Pantoprazole Sodium: Package Insert and Label Information (Page 4 of 4)

12.5 Pharmacogenomics

CYP2C19 displays a known genetic polymorphism due to its deficiency in some subpopulations (e.g., approximately 3% of Caucasians and African-Americans and 17% to 23% of Asians are poor metabolizers). Although these subpopulations of pantoprazole poor metabolizers have elimination half-life values of 3.5 to 10.0 hours in adults, they still have minimal accumulation (23% or less) with once-daily dosing. For adult patients who are CYP2C19 poor metabolizers, no dosage adjustment is needed.

Similar to adults, pediatric patients who have the poor metabolizer genotype of CYP2C19 (CYP2C19 *2/*2) exhibited greater than a 6-fold increase in AUC compared to pediatric extensive (CYP2C19 *1/*1) and intermediate (CYP2C19 *1/*x) metabolizers. Poor metabolizers exhibited approximately 10-fold lower apparent oral clearance compared to extensive metabolizers.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

In a 24-month carcinogenicity study, Sprague-Dawley rats were treated orally with pantoprazole doses of 0.5 to 200 mg/kg/day, about 0.1 to 40 times the exposure on a body surface area basis of a 50-kg person dosed at 40 mg/day. In the gastric fundus, treatment with 0.5 to 200 mg/kg/day produced enterochromaffin-like (ECL) cell hyperplasia and benign and malignant neuroendocrine cell tumors in a dose-related manner. In the forestomach, treatment with 50 and 200 mg/kg/day (about 10 and 40 times the recommended human dose on a body surface area basis) produced benign squamous cell papillomas and malignant squamous cell carcinomas. Rare gastrointestinal tumors associated with pantoprazole treatment included an adenocarcinoma of the duodenum with 50 mg/kg/day and benign polyps and adenocarcinomas of the gastric fundus with 200 mg/kg/day. In the liver, treatment with 0.5 to 200 mg/kg/day produced dose-related increases in the incidences of hepatocellular adenomas and carcinomas. In the thyroid gland, treatment with 200 mg/kg/day produced increased incidences of follicular cell adenomas and carcinomas for both male and female rats.

In a 24-month carcinogenicity study, Fischer 344 rats were treated orally with pantoprazole doses of 5 to 50 mg/kg/day, approximately 1 to 10 times the recommended human dose based on body surface area. In the gastric fundus, treatment with 5 to 50 mg/kg/day produced enterochromaffin-like (ECL) cell hyperplasia and benign and malignant neuroendocrine cell tumors. Dose selection for this study may not have been adequate to comprehensively evaluate the carcinogenic potential of pantoprazole.

In a 24-month carcinogenicity study, B6C3F1 mice were treated orally with pantoprazole doses of 5 to 150 mg/kg/day, 0.5 to 15 times the recommended human dose based on body surface area. In the liver, treatment with 150 mg/kg/day produced increased incidences of hepatocellular adenomas and carcinomas in female mice. Treatment with 5 to 150 mg/kg/day also produced gastric fundic ECL cell hyperplasia.

A 26-week p53 +/- transgenic mouse carcinogenicity study was not positive.

Pantoprazole was positive in the in vitro human lymphocyte chromosomal aberration assays, in one of two mouse micronucleus tests for clastogenic effects, and in the in vitro Chinese hamster ovarian cell/HGPRT forward mutation assay for mutagenic effects. Equivocal results were observed in the in vivo rat liver DNA covalent binding assay. Pantoprazole was negative in the in vitro Ames mutation assay, the in vitro unscheduled DNA synthesis (UDS) assay with rat hepatocytes, the in vitro AS52/GPT mammalian cell-forward gene mutation assay, the in vitro thymidine kinase mutation test with mouse lymphoma L5178Y cells, and the in vivo rat bone marrow cell chromosomal aberration assay.

There were no effects on fertility or reproductive performance when pantoprazole was given at oral doses up to 500 mg/kg/day in male rats (98 times the recommended human dose based on body surface area) and 450 mg/kg/day in female rats (88 times the recommended human dose based on body surface area).

14 CLINICAL STUDIES

14.1 Gastroesophageal Reflux Disease (GERD) Associated with a History of Erosive Esophagitis

A multicenter, double-blind, two-period placebo-controlled study was conducted to assess the ability of pantoprazole sodium for injection to maintain gastric acid suppression in patients switched from Pantoprazole Delayed-Release Tablets to pantoprazole sodium for injection GERD patients (n=65, 26 to 64 years; 35 female; 9 Black, 11 Hispanic, 44 White, 1 other) with a history of EE were randomized to receive either 20 or 40 mg of oral pantoprazole once per day for 10 days (period 1), and then were switched in period 2 to either daily pantoprazole sodium for injection or placebo for 7 days, matching their respective dose level from period 1. Patients were administered all test medication with a light meal. Maximum acid output (MAO) and basal acid output (BAO) were determined 24 hours following the last day of oral medication (day 10), the first day (day 1) of intravenous administration and the last day of intravenous administration (day 7). MAO was estimated from a 1 hour continuous collection of gastric contents following subcutaneous injection of 6.0 mcg/kg of pentagastrin.

This study demonstrated that, after 10 days of repeated oral administration followed by 7 days of intravenous administration, the oral and intravenous dosage forms of pantoprazole 40 mg are similar in their ability to suppress MAO and BAO in patients with GERD and a history of EE (see Table 4). Also, patients on oral pantoprazole who were switched to intravenous placebo experienced a significant increase in acid output within 48 hours of their last oral dose (see Table 4). However, at 48 hours after their last oral dose, patients treated with pantoprazole sodium for injection had a significantly lower mean basal acid output (see Table 4) than those treated with placebo.

Table 4: Antisecretory Effects (mEq/h) of 40 mg Pantoprazole Sodium for Injection and 40 mg Pantoprazole Delayed-Release Tablets in GERD Patients with a History of EE

* p<0.0001 Significantly different from pantoprazole sodium for injection.
Parameter	PantoprazoleDelayed-Release TabletsDAY 10	Pantoprazole Sodium for InjectionDAY 7	Intravenous PlaceboDAY 7
Mean maximum acidoutput	6.49n=30	6.62n=23	29.19*n=7
Mean basal acidoutput	0.80n=30	0.53n=23	4.14*n=7

To evaluate the effectiveness of pantoprazole sodium for injection as an initial treatment to suppress gastric acid secretion, two studies were conducted.

Study 1 was a multicenter, double-blind, placebo-controlled, study of the pharmacodynamic effects of pantoprazole sodium for injection and Pantoprazole Delayed-Release Tablets. Patients with GERD and a history of EE (n=78, 20 to 67 years; 39 females; 7 Black, 19 Hispanic, 52 White) were randomized to receive either 40 mg pantoprazole sodium for injection, 40 mg pantoprazole Delayed-Release Tablets, or placebo once daily for 7 days. Following an overnight fast, test medication was administered and patients were given a light meal within 15 minutes. MAO and BAO were determined 24 hours following the last day of study medication. MAO was estimated from a 1 hour continuous collection of gastric contents following subcutaneous injection of 6.0 mcg/kg of pentagastrin to stimulate acid secretion. This study demonstrated that, after treatment for 7 days, patients treated with pantoprazole sodium for injection had a significantly lower MAO and BAO than those treated with placebo (p<0.001), and results were comparable to those of patients treated with Pantoprazole Delayed-Release Tablets (see Table 5).

Table 5: Antisecretory Effects (mEq/h) of Initial Treatment with 40 mg Pantoprazole Sodium for Injection and 40 mg Pantoprazole Delayed-Release Tablets in GERD Patients with a History of EE

* p<0.001 Significantly different from pantoprazole sodium for injection.
Parameter	Pantoprazole Sodiumfor InjectionDAY 7	PantoprazoleDelayed-Release TabletsDAY 7	PlaceboDAY 7
Maximum acid output(mean ± SD)	8.4 ± 5.9n=25	6.3 ± 6.6n=22	20.9 ± 14.5*n=24
Basal acid output(mean ± SD)	0.4 ± 0.5n=25	0.6 ± 0.8n=22	2.8 ± 3.0*n=23

Study 2 was a single-center, double-blind, parallel-group study to compare the clinical effects of pantoprazole sodium for injection and Pantoprazole Delayed-Release Tablets. Patients (n=45, median age 56 years, 21 males and 24 females) with acute endoscopically proven reflux esophagitis (Savary/Miller Stage II or III) with at least 1 of 3 symptoms typical for reflux esophagitis (acid eructation, heartburn, or pain on swallowing) were randomized to receive either 40 mg pantoprazole sodium for injection or 40 mg Pantoprazole Delayed-Release Tablets once daily for 5 days. After the initial 5 days, all patients were treated with 40 mg oral pantoprazole daily to complete a total of 8 weeks of treatment. Symptom relief was assessed by calculating the daily mean of the sums of the average scores for these 3 symptoms and the daily mean of the average score for each of the symptoms separately. There was no significant difference in symptom relief between pantoprazole sodium for injection and Pantoprazole Delayed-Release Tablets within the first 5 days. A repeat endoscopy after 8 weeks of treatment revealed that 20 out of 23 (87%) patients treated with pantoprazole sodium for injection plus Pantoprazole Delayed-Release Tablets and 19 out of 22 (86%) of the patients treated with Pantoprazole Delayed-Release Tablets had endoscopically proven healing of their esophageal lesions.

Data comparing pantoprazole sodium for injection to other PPIs (oral or intravenous) or H₂ -receptor antagonists (oral or intravenous) are limited, and therefore, are inadequate to support any conclusions regarding comparative efficacy.

14.2 Pathological Hypersecretion Associated with Zollinger-Ellison Syndrome

Two studies measured the pharmacodynamic effects of 6 day treatment with pantoprazole sodium for injection in patients with ZE Syndrome (with and without multiple endocrine neoplasia type I). In one of these studies, an initial treatment with pantoprazole sodium for injection in 21 patients (29 to 75 years; 8 female; 4 Black, 1 Hispanic, 16 White) reduced acid output to the target level (10 mEq/h or less) and significantly reduced H⁺ concentration and the volume of gastric secretions; target levels were achieved within 45 minutes of drug administration.

In the other study of 14 patients (38 to 67 years; 5 female; 2 Black, 12 White) with ZE Syndrome, treatment was switched from an oral PPI to pantoprazole sodium for injection. Pantoprazole sodium for injection maintained or improved control of gastric acid secretion.

In both studies, total doses of 160 or 240 mg per day of pantoprazole sodium for injection administered in divided doses, maintained basal acid secretion below target levels in all patients. Target levels were 10 mEq/h in patients without prior gastric surgery, and 5 mEq/h in all patients with prior gastric acid-reducing surgery. Once gastric acid secretion was controlled, there was no evidence of tolerance during this 7 day study. Basal acid secretion was maintained below target levels for at least 24 hours in all patients and through the end of treatment in these studies (3 to 7 days) in all but 1 patient who required a dose adjustment guided by acid output measurements until acid control was achieved. In both studies, doses were adjusted to the individual patient need, but gastric acid secretion was controlled in greater than 80% of patients by a starting regimen of 80 mg every 12 hours.

16 HOW SUPPLIED/STORAGE AND HANDLING

Pantoprazole Sodium for Injection is available as follows:

NDC	Pantoprazole Sodium for Injection	Package Factor
25021-751-10	40 mg Single-Dose Vial	10 vials per carton
25021-751-11	40 mg Single-Dose Vial	25 vials per carton

Pantoprazole Sodium for Injection is a white to off-white freeze-dried powder for reconstitution.

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.

17 PATIENT COUNSELING INFORMATION

Adverse Reactions

Advise patients to report to their healthcare provider if they experience any signs or symptoms consistent with:

• 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 Contraindications (4), 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)]

Drug Interactions

Instruct patients to inform their healthcare provider of any other medications they are currently taking, including rilpivirine-containing products [see Contraindications (4)] and high dose methotrexate [see Warnings and Precautions (5.14)].

Pregnancy

Advise a pregnant woman of the potential risk to a fetus. Advise females of reproductive potential to inform their healthcare provider of a known or suspected pregnancy [see Use in Specific Populations (8.1)].

SAGENT^®
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Schaumburg, IL 60195 (USA)
Made in India ©2022 Sagent Pharmaceuticals, Inc.

May 2022

SAGENT Pharmaceuticals ^®

PACKAGE LABEL – PRINCIPAL DISPLAY PANEL – Vial Label

NDC 25021-751-10

Rx only

Pantoprazole Sodium for Injection

40 mg per vial

For Intravenous Infusion Only

Single-Dose Vial

PANTOPRAZOLE SODIUM pantoprazole sodium injection, powder, lyophilized, for solution

Product Information Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:25021-751 Route of Administration INTRAVENOUS DEA Schedule

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength Pantoprazole Sodium (Pantoprazole) Pantoprazole 40 mg in 10 mL

Inactive Ingredients Ingredient Name Strength Sodium Hydroxide Edetate Disodium

Packaging # Item Code Package Description Multilevel Packaging 1 NDC:25021-751-10 10 VIAL in 1 CARTON contains a VIAL 1 10 mL in 1 VIAL This package is contained within the CARTON (25021-751-10) 2 NDC:25021-751-11 25 VIAL in 1 CARTON contains a VIAL 2 10 mL in 1 VIAL This package is contained within the CARTON (25021-751-11)

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date ANDA ANDA204400 07/15/2022

Labeler — Sagent Pharmaceuticals (796852890)

Revised: 05/2022 Sagent Pharmaceuticals