatment-naive patients >= 40 kg, the PPI dose should not exceed the equivalent of omeprazole 20 mg/day, and the PPI must be administered 12 hours before atazanavir and ritonavir; use the dosage regimen of atazanavir 300 mg boosted with ritonavir 100 mg given once daily with food. While data are insufficient to recommend atazanavir dosing in children < 40 kg receiving concomitant PPIs, the same recommendations regarding timing and maximum doses of concomitant PPIs should be followed. Closely monitor patients for antiretroviral therapeutic failure and resistance development during treatment with a PPI. A randomized, open-label, multiple-dose drug interaction study of atazanavir (300 mg) with ritonavir (100 mg) coadministered with omeprazole 40 mg found a reduction in atazanavir AUC and Cmin of 76% and 78%, respectively. Additionally, after multiple doses of omeprazole (40 mg/day) and atazanavir (400 mg/day, 2 hours after omeprazole) without ritonavir, the AUC of atazanavir was decreased by 94%, Cmax by 96%, and Cmin by 95%.
    Atenolol; Chlorthalidone: (Moderate) Proton pump inhibitors have been associated with hypomagnesemia. Hypomagnesemia occurs with thiazide diuretics (chlorothiazide, hydrochlorothiazide, indapamide, and metolazone). Low serum magnesium may lead to serious adverse events such as muscle spasm, seizures, and arrhythmias. Therefore, clinicians should monitor serum magnesium concentrations periodically in patients taking a PPI and diuretics concomitantly. Patients who develop hypomagnesemia may require PPI discontinuation in addition to magnesium replacement.
    Atropine: (Moderate) The American College of Gastroenterology states that the effectiveness of proton pump inhibitors (PPIs) may be theoretically decreased if given with other antisecretory agents (e.g., anticholinergics). Proton pump inhibitors (PPIs) inhibit only actively secreting H+-pumps.
    Atropine; Benzoic Acid; Hyoscyamine; Methenamine; Methylene Blue; Phenyl Salicylate: (Moderate) The American College of Gastroenterology states that the effectiveness of proton pump inhibitors (PPIs) may be theoretically decreased if given with other antisecretory agents (e.g., anticholinergics). Proton pump inhibitors (PPIs) inhibit only actively secreting H+-pumps.
    Atropine; Difenoxin: (Moderate) The American College of Gastroenterology states that the effectiveness of proton pump inhibitors (PPIs) may be theoretically decreased if given with other antisecretory agents (e.g., anticholinergics). Proton pump inhibitors (PPIs) inhibit only actively secreting H+-pumps.
    Atropine; Diphenoxylate: (Moderate) The American College of Gastroenterology states that the effectiveness of proton pump inhibitors (PPIs) may be theoretically decreased if given with other antisecretory agents (e.g., anticholinergics). Proton pump inhibitors (PPIs) inhibit only actively secreting H+-pumps.
    Atropine; Edrophonium: (Moderate) The American College of Gastroenterology states that the effectiveness of proton pump inhibitors (PPIs) may be theoretically decreased if given with other antisecretory agents (e.g., anticholinergics). Proton pump inhibitors (PPIs) inhibit only actively secreting H+-pumps.
    Atropine; Hyoscyamine; Phenobarbital; Scopolamine: (Moderate) The American College of Gastroenterology states that the effectiveness of proton pump inhibitors (PPIs) may be theoretically decreased if given with other antisecretory agents (e.g., anticholinergics). Proton pump inhibitors (PPIs) inhibit only actively secreting H+-pumps.
    Azilsartan; Chlorthalidone: (Moderate) Proton pump inhibitors have been associated with hypomagnesemia. Hypomagnesemia occurs with thiazide diuretics (chlorothiazide, hydrochlorothiazide, indapamide, and metolazone). Low serum magnesium may lead to serious adverse events such as muscle spasm, seizures, and arrhythmias. Therefore, clinicians should monitor serum magnesium concentrations periodically in patients taking a PPI and diuretics concomitantly. Patients who develop hypomagnesemia may require PPI discontinuation in addition to magnesium replacement.
    Belladonna Alkaloids; Ergotamine; Phenobarbital: (Moderate) The American College of Gastroenterology states that the effectiveness of proton pump inhibitors (PPIs) may be theoretically decreased if given with other antisecretory agents (e.g., anticholinergics). Proton pump inhibitors (PPIs) inhibit only actively secreting H+-pumps.
    Belladonna; Opium: (Moderate) The American College of Gastroenterology states that the effectiveness of proton pump inhibitors (PPIs) may be theoretically decreased if given with other antisecretory agents (e.g., anticholinergics). Proton pump inhibitors (PPIs) inhibit only actively secreting H+-pumps.
    Benazepril; Hydrochlorothiazide, HCTZ: (Moderate) Proton pump inhibitors have been associated with hypomagnesemia. Hypomagnesemia occurs with thiazide diuretics (chlorothiazide, hydrochlorothiazide, indapamide, and metolazone). Low serum magnesium may lead to serious adverse events such as muscle spasm, seizures, and arrhythmias. Therefore, clinicians should monitor serum magnesium concentrations periodically in patients taking a PPI and diuretics concomitantly. Patients who develop hypomagnesemia may require PPI discontinuation in addition to magnesium replacement.
    Bendroflumethiazide; Nadolol: (Moderate) Proton pump inhibitors have been associated with hypomagnesemia. Hypomagnesemia occurs with thiazide diuretics (chlorothiazide, hydrochlorothiazide, indapamide, and metolazone). Low serum magnesium may lead to serious adverse events such as muscle spasm, seizures, and arrhythmias. Therefore, clinicians should monitor serum magnesium concentrations periodically in patients taking a PPI and diuretics concomitantly. Patients who develop hypomagnesemia may require PPI discontinuation in addition to magnesium replacement.
    Benzoic Acid; Hyoscyamine; Methenamine; Methylene Blue; Phenyl Salicylate: (Moderate) The American College of Gastroenterology states that the effectiveness of proton pump inhibitors (PPIs) may be theoretically decreased if given with other antisecretory agents (e.g., anticholinergics). Proton pump inhibitors (PPIs) inhibit only actively secreting H+-pumps.
    Benztropine: (Moderate) The American College of Gastroenterology states that the effectiveness of proton pump inhibitors (PPIs) may be theoretically decreased if given with other antisecretory agents (e.g., anticholinergics). Proton pump inhibitors (PPIs) inhibit only actively secreting H+-pumps.
    Bisacodyl: (Minor) The concomitant use of bisacodyl oral tablets with drugs that raise gastric pH like proton pump inhibitors can cause the enteric coating of the bisacodyl tablets to dissolve prematurely, leading to possible gastric irritation or dyspepsia. When taking bisacodyl tablets, it is advisable to avoid PPIs within 1 hour before or after the bisacodyl dosage.
    Bisoprolol; Hydrochlorothiazide, HCTZ: (Moderate) Proton pump inhibitors have been associated with hypomagnesemia. Hypomagnesemia occurs with thiazide diuretics (chlorothiazide, hydrochlorothiazide, indapamide, and metolazone). Low serum magnesium may lead to serious adverse events such as muscle spasm, seizures, and arrhythmias. Therefore, clinicians should monitor serum magnesium concentrations periodically in patients taking a PPI and diuretics concomitantly. Patients who develop hypomagnesemia may require PPI discontinuation in addition to magnesium replacement.
    Bosutinib: (Major) Bosutinib displays pH-dependent aqueous solubility; therefore, concomitant use of bosutinib and proton-pump inhibitors, such as pantoprazole, may result in decreased plasma exposure of bosutinib. Consider using a short-acting antacid or H2 blocker if acid suppression therapy is needed; separate the administration of bosutinib and antacids or H2-blockers by more than 2 hours.
    Budesonide: (Minor) Enteric-coated budesonide granules dissolve at a pH greater than 5.5. Concomitant use of budesonide oral capsules and drugs that increase gastric pH levels can cause the coating of the granules to dissolve prematurely, possibly affecting release properties and absorption of the drug in the duodenum.
    Budesonide; Formoterol: (Minor) Enteric-coated budesonide granules dissolve at a pH greater than 5.5. Concomitant use of budesonide oral capsules and drugs that increase gastric pH levels can cause the coating of the granules to dissolve prematurely, possibly affecting release properties and absorption of the drug in the duodenum.
    Budesonide; Glycopyrrolate; Formoterol: (Moderate) The American College of Gastroenterology states that the effectiveness of proton pump inhibitors (PPIs) may be theoretically decreased if given with other antisecretory agents (e.g., anticholinergics). Proton pump inhibitors (PPIs) inhibit only actively secreting H+-pumps. (Minor) Enteric-coated budesonide granules dissolve at a pH greater than 5.5. Concomitant use of budesonide oral capsules and drugs that increase gastric pH levels can cause the coating of the granules to dissolve prematurely, possibly affecting release properties and absorption of the drug in the duodenum.
    Bumetanide: (Moderate) Proton pump inhibitors have been associated with hypomagnesemia. Hypomagnesemia occurs with loop diuretics (furosemide, bumetanide, torsemide, and ethacrynic acid). Low serum magnesium may lead to serious adverse events such as muscle spasm, seizures, and arrhythmias. Therefore, clinicians should monitor serum magnesium concentrations periodically in patients taking a PPI and diuretics concomitantly. Patients who develop hypomagnesemia may require PPI discontinuation in addition to magnesium replacement.
    Calcium Carbonate; Risedronate: (Moderate) Use of proton pump inhibitors (PPIs) with delayed-release risedronate tablets (Atelvia) is not recommended. Co-administration of drugs that raise stomach pH increases risedronate bioavailability due to faster release of the drug from the enteric coated tablet. This interaction does not apply to risedronate immediate-release tablets. In healthy subjects who received esomeprazole for 6 days, the Cmax and AUC of a single dose of risedronate delayed-release tablets (Atelvia) increased by 60% and 22%, respectively. PPIsare widely used and are frequently coadministered in users of oral bisphosphonates. A national register-based, open cohort study of 38,088 elderly patients suggests that those who use PPIs in conjunction with alendronate have a dose-dependent loss of protection against hip fracture. While causality was not investigated, the dose-response relationship noted during the study suggested that PPIs may reduce oral alendronate efficacy, perhaps through an effect on absorption or other mechanism, and therefore PPIs may not be optimal agents to control gastrointestinal complaints. Study results suggest that the interaction may occur across the class; however, other interactions have not been confirmed and data suggest that fracture protection is not diminished when risedronate is used with PPIs. A post hoc analysis of patients who took risedronate 5 mg daily during placebo-controlled clinical trials determined that risedronate significantly reduced the risk of new vertebral fractures compared to placebo, regardless of concomitant PPI use. PPI users (n = 240) and PPI non-users (n = 2489) experienced fracture risk reductions of 57% (p = 0.009) and 38% (p < 0.001), respectively.
    Candesartan; Hydrochlorothiazide, HCTZ: (Moderate) Proton pump inhibitors have been associated with hypomagnesemia. Hypomagnesemia occurs with thiazide diuretics (chlorothiazide, hydrochlorothiazide, indapamide, and metolazone). Low serum magnesium may lead to serious adverse events such as muscle spasm, seizures, and arrhythmias. Therefore, clinicians should monitor serum magnesium concentrations periodically in patients taking a PPI and diuretics concomitantly. Patients who develop hypomagnesemia may require PPI discontinuation in addition to magnesium replacement.
    Capecitabine: (Moderate) Use caution if treatment with a proton pump inhibitor (PPI) is necessary in patients taking capecitabine, as progression-free survival (PFS) and overall survival (OS) may be adversely affected. The mechanism of this potential interaction is unknown and data are conflicting. In a posthoc, retrospective, subgroup analysis of a phase 3 clinical trial in patients with advanced or metastatic gastroesophageal cancer, administration of a PPI was associated with a significant decrease in PFS and OS in patients treated with capecitabine plus oxaliplatin (CapeOx) vs. patients who did not receive a PPI; a significant difference was not observed in the CapeOx plus lapatinib arm. Demographically, there were significantly more Asian patients in the PPI arm of this analysis; according to the manufacturer of capecitabine, Japanese patients have a 36% lower Cmax and 24% lower AUC for capecitabine compared with Caucasian patients. Additionally, there was not a significant increase in concentration dependent toxicities (e.g., hand-foot syndrome, rash, and diarrhea) or dose reductions in either arm. These observations are in line with a previous retrospective study in which patients with colorectal cancer receiving PPI treatment and adjuvant capecitabine also experienced poorer relapse-free survival compared with patients not receiving a PPI. Coadministration with antacids increased exposure to capecitabine and its metabolites, but this was not clinically significant or clinically relevant. Pharmacokinetic data on the impact of a PPI on capecitabine exposure are not available.
    Captopril; Hydrochlorothiazide, HCTZ: (Moderate) Proton pump inhibitors have been associated with hypomagnesemia. Hypomagnesemia occurs with thiazide diuretics (chlorothiazide, hydrochlorothiazide, indapamide, and metolazone). Low serum magnesium may lead to serious adverse events such as muscle spasm, seizures, and arrhythmias. Therefore, clinicians should monitor serum magnesium concentrations periodically in patients taking a PPI and diuretics concomitantly. Patients who develop hypomagnesemia may require PPI discontinuation in addition to magnesium replacement.
    Cefpodoxime: (Moderate) Cefpodoxime proxetil requires a low gastric pH for dissolution; therefore, concurrent administration with medications that increase gastric pH, such as proton pump inhibitors (PPIs) may decrease the bioavailability of cefpodoxime. When cefpodoxime was administered with high doses of antacids and H2-blockers, peak plasma concentrations were reduced by 24% and 42% and the extent of absorption was reduced by 27% and 32%, respectively. The rate of absorption is not affected.
    Ceftibuten: (Minor) Coadministration of 150 mg of ranitidine every 12 hours for 3 days increased the ceftibuten Cmax by 23 percent and ceftibuten AUC by 16 percent. Based on this information, increased gastric pH caused by PPIs may possibly affect the kinetics of ceftibuten.
    Cefuroxime: (Major) Avoid the concomitant use of proton pump inhibitors (PPIs) and cefuroxime. Drugs that reduce gastric acidity, such as PPIs, can interfere with the oral absorption of cefuroxime axetil and may result in reduced antibiotic efficacy.
    Chlordiazepoxide; Clidinium: (Moderate) The American College of Gastroenterology states that the effectiveness of proton pump inhibitors (PPIs) may be theoretically decreased if given with other antisecretory agents (e.g., anticholinergics). Proton pump inhibitors (PPIs) inhibit only actively secreting H+-pumps.
    Chlorothiazide: (Moderate) Proton pump inhibitors have been associated with hypomagnesemia. Hypomagnesemia occurs with thiazide diuretics (chlorothiazide, hydrochlorothiazide, indapamide, and metolazone). Low serum magnesium may lead to serious adverse events such as muscle spasm, seizures, and arrhythmias. Therefore, clinicians should monitor serum magnesium concentrations periodically in patients taking a PPI and diuretics concomitantly. Patients who develop hypomagnesemia may require PPI discontinuation in addition to magnesium replacement.
    Chlorthalidone: (Moderate) Proton pump inhibitors have been associated with hypomagnesemia. Hypomagnesemia occurs with thiazide diuretics (chlorothiazide, hydrochlorothiazide, indapamide, and metolazone). Low serum magnesium may lead to serious adverse events such as muscle spasm, seizures, and arrhythmias. Therefore, clinicians should monitor serum magnesium concentrations periodically in patients taking a PPI and diuretics concomitantly. Patients who develop hypomagnesemia may require PPI discontinuation in addition to magnesium replacement.
    Chlorthalidone; Clonidine: (Moderate) Proton pump inhibitors have been associated with hypomagnesemia. Hypomagnesemia occurs with thiazide diuretics (chlorothiazide, hydrochlorothiazide, indapamide, and metolazone). Low serum magnesium may lead to serious adverse events such as muscle spasm, seizures, and arrhythmias. Therefore, clinicians should monitor serum magnesium concentrations periodically in patients taking a PPI and diuretics concomitantly. Patients who develop hypomagnesemia may require PPI discontinuation in addition to magnesium replacement.
    Cyanocobalamin, Vitamin B12: (Moderate) Proton pump inhibitors may cause a decrease in the oral absorption of cyanocobalamin, vitamin B12. Patients receiving long-term therapy with proton pump inhibitors should be monitored for signs of B12 deficiency.
    Cysteamine: (Major) Monitor white blood cell (WBC) cystine concentration closely when administering delayed-release cysteamine (Procysbi) with proton pump inhibitors (PPIs). Drugs that increase the gastric pH may cause the premature release of cysteamine from delayed-release capsules, leading to an increase in WBC cystine concentration. Concomitant administration of omeprazole 20 mg did not alter the pharmacokinetics of delayed-release cysteamine when administered with orange juice; however, the effect of omeprazole on the pharmacokinetics of delayed-release cysteamine when administered with water have not been studied.
    Dacomitinib: (Major) Avoid coadministration of pantoprazole with dacomitinib due to decreased plasma concentrations of dacomitinib which may impact efficacy. Coadministration with another proton pump inhibitor decreased the dacomitinib Cmax and AUC by 51% and 39%, respectively.
    Dasatinib: (Major) Do not administer proton pump inhibitors with dasatinib due to the potential for decreased dasatinib exposure and reduced efficacy. Consider using an antacid if acid suppression therapy is needed. Administer the antacid at least 2 hours prior to or 2 hours after the dose of dasatinib. Concurrent use of an proton pump inhibitor reduced the mean Cmax and AUC of dasatinib by 42% and 43%, respectively.
    Delavirdine: (Major) Because proton pump inhibitors (PPIs) increase gastric pH, decreased delavirdine absorption may occur. However, since these agents affect gastric pH for an extended period, separation of doses may not eliminate the interaction. Chronic use of PPIs with delavirdine is not recommended.
    Dexmethylphenidate: (Minor) The effects of gastrointestinal pH alterations on the absorption of extended-release dexmethylphenidate (Focalin XR) have not been studied. Per the manufacturer of extended-release dexmethylphenidate, the modified release characteristics are pH-dependent. It is possible that the administration of proton pump inhibitors (PPIs) or other acid suppressants could alter the release of extended-release dexmethylphenidate, resulting in reduced or increased absorption. Patients receiving a PPI should be monitored for adverse effects and reduced therapeutic efficacy of extended-release dexmethylphenidate.
    Dextroamphetamine: (Moderate) The use of proton pump inhibitors (PPIs) with amphetamine and/or dextroamphetamine therapy may change the onset of action of these amphetamines due to the increase in gastric pH. The time to maximum concentration (Tmax) of amphetamines is decreased compared to when administered alone, thus increasing amphetamine concentrations and exposure, which may be of particular significance with extended-release dosage forms. Monitor clinical response and adjust if needed. Some extended-release dosage forms of amphetamine or dextroamphetamine salts should not be given with PPIs. The concomitant use of PPIs with some extended-release dosage forms may result in amphetamine dose-dumping.
    Dicyclomine: (Moderate) The American College of Gastroenterology states that the effectiveness of proton pump inhibitors (PPIs) may be theoretically decreased if given with other antisecretory agents (e.g., anticholinergics). Proton pump inhibitors (PPIs) inhibit only actively secreting H+-pumps.
    Digoxin: (Moderate) Monitor serum magnesium concentrations periodically in patients taking pantoprazole and digoxin concomitantly. Patients who develop hypomagnesemia may require pantoprazole discontinuation in addition to magnesium replacement. Proton pump inhibitors (PPIs) have been associated with hypomagnesemia which may lead to irregular heartbeat and increase the likelihood of serious cardiac arrhythmias. Additionally, monitor patients with digoxin serum concentrations at the upper end of the therapeutic range for potential increases in serum digoxin concentrations when coadministered with pantoprazole. Although pantoprazole has not been shown to increase digoxin bioavailability, other PPIs have slightly increased digoxin levels due to the long-lasting effect of the PPIs on gastric acid secretion, which affects the absorption of digoxin.
    Dolutegravir; Rilpivirine: (Severe) Concurrent use of proton pump inhibitors and rilpivirine is contraindicated; when these drugs are coadministered, there is a potential for treatment failure and/or the development of rilpivirine or NNRTI resistance. Proton pump inhibitors inhibit secretion of gastric acid by proton pumps thereby increasing the gastric pH; for optimal absorption, rilpivirine requires an acidic environment. Coadministration of a proton pump inhibitor and rilpivirine may result in decreased rilpivirine absorption/serum concentrations, which could cause impaired virologic response to rilpivirine.
    Emtricitabine; Rilpivirine; Tenofovir alafenamide: (Severe) Concurrent use of proton pump inhibitors and rilpivirine is contraindicated; when these drugs are coadministered, there is a potential for treatment failure and/or the development of rilpivirine or NNRTI resistance. Proton pump inhibitors inhibit secretion of gastric acid by proton pumps thereby increasing the gastric pH; for optimal absorption, rilpivirine requires an acidic environment. Coadministration of a proton pump inhibitor and rilpivirine may result in decreased rilpivirine absorption/serum concentrations, which could cause impaired virologic response to rilpivirine.
    Emtricitabine; Rilpivirine; Tenofovir disoproxil fumarate: (Severe) Concurrent use of proton pump inhibitors and rilpivirine is contraindicated; when these drugs are coadministered, there is a potential for treatment failure and/or the development of rilpivirine or NNRTI resistance. Proton pump inhibitors inhibit secretion of gastric acid by proton pumps thereby increasing the gastric pH; for optimal absorption, rilpivirine requires an acidic environment. Coadministration of a proton pump inhibitor and rilpivirine may result in decreased rilpivirine absorption/serum concentrations, which could cause impaired virologic response to rilpivirine.
    Enalapril; Hydrochlorothiazide, HCTZ: (Moderate) Proton pump inhibitors have been associated with hypomagnesemia. Hypomagnesemia occurs with thiazide diuretics (chlorothiazide, hydrochlorothiazide, indapamide, and metolazone). Low serum magnesium may lead to serious adverse events such as muscle spasm, seizures, and arrhythmias. Therefore, clinicians should monitor serum magnesium concentrations periodically in patients taking a PPI and diuretics concomitantly. Patients who develop hypomagnesemia may require PPI discontinuation in addition to magnesium replacement.
    Eprosartan; Hydrochlorothiazide, HCTZ: (Moderate) Proton pump inhibitors have been associated with hypomagnesemia. Hypomagnesemia occurs with thiazide diuretics (chlorothiazide, hydrochlorothiazide, indapamide, and metolazone). Low serum magnesium may lead to serious adverse events such as muscle spasm, seizures, and arrhythmias. Therefore, clinicians should monitor serum magnesium concentrations periodically in patients taking a PPI and diuretics concomitantly. Patients who develop hypomagnesemia may require PPI discontinuation in addition to magnesium replacement.
    Erlotinib: (Major) Avoid coadministration of erlotinib with pantoprazole if possible due to decreases in erlotinib plasma concentrations. Erlotinib solubility is pH dependent and solubility decreases as pH increases. Coadministration of erlotinib with medications that increase the pH of the upper gastrointestinal tract may decrease the absorption of erlotinib. Separation of doses may not eliminate the interaction since proton pump inhibitors affect the pH of the upper GI tract for an extended period of time. Increasing the dose of erlotinib is also not likely to compensate for the loss of exposure. Coadministration with another proton pump inhibitor decreased erlotinib exposure by 46% and the erlotinib Cmax by 61%.
    Ethacrynic Acid: (Moderate) Proton pump inhibitors have been associated with hypomagnesemia. Hypomagnesemia occurs with loop diuretics (furosemide, bumetanide, torsemide, and ethacrynic acid). Low serum magnesium may lead to serious adverse events such as muscle spasm, seizures, and arrhythmias. Therefore, clinicians should monitor serum magnesium concentrations periodically in patients taking a PPI and diuretics concomitantly. Patients who develop hypomagnesemia may require PPI discontinuation in addition to magnesium replacement.
    Flavoxate: (Moderate) The American College of Gastroenterology states that the effectiveness of proton pump inhibitors (PPIs) may be theoretically decreased if given with other antisecretory agents (e.g., anticholinergics). Proton pump inhibitors (PPIs) inhibit only actively secreting H+-pumps.
    Fosinopril; Hydrochlorothiazide, HCTZ: (Moderate) Proton pump inhibitors have been associated with hypomagnesemia. Hypomagnesemia occurs with thiazide diuretics (chlorothiazide, hydrochlorothiazide, indapamide, and metolazone). Low serum magnesium may lead to serious adverse events such as muscle spasm, seizures, and arrhythmias. Therefore, clinicians should monitor serum magnesium concentrations periodically in patients taking a PPI and diuretics concomitantly. Patients who develop hypomagnesemia may require PPI discontinuation in addition to magnesium replacement.
    Furosemide: (Moderate) Proton pump inhibitors have been associated with hypomagnesemia. Hypomagnesemia occurs with loop diuretics (furosemide, bumetanide, torsemide, and ethacrynic acid). Low serum magnesium may lead to serious adverse events such as muscle spasm, seizures, and arrhythmias. Therefore, clinicians should monitor serum magnesium concentrations periodically in patients taking a PPI and diuretics concomitantly. Patients who develop hypomagnesemia may require PPI discontinuation in addition to magnesium replacement.
    Gefitinib: (Moderate) Avoid coadministration of pantoprazole with gefitinib if possible due to decreased exposure to gefitinib, which may lead to reduced efficacy. If concomitant use is unavoidable, take gefitinib 12 hours after the last dose or 12 hours before the next dose of pantoprazole. Gefitinib exposure is affected by gastric pH. Coadministration with another drug to maintain gastric pH above 5 decreased gefitinib exposure by 47%.
    Glycopyrrolate: (Moderate) The American College of Gastroenterology states that the effectiveness of proton pump inhibitors (PPIs) may be theoretically decreased if given with other antisecretory agents (e.g., anticholinergics). Proton pump inhibitors (PPIs) inhibit only actively secreting H+-pumps.
    Glycopyrrolate; Formoterol: (Moderate) The American College of Gastroenterology states that the effectiveness of proton pump inhibitors (PPIs) may be theoretically decreased if given with other antisecretory agents (e.g., anticholinergics). Proton pump inhibitors (PPIs) inhibit only actively secreting H+-pumps.
    Homatropine; Hydrocodone: (Moderate) The American College of Gastroenterology states that the effectiveness of proton pump inhibitors (PPIs) may be theoretically decreased if given with other antisecretory agents (e.g., anticholinergics). Proton pump inhibitors (PPIs) inhibit only actively secreting H+-pumps.
    Hydralazine; Hydrochlorothiazide, HCTZ: (Moderate) Proton pump inhibitors have been associated with hypomagnesemia. Hypomagnesemia occurs with thiazide diuretics (chlorothiazide, hydrochlorothiazide, indapamide, and metolazone). Low serum magnesium may lead to serious adverse events such as muscle spasm, seizures, and arrhythmias. Therefore, clinicians should monitor serum magnesium concentrations periodically in patients taking a PPI and diuretics concomitantly. Patients who develop hypomagnesemia may require PPI discontinuation in addition to magnesium replacement.
    Hydrochlorothiazide, HCTZ: (Moderate) Proton pump inhibitors have been associated with hypomagnesemia. Hypomagnesemia occurs with thiazide diuretics (chlorothiazide, hydrochlorothiazide, indapamide, and metolazone). Low serum magnesium may lead to serious adverse events such as muscle spasm, seizures, and arrhythmias. Therefore, clinicians should monitor serum magnesium concentrations periodically in patients taking a PPI and diuretics concomitantly. Patients who develop hypomagnesemia may require PPI discontinuation in addition to magnesium replacement.
    Hydrochlorothiazide, HCTZ; Irbesartan: (Moderate) Proton pump inhibitors have been associated with hypomagnesemia. Hypomagnesemia occurs with thiazide diuretics (chlorothiazide, hydrochlorothiazide, indapamide, and metolazone). Low serum magnesium may lead to serious adverse events such as muscle spasm, seizures, and arrhythmias. Therefore, clinicians should monitor serum magnesium concentrations periodically in patients taking a PPI and diuretics concomitantly. Patients who develop hypomagnesemia may require PPI discontinuation in addition to magnesium replacement.
    Hydrochlorothiazide, HCTZ; Lisinopril: (Moderate) Proton pump inhibitors have been associated with hypomagnesemia. Hypomagnesemia occurs with thiazide diuretics (chlorothiazide, hydrochlorothiazide, indapamide, and metolazone). Low serum magnesium may lead to serious adverse events such as muscle spasm, seizures, and arrhythmias. Therefore, clinicians should monitor serum magnesium concentrations periodically in patients taking a PPI and diuretics concomitantly. Patients who develop hypomagnesemia may require PPI discontinuation in addition to magnesium replacement.
    Hydrochlorothiazide, HCTZ; Losartan: (Moderate) Proton pump inhibitors have been associated with hypomagnesemia. Hypomagnesemia occurs with thiazide diuretics (chlorothiazide, hydrochlorothiazide, indapamide, and metolazone). Low serum magnesium may lead to serious adverse events such as muscle spasm, seizures, and arrhythmias. Therefore, clinicians should monitor serum magnesium concentrations periodically in patients taking a PPI and diuretics concomitantly. Patients who develop hypomagnesemia may require PPI discontinuation in addition to magnesium replacement.
    Hydrochlorothiazide, HCTZ; Methyldopa: (Moderate) Proton pump inhibitors have been associated with hypomagnesemia. Hypomagnesemia occurs with thiazide diuretics (chlorothiazide, hydrochlorothiazide, indapamide, and metolazone). Low serum magnesium may lead to serious adverse events such as muscle spasm, seizures, and arrhythmias. Therefore, clinicians should monitor serum magnesium concentrations periodically in patients taking a PPI and diuretics concomitantly. Patients who develop hypomagnesemia may require PPI discontinuation in addition to magnesium replacement.
    Hydrochlorothiazide, HCTZ; Metoprolol: (Moderate) Proton pump inhibitors have been associated with hypomagnesemia. Hypomagnesemia occurs with thiazide diuretics (chlorothiazide, hydrochlorothiazide, indapamide, and metolazone). Low serum magnesium may lead to serious adverse events such as muscle spasm, seizures, and arrhythmias. Therefore, clinicians should monitor serum magnesium concentrations periodically in patients taking a PPI and diuretics concomitantly. Patients who develop hypomagnesemia may require PPI discontinuation in addition to magnesium replacement.
    Hydrochlorothiazide, HCTZ; Moexipril: (Moderate) Proton pump inhibitors have been associated with hypomagnesemia. Hypomagnesemia occurs with thiazide diuretics (chlorothiazide, hydrochlorothiazide, indapamide, and metolazone). Low serum magnesium may lead to serious adverse events such as muscle spasm, seizures, and arrhythmias. Therefore, clinicians should monitor serum magnesium concentrations periodically in patients taking a PPI and diuretics concomitantly. Patients who develop hypomagnesemia may require PPI discontinuation in addition to magnesium replacement.
    Hydrochlorothiazide, HCTZ; Olmesartan: (Moderate) Proton pump inhibitors have been associated with hypomagnesemia. Hypomagnesemia occurs with thiazide diuretics (chlorothiazide, hydrochlorothiazide, indapamide, and metolazone). Low serum magnesium may lead to serious adverse events such as muscle spasm, seizures, and arrhythmias. Therefore, clinicians should monitor serum magnesium concentrations periodically in patients taking a PPI and diuretics concomitantly. Patients who develop hypomagnesemia may require PPI discontinuation in addition to magnesium replacement.
    Hydrochlorothiazide, HCTZ; Propranolol: (Moderate) Proton pump inhibitors have been associated with hypomagnesemia. Hypomagnesemia occurs with thiazide diuretics (chlorothiazide, hydrochlorothiazide, indapamide, and metolazone). Low serum magnesium may lead to serious adverse events such as muscle spasm, seizures, and arrhythmias. Therefore, clinicians should monitor serum magnesium concentrations periodically in patients taking a PPI and diuretics concomitantly. Patients who develop hypomagnesemia may require PPI discontinuation in addition to magnesium replacement.
    Hydrochlorothiazide, HCTZ; Quinapril: (Moderate) Proton pump inhibitors have been associated with hypomagnesemia. Hypomagnesemia occurs with thiazide diuretics (chlorothiazide, hydrochlorothiazide, indapamide, and metolazone). Low serum magnesium may lead to serious adverse events such as muscle spasm, seizures, and arrhythmias. Therefore, clinicians should monitor serum magnesium concentrations periodically in patients taking a PPI and diuretics concomitantly. Patients who develop hypomagnesemia may require PPI discontinuation in addition to magnesium replacement.
    Hydrochlorothiazide, HCTZ; Spironolactone: (Moderate) Proton pump inhibitors have been associated with hypomagnesemia. Hypomagnesemia occurs with thiazide diuretics (chlorothiazide, hydrochlorothiazide, indapamide, and metolazone). Low serum magnesium may lead to serious adverse events such as muscle spasm, seizures, and arrhythmias. Therefore, clinicians should monitor serum magnesium concentrations periodically in patients taking a PPI and diuretics concomitantly. Patients who develop hypomagnesemia may require PPI discontinuation in addition to magnesium replacement.
    Hydrochlorothiazide, HCTZ; Telmisartan: (Moderate) Proton pump inhibitors have been associated with hypomagnesemia. Hypomagnesemia occurs with thiazide diuretics (chlorothiazide, hydrochlorothiazide, indapamide, and metolazone). Low serum magnesium may lead to serious adverse events such as muscle spasm, seizures, and arrhythmias. Therefore, clinicians should monitor serum magnesium concentrations periodically in patients taking a PPI and diuretics concomitantly. Patients who develop hypomagnesemia may require PPI discontinuation in addition to magnesium replacement.
    Hydrochlorothiazide, HCTZ; Triamterene: (Moderate) Proton pump inhibitors have been associated with hypomagnesemia. Hypomagnesemia occurs with thiazide diuretics (chlorothiazide, hydrochlorothiazide, indapamide, and metolazone). Low serum magnesium may lead to serious adverse events such as muscle spasm, seizures, and arrhythmias. Therefore, clinicians should monitor serum magnesium concentrations periodically in patients taking a PPI and diuretics concomitantly. Patients who develop hypomagnesemia may require PPI discontinuation in addition to magnesium replacement.
    Hydrochlorothiazide, HCTZ; Valsartan: (Moderate) Proton pump inhibitors have been associated with hypomagnesemia. Hypomagnesemia occurs with thiazide diuretics (chlorothiazide, hydrochlorothiazide, indapamide, and metolazone). Low serum magnesium may lead to serious adverse events such as muscle spasm, seizures, and arrhythmias. Therefore, clinicians should monitor serum magnesium concentrations periodically in patients taking a PPI and diuretics concomitantly. Patients who develop hypomagnesemia may require PPI discontinuation in addition to magnesium replacement.
    Hyoscyamine: (Moderate) The American College of Gastroenterology states that the effectiveness of proton pump inhibitors (PPIs) may be theoretically decreased if given with other antisecretory agents (e.g., anticholinergics). Proton pump inhibitors (PPIs) inhibit only actively secreting H+-pumps.
    Hyoscyamine; Methenamine; Methylene Blue; Phenyl Salicylate; Sodium Biphosphate: (Moderate) The American College of Gastroenterology states that the effectiveness of proton pump inhibitors (PPIs) may be theoretically decreased if given with other antisecretory agents (e.g., anticholinergics). Proton pump inhibitors (PPIs) inhibit only actively secreting H+-pumps.
    Indacaterol; Glycopyrrolate: (Moderate) The American College of Gastroenterology states that the effectiveness of proton pump inhibitors (PPIs) may be theoretically decreased if given with other antisecretory agents (e.g., anticholinergics). Proton pump inhibitors (PPIs) inhibit only actively secreting H+-pumps.
    Iron: (Moderate) The bioavailability of oral iron salts is influenced by gastric pH, and the concomitant administration of proton pump inhibitors can decrease iron absorption. The non-heme ferric form of iron needs an acidic intragastric pH to be reduced to ferrous and to be absorbed. Iron salts and polysaccharide-iron complex provide non-heme iron. Proton pump inhibitors have long-lasting effects on the secretion of gastric acid and thus, increase the pH of the stomach. The increase in intragastric pH can interfere with the absorption of iron salts.
    Itraconazole: (Moderate) When administering proton pump inhibitors with the 100 mg itraconazole capsule and 200 mg itraconazole tablet formulations, systemic exposure to itraconazole is decreased. Conversely, exposure to itraconazole is increased when proton pump inhibitors are administered with the 65 mg itraconazole capsule. Administer proton pump inhibitors at least 2 hours before or 2 hours after the 100 mg capsule or 200 mg tablet. Monitor for increased itraconazole-related adverse effects if proton pump inhibitors are administered with itraconazole 65 mg capsules.
    Ketoconazole: (Major) Because ketoconazole requires an acidic pH for absorption, coadministration of a proton pump inhibitor (PPI) with ketoconazole can cause a notable decrease in the bioavailability of ketoconazole. PPIs have a prolonged duration of action, and staggering their time of administration with ketoconazole by several hours may not prevent the drug interaction. An alternative imidazole antifungal should be chosen if any of these gastrointestinal medications are required. If these drugs must be coadministered, administer ketoconazole tablets with an acidic beverage and closely monitor for breakthrough infection.
    Ledipasvir; Sofosbuvir: (Major) Solubility of ledipasvir decreases as gastric pH increases; thus, coadministration of ledipasvir; sofosbuvir with proton pump inhibitors (PPIs) may result in lower ledipasvir plasma concentrations. Ledipasvir can be administered with PPIs if given simultaneously under fasting conditions. The PPI dose should not exceed a dose that is comparable to omeprazole 20 mg/day.
    Letermovir: (Moderate) Monitor for reduced pantoprazole efficacy and adjust the dose of pantoprazole if needed during concurrent use of letermovir. Coadministration may result in a clinically relevant decrease in the plasma concentration of pantoprazole. Pantoprazole is a substrate of CYP2C19. Letermovir is a CYP2C19 inducer.
    Loop diuretics: (Moderate) Proton pump inhibitors have been associated with hypomagnesemia. Hypomagnesemia occurs with loop diuretics (furosemide, bumetanide, torsemide, and ethacrynic acid). Low serum magnesium may lead to serious adverse events such as muscle spasm, seizures, and arrhythmias. Therefore, clinicians should monitor serum magnesium concentrations periodically in patients taking a PPI and diuretics concomitantly. Patients who develop hypomagnesemia may require PPI discontinuation in addition to magnesium replacement.
    Mefloquine: (Moderate) Proton pump inhibitors (PPIs) may increase plasma concentrations of mefloquine. Patients on chronic mefloquine therapy might be at increased risk of adverse reactions, especially patients with a neurological or psychiatric history.
    Mepenzolate: (Moderate) The American College of Gastroenterology states that the effectiveness of proton pump inhibitors (PPIs) may be theoretically decreased if given with other antisecretory agents (e.g., anticholinergics). Proton pump inhibitors (PPIs) inhibit only actively secreting H+-pumps.
    Methenamine; Sodium Acid Phosphate; Methylene Blue; Hyoscyamine: (Moderate) The American College of Gastroenterology states that the effectiveness of proton pump inhibitors (PPIs) may be theoretically decreased if given with other antisecretory agents (e.g., anticholinergics). Proton pump inhibitors (PPIs) inhibit only actively secreting H+-pumps.
    Methotrexate: (Major) Use caution when administering high-dose methotrexate to patients receiving proton pump inhibitors (PPIs); a temporary withdrawal of the PPI should be considered in some patients receiving high-dose methotrexate. Case reports and published population pharmacokinetic studies suggest that concomitant use of some PPIs such as omeprazole, pantoprazole, or esomeprazole with methotrexate primarily at high dose may elevate and prolong serum methotrexate concentrations and/or its metabolite hydroxymethotrexate, which may lead to methotrexate toxicities. In two of these cases, delayed methotrexate elimination was observed when high-dose methotrexate was coadministered with PPIs but was not observed when methotrexate was coadministered with ranitidine. However, no formal drug interaction studies of methotrexate with ranitidine have been conducted. Among adults who received high-dose methotrexate (median dose of 3500 mg/m2, range of 1000-5000 mg/m2), coadministration of PPIs such as omeprazole, lansoprazole, or rabeprazole was identified as a risk factor for delayed methotrexate elimination with an OR of 2.65 (95% confidence interval 1.036.82). The interaction may be partially explained by the inhibitory effects of PPIs on breast cancer resistance protein (BCRP, ABCG2) -mediated methotrexate transport. Altered methotrexate elimination may not be present or problematic among patients who receive lower methotrexate doses. For example, coadministration of lansoprazole 30 mg daily and naproxen 500 mg twice daily for 7 days to recipients of stable oral methotrexate doses (7.515 mg/week) for a minimum of 3 months did not alter the pharmacokinetic profile of either methotrexate or 7-hydroxymethotrexate. Specifically, the peak plasma concentration and area under the plasma concentration-time curve of methotrexate and 7-hydroxymethotrexate were within the 0.80 to 1.25 boundaries.
    Methscopolamine: (Moderate) The American College of Gastroenterology states that the effectiveness of proton pump inhibitors (PPIs) may be theoretically decreased if given with other antisecretory agents (e.g., anticholinergics). Proton pump inhibitors (PPIs) inhibit only actively secreting H+-pumps.
    Methyclothiazide: (Moderate) Proton pump inhibitors have been associated with hypomagnesemia. Hypomagnesemia occurs with thiazide diuretics (chlorothiazide, hydrochlorothiazide, indapamide, and metolazone). Low serum magnesium may lead to serious adverse events such as muscle spasm, seizures, and arrhythmias. Therefore, clinicians should monitor serum magnesium concentrations periodically in patients taking a PPI and diuretics concomitantly. Patients who develop hypomagnesemia may require PPI discontinuation in addition to magnesium replacement.
    Methylphenidate: (Minor) The effects of gastrointestinal pH alterations on the absorption of extended-release methylphenidate (Ritalin LA) have not been studied. Per the manufacturer of extended-release methylphenidate, the modified release characteristics are pH-dependent. It is possible that the administration of proton pump inhibitors (PPIs) or other acid suppressants could alter the release of extended-release methylphenidate, resulting in reduced or increased absorption. Patients receiving a PPI should be monitored for adverse effects and reduced therapeutic efficacy of extended-release methylphenidate.
    Metolazone: (Moderate) Proton pump inhibitors have been associated with hypomagnesemia. Hypomagnesemia occurs with thiazide diuretics (chlorothiazide, hydrochlorothiazide, indapamide, and metolazone). Low serum magnesium may lead to serious adverse events such as muscle spasm, seizures, and arrhythmias. Therefore, clinicians should monitor serum magnesium concentrations periodically in patients taking a PPI and diuretics concomitantly. Patients who develop hypomagnesemia may require PPI discontinuation in addition to magnesium replacement.
    Mycophenolate: (Moderate) Concomitant administration of proton pump inhibitors (PPIs) with mycophenolate mofetil (Cellcept) appears to reduce MPA exposure AUC-12h (25.8 +/- 6.4 mg/L x h with omeprazole vs. 33.3 +/- 11.5 mg//L x h without omeprazole); however, the interaction does not appear to exist with mycophenolate sodium delayed-release tablets (Myfortic). Reduced systemic exposure of MPA after mycophenolate mofetil in the presence of a PPI appears to be due to impaired absorption of mycophenolate mofetil which may occur because of incomplete dissolution of mycophenolate mofetil in the stomach at elevated pH. The clinical significance of reduced MPA exposure is unknown; however patients should be evaluated periodically if mycophenolate mofetil is administered with a PPI. Of note, MPA concentrations appear to be reduced in the initial hours after mycophenolate mofetil receipt but increase later in the dosing interval because of enterohepatic recirculation. A second peak in the concentration-time profile of MPA is observed 612 hours after dosing due to enterohepatic recirculation. For example, the 12-hour plasma concentrations of MPA were similar among patients who received mycophenolate mofetil with or without omeprazole. The biphasic plasma concentration-time course of MPA due to extensive enterohepatic circulation hampers therapeutic drug monitoring of MPA. Drug exposure as measured by AUC-12h is the best estimator for the clinical effectiveness of mycophenolate, but measurement of full-dose interval MPA AUC-12h requires collection of multiple samples over a 12-hour period; MPA predose concentrations correlate poorly with MPA AUC-12h. The interaction does not appear to exist with Mycophenolate sodium (Myfortic).
    Nelfinavir: (Major) Use of proton pump inhibitors with nelfinavir is not recommended. Coadministration may result in decreased nelfinavir exposure, subtherapeutic antiretroviral activity, and possibility resistant HIV mutations. In one study, concurrent use of nelfinavir with omeprazole resulted in decreased nelfinavir AUC, Cmax, and Cmin by 36%, 37%, and 39%, respectively.
    Neratinib: (Major) Avoid concomitant use of neratinib with proton pump inhibitors due to decreased absorption and systemic exposure of neratinib; the solubility of neratinib decreases with increasing pH of the GI tract. Concomitant use with lansoprazole decreased neratinib exposure by 65%.
    Nilotinib: (Major) Avoid the concomitant use of nilotinib and proton pump inhibitors (PPIs), as PPIs may cause a reduction in nilotinib bioavailability. Nilotinib displays pH-dependent solubility with decreased solubility at a higher pH. PPIs inhibit gastric acid secretion and elevate the gastric pH. Administration of a single 400-mg nilotinib dose with multiple oral doses of esomeprazole 40 mg/day reduced the nilotinib AUC by 34% in a study in healthy subjects. Increasing the dose is unlikely to compensate for the loss of nilotinib exposure; additionally, separating the administration of these agents may not eliminate the interaction as PPIs affect the pH of the upper GI tract for an extended period of time.
    Octreotide: (Moderate) Coadministration of oral octreotide with proton pump inhibitors (PPIs) may require increased doses of octreotide. Coadministration of oral octreotide with drugs that alter the pH of the upper GI tract, including PPIs, may alter the absorption of octreotide and lead to a reduction in bioavailability. This interaction has been documented with esomeprazole and can occur with the other PPIs.
    Oxybutynin: (Moderate) The American College of Gastroenterology states that the effectiveness of proton pump inhibitors (PPIs) may be theoretically decreased if given with other antisecretory agents (e.g., anticholinergics). Proton pump inhibitors (PPIs) inhibit only actively secreting H+-pumps.
    Pazopanib: (Major) Avoid coadministration of pazopanib with proton-pump inhibitors due to decreased absorption of pazopanib, which may decrease efficacy. If concomitant administration with a gastric acid-reducing agent is unavoidable, consider the use of a short-acting antacid in place of the proton pump inhibitor; separate administration of the short-acting antacid and pazopanib by several hours to avoid a reduction in pazopanib exposure. Concomitant use of pazopanib with esomeprazole decreased pazopanib exposure (AUC and Cmax) by approximately 40%.
    Pexidartinib: (Major) Avoid coadministration of pexidartinib with pantoprazole as concurrent use may decrease pexidartinib exposure which may result in decreased therapeutic response. As an alternative to a proton pump inhibitor (PPI), use locally-acting antacids or H2-receptor antagonists. Coadministration of another PPI decreased pexidartinib exposure by 50%.
    Polyethylene Glycol; Electrolytes; Bisacodyl: (Minor) The concomitant use of bisacodyl oral tablets with drugs that raise gastric pH like proton pump inhibitors can cause the enteric coating of the bisacodyl tablets to dissolve prematurely, leading to possible gastric irritation or dyspepsia. When taking bisacodyl tablets, it is advisable to avoid PPIs within 1 hour before or after the bisacodyl dosage.
    Ponatinib: (Major) Avoid concomitant use of ponatinib with proton-pump inhibitors unless the benefit outweighs the possible risk of ponatinib underexposure. If the use of both agents is necessary, monitor patients for signs of reduced efficacy. Ponatinib displays pH-dependent aqueous solubility; therefore, concomitant use of ponatinib and proton-pump inhibitors, such as pantoprazole, may result in decreased bioavailability and plasma exposure of ponatinib.
    Posaconazole: (Major) The concurrent use of posaconazole oral suspension and proton pump inhibitors (PPIs) should be avoided, if possible, due to the potential for decreased posaconazole efficacy. If used in combination, closely monitor for breakthrough fungal infections. PPIs increase gastric pH, resulting in decreased posaconazole absorption and lower posaconazole plasma concentrations. When a single 400 mg dose of posaconazole oral suspension was administered with esomeprazole (40 mg PO daily), the mean reductions in Cmax were 46% and the mean reductions in AUC were 32% for posaconazole. The pharmacokinetics of posaconazole delayed-release tablets are not significantly affected by PPIs. Additionally, posaconazole is a potent inhibitor of CYP3A4, an isoenzyme partially responsible for the metabolism of many PPIs (dexlansoprazole, esomeprazole, lansoprazole, omeprazole, pantoprazole, and rabeprazole). Coadministration may result in increased plasma concentration of the PPIs.
    Propantheline: (Moderate) The American College of Gastroenterology states that the effectiveness of proton pump inhibitors (PPIs) may be theoretically decreased if given with other antisecretory agents (e.g., anticholinergics). Proton pump inhibitors (PPIs) inhibit only actively secreting H+-pumps.
    Rilpivirine: (Severe) Concurrent use of proton pump inhibitors and rilpivirine is contraindicated; when these drugs are coadministered, there is a potential for treatment failure and/or the development of rilpivirine or NNRTI resistance. Proton pump inhibitors inhibit secretion of gastric acid by proton pumps thereby increasing the gastric pH; for optimal absorption, rilpivirine requires an acidic environment. Coadministration of a proton pump inhibitor and rilpivirine may result in decreased rilpivirine absorption/serum concentrations, which could cause impaired virologic response to rilpivirine.
    Risedronate: (Moderate) Use of proton pump inhibitors (PPIs) with delayed-release risedronate tablets (Atelvia) is not recommended. Co-administration of drugs that raise stomach pH increases risedronate bioavailability due to faster release of the drug from the enteric coated tablet. This interaction does not apply to risedronate immediate-release tablets. In healthy subjects who received esomeprazole for 6 days, the Cmax and AUC of a single dose of risedronate delayed-release tablets (Atelvia) increased by 60% and 22%, respectively. PPIsare widely used and are frequently coadministered in users of oral bisphosphonates. A national register-based, open cohort study of 38,088 elderly patients suggests that those who use PPIs in conjunction with alendronate have a dose-dependent loss of protection against hip fracture. While causality was not investigated, the dose-response relationship noted during the study suggested that PPIs may reduce oral alendronate efficacy, perhaps through an effect on absorption or other mechanism, and therefore PPIs may not be optimal agents to control gastrointestinal complaints. Study results suggest that the interaction may occur across the class; however, other interactions have not been confirmed and data suggest that fracture protection is not diminished when risedronate is used with PPIs. A post hoc analysis of patients who took risedronate 5 mg daily during placebo-controlled clinical trials determined that risedronate significantly reduced the risk of new vertebral fractures compared to placebo, regardless of concomitant PPI use. PPI users (n = 240) and PPI non-users (n = 2489) experienced fracture risk reductions of 57% (p = 0.009) and 38% (p < 0.001), respectively.
    Saquinavir: (Major) Coadministration with omeprazole results in significantly increased saquinavir concentrations. A similar interaction is expected with all proton pump inhibitors (PPIs). If saquinavir must be administered with PPIs, the patient should be closely monitored for saquinavir-related toxicities, including gastrointestinal symptoms, increased triglycerides, and deep vein thrombosis (DVT). Coadministration with omeprazole results in significantly increased saquinavir concentrations. In a small study, 18 healthy individuals received saquinavir 1000 mg (with ritonavir 100 mg) twice daily for 15 days; on days 11 through 15 omeprazole 40 mg was given once daily, which resulted in an 82% increase in the saquinavir AUC. A similar interaction is expected with all PPIs.
    Scopolamine: (Moderate) The American College of Gastroenterology states that the effectiveness of proton pump inhibitors (PPIs) may be theoretically decreased if given with other antisecretory agents (e.g., anticholinergics). Proton pump inhibitors (PPIs) inhibit only actively secreting H+-pumps.
    Secretin: (Major) Discontinue use of proton pump inhibitors before administering secretin. Patients who are receiving proton pump inhibitors at the time of stimulation testing may be hyperresponsive to secretin stimulation, falsely suggesting gastrinoma. The time required for serum gastrin concentrations to return to baseline after discontinuation of a proton pump inhibitor is specific to the individual drug.
    Selpercatinib: (Major) Avoid coadministration of selpercatinib with pantoprazole due to the risk of decreased selpercatinib exposure which may reduce its efficacy. If concomitant use is unavoidable, selpercatinib must be taken with food. Coadministration under fasting conditions with another proton pump inhibitor decreased selpercatinib exposure by 69%; however, concomitant use increased selpercatinib exposure by 2% or less when it was administered with a meal.
    Sofosbuvir; Velpatasvir: (Major) Coadministration of proton pump inhibitors (PPIs) with velpatasvir is not recommended. If it is considered medically necessary to coadminister, velpatasvir should be administered with food and taken 4 hours before omeprazole 20 mg. Other PPIs have not been studied; however, it may be prudent to separate the administration of the other PPIs similarly. Velpatasvir solubility decreases as pH increases; therefore, drugs that increase gastric pH are expected to decrease the concentrations of velpatasvir, potentially resulting in loss of antiviral efficacy.
    Sofosbuvir; Velpatasvir; Voxilaprevir: (Major) Coadministration of proton pump inhibitors (PPIs) with velpatasvir is not recommended. If it is considered medically necessary to coadminister, velpatasvir should be administered with food and taken 4 hours before omeprazole 20 mg. Other PPIs have not been studied; however, it may be prudent to separate the administration of the other PPIs similarly. Velpatasvir solubility decreases as pH increases; therefore, drugs that increase gastric pH are expected to decrease the concentrations of velpatasvir, potentially resulting in loss of antiviral efficacy.
    Solifenacin: (Moderate) The American College of Gastroenterology states that the effectiveness of proton pump inhibitors (PPIs) may be theoretically decreased if given with other antisecretory agents (e.g., anticholinergics). Proton pump inhibitors (PPIs) inhibit only actively secreting H+-pumps.
    St. John's Wort, Hypericum perforatum: (Major) Coadministration of St. John's Wort, Hypericum perforatum (300 mg three times daily) for 14 days with a one time dose of omeprazole (20 mg) on day 15 resulted in decreased omeprazole plasma concentrations in healthy subjects. Omeprazole AUC was reduced by approximately 40% in both poor and extensive metabolizers of CYP2C19. The clinical significance of this interaction is not clear; however, due to variations in the amounts of active ingredient in herbal products, the magnitude of this interaction and the resultant clinical effect may vary. St. John's Wort induces both CYP3A4 and CYP2C19 dependent metabolism of omeprazole. Since, proton pump inhibitors (PPIs) are primary substrates of the CYP2C19 enzyme, patients taking St. John's Wort concomitantly with a PPI should be monitored for PPI efficacy.
    Thiazide diuretics: (Moderate) Proton pump inhibitors have been associated with hypomagnesemia. Hypomagnesemia occurs with thiazide diuretics (chlorothiazide, hydrochlorothiazide, indapamide, and metolazone). Low serum magnesium may lead to serious adverse events such as muscle spasm, seizures, and arrhythmias. Therefore, clinicians should monitor serum magnesium concentrations periodically in patients taking a PPI and diuretics concomitantly. Patients who develop hypomagnesemia may require PPI discontinuation in addition to magnesium replacement.
    Thyroid hormones: (Moderate) The use of proton pump inhibitors may result in decreased effectiveness of thyroid hormone therapy. Monitor clinically for signs and symptoms of hypothyroidism and altered response to thyroid hormone therapy. Periodically assess the TSH during use of these drugs together. Gastric acidity is an essential requirement for proper and adequate absorption of levothyroxine and other thyroid hormones. Proton pump inhibitors may cause hypochlorhydria, affect intragastric pH, and reduce thyroid hormone absorption.
    Tipranavir: (Moderate) Some manufacturers recommend avoiding the coadministration of hepatic cytochrome P-450 enzyme inducers and proton pump inhibitors (PPIs). Tipranavir markedly induces the hepatic cytochrome P-450 enzyme CYP2C19, an enzyme responsible for the metabolism of PPIs. However, since tipranavir is not given unless it is co-prescribed with ritonavir, a known marked enzyme inhibitor, a reduction in PPI metabolism may be unlikely to occur. A reduction in PPI concentrations may increase the risk of gastrointestinal (GI) adverse events such as GI bleeding. If tipranavir and PPIs must be used together, monitor the patient closely for signs and symptoms of GI bleeding or other signs and symptoms of reduced PPI efficacy.
    Tolterodine: (Moderate) The American College of Gastroenterology states that the effectiveness of proton pump inhibitors (PPIs) may be theoretically decreased if given with other antisecretory agents (e.g., anticholinergics). Proton pump inhibitors (PPIs) inhibit only actively secreting H+-pumps.
    Torsemide: (Moderate) Proton pump inhibitors have been associated with hypomagnesemia. Hypomagnesemia occurs with loop diuretics (furosemide, bumetanide, torsemide, and ethacrynic acid). Low serum magnesium may lead to serious adverse events such as muscle spasm, seizures, and arrhythmias. Therefore, clinicians should monitor serum magnesium concentrations periodically in patients taking a PPI and diuretics concomitantly. Patients who develop hypomagnesemia may require PPI discontinuation in addition to magnesium replacement.
    Trihexyphenidyl: (Moderate) The American College of Gastroenterology states that the effectiveness of proton pump inhibitors (PPIs) may be theoretically decreased if given with other antisecretory agents (e.g., anticholinergics). Proton pump inhibitors (PPIs) inhibit only actively secreting H+-pumps.
    Trospium: (Moderate) The American College of Gastroenterology states that the effectiveness of proton pump inhibitors (PPIs) may be theoretically decreased if given with other antisecretory agents (e.g., anticholinergics). Proton pump inhibitors (PPIs) inhibit only actively secreting H+-pumps.
    Warfarin: (Moderate) Monitor the INR in patients receiving warfarin with proton pump inhibitors. Increases in INR may lead to abnormal bleeding. Adjust the warfarin dose to maintain the target INR.

    PREGNANCY AND LACTATION

    Pregnancy

    There are no adequate and well-controlled studies of pantoprazole in pregnant women. Although data from published observational studies in humans failed to demonstrate an association of adverse pregnancy-related outcomes and pantoprazole use, methodological limitations of these observational studies cannot definitely establish or exclude any drug-associated risk during pregnancy. Animal reproductive studies have been conducted in rats and rabbits using doses up to 88 and 16 times, respectively, that of humans based on body surface area; there was no evidence of fetal harm. It is not known if pantoprazole crosses the human placenta, although another PPI with a similar molecular weight, omeprazole, is known to cross the human placenta. In one study, pregnancy outcomes were reported with exposure to omeprazole (n = 295), lansoprazole (n = 62), and pantoprazole (n = 53). Compared to non-exposed control groups, there was no difference in the rate of major malformations with the use of pantoprazole (RR 0.55, 95% CI 0.8 to 3.95). However, there is a possibility that the true risk of malformation was missed due to study design and/or sample size. In another study, there was no significant increase in major birth defects during analysis of first trimester exposure to pantoprazole in 549 live births. In addition, a meta-analysis that compared 1,530 pregnant women exposed to PPIs in at least the first trimester with 133,410 unexposed pregnant women showed no significant increases in risk for congenital malformations or spontaneous abortion with exposure to PPIs (for major malformations OR = 1.12 [95% CI 0.86 to 1.45] and for spontaneous abortions OR = 1.29 [95% CI 0.84 to 1.97]). Pantoprazole likely represents a low risk in pregnancy, but should be used during pregnancy only when clearly needed. In 2009, a population-based observational cohort study explored a possible link between gastric acid suppressive therapy (e.g., proton pump inhibitors) during pregnancy and a diagnosis of allergic disease or a prescription for asthma or allergy medications in the exposed child. Among the cohort (n = 585,716), 1% of children exposed to gastric acid suppressive drugs in pregnancy received a diagnosis of allergic diease. For developing allergy or asthma, an increased OR of 1.43 and 1.51, respectively, were observed regardless of drug used, time of exposure during pregnancy, and maternal history of disease. Proposed possible mechanisms for a link include: (1) exposure to increased amounts of allergens could cause sensitization to digestion-labile antigens in the fetus; (2) the maternal Th2 cytokine pattern could promote an allergy prone phenotype in the fetus; (3) maternal allergen specific immunoglobulin could cross the placenta and sensitize fetal immune cells to food and airborne allergens. Study limitations were present and confirmation of results are necessary before further conclusions can be drawn from this data. Risk versus benefit should be considered prior to use.

    According to the manufacturer, pantoprazole and its metabolites are excreted in the milk of rats. Pantoprazole excretion in human milk has also been detected, but the clinical relevance of this finding is unknown. Because of the potential for tumorigenicity and carcinogenicity found in animal studies, the manufacturer suggests that a decision should be made whether to discontinue nursing or pantoprazole, taking into account the benefit of the drug to the mother. In one study, a partially breast-feeding mother was 10 months postpartum and received a single 40 mg dose of oral pantoprazole. Although small quantities of the drug were present in breast milk at 2 and 4 hours after the dose (36 mcg/L and 24 mcg/L, respectively), the drug was undetectable in expressed milk 6, 8, and 24 hours after the dose. Using the above case, authors estimated that a fully breast fed infant would receive 0.14% of the maternal weight-adjusted dosage. Because of limited human data and the potential for serious adverse reactions from pantoprazole in the breast-fed infant (including suppression of gastric acid secretion), pantoprazole should be used with caution in breast-feeding women. Alternative therapies for consideration include antacids and H2 blockers.

    MECHANISM OF ACTION

    Mechanism of Action: Pantoprazole is a substituted benzimidazole proton-pump inhibitor (PPI) that suppresses gastric acid secretion by inhibiting the gastric (H+,K+)-ATPase enzyme pump. Pantoprazole forms a covalent bond to two sites of the (H+,K+)-ATPase enzyme system at the secretory surface of the gastric parietal cell; this binding results in antisecretory effects that persists > 24 hours, which allows for once-daily dosing. A significant increase in gastric pH and decrease in basal acid output follow oral and IV administration of pantoprazole. Pantoprazole does not antagonize H2 or cholinergic receptors.
     
    Most studies report that gastric acid suppression is dose-related following IV and oral administration of pantoprazole, resulting in inhibition of both basal and stimulated gastric acid secretion (irrespective of the stimulus). In a series of basal gastric acid secretion studies, at oral doses ranging from 20 to 120 mg, pantoprazole resulted in dose-related increases in the median basal gastric pH and in the percent of time the gastric pH exceeded 3.0 and 4.0. Treatment with 40 mg pantoprazole produced optimal increases in gastric pH which were significantly higher than gastric pH following the 20 mg dose. Doses higher than 40 mg (60, 80, 120 mg) generally did not result in further significant increases in median gastric pH. Under stimulated gastric acid secretion using pentagastrin, a dose-dependent decrease in gastric acid output occurs following single oral (20—80 mg) or IV (20—120 mg) doses of pantoprazole in healthy volunteers. Following the initial oral dose of 40 mg, a 51% mean inhibition is achieved in about 2.5 hours. With once daily dosing (7 days), the mean inhibition increases to 85%. Acid secretion returns to normal within 7 days of discontinuing pantoprazole, without evidence of rebound hypersecretion.
     
    Significant in vitro activity against Helicobacter pylori (H. Pylori) has been demonstrated for pantoprazole. In one report, the minimum inhibitory concentration (MIC90) for pantoprazole (100 mcg/ml) was higher than that observed for omeprazole (25 mcg/ml) and lansoprazole (6.25 mcg/ml); however, the clinical significance of this finding is unknown. Pantoprazole monotherapy increases the clearance rate of H. pylori; however, eradication does not occur without appropriate antimicrobial therapy.
     
    Similar to omeprazole and other PPIs, hypergastrinemia can occur during pantoprazole therapy. Although prolonged hypergastrinemia has been associated with gastric tumors in rats, long-term studies of proton pump inhibitors do not suggest the development of tumors in humans.
     
    Pantoprazole does not significantly inhibit hepatic microsomal enzymes and has been documented in numerous drug interaction studies to lack significant drug interactions with hepatic substrates for multiple CYP isoenzymes.
     
    No clinically relevant effects of pantoprazole on cardiovascular, respiratory, ophthalmic, or central nervous system function have been detected. A short-term (2-week) evaluation showed that oral pantoprazole had no effect on endocrine hormones including: cortisol, testosterone, triiodothyronine (T3), thyroxine (T4), thyroid-stimulating hormone, thyronine-binding protein, parathyroid hormone, insulin, glucagon, renin, aldosterone, follicle-stimulating hormone, luteinizing hormone, prolactin and growth hormone.

    PHARMACOKINETICS

    Pantoprazole is administered orally or intravenously. It  is 99% bound to human plasma proteins, primarily to albumin. 
     
    Affected cytochrome P450 isoenzymes and drug transporters: CYP2C19, CYP2C9, CYP3A4
    Pantoprazole is extensively metabolized in the liver to inactive metabolites by the cytochrome P450 (CYP) system. The primary metabolic pathway is demethylation by CYP2C19, with subsequent sulfation; a minor metabolic pathway is oxidation by CYP3A4. In vitro data suggest that pantoprazole is a competitive inhibitor of CYP2C9 and CYP3A4 isoenzymes; however, the effects do not appear to result in clinically relevant drug interactions. In vitro and clinical data suggest it is a weak inhibitor of CYP2C19 isoenzymes.  
     
    The terminal elimination half-life following IV or oral administration is approximately one hour. Poor metabolizers have longer elimination half-life values ranging from 3.5 to 10 hours; however, they have minimal drug accumulation (23% or less) with once daily dosing. About 71% of the dose is excreted renally and 18% is eliminated by biliary excretion. No unchanged pantoprazole is recovered in the urine.

    Oral Route

    Protonix delayed-release tablets are enteric-coated to allow pantoprazole sodium sesquihydrate, which is acid labile, to pass though the stomach intact. After oral administration of delayed-release tablets, peak plasma concentrations occur in about 2.5 hours. Pantoprazole is well absorbed; it undergoes little first-pass metabolism resulting in an absolute bioavailability of approximately 77%. Food delays, but does not affect the extent of absorption of the tablets; tablets may be administered without regard to meals. However, the delayed-release oral suspension should be administered approximately 30 minutes before a meal.

    Intravenous Route

    The onset of antisecretory effects of pantoprazole following IV administration is approximately 15 to 30 minutes, with a duration of action of 24 hours.