Pantoprazole Sodium

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 Pantoprazole sodium for injection is indicated for treatment of: gastroesophageal reflux disease (GERD) and a history of erosive esophagitis (EE) for up to 10 days in adults. pathological hypersecretory conditions including Zollinger-Ellison (ZE) Syndrome in adults. Limitations of Use The safety and effectiveness of pantoprazole sodium for injection for the treatment of upper gastrointestinal bleeding have not been established in adult or pediatric patients. 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. Pantoprazole sodium 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. (1) pathological hypersecretion conditions including Zollinger-Ellison (ZE) Syndrome in adults. (1) Limitations of Use The safety and effectiveness of pantoprazole sodium for injection 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 pantoprazole sodium for injection. (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 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. Switch to an appropriate oral medication within 10 days of starting pantoprazole sodium for injection. 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 sodium 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/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 a adult dose. 6. Infuse intravenously over a period of approximately 15 minutes through a dedicated line or through a Y-site [see Dosage and Administration (2.5)]. 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. Storage a. Store the reconstituted solution may be 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 f …

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

4 CONTRAINDICATIONS Pantoprazole sodium for injection 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 ), Adverse Reactions ( 6 )] . Proton pump inhibitors (PPIs), including pantoprazole sodium for injection, are contraindicated in patients receiving rilpivirine-containing products [see Drug Interactions ( 7 )] . Patients with a 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) ] • Acute Tubulointerstitial Nephritis [see Warnings and Precautions (5.3) ] • C lostridium difficile- Associated Diarrhea [see Warnings and Precautions (5.4) ] • Bone Fracture [see Warnings and Precautions (5.5) ] • Severe Cutaneous Adverse Reactions [See Warnings and Precautions (5.6) ] • Cutaneous and Systemic Lupus Erythematosus [see Warnings and Precautions (5.7) ] • Hepatic Effects [see Warnings and Precautions (5.8) ] • Hypomagnesemia and Mineral Metabolism [see Warnings and Precautions (5.9) ] • Fundic Gland Polyps [see Warnings and Precautions (5.10) ] Most common adverse reactions (>2%) are: headache, diarrhea, nausea, abdominal pain, vomiting, flatulence, dizziness, and arthralgia. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Hikma Pharmaceuticals USA Inc. at 1-877-845-0689 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. The safety of Pantoprazole Sodium for Injection has been established from adequate and well-controlled studies of another intravenous pantoprazole sodium product [see Clinical Studies (14) ] . Below is a display of the adverse reactions of pantoprazole sodium in these adequate and well-controlled studies. Gastroesophageal Reflux Disease (GERD) 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 1. The number of patients treated in comparative studies with intravenous pantoprazole sodium 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 intravenous pantoprazole sodium. T able 1: Adverse Reactions Reported in Clinical Trials of Adult Patients with GERD at a Frequency of >2% O ral Pantoprazole Sodium ( n=1473) % C o m parators ( n=345) % P lacebo ( n=82) % Headache 12.2 12.8 8.5 Diarrhea 8.8 9.6 4.9 Nausea 7 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 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% or less 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 Me tabolic/Nutritional: elevated CPK (creatine phosphokinase), generalized edema, elevated triglycerides, liver function tests abnormal M usculoskeletal: myalgia N e rvous: depression, vertigo Skin and Appendages: urticaria, rash, pruritus Special Senses: blurred vision Z ollinger-Ellison Syndrome In clinical studies of Zollinger-Ellison Syndrome, adverse reactions reported in 35 patients administered oral pantoprazole 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 postapproval use of other 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: G …

7 DRUG INTERACTIONS Table 2 includes drugs with clinically important drug interactions and interaction with diagnostics when administered concomitantly with Pantoprazole Sodium for Injection and instructions for preventing or managing them. Consult the labeling of concomitantly used drugs to obtain further information about interactions with PPIs. T able 2: Clinically Relevant Interactions Affecting Drugs Co-Administered with P antoprazole Sodium for Injection and Interaction with Diagnostics Antiretrovirals C linical 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 [see Clinical Pharmacology (12.3 )] . • There are other antiretroviral drugs which do not result in clinically relevant interactions with pantoprazole. I ntervention: R ilpivirine-containing products: Concomitant use with Pantoprazole Sodium for Injection is contraindicated [see Contraindications (4) ] . See prescribing information. Atazanavir: See prescribing information for atazanavir for dosing information. Nelfinavir: Avoid concomitant use with Pantoprazole Sodium for Injection. See prescribing information for nelfinavir. S a quinavir: See the prescribing information for saquinavir and for monitoring of potential saquinavir-related toxicities. Other antiretrovirals: See prescribing information for specific antiretroviral drugs. Warfarin C linical 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. I ntervention: Monitor INR and prothrombin time and adjust the dose of warfarin, if needed, to maintain the target INR range. See prescribing information for warfarin. Clopidogrel C linical Impact: Concomitant administration of pantoprazole and clopidogrel in healthy subjects had no clinically important effect on exposure to the active metabolite of clopidogrel-induced platelet inhibition [see Clinical Pharmacology (12.3) ]. I ntervention: No dose adjustment of clopidogrel is necessary when administered with an approved dose of Pantoprazole Sodium for Injection. Met h otrexate C linical 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 (5.13) ]. I ntervention: A temporary withdrawal of Pantoprazole Sodium for Injection may be considered in some patients receiving high-dose methotrexate. Drugs Dependent on Gastric pH for Absorption (e.g., iron salts, erlotinib, dasatinib, n ilotinib, mycophenoloate mofetil, ketoconazole/itraconazole) C linical Impact: Pantoprazole can reduce the absorption of other drugs due to its effect on reducing intragastric acidity I ntervention: 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 Pantoprazole Sodium for Injection and MMF. Use Pantoprazole Sodium for Injection with caution in transplant patients receiving MMF [see Clinical Pharmacology (12.3) …

8 USE IN SPECIFIC POPULATIONS Pregnancy : Based on animal data, may cause fetal harm. (8.1) 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. 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 mg/kg/day, 15 mg/kg/day, 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 p …

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 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 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 stability of the compound in aqueous solution is pH-dependent. The rate of degradation increases with decreasing pH. The reconstituted solution of pantoprazole sodium for injection is in the pH range 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), edetate disodium (1 mg), and sodium hydroxide to adjust pH. Structural Formula

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 Pantoprazole sodium for injection is supplied as a white to off white colored lyophilized powder or cake containing 40 mg of pantoprazole in a single-dose vial for reconstitution and dilution. Pantoprazole sodium for injection is available as follows: NDC 62756-129-40 – Package of 1 carton. 1 carton contains 1 vial of pantoprazole sodium for injection (1 vial contains 40 mg pantoprazole). NDC 62756-129-44 – Package of 1 carton. 1 carton contains 10 vials of pantoprazole sodium for injection (each vial containing 40 mg pantoprazole). NDC 62756-129-45 – Package of 25 cartons. Each carton (NDC 62756-129-40) contains 1 vial of pantoprazole sodium for injection (each vial containing 40 mg pantoprazole). Storage and Handling Store pantoprazole sodium for injection at 20° to 25°C (68° to 77°F); excursions permitted between 15° and 30°C (59° and 86°F) [ see USP Controlled Room Temperature ]. Protect from light.