PANTOPRAZOLE SODIUM

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

Pantoprazole sodium is a proton pump inhibitor (PPI) indicated in adults for the following: Short-term treatment (7 to 10 days) of gastroesophageal reflux disease (GERD) associated with a history of Erosive Esophagitis (EE). ( 1.1 ) Pathological hypersecretion conditions including Zollinger-Ellison (ZE) Syndrome. ( 1.2 ) 1.1 Gastroesophageal Reflux Disease Associated with a History of Erosive Esophagitis Pantoprazole sodium for injection is indicated for short-term treatment (7 to 10 days) of adult patients with gastroesophageal reflux disease (GERD) and a history of erosive esophagitis (EE). Safety and efficacy of pantoprazole sodium for injection as a treatment of patients with GERD and a history of EE for more than 10 days have not been demonstrated. 1.2 Pathological Hypersecretion Including Zollinger-Ellison Syndrome Pantoprazole sodium for injection is indicated for the treatment of pathological hypersecretory conditions including Zollinger-Ellison (ZE) Syndrome in adults.

GERD Associated with EE ( 2.1 ) The recommended adult dosage is 40 mg given once daily by intravenous infusion for 7 to 10 days. ( 2.1 ) Pathological Hypersecretion Conditions, Including ZE Syndrome ( 2.3 ): The recommended adult dosage is 80 mg administered every 12 hours by intravenous infusion. For information on how to adjust dosing for individual patient needs, see the full prescribing information. Administration ( 2.2 , 2.4 ): Only for intravenous infusion. The intravenous infusion can be administered over 2 minutes or 15 minutes. For information on how to prepare and administer for each indication, see the full prescribing information. 2.1 Dosage for Gastroesophageal Reflux Disease Associated With a History of Erosive Esophagitis The recommended adult dosage of pantoprazole sodium for injection is 40 mg given once daily by intravenous infusion for 7 to 10 days. Discontinue treatment with pantoprazole sodium for injection as soon as the patient is able to receive treatment with Pantoprazole Delayed-Release Tablets or Oral Suspension. Data on the safe and effective dosing for conditions other than those described [see Indications and Usage ( 1 )] such as life-threatening upper gastrointestinal bleeds, are not available. Pantoprazole sodium for injection 40 mg once daily does not raise gastric pH to levels sufficient to contribute to the treatment of such life-threatening conditions. 2.2 Preparation and Administration Instructions for Gastroesophageal Reflux Disease Associated With a History of Erosive Esophagitis Only for intravenous infusion; other parenteral routes of administration are not recommended. Fifteen Minute Infusion Reconstitute pantoprazole sodium for injection with 10 mL of 0.9% Sodium Chloride Injection, USP. Further dilute with 100 mL of 5% Dextrose Injection, USP, 0.9% Sodium Chloride Injection, USP, or Lactated Ringer's Injection, USP, to a final concentration of approximately 0.4 mg per mL. Inspect the diluted pantoprazole sodium for injection solution visually for particular 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. Storage The reconstituted solution may be stored for up to 6 hours at room temperature prior to further dilution. The admixed solution may be stored at room temperature and must be used within 24 hours from the time of initial reconstitution. Both the reconstituted solution and the admixed solution do not need to be protected from light. Do not freeze the reconstituted solution. Two Minute Infusion Reconstitute pantoprazole sodium for injection with 10 mL of 0.9% Sodium Chloride Injection, USP, to a final concentration of approximately 4 mg per mL. Inspect the diluted pantoprazole sodium for injection solution visually for particular matter and discoloration prior to and during administration. Administer intravenously over a period of at least 2 minutes. Storage The reconstituted solution may be stored for up to 24 hours at room temperature prior to intravenous infusion and does not need to be protected from light. Do not freeze the reconstituted solution. 2.3 Dosage for Pathological Hypersecretion Including Zollinger-Ellison Syndrome The recommended adult dosage of pantoprazole sodium for injection is 80 mg intravenously every 12 hours. The frequency of dosing can be adjusted 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. Daily doses higher than 240 mg or administered for more than 6 days have not been studied [see Clinical Studies ( 14 )]. Transition from oral to intravenous and from intravenous to oral formulations of gastric acid inhibitors should be performed in such a manner to ensure continuity of effect of suppression of acid secretion. Patients with ZE Syndrome may be vulnerable to serious clinical complications of increased acid production even after a short period of loss of effective inhibition. 2.4 Preparation and Administration Instructions for Pathological Hypersecretion Including Zollinger-Ellison Syndrome Only for intravenous infusion; other parenteral routes of administration are not recommended. Fifteen Minute Infusion Reconstitute each vial of pantoprazole sodium for injection with 10 mL of 0.9% Sodium Chloride Injection, USP. Combine the contents of the two vials and further dilute with 80 mL of 5% Dextrose Injection, USP, 0.9% Sodium Chloride Injection, USP, or Lactated Ringer's Injection, USP, 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 particular 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. Storage The reconstituted solution may be stored for up to 6 hours at room temperature prior to further dilution. The admixed solution may be stored at room temperature and must be used within 24 hours from the time of initial reconstitution. Both the reconstituted solution and the admixed solution do not need to be protected from light. Do not freeze the reconstituted solution. Two Minute Infusion Reconstitute pantoprazole sodium for injection with 10 mL of 0.9% Sodium Chloride Injection, USP, per vial to a final concentration of approximately 4 mg per mL. Inspect the diluted pantoprazole sodium for injection solution visually for particular matter and discoloration prior to and during administration. Administer the total volume from both vials intravenously over a period of at least 2 minutes. Storage The reconstituted solution may be stored for up to 24 hours at room temperature prior to intravenous infusion and does not need to be protected from light. 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. Flush the intravenous line before and after administration of pantoprazole sodium for injection with either 5% Dextrose Injection, USP, 0.9% Sodium Chloride Injection, USP, or Lactated Ringer's Injection, USP. When administered through a Y-site, pantoprazole sodium for injection is compatible with the following solutions: 5% Dextrose Injection, USP, 0.9% Sodium Chloride Injection, USP, or Lactated Ringer's Injection, USP. Midazolam HCl has been shown to be 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 )]. When pantoprazole sodium for injection is administered through a Y-site, immediately stop use if precipitation or discoloration occurs.

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 )

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 )] Clostridium 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 Sagent Pharmaceuticals at 1-866-625-1618 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. Worldwide, approximately 80,500 patients have been treated with pantoprazole in clinical trials involving various dosages and duration of treatment. 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 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 1: Adverse Reactions Reported in Clinical Trials of Adult Patients with GERD at a Frequency of > 2% Oral Pantoprazole (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 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 (I.V. 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. 6.2 Postmarketing Experience The following adverse reactions have been identified during postapproval use of pantoprazole and pantoprazole sodium for injection. 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: Clostridium difficile associated diarrhea Hematologic: pancytopenia, agranulocytosis Nervous: ageusia, dysgeusia Gastrointestinal Disorders: fundic gland polyps

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. Table 2: Clinically Relevant Interactions Affecting Drugs Co-Administered with Pantoprazole Sodium for Injection 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 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. 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 pantoprazole sodium for injection. 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 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, 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 pantoprazole sodium for injection and MMF. Use pantoprazole sodium for injection 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 level may cause false positive results in diagnostic investigations for neuroendocrine tumors [see Warnings and Precautions ( 5.12 ), Clinical Pharmacology ( 12.2 )] . Intervention: Temporarily stop pantoprazole sodium for injection 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. False Positive Urine Tests for THC Clinical Impact: There have been reports of false positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving PPIs [see Warnings and Precautions ( 5.13 )] . Intervention: An alternative confirmatory method should be considered to verify positive results. See the full prescribing information for a list of clinically important drug interactions ( 7 )

Storage Conditions Store 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. Retain in carton until time of use. Discard unused portion. Sterile, Nonpyrogenic, Preservative-free. The container closure is not made with natural rubber latex.