Protonix

Indications and Usage ( 1 ) 8/2024 Dosage and Administration ( 2.1 , 2.3 ) 8/2024 Warnings and Precautions ( 5.2 , 5.5 ) 8/2024

1 INDICATIONS AND USAGE PROTONIX I.V. is indicated for treatment of: • gastroesophageal reflux disease (GERD) and a history of erosive esophagitis (EE) for up to 10 days in adults and up to 7 days in pediatric patients 3 months and older . • pathological hypersecretory conditions including Zollinger-Ellison (ZE) Syndrome in adults. Limitations of Use The safety and effectiveness of PROTONIX I.V. for the treatment of upper gastrointestinal bleeding have not been established in adult or pediatric patients. PROTONIX I.V. is a proton pump inhibitor (PPI) indicated for treatment of: • gastroesophageal reflux disease (GERD) and a history of erosive esophagitis (EE) for up to 10 days in adults and up to 7 days in pediatric patients 3 months and older. ( 1 ) • pathological hypersecretion conditions including Zollinger-Ellison (ZE) Syndrome in adults. ( 1 ) Limitations of Use The safety and effectiveness of PROTONIX I.V. for the treatment of upper gastrointestinal bleeding have not been established in adult or pediatric patients. ( 1 )

2 DOSAGE AND ADMINISTRATION GERD 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. ( 2.1 ) • Discontinue as soon as the patient is able to receive oral treatment. Switch to an appropriate oral medication within 10 days of starting PROTONIX I.V. ( 2.1 ) Pediatrics 3 Months of Age and Older: • The recommended dosage for pediatric patients 3 months of age and older is based on age and actual body weight as shown in the table. ( 2.1 ) • Administer as an intravenous infusion over 15 minutes once daily. ( 2.1 ) Age and Body Weight Recommended Dosage Regimen (up to 7 days) 3 months to less than 1 year of age Less than 12.5 kg 0.8 mg/kg once daily 12.5 kg and above 10 mg once daily 1 year to 17 years of age Up to 15 kg 10 mg once daily Greater than 15 kg up to 40 kg 20 mg once daily Greater than 40 kg 40 mg once daily • Discontinue PROTONIX I.V. as soon as the patient is able to tolerate oral treatment. Switch to an appropriate oral medication within 7 days of starting PROTONIX I.V. ( 2.1 ) Pathological Hypersecretion 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). ( 2.2 ) • For information on how to adjust dosing for individual patient needs, see the full prescribing information. ( 2.2 ) • When switching between intravenous to oral formulations of gastric acid inhibitors, consider the pharmacodynamic action of the drugs to ensure continuity of acid suppression. ( 2.2 ) Preparation and Administration Instructions • See full prescribing information for preparation and administration instructions by indication. ( 2.3 , 2.4 ) 2.1 Recommended Dosage for GERD Associated with a History of EE Adult Patients The recommended adult dosage of PROTONIX I.V. 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 PROTONIX I.V. as soon as the patient is able to tolerate oral treatment. Switch to an appropriate oral medication within 10 days of starting PROTONIX I.V. Pediatric Patients • The recommended dosage for pediatric patients 3 months of age and older is based on age and actual body weight as shown in Table 1 below. • Administer as an intravenous infusion over 15 minutes once daily. Table 1: Recommended Pediatric Dosage Regimen for GERD and a History of EE Age and Body Weight Recommended Dosage Regimen (up to 7 days) 3 months to less than 1 year of age Less than 12.5 kg 0.8 mg/kg once daily 12.5 kg and above 10 mg once daily 1 year to 17 years of age Up to 15 kg 10 mg once daily Greater than 15 kg up to 40 kg 20 mg once daily Greater than 40 kg 40 mg once daily • Discontinue PROTONIX I.V. as soon as the patient is able to tolerate oral treatment. Switch to an appropriate oral medication within 7 days of starting PROTONIX I.V. 2.2 Recommended Dosage for Pathological Hypersecretion Including Zollinger-Ellison Syndrome • The recommended adult dosage of PROTONIX I.V. 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 Pediatric or Adult Patients 1. Reconstitute each vial of PROTONIX I.V. with 10 mL of 0.9% Sodium Chloride Injection. 2. Dilute the resulting solution to a final concentration as described below: • Pedia …

3 DOSAGE FORMS AND STRENGTHS For Injection: 40 mg of pantoprazole white to off-white freeze-dried powder in a single-dose vial for reconstitution or dilution. For Injection: 40 mg pantoprazole freeze-dried powder in a single-dose vial for reconstitution or dilution. ( 3 )

4 CONTRAINDICATIONS • PROTONIX I.V. 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 [see Warnings and Precautions (5.2 , 5.4) and Adverse Reactions (6) ] . • Proton pump inhibitors (PPIs), including PROTONIX I.V., are contraindicated in patients receiving rilpivirine-containing products [see Drug Interactions (7) ] . • Known hypersensitivity to any component of the formulation or to substituted benzimidazoles. ( 4 ) • Patients receiving rilpivirine-containing products. ( 4 , 7 )

6 ADVERSE REACTIONS The following serious adverse reactions are described below and elsewhere in labeling: • Injection Site Reactions [see Warnings and Precautions (5.2) ] • Potential for Exacerbation of Zinc Deficiency [see Warnings and Precautions (5.3) ] • Acute Tubulointerstitial Nephritis [see Warnings and Precautions (5.4) ] • Clostridioides difficile- Associated Diarrhea [see Warnings and Precautions (5.5) ] • Bone Fracture [see Warnings and Precautions (5.6) ] • Severe Cutaneous Adverse Reactions [see Warnings and Precautions (5.7) ] • Cutaneous and Systemic Lupus Erythematosus [see Warnings and Precautions (5.8) ] • Hepatic Effects [see Warnings and Precautions (5.9) ] • Hypomagnesemia and Mineral Metabolism [see Warnings and Precautions (5.10) ] • Fundic Gland Polyps [see Warnings and Precautions (5.11) ] Most common adverse reactions (> 2%) are: headache, diarrhea, nausea, abdominal pain, vomiting, flatulence, dizziness, and arthralgia. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Pfizer Inc. at 1-800-438-1985 or FDA at 1-800-FDA-1088 or www.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. Gastroesophageal Reflux 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 PROTONIX I.V. 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 PROTONIX I.V. 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 Pediatrics Adverse reactions reported with single and multiple doses of PROTONIX I.V. in 18 hospitalized pediatric patients 1 to 16 years of age were generally similar to those reported in adults treated with intravenous or oral pantoprazole sodium and in pediatric patients treated with oral pantoprazole sodium in clinical trials. Additionally, upper respiratory tract infections in pediatric patients less than 16 years of age and otitis media in pediatric patients less than 1 year of age were reported with oral pantoprazole sodium. Zollinger-Ellison (ZE) Syndrome In clinical studies of ZE Syndrome, adverse reactions reported in 35 patients administered PROTONIX I.V. doses of 80 mg to 240 mg per day for up to 2 years were similar to those reported in adult patients with GERD. 6.2 Postmarketing Experience The following adverse reactions have been identified during post approval use of pantoprazole sodium products. Because these reactions …

7 DRUG INTERACTIONS Table 3 includes drugs with clinically important drug interactions and interaction with diagnostics when administered concomitantly with PROTONIX I.V. and instructions for preventing or managing them. Consult the labeling of concomitantly used drugs to obtain further information about interactions with PPIs. Table 3: Clinically Relevant Interactions Affecting Drugs Co-Administered with PROTONIX I.V. and Interaction with Diagnostics Antiretrovirals Clinical Impact: The effect of PPIs on antiretroviral drugs is variable. The clinical importance and the mechanisms behind these interactions are not always known. • Decreased exposure of some antiretroviral drugs (e.g., rilpivirine atazanavir, and nelfinavir) when used concomitantly with pantoprazole may reduce antiviral effect and promote the development of drug resistance. • Increased exposure of other antiretroviral drugs (e.g., saquinavir) when used concomitantly with pantoprazole may increase toxicity of the antiretroviral drugs . • There are other antiretroviral drugs which do not result in clinically relevant interactions with pantoprazole. Intervention: Rilpivirine-containing products: Concomitant use with PROTONIX I.V. is contraindicated [see Contraindications (4) ] . See prescribing information. Atazanavir: See prescribing information for atazanavir for dosing information. Nelfinavir: Avoid concomitant use with PROTONIX I.V. See prescribing information for nelfinavir. Saquinavir: See the prescribing information for saquinavir and monitor for potential saquinavir toxicities. Other antiretrovirals: See prescribing information. Warfarin Clinical Impact: Increased INR and prothrombin time in patients receiving PPIs, including pantoprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Intervention: Monitor INR and prothrombin time. Dose adjustment of warfarin may be needed to maintain target INR range. See prescribing information for warfarin. Clopidogrel Clinical Impact: Concomitant administration of pantoprazole and clopidogrel in healthy subjects had no clinically important effect on exposure to the active metabolite of clopidogrel or clopidogrel-induced platelet inhibition [see Clinical Pharmacology (12.3) ]. Intervention: No dose adjustment of clopidogrel is necessary when administered with an approved dose of PROTONIX I.V. Methotrexate Clinical Impact: Concomitant use of PPIs with methotrexate (primarily at high dose) may elevate and prolong serum concentrations of methotrexate and/or its metabolite hydroxymethotrexate, possibly leading to methotrexate toxicities. No formal drug interaction studies of high-dose methotrexate with PPIs have been conducted [see Warnings and Precautions (5.14) ] . Intervention: A temporary withdrawal of PROTONIX I.V. may be considered in some patients receiving high-dose methotrexate. Drugs Dependent on Gastric pH for Absorption (e.g., iron salts, erlotinib, dasatinib, nilotinib, mycophenolate mofetil, ketoconazole/itraconazole) Clinical Impact: Pantoprazole can reduce the absorption of other drugs due to its effect on reducing intragastric acidity. Intervention: Mycophenolate mofetil (MMF): Co-administration of pantoprazole sodium in healthy subjects and in transplant patients receiving MMF has been reported to reduce the exposure to the active metabolite, mycophenolic acid (MPA), possibly due to a decrease in MMF solubility at an increased gastric pH [see Clinical Pharmacology (12.3) ] . The clinical relevance of reduced MPA exposure on organ rejection has not been established in transplant patients receiving PROTONIX I.V. and MMF. Use PROTONIX I.V. with caution in transplant patients receiving MMF. See the prescribing information for other drugs dependent on gastric pH for absorption. Interactions with Investigations of Neuroendocrine Tumors Clinical Impact: CgA levels increase secondary to PPI-induced decreases in gastric acidity. The increased CgA leve …

8 USE IN SPECIFIC POPULATIONS Pregnancy : Based on animal data, may cause fetal harm. ( 8.1 ) 8.1 Pregnancy Risk Summary 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 during organogenesis in pregnant animals and have revealed no evidence of harm to the fetus due to pantoprazole in this study (see Data ) . 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 [see Use in Specific Populations (8.4) ] . 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 2 to 4% and 15 to 20%, respectively. Data Human Data Available data from published observational studies 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. 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 1996 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]). Animal Data 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 (approximatel …

12.1 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).

11 DESCRIPTION The active ingredient in PROTONIX ® I.V. (pantoprazole sodium), 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 is a white to off-white crystalline powder and is racemic. Pantoprazole has weakly basic and acidic properties. Pantoprazole sodium 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 PROTONIX I.V. is in the pH range of 9.0 to 10.5. PROTONIX I.V. 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), edetate disodium (1 mg), and sodium hydroxide to adjust pH. Chemical Structure

10 OVERDOSAGE 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. 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.

16 HOW SUPPLIED/STORAGE AND HANDLING PROTONIX ® I.V. (pantoprazole sodium) is supplied in a single-dose vial as a white to off-white freeze-dried powder for reconstitution and dilution containing 40 mg of pantoprazole. PROTONIX I.V. is available as follows: NDC Number Strength Package Size 55154-4236-5 40 mg/vial pantoprazole Overbagged with 5 x 40 mg single-dose vials in each bag WARNING: This Unit Dose package is not child resistant and is Intended for Institutional Use Only. Keep this and all drugs out of the reach of children. Storage and Handling Store PROTONIX I.V. at 20° to 25°C (68° to 77°F); excursions permitted to 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature]. Protect from light.