Pantoprazole Sodium: Package Insert and Label Information (Page 4 of 5)

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 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.

For known pediatric poor metabolizers, a dose reduction should be considered.

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 with 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 doses of 5 to 50 mg/kg/day of pantoprazole, 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 doses of 5 to 150 mg/kg/day of pantoprazole, 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

Pantoprazole sodium delayed-release tablets were used in the following clinical trials.

14.1 Erosive Esophagitis (EE) Associated with Gastroesophageal Reflux Disease (GERD)

Adult Patients

A US multicenter, double-blind, placebo-controlled study of pantoprazole 10 mg, 20 mg, or 40 mg once daily was conducted in 603 patients with reflux symptoms and endoscopically diagnosed EE of grade 2 or above (Hetzel-Dent scale). In this study, approximately 25% of enrolled patients had severe EE of grade 3, and 10% had grade 4. The percentages of patients healed (per protocol, n = 541) in this study are shown in Table 8.

Table 8 Erosive Esophagitis Healing Rates (Per Protocol)

––––––––––––––– Pantoprazole –––––––––––––––

Placebo

Week

10 mg daily (n = 153)

20 mg daily (n = 158)

40 mg daily (n = 162)

(n = 68)

4 8

45.6%+ 66.0%+

58.4%+# 83.5 %+#

75.0%+* 92.6%+*

14.3% 39.7%

+ (p < 0.001) pantoprazole versus placebo
* (p < 0.05) versus 10 mg or 20 mg pantoprazole# (p < 0.05) versus 10 mg pantoprazole

In this study, all pantoprazole treatment groups had significantly greater healing rates than the placebo group. This was true regardless of H.pylori status for the 40 mg and 20 mg pantoprazole treatment groups. The 40 mg dose of pantoprazole resulted in healing rates significantly greater than those found with either the 20 mg or 10 mg dose.

A significantly greater proportion of patients taking pantoprazole 40 mg experienced complete relief of daytime and nighttime heartburn and the absence of regurgitation, starting from the first day of treatment, compared with placebo. Patients taking pantoprazole consumed significantly fewer antacid tablets per day than those taking placebo.

Pantoprazole 40 mg and 20 mg once daily were also compared with nizatidine 150 mg twice daily in a US multicenter, double-blind study of 243 patients with reflux symptoms and endoscopically diagnosed EE of grade 2 or above. The percentages of patients healed (per protocol, n = 212) are shown in Table 9.

Table 9 Erosive Esophagitis Healing Rates (Per Protocol)

–––––––––––– Pantoprazole ––––––––––––

Nizatidine

Week

20 mg daily (n = 72)

40 mg daily (n = 70)

150 mg twice daily (n = 70)

4 8

61.4%+ 79.2%+

64.0%+ 82.9%+

22.2% 41.4%

+ (p < 0.001) pantoprazole versus nizatidine

Once-daily treatment with pantoprazole 40 mg or 20 mg resulted in significantly superior rates of healing at both 4 and 8 weeks compared with twice-daily treatment with 150 mg of nizatidine. For the 40 mg treatment group, significantly greater healing rates compared to nizatidine were achieved regardless of the H.pylori status.

A significantly greater proportion of the patients in the pantoprazole treatment groups experienced complete relief of nighttime heartburn and regurgitation, starting on the first day and of daytime heartburn on the second day, compared with those taking nizatidine 150 mg twice daily. Patients taking pantoprazole consumed significantly fewer antacid tablets per day than those taking nizatidine.

Pediatric Patients Ages 5 Years through 16 Years

The efficacy of pantoprazole in the treatment of EE associated with GERD in pediatric patients ages 5 years through 16 years is extrapolated from adequate and well-conducted trials in adults, as the pathophysiology is thought to be the same. Four pediatric patients with endoscopically diagnosed EE were studied in multicenter, randomized, double-blind, parallel-treatment trials. Children with endoscopically diagnosed EE (defined as an endoscopic Hetzel-Dent score ≥2) were treated once daily for 8 weeks with one of two dose levels of pantoprazole (20 mg or 40 mg). All 4 patients with EE were healed (Hetzel-Dent score of 0 or 1) at 8 weeks.

14.2 Long-Term Maintenance of Healing of Erosive Esophagitis

Two independent, multicenter, randomized, double-blind, comparator-controlled trials of identical design were conducted in adult GERD patients with endoscopically confirmed healed EE to demonstrate efficacy of pantoprazole in long-term maintenance of healing. The two US studies enrolled 386 and 404 patients, respectively, to receive either 10 mg, 20 mg, or 40 mg of pantoprazole sodium delayed-release tablets once daily or 150 mg of ranitidine twice daily. As demonstrated in Table 10, pantoprazole 40 mg and 20 mg were significantly superior to ranitidine at every timepoint with respect to the maintenance of healing. In addition, pantoprazole 40 mg was superior to all other treatments studied.

Table 10 Long-Term Maintenance of Healing of Erosive Gastroesophageal Reflux Disease (GERD Maintenance): Percentage of Patients Who Remained Healed

Pantoprazole 20 mg daily

Pantoprazole 40 mg daily

Ranitidine 150 mg twice daily

Study 1

n = 75

n = 74

n = 75

Month 1

91*

99*

68

Month 3

82*

93*#

54

Month 6

76*

90*#

44

Month 12

70*

86*#

35

Study 2

n = 74

n = 88

n = 84

Month 1

89*

92*#

62

Month 3

78*

91*#

47

Month 6

72*

88*#

39

Month 12

72*

83*

37

* (p <0.05 vs. ranitidine)
# (p <0.05 vs. pantoprazole 20 mg)Note: pantoprazole 10 mg was superior (p <0.05) to ranitidine in Study 2, but not Study 1.

Pantoprazole 40 mg was superior to ranitidine in reducing the number of daytime and nighttime heartburn episodes from the first through the twelfth month of treatment. Pantoprazole 20 mg, administered once daily, was also effective in reducing episodes of daytime and nighttime heartburn in one trial, as presented in Table 11.

Table 11 Number of Episodes of Heartburn (mean ± SD)

Pantoprazole 40 mg daily

Ranitidine 150 mg twice daily

Month 1

Daytime Nighttime

5.1 ± 1.6* 3.9 ± 1.1*

18.3 ± 1.6 11.9 ± 1.1

Month 12

Daytime Nighttime

2.9 ± 1.5* 2.5 ± 1.2*

17.5 ± 1.5 13.8 ± 1.3

*(p <0.001 vs. ranitidine, combined data from the two US studies)

14.3 Pathological Hypersecretory Conditions Including Zollinger-Ellison Syndrome

In a multicenter, open-label trial of 35 patients with pathological hypersecretory conditions, such as Zollinger-Ellison Syndrome, with or without multiple endocrine neoplasia-type I, pantoprazole successfully controlled gastric acid secretion. Doses ranging from 80 mg daily to 240 mg daily maintained gastric acid output below 10 mEq/h in patients without prior acid-reducing surgery and below 5 mEq/h in patients with prior acid-reducing surgery.

Doses were initially titrated to the individual patient needs, and adjusted in some patients based on the clinical response with time [see Dosage and Administration (2)]. Pantoprazole was well tolerated at these dose levels for prolonged periods (greater than 2 years in some patients).

16 HOW SUPPLIED/STORAGE AND HANDLING

How Supplied

Pantoprazole sodium delayed-release tablets, USP are supplied as 40 mg white to pale yellow colored, oval shape, biconvex, enteric-coated tablets, plain on one side and “97” printed with brown ink on the other side.

They are available as follows:

Carton of 80 tablets (10 tablets each blister pack x 8) NDC 0904-6474-45

Carton of 100 tablets (10 tablets each blister pack x 10) NDC 0904-6474-61

Storage

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].

17 PATIENT COUNSELING INFORMATION

Advise the patient to read the FDA-approved patient labeling (Medication Guide).

Gastric Malignancy

Advise patients to return to their healthcare provider if they have a suboptimal response or an early symptomatic relapse [see Warnings and Precautions (5.1)].

Acute Tubulointerstitial Nephritis

Advise patients to call their healthcare provider immediately if they experience signs and/or symptoms associated with acute tubulointerstitial nephritis [see Contraindications (4),Warnings and Precautions (5.2)].

Clostridium difficile- Associated Diarrhea

Advise patients to immediately call their healthcare provider if they experience diarrhea that does not improve [see Warnings and Precautions (5.3)].

Bone Fracture

Advise patients to report any fractures, especially of the hip, wrist or spine, to their healthcare provider [see Warnings and Precautions (5.4)].

Severe Cutaneous Adverse Reactions

Advise patients to discontinue Pantoprazole sodium and immediately call their healthcare provider for further evaluation [see Warnings and Precautions (5.5)]

Cutaneous and Systemic Lupus Erythematosus

Advise patients to immediately call their healthcare provider for any new or worsening of symptoms associated with cutaneous or systemic lupus erythematosus [see Warnings and Precautions (5.6)].

Cyanocobalamin (Vitamin B-12) Deficiency

Advise patients to report any clinical symptoms that may be associated with cyancobalamin deficiency to their healthcare provider if they have been receiving Pantoprazole sodium delayed-release tablets for longer than 3 years [see Warnings and Precautions (5.7)].

Hypomagnesemia and Mineral Metabolism

Advise patients to report any clinical symptoms that may be associated with hypomagnesemia, hypocalcemia, and/or hypokalemia to their healthcare provider, if they have been receiving Pantoprazole sodium delayed-release tablets for at least 3 months [see Warnings and Precautions (5.8)].

Drug Interactions

Instruct patients to inform their healthcare provider of any other medications they are currently taking, including rilpivirine-containing products [see Contraindications (4)] digoxin [see Warnings and Precautions (5.8)] and high dose methotrexate [see Warnings and Precautions (5.13)].

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)].

Administration

Do not split, crush, or chew pantoprazole sodium delayed-release tablets.
Swallow pantoprazole sodium delayed-release tablets whole, with or without food in the stomach.
Concomitant administration of antacids does not affect the absorption of pantoprazole sodium delayed-release tablets
Take a missed dose as soon as possible. If it is almost time for the next dose, skip the missed dose and take the next dose at the regular scheduled time. Do not take 2 doses at the same time.

This product’s label may have been updated. For current full prescribing information, please visit www.torrentpharma.com

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Manufactured by:

TORRENT PHARMACEUTICALS LTD., INDIA

Manufactured For:

TORRENT PHARMA INC., Levittown, PA 19057.

Distributed by:

MAJOR® PHARMACEUTICALS

Livonia, MI 48152 USA

Refer to package label for Distributor’s NDC Number

8087104 Revised: April 2022

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