POTONEX

The active ingredient in Pantoprazole Sodium for Injection, a PPI, is a substituted benzimidazole, sodium 5-(difluoromethoxy)-2-[[(3,4-dimethoxy-2-pyridinyl)methyl] sulfinyl]-1 H -benzimidazole, a compound that inhibits gastric acid secretion.

Its empirical formula is

C 16 H 14 F 2 N 3 NaO 4 S, with a molecular weight of 405.4.

The structural formula is

Pantoprazole sodium, USP is a white to off-white crystalline powder and is racemic.

Pantoprazole sodium, USP has weakly basic and acidic properties.

Pantoprazole sodium, USP is freely soluble in water, very slightly soluble in phosphate buffer at pH 7.4, and practically insoluble in n-hexane.

The reconstituted solution of Pantoprazole Sodium for Injection is in the pH range of 9.0 to 10.5.

Pantoprazole Sodium for

Injection is supplied for intravenous administration as a sterile, freeze-dried powder in a single-dose clear glass vial fitted with a rubber stopper and crimp seal.

Each vial contains 40 mg pantoprazole (equivalent to 45.1 mg of pantoprazole sodium, USP), edetate disodium dihydrate, USP (1 mg), and sodium hydroxide, NF to adjust pH.

Pantoprasol is used to treat a number of cases associated with increased stomach acid release, including: visible or esophagitis retrograde retrograde retrograde (GERD), for adults and children aged 5 years and over.

Erosive pulmonary infections (Esophagitis) associated with esophagitis.

Syndrome (Zollinger-Ellison Syndrome), a case in which acid stomach is produced in excessive quantities.

Pantobrasol may be used for the stomach sore as an informal use.

Pantoprasol is used with caution and after consultation with a doctor in the following cases: low level of magnesium blood.

Hepatic diseases. osteoporosis, where the bantoprasol increases the risk of bone fractures, especially when used for long periods and high doses.

It is therefore recommended that the doctor be consulted on the best preventive methods to protect against osteoporosis.

Pantoprasol in pregnancy and lactation is classified as B safety category during pregnancy, i.e. there are no studies showing the safety of its use of pregnant women, so the competent doctor should be consulted prior to its use.

Bantoprasol is not used during breastfeeding, unless the doctor recommends.

Mechanism of Action Pantoprazole is a

PPI that suppresses the final step in gastric acid production by covalently binding to the (H + , K + )-ATPase enzyme system at the secretory surface of the gastric parietal cell.

This effect leads to inhibition of both basal and stimulated gastric acid secretion irrespective of the stimulus.

The binding to the (H + , K + )-ATPase results in a duration of antisecretory effect that persists longer than 24 hours for all doses tested (20 mg to 120 mg). 12.2 Pharmacodynamics Antisecretory Activity The magnitude and time course for inhibition of pentagastrin-stimulated acid output (PSAO) by single doses (20 to 120 mg) of pantoprazole sodium for injection were assessed in a single-dose, open-label, placebo-controlled, dose-response study.

The results of this study are shown in Table 4.

Healthy subjects received a continuous infusion for 25 hours of pentagastrin (PG) at 1 mcg/kg/h, a dose known to produce submaximal gastric acid secretion.

The placebo group showed a sustained, continuous acid output for 25 hours, validating the reliability of the testing model.

Pantoprazole sodium for injection had an onset of antisecretory activity within to 30 minutes of administration.

Doses of to 80 mg of pantoprazole sodium for injection substantially reduced the 24-hour cumulative PSAO in a dose-dependent manner, despite a short plasma elimination half-life.

Complete suppression of

PSAO was achieved with 80 mg within approximately 2 hours and no further significant suppression was seen with 120 mg. The duration of action of pantoprazole sodium for injection was 24 hours.

Table 4: Gastric Acid Output (mEq/hr, Mean ± SD) and Percent Inhibition a (Mean ± SD) of Pentagastrin Stimulated Acid Output Over 24 Hours Following a Single Dose of Pantoprazole Sodium for Injection b in Healthy Subjects ------2 hours-----

• Treatment Dose Acid Output % Inhibition Acid Output % Inhibition Acid Output % Inhibition Acid Output % Inhibition 0 mg (Placebo, n=4) 39 ± 21 NA 26 ± 14 NA 32 ± 20 NA 38 ± 24 NA 20 mg (n=4-6) 13 ± 18 47 ± 27 6 ± 8 83 ± 21 20 ± 20 54 ± 44 30 ± 23 45 ± 43 40 mg (n=8) 5 ± 5 82 ± 11 4 ± 4 90 ± 11 11 ± 10 81 ± 13 16 ± 12 52 ± 36 80 mg (n=8) 0.1 ± 0.2 96 ± 6 0.3 ± 0.4 99 ± 1 2 ± 2 90 ± 7 7 ± 4 63 ± 18 a Compared to individual subject baseline prior to treatment with pantoprazole sodium for injection. b Inhibition of gastric acid output and the percent inhibition of stimulated acid output in response to pantoprazole sodium for injection may be higher after repeated doses.

NA = not applicable.

In one study of gastric pH in healthy subjects, pantoprazole was administered orally (40 mg enteric coated tablets) or pantoprazole sodium for injection (40 mg) once daily for 5 days and pH was measured for 24 hours following the fifth dose.

The outcome measure was median percent of time that pH was ≥4 and the results were similar for intravenous and oral medications; however, the clinical significance of this parameter is unknown.

Serum gastrin concentrations were assessed in two placebo-controlled studies.

In a 5-day study of oral pantoprazole with and 60 mg doses in healthy subjects, following the last dose on day 5, median 24-hour serum gastrin concentrations were elevated by 3.

• to 4-fold compared to placebo in both and 60 mg dose groups.

However, by 24 hours following the last dose, median serum gastrin concentrations for both groups returned to normal levels.

In another placebo-controlled, 7-day study of 40 mg intravenous or oral pantoprazole in patients with GERD and a history of EE, the mean serum gastrin concentration increased approximately 50% from baseline and as compared with placebo, but remained within the normal range.

During 6 days of repeated administration of pantoprazole sodium for injection in patients with ZE Syndrome, consistent changes of serum gastrin concentrations from baseline were not observed.

Enterochromaffin-Like (ECL) Cell Effects There are no data available on the effects of intravenous pantoprazole sodium on ECL cells.

In a nonclinical study in

Sprague-Dawley rats, lifetime exposure (24 months) to oral pantoprazole at doses of 0.5 to 200 mg/kg/day resulted in dose-related increases in gastric ECL-cell proliferation and gastric neuroendocrine (NE)-cell tumors.

NE-cell tumors in rats may result from chronic elevation of serum gastrin concentrations.

The high density of

ECL cells in the rat stomach makes this species highly susceptible to the proliferative effects of elevated gastrin concentrations produced by PPIs.

However, there were no observed elevations in serum gastrin following the administration of oral pantoprazole at a dose of 0.5 mg/kg/day. In a separate study, a gastric NE-cell tumor without concomitant ECL-cell proliferative changes was observed in 1 female rat following 12 months of dosing with oral pantoprazole at 5 mg/kg/day and a 9 month off-dose recovery.

In a clinical pharmacology study, pantoprazole 40 mg given orally once daily for 2 weeks had no effect on the levels of the following hormones: cortisol, testosterone, triiodothyronine (T 3 ), thyroxine (T 4 ), thyroid-stimulating hormone, thyronine-binding protein, parathyroid hormone, insulin, glucagon, renin, aldosterone, follicle-stimulating hormone, luteinizing hormone, prolactin and growth hormone.

In a 1-year study of GERD patients treated with pantoprazole 40 mg or 20 mg, there were no changes from baseline in overall levels of T 3, T 4, and TSH. 12.3 Pharmacokinetics Pantoprazole sodium for injection peak serum concentration (C max ) and area under the serum concentration-time curve (AUC) increase in a manner proportional to intravenous doses from 10 mg to 80 mg. Pantoprazole sodium for injection does not accumulate and its pharmacokinetics are unaltered with multiple daily dosing.

Following the administration of pantoprazole sodium for injection, the serum concentration of pantoprazole sodium for injection declines biexponentially with a terminal elimination half-life of approximately one hour.

In CYP2C19 extensive metabolizers with normal liver function receiving a 40 mg dose of pantoprazole sodium for injection by constant rate over 15 minutes, the peak concentration (C max ) is 5.52 ±1.42 mcg/mL and the total area under the plasma concentration versus time curve (AUC) is 5.4 ±1.5 mcg hr/mL.

The total clearance is 7.6 to 14 L/h.

The apparent volume of distribution of pantoprazole is approximately to 23.6 L, distributing mainly in extracellular fluid.

The serum protein binding of pantoprazole is about 98%, primarily to albumin.

Pantoprazole is extensively metabolized in the liver through the cytochrome P450 (CYP) system.

Pantoprazole metabolism is independent of the route of administration (intravenous or oral).

The main metabolic pathway is demethylation, by CYP2C19, with subsequent sulfation; other metabolic pathways include oxidation by CYP3A4.

There is no evidence that any of the pantoprazole metabolites have significant pharmacologic activity.

CYP2C19 displays a known genetic polymorphism due to its deficiency in some sub-populations (e.g., 3% of Whites and African-Americans and to 23% of Asians).

Although these sub-populations of slow pantoprazole metabolizers have elimination half-life values from 3.5 to 10 hours, they still have minimal accumulation (23% or less) with once daily dosing.

After administration of a single intravenous dose of 14 C-labeled pantoprazole sodium to healthy, extensive CYP2C19 metabolizers, approximately 71% of the dose was excreted in the urine with 18% excreted in the feces through biliary excretion.

There was no renal excretion of unchanged pantoprazole.

After repeated intravenous administration in elderly subjects (65 to 76 years of age), the AUC and elimination half-life values of pantoprazole were similar to those observed in younger subjects.

After oral administration there was a modest increase in the AUC and C max of pantoprazole in women compared to men.

However, weight-normalized clearance values are similar in women and men.

In patients with severe renal impairment, pharmacokinetic parameters for pantoprazole were similar to those of healthy subjects.

In patients with mild to severe hepatic impairment (Child-Pugh Class A to C), maximum pantoprazole concentrations increased only slightly (1.5-fold) relative to healthy subjects when pantoprazole sodium was administered orally.

Although serum half-life values increased to to 9 hours and AUC values increased by 5­.

• to 7-fold in hepatic-impaired patients, these increases were no greater than those observed in CYP2C19 poor metabolizers, where no dosage adjustment is warranted.

These pharmacokinetic changes in hepatic-impaired patients result in minimal drug accumulation following once daily, multiple-dose administration.

Oral pantoprazole doses higher than 40 mg per day have not been studied in hepatically impaired patients.

Drug Interaction Studies Effect of Other Drugs on Pantoprazole Pantoprazole is metabolized mainly by CYP2C19 and to minor extents by CYPs 3A4, 2D6 and 2C9.

In in vivo drug-drug interaction studies with CYP2C19 substrates (diazepam [also a CYP3A4 substrate] and phenytoin [also a CYP3A4 inducer]), nifedipine, midazolam, and clarithromycin (CYP3A4 substrates), metoprolol (a CYP2D6 substrate), diclofenac, naproxen and piroxicam (CYP2C9 substrates) and theophylline (a CYP1A2 substrate) in healthy subjects, the pharmacokinetics of pantoprazole were not significantly altered.

Effect of Pantoprazole on Other Drugs Clopidogrel Clopidogrel is metabolized to its active metabolite in part by CYP2C19.

In a crossover clinical study, 66 healthy subjects were administered clopidogrel (300 mg loading dose followed by 75 mg per day) alone and with oral pantoprazole (80 mg at the same time as clopidogrel) for 5 days.

On Day 5, the mean AUC of the active metabolite of clopidogrel was reduced by approximately 14% (geometric mean ratio was 86%, with 90% CI of to 93%) when pantoprazole sodium was coadministered with clopidogrel as compared to clopidogrel administered alone.

Pharmacodynamic parameters were also measured and demonstrated that the change in inhibition of platelet aggregation (induced by 5 micromolar ADP) was correlated with the change in the exposure to clopidogrel active metabolite.

The clinical significance of this finding is not clear.

Mofetil (MMF) Administration of oral pantoprazole 40 mg twice daily for 4 days and a single 1,000 mg dose of MMF approximately one hour after the last dose of pantoprazole sodium to 12 healthy subjects in a cross-over study resulted in a 57% reduction in the C max and 27% reduction in the AUC of MPA.

Transplant patients receiving approximately 2,000 mg per day of MMF (n=12) were compared to transplant patients receiving approximately the same dose of MMF and oral pantoprazole 40 mg per day (n=21).

There was a 78% reduction in the C max and a 45% reduction in the AUC of MPA in patients receiving both pantoprazole sodium and MMF.

In vivo studies also suggest that pantoprazole does not significantly affect the kinetics of other drugs (theophylline, diazepam [and its active metabolite, desmethyldiazepam], phenytoin, metoprolol, nifedipine, carbamazepine, midazolam, clarithromycin, diclofenac, naproxen, piroxicam and oral contraceptives [levonorgestrel/ethinyl estradiol]).

In other in vivo studies, digoxin, ethanol, glyburide, antipyrine, caffeine, metronidazole, and amoxicillin had no clinically relevant interactions with pantoprazole.

Although no significant dru.

Pantoprazole belongs to a proton pump group of inhibitors, used to treat vascular retrogrades in children and adults, reducing the amount of acid produced in the stomach.

Pantoprasol mechanism works to reduce the amount of acid produced by the stomach; by disrupting the final stage of the acid production process, thereby helping to reduce the acidity and the incineration of the stomach, thereby helping to heal and recover the stomach lining from irritation and sores.

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The following serious adverse reactions are described below and elsewhere in labeling: Injection Site Reactions Potential for Exacerbation of Zinc Deficiency Acute Tubulointerstitial Nephritis Clostridioides difficile -Associated Diarrhea Bone Fracture Severe Cutaneous Adverse Reactions Cutaneous and Systemic Lupus Erythematosus Hepatic Effects Hypomagnesemia and Mineral Metabolism Fundic Gland Polyps Most common adverse reactions (> 2%) are: headache, diarrhea, nausea, abdominal pain, vomiting, flatulence, dizziness, and arthralgia.

To report SUSPECTED ADVERSE

REACTIONS, contact Meitheal Pharmaceuticals Inc.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.

Disease (GERD) Adults Safety in nine randomized comparative US clinical trials in patients with GERD included 1,473 patients on oral pantoprazole (20 mg or 40 mg), 299 patients on an H 2 -receptor antagonist, 46 patients on another PPI, and 82 patients on placebo.

The most frequently occurring adverse reactions are listed in Table 2.

The number of patients treated in comparative studies with pantoprazole sodium for injection is limited; however, the adverse reactions seen were similar to those seen in the oral studies.

Thrombophlebitis was the only new adverse reaction identified with pantoprazole sodium for injection.

Table 2: Adverse Reactions Reported in Clinical Trials of Adult Patients with GERD at a Frequency of > 2% Oral Pantoprazole Sodium (n=1473) % Comparators (n=345) % Placebo (n=82) % Headache 12.2 12.8 8.5 Diarrhea 8.8 9.6 4.9 Nausea 7.0 5.2 9.8 Abdominal pain 6.2 4.1 6.1 Vomiting 4.3 3.5 2.4 Flatulence 3.9 2.9 3.7 Dizziness 3.0 2.9 1.2 Arthralgia 2.8 1.4 1.2 Additional adverse reactions that were reported for oral pantoprazole sodium in US clinical trials with a frequency of ≤2% are listed below by body system: Body as a Whole: allergic reaction, fever, photosensitivity reaction, facial edema, thrombophlebitis (intravenous only) Gastrointestinal: constipation, dry mouth, hepatitis Hematologic: leukopenia (reported in ex-US clinical trials only), thrombocytopenia Metabolic/Nutritional: elevated CPK (creatine phosphokinase), generalized edema, elevated triglycerides, liver function tests abnormal Musculoskeletal: myalgia Nervous: depression, vertigo Skin and Appendages: urticaria, rash, pruritus Special Senses: blurred vision Zollinger-Ellison (ZE) Syndrome In clinical studies of ZE Syndrome, adverse reactions reported in 35 patients administered pantoprazole sodium for injection doses of 80 mg to 240 mg per day for up to 2 years were similar to those reported in adult patients with GERD.

Pediatric use information is approved for Pfizer Inc.'s PROTONIX® I.V. (pantoprazole sodium) for Injection.

However, due to Pfizer Inc.'s marketing exclusivity rights, this drug product is not labeled with that information. 6.2 Postmarketing Experience The following adverse reactions have been identified during post approval use of pantoprazole sodium products.

Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

These adverse reactions are listed below by body system: General disorders and administration conditions: asthenia, fatigue, malaise Immune system disorders: anaphylaxis (including anaphylactic shock), systemic lupus erythematosus.

Investigations: weight changes Skin and subcutaneous tissue disorders: severe dermatologic reactions (some fatal), including erythema multiforme, SJS/TEN, DRESS, AGEP, angioedema (Quincke’s edema) and cutaneous lupus erythematosus Musculoskeletal disorders: rhabdomyolysis, bone fracture Renal and genitourinary disorders: acute tubulointerstitial nephritis, erectile dysfunction Hepatobiliary disorders: hepatocellular damage leading to jaundice and hepatic failure Psychiatric disorder: hallucinations, confusion, insomnia, somnolence Metabolism and nutritional disorders: hyponatremia, hypomagnesemia, hypocalcemia, hypokalemia, hyponatremia.

Infections and infestations: Clostridioides difficile associated diarrhea Hematologic: pancytopenia, agranulocytosis Nervous: ageusia, dysgeusia Gastrointestinal disorders: fundic gland polyps.

Experience in patients taking very high doses of pantoprazole (greater than 240 mg) is limited.

Adverse reactions seen in spontaneous reports of overdose generally reflect the known safety profile of pantoprazole sodium.

Pantoprazole is not removed by hemodialysis.

In case of overdose, treatment should be symptomatic and supportive.

Single intravenous doses of pantoprazole at 378, 230, and 266 mg/kg (38, 46, and 177 times the recommended human dose based on body surface area) were lethal to mice, rats and dogs, respectively.

The symptoms of acute toxicity were hypoactivity, ataxia, hunched sitting, limb-splay, lateral position, segregation, absence of ear reflex, and tremor.

Pantoprazole sodium is contraindicated in patients with known hypersensitivity reactions including anaphylaxis to the formulation or any substituted benzimidazole.

Hypersensitivity reactions may include anaphylaxis, anaphylactic shock, angioedema, bronchospasm, acute tubulointerstitial nephritis, and urticaria.

Proton pump inhibitors (PPIs), including pantoprazole sodium, are contraindicated in patients receiving rilpivirine-containing products.

Known hypersensitivity to any component of the formulation or to substituted benzimidazoles.

Patients receiving rilpivirine-containing products.

and a History of EE Adults: The recommended dosage is 40 mg once daily by intravenous injection (over at least 2 minutes) or intravenous infusion (for 15 minutes) for up to 10 days.

Discontinue as soon as the patient is able to receive oral treatment.

Switch to an appropriate oral medication within 10 days of starting pantoprazole sodium for injection.

Conditions, Including ZE Syndrome The recommended adult dosage is 80 mg every 12 hours by intravenous injection (over at least 2 minutes) or intravenous infusion (for 15 minutes).

For information on how to adjust dosing for individual patient needs, see the full prescribing information.

When switching between intravenous to oral formulations of gastric acid inhibitors, consider the pharmacodynamic action of the drugs to ensure continuity of acid suppression.

See full prescribing information for preparation and administration instructions by indication. 2.1 Recommended Dosage for GERD Associated with a History of EE Adult Patients The recommended adult dosage of pantoprazole sodium for injection is 40 mg once daily by intravenous injection (over at least 2 minutes) or intravenous infusion (for 15 minutes) for up to 10 days.

Discontinue pantoprazole sodium for injection as soon as the patient is able to tolerate oral treatment.

Pediatric use information is approved for Pfizer Inc.'s PROTONIX® I.V. (pantoprazole sodium) for Injection.

However, due to Pfizer Inc.'s marketing exclusivity rights, this drug product is not labeled with that information. 2.2 Recommended Dosage for Pathological Hypersecretion Including Zollinger-Ellison Syndrome The recommended adult dosage of pantoprazole for injection is 80 mg every 12 hours by intravenous injection (over at least 2 minutes) or intravenous infusion (for 15 minutes).

Adjust the frequency of dosing to individual patient needs based on acid output measurements.

In those patients who need a higher dosage, 80 mg intravenously every 8 hours is expected to maintain acid output below 10 mEq/h.

When switching between intravenous to oral formulations of gastric acid inhibitors, consider the pharmacodynamic action of the drugs to ensure continuity of acid suppression. 2.3 Preparation and Administration Instructions for GERD Associated with a History of EE 15-Minute Intravenous Infusion for Adult Patients 1.

Reconstitute each vial of pantoprazole sodium for injection with 10 mL of 0.9% Sodium Chloride Injection. 2.

Dilute the resulting solution to a final concentration as described below: Adult patients: Further dilute with 100 mL 5% Dextrose Injection or 0.9% Sodium Chloride Injection to a final concentration of approximately 0.4 mg per mL. 3.

Inspect the diluted pantoprazole sodium for injection solution visually for particulate matter and discoloration prior to and during administration. 4.

Withdraw the dose of the diluted pantoprazole sodium for injection solution for an adult dose. 6.

Infuse intravenously over a period of approximately 15 minutes through a dedicated line or through a Y-site. 7.

Flush the intravenous line before and after administration of pantoprazole sodium for injection with either 5% Dextrose Injection or 0.9% Sodium Chloride Injection.

Store the reconstituted solution for up to 6 hours at room temperature up to 30°C (86°F) prior to further dilution. b.

Store the diluted solution at room temperature up to 30°C (86°F) and must be used within 24 hours from the time of initial reconstitution. c.

Do not freeze the reconstituted or diluted solution. 2-Minute Intravenous Injection for Adult Patients 1.

Reconstitute each vial of pantoprazole sodium for injection with 10 mL of 0.9% Sodium Chloride Injection, to a final concentration of approximately 4 mg per mL. 2.

Withdraw the dose of 40 mg of reconstituted pantoprazole sodium for injection solution. 3.

Administer intravenously over a period of at least 2 minutes. 5.

Store the reconstituted solution for up to 24 hours at room temperature up to 30°C (86°F) prior to intravenous infusion.

Do not freeze the reconstituted solution.

However, due to Pfizer Inc.'s marketing exclusivity rights, this drug product is not labeled with that information. 2.4 Preparation and Administration Instructions for Pathological Hypersecretion Including Zollinger-Ellison Syndrome 15-Minute Intravenous Infusion Reconstitute each vial of pantoprazole sodium for injection with 10 mL of 0.9% Sodium Chloride Injection.

Combine the contents of the two vials and dilute with 80 mL of 5% Dextrose Injection or Sodium Chloride Injection to a total volume of 100 mL with a final concentration of approximately 0.8 mg per mL.

Inspect the diluted pantoprazole sodium for injection solution visually for particulate matter and discoloration prior to and during administration.

Administer intravenously over a period of approximately 15 minutes at a rate of approximately 7 mL/min. Flush the intravenous line before and after administration of pantoprazole sodium for injection with either 5% Dextrose Injection or 0.9% Sodium Chloride Injection.

The reconstituted solution can be stored at room temperature up to 30°C (86°F) for up to 6 hours prior to further dilution.

Once further diluted, the diluted solution can be stored at room temperature up to 30°C (86°F) for up to 24 hours from the time of initial reconstitution.

Do not freeze the reconstituted or diluted solution. 2-Minute Intravenous Injection Reconstitute each vial of pantoprazole sodium for injection with 10 mL of 0.9% Sodium Chloride Injection, per vial to a final concentration of approximately 4 mg per mL.

Administer the total volume from both vials intravenously over a period of at least 2 minutes.

The reconstituted solution may be stored for up to 24 hours at room temperature.

Do not freeze the reconstituted solution. 2.5 Compatibility Information Administer pantoprazole sodium for injection intravenously through a dedicated line or through a Y-site.

When administering through a

Y-site, pantoprazole sodium for injection is compatible with the following solutions: o 5% Dextrose Injection o 0.9% Sodium Chloride Injection Midazolam hydrochloride is incompatible with Y-site administration of pantoprazole sodium for injection.

Pantoprazole sodium for injection may not be compatible with products containing zinc.

Stop administering pantoprazole sodium for injection immediately through a Y-site if precipitation or discoloration occurs.

Pantoprazole Sodium for

Injection is a white to off-white freeze-dried powder for reconstitution and dilution is supplied as follows: NDC Pantoprazole Sodium for Injection Package Factor 71288.

• 600 -92 40 mg of pantoprazole in a Single-Dose Vial 10 vials per carton Storage and Handling Store Pantoprazole Sodium for Injection at 20° to 25°C (68° to 77°F); excursions permitted to 15° to 30°C (59° to 86°F).

Protect from light.

Discard unused portion.

The container closure is not made with natural rubber latex.

Available data from published observational studies did not demonstrate an association of major malformations or other adverse pregnancy outcomes with pantoprazole.

In animal reproduction studies, no evidence of adverse development outcomes was observed with pantoprazole sodium.

Reproduction studies have been performed in rats at intravenous doses up to 20 mg/kg/day (4 times the recommended human dose) and rabbits at intravenous doses up to 15 mg/kg/day (6 times the recommended human dose) with administration of pantoprazole sodium during organogenesis in pregnant animals and have revealed no evidence of harm to the fetus due to pantoprazole in this study.

A pre-and post-natal development toxicity study in rats with additional endpoints to evaluate the effect on bone development was performed with pantoprazole sodium.

Oral pantoprazole doses of 5, 15, and 30 mg/kg/day (approximately 1, 3, and 6 times the human dose of 40 mg/day) were administered to pregnant females from gestation day (GD) 6 through lactation day (LD) 21.

Changes in bone morphology were observed in pups exposed to pantoprazole in utero and through milk during the period of lactation as well as by oral dosing from postnatal day (PND) 4 through PND 21.

There were no drug-related findings in maternal animals.

Advise pregnant women of the potential risk of fetal harm.

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown.

All pregnancies have a background risk of birth defect, loss or other adverse outcomes.

In the

U.S. general population, the estimated background risk of major birth defects and miscarriage in the clinically recognized pregnancies is to 4% and to 20%, respectively.

Available data from published observational studies failed to demonstrate an association of adverse pregnancy-related outcomes and pantoprazole sodium use.

Methodological limitations of these observational studies cannot definitely establish or exclude any drug-associated risk during pregnancy.

In a prospective study by the European Network of Teratology Information Services, outcomes from a group of 53 pregnant women administered median daily doses of 40 mg pantoprazole were compared to a control group of 868 pregnant women who did not take any proton pump inhibitors (PPIs).

There was no difference in the rate of major malformations between women exposed to PPIs and the control group, corresponding to a Relative Risk (RR)=0.55, [95% Confidence Interval (CI) 0.08-3.95. In a population-based retrospective cohort study covering all live births in Denmark from to 2008, there was no significant increase in major birth defects during analysis of first trimester exposure to pantoprazole in 549 live births. 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 0.86-1.45] and for spontaneous abortions OR=1.29 [95% CI 0.84-1.97]).

Reproduction studies have been performed in rats at intravenous pantoprazole doses up to 20 mg/kg/day (4 times the recommended human dose based on body surface area) and rabbits at intravenous doses up to 15 mg/kg/day (6 times the recommended human dose based on body surface area) with administration of pantoprazole sodium during organogenesis in pregnant animals and have revealed no evidence of impaired fertility or harm to the fetus due to pantoprazole.

A pre.

• and post-natal development toxicity study in rats with additional endpoints to evaluate the effect on bone development was performed with pantoprazole sodium.

Oral pantoprazole doses of 5, 15, and 30 mg/kg/day (approximately 1, 3, and 6 times the human dose of 40 mg/day on a body surface area basis) were administered to pregnant females from gestation day (GD) 6 through lactation day (LD) 21.

On postnatal day (PND 4) through PND 21, the pups were administered oral doses at 5, 15, and 30 mg/kg/day (approximately 1, 2.3, and 3.2 times the exposure (AUC) in humans at a dose of 40 mg).

During the preweaning dosing phase (PND to 21) of the pups, there were increased mortality and/or moribundity and decreased body weight and body weight gain at 5 mg/kg/day (approximately equal exposures (AUC) in humans receiving the 40 mg dose) and higher doses.

On PND 21, decreased mean femur length and weight and changes in femur bone mass and geometry were observed in the offspring at 5 mg/kg/day (approximately equal exposures (AUC) in humans at the 40 mg dose) and higher doses.

The femur findings included lower total area, bone mineral content and density, periosteal and endosteal circumference, and cross-sectional moment of inertia.

There were no microscopic changes in the distal femur, proximal tibia, or stifle joints.

Changes in bone parameters were partially reversible following a recovery period, with findings on PND 70 limited to lower femur metaphysis cortical/subcortical bone mineral density in female pups at 5 mg/kg/day (approximately equal exposures (AUC) in humans at the 40 mg dose) and higher doses.

The safety and effectiveness of pantoprazole sodium for injection have not been established in patients less than 3 months of age for the treatment of GERD and a history of EE.

The safety and effectiveness of pantoprazole sodium for injection have not been established in pediatric patients for the treatment of pathological hypersecretory conditions including ZE syndrome.

In neonatal/juvenile animals (rats and dogs) toxicities were similar to those observed in adult animals, including gastric alterations, decreases in red cell mass, increases in lipids, enzyme induction and hepatocellular hypertrophy.

An increased incidence of eosinophilic chief cells in adult and neonatal/juvenile rats, and atrophy of chief cells in adult rats and in neonatal/juvenile dogs, was observed in the fundic mucosa of stomachs in repeated-dose studies.

Full to partial recovery of these effects were noted in animals of both age groups following a recovery period.

Pediatric use information is approved for Pfizer Inc.'s PROTONIX® I.V. (pantoprazole sodium) for Injection.

However, due to Pfizer Inc.'s marketing exclusivity rights, this drug product is not labeled with that information.

Of 286 patients in clinical studies of intravenous pantoprazole sodium in patients with GERD and a history of EE, 86 (43%) were 65 years of age and over.

No overall differences in safety or effectiveness were observed between these geriatric and younger adult patients, and other reported clinical experience with oral pantoprazole sodium has not identified differences in responses between geriatric and younger adult patients, but greater sensitivity of some older individuals cannot be ruled out.

No clinically meaningful differences in the pharmacokinetics of pantoprazole were observed in geriatric subjects compared to younger adult subjects.