Pantoprazole Sodium

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 for Injection 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 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 [ 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 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. Inspect the diluted pantoprazole sodium for injection solution visually for particulate matter and discoloration prior to and during administration. 4. Administer intravenously over a period of at least 2 minutes. 5. 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 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. 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. 2.4 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. Storage 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. Inspect the diluted pantoprazole sodium for injection solution visually for particulate matter and discoloration prior to and during administration. Administer the total volume from both vials intravenously over a period of at least 2 minutes. 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 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 [see Warnings and Precautions (5.3) ] . Stop administering pantoprazole sodium for injection immediately through a Y-site if precipitation or discoloration occurs.

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 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 [see Warnings and Precautions (5.2 , 5.4 ) and Adverse Reactions (6) ] . Proton pump inhibitors (PPIs), including pantoprazole sodium, 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 )

5 WARNINGS AND PRECAUTIONS Gastric Malignancy : In adults, symptomatic response to therapy with pantoprazole sodium does not preclude the presence of gastric malignancy. Consider additional follow-up and diagnostic testing. ( 5.1 ) Injection Site Reactions : Thrombophlebitis is associated with the administration of intravenous pantoprazole sodium. Assess the patient and remove the catheter if clinically indicated. ( 5.2 ) Potential Exacerbation of Zinc Deficiency : Consider zinc supplementation in patients who are prone to zinc deficiency. Caution should be used when other EDTA containing products are also co-administered intravenously. ( 5.3 ) Acute Tubulointerstitial Nephritis : Discontinue treatment and evaluate patients. ( 5.4 ) Clostridioides difficile -Associated Diarrhea : PPI therapy may be associated with increased risk. ( 5.5 ) Bone Fracture : Long-term and multiple daily dose PPI therapy may be associated with an increased risk for osteoporosis-related fractures of the hip, wrist, or spine. ( 5.6 ) Severe Cutaneous Adverse Reactions : Discontinue at the first signs or symptoms of severe cutaneous adverse reactions or other signs of hypersensitivity and consider further evaluation. ( 5.7 ) Cutaneous and Systemic Lupus Erythematosus : Mostly cutaneous; new onset or exacerbation of existing disease; discontinue treatment and refer to specialist for evaluation. ( 5.8 ) Hepatic Effects : Elevations of transaminases observed. ( 5.9 ) Hypomagnesemia and Mineral Metabolism : Reported rarely with prolonged treatment with PPIs. ( 5.10 ) Fundic Gland Polyp s : Risk increases with long-term use, especially beyond one year. Use the shortest duration of therapy. ( 5.11 ) 5.1 Presence of Gastric Malignancy In adults, symptomatic response to therapy with pantoprazole sodium does not preclude the presence of gastric malignancy. Consider additional follow-up and diagnostic testing in adult patients who have a suboptimal response or an early symptomatic relapse after completing treatment with a PPI. In older patients, also consider an endoscopy. 5.2 Injection Site Reactions Thrombophlebitis was associated with the administration of pantoprazole sodium. Assess the patient and remove the catheter if clinically indicated. 5.3 Potential for Exacerbation of Zinc Deficiency Pantoprazole sodium for injection contains edetate disodium (the salt form of EDTA), a chelator of metal ions including zinc. Therefore, zinc supplementation should be considered in patients treated with pantoprazole sodium for injection who are prone to zinc deficiency. Caution should be used when other EDTA containing products are also co-administered intravenously [see Dosage and Administration (2.5) ] . 5.4 Acute Tubulointerstitial Nephritis Acute tubulointerstitial nephritis (TIN) 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). 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 sodium and evaluate patients with suspected acute TIN [see Contraindications (4) ] . 5.5 Clostridioides difficile -Associated Diarrhea Published observational studies suggest that PPI therapy like pantoprazole sodium may be associated with an increased risk of Clostridioides difficile associated diarrhea, especially in hospitalized patients. This diagnosis should be considered for diarrhea that does not improve [see Adverse Reactions (6.2) ]. Patients should use the lowest dose and shortest duration of PPI therapy appropriate to the condition being treated. 5.6 Bone Fracture Several published observational studies suggest that PPI therapy may be associated with an increased risk for osteoporosis-related fractures of the hip, wrist, or spine. The risk of fracture was increased in patients who received high-dose, defined as multiple daily doses, and long-term PPI therapy (a year or longer). Patients should use the lowest dose and shortest duration of PPI therapy appropriate to the condition being treated. Patients at risk for osteoporosis-related fractures should be managed according to established treatment guidelines [see Dosage and Administration (2.2 , 2.4 ) and Adverse Reactions (6) ] . 5.7 Severe Cutaneous Adverse Reactions Severe cutaneous adverse reactions, including erythema multiforme, Stevens-Johnson syndrome (SJS), 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 [see Adverse Reactions (6.2) ] . Discontinue pantoprazole sodium at the first signs or symptoms of severe cutaneous adverse reactions or other signs of hypersensitivity and consider further evaluation. 5.8 Cutaneous and Systemic Lupus Erythematosus Cutaneous lupus erythematosus (CLE) and systemic lupus erythematosus (SLE) have been reported in patients taking PPIs, including pantoprazole sodium. These events have occurred as both new onset and an exacerbation of existing autoimmune disease. The majority of PPI-induced lupus erythematous cases were CLE. The most common form of CLE reported in patients treated with PPIs was subacute CLE (SCLE) and occurred within weeks to years after continuous drug therapy in patients ranging from infants to the elderly. Generally, histological findings were observed without organ involvement. Systemic lupus erythematosus (SLE) is less commonly reported than CLE in patients receiving PPIs. PPI associated SLE is usually milder than non-drug induced SLE. Onset of SLE typically occurred within days to years after initiating treatment primarily in patients ranging from young adults to the elderly. The majority of patients presented with rash; however, arthralgia and cytopenia were also reported. Avoid administration of PPIs for longer than medically indicated. If signs or symptoms consistent with CLE or SLE are noted in patients receiving pantoprazole sodium, 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 (e.g., ANA) may be positive and elevated serological test results may take longer to resolve than clinical manifestations. 5.9 Hepatic Effects Mild, transient transaminase elevations have been observed in clinical studies. The clinical significance of this finding in a large population of subjects administered pantoprazole sodium is unknown [see Adverse Reactions (6) ]. 5.10 Hypomagnesemia and Mineral Metabolism Hypomagnesemia, symptomatic and asymptomatic, has been reported rarely in patients treated with PPIs for at least three months, and in most cases after a year of therapy. Serious adverse events include tetany, arrhythmias, and seizures. Hypomagnesemia may lead to hypocalcemia and/or hypokalemia and may exacerbate underlying hypocalcemia in at-risk patients. In most patients, treatment of hypomagnesemia required magnesium replacement and discontinuation of the PPI. For patients expected to be on prolonged treatment or who take PPIs with medications such as digoxin or drugs that may cause hypomagnesemia (e.g., diuretics), health care professionals may consider monitoring magnesium levels prior to initiation of PPI treatment and periodically [see Adverse Reactions (6.2) ]. Consider monitoring magnesium and calcium levels prior to initiation of pantoprazole sodium and periodically while on treatment in patients with a preexisting risk of hypocalcemia (e.g., hypoparathyroidism). Supplement with magnesium and/or calcium as necessary. If hypocalcemia is refractory to treatment, consider discontinuing the PPI. 5.11 Fundic Gland Polyps PPI use is associated with an increased risk of fundic gland polyps that increases with long-term use, especially beyond one year. Most PPI users who developed fundic gland polyps were asymptomatic and fundic gland polyps were identified incidentally on endoscopy. Use the shortest duration of PPI therapy appropriate to the condition being treated. 5.12 Interference with Investigations for Neuroendocrine Tumors Serum chromogranin A (CgA) levels increase secondary to drug-induced decreases in gastric acidity. The increased CgA level may cause false positive results in diagnostic investigations for neuroendocrine tumors. Healthcare providers should temporarily stop pantoprazole sodium treatment at least 14 days before assessing CgA levels and consider repeating the test if initial CgA levels are high. If serial tests are performed (e.g., for monitoring), the same commercial laboratory should be used for testing, as reference ranges between tests may vary [see Clinical Pharmacology (12.2) ] . 5.13 Interference with Urine Screen for THC Pantoprazole sodium may produce false-positive urine screen for THC (tetrahydrocannabinol) [see Drug Interactions (7) ]. 5.14 Concomitant Use of Pantoprazole Sodium with Methotrexate Literature suggests that concomitant use of PPIs with methotrexate (primarily at high dose; see methotrexate prescribing information) may elevate and prolong serum levels of methotrexate and/or its metabolite, possibly leading to methotrexate toxicities. In high-dose methotrexate administration, a temporary withdrawal of the PPI may be considered in some patients [see Drug Interactions (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 Meitheal Pharmaceuticals Inc. at 1-844-824-8426 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 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

16 HOW SUPPLIED/STORAGE AND HANDLING 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). [See USP Controlled Room Temperature.] Protect from light. Discard unused portion. Sterile, Nonpyrogenic, Preservative-free. The container closure is not made with natural rubber latex.