PANTOPRAZOLE SODIUM DELAYED-RELEASE tablet

United States - English - NLM (National Library of Medicine)

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Active ingredient:
PANTOPRAZOLE SODIUM (UNII: 6871619Q5X) (PANTOPRAZOLE - UNII:D8TST4O562)
Available from:
Lake Erie Medical DBA Quality Care Products LLC
INN (International Name):
PANTOPRAZOLE SODIUM
Composition:
PANTOPRAZOLE 20 mg
Prescription type:
PRESCRIPTION DRUG
Authorization status:
New Drug Application

PANTOPRAZOLE SODIUM DELAYED-RELEASE- pantoprazole sodium tablet, delayed

release

Lake Erie Medical DBA Quality Care Products LLC

----------

HIGHLIGHTS OF PRESCRIBING INFORMATION

These highlights do not include all the information needed to use Pantoprazole Sodium Delayed-Release

Tablets safely and effectively. See full prescribing information for Pantoprazole Sodium Delayed-Release

T able ts.

PANTOPRAZOLE SODIUM delayed-release tablets

Initial U.S. approval: 2000

RECENT MAJOR CHANGES

Dosage and Administration, Recommended Dosing Schedule (2.1)

1/2015

Contraindications (4)

1/2015

Warnings and Precautions, Acute Interstitial Nephritis (5.3)

1/2015

INDICATIONS AND USAGE

Pantoprazole sodium is a proton pump inhibitor indicated for the following:

Short-Term Treatment of Erosive Esophagitis Associated with Gastroesophageal Reflux Disease (GERD) (1.1)

Maintenance of Healing of Erosive Esophagitis (1.2)

Pathological Hypersecretory Conditions Including Zollinger-Ellison Syndrome (1.3)

DOSAGE AND ADMINISTRATION

Indic atio n

Do se

Frequency

Short-Term Treatment of Erosive Esophagitis Associated With GERD (2.1)

Adults

40 mg

Once Daily for up to 8 wks

Children (5 years and older)

≥ 15 kg to < 40 kg

20 mg

Once Daily for up to 8 wks

≥ 40 kg

40 mg

Maintenance of Healing of Erosive Esophagitis (2.1)

Adults

40 mg

Once Daily

Pathological Hypersecretory Conditions Including Zollinger-Ellison Syndrome (2.1)

Adults

40 mg

Twice Daily

See full prescribing information for administration instructions

DOSAGE FORMS AND STRENGTHS

Delayed-Release Tablets, 20 mg and 40 mg (3)

CONTRAINDICATIONS

Known hypersensitivity to any component of the formulation or to substituted benzimidazoles (4)

WARNINGS AND PRECAUTIONS

Symptomatic response does not preclude presence of gastric malignancy (5.1)

Atrophic gastritis has been noted with long-term therapy (5.2)

Acute interstitial nephritis has been observed in patients taking PPIs. (5.3)

Cyanocobalamin (vitamin B-12) Deficiency: Daily long-term use (e.g., longer than 3 years) may lead to malabsorption or

a deficiency of cyanocobalamin. (5.4)

PPI therapy may be associated with increased risk of Clostridium difficile associated diarrhea. (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)

Hypomagnesemia has been reported rarely with prolonged treatment with PPIs (5.7)

ADVERSE REACTIONS

Controlled studies did not extend beyond 12 months

ADVERSE REACTIONS

The most frequently occurring adverse reactions are as follows:

For adult use (>2%) are headache, diarrhea, nausea, abdominal pain, vomiting, flatulence, dizziness, and arthralgia. (6)

For pediatric use (>4%) are URI, headache, fever, diarrhea, vomiting, rash, and abdominal pain. (6)

To report SUSPECTED ADVERSE REACTIONS, contact Pfizer Inc. at 1-800-438-1985 or FDA at 1-800-FDA-

1088 or www.fda.gov/medwatch

DRUG INTERACTIONS

Do not co-administer with atazanavir or nelfinavir (7.1)

Concomitant warfarin use may require monitoring (7.2)

May interfere with the absorption of drugs where gastric pH is important for bioavailability (e.g. ketoconazole, ampicillin

esters, atazanavir, iron salts, erlotinib and mycophenolate mofetil) (7.4)

May produce false-positive urine screen for THC (7.5)

Methotrexate: Pantoprazole sodium may increase serum level of methotrexate (7.6)

See 17 for PATIENT COUNSELING INFORMATION and Medication Guide.

Revised: 2/2017

FULL PRESCRIBING INFORMATION: CONTENTS*

1 INDICATIONS AND USAGE

1.1 Short-Term Treatment of Erosive Esophagitis Associated With Gastroesophageal Reflux

Disease (GERD)

1.2 Maintenance of Healing of Erosive Esophagitis

1.3 Pathological Hypersecretory Conditions Including Zollinger-Ellison Syndrome

2 DOSAGE AND ADMINISTRATION

2.1 Recommended Dosing Schedule

2.2 Administration Instructions

3 DOSAGE FORMS AND STRENGTHS

4 CONTRAINDICATIONS

5 WARNINGS AND PRECAUTIONS

5.1 Concurrent Gastric Malignancy

5.2 Atrophic Gastritis

5.3 Acute Interstitial Nephritis

5.4 Cyanocobalamin (Vitamin B-12) Deficiency

5.5 Clostridium difficile associated diarrhea

5.6 Bone Fracture

5.7 Hypomagnesemia

5.8 Tumorigenicity

5.9 Interference with Urine Screen for THC

5.10 Concomitant use of pantoprazole sodium with Methotrexate

6 ADVERSE REACTIONS

6.1 Clinical Trial Experience

6.2 Postmarketing Experience

7 DRUG INTERACTIONS

7.1 Interference with Antiretroviral Therapy

7.2 Coumarin Anticoagulants

7.3 Clopidogrel

7.4 Drugs for Which Gastric pH Can Affect Bioavailability

7.5 False Positive Urine Tests for THC

7.6 Methotrexate

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

8.3 Nursing Mothers

8.4 Pediatric Use

8.5 Geriatric Use

8.6 Gender

8.7 Patients with Hepatic Impairment

10 OVERDOSAGE

11 DESCRIPTION

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

12.2 Pharmacodynamics

12.3 Pharmacokinetics

12.4 Pharmacogenomics

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

13.2 Animal Toxicology and/or Pharmacology

14 CLINICAL STUDIES

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

14.2 Long-Term Maintenance of Healing of Erosive Esophagitis

14.3 Pathological Hypersecretory Conditions Including Zollinger-Ellison Syndrome

16 HOW SUPPLIED/STORAGE AND HANDLING

17 PATIENT COUNSELING INFORMATION

FULL PRESCRIBING INFORMATION

1 INDICATIONS AND USAGE

Pantoprazole Sodium Delayed-Release Tablets are indicated for:

1.1 Short-Term Treatment of Erosive Esophagitis Associated With Gastroesophageal Reflux

Disease (GERD)

Pantoprazole Sodium Delayed-Release Tablets are indicated in adults and pediatric patients five years

of age and older for the short-term treatment (up to 8 weeks) in the healing and symptomatic relief of

erosive esophagitis. For those adult patients who have not healed after 8 weeks of treatment, an

additional 8-week course of pantoprazole sodium may be considered. Safety of treatment beyond 8

weeks in pediatric patients has not been established.

1.2 Maintenance of Healing of Erosive Esophagitis

Pantoprazole Sodium Delayed-Release Tablets are indicated for maintenance of healing of erosive

esophagitis and reduction in relapse rates of daytime and nighttime heartburn symptoms in adult patients

with GERD. Controlled studies did not extend beyond 12 months.

1.3 Pathological Hypersecretory Conditions Including Zollinger-Ellison Syndrome

Pantoprazole Sodium Delayed-Release Tablets are indicated for the long-term treatment of pathological

hypersecretory conditions, including Zollinger-Ellison syndrome.

2 DOSAGE AND ADMINISTRATION

2.1 Recommended Dosing Schedule

Sections or subsections omitted from the full prescribing information are not listed.

Pantoprazole sodium is supplied as delayed-release tablets. The recommended dosages are outlined in

Table 1.

Table 1: Recommended Dosing Schedule for Pantoprazole Sodium Delayed-

Release Tablets

Indication

Dos e

Frequency

Short-Term Treatment of Erosive Esophagitis Associated With GERD

Adults

40 mg

Once daily for up to 8 weeks

Children (5 years and older)

≥ 15 kg to < 40 kg

20 mg

Once daily for up to 8 weeks

≥ 40 kg

40 mg

Maintenance of Healing of Erosive Esophagitis

Adults

40 mg

Once daily

Pathological Hypersecretory Conditions Including Zollinger-Ellison Syndrome

Adults

40 mg

Twice daily

2.2 Administration Instructions

Directions for method of administration for each dosage form are presented in Table 2.

Table 2: Administration Instructions

Formulation

Route

Ins tructions

Delayed-Release Tablets

Oral

Swallowed whole, with or without

food

Pantoprazole Sodium Delayed-Release Tablets

Pantoprazole Sodium Delayed-Release Tablets should be swallowed whole, with or without food in

the stomach. If patients are unable to swallow a 40 mg tablet, two 20 mg tablets may be taken.

Concomitant administration of antacids does not affect the absorption of Pantoprazole Sodium Delayed-

Release Tablets.

3 DOSAGE FORMS AND STRENGTHS

Delayed-Release Tablets:

40 mg, yellow oval biconvex tablets imprinted with P40 (brown ink) on one side

20 mg, yellow oval biconvex tablets imprinted with P20 (brown ink) on one side

4 CONTRAINDICATIONS

Pantoprazole Sodium Delayed-Release Tablets are contraindicated in patients with known

hypersensitivity to any component of the formulation or any substituted benzimidazole. Hypersensitivity

reactions may include anaphylaxis, anaphylactic shock, angioedema, bronchospasm, acute interstitial

For adult patients who have not healed after 8 weeks of treatment, an additional 8-week course

of pantoprazole sodium may be considered.

Controlled studies did not extend beyond 12 months.

Dosage regimens should be adjusted to individual patient needs and should continue for as long

as clinically indicated. Doses up to 24 0 mg daily have been administered.

*

Patients should be cautioned that Pantoprazole Sodium Delayed-Release Tablets should not be

split, chewed, or crushed.

nephritis, and urticaria [see Adverse Reactions (6)].

5 WARNINGS AND PRECAUTIONS

5.1 Concurrent Gastric Malignancy

Symptomatic response to therapy with pantoprazole sodium does not preclude the presence of gastric

malignancy.

5.2 Atrophic Gastritis

Atrophic gastritis has been noted occasionally in gastric corpus biopsies from patients treated long-

term with pantoprazole sodium, particularly in patients who were H. pylori positive.

5.3 Acute Interstitial Nephritis

Acute interstitial nephritis has been observed in patients taking PPIs including pantoprazole sodium.

Acute interstitial nephritis may occur at any point during PPI therapy and is generally attributed to an

idiopathic hypersensitivity reaction. Discontinue pantoprazole sodium if acute interstitial nephritis

develops [see Contraindications (4)].

5.4 Cyanocobalamin (Vitamin B-12) Deficiency

Generally, daily treatment with any acid-suppressing medications over a long period of time (e.g.,

longer than 3 years) may lead to malabsorption of cyanocobalamin (Vitamin B-12) caused by hypo- or

achlorhydria. Rare reports of cyanocobalamin deficiency occurring with acid-suppressing therapy have

been reported in the literature. This diagnosis should be considered if clinical symptoms consistent

with cyanocobalamin deficiency are observed.

5.5 Clostridium difficile associated diarrhea

Published observational studies suggest that PPI therapy like pantoprazole sodium may be associated

with an increased risk of Clostridium 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 proton pump inhibitor (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) and

Adverse Reactions (6.2)].

5.7 Hypomagnesemia

Hypomagnesemia, symptomatic and asymptomatic, has been reported rarely in patients treated with PPIs

for at least three months, in most cases after a year of therapy. Serious adverse events include tetany,

arrhythmias, and seizures. 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)].

5.8 Tumorigenicity

Due to the chronic nature of GERD, there may be a potential for prolonged administration of

pantoprazole sodium. In long-term rodent studies, pantoprazole sodium was carcinogenic and caused

rare types of gastrointestinal tumors. The relevance of these findings to tumor development in humans is

unknown [see Nonclinical Toxicology (13.1)].

5.9 Interference with Urine Screen for THC

See Drug Interactions (7.5).

5.10 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)].

6 ADVERSE REACTIONS

6.1 Clinical Trial 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.

Adults

Safety in nine randomized comparative US clinical trials in patients with GERD included 1,473 patients

on oral pantoprazole sodium (20 mg or 40 mg), 299 patients on an H -receptor antagonist, 46 patients on

another proton pump inhibitor, and 82 patients on placebo. The most frequently occurring adverse

reactions are listed in Table 3.

Table 3: Adverse Reactions Reported in Clinical Trials of Adult Patients

with GERD at a Frequency of > 2%

Pantoprazole

s odium

(n=1473)

%

Comparators

(n=345)

%

Placebo

(n=82)

%

Headache

12.2

12.8

Diarrhea

Nausea

Abdominal pain

Vomiting

Flatulence

Dizziness

Arthralgia

Additional adverse reactions that were reported for pantoprazole sodium in clinical trials with a

frequency of ≤ 2% are listed below by body system:

Body as a Whole: allergic reaction, pyrexia, photosensitivity reaction, facial edema

Gastrointestinal: constipation, dry mouth, hepatitis

Hematologic: leukopenia, thrombocytopenia

Metabolic/Nutritional: elevated CK (creatine kinase), generalized edema, elevated triglycerides, liver

enzymes elevated

Musculoskeletal: myalgia

Nervous: depression, vertigo

Skin and Appendages: urticaria, rash, pruritus

Special Senses: blurred vision

Pediatric Patients

Safety of pantoprazole sodium in the treatment of Erosive Esophagitis (EE) associated with GERD was

evaluated in pediatric patients ages 1 year through 16 years in three clinical trials. Safety trials involved

pediatric patients with EE; however, as EE is uncommon in the pediatric population, 249 pediatric

patients with endoscopically-proven or symptomatic GERD were also evaluated. All adult adverse

reactions to pantoprazole sodium are considered relevant to pediatric patients. In patients ages 1 year

through 16 years, the most commonly reported (> 4%) adverse reactions include: URI, headache, fever,

diarrhea, vomiting, rash, and abdominal pain.

For safety information in patients less than 1 year of age see Use in Specific Populations (8.4).

Additional adverse reactions that were reported for pantoprazole sodium in pediatric patients in clinical

trials with a frequency of ≤ 4% are listed below by body system:

Body as a Whole: allergic reaction, facial edema

Gastrointestinal: constipation, flatulence, nausea

Metabolic/Nutritional: elevated triglycerides, elevated liver enzymes, elevated CK (creatine kinase)

Musculoskeletal: arthralgia, myalgia

Nervous: dizziness, vertigo

Skin and Appendages: urticaria

The following adverse reactions seen in adults in clinical trials were not reported in pediatric patients

in clinical trials, but are considered relevant to pediatric patients: photosensitivity reaction, dry mouth,

hepatitis, thrombocytopenia, generalized edema, depression, pruritus, leukopenia, and blurred vision.

Zollinger-Ellison Syndrome

In clinical studies of Zollinger-Ellison Syndrome, adverse reactions reported in 35 patients taking

pantoprazole sodium 80 mg/day to 240 mg/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 post approval use of pantoprazole sodium.

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

Hematologic: pancytopenia, agranulocytosis

Hepatobiliary Disorders: hepatocellular damage leading to jaundice and hepatic failure

Immune System Disorders: anaphylaxis (including anaphylactic shock)

Infections and Infestations: Clostridium difficile associated diarrhea

Investigations: weight changes

Metabolism and Nutritional Disorders: hyponatremia, hypomagnesemia

Musculoskeletal Disorders: rhabdomyolysis, bone fracture

Nervous: ageusia, dysgeusia

Psychiatric Disorders: hallucination, confusion, insomnia, somnolence

Renal and Urinary Disorders: interstitial nephritis

Skin and Subcutaneous Tissue Disorders: severe dermatologic reactions (some fatal), including

erythema multiforme, Stevens-Johnson syndrome, and toxic epidermal necrolysis (TEN, some fatal), and

angioedema (Quincke's edema).

7 DRUG INTERACTIONS

7.1 Interference with Antiretroviral Therapy

Concomitant use of atazanavir or nelfinavir with proton pump inhibitors is not recommended. Co-

administration of atazanavir or nelfinavir with proton pump inhibitors is expected to substantially

decrease atazanavir or nelfinavir plasma concentrations and may result in a loss of therapeutic effect and

development of drug resistance.

7.2 Coumarin Anticoagulants

There have been postmarketing reports of increased INR and prothrombin time in patients receiving

proton pump inhibitors, including pantoprazole sodium, and warfarin concomitantly. Increases in INR

and prothrombin time may lead to abnormal bleeding and even death. Patients treated with proton pump

inhibitors and warfarin concomitantly should be monitored for increases in INR and prothrombin time.

7.3 Clopidogrel

Concomitant administration of pantoprazole sodium 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)]. No dose adjustment of clopidogrel is necessary when

administered with an approved dose of pantoprazole sodium.

7.4 Drugs for Which Gastric pH Can Affect Bioavailability

Due to its effects on gastric acid secretion, pantoprazole can reduce the absorption of drugs where

gastric pH is an important determinant of their bioavailability. Like with other drugs that decrease the

intragastric acidity, the absorption of drugs such as ketoconazole, ampicillin esters, atazanavir, iron

salts, erlotinib, and mycophenolate mofetil (MMF) can decrease.

Co-administration of pantoprazole 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. The clinical relevance of reduced MPA

exposure on organ rejection has not been established in transplant patients receiving pantoprazole

sodium and MMF. Use pantoprazole sodium with caution in transplant patients receiving MMF [see

Clinical Pharmacology (12.3)].

7.5 False Positive Urine Tests for THC

There have been reports of false positive urine screening tests for tetrahydrocannabinol (THC) in

patients receiving proton pump inhibitors. An alternative confirmatory method should be considered to

verify positive results.

7.6 Methotrexate

Case reports, published population pharmacokinetic studies, and retrospective analyses suggest that

concomitant administration of PPIs and methotrexate (primarily at high dose; see methotrexate

prescribing information) may elevate and prolong serum levels of methotrexate and/or its metabolite

hydroxymethotrexate. However, no formal drug interaction studies of methotrexate with PPIs have been

conducted [see Warnings and Precautions (5.10)].

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Teratogenic Effects

Pregnancy Category B

Reproduction studies have been performed in rats at oral doses up to 88 times the recommended human

dose and in rabbits at oral doses up to 16 times the recommended human dose and have revealed no

evidence of impaired fertility or harm to the fetus due to pantoprazole sodium. There are, however, no

adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not

always predictive of human response, this drug should be used during pregnancy only if clearly needed

[see Nonclinical Toxicology (13.2)].

8.3 Nursing Mothers

Pantoprazole sodium and its metabolites are excreted in the milk of rats. Pantoprazole sodium excretion

in human milk has been detected in a study of a single nursing mother after a single 40 mg oral dose.

The clinical relevance of this finding is not known. Many drugs which are excreted in human milk have a

potential for serious adverse reactions in nursing infants. Based on the potential for tumorigenicity

shown for pantoprazole sodium in rodent carcinogenicity studies, a decision should be made whether to

discontinue nursing or to discontinue the drug, taking into account the benefit of the drug to the mother.

8.4 Pediatric Use

The safety and effectiveness of pantoprazole sodium for short-term treatment (up to eight weeks) of

erosive esophagitis (EE) associated with GERD have been established in pediatric patients 1 year

through 16 years of age. Effectiveness for EE has not been demonstrated in patients less than 1 year of

age. In addition, for patients less than 5 years of age, there is no appropriate dosage strength in an age-

appropriate formulation available. Therefore, pantoprazole sodium is indicated for the short-term

treatment of EE associated with GERD for patients 5 years and older. The safety and effectiveness of

pantoprazole sodium for pediatric uses other than EE have not been established.

1 year through 16 years of age

Use of pantoprazole sodium in pediatric patients 1 year through 16 years of age for short-term treatment

(up to eight weeks) of EE associated with GERD is supported by: a) extrapolation of results from

adequate and well-controlled studies that supported the approval of pantoprazole sodium for treatment

of EE associated with GERD in adults, and b) safety, effectiveness, and pharmacokinetic studies

performed in pediatric patients [see Clinical Studies (14.1), and Clinical Pharmacology (12.3)].

Safety of pantoprazole sodium in the treatment of EE associated with GERD in pediatric patients 1

through 16 years of age was evaluated in three multicenter, randomized, double-blind, parallel-treatment

studies, involving 249 pediatric patients, including 8 with EE (4 patients ages 1 year to 5 years and 4

patients 5 years to 11 years). The children ages 1 year to 5 years 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 sodium (approximating 0.6 mg/kg or 1.2 mg/kg). All 4 of these patients with

EE were healed (Hetzel-Dent score of 0 or 1) at 8 weeks. Because EE is uncommon in the pediatric

population, predominantly pediatric patients with endoscopically-proven or symptomatic GERD were

also included in these studies. Patients were treated with a range of doses of pantoprazole sodium once

daily for 8 weeks. For safety findings see Adverse Reactions (6.1). Because these pediatric trials had no

placebo, active comparator, or evidence of a dose response, the trials were inconclusive regarding the

clinical benefit of pantoprazole sodium for symptomatic GERD in the pediatric population. The

effectiveness of pantoprazole sodium for treating symptomatic GERD in pediatric patients has not been

established.

Although the data from the clinical trials support use of pantoprazole sodium for the short-term

treatment of EE associated with GERD in pediatric patients 1 year through 5 years, there is no

commercially available dosage formulation appropriate for patients less than 5 years of age [see Dosage

and Administration (2)].

In a population pharmacokinetic analysis, clearance values in the children 1 to 5 years old with

endoscopically proven GERD had a median value of 2.4 L/h. Following a 1.2 mg/kg equivalent dose (15

mg for ≤ 12.5 kg and 20 mg for > 12.5 to < 25 kg), the plasma concentrations of pantoprazole sodium

were highly variable and the median time to peak plasma concentration was 3 to 6 hours. The estimated

AUC for patients 1 to 5 years old was 37% higher than for adults receiving a single 40 mg tablet, with a

geometric mean AUC value of 6.8 µghr/mL.

Neonates to less than one year of age

Pantoprazole sodium was not found to be effective in a multicenter, randomized, double-blind, placebo-

controlled, treatment-withdrawal study of 129 pediatric patients 1 through 11 months of age. Patients

were enrolled if they had symptomatic GERD based on medical history and had not responded to non-

pharmacologic interventions for GERD for two weeks. Patients received pantoprazole sodium daily for

four weeks in an open-label phase, then patients were randomized in equal proportion to receive

pantoprazole sodium treatment or placebo for the subsequent four weeks in a double-blind manner.

Efficacy was assessed by observing the time from randomization to study discontinuation due to

symptom worsening during the four-week treatment-withdrawal phase. There was no statistically

significant difference between pantoprazole sodium and placebo in the rate of discontinuation.

In this trial, the adverse reactions that were reported more commonly (difference of ≥ 4%) in the treated

population compared to the placebo population were elevated CK, otitis media, rhinitis, and laryngitis.

In a population pharmacokinetic analysis, the systemic exposure was higher in patients less than 1 year

of age with GERD compared to adults who received a single 40 mg dose (geometric mean AUC was

103% higher in preterm infants and neonates receiving single dose of 2.5 mg of pantoprazole sodium,

and 23% higher in infants 1 through 11 months of age receiving a single dose of approximately 1.2

mg/kg). In these patients, the apparent clearance (CL/F) increased with age (median clearance: 0.6 L/hr,

range: 0.03 to 3.2 L/hr).

These doses resulted in pharmacodynamic effects on gastric but not esophageal pH. Following once

daily dosing of 2.5 mg of pantoprazole sodium in preterm infants and neonates, there was an increase in

the mean gastric pH (from 4.3 at baseline to 5.2 at steady-state) and in the mean % time that gastric pH

was > 4 (from 60% at baseline to 80% at steady-state). Following once daily dosing of approximately

1.2 mg/kg of pantoprazole sodium in infants 1 through 11 months of age, there was an increase in the

mean gastric pH (from 3.1 at baseline to 4.2 at steady-state) and in the mean % time that gastric pH was >

4 (from 32% at baseline to 60% at steady-state). However, no significant changes were observed in

mean intraesophageal pH or % time that esophageal pH was < 4 in either age group.

Because pantoprazole sodium was not shown to be effective in the randomized, placebo-controlled

study in this age group, the use of pantoprazole sodium for treatment of symptomatic GERD in infants

less than 1 year of age is not indicated.

8.5 Geriatric Use

In short-term US clinical trials, erosive esophagitis healing rates in the 107 elderly patients (≥ 65 years

old) treated with pantoprazole sodium were similar to those found in patients under the age of 65. The

incidence rates of adverse reactions and laboratory abnormalities in patients aged 65 years and older

were similar to those associated with patients younger than 65 years of age.

8.6 Gender

Erosive esophagitis healing rates in the 221 women treated with Pantoprazole Sodium Delayed-Release

Tablets in US clinical trials were similar to those found in men. In the 122 women treated long-term with

pantoprazole sodium 40 mg or 20 mg, healing was maintained at a rate similar to that in men. The

incidence rates of adverse reactions were also similar for men and women.

8.7 Patients with Hepatic Impairment

Doses higher than 40 mg/day have not been studied in patients with hepatic impairment [see Clinical

Pharmacology (12.3)].

10 OVERDOSAGE

Experience in patients taking very high doses of pantoprazole sodium (> 240 mg) is limited.

Spontaneous post-marketing reports of overdose are generally within the known safety profile of

pantoprazole sodium.

Pantoprazole sodium is not removed by hemodialysis. In case of overdosage, treatment should be

symptomatic and supportive.

Single oral doses of pantoprazole sodium at 709 mg/kg, 798 mg/kg, and 887 mg/kg 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.

11 DESCRIPTION

The active ingredient in Pantoprazole Sodium Delayed-Release Tablets is a substituted benzimidazole,

sodium 5-(difluoromethoxy)-2-[[(3,4-dimethoxy-2-pyridinyl)methyl] sulfinyl]-1H-benzimidazole

sesquihydrate, a compound that inhibits gastric acid secretion. Its empirical formula is

H F N NaO S × 1.5 H O, with a molecular weight of 432.4. The structural formula is:

Pantoprazole sodium sesquihydrate is a white to off-white crystalline powder and is racemic.

Pantoprazole sodium has weakly basic and acidic properties. Pantoprazole sodium sesquihydrate 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. At ambient temperature, the degradation half-life is approximately 2.8 hours at pH

5 and approximately 220 hours at pH 7.8.

Pantoprazole sodium is supplied as a delayed-release tablet, available in two strengths (20 mg and 40

mg).

Each Pantoprazole Sodium Delayed-Release Tablet contains 45.1 mg or 22.56 mg of pantoprazole

sodium sesquihydrate (equivalent to 40 mg or 20 mg pantoprazole sodium, respectively) with the

following inactive ingredients: calcium stearate, crospovidone, hypromellose, iron oxide, mannitol,

methacrylic acid copolymer, polysorbate 80, povidone, propylene glycol, sodium carbonate, sodium

lauryl sulfate, titanium dioxide, and triethyl citrate. Pantoprazole Sodium Delayed-Release Tablets (40

mg and 20 mg) complies with USP dissolution test 2.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Pantoprazole sodium is a proton pump inhibitor (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).

12.2 Pharmacodynamics

Pantoprazole Sodium Delayed-Release Tablets suppressed pentagastrin-stimulated MAO in patients (n =

49) with GERD and a history of EE. In this multicenter, pharmacodynamic crossover study, a 40 mg oral

dose of Pantoprazole Sodium Delayed-Release Tablets was administered once daily for 7 days, thirty

minutes before breakfast. Pentagastrin-stimulated (MAO) was assessed from hour 23 to 24 at steady

state.

Antisecretory Activity

Under maximal acid stimulatory conditions using pentagastrin, a dose-dependent decrease in gastric acid

output occurs after a single dose of oral (20–80 mg) or a single dose of intravenous (20–120 mg)

pantoprazole sodium in healthy volunteers. Pantoprazole sodium given once daily results in increasing

inhibition of gastric acid secretion. Following the initial oral dose of 40 mg pantoprazole sodium, a

51% mean inhibition was achieved by 2.5 hours. With once-a-day dosing for 7 days, the mean inhibition

was increased to 85%. Pantoprazole sodium suppressed acid secretion in excess of 95% in half of the

subjects. Acid secretion had returned to normal within a week after the last dose of pantoprazole

sodium; there was no evidence of rebound hypersecretion.

In a series of dose-response studies, pantoprazole sodium, at oral doses ranging from 20 to 120 mg,

caused dose-related increases in median basal gastric pH and in the percent of time gastric pH was > 3

and > 4. Treatment with 40 mg of pantoprazole sodium produced significantly greater increases in

gastric pH than the 20 mg dose. Doses higher than 40 mg (60, 80, 120 mg) did not result in further

significant increases in median gastric pH. The effects of pantoprazole sodium on median pH from one

double-blind crossover study are shown in Table 4.

Table 4: Effect of Single Daily Doses of Oral Pantoprazole Sodium on

Intragastric pH

–––––––—––––––––Median pH on day 7—–––––––––––––

Time

Placebo

20 mg

40 mg

80 mg

8 a.m. – 8 a.m.

(24 hours)

8 a.m. – 10

p.m.

(Daytime)

10 p.m. – 8

*†

*†

*†

*†

a.m.

(Nighttime)

Serum Gastrin Effects

Fasting serum gastrin levels were assessed in two double-blind studies of the acute healing of erosive

esophagitis (EE) in which 682 patients with gastroesophageal reflux disease (GERD) received 10, 20,

or 40 mg of pantoprazole sodium for up to 8 weeks. At 4 weeks of treatment there was an increase in

mean gastrin levels of 7%, 35%, and 72% over pretreatment values in the 10, 20, and 40 mg treatment

groups, respectively. A similar increase in serum gastrin levels was noted at the 8-week visit with mean

increases of 3%, 26%, and 84% for the three pantoprazole sodium dose groups. Median serum gastrin

levels remained within normal limits during maintenance therapy with Pantoprazole Sodium Delayed-

Release Tablets.

In long-term international studies involving over 800 patients, a 2- to 3-fold mean increase from the

pretreatment fasting serum gastrin level was observed in the initial months of treatment with

pantoprazole sodium at doses of 40 mg per day during GERD maintenance studies and 40 mg or higher

per day in patients with refractory GERD. Fasting serum gastrin levels generally remained at

approximately 2 to 3 times baseline for up to 4 years of periodic follow-up in clinical trials.

Following short-term treatment with pantoprazole sodium, elevated gastrin levels return to normal by at

least 3 months.

Enterochromaffin-Like (ECL) Cell Effects

In 39 patients treated with oral pantoprazole sodium 40 mg to 240 mg daily (majority receiving 40 mg to

80 mg) for up to 5 years, there was a moderate increase in ECL-cell density, starting after the first year

of use, which appeared to plateau after 4 years.

In a nonclinical study in Sprague-Dawley rats, lifetime exposure (24 months) to pantoprazole sodium at

doses of 0.5 to 200 mg/kg/day resulted in dose-related increases in gastric ECL cell proliferation and

gastric neuroendocrine (NE)-cell tumors. Gastric NE-cell tumors in rats may result from chronic

elevation of serum gastrin concentrations. The high density of ECL cells in the rat stomach makes this

species highly susceptible to the proliferative effects of elevated gastrin concentrations produced by

proton pump inhibitors. However, there were no observed elevations in serum gastrin following the

administration of pantoprazole sodium at a dose of 0.5 mg/kg/day. In a separate study, a gastric NE-cell

tumor without concomitant ECL-cell proliferative changes was observed in 1 female rat following 12

months of dosing with pantoprazole sodium at 5 mg/kg/day and a 9 month off-dose recovery [see

Nonclinical Toxicology (13.1)].

12.3 Pharmacokinetics

Pantoprazole Sodium Delayed-Release Tablets are prepared as enteric-coated tablets so that absorption

of pantoprazole sodium begins only after the tablet leaves the stomach. Peak serum concentration (C

and area under the serum concentration time curve (AUC) increase in a manner proportional to oral and

intravenous doses from 10 mg to 80 mg. Pantoprazole sodium does not accumulate, and its

pharmacokinetics are unaltered with multiple daily dosing. Following oral or intravenous administration,

the serum concentration of pantoprazole sodium declines biexponentially, with a terminal elimination

half-life of approximately one hour.

In extensive metabolizers with normal liver function receiving an oral dose of the enteric-coated 40 mg

pantoprazole sodium tablet, the peak concentration (C

) is 2.5 μg/mL; the time to reach the peak

concentration (t

) is 2.5 h, and the mean total area under the plasma concentration versus time curve

(AUC) is 4.8 μgh/mL (range 1.4 to 13.3 μgh/mL). Following intravenous administration of

pantoprazole sodium to extensive metabolizers, its total clearance is 7.6–14.0 L/h, and its apparent

Significantly different from placebo

Significantly different from 20 mg

volume of distribution is 11.0–23.6 L.

Abs orption

After administration of a single or multiple oral 40 mg doses of Pantoprazole Sodium Delayed-Release

Tablets, the peak plasma concentration of pantoprazole sodium was achieved in approximately 2.5

hours, and C

was 2.5 μg/mL. Pantoprazole sodium undergoes little first-pass metabolism, resulting

in an absolute bioavailability of approximately 77%. Pantoprazole sodium absorption is not affected by

concomitant administration of antacids.

Administration of Pantoprazole Sodium Delayed-Release Tablets with food may delay its absorption up

to 2 hours or longer; however, the C

and the extent of pantoprazole sodium absorption (AUC) are

not altered. Thus, Pantoprazole Sodium Delayed-Release Tablets may be taken without regard to timing

of meals.

Dis tribution

The apparent volume of distribution of pantoprazole sodium is approximately 11.0–23.6 L, distributing

mainly in extracellular fluid. The serum protein binding of pantoprazole sodium is about 98%, primarily

to albumin.

Metabolis m

Pantoprazole sodium is extensively metabolized in the liver through the cytochrome P450 (CYP)

system. Pantoprazole sodium metabolism is independent of the route of administration (intravenous or

oral). The main metabolic pathway is demethylation, by CYP2C19, with subsequent sulfation; other

metabolic pathways include oxidation by CYP3A4. There is no evidence that any of the pantoprazole

sodium metabolites have significant pharmacologic activity.

Elimination

After a single oral or intravenous dose of

C-labeled pantoprazole sodium to healthy, normal

metabolizer volunteers, approximately 71% of the dose was excreted in the urine, with 18% excreted in

the feces through biliary excretion. There was no renal excretion of unchanged pantoprazole sodium.

Geriatric

Only slight to moderate increases in pantoprazole sodium AUC (43%) and C

(26%) were found in

elderly volunteers (64 to 76 years of age) after repeated oral administration, compared with younger

subjects. No dosage adjustment is recommended based on age.

Pediatric

The pharmacokinetics of pantoprazole sodium were studied in children less than 16 years of age in four

randomized, open-label clinical trials in pediatric patients with presumed/proven GERD. A pediatric

granule formulation was studied in children through 5 years of age, and Pantoprazole Sodium Delayed-

Release Tablets were studied in children older than 5 years.

In a population PK analysis, total clearance increased with increasing bodyweight in a non-linear

fashion. The total clearance also increased with increasing age only in children under 3 years of age.

Neonate through 5 years of age

See Use in Specific Populations (8.4).

Children and Adolescents 6 through 16 Years of Age

The pharmacokinetics of Pantoprazole Sodium Delayed-Release Tablets were evaluated in children

ages 6 through 16 years with a clinical diagnosis of GERD. The PK parameters following a single oral

dose of 20 mg or 40 mg of pantoprazole sodium tablets in children ages 6 through 16 years were

highly variable (%CV ranges 40 to 80%). The geometric mean AUC estimated from population PK

analysis after a 40 mg pantoprazole sodium tablet in pediatric patients was about 39% and 10% higher

respectively in 6 to 11 and 12 to 16 year-old children, compared to that of adults (Table 5).

Table 5: PK Parameters in Children and Adolescents 6 through 16 years

with GERD receiving 40 mg Pantoprazole Sodium Tablets

6–11 years (n=12)

12–16 years (n=11)

(µg/mL)

AUC (µgh/mL)

CL/F (L/h)

Gender

There is a modest increase in pantoprazole sodium AUC and C

in women compared to men.

However, weight-normalized clearance values are similar in women and men. No dosage adjustment is

recommended based on gender. In pediatric patients ages 1 through 16 years there were no clinically

relevant effects of gender on clearance of pantoprazole sodium, as shown by population

pharmacokinetic analysis.

Renal Impairment

In patients with severe renal impairment, pharmacokinetic parameters for pantoprazole sodium were

similar to those of healthy subjects. No dosage adjustment is necessary in patients with renal impairment

or in patients undergoing hemodialysis.

Hepatic Impairment

In patients with mild to severe hepatic impairment (Child-Pugh A to C cirrhosis), maximum pantoprazole

sodium concentrations increased only slightly (1.5-fold) relative to healthy subjects. Although serum

half-life values increased to 7–9 hours and AUC values increased by 5- to 7-fold in hepatic-impaired

patients, these increases were no greater than those observed in CYP2C19 poor metabolizers, where no

dosage adjustment is warranted. These pharmacokinetic changes in hepatic-impaired patients result in

minimal drug accumulation following once-daily, multiple-dose administration. No dosage adjustment is

needed in patients with mild to severe hepatic impairment. Doses higher than 40 mg/day have not been

studied in hepatically impaired patients.

Drug-Drug Interactions

Pantoprazole sodium is metabolized mainly by CYP2C19 and to minor extents by CYPs 3A4, 2D6, and

2C9. In in vivo drug-drug interaction studies with CYP2C19 substrates (diazepam [also a CYP3A4

substrate] and phenytoin [also a CYP3A4 inducer], and clopidogrel), nifedipine, midazolam, and

clarithromycin (CYP3A4 substrates), metoprolol (a CYP2D6 substrate), diclofenac, naproxen and

piroxicam (CYP2C9 substrates), and theophylline (a CYP1A2 substrate) in healthy subjects, the

pharmacokinetics of pantoprazole sodium were not significantly altered.

Clopidogrel: Clopidogrel is metabolized to its active metabolite in part by CYP2C19. In a crossover

clinical study, 66 healthy subjects were administered clopidogrel (300 mg loading dose followed by 75

mg per day) alone and with pantoprazole (80 mg at the same time as clopidogrel) for 5 days. On Day 5,

the mean AUC of the active metabolite of clopidogrel was reduced by approximately 14% (geometric

mean ratio was 86%, with 90% CI of 79 to 93%) when pantoprazole was coadministered with

clopidogrel as compared to clopidogrel administered alone. Pharmacodynamic parameters were also

measured and demonstrated that the change in inhibition of platelet aggregation (induced by 5 µM ADP)

was correlated with the change in the exposure to clopidogrel active metabolite. The clinical

significance of this finding is not clear.

Mycophenolate Mofetil (MMF): Administration of pantoprazole 40 mg twice daily for 4 days and a

Geometric mean values

Median values

single 1000 mg dose of MMF approximately one hour after the last dose of pantoprazole to 12 healthy

subjects in a cross-over study resulted in a 57% reduction in the C

and 27% reduction in the AUC of

MPA. Transplant patients receiving approximately 2000 mg per day of MMF (n=12) were compared to

transplant patients receiving approximately the same dose of MMF and pantoprazole 40 mg per day

(n=21). There was a 78% reduction in the C

and a 45% reduction in the AUC of MPA in patients

receiving both pantoprazole and MMF.

In vivo studies also suggest that pantoprazole sodium does not significantly affect the kinetics of the

following drugs (cisapride, theophylline, diazepam [and its active metabolite, desmethyldiazepam],

phenytoin, warfarin, metoprolol, nifedipine, carbamazepine, midazolam, clarithromycin, naproxen,

piroxicam, and oral contraceptives [levonorgestrel/ethinyl estradiol]). Dosage adjustment of these drugs

is not necessary when they are coadministered with pantoprazole sodium. In other in vivo studies,

digoxin, ethanol, glyburide, antipyrine, caffeine, metronidazole, and amoxicillin had no clinically

relevant interactions with pantoprazole sodium.

Based on studies evaluating possible interactions of pantoprazole sodium with other drugs, no dosage

adjustment is needed with concomitant use of the following: theophylline, cisapride, antipyrine,

caffeine, carbamazepine, diazepam (and its active metabolite, desmethyldiazepam), diclofenac, naproxen,

piroxicam, digoxin, ethanol, glyburide, an oral contraceptive (levonorgestrel/ethinyl estradiol),

metoprolol, nifedipine, phenytoin, warfarin, midazolam, clarithromycin, metronidazole, or amoxicillin.

There was also no interaction with concomitantly administered antacids.

There have been postmarketing reports of increased INR and prothrombin time in patients receiving

proton pump inhibitors, including pantoprazole sodium, and warfarin concomitantly [see Drug

Interactions (7.2)].

Although no significant drug-drug interactions have been observed in clinical studies, the potential for

significant drug-drug interactions with more than once-daily dosing with high doses of pantoprazole

sodium has not been studied in poor metabolizers or individuals who are hepatically impaired.

Other Effects

In a clinical pharmacology study, pantoprazole sodium 40 mg given once daily for 2 weeks had no

effect on the levels of the following hormones: cortisol, testosterone, triiodothyronine (T ), thyroxine

(T ), thyroid-stimulating hormone (TSH), thyronine-binding protein, parathyroid hormone, insulin,

glucagon, renin, aldosterone, follicle-stimulating hormone, luteinizing hormone, prolactin, and growth

hormone.

In a 1-year study of GERD patients treated with pantoprazole sodium 40 mg or 20 mg, there were no

changes from baseline in overall levels of T , T , and TSH.

12.4 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 sodium poor metabolizers have

elimination half-life values of 3.5 to 10.0 hours in adults, they still have minimal accumulation (≤ 23%)

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 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

In a 24-month carcinogenicity study, Sprague-Dawley rats were treated orally with 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 at 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 at 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 sodium treatment included an

adenocarcinoma of the duodenum at 50 mg/kg/day and benign polyps and adenocarcinomas of the gastric

fundus at 200 mg/kg/day. In the liver, treatment at 0.5 to 200 mg/kg/day produced dose-related increases

in the incidences of hepatocellular adenomas and carcinomas. In the thyroid gland, treatment at 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, approximately 1 to 10 times the recommended human dose based on body surface area. In the

gastric fundus, treatment at 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 sodium.

In a 24-month carcinogenicity study, B6C3F1 mice were treated orally with 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 at 150 mg/kg/day produced increased incidences of hepatocellular adenomas and carcinomas

in female mice. Treatment at 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 sodium 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 sodium 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 sodium 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).

13.2 Animal Toxicology and/or Pharmacology

Studies in neonatal/juvenile and adult rats and dogs were performed. The data from these studies

revealed that animals in both age groups respond to pantoprazole sodium in a similar manner. Gastric

alterations, including increased stomach weights, increased incidence of eosinophilic chief cells in

adult and neonatal/juvenile rats, and atrophy of chief cells in adult rats and in neonatal/juvenile dogs,

were observed in the fundic mucosa of stomachs in repeated-dose studies. Decreases in red cell mass

parameters, increases in cholesterol and triglycerides, increased liver weight, enzyme induction, and

hepatocellular hypertrophy were also seen in repeated-dose studies in rats and/or dogs. Full to partial

recovery of these effects were noted in animals of both age groups following a recovery period.

Reproductive Toxicology Studies

Reproduction studies have been performed in rats at oral doses up to 450 mg/kg/day (88 times the

recommended human dose based on body surface area) and rabbits at oral doses up to 40 mg/kg/day (16

times the recommended human dose based on body surface area) and have revealed no evidence of

impaired fertility or harm to the fetus due to pantoprazole sodium.

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 sodium 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 6.

Table 6: Erosive Esophagitis Healing Rates (Per Protocol)

––––––––––Pantoprazole Sodium–––––––––

Placebo

Week

10 mg daily

(n = 153)

20 mg daily

(n = 158)

40 mg daily

(n = 162)

(n = 68)

45.6%

58.4%

75.0%

14.3%

66.0%

83.5 %

92.6%

39.7%

In this study, all pantoprazole sodium 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

sodium treatment groups. The 40 mg dose of pantoprazole sodium 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 sodium 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 sodium consumed significantly fewer

antacid tablets per day than those taking placebo.

Pantoprazole sodium 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 7.

Table 7: Erosive Esophagitis Healing Rates (Per Protocol)

––––––Pantoprazole Sodium––––––

Nizatidine

Week

20 mg daily

(n = 72)

40 mg daily

(n = 70)

150 mg twice daily

(n = 70)

61.4%

64.0%

22.2%

79.2%

82.9%

41.4%

Once-daily treatment with pantoprazole sodium 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

(p < 0.001) pantoprazole sodium versus placebo

(p < 0.05) versus 10 mg pantoprazole sodium

(p < 0.05) versus 10 mg or 20 mg pantoprazole sodium

*†

*‡

*†

*‡

(p < 0.001) pantoprazole sodium versus nizatidine

regardless of the H. pylori status.

A significantly greater proportion of the patients in the pantoprazole sodium 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 sodium consumed significantly fewer antacid tablets per day than those taking

nizatidine.

Pediatric Patients Ages 5 Years through 16 Years

The efficacy of pantoprazole sodium 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 sodium (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 erosive

esophagitis to demonstrate efficacy of pantoprazole sodium 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 8, pantoprazole sodium 40 mg and 20 mg were significantly superior to ranitidine

at every timepoint with respect to the maintenance of healing. In addition, pantoprazole sodium 40 mg

was superior to all other treatments studied.

Table 8: Long-Term Maintenance of Healing of Erosive

Gastroesophageal Reflux Disease (GERD Maintenance): Percentage of

Patients Who Remained Healed

Pantoprazole

Sodium

20 mg daily

Pantoprazole

Sodium

40 mg daily

Ranitidine

150 mg twice

daily

Note: Pantoprazole sodium 10 mg was superior (p < 0.05) to ranitidine in

Study 2, but not Study 1.

Study 1

n = 75

n = 74

n = 75

Month 1

Month 3

Month 6

Month 12

Study 2

n = 74

n = 88

n = 84

Month 1

Month 3

Month 6

Month 12

Pantoprazole sodium 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 sodium 20 mg,

administered once daily, was also effective in reducing episodes of daytime and nighttime heartburn in

(p < 0.05 vs. ranitidine)

(p < 0.05 vs. pantoprazole sodium 20 mg)

*†

*†

*†

*†

*†

*†

one trial, as presented in Table 9.

Table 9: Number of Episodes of Heartburn (mean ± SD)

Pantoprazole

Sodium

40 mg daily

Ranitidine

150 mg twice

daily

Month 1

Daytime

5.1 ± 1.6

18.3 ± 1.6

Nighttime

3.9 ± 1.1

11.9 ± 1.1

Month 12

Daytime

2.9 ± 1.5

17.5 ± 1.5

Nighttime

2.5 ± 1.2

13.8 ± 1.3

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 sodium

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 sodium 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 are supplied as 40 mg yellow, oval biconvex delayed-

release tablets imprinted with P40 (brown ink) on one side and are available as follows:

NDC 0008-0607-01 bottles of 90 tablets

NDC 0008-0607-04 cartons of 10 Redipak blister strips of 10 tablets

Pantoprazole Sodium Delayed-Release Tablets are supplied as 20 mg yellow oval biconvex delayed-

release tablets imprinted with P20 (brown ink) on one side and are available as follows:

NDC 0008-0606-01 bottles of 90 tablets

Storage

Store Pantoprazole Sodium Delayed-Release Tablets 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

See FDA-Approved Medication Guide.

Caution patients that Pantoprazole Sodium Delayed-Release Tablets should not be split, crushed, or

chewed.

Tell patients that Pantoprazole Sodium Delayed-Release Tablets should be swallowed whole, with

or without food in the stomach.

Let patients know that concomitant administration of antacids does not affect the absorption of

Pantoprazole Sodium Delayed-Release Tablets.

Advise patients to immediately report and seek care for any cardiovascular or neurological

symptoms including palpitation, dizziness, seizures, and tetany as these may be signs of

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

hypomagnesemia [see Warnings and Precautions (5.7)].

Advise patients to immediately report and seek care for diarrhea that does not improve. This may be

a sign of Clostridium difficile associated diarrhea [see Warnings and Precautions (5.5)].

This product's label may have been updated. For current full prescribing information, please visit

www.pfizer.com.

Marketed by:

esiLederle Division of Wyeth

Philadelphia, PA 19101

Under license from:

Takeda GmbH

D78467 Konstanz, Germany

LAB-0522-3.0

MEDICATION GUIDE

Pantoprazole sodium

Delayed-Release Tablets

Read this Medication Guide before you start taking pantoprazole sodium and each time you get a refill.

There may be new information. This information does not take the place of talking with your doctor

about your medical condition or your treatment.

What is the most important information I should know about pantoprazole sodium?

Pantoprazole sodium may help your acid-related symptoms, but you could still have serious

stomach problems. Talk with your doctor.

Pantoprazole sodium can cause serious side effects, including:

Diarrhea. Pantoprazole sodium may increase your risk of getting severe diarrhea. This diarrhea

may be caused by an infection (Clostridium difficile) in your intestines.

Call your doctor right away if you have watery stool, stomach pain, and fever that does not go away.

Bone fractures. People who take multiple daily doses of proton pump inhibitor medicines for a

long period of time (a year or longer) may have an increased risk of fractures of the hip, wrist or

spine. You should take pantoprazole sodium exactly as prescribed, at the lowest dose possible for

your treatment and for the shortest time needed. Talk to your doctor about your risk of bone fracture

if you take pantoprazole sodium.

Pantoprazole sodium can have other serious side effects. See "What are the possible side effects of

pantoprazole sodium?"

What is pantoprazole sodium?

Pantoprazole sodium is a prescription medicine called a proton pump inhibitor (PPI).

Pantoprazole sodium reduces the amount of acid in your stomach.

Pantoprazole sodium is used in adults:

for up to 8 weeks to heal acid-related damage to the lining of the esophagus (erosive esophagitis or

EE) and to relieve symptoms caused by gastroesophageal reflux disease (GERD). If needed, your

doctor may decide to prescribe another 8 weeks of pantoprazole sodium.

to maintain the healing of acid-related damage to the lining of the esophagus and help prevent return

of heartburn symptoms caused by GERD. It is not known if pantoprazole sodium is safe and effective

if used longer than 12 months (1 year).

GERD happens when acid in your stomach backs up into the tube (esophagus) that connects your

mouth to your stomach. This may cause a burning feeling in your chest or throat, sour taste, or

burping.

for the long-term treatment of conditions where your stomach makes too much acid. This includes a

rare condition called Zollinger-Ellison syndrome.

Pantoprazole sodium is used in children 5 years of age and older for up to 8 weeks to heal acid-related

damage to the lining of the esophagus (erosive esophagitis or EE) caused by GERD.

It is not known if pantoprazole sodium is safe if used longer than 8 weeks in children. Pantoprazole

sodium is not for use in children under 5 years of age.

Who should not take pantoprazole sodium?

Do not take pantoprazole sodium if you are:

allergic to pantoprazole sodium or any of the other ingredients in Pantoprazole Sodium Delayed-

Release Tablets. See the end of this Medication Guide for a complete list of ingredients in

pantoprazole sodium.

allergic to any proton pump inhibitor (PPI) medicine.

What should I tell my doctor before taking pantoprazole sodium?

Before taking pantoprazole sodium, tell your doctor if you:

have been told that you have low magnesium levels in your blood

have liver problems

have any other medical conditions

are pregnant, or plan to become pregnant. It is not known if pantoprazole sodium will harm your

unborn baby.

are breastfeeding or plan to breastfeed. Pantoprazole sodium may pass into your milk. You and your

doctor should decide if you will take pantoprazole sodium or breastfeed. You should not do both.

Talk with your doctor about the best way to feed your baby if you take pantoprazole sodium.

Tell your doctor about all of the medicines you take, including prescription and non-prescription

drugs, vitamins and herbal supplements. Pantoprazole sodium may affect how other medicines work, and

other medicines may affect how pantoprazole sodium works.

Especially tell your doctor if you take:

atazanavir (Reyataz)

nelfinavir (Viracept)

warfarin (Coumadin, Jantoven)

ketoconazole (Nizoral)

a product that contains iron

an antibiotic that contains ampicillin

methotrexate

mycophenolate mofetil (Cellcept)

Ask your doctor or pharmacist for a list of these medicines, if you are not sure.

Know the medicines that you take. Keep a list of them to show your doctor and pharmacist when you get

a new medicine.

How should I take pantoprazole sodium?

Take pantoprazole sodium exactly as prescribed by your doctor.

Do not change your dose or stop pantoprazole sodium without talking to your doctor.

If you forget to take a dose of pantoprazole sodium, take it as soon as you remember. If it is almost

time for your next dose, do not take the missed dose. Take the next dose at your regular time. Do not

take two doses to try to make up for a missed dose.

If you take too much pantoprazole sodium, call your doctor right away or go to the nearest hospital

emergency room.

See the Instructions for Use at the end of this Medication Guide for detailed instructions about how

to take pantoprazole sodium tablets.

What are the possible side effects of pantoprazole sodium?

Pantoprazole sodium may cause serious side effects, including:

See "What is the most important information I should know about pantoprazole sodium?"

Chronic (lasting a long time) inflammation of the lining of the stomach (Atrophic Gastritis).

Taking pantoprazole sodium for a long period of time may increase the risk of inflammation to your

stomach lining. You may or may not have symptoms. Tell your doctor if you have stomach pain,

nausea, vomiting or weight loss.

Vitamin B-12 deficiency. Pantoprazole sodium reduces the amount of acid in your stomach.

Stomach acid is needed to absorb vitamin B-12 properly. Talk with your doctor about the possibility

of vitamin B-12 deficiency if you have been on pantoprazole sodium for a long time (more than 3

years).

Low magnesium levels in your body. This problem can be serious. Low magnesium can happen in

some people who take a proton pump inhibitor medicine for at least 3 months. If low magnesium

levels happen, it is usually after a year of treatment. You may or may not have symptoms of low

magnesium.

Tell your doctor right away if you have any of these symptoms:

seizures

dizziness

abnormal or fast heartbeat

jitteriness

jerking movements or shaking (tremors)

muscle weakness

spasms of the hands and feet

cramps or muscle aches

spasm of the voice box

Your doctor may check the level of magnesium in your body before you start taking pantoprazole

sodium or during treatment, if you will be taking pantoprazole sodium for a long period of time.

The most common side effects with pantoprazole sodium in adults include:

Headache

Diarrhea

Nausea

Stomach pain

Vomiting

Dizziness

Pain in your

joints

The most common side effects with pantoprazole sodium in children include:

Upper respiratory

infection

Headache

Fever

Diarrhea

Vomiting

Rash

Stomach pain

Other side effects:

Serious allergic reactions. Tell your doctor if you get any of the following symptoms with

pantoprazole sodium:

rash

face swelling

throat tightness

difficult breathing

Your doctor may stop pantoprazole if these symptoms happen.

Tell your doctor about any side effects that bother you or that do not go away.

These are not all the possible side effects with pantoprazole sodium. For more information, ask your

doctor or pharmacist.

Call your doctor for medical advice about side effects. You may report side effects to the FDA at 1-

800-FDA-1088.

How should I store pantoprazole sodium?

Store pantoprazole sodium at room temperature between 68° to 77°F (20° to 25°C).

Keep pantoprazole sodium and all medicines out of the reach of children.

General information about pantoprazole sodium

Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not

use pantoprazole sodium for a condition for which it was not prescribed. Do not give pantoprazole

sodium to other people, even if they have the same symptoms you have. It may harm them.

This Medication Guide summarizes the most important information about pantoprazole sodium. For more

information, ask your doctor. You can ask your doctor or pharmacist for information that is written for

healthcare professionals.

For more information, go to www.pfizer.com or call toll-free 1-800-438-1985.

What are the ingredients in pantoprazole sodium?

Active ingredient: pantoprazole sodium sesquihydrate

Inactive ingredients in Pantoprazole Sodium Delayed-Release Tablets: calcium stearate,

crospovidone, hypromellose, iron oxide, mannitol, methacrylic acid copolymer, polysorbate 80,

povidone, propylene glycol, sodium carbonate, sodium lauryl sulfate, titanium dioxide, and triethyl

citrate.

Instructions for Use

Pantoprazole sodium Delayed-Release tablets

You can take Pantoprazole Sodium Delayed-Release Tablets with food or on an empty stomach.

Swallow Pantoprazole Sodium Delayed-Release tablets whole.

If you have trouble swallowing a Pantoprazole Sodium 40 mg Delayed-Release Tablet, you can take

two 20 mg tablets instead.

Do not split, chew, or crush Pantoprazole Sodium Delayed-Release tablets.

This Medication Guide has been approved by the U.S. Food and Drug Administration.

This product's label may have been updated. For current full prescribing information, please visit

www.pfizer.com.

Marketed by:

esiLederle Division of Wyeth

Philadelphia, PA 19101

Under license from:

Takeda GmbH

D78467 Konstanz, Germany

LAB-0653-3.0

January 2015

Image of Label

PANTOPRAZOLE SODIUM DELAYED-RELEASE

pantoprazole sodium tablet, delayed release

Product Information

Product T ype

HUMAN PRESCRIPTION DRUG

Ite m Code (Source )

NDC:5570 0 -118 (NDC:0 0 0 8 -0 6 0 6 )

Route of Administration

ORAL

Active Ingredient/Active Moiety

Ingredient Name

Basis of Strength

Stre ng th

PANTO PRAZO LE SO DIUM (UNII: 6 8 716 19 Q5X) (PANTOPRAZOLE - UNII:D8 TST4O56 2)

PANTOPRAZOLE

20 mg

Inactive Ingredients

Ingredient Name

Stre ng th

CALCIUM STEARATE (UNII: 776 XM70 47L)

CRO SPO VIDO NE (UNII: 2S78 30 E56 1)

FERRIC O XIDE YELLO W (UNII: EX438 O2MRT)

MANNITO L (UNII: 3OWL53L36 A)

METHACRYLIC ACID - ETHYL ACRYLATE CO PO LYMER ( 1:1) TYPE A (UNII: NX76 LV5T8 J)

PO LYSO RBATE 8 0 (UNII: 6 OZP39 ZG8 H)

PO VIDO NE K2 5 (UNII: K0 KQV10 C35)

Lake Erie Medical DBA Quality Care Products LLC

PO VIDO NE K9 0 (UNII: RDH8 6 HJV5Z)

PRO PYLENE GLYCO L (UNII: 6 DC9 Q16 7V3)

SO DIUM CARBO NATE (UNII: 45P326 1C7T)

SO DIUM LAURYL SULFATE (UNII: 36 8 GB5141J)

TITANIUM DIO XIDE (UNII: 15FIX9 V2JP)

TRIETHYL CITRATE (UNII: 8 Z9 6 QXD6 UM)

HYPRO MELLO SE 2 2 0 8 ( 10 0 MPA.S) (UNII: B1QE5P712K)

Product Characteristics

Color

YELLOW (YELLOW)

S core

no sco re

S hap e

OVAL (BICONVEX)

S iz e

9 mm

Flavor

Imprint Code

P;20

Contains

Packag ing

#

Item Code

Package Description

Marketing Start Date

Marketing End Date

1

NDC:5570 0 -118 -30

30 in 1 BOTTLE; Type 0 : No t a Co mbinatio n Pro duct

0 1/31/20 0 8

0 6 /0 1/20 14

2

NDC:5570 0 -118 -6 0

6 0 in 1 BOTTLE; Type 0 : No t a Co mbinatio n Pro duct

0 1/31/20 0 8

3

NDC:5570 0 -118 -9 0

9 0 in 1 BOTTLE; Type 0 : No t a Co mbinatio n Pro duct

0 1/31/20 0 8

0 6 /0 1/20 14

Marketing Information

Marke ting Cate gory

Application Numbe r or Monograph Citation

Marke ting Start Date

Marke ting End Date

NDA0 20 9 8 7

0 1/31/20 0 8

Labeler -

Lake Erie Medical DBA Quality Care Products LLC (831276758)

Establishment

Name

Ad d re s s

ID/FEI

Busine ss Ope rations

Lake Erie Medical DBA Quality Care Pro ducts LLC

8 31276 758

re pa c k(5570 0 -118 )

Revised: 2/2017

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