PANTOPRAZOLE SODIUM- pantoprazole tablet, delayed release

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

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Active ingredient:
PANTOPRAZOLE SODIUM (UNII: 6871619Q5X) (PANTOPRAZOLE - UNII:D8TST4O562)
Available from:
Quality Care Products, LLC
Administration route:
ORAL
Prescription type:
PRESCRIPTION DRUG
Therapeutic indications:
Pantoprazole Sodium Delayed-Release Tablets are indicated for: Pantoprazole Sodium Delayed-Release Tablet is 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 (EE). For those adult patients who have not healed after 8 weeks of treatment, an additional 8-week course of pantoprazole sodium delayed-release tablets may be considered. Safety of treatment beyond 8 weeks in pediatric patients has not been established. Pantoprazole Sodium Delayed-Release Tablets are indicated for maintenance of healing of EE and reduction in relapse rates of daytime and nighttime heartburn symptoms in adult patients with GERD. Controlled studies did not extend beyond 12 months. Pantoprazole Sodium Delayed-Release Tablets are indicated for the long-term treatment of pathological hypersecretory conditions, including Zollinger-Ellison (ZE) syndrome. •  Pantoprazole Sodium Delayed-Release Tablets are contraindica
Product summary:
How Supplied Pantoprazole Sodium Delayed-Release Tablets, USP are supplied as 20 mg yellow to pale yellow, oval, biconvex, delayed-release tablets imprinted “H125” on one side with black ink and plain on the other side. They are supplied as follows: 55700-790-30 55700-790-60 Pantoprazole Sodium Delayed-Release Tablets, USP are supplied as 40 mg yellow to pale yellow, oval, biconvex, delayed-release tablets imprinted “H126” on one side with black ink and plain on the other side. They are supplied as follows: Storage Store pantoprazole sodium delayed-release tablets, USP at 20 to 25°C (68 to 77°F) [see USP Controlled Room Temperature].
Authorization status:
Abbreviated New Drug Application
Authorization number:
55700-790-30, 55700-790-60

Quality Care Products, LLC

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MEDICATION GUIDE

MEDICATION GUIDE

Pantoprazole Sodium Delayed-Release Tablets USP

(pan toe’ pra zole soe’dee um)

What is the most important information I should know about pantoprazole sodium delayed-release tablets?

You should take pantoprazole sodium delayed-release tablets exactly as prescribed, at the lowest dose

possible and for the shortest time needed.

Pantoprazole sodium delayed-release tablets may help your acid-related symptoms, but you could still have

serious stomach problems. Talk with your doctor.

Pantoprazole sodium delayed-release tablets can cause serious side effects, including:

A type of kidney problem (acute interstitial nephritis). Some people who take proton pump inhibitor (PPI)

medicines, including pantoprazole sodium delayed-release tablets, may develop a kidney problem called

acute interstitial nephritis that can happen at any time during treatment with pantoprazole sodium delayed-

release tablets. Call your doctor right away if you have a decrease in the amount that you urinate or if you

have blood in your urine.

Diarrhea caused by an infection (Clostridium difficile) in your intestines. Call your doctor right away if

you have watery stools or stomach pain that does not go away. You may or may not have a fever.

Bone fractures (hip, wrist, or spine). Bone fractures in the hip, wrist, or spine may happen in people who

take multiple daily doses of PPI medicines and for a long period of time (a year or longer). Tell your doctor if

you have a bone fracture, especially in the hip, wrist, or spine.

Certain types of lupus erythematosus. Lupus erythematosus is an autoimmune disorder (the body’s immune

cells attack other cells or organs in the body). Some people who take PPI medicines, including pantoprazole

sodium delayed-release tablet, may develop certain types of lupus erythematosus or have worsening of the

lupus they already have. Call your doctor right away if you have new or worsening joint pain or a rash on

your cheeks or arms that gets worse in the sun.

Talk to your doctor about your risk of these serious side effects.

Pantoprazole sodium delayed-release tablets can have other serious side effects. See “What are the possible

side effects of pantoprazole sodium delayed-release tablets?”

What are pantoprazole sodium delayed-release tablets?

A prescription medicine called a proton pump inhibitor (PPI) used to reduce the amount of acid in your

stomach.

In adults, pantoprazole sodium delayed-release tablets are used for:

up to 8 weeks for the healing and symptom relief of acid-related damage to the lining of the esophagus

(called erosive esophagitis or EE). Your doctor may prescribe another 8 weeks of pantoprazole sodium

delayed-release tablets in patients whose EE does not heal.

maintaining healing of EE and to help prevent the return of heartburn symptoms caused by GERD. It is not

known if pantoprazole sodium delayed-release tablets are safe and effective when used for longer than 12

months for this purpose.

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

condition called Zollinger-Ellison Syndrome.

In children 5 years of age and older, pantoprazole sodium delayed-release tablets are used for:

up to 8 weeks for the healing and symptom relief of EE.

It is not known if pantoprazole sodium delayed-release tablets are safe if used longer than 8 weeks in

children.

Pantoprazole sodium delayed-release tablets are not for use in children under 5 years of age.

It is not known if pantoprazole sodium delayed-release tablets are safe and effective in children for treatment

other than EE.

Do not take pantoprazole sodium delayed-release tablets if you are:

allergic to pantoprazole sodium, any other PPI medicine, or any of the ingredients in pantoprazole sodium

delayed-release tablets. See the end of this Medication Guide for a complete list of ingredients.

taking a medicine that contains rilpivirine (EDURANT, COMPLERA, ODEFSEY) used to treat HIV-1

(Human Immunodeficiency Virus).

Before taking pantoprazole sodium delayed-release tablets, tell your doctor about all of your medical

conditions, including if you:

have low magnesium levels in your blood

are pregnant or plan to become pregnant. Pantoprazole sodium delayed-release tablets may harm your

unborn baby. Tell your doctor if you become pregnant or think you may be pregnant during treatment with

pantoprazole sodium delayed-release tablets.

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

doctor should decide if you will take pantoprazole sodium delayed-release tablets or breastfeed. You should

not do both. Talk with your doctor about the best way to feed your baby if you take pantoprazole sodium

delayed-release tablets.

Tell your doctor about all the medicines you take, including prescription and over-the-counter medicines,

vitamins and herbal supplements. Especially tell your doctor if you take methotrexate (Otrexup, Rasuvo,

Trexall, XATMEP), digoxin (LANOXIN), or a water pill (diuretic).

How should I take pantoprazole sodium delayed-release tablets?

Take pantoprazole sodium delayed-release tablets exactly as prescribed by your doctor.

Pantoprazole sodium delayed-release tablets:

o Do not split, chew, or crush pantoprazole sodium delayed-release tablets.

o Swallow pantoprazole sodium delayed-release tablets whole, with or without food.

o Tell your doctor if you are not able to swallow your pantoprazole sodium delayed-release tablets.

o You may use antacids while taking pantoprazole sodium delayed-release tablets.

If you miss a dose of pantoprazole sodium delayed-release tablets, take it as soon as possible. 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 2

doses at the same time.

If you take too much pantoprazole sodium, call your doctor or your poison control center at 1-800-222-1222

right away or go to the nearest emergency room.

What are the possible side effects of pantoprazole sodium delayed-release tablets?

Pantoprazole sodium delayed-release tablets can cause serious side effects, including:

See “What is the most important information I should know about pantoprazole sodium delayed-release

tablets?”

Low vitamin B-12 levels in your body can happen in people who have taken pantoprazole sodium delayed-

release tablets for a long time (more than 3 years). Tell your doctor if you have symptoms of low vitamin B-

12 levels, including shortness of breath, lightheadedness, irregular heartbeat, muscle weakness, pale skin,

feeling tired, mood changes, and tingling or numbness in the arms and legs.

Low magnesium levels in your body can happen in people who have taken pantoprazole sodium delayed-

release tablets for at least 3 months. Tell your doctor if you have symptoms of low magnesium levels,

including seizures, dizziness, irregular heartbeat, jitteriness, muscle aches or weakness, and spasms of hands,

feet or voice.

Stomach growths (fundic gland polyps). People who take PPI medicines for a long time have an increased

risk of developing a certain type of stomach growths called fundic gland polyps, especially after taking PPI

medicines for more than 1 year.

The most common side effects of pantoprazole sodium delayed-release tablets in adults include: headache,

diarrhea, nausea, stomach-area (abdominal) pain, vomiting, gas, dizziness, and joint pain.

The most common side effects of pantoprazole sodium delayed-release tablets in children include: upper

respiratory infection, headache, fever, diarrhea, vomiting, rash, and stomach-area (abdominal) pain.

These are not all the possible side effects of pantoprazole sodium delayed-release tablets. Call your doctor for

medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

How should I store pantoprazole sodium delayed-release tablets?

Store pantoprazole sodium delayed-release tablets at 20° to 25°C (68° to 77°F) [see USP Controlled Room

Temperature].

Keep pantoprazole sodium delayed-release tablets and all medicines out of the reach of children.

General information about the safe and effective use of pantoprazole sodium delayed-release tablets.

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

pantoprazole sodium delayed-release tablets for a condition for which it was not prescribed. Do not give

pantoprazole sodium delayed-release tablets to other people, even if they have the same symptoms that you

have. It may harm them. You can ask your doctor or pharmacist for information about pantoprazole sodium

delayed-release tablets that is written for health professionals.

What are the ingredients in pantoprazole sodium delayed-release tablets?

Active ingredient: pantoprazole sodium sesquihydrate USP

Inactive ingredients: calcium stearate, ferric oxide yellow, hydroxy propyl cellulose, hypromellose, lactose

monohydrate, methacrylic acid copolymer, polysorbate 80, propylene glycol, sodium carbonate anhydrous,

sodium lauryl sulfate, titanium dioxide, and triethyl citrate. The tablets are imprinted with opacode black

containing ammonium hydroxide, iron oxide black, propylene glycol and shellac.

For more information call 866-495-1995

The brands listed are trademarks of their respective owners and are not trademarks of Hetero Labs Limited.

This Medication Guide and Instructions for Use has been approved by the U.S. Food and Drug

Administration.

Manufactured for:

Camber Pharmaceuticals Inc.

Piscataway, NJ 08854

By: HETEROTM

Hetero Labs Limited Unit V, Polepally,

Jadcherla, Mahabubnagar – 509 301, India.

Revised: July 2018

Revised: 9/2019

Document Id: 4656a760-949d-42c7-a6e0-780128494a67

34391-3

Set id: d141bf61-8bcf-4edc-8d3c-412cada4702f

Version: 1

Effective Time: 20190910

Quality Care Products, LLC

PANTOPRAZOLE SODIUM- pantoprazole tablet, delayed release

Quality Care Products, LLC

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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 TABLETS.

PANTOPRAZOLE SODIUM delayed-release tablets, for oral use

Initial U.S. approval: 2000

RECENT MAJOR CHANGES

Warnings and Precautions, Fundic Gland Polyps (5.9) 06/2018

Warnings and Precautions, Interference with Investigations for Neuroendocrine Tumors (5.10) 12/2017

INDICATIONS AND USAGE

Pantoprazole sodium delayed-release tablet is a proton pump inhibitor (PPI) 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 (ZE) Syndrome (1.3)

DOSAGE AND ADMINISTRATION

Indication

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

olde r)

≥ 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

*Controlled studies did not extend beyond 12 months

See full prescribing information for administration instructions (2)

DOSAGE FORMS AND STRENGTHS

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

CONTRAINDICATIONS

Patients with known hypersensitivity to any component of the formulation or to substituted benzimidazoles (4)

Patients receiving rilpivirine-containing products (4, 7)

WARNINGS AND PRECAUTIONS

Gastric Malignancy: In adults, Symptomatic response does not preclude presence of gastric malignancy. Consider

additional follow-up and diagonostic testing. (5.1)

Acute interstitial nephritis:Observed in patients taking PPIs. (5.2)

Clostridium difficile-associated diarrhea: PPI therapy may be associated with increased risk .(5.3)

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. (5.4)

Cutaneous and Systemic Lupus Erythematosus: mostly cutaneous; new onset or exacerbation of existing disease;

discontinue pantoprazole sodium delayed-release tablet and refer to specialist for evalution. (5.5)

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

deficiency of cyanocobalamin. (5.6)

Hypomagnesemia: Reported rarely with prolonged treatment with PPIs (5.7)

Fundic Gland Polyps: Risk increases with long-term use, especially beyond one year. Use the shortest duration of

therapy. (5.9)

ADVERSE REACTIONS

Most common adverse reactions are:

For adult use (>2%): headache, diarrhea, nausea, abdominal pain, vomiting, flatulence, dizziness, and arthralgia. (6.1)

For pediatric use (>4%): URI, headache, fever, diarrhea, vomiting, rash, and abdominal pain.(6.1)

To report SUSPECTED ADVERSE REACTIONS, contact Hetero Labs Limited at 866-495-1995 or FDA at 1-800-

FDA-1088 or www.fda.gov/medwatch.

DRUG INTERACTIONS

See full prescribing information for a list of clinically important drug interactions (7)

USE IN SPECIFIC POPULATIONS

Pregnancy: Based on animal data, may cause fetal harm. (8.1)

See 17 for PATIENT COUNSELING INFORMATION and Medication Guide.

Revised: 9/2019

FULL PRESCRIBING INFORMATION: CONTENTS*

1 INDICATIONS & 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 & ADMINISTRATION

2.1 Recommended Dosing Schedule

2.2 Administration Instructions

3 DOSAGE FORMS & STRENGTHS

4 CONTRAINDICATIONS

5 WARNINGS AND PRECAUTIONS

5.1 Presence of Gastric Malignancy

5.2 Acute interstitial Nephritis

5.3 Clostridium difficile- Associated Diarrhea

5.4 Bone Fracture

5.5 Cutaneous and Systemic Lupus Erythematosus

5.6 Cyanocobalamin (Vitamin B-12) Deficiency

5.7 Hypomagnesemia

5.8 Tumorigenicity

5.9 Fundic Gland Polyps

5.10 Interference with Urine Screen for THC

5.11 Interference with Urine Screen for THC

5.12 Concomitant Use of Pantoprazole Sodium with Methotrexate

6 ADVERSE REACTIONS

6.1 Clinical Trials Experience

6.2 Postmarketing Experience

7 DRUG INTERACTIONS

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

8.3 Nursing Mothers

8.4 Pediatric Use

8.5 Geriatric Use

10 OVERDOSAGE

11 DESCRIPTION

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

12.2 Pharmacodynamics

12.3 Pharmacokinetics

12.5 Pharmacogenomics

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis,Mutagenesis,Impairment of Fertility

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

BOXED WARNING

1 INDICATIONS & 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 Tablet is 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 (EE). For those adult patients who have not healed after 8 weeks of treatment, an

additional 8-week course of pantoprazole sodium delayed-release tablets 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 EE 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 (ZE) syndrome.

2 DOSAGE & ADMINISTRATION

2.1 Recommended Dosing Schedule

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

Dose

Frequency

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

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

≥ 40 kg

20 mg Once daily for up to 8 weeks

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 **

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

pantoprazole sodium delayed-release tablets may be considered.

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

clinically indicated. Doses up to 240 mg daily have been administered.

*** Controlled studies did not extend beyond 12 months

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-Releas e

Tablets

Oral

Swallowed whole, with or without food

* Do not split, chew, or crush 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.

Pantoprazole Sodium Delayed-Release Tablets

Swallowed Pantoprazole Sodium Delayed-Release Tablets whole, with or without food in the stomach.

For patients 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

T ablets.

3 DOSAGE FORMS & STRENGTHS

20 mg, yellow to pale yellow, oval, biconvex, delayed-release tablets imprinted “H125” on one side

with black ink and plain on the other side.

40 mg, yellow to pale yellow, oval, biconvex, delayed-release tablets imprinted “H126” on one side

with black ink and plain on the other 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

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

Proton pump inhibitors (PPIs), including pantoprazole sodium delayed-release tablets, are

contraindicated with rilpivirine-containing products [see Drug Interactions (7)].

5 WARNINGS AND PRECAUTIONS

5.1 Presence of Gastric Malignancy

In adults, symptomatic response to therapy with pantoprazole sodium does not preclude the presence of

gastric malignancy. Consider additional follow-up and diagnostic testing in adult patients who have a

suboptimal response or an early symptomatic relapse after completing treatment with a PPI. In older

patients, also consider an endoscopy.

5.2 Acute interstitial Nephritis

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

delayed-release tablets. Acute interstitial nephritis may occur at any point during PPI therapy and is

generally attributed to an idiopathic hypersensitivity reaction. Discontinue pantoprazole sodium

delayed-release tablets if acute interstitial nephritis develops [see Contraindications (4)].

5.3 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.

5.4 Bone Fracture

Several published observational studies suggest that PPI therapy may be associated with an increased

risk for osteoporosis-related fractures of the hip, wrist, or spine. The risk of fracture was increased in

patients who received high-dose, defined as multiple daily doses, and long-term PPI therapy (a year or

longer). Patients should use the lowest dose and shortest duration of PPI therapy appropriate to the

condition being treated. Patients at risk for osteoporosis-related fractures should be managed according

to established treatment guidelines [see Dosage and Administration (2) and Adverse Reactions (6.2)].

5.5 Cutaneous and Systemic Lupus Erythematosus

Cutaneous lupus erythematosus (CLE) and systemic lupus erythematosus (SLE) have been reported in

patients taking PPIs, including pantoprazole sodium. These events have occurred as both new onset and

an exacerbation of existing autoimmune disease. The majority of PPI-induced lupus erythematous cases

were CLE.

The most common form of CLE reported in patients treated with PPIs was subacute CLE (SCLE) and

occurred within weeks to years after continuous drug therapy in patients ranging from infants to the

elderly. Generally, histological findings were observed without organ involvement.

Systemic lupus erythematosus (SLE) is less commonly reported than CLE in patients receiving PPIs. PPI

associated SLE is usually milder than non-drug induced SLE. Onset of SLE typically occurred within

days to years after initiating treatment primarily in patients ranging from young adults to the elderly. The

majority of patients presented with rash; however, arthralgia and cytopenia were also reported.

Avoid administration of PPIs for longer than medically indicated. If signs or symptoms consistent with

Avoid administration of PPIs for longer than medically indicated. If signs or symptoms consistent with

CLE or SLE are noted in patients receiving pantoprazole sodium delayed-release tablets, discontinue

the drug and refer the patient to the appropriate specialist for evaluation. Most patients improve with

discontinuation of the PPI alone in 4 to 12 weeks. Serological testing (e.g. ANA) may be positive and

elevated serological test results may take longer to resolve than clinical manifestations.

5.6 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.

5.7 Hypomagnesemia

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

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

tetany, arrhythmias, and seizures. 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 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 Fundic Gland Polyps

PPI use is associated with an increased risk of fundic gland polyps that increases with long-term use,

especially beyond one year. Most PPI users who developed fundic gland polyps were asymptomatic and

fundic gland polyps were identified incidentally on endoscopy. Use the shortest duration of PPI therapy

appropriate to the condition being treated.

5.10 Interference with Urine Screen for THC

Serum chromogranin A (CgA) levels increase secondary to drug-induced decreases in gastric acidity.

The increased CgA level may cause false positive results in diagnostic investigations for

neuroendocrine tumors. Healthcare providers should temporarily stop pantoprazole sodium delayed-

release tablets treatment at least 14 days before assessing CgA levels and consider repeating the test if

initial CgA levels are high. If serial tests are performed (e.g. for monitoring), the same commercial

laboratory should be used for testing, as reference ranges between tests may vary [see Clinical

Pharmacology (12.2)].

5.11 Interference with Urine Screen for THC

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

patients receiving PPIs, including pantoprazole sodium delayed-release tablets [see Drug Interactions

(7)].

5.12 Concomitant Use of Pantoprazole Sodium with Methotrexate

Literature suggests that concomitant use of PPIs with methotrexate (primarily at high dose; see

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

metabolite, possibly leading to methotrexate toxicities. In high-dose methotrexate administration, a

temporary withdrawal of the PPI may be considered in some patients [see Drug Interactions (7)].

6 ADVERSE REACTIONS

The following serious adverse reactions are described below and elsewhere in labeling:

Acute Interstitial Nephritis [see Warnings and Precautions (5.2)]

Clostridium difficile-Associated Diarrhea [see Warnings and Precautions (5.3)]

Bone Fracture [see Warnings and Precautions (5.4)]

Cutaneous and Systemic Lupus Erythematosus [see Warnings and Precautions (5.5)]

Cyanocobalamin (Vitamin B-12) Deficiency [see Warningsand Precautions (5.6)]

Hypomagnesemia [see Warnings and Precautions (5.7)]

Fundic Gland Polyps [see Warnings and Precautions (5.9)]

6.1 Clinical Trials Experience

The adverse reaction profiles for Pantoprazole Sodium For Delayed-Release Oral Suspension and

Pantoprazole Sodium Delayed-Release Tablets are similar.

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 H2-receptor antagonist, 46 patients

on another PPI, 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 sodium

(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 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 (ZE) Syndrome

In clinical studies of ZE 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 postapproval use of pantoprazole sodium

delayed-release tablets. 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:

Gastrointestinal Disorders: fundic gland polyps

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), systemic lupus erythematosus

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, toxic epidermal necrolysis (TEN, some fatal), angioedema

(Quincke’s edema) and cutaneous lupus erythematosus

7 DRUG INTERACTIONS

Table 4 includes drugs with clinically important drug interactions and interaction with diagnostics when

administered concomitantly with pantoprazole sodium delayed-release tablets and instructions for

preventing or managing them.

Consult the labeling of concomitantly used drugs to obtain further information about interactions with

PPIs.

Table 4: Clinically Relevant Interactions Affecting Drugs Co-Administered with pantoprazole

sodium and Interactions with Diagnostics

Antiretrovirals

Clinical Impact:

effect

PPIs

antiretroviral

drugs

variable.

clinical

importance and the mechanisms behind these interactions are not always

known.

Decreased exposure of some antiretroviral drugs (e.g., rilpivirine

atazanavir, and nelfinavir) when used concomitantly with pantoprazole

sodium may reduce antiviral effect and promote the development of drug

resistance.

Increased exposure of other antiretroviral drugs (e.g., saquinavir)

when used concomitantly with pantoprazole sodium may increase toxicity

of the antiretroviral drugs.

There are other antiretroviral drugs which do not result in clinically

relevant interactions with pantoprazole.

Intervention:

Rilpivirine-containing

products:

Concomitant

with

pantoprazole

sodium

contraindicated [see

Contraindications

(4)]

.See

prescribing

information.

Atazanavir:

prescribing

information

atazanavir

dosing

information.

Nelfinavir:

Avoid

concomitant

with

pantoprazole

sodium.

prescribing information for nelfinavir.

Saquinavir: See the prescribing information for saquinavir and monitor for

potential saquinavir toxicities.

Other antiretrovirals: See prescribing information.

Warfarin

Clinical Impact:

Increased INR and prothrombin time in patients receiving PPIs, including

pantoprazole,

warfarin

concomitantly.

Increases

prothrombin time may lead to abnormal bleeding and even death.

Intervention:

Monitor INR and prothrombin time. Dose adjustment of warfarin may be

needed to maintain target INR range. See prescribing information for

warfarin.

Clopidogrel

Clinical Impact:

Concomitant administration of pantoprazole and clopidogrel in healthy

subjects had no clinically important effect on exposure to the active

metabolite of clopidogrel or clopidogrel-induced platelet inhibition [see

Clinical Pharmacology (12.3)].

Intervention:

No dose adjustment of clopidogrel is necessary when administered with an

approved dose of pantoprazole sodium delayed-release tablets.

Methotrexate

Clinical Impact:

Concomitant use of PPIs with methotrexate (primarily at high dose) may

elevate

prolong

serum

concentrations

methotrexate

and/or

metabolite

hydroxymethotrexate,

possibly

leading

methotrexate

toxicities. No formal drug interaction studies of high-dose methotrexate

with PPIs have been conducted [see Warnings and Precautions (5.12)] .

Intervention:

A temporary withdrawal of pantoprazole sodium may be considered in

some patients receiving high-dose methotrexate.

Drugs Dependent on Gastric pH for Absorption (e.g., iron salts, erlotinib, dasatinib,

nilotinib, mycophenolate mofetil, ketoconazole/itraconazole)

Clinical Impact:

Pantoprazole sodium can reduce the absorption of other drugs due to its

effect on reducing intragastric acidity.

Intervention:

Mycophenolate mofetil (MMF): Co-administration of pantoprazole sodium

in healthy subjects and in transplant patients receiving MMF has been

reported to reduce the exposure to the active metabolite, mycophenolic

acid (MPA), possibly due to a decrease in MMF solubility at an increased

gastric pH [see Clinical Pharmacology (12.3)] .

The clinical relevance of reduced MPA exposure on organ rejection has

not been established in transplant patients receiving pantoprazole sodium

and MMF. Use pantoprazole sodium with caution in transplant patients

receiving MMF.

See the prescribing information for other drugs dependent on gastric pH

for absorption.

Interactions with Investigations of Neuroendocrine Tumors

Clinical Impact:

levels

increase

secondary

PPI-induced

decreases

gastric

acidity. The increased CgA level may cause false positive results in

diagnostic investigations for neuroendocrine tumors [see Warnings and

Precautions (5.10), Clinical Pharmacology (12.2)] .

Intervention:

Temporarily stop pantoprazole sodium delayed-release tablets treatment at

least 14 days before assessing CgA levels and consider repeating the test

if initial CgA levels are high. If serial tests are performed (e.g. for

monitoring), the same commercial laboratory should be used for testing, as

reference ranges between tests may vary.

False Positive Urine Tests for THC

Clinical Impact:

There have been reports of false positive urine screening tests for

tetrahydrocannabinol (THC) in patients receiving PPIs [see Warnings and

Precautions (5.11)] .

Intervention:

An alternative confirmatory method should be considered to verify

positive results.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Teratogenic Effects

Pregnancy Category C

Reproduction studies have been performed in rats at oral pantoprazole doses up to 450 mg/kg/day (about

88 times the recommended human dose based on body surface area) and in rabbits at oral doses up to 40

mg/kg/day (about 16 times the recommended human dose based on body surface area) with

administration of pantoprazole sodium during organogenesis in pregnant animals. The studies have

revealed no evidence of impaired fertility or harm to the fetus due to pantoprazole.

A pre- and postnatal development toxicity study in rats with additional endpoints to evaluate the effect on

bone development was performed with pantoprazole sodium. Oral pantoprazole doses of 5, 15, and 30

mg/kg/day (approximately 1, 3, and 6 times the human dose of 40 mg/day on a body surface area basis)

were administered to pregnant females from gestation day (GD) 6 through lactation day (LD) 21. On

postnatal day (PND 4) through PND 21, the pups were administered oral doses at 5, 15, and 30

mg/kg/day (approximately 1, 2.3, and 3.2 times the exposure (AUC) in humans at a dose of 40 mg). There

were no drug-related findings in maternal animals. During the preweaning dosing phase (PND 4 to 21)

of the pups, there were increased mortality and/or moribundity and decreased body weight and body

weight gain at 5 mg/kg/day (approximately equal exposures (AUC) in humans receiving the 40 mg dose)

and higher doses. On PND 21, decreased mean femur length and weight and changes in femur bone mass

and geometry were observed in the offspring at 5 mg/kg/day (approximately equal exposures (AUC) in

humans at the 40 mg dose) and higher doses. The femur findings included lower total area, bone mineral

content and density, periosteal and endosteal circumference, and cross-sectional moment of inertia.

There were no microscopic changes in the distal femur, proximal tibia, or stifle joints. Changes in bone

parameters were partially reversible following a recovery period, with findings on PND 70 limited to

lower femur metaphysis cortical/subcortical bone mineral density in female pups at 5 mg/kg/day

(approximately equal exposures (AUC) in humans at the 40 mg dose) and higher doses.

There are no adequate and well-controlled studies in pregnant women. Advise pregnant women of

the potential risk of fetal harm. Because animal reproduction studies are not always predictive of human

response, this drug should be used during pregnancy only if the potential benefit justifies the potential

risk to the fetus.

8.2 Labor & Delivery

8.3 Nursing Mothers

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

has been detected in a study of a single nursing mother after a single 40 mg oral dose of pantoprazole

sodium. 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 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 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 mcghr/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.

Animal Toxicity Data

In a pre- and post-natal development study in rats, the pups were administered oral doses of pantoprazole

at 5, 15, and 30 mg/kg/day (approximately 1, 2.3, and 3.2 times the exposure(AUC) in children aged 6 to

11 years at a dose of 40 mg) on postnatal day (PND 4) through PND 21, in addition to lactational

exposure through milk. On PND 21, decreased mean femur length and weight and changes in femur bone

mass and geometry were observed in the offspring at 5 mg/kg/day (approximately equal exposures

(AUC) in children aged 6 to 11 years at the 40 mg dose) and higher doses. Changes in bone parameters

were partially reversible following a recovery period.

In neonatal/juvenile animals (rats and dogs) toxicities were similar to those observed in adult animals,

including gastric alterations, decreases in red cell mass, increases in lipids, enzyme induction and

hepatocellular hypertrophy. An 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, was

observed in the fundic mucosa of stomachs in repeated-dose studies. Full to partial recovery of these

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

8.5 Geriatric Use

In short-term US clinical trials, EE 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.

10 OVERDOSAGE

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

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

pantoprazole sodium.

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

and supportive.

Single oral doses of pantoprazole 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.

If overexposure to pantoprazole sodium delayed-release tablets occurs, call your Poison Control

Center at 1-800-222-1222 for current information on the management of poisoning or overdosage.

11 DESCRIPTION

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

benzimidazole, 5-(Difluoromethoxy) -2- [[(3,4-dimethoxy-2- pyridyl)methyl] sulfinyl]benzimidazole,

sodium salt, 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, USP is a white to off-white powder. Pantoprazole sodium

sesquihydrate, USP is freely soluble in water, in methanol, in dehydrated alcohol, practically insoluble

in hexane and dichloromethane.

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, USP contains 45.11 mg or 22.55 mg of

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

with the following inactive ingredients: calcium stearate, ferric oxide yellow, hydroxy propyl

cellulose, hypromellose, lactose monohydrate, methacrylic acid copolymer, polysorbate 80, propylene

glycol, sodium carbonate anhydrous, sodium lauryl sulfate, titanium dioxide and triethyl citrate. The

tablets are imprinted with opacode black containing ammonium hydroxide, iron oxide black, propylene

glycol and shellac. 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 is a 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

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 to 80 mg) or a single dose of intravenous (20 to 120 mg)

pantoprazole in healthy subjects. Pantoprazole given once daily results in increasing inhibition of

gastric acid secretion. Following the initial oral dose of 40 mg pantoprazole, 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 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; there was no evidence of

rebound hypersecretion.

In a series of dose-response studies, pantoprazole, 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 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 on median pH from one double-blind crossover study

are shown in Table 5.

Table 5: Effect of Single Daily Doses of Oral Pantoprazole on Intragastric pH

———————Median pH on day 7———————

Time

Placebo

20 mg

40 mg

80 mg

8 a.m. - 8 a.m.

(24 hours)

2.9*

3.8*#

3.9*#

8 a.m. - 10 p.m.

(Daytime)

3.2*

4.4*#

4.8*#

10 p.m. - 8 a.m.

(Nighttime)

2.1*

2.6*

* Significantly different from placebo

# Significantly different from 20 mg

Serum Gastrin Effects

Fasting serum gastrin levels were assessed in two double-blind studies of the acute healing of 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 dose groups. Median serum gastrin levels

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

T ablets.

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 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 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 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 PPIs.

However, there were no observed elevations in serum gastrin following the administration of

pantoprazole 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 at 5 mg/kg/day and a 9 month off-dose recovery [see Nonclinical Toxicology

(13.1)].

Endocrine Effects

In a clinical pharmacology study, pantoprazole sodium delayed-release tablets 40 mg given once daily

for 2 weeks had no effect on the levels of the following hormones: cortisol, testosterone,

triiodothyronine (T3), thyroxine (T4), 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 delayed-release tablets 40 mg or

20 mg, there were no changes from baseline in overall levels of T , T , and TSH.

12.3 Pharmacokinetics

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

of pantoprazole 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 does not accumulate, and its pharmacokinetics are

unaltered with multiple daily dosing. Following oral or intravenous administration, the serum

concentration of pantoprazole 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 tablet, the peak concentration (C

) is 2.5 mcg/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 mcgh/mL (range 1.4 to 13.3 mcgh/mL). Following intravenous administration of

pantoprazole to extensive metabolizers, its total clearance is 7.6 to14 L/h, and its apparent volume of

distribution is 11 to 23.6 L.

Absorption

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

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

was 2.5 mcg/mL. Pantoprazole undergoes little first-pass metabolism, resulting in an absolute

bioavailability of approximately 77%. Pantoprazole 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 absorption (AUC) are not

altered. Thus, Pantoprazole Sodium Delayed-Release Tablets may be taken without regard to timing of

meals.

Distribution

The apparent volume of distribution of pantoprazole is approximately 11 to 23.6 L, distributing mainly in

extracellular fluid. The serum protein binding of pantoprazole is about 98%, primarily to albumin.

Elimination

Metabolism

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

Pantoprazole 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 metabolites have

significant pharmacologic activity.

Excretion

After a single oral or intravenous dose of

C-labeled pantoprazole to healthy, normal metabolizer

subjects, 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.

Specific Populations

Geriatric Patients

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

(26%) of pantoprazole were found in

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

subjects [see Use in Specific Populations (8.5)].

Pediatric Patients

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

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

delayed-release 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 delayed-release 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 7).

Table 7: PK Parameters in Children and Adolescents 6 through 16 years with GERD receiving 40

mg Pantoprazole Sodium Delayed-Release Tablets

6 to 11 years (n=12)

12 to 16 years (n=11)

(mcg/mL)

AUC (mcgh/mL)

CL/F (L/h)

Geometric mean values

Median values

Male and Female Patients

There is a modest increase in pantoprazole AUC and Cmax in women compared to men. However,

weight-normalized clearance values are similar in women and men.

In pediatric patients ages 1 through 16 years there were no clinically relevant effects of gender on

clearance of pantoprazole, as shown by population pharmacokinetic analysis.

Patients with Renal Impairment

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

those of healthy subjects.

Patients with Hepatic Impairment

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

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

values increased to 7 to 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. Doses higher than 40 mg/day

have not been studied in hepatically impaired patients.

Drug Interaction Studies

Effect of Other Drugs on Pantoprazole

Pantoprazole 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 were not significantly altered.

Effect of Pantoprazole on Other Drugs

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 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 [see Drug Interactions (7)].

Other Drugs

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

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

metoprolol, nifedipine, carbamazepine, midazolam, clarithromycin, diclofenac, naproxen, piroxicam, and

oral contraceptives [levonorgestrel/ethinyl estradiol]). In other in vivo studies, digoxin, ethanol,

glyburide, antipyrine, caffeine, metronidazole, and amoxicillin had no clinically relevant interactions

with pantoprazole.

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

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

Antacids

There was also no interaction with concomitantly administered antacids.

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 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 8.

Table 8: 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% *

14.3%

83.5% #

92.6% *

39.7%

+ (p < 0.001) pantoprazole sodium versus placebo

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

# (p < 0.05) versus 10 mg pantoprazole sodium

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 9.

Table 9: 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%

22.2%

79.2%

82.9%

41.4%

+ (p < 0.001) pantoprazole sodium versus nizatidine

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

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 delayed-release tablets (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 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

10, 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 10: 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

Study 1

n = 75

n = 74

n = 75

Month 1

Month 3

93*#

Month 6

90*#

Month 12

86*#

Study 2

n = 74

n = 88

n = 84

Month 1

92*#

Month 3

91*#

Month 6

88*#

Month 12

* (p < 0.05 vs. ranitidine)

# (p < 0.05 vs. pantoprazole sodium 20 mg)

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

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

one trial, as presented in Table 11.

Table 11: 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

* (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 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, USP are supplied as 20 mg yellow to pale yellow,

oval, biconvex, delayed-release tablets imprinted “H125” on one side with black ink and plain on the

other side. They are supplied as follows:

55700-790-30

55700-790-60

Pantoprazole Sodium Delayed-Release Tablets, USP are supplied as 40 mg yellow to pale yellow,

oval, biconvex, delayed-release tablets imprinted “H126” on one side with black ink and plain on the

other side. They are supplied as follows:

Storage

Store pantoprazole sodium delayed-release tablets, USP at 20 to 25°C (68 to 77°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 Interstitial Nephritis

Advise patients to call their healthcare provider immediately if they experience signs and/or symptoms

associated with acute interstitial nephritis [see 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)].

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 (5.5)].

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 (5.6)].

Hypomagnesemia

Advise patients to report any clinical symptoms that may be associated with hypomagnesemia to their

Advise patients to report any clinical symptoms that may be associated with hypomagnesemia to their

healthcare provider, if they have been receiving pantoprazole sodium delayed-release tablets for at

least 3 months [see Warnings and Precautions (5.7)].

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 (5.7)]and high dose methotrexate [see Warnings and Precautions (5.12)].

Pregnancy

Inform female patients of reproductive potential that pantoprazole sodium delayed-release tablets may

cause fetal harm and to inform their prescriber 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.

Manufactured for:

Camber Pharmaceuticals Inc.

Piscataway, NJ 08854

By: HETERO

Hetero Labs Limited Unit V, Polepally,

Jadcherla, Mahabubnagar – 509 301, India.

Barcode

Revised: July 2018

MEDICATION GUIDE

MEDICATION GUIDE

Pantoprazole Sodium Delayed-Release Tablets USP

(pan toe’ pra zole soe’dee um)

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

release tablets?

You should take pantoprazole sodium delayed-release tablets exactly as prescribed, at the lowest

dose possible and for the shortest time needed.

Pantoprazole sodium delayed-release tablets may help your acid-related symptoms, but you

could still have serious stomach problems. Talk with your doctor.

Pantoprazole sodium delayed-release tablets can cause serious side effects, including:

A type of kidney problem (acute interstitial nephritis). Some people who take proton pump inhibitor

(PPI) medicines, including pantoprazole sodium delayed-release tablets, may develop a kidney problem

called acute interstitial nephritis that can happen at any time during treatment with pantoprazole sodium

delayed-release tablets. Call your doctor right away if you have a decrease in the amount that you

urinate or if you have blood in your urine.

Diarrhea caused by an infection (Clostridium difficile) in your intestines. Call your doctor right

away if you have watery stools or stomach pain that does not go away. You may or may not have a fever.

Bone fractures (hip, wrist, or spine). Bone fractures in the hip, wrist, or spine may happen in

people who take multiple daily doses of PPI medicines and for a long period of time (a year or longer).

Tell your doctor if you have a bone fracture, especially in the hip, wrist, or spine.

Certain types of lupus erythematosus. Lupus erythematosus is an autoimmune disorder (the body’s

immune cells attack other cells or organs in the body). Some people who take PPI medicines, including

pantoprazole sodium delayed-release tablet, may develop certain types of lupus erythematosus or have

worsening of the lupus they already have. Call your doctor right away if you have new or worsening

joint pain or a rash on your cheeks or arms that gets worse in the sun.

Talk to your doctor about your risk of these serious side effects.

Pantoprazole sodium delayed-release tablets can have other serious side effects. See “What are the

possible side effects of pantoprazole sodium delayed-release tablets?”

What are pantoprazole sodium delayed-release tablets?

A prescription medicine called a proton pump inhibitor (PPI) used to reduce the amount of acid in your

stomach.

In adults, pantoprazole sodium delayed-release tablets are used for:

up to 8 weeks for the healing and symptom relief of acid-related damage to the lining of the

esophagus (called erosive esophagitis or EE). Your doctor may prescribe another 8 weeks of

pantoprazole sodium delayed-release tablets in patients whose EE does not heal.

maintaining healing of EE and to help prevent the return of heartburn symptoms caused by GERD. It is

not known if pantoprazole sodium delayed-release tablets are safe and effective when used for longer

than 12 months for this purpose.

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

condition called Zollinger-Ellison Syndrome.

In children 5 years of age and older, pantoprazole sodium delayed-release tablets are used for:

up to 8 weeks for the healing and symptom relief of EE.

It is not known if pantoprazole sodium delayed-release tablets are safe if used longer than 8 weeks in

children.

Pantoprazole sodium delayed-release tablets are not for use in children under 5 years of age.

It is not known if pantoprazole sodium delayed-release tablets are safe and effective in children for

treatment other than EE.

Do not take pantoprazole sodium delayed-release tablets if you are:

allergic to pantoprazole sodium, any other PPI medicine, or any of the ingredients in pantoprazole

sodium delayed-release tablets. See the end of this Medication Guide for a complete list of ingredients.

taking a medicine that contains rilpivirine (EDURANT, COMPLERA, ODEFSEY) used to treat HIV-

1 (Human Immunodeficiency Virus).

Before taking pantoprazole sodium delayed-release tablets, tell your doctor about all of your

medical conditions, including if you:

have low magnesium levels in your blood

are pregnant or plan to become pregnant. Pantoprazole sodium delayed-release tablets may harm your

unborn baby. Tell your doctor if you become pregnant or think you may be pregnant during treatment

with pantoprazole sodium delayed-release tablets.

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

your doctor should decide if you will take pantoprazole sodium delayed-release tablets or breastfeed.

You should not do both. Talk with your doctor about the best way to feed your baby if you take

pantoprazole sodium delayed-release tablets.

Tell your doctor about all the medicines you take, including prescription and over-the-counter

medicines, vitamins and herbal supplements. Especially tell your doctor if you take methotrexate

(Otrexup, Rasuvo, Trexall, XATMEP), digoxin (LANOXIN), or a water pill (diuretic).

How should I take pantoprazole sodium delayed-release tablets?

Take pantoprazole sodium delayed-release tablets exactly as prescribed by your doctor.

Pantoprazole sodium delayed-release tablets:

o Do not split, chew, or crush pantoprazole sodium delayed-release tablets.

o Swallow pantoprazole sodium delayed-release tablets whole, with or without food.

o Tell your doctor if you are not able to swallow your pantoprazole sodium delayed-release tablets.

o You may use antacids while taking pantoprazole sodium delayed-release tablets.

If you miss a dose of pantoprazole sodium delayed-release tablets, take it as soon as possible. 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 2 doses at the same time.

If you take too much pantoprazole sodium, call your doctor or your poison control center at 1-800-222-

1222 right away or go to the nearest emergency room.

What are the possible side effects of pantoprazole sodium delayed-release tablets?

Pantoprazole sodium delayed-release tablets can cause serious side effects, including:

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

delayed-release tablets?”

Low vitamin B-12 levels in your body can happen in people who have taken pantoprazole sodium

delayed-release tablets for a long time (more than 3 years). Tell your doctor if you have symptoms of

low vitamin B-12 levels, including shortness of breath, lightheadedness, irregular heartbeat, muscle

weakness, pale skin, feeling tired, mood changes, and tingling or numbness in the arms and legs.

Low magnesium levels in your body can happen in people who have taken pantoprazole sodium

delayed-release tablets for at least 3 months. Tell your doctor if you have symptoms of low magnesium

levels, including seizures, dizziness, irregular heartbeat, jitteriness, muscle aches or weakness, and

spasms of hands, feet or voice.

Stomach growths (fundic gland polyps). People who take PPI medicines for a long time have an

increased risk of developing a certain type of stomach growths called fundic gland polyps, especially

after taking PPI medicines for more than 1 year.

The most common side effects of pantoprazole sodium delayed-release tablets in adults include:

headache, diarrhea, nausea, stomach-area (abdominal) pain, vomiting, gas, dizziness, and joint pain.

The most common side effects of pantoprazole sodium delayed-release tablets in children

include: upper respiratory infection, headache, fever, diarrhea, vomiting, rash, and stomach-area

(abdominal) pain.

These are not all the possible side effects of pantoprazole sodium delayed-release tablets. Call your

doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

How should I store pantoprazole sodium delayed-release tablets?

Store pantoprazole sodium delayed-release tablets at 20° to 25°C (68° to 77°F) [see USP Controlled

Room Temperature].

Keep pantoprazole sodium delayed-release tablets and all medicines out of the reach of children.

General information about the safe and effective use of pantoprazole sodium delayed-release

tablets.

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

use pantoprazole sodium delayed-release tablets for a condition for which it was not prescribed. Do not

give pantoprazole sodium delayed-release tablets to other people, even if they have the same symptoms

that you have. It may harm them. You can ask your doctor or pharmacist for information about

pantoprazole sodium delayed-release tablets that is written for health professionals.

What are the ingredients in pantoprazole sodium delayed-release tablets?

Active ingredient: pantoprazole sodium sesquihydrate USP

Inactive ingredients: calcium stearate, ferric oxide yellow, hydroxy propyl cellulose, hypromellose,

lactose monohydrate, methacrylic acid copolymer, polysorbate 80, propylene glycol, sodium carbonate

anhydrous, sodium lauryl sulfate, titanium dioxide, and triethyl citrate. The tablets are imprinted with

opacode black containing ammonium hydroxide, iron oxide black, propylene glycol and shellac.

For more information call 866-495-1995

The brands listed are trademarks of their respective owners and are not trademarks of Hetero Labs

Limited.

This Medication Guide and Instructions for Use has been approved by the U.S. Food and Drug

Administration.

Manufactured for:

Camber Pharmaceuticals Inc.

Piscataway, NJ 08854

By: HETERO

Hetero Labs Limited Unit V, Polepally,

Jadcherla, Mahabubnagar – 509 301, India.

TM

Jadcherla, Mahabubnagar – 509 301, India.

Revised: July 2018

PANTOPRAZOLE SODIUM

pantoprazole tablet, delayed release

Product Information

Product T ype

HUMAN PRESCRIPTION DRUG

Ite m Code (Source )

NDC:5570 0 -79 0 (NDC:31722-712)

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)

FERRIC O XIDE YELLO W (UNII: EX438 O2MRT)

HYPRO MELLO SES (UNII: 3NXW29 V3WO)

LACTO SE MO NO HYDRATE (UNII: EWQ57Q8 I5X)

METHACRYLIC ACID - METHYL METHACRYLATE CO PO LYMER ( 1:1) (UNII: 74G4R6 TH13)

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

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)

AMMO NIA (UNII: 5138 Q19 F1X)

FERRO SO FERRIC O XIDE (UNII: XM0 M8 7F357)

SHELLAC (UNII: 46 N10 7B71O)

HYDRO XYPRO PYL CELLULO SE, UNSPECIFIED (UNII: 9 XZ8 H6 N6 OH)

Product Characteristics

Color

YELLOW

S core

no sco re

Quality Care Products, LLC

S hap e

OVAL (o val)

S iz e

9 mm

Flavor

Imprint Code

H;125

Contains

Packag ing

#

Item Code

Package Description

Marketing Start Date

Marketing End Date

1

NDC:5570 0 -79 0 -30

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

0 9 /13/20 19

2

NDC:5570 0 -79 0 -6 0

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

0 9 /13/20 19

Marketing Information

Marke ting Cate gory

Application Numbe r or Monograph Citation

Marke ting Start Date

Marke ting End Date

ANDA

ANDA20 28 8 2

0 9 /13/20 19

Labeler -

Quality Care Products, LLC (831276758)

Establishment

Name

Ad d re s s

ID/FEI

Busine ss Ope rations

Quality Care Pro ducts, LLC

8 31276 758

re pa c k(5570 0 -79 0 )

Revised: 9/2019

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