PROTONIX (Brand for PANTOPRAZOLE SODIUM)

General Administration Information
For storage information, see the specific product information within the How Supplied section.

Route-Specific Administration

Oral Administration
Oral Solid Formulations
Delayed release tablets
-Administer approximately 30 minutes prior to a meal for maximum efficacy. May administer without regard to meals.
-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.
-Administer approximately 30 minutes before a meal.
-Do not crush or chew the granules.
-May sprinkle on 5 mL (1 teaspoonful) of cool applesauce; administer within 10 minutes. Alternatively, mix in a small cup with 5 mL (1 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 1 packet of 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
-Count out 20 of the Protonix 40-mg oral tablets.
-Remove the Protonix imprint from all 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 for 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.
-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 to 46.4 degrees F (2 to 8 degrees C) and protected from light. Label with "shake well" and "refrigerate".



Injectable Administration
-Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit.
Intravenous Administration
-Administer 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.

Intermittent IV Infusion
-Studies in pediatrics have utilized IV infusion administration for IV pantoprazole.
-Dilute each 40 mg vial with 10 mL 0.9% Sodium Chloride Injection.
-Prior to infusion, further admix the reconstituted vial with 100 mL (for 1 vial) or 80 mL (for 2 vials) of 5% Dextrose Injection, 0.9% Sodium Chloride Injection, or Lactated Ringer's Injection to a final infusion concentration of approximately 0.4 mg/mL or 0.8 mg/mL, respectively.
-Flush the IV line with 5% Dextrose Injection, 0.9% Sodium Chloride Injection, or Lactated Ringer's Injection before and after each dose.
-Infuse over approximately 15 minutes, not to exceed a rate of 7 mL/minute.
-Do not administer with other IV fluids or medications.
-Storage: Store at room temperature and use within 24 hours from the time of initial reconstitution.

IV Push
-Slow IV push administration has been used for adult patients.
-Dilute each 40 mg vial with 10 mL 0.9% Sodium Chloride Injection. Each vial will have a final concentration of 4 mg/mL.
-Flush the IV line with 5% Dextrose Injection, 0.9% Sodium Chloride Injection, or Lactated Ringer's Injection 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: 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 to 5 degrees C) or at room temperature (23 to 25 degrees C). To minimize the potential for solution discoloration, refrigerate if stored beyond 48 hours.

Continuous IV Infusion
-ASHP Recommended Standard Concentration for Pediatric Continuous Infusions: 0.8 mg/mL.

Significant elevations in serum gastrin have been reported with pantoprazole similar to other proton pump inhibitors (PPIs); this effect may be dose-related. Carcinoid tumors are a potential sequelae of prolonged hypergastrinemia secondary to the use of PPIs due to inhibited gastric acid secretion. In 39 patients treated with oral pantoprazole 40-240 mg daily (majority receiving 40-80 mg) for up to 5 years, there was a moderate increase in enterochromaffin-like (ECL) cell density starting after the first year of use which appeared to plateau after 4 years. In rodents, pantoprazole is carcinogenic and caused rare types of gastrointestinal tumors. In long-term rodent studies, tumors, including rare types of gastrointestinal tumors, were observed. The relevance of animal findings to human risk is unknown. The safety and efficacy of pantoprazole beyond 12 months have not been established. The risk of carcinoid tumors during therapy with PPIs is low based on cumulative safety experience; monitoring of serum gastrin levels during PPI therapy is generally not necessary.

Some reports of overdosage with pantoprazole have been received. A spontaneous report of a suicide involving an overdosage of pantoprazole (560 mg) has been received; however, the death was more reasonably attributed to the unknown doses of chloroquine and zopiclone which were also taken. Two other reported cases of pantoprazole overdosage involved similar amounts of oral pantoprazole (400 and 600 mg) with no adverse effects observed. One study patient with refractory peptic ulcer disease received 320 mg/day PO for 3 months; the treatment was well tolerated. Doses of up to 240 mg/day IV, have been administered to healthy subjects for 7 days and have been well tolerated.

The safety profile of oral pantoprazole is consistent with that of other proton pump inhibitors, with the most frequently reported adverse reactions being GI-related. The most common GI adverse reactions reported in more than 4% of pediatric patients (1 to 16 years) receiving pantoprazole in clinical trials were diarrhea (more than 4%; more than 1% IV), vomiting, and abdominal pain. GI adverse reactions reported in 4% or less of pediatric patients include constipation, flatulence, and nausea. Additional GI-related adverse reactions reported in adult studies of oral pantoprazole include xerostomia (2% or less) and GI bleeding (less than 1%). Adverse reactions reported for adult patients receiving high-dose oral pantoprazole in Zollinger-Ellison Syndrome trials (80 to 240 mg/day for up to 2 years) were similar to those seen in adult GERD trials. Abdominal pain, nausea, constipation, and dyspepsia have also been reported in more than 1% of adult patient receiving IV pantoprazole. During postmarketing surveillance of IV pantoprazole, increased salivation and pancreatitis have been reported. Postmarketing surveillance of oral pantoprazole has identified reports of gastric polyps/fundic gland polyps, weight gain, weight loss, and ageusia/dysgeusia, which may have a relationship to drug exposure.

Elevated hepatic enzymes have been reported in <= 4% of pediatric patients receiving pantoprazole. In adult oral pantoprazole studies, hepatitis was reported in <= 2% of patients receiving pantoprazole. Hyperbilirubinemia, cholecystitis, cholelithiasis have been reported in < 1% of patients receiving oral pantoprazole. In addition, hepatocellular damage leading to jaundice and hepatic failure have been reported during post-marketing surveillance of oral and IV pantoprazole.

In IV pantoprazole trials, rhinitis was reported in > 1% of patients receiving pantoprazole. During oral pantoprazole therapy studies, fever was reported in <= 2 % of patients. Both upper respiratory tract infections and fever were commonly reported (> 4%) among patients in oral pantoprazole pediatric trials. Gastric acid suppression with proton pump inhibitors (PPIs) have been associated with an increased risk of infection in pediatric patients. A prospective, multi-center study in previously healthy infants and young children found an increased risk of pneumonia (OR: 6.39; 95% CI = 1.38-29.7) and acute gastroenteritis (OR: 3.58; 95% CI = 1.87-6.86) in patients receiving gastric acid inhibitors (n = 91) compared to controls (n = 95). Another study in critically ill pediatric patients (n = 60) did not find an increased incidence of ventilator-associated pneumonia in patients receiving acid-suppression therapy compared to those not receiving treatment. Until more is known about the relationship between acid-suppression and pneumonia, clinicians are encouraged to carefully select patients before empirically initiating acid-suppressive therapy with H2-blockers or PPIs. A causal relationship between the use of pantoprazole and pneumonia has not been established. Increasing evidence in adults suggests a link between acid-suppression therapy and pneumonia (community- and hospital-acquired). Several mechanisms have been proposed to account for this association. One such mechanism states that gastric pH serves as a barrier against pathogenic colonization of the gastrointestinal tract. An increase in gastric pH allows for bacterial and viral invasion which, in theory, can precipitate respiratory infections. Another proposed mechanism accounts for the role that gastric acid may have on stimulating the cough reflex that allows for the clearing of infectious agents from the respiratory tract. Finally, the fact that acid-suppressive therapy may impair white blood cell function, which in turn may lead to a depressed immune response to an infection, is listed among possible mechanisms.

During oral pantoprazole clinical studies, hematological reactions that have been reported in < 2% of patients include leukopenia and thrombocytopenia. Anemia, ecchymosis, eosinophilia, hypochromic anemia, iron deficiency anemia, leukocytosis have also been identified in < 1% of oral pantoprazole treated patients. Pancytopenia and agranulocytosis have been reported during pantoprazole post-marketing surveillance. Generally, long-term (e.g., >= 2-3 years) treatment with acid-suppressing agents can lead to malabsorption of vitamin B12 (cyanocobalamin). In a study of healthy adult volunteers, it was shown that omeprazole caused a significant reduction in cyanocobalamin absorption. In a large case-controlled study, adult patients with and without an incident diagnosis of vitamin B12 deficiency (n = 25,956 and 184,199, respectively) were compared, and a correlation between vitamin B12 deficiency and gastric acid-suppression therapy was found. Receipt of >= 2 years of a proton pump inhibitor or H2-receptor antagonist was associated with an increased risk for vitamin B12 deficiency. A dose-dependent relationship was evident, as daily doses > 1.5 PPI pills/day were more strongly associated with vitamin B12 deficiency compared to daily doses < 0.75 pills/day. The precise risk in pediatric patients has not been defined. It may be prudent to monitor patients for signs of pernicious anemia. Neurological manifestations of pernicious anemia can occur in the absence of hematologic changes.

Vertigo was reported in <= 4% of pediatric patients (1-16 years) receiving oral pantoprazole for the treatment of erosive esophagitis associated with GERD as well as during IV pantoprazole post-marketing surveillance. During clinical evaluation of oral pantoprazole in adult patients with GERD, depression was reported in <= 2% of pantoprazole treated patients. Asthenia, confusion, drowsiness (somnolence), fatigue, hallucinations, insomnia and malaise were reported during post-marketing surveillance of oral pantoprazole. Seizures were noted in < 1% of oral pantoprazole treated patients in clinical studies. In IV pantoprazole studies, insomnia was reported in > 1% of patients. Other nervous system or special senses adverse events reported during IV pantoprazole post-marketing surveillance include anterior ischemic optic neuropathy, blurred vision, hypokinesia, speech disorder, and tinnitus.

Allergic reactions (4% or less), including urticaria (4% or less) and rash (more than 4%), have been reported in pediatric patients treated with oral pantoprazole. Facial edema has been reported in 4% or less of subjects in pediatric studies as well. Adult patients (2% or less) have also reported photosensitivity reaction and pruritus. During postmarketing surveillance of oral and/or IV pantoprazole, the following adverse reactions were identified: anaphylactoid reactions (including anaphylactic shock), angioedema (Quincke's edema), and severe dermatologic reactions (some fatal) including erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis (TEN, some fatal), drug reaction with eosinophilia and systemic symptoms (DRESS), and acute generalized exanthematous pustulosis (AGEP). Injection site reaction including thrombo-phlebitis and abscess have been reported in more than 1% of patients treated with IV pantoprazole. Discontinue pantoprazole and consider further evaluation if patient develops signs or symptoms of severe cutaneous adverse reactions or other signs of hypersensitivity.

Acute tubulo-interstitial nephritis (AIN or TIN) has been observed in patients taking PPIs including with pantoprazole. Acute interstitial nephritis may occur at any point during PPI therapy and is generally attributed to an idiopathic hypersensitivity reaction. Patients may present with varying signs and symptoms from symptomatic hypersensitivity reactions to non-specific symptoms of decreased renal function (e.g., malaise, nausea, anorexia). In reported case series, some patients were diagnosed on biopsy and in the absence of extra-renal manifestations (e.g., fever, rash or arthralgia). Discontinue pantoprazole and evaluate patients with suspected acute AIN. In some cases, corticosteroid treatment and withdrawal of pantoprazole resulted in recovery of renal function.

Cutaneous lupus erythematosus (CLE), systemic lupus erythematosus (SLE), and lupus-like symptoms have occurred in patients taking PPIs, including pantoprazole. Both exacerbation and new onset of existing autoimmune disease have be reported, with the majority of PPI-induced lupus erythematosus cases being CLE. Subacute CLE (SCLE) is the most common form of CLE reported in patients treated with PPIs, occurring within weeks to years after continuous drug therapy in patients ranging from infants to the elderly. Histological findings were usually observed without organ involvement. SLE is less commonly reported; PPI associated SLE is generally milder than non-drug induced SLE. Onset of SLE typically occurred within days to years after initiating treatment primarily in patients ranging from infants to the elderly. Most patients presented with rash; however, arthralgia and cytopenia were also reported. Do not administer PPIs for longer than medically indicated. If signs or symptoms consistent with CLE or SLE occur, discontinue the drug and refer the patient to the appropriate specialist for evaluation. Most patients improve with discontinuation of the PPI alone in 4 to 12 weeks; serological testing (ANA) may be positive and elevated serological test results may take longer to resolve than clinical manifestations.

Pantoprazole therapy has been associated with certain musculoskeletal adverse reactions. Arthralgia and myalgia were reported in <= 4% of pediatric patients (1-16 years) receiving oral pantoprazole in clinical studies. During post-marketing surveillance of oral and/or IV pantoprazole, bone fractures, elevated creatine phosphokinase (<= 4% of patients), and rhabdomyolysis have been reported. Proton pump inhibitors (PPIs) have been associated with a possible increased risk of bone fractures of the hip, wrist, and spine. There have been six epidemiological studies that 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. Depending on the study, exposure to PPIs ranged between 1-12 years. The emergence of fractures varied among studies; one study reported an increase in fractures with use of PPIs in the previous year and another study found an increase after 5-7 years of PPI use. Increased risk was primarily observed in adults, patients taking prescription PPIs for at least one year, and patients who had been taking high doses (doses greater than those recommended with OTC use). Alternatively, in another epidemiological study with similar study design, a relationship between PPI use and fractures was not established; the study population did not have major risk factors for fracture at study entry. It should be noted that randomized clinical trials (RCTs) of PPIs have not found an increased risk of fractures of the hip, wrist, or spine; some limitations of these RCTs were study duration (generally six months) and insufficient information on effects of higher than recommended doses. Until more data are available, when prescribing PPIs, consider whether a lower dose or shorter duration of therapy would adequately treat the patient's condition. In patients at risk for or who have osteoporosis, manage their bone status according to current clinical practice, and ensure adequate vitamin D and calcium supplementation.

Headache and dizziness were reported in > 4% and <= 4%, respectively, of pediatric patients (1-16 years) receiving pantoprazole in clinical trials. In adult patients receiving oral and IV pantoprazole in clinical trials, headache (oral: 12.2%; IV: > 1%) and dizziness (oral: 3%; IV: > 1%) have also been reported.

Hypomagnesemia, hypocalcemia, hypokalemia, and hyponatremia have been reported during postmarketing pantoprazole use. Cases of hypomagnesemia have been reported in association with prolonged (3 months to more than 1 year) proton pump inhibitor (PPI) use. Hypomagnesemia may lead to hypocalcemia and/or hypokalemia and may exacerbate underlying hypocalcemia in patients at risk. Low serum magnesium may lead to serious adverse reactions such as muscle spasm (tetany), seizures, and irregular heartbeat (arrhythmias). Consider monitoring electrolyte concentrations and supplementing electrolytes when needed. Discontinuation of PPI therapy may be necessary.

Hypertriglyceridemia (<= 4%) has been reported in pediatric patients during oral pantoprazole clinical trials. During clinical evaluation of adult patients with erosive esophagitis associated GERD receiving oral pantoprazole, reported cardiovascular adverse events occurring in < 1% include: abnormal electrocardiogram, angina pectoris, arrhythmia exacerbation, atrial fibrillation, atrial flutter, cardiovascular disorder, chest pain substernal, congestive heart failure, hemorrhage/bleeding, hypertension, hypotension, migraine, myocardial infarction, palpitations, peripheral vasodilation, retinal vascular disorder, syncope, sinus tachycardia, and thrombosis. In most instances, the relationship to pantoprazole therapy was unclear.

C. difficile-associated diarrhea (CDAD) or pseudomembranous colitis has been reported with pantoprazole. PPI therapy, such as pantoprazole, may be associated with an increased risk of CDAD, especially in hospitalized patients. The use of gastric acid suppressive therapy, such as PPIs, may increase the risk of enteric infection or superinfection by encouraging the growth of gut microflora. If pseudomembranous colitis is suspected or confirmed, institute appropriate fluid and electrolyte management, protein supplementation, C. difficile-directed antibacterial therapy, and surgical evaluation as clinically appropriate.

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). There has been evidence of PPI cross-sensitivity in some sensitive individuals in literature reports, and some cases have been serious (e.g., angioedema or anaphylaxis). Serious rash and severe cutaneous adverse reactions, including Stevens-Johnson syndrome (SJS), erythema multiforme, and toxic epidermal necrolysis (TEN), drug reaction with eosinophilia and systemic symptoms (DRESS), and acute generalized exanthematous pustulosis (AGEP) have been reported in association with the use of PPIs. Discontinue the PPI at the first signs or symptoms of severe cutaneous adverse reactions or other hypersensitivity and consider further evaluation. Acute tubulo-interstitial nephritis (TIN or AIN) has been observed in patients taking PPIs and may occur at any point during PPI therapy. Patients may present with varying signs and symptoms from symptomatic hypersensitivity reactions to non-specific symptoms of decreased renal function (e.g., malaise, nausea, anorexia). There have been reports of patients who were diagnosed on biopsy and in the absence of extra-renal manifestations (e.g., fever, rash or arthralgia). Discontinue pantoprazole and evaluate patients with suspected acute TIN.

Use pantoprazole with caution in patients with severe hepatic disease or impairment; sufficient data are lacking in this subgroup. Modest accumulation (<= 21%) of pantoprazole occurs during once daily dosing in adult patients with hepatic impairment but no dosage adjustment is considered necessary. Pediatric data in hepatic impairment are not available.

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.

Consider pseudomembranous colitis in patients presenting with diarrhea after PPI use. PPI therapy, such as pantoprazole, may be associated with an increased risk of C. difficile-associated diarrhea (CDAD), especially in hospitalized patients. CDAD may range in severity from mild to life-threatening. Patients should use the lowest dose and shortest duration of PPI therapy appropriate to the condition being treated.

Chronic use of gastric acid-suppressing agents should be used cautiously and with monitoring in patients who are prone to vitamin B12 deficiency. Daily treatment with a gastric acid-suppressing medication, such as pantoprazole, over a long period of time (e.g., generally >= 2-3 years) has been associated with malabsorption of cyanocobalamin in adults. Consider the possibility of cyanocobalamin deficiency if clinical symptoms are observed.

Use pantoprazole with caution in pediatric patients with low bone density. Observational studies have suggested that proton pump inhibitors (PPIs) may be associated with an increased risk for osteoporosis related fractures of the hip, wrist, or spine. In studies, patients at highest risk of fracture were those who received high-dose (defined as multiple daily doses) and long-term PPI therapy (a year or longer). Until more data are available, 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 osteoporosis, manage their bone status according to current clinical practice, and ensure adequate vitamin D and calcium supplementation.

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.

Use pantoprazole with caution in patients with a pre-existing risk of hypocalcemia (e.g., hypoparathyroidism), hypokalemia, or hypomagnesemia; consider monitoring magnesium and calcium concentrations prior to initiating therapy and periodically while on treatment in these patients. Supplement with magnesium and/or calcium as needed and consider discontinuing proton pump inhibitor (PPI) therapy if hypomagnesemia or hypocalcemia is refractory to treatment. For patients expected to be on PPI therapy for a prolonged period of time or who take concomitant medications such as digoxin or those that may cause hypomagnesemia (e.g., diuretics), consider monitoring of serum magnesium prior to initiation and periodically during treatment. Daily treatment with a PPI over a long period of time (e.g., 3 months to more than 1 year) may lead to hypomagnesemia; cases have been reported in patients taking pantoprazole. Hypomagnesemia may lead to hypocalcemia and/or hypokalemia and may exacerbate underlying hypocalcemia in patients at risk. In most patients, the treatment of hypomagnesemia required magnesium replacement and PPI discontinuation. Low serum magnesium may lead to serious adverse reactions such as muscle spasm (tetany), seizures, and irregular heartbeat (arrhythmias). Use PPIs with caution and, if possible, avoid long term (greater than 14 days) use in patients with congenital long QT syndrome, as they may be at higher risk for arrhythmias.

The intravenous pantoprazole formulation should not be given by IV push or other parenteral routes other than IV infusion (i.e., intramuscular administration, subcutaneous administration).

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.

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.

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

Description: Pantoprazole is a gastric proton pump inhibitor (PPI), available in oral and intravenous formulations. In pediatrics, pantoprazole is primarily used for short-term treatment of symptomatic gastroesophageal reflux disease (GERD) and for short-term therapy of erosive esophagitis associated with GERD. Although many studies have demonstrated some level of benefit from the use of PPIs in the treatment of GERD or erosive esophagitis when compared to placebo, conflicting evidence on the safety and efficacy of PPIs warrants cautious use of these drugs in pediatric patients, particularly infants. PPIs are not recommended as first-line therapy for symptomatic GERD in otherwise healthy infants (1 to 11 months); nonpharmacologic measures such as diet modification and positioning strategies are recommended first-line and treatment with PPIs should be reserved for use in infants with acid reflux disease diagnosed by endoscopy (e.g., erosive esophagitis). On the basis of available research, no clear advantage has been demonstrated for the use of one PPI over another in the treatment of GERD. Instead, a key to optimizing effectiveness is tailoring dosage timing; administer traditional delayed-release PPIs 30 to 60 minutes before a meal for maximal pH control. A one-time switch to a different PPI in a refractory patient may be useful. Pantoprazole has been shown to be effective in adults for the management of duodenal ulcer or gastric ulcer, including those ulcers caused by Helicobacter pylori (H. pylori), and for Zollinger-Ellison syndrome or other hypersecretory conditions. PPIs are often used for stress ulcer prophylaxis in critically ill patients; however, evidence for benefit is lacking, and use may increase the risk of adverse reactions such as pneumonia and Clostridioides difficile (C. diff) infection. Reserve stress ulcer prophylaxis for patients with risk factors for clinically significant gastrointestinal bleeding (e.g., multiple organ dysfunction, prolonged mechanical ventilation, coagulopathy, persistent shock, concomitant corticosteroid therapy). In a retrospective case-controlled trial in 136 pediatric patients, the use of a PPI was significantly higher in the C. diff positive group compared with the C. diff negative group (OR = 4.5; 95% CI = 1.4 to 14.4). Pantoprazole does not significantly inhibit hepatic CYP isoenzymes, and compared to other currently available PPIs, it has the lowest potential for hepatic drug interactions. Pantoprazole has been used off-label clinically in pediatric patients as young as neonates and is FDA-approved for oral use in children 5 years of age and older.

For the treatment of symptomatic gastroesophageal reflux disease (GERD)* and for short-term treatment of erosive esophagitis associated with GERD:
Oral dosage:
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).
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.
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.
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 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.

For stress gastritis prophylaxis* in patients unable to take oral therapy:
Intravenous dosage:
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.
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.

For Helicobacter pylori (H. pylori) eradication*:
-in combination with amoxicillin and clarithromycin:
Oral dosage:
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.
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 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.
-in combination with amoxicillin and metronidazole:
Oral dosage:
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.
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 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.
-as part of a sequential therapy regimen:
Oral dosage:
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.
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 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.
-as part of a quadruple therapy regimen:
Oral dosage:
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.
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 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.

Maximum Dosage Limits:
-Neonates
1.2 mg/kg/day PO suggested by limited off-label data; very 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.
-Children
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.
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 PO (Max: 80 mg/day) has been used off-label for H. pylori eradication; limited data available for off-label IV use.
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.
-Adolescents
weight less than 40 kg: 20 mg/day PO is FDA-approved maximum; however, up to 2.5 mg/kg/day PO (Max: 80 mg/day) has been used off-label for H. pylori eradication; limited data available for off-label IV use.
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.

Patients with Hepatic Impairment Dosing
No dosage adjustment is necessary in adults. Use pantoprazole with caution in patients with severe hepatic disease or impairment; sufficient data are lacking in this subgroup. Specific pediatric data in hepatic impairment are not available.

Patients with Renal Impairment Dosing
Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are needed.

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

*non-FDA-approved indication

Monograph content under development

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 20-120 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.

Pharmacokinetics: Pantoprazole is administered orally or intravenously. Pantoprazole is 99% bound to human plasma proteins, primarily to albumin. 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 isoenzymes. The terminal elimination half-life of pantoprazole following IV or oral administration in adults is approximately 1 hour. About 71% of the dose is excreted renally and 18% is eliminated by biliary excretion. No unchanged pantoprazole is recovered in the urine.

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.


-Route-Specific Pharmacokinetics
Oral Route
Pantoprazole delayed-release tablets and oral suspension pellets 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.

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


-Special Populations
Pediatrics
Neonates and Infants
The pharmacokinetics of pantoprazole have been found to be highly variable in pediatric patients; although the exposure after oral doses in neonates and infants appears similar to that seen after oral doses in adults, the predicted clearance has been shown to be faster in younger pediatric patients compared to adults. One study analyzed the results of either a 0.6 mg/kg PO dose or a 1.2 mg/kg PO dose of oral granules in infants aged 1 to less than 12 months (n = 42) as compared with exposures obtained in adults at 40-mg/day dosing. Exposure increased with increasing doses of pantoprazole granules, even though wide interindividual variability was observed. Compared with that in adults receiving pantoprazole 40 mg, exposure obtained with the 1.2 mg/kg dose was similar to that obtained with adult usual dosing. The average half-life was 1.78 +/- 1.3 hours. In a trial of 20 patients (age, 10 days to 16.4 years), 156 pantoprazole concentration measurements were used to analyze the pharmacokinetics of pantoprazole doses ranging from 19.9 to 140.6 mg/1.73 m2/day. Data showed that pantoprazole clearance increased with age and weight and for typical patients aged 6 months to 5 years, the predicted pantoprazole clearance is faster than that reported in adults.

Children and Adolescents
The pharmacokinetics of pantoprazole have been found to be highly variable in pediatric patients; the predicted clearance has been shown to be faster in younger pediatric patients compared to adults. One study analyzed the results of either a 0.6 mg/kg PO dose or a 1.2 mg/kg PO dose of oral granules in children aged 1 year to less than 6 years (n = 17) as compared with exposures obtained in adults at 40-mg/day dosing. Exposure increased with increasing doses of pantoprazole granules, even though wide interindividual variability was observed. Compared with that in adults receiving pantoprazole 40 mg, exposure obtained with the 1.2 mg/kg dose was slightly lower to that obtained with adult usual dosing. The average half-life was 1.7 +/- 0.6 hours. In another trial of 20 patients (age, 10 days to 16.4 years), 156 pantoprazole concentration measurements were used to analyze the pharmacokinetics of pantoprazole doses ranging from 19.9 to 140.6 mg/1.73 m2/day. Data showed that pantoprazole clearance increased with age and weight and for typical patients aged 6 months to 5 years, the predicted pantoprazole clearance is faster than that reported in adults. In a population pharmacokinetic analysis, total clearance increased in a non-linear fashion as bodyweight increased. In a separate analysis, the pharmacokinetics of pantoprazole tablets were evaluated in pediatric patients 6 to 16 years of age. After a single 40 mg dose, the mean estimated AUC was about 39% higher in 6 to 11 year old (n = 12) and 10% higher in 12 to 16 year old (n = 11) patients, compared to AUC values in adults. The median time to peak plasma concentration (Tmax) was 2 hours.

Hepatic Impairment
Pantoprazole serum concentrations are increased in adult patients with hepatic disease. In adult patients with mild to moderate hepatic impairment, the Cmax increased 1.5-fold, elimination half-life values increased to 7 to 9 hours, and the AUC increased 5 to 7-fold relative to healthy adult subjects; minimal accumulation occurred. Modest accumulation (21% or less) of pantoprazole occurs during once daily dosing in adult patients with severe hepatic impairment but no dosage adjustment is considered necessary. Pediatric data in hepatic impairment are not available.

Renal Impairment
Pantoprazole serum concentrations are not affected by renal dysfunction. In adult patients with severe renal impairment, the pharmacokinetic parameters for pantoprazole were similar to those of healthy adult subjects. Pantoprazole is not removed by hemodialysis.

Ethnic Differences
The primary metabolic pathway of pantoprazole is demethylation by CYP2C19, with subsequent sulfation; a minor metabolic pathway is oxidation by CYP3A4 isoenzymes. CYP2C19 displays a known genetic polymorphism due to its deficiency in some sub-populations (e.g., 3% of Caucasians and African-Americans and 17% to 23% of Asians are poor metabolizers). In Japanese patients who were either poor metabolizers or extensive metabolizers of pantoprazole, there was no evidence of drug accumulation with multiple oral dosing. Poor metabolizers of pantoprazole have longer elimination half-life values ranging from 3.5 to 10 hours in adults; however, they have minimal drug accumulation (23% or less) with once daily dosing.