PROTONIX DELAYED-RELEASE- pantoprazole sodium 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:
Avera McKennan Hospital
INN (International Name):
PANTOPRAZOLE SODIUM
Composition:
PANTOPRAZOLE 40 mg
Administration route:
ORAL
Prescription type:
PRESCRIPTION DRUG
Therapeutic indications:
PROTONIX For Delayed-Release Oral Suspension and PROTONIX Delayed-Release Tablets are indicated for: PROTONIX 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. For those adult patients who have not healed after 8 weeks of treatment, an additional 8-week course of PROTONIX may be considered. Safety of treatment beyond 8 weeks in pediatric patients has not been established. PROTONIX is indicated for maintenance of healing of erosive esophagitis and reduction in relapse rates of daytime and nighttime heartburn symptoms in adult patients with GERD. Controlled studies did not extend beyond 12 months. PROTONIX is indicated for the long-term treatment of pathological hypersecretory conditions, including Zollinger-Ellison syndrome. PROTONIX is contraindicated in patients with known hypersensitivity to any component of the formulation or any substituted benzimidazole. Hypersensitivity reac
Product summary:
How Supplied PROTONIX (pantoprazole sodium) Delayed-Release Tablets are supplied as 40 mg yellow, oval biconvex delayed-release tablets imprinted with PROTONIX (brown ink) on one side and are available as follows: Storage Store PROTONIX For Delayed-Release Oral Suspension and PROTONIX Delayed-Release Tablets at 20° to 25°C (68° to 77°F); excursions permitted to 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature] .
Authorization status:
New Drug Application
Authorization number:
69189-0841-1

PROTONIX DELAYED-RELEASE- pantoprazole sodium tablet, delayed release

Avera McKennan Hospital

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MEDICATION GUIDE

PROTONIX (pro-TAH-nix)

(pantoprazole sodium)

Delayed-Release Tablets

For Delayed-Release Oral Suspension

Read this Medication Guide before you start taking PROTONIX and each time you get a refill. There

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

medical condition or your treatment.

What is the most important information I should know about PROTONIX?

PROTONIX may help your acid-related symptoms, but you could still have serious stomach problems.

Talk with your doctor.

PROTONIX can cause serious side effects, including:

Diarrhea. PROTONIX may increase your risk of getting severe diarrhea. This diarrhea may be

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

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

away.

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

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

spine. You should take PROTONIX exactly as prescribed, at the lowest dose possible for your

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

you take PROTONIX.

PROTONIX can have other serious side effects. See "What are the possible side effects of PROTONIX?"

What is PROTONIX?

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

PROTONIX reduces the amount of acid in your stomach.

PROTONIX is used in adults:

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

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

doctor may decide to prescribe another 8 weeks of PROTONIX.

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

return of heartburn symptoms caused by GERD. It is not known if PROTONIX is safe and

effective if used longer than 12 months (1 year).

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

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

burping.

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

a rare condition called Zollinger-Ellison syndrome.

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

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

It is not known if PROTONIX is safe if used longer than 8 weeks in children. PROTONIX is not for use

in children under 5 years of age.

Who should not take PROTONIX?

Do not take PROTONIX if you are:

allergic to pantoprazole sodium or any of the other ingredients in PROTONIX. See the end of this

Medication Guide for a complete list of ingredients in PROTONIX.

allergic to any proton pump inhibitor (PPI) medicine.

What should I tell my doctor before taking PROTONIX?

Before taking PROTONIX, tell your doctor if you:

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

have liver problems

have any other medical conditions

are pregnant or plan to become pregnant. It is not known if PROTONIX will harm your unborn

baby.

are breastfeeding or plan to breastfeed. PROTONIX may pass into your milk. You and your doctor

should decide if you will take PROTONIX or breastfeed. You should not do both. Talk with your

doctor about the best way to feed your baby if you take PROTONIX.

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

vitamins and herbal supplements. PROTONIX may affect how other medicines work, and other

medicines may affect how PROTONIX works.

Especially tell your doctor if you take:

atazanavir (Reyataz)

nelfinavir (Viracept)

warfarin (Coumadin, Jantoven)

ketoconazole (Nizoral)

a product that contains iron

an antibiotic that contains ampicillin

methotrexate

mycophenolate mofetil (Cellcept)

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

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

a new medicine.

How should I take PROTONIX?

Take PROTONIX exactly as prescribed by your doctor.

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

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

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

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

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

emergency room.

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

how to take PROTONIX Tablets

how to take PROTONIX Delayed-Release Oral Suspension

how to mix and give PROTONIX For Delayed-Release Oral Suspension through a

nasogastric tube or gastric tube.

What are the possible side effects of PROTONIX?

PROTONIX may cause serious side effects, including:

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

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

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

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

nausea, vomiting or weight loss.

Vitamin B-12 deficiency. PROTONIX reduces the amount of acid in your stomach. Stomach acid

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

B-12 deficiency if you have been on PROTONIX for a long time (more than 3 years).

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

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

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

magnesium.

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

seizures

dizziness

abnormal or fast heartbeat

jitteriness

jerking movements or shaking (tremors)

muscle weakness

spasms of the hands and feet

cramps or muscle aches

spasm of the voice box

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

during treatment, if you will be taking PROTONIX for a long period of time.

The most common side effects with PROTONIX in adults include:

Headache

Diarrhea

Nausea

Stomach pain

Vomiting

Dizziness

Pain in your joints

The most common side effects with PROTONIX in children include:

Upper respiratory infection

Headache

Fever

Diarrhea

Vomiting

Rash

Stomach pain

Other side effects:

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

PROTONIX:

rash

face swelling

throat tightness

difficult breathing

Your doctor may stop PROTONIX if these symptoms happen.

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

These are not all the possible side effects with PROTONIX. For more information, ask your doctor or

pharmacist.

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 PROTONIX?

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

Keep PROTONIX and all medicines out of the reach of children.

General information about PROTONIX

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

use PROTONIX for a condition for which it was not prescribed. Do not give PROTONIX to other people,

even if they have the same symptoms you have. It may harm them.

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

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

healthcare professionals.

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

What are the ingredients in PROTONIX?

Active ingredient: pantoprazole sodium sesquihydrate

Inactive ingredients in PROTONIX Delayed-Release Tablets: calcium stearate, crospovidone,

hypromellose, iron oxide, mannitol, methacrylic acid copolymer, polysorbate 80, povidone, propylene

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

Inactive ingredients in PROTONIX For Delayed-Release Oral Suspension: crospovidone, hypromellose,

methacrylic acid copolymer, microcrystalline cellulose, polysorbate 80, povidone, sodium carbonate,

sodium lauryl sulfate, talc, titanium dioxide, triethyl citrate, and yellow ferric oxide.

Revised: 11/2015

Document Id: 9b04facd-97eb-4e60-8ded-f4c97251427b

Set id: efd8122a-021b-4e1d-a805-37e736738424

Version: 1

Effective Time: 20151123

Avera McKennan Hospital

PROTONIX DELAYED-RELEASE- pantoprazole sodium tablet, delayed release

Avera McKennan Hospital

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HIGHLIGHTS OF PRESCRIBING INFORMATION

These highlights do not include all the information needed to use PROTONIX safely and effectively. See full

prescribing information for PROTONIX.

PROTONIX (pantoprazole sodium) delayed-release tablets PROTONIX (pantoprazole sodium) for delayed-

release oral suspension

Initial U.S. approval: 2000

RECENT MAJOR CHANGES

Dosage and Administration, Recommended Dosing Schedule (2.1)

12/2014

Contraindications (4)

12/2014

Warnings and Precautions, Acute Interstitial Nephritis (5.3)

12/2014

INDICATIONS AND USAGE

PROTONIX is a proton pump inhibitor indicated for the following:

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

Maintenance of Healing of Erosive Esophagitis (1.2)

Pathological Hypersecretory Conditions Including Zollinger-Ellison Syndrome (1.3)

DOSAGE AND ADMINISTRATION

Indic atio n

Do se

Frequency

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

Adults

40 mg

Once Daily for up to 8 wks

Children (5 years and older)

≥ 15 kg to < 40 kg

20 mg

Once Daily for up to 8 wks

≥ 40 kg

40 mg

Maintenance of Healing of Erosive Esophagitis (2.1)

Adults

40 mg

Once Daily

Pathological Hypersecretory Conditions Including Zollinger-Ellison Syndrome (2.1)

Adults

40 mg

Twice Daily

See full prescribing information for administration instructions

DOSAGE FORMS AND STRENGTHS

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

For Delayed-Release Oral Suspension, 40 mg (3)

CONTRAINDICATIONS

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

WARNINGS AND PRECAUTIONS

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

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

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

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

a deficiency of cyanocobalamin. (5.4)

PPI therapy may be associated with increased risk of Clostridium difficile associated diarrhea. (5.5)

Bone Fracture:

Long-term and multiple daily dose PPI therapy may be associated with an increased risk for osteoporosis-related

fractures of the hip, wrist or spine. (5.6)

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

Controlled studies did not extend beyond 12 months

ADVERSE REACTIONS

The most frequently occurring adverse reactions are as follows:

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

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

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

1088 or www.fda.gov/medwatch.

DRUG INTERACTIONS

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

Concomitant warfarin use may require monitoring (7.2)

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

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

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

Methotrexate: PROTONIX may increase serum level of methotrexate (7.6)

See 17 for PATIENT COUNSELING INFORMATION and Medication Guide.

Revised: 11/2015

FULL PRESCRIBING INFORMATION: CONTENTS*

1 INDICATIONS AND USAGE

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

Disease (GERD)

1.2 Maintenance of Healing of Erosive Esophagitis

1.3 Pathological Hypersecretory Conditions Including Zollinger-Ellison Syndrome

2 DOSAGE AND ADMINISTRATION

2.1 Recommended Dosing Schedule

2.2 Administration Instructions

3 DOSAGE FORMS AND STRENGTHS

4 CONTRAINDICATIONS

5 WARNINGS AND PRECAUTIONS

5.1 Concurrent Gastric Malignancy

5.2 Atrophic Gastritis

5.3 Acute Interstitial Nephritis

5.4 Cyanocobalamin (Vitamin B-12) Deficiency

5.5 Clostridium difficile associated diarrhea

5.6 Bone Fracture

5.7 Hypomagnesemia

5.8 Tumorigenicity

5.9 Interference with Urine Screen for THC

5.10 Concomitant use of PROTONIX with Methotrexate

6 ADVERSE REACTIONS

6.1 Clinical Trial Experience

6.2 Postmarketing Experience

7 DRUG INTERACTIONS

7.1 Interference with Antiretroviral Therapy

7.2 Coumarin Anticoagulants

7.3 Clopidogrel

7.4 Drugs for Which Gastric pH Can Affect Bioavailability

7.5 False Positive Urine Tests for THC

7.6 Methotrexate

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

8.3 Nursing Mothers

8.4 Pediatric Use

8.5 Geriatric Use

8.6 Gender

8.7 Patients with Hepatic Impairment

10 OVERDOSAGE

11 DESCRIPTION

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

12.2 Pharmacodynamics

12.3 Pharmacokinetics

12.4 Pharmacogenomics

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

13.2 Animal Toxicology and/or Pharmacology

14 CLINICAL STUDIES

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

14.2 Long-Term Maintenance of Healing of Erosive Esophagitis

14.3 Pathological Hypersecretory Conditions Including Zollinger-Ellison Syndrome

16 HOW SUPPLIED/STORAGE AND HANDLING

17 PATIENT COUNSELING INFORMATION

FULL PRESCRIBING INFORMATION

1 INDICATIONS AND USAGE

PROTONIX For Delayed-Release Oral Suspension and PROTONIX Delayed-Release Tablets are

indicated for:

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

Disease (GERD)

PROTONIX 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. For those adult

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

may be considered. Safety of treatment beyond 8 weeks in pediatric patients has not been established.

1.2 Maintenance of Healing of Erosive Esophagitis

PROTONIX is indicated for maintenance of healing of erosive esophagitis and reduction in relapse

rates of daytime and nighttime heartburn symptoms in adult patients with GERD. Controlled studies did

not extend beyond 12 months.

1.3 Pathological Hypersecretory Conditions Including Zollinger-Ellison Syndrome

PROTONIX is indicated for the long-term treatment of pathological hypersecretory conditions,

including Zollinger-Ellison syndrome.

2 DOSAGE AND ADMINISTRATION

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

2.1 Recommended Dosing Schedule

PROTONIX is supplied as delayed-release granules in packets for preparation of oral suspensions or

as delayed-release tablets. The recommended dosages are outlined in Table 1.

Table 1: Recommended Dosing Schedule for PROTONIX

Indication

Dos e

Frequency

Short-Term Treatment of Erosive Esophagitis Associated With GERD

Adults

40 mg Once daily for up to 8 weeks

Children (5 years and older)

≥ 15 kg to < 40 kg

20 mg Once daily for up to 8 weeks

≥ 40 kg

40 mg

Maintenance of Healing of Erosive Esophagitis

Adults

40 mg Once daily

Pathological Hypersecretory Conditions Including Zollinger-Ellison

Syndrome

Adults

40 mg Twice daily

2.2 Administration Instructions

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

Table 2: Administration Instructions

Formulation

Route

Ins tructions

Delayed-Releas e

Tablets

Oral

Swallowed whole, with or without

food

For Delayed-Release

Oral Suspension

Oral

Administered in 1 teaspoonful of

applesauce or apple juice

approximately 30 minutes prior to a

meal

For Delayed-Release

Oral Suspension

Nasogastric

tube

See instructions below

PROTONIX Delayed-Release Tablets

PROTONIX Delayed-Release Tablets should be swallowed whole, with or without food in the

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

administration of antacids does not affect the absorption of PROTONIX Delayed-Release Tablets.

PROTONIX For Delayed-Release Oral Suspension

PROTONIX For Delayed-Release Oral Suspension should only be administered approximately 30

minutes prior to a meal via oral administration in apple juice or applesauce or nasogastric tube in apple

juice only. Because proper pH is necessary for stability, do not administer PROTONIX For Delayed-

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

course of PROTONIX may be considered.

Controlled studies did not extend beyond 12 months

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

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

*

Patients should be cautioned that PROTONIX Delayed-Release Tablets and

PROTONIX For Delayed-Release Oral Suspension should not be split, chewed, or

crushed.

Release Oral Suspension in liquids other than apple juice, or foods other than applesauce.

Do not divide the 40 mg PROTONIX For Delayed-Release Oral Suspension packet to create a 20 mg

dosage for pediatric patients who are unable to take the tablet formulation.

PROTONIX For Delayed-Release Oral Suspension - Oral Administration in Applesauce

Open packet.

Sprinkle granules on one teaspoonful of applesauce. DO NOT USE OTHER FOODS OR CRUSH

OR CHEW THE GRANULES.

Take within 10 minutes of preparation.

Take sips of water to make sure granules are washed down into the stomach. Repeat water sips as

necessary.

PROTONIX For Delayed-Release Oral Suspension - Oral Administration in Apple Juice

Open packet.

Empty granules into a small cup or teaspoon containing one teaspoon of apple juice.

Stir for 5 seconds (granules will not dissolve) and swallow immediately.

To make sure that the entire dose is taken, rinse the container once or twice with apple juice to

remove any remaining granules. Swallow immediately.

PROTONIX For Delayed-Release Oral Suspension - Nasogastric (NG) Tube or Gastrostomy Tube

Administration

For patients who have a nasogastric tube or gastrostomy tube in place, PROTONIX For Delayed-

Release Oral Suspension can be given as follows:

Remove the plunger from the barrel of a 2 ounce (60 mL) catheter-tip syringe. Discard the plunger.

Connect the catheter tip of the syringe to a 16 French (or larger) tube.

Hold the syringe attached to the tubing as high as possible while giving PROTONIX For Delayed-

Release Oral Suspension to prevent any bending of the tubing.

Empty the contents of the packet into the barrel of the syringe.

Add 10 mL (2 teaspoonfuls) of apple juice and gently tap and/or shake the barrel of the syringe to

help rinse the syringe and tube. Repeat at least twice more using the same amount of apple juice (10

mL or 2 teaspoonfuls) each time. No granules should remain in the syringe.

3 DOSAGE FORMS AND STRENGTHS

Delayed-Release Tablets:

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

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

For Delayed-Release Oral Suspension:

40 mg, pale yellowish to dark brownish, enteric-coated granules in a unit dose packet

4 CONTRAINDICATIONS

PROTONIX is 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)].

5 WARNINGS AND PRECAUTIONS

5.1 Concurrent Gastric Malignancy

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

malignancy.

5.2 Atrophic Gastritis

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

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

5.3 Acute Interstitial Nephritis

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

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

hypersensitivity reaction. Discontinue PROTONIX if acute interstitial nephritis develops [see

Contraindications (4)].

5.4 Cyanocobalamin (Vitamin B-12) Deficiency

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

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

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

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

with cyanocobalamin deficiency are observed.

5.5 Clostridium difficile associated diarrhea

Published observational studies suggest that PPI therapy like PROTONIX may be associated with an

increased risk of Clostridium difficile associated diarrhea, especially in hospitalized patients. This

diagnosis should be considered for diarrhea that does not improve [see Adverse Reactions (6.2)].

Patients should use the lowest dose and shortest duration of PPI therapy appropriate to the condition

being treated.

5.6 Bone Fracture

Several published observational studies suggest that proton pump inhibitor (PPI) therapy may be

associated with an increased risk for osteoporosis-related fractures of the hip, wrist, or spine. The risk

of fracture was increased in patients who received high-dose, defined as multiple daily doses, and

long-term PPI therapy (a year or longer). Patients should use the lowest dose and shortest duration of

PPI therapy appropriate to the condition being treated. Patients at risk for osteoporosis-related fractures

should be managed according to established treatment guidelines [see Dosage and Administration (2) and

Adverse Reactions (6.2)].

5.7 Hypomagnesemia

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

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

arrhythmias, and seizures. In most patients, treatment of hypomagnesemia required magnesium

replacement and discontinuation of the PPI.

For patients expected to be on prolonged treatment or who take PPIs with medications such as digoxin

or drugs that may cause hypomagnesemia (e.g., diuretics), health care professionals may consider

monitoring magnesium levels prior to initiation of PPI treatment and periodically [see Adverse Reactions

6.2)].

5.8 Tumorigenicity

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

PROTONIX. 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 Interference with Urine Screen for THC

See Drug Interactions (7.5).

5.10 Concomitant use of PROTONIX with Methotrexate

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

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

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

temporary withdrawal of the PPI may be considered in some patients [see Drug Interactions (7.6)].

6 ADVERSE REACTIONS

The adverse reaction profiles for PROTONIX (pantoprazole sodium) For Delayed-Release Oral

Suspension and PROTONIX (pantoprazole sodium) Delayed-Release Tablets are similar.

6.1 Clinical Trial Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed

in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug

and may not reflect the rates observed in clinical practice.

Adults

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

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

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

listed in Table 3.

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

with GERD at a Frequency of > 2%

PROTONIX

(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 PROTONIX 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 PROTONIX in the treatment of Erosive Esophagitis (EE) associated with GERD was

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

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

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

reactions to PROTONIX 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 PROTONIX in pediatric patients in clinical trials

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

Body as a Whole: allergic reaction, facial edema

Gastrointestinal: constipation, flatulence, nausea

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

Musculoskeletal: arthralgia, myalgia

Nervous: dizziness, vertigo

Skin and Appendages: urticaria

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

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

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

Zollinger-Ellison Syndrome

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

PROTONIX 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 PROTONIX.

Because these reactions are reported voluntarily from a population of uncertain size, it is not always

possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

These adverse reactions are listed below by body system:

General Disorders and Administration Conditions: asthenia, fatigue, malaise

Hematologic: pancytopenia, agranulocytosis

Hepatobiliary Disorders: hepatocellular damage leading to jaundice and hepatic failure

Immune System Disorders: anaphylaxis (including anaphylactic shock)

Infections and Infestations:Clostridium difficile associated diarrhea

Investigations: weight changes

Metabolism and Nutritional Disorders: hyponatremia, hypomagnesemia

Musculoskeletal Disorders: rhabdomyolysis, bone fracture

Nervous: ageusia, dysgeusia

Psychiatric Disorders: hallucination, confusion, insomnia, somnolence

Renal and Urinary Disorders: interstitial nephritis

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

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

angioedema (Quincke's edema)

7 DRUG INTERACTIONS

7.1 Interference with Antiretroviral Therapy

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

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

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

development of drug resistance.

7.2 Coumarin Anticoagulants

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

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

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

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

7.3 Clopidogrel

Concomitant administration of pantoprazole and clopidogrel in healthy subjects had no clinically

important effect on exposure to the active metabolite of clopidogrel or clopidogrel-induced platelet

inhibition [see Clinical Pharmacology (12.3)]. No dose adjustment of clopidogrel is necessary when

administered with an approved dose of PROTONIX.

7.4 Drugs for Which Gastric pH Can Affect Bioavailability

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

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

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

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

Co-administration of pantoprazole in healthy subjects and in transplant patients receiving MMF has been

reported to reduce the exposure to the active metabolite, mycophenolic acid (MPA), possibly due to a

decrease in MMF solubility at an increased gastric pH. The clinical relevance of reduced MPA

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

MMF. Use PROTONIX with caution in transplant patients receiving MMF [see Clinical Pharmacology

(12.3)].

7.5 False Positive Urine Tests for THC

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

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

verify positive results.

7.6 Methotrexate

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

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

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

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

conducted [see Warnings and Precautions (5.10)].

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Teratogenic Effects

Pregnancy Category B

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

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

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

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

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

Nonclinical Toxicology (13.2)].

8.3 Nursing Mothers

Pantoprazole 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. 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 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 PROTONIX for short-term treatment (up to eight weeks) of erosive

esophagitis (EE) associated with GERD have been established in pediatric patients 1 year through 16

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

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

appropriate formulation available. Therefore, PROTONIX is indicated for the short-term treatment of

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

for pediatric uses other than EE have not been established.

1 year through 16 years of age

Use of PROTONIX 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 PROTONIX 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 PROTONIX 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

PROTONIX (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 PROTONIX 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 PROTONIX for symptomatic GERD in the pediatric population. The effectiveness of PROTONIX

for treating symptomatic GERD in pediatric patients has not been established.

Although the data from the clinical trials support use of PROTONIX 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 µg·hr/mL.

Neonates to less than one year of age

PROTONIX 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 PROTONIX daily for four

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

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

PROTONIX 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 PROTONIX, 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 PROTONIX 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 PROTONIX 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 PROTONIX was not shown to be effective in the randomized, placebo-controlled study in this

age group, the use of PROTONIX for treatment of symptomatic GERD in infants less than 1 year of age

is not indicated.

8.5 Geriatric Use

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

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

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

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

8.6 Gender

Erosive esophagitis healing rates in the 221 women treated with PROTONIX Delayed-Release Tablets

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

PROTONIX 40 mg or 20 mg, healing was maintained at a rate similar to that in men. The incidence rates

of adverse reactions were also similar for men and women.

8.7 Patients with Hepatic Impairment

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

Pharmacology (12.3)].

10 OVERDOSAGE

Experience in patients taking very high doses of PROTONIX (> 240 mg) is limited. Spontaneous post-

marketing reports of overdose are generally within the known safety profile of PROTONIX.

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.

11 DESCRIPTION

The active ingredient in PROTONIX (pantoprazole sodium) For Delayed-Release Oral Suspension and

PROTONIX (pantoprazole sodium) Delayed-Release Tablets is a substituted benzimidazole, sodium 5-

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

compound that inhibits gastric acid secretion. Its empirical formula is C

H F N NaO S × 1.5 H O,

with a molecular weight of 432.4. The structural formula is:

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

Pantoprazole has weakly basic and acidic properties. Pantoprazole sodium sesquihydrate is freely

soluble in water, very slightly soluble in phosphate buffer at pH 7.4, and practically insoluble in n-

hexane.

The stability of the compound in aqueous solution is pH-dependent. The rate of degradation increases

with decreasing pH. At ambient temperature, the degradation half-life is approximately 2.8 hours at pH

5 and approximately 220 hours at pH 7.8.

PROTONIX (pantoprazole sodium) is supplied as a for delayed-release oral suspension, available in

one strength (40 mg), and as a delayed-release tablet, available in two strengths (20 mg and 40 mg).

Each PROTONIX (pantoprazole sodium) Delayed-Release Tablet contains 45.1 mg or 22.56 mg of

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

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

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

lauryl sulfate, titanium dioxide, and triethyl citrate. PROTONIX Delayed-Release Tablets (40 mg and

20 mg) complies with USP dissolution test 2.

PROTONIX (pantoprazole sodium) For Delayed-Release Oral Suspension, 40 mg, contains the active

ingredient pantoprazole sodium sesquihydrate in the form of enteric-coated granules in unit dose

packets. Each unit dose packet contains enteric-coated granules containing 45.1 mg pantoprazole sodium

sesquihydrate (equivalent to 40 mg of pantoprazole) with the following inactive ingredients:

crospovidone, hypromellose, methacrylic acid copolymer, microcrystalline cellulose, polysorbate 80,

povidone, sodium carbonate, sodium lauryl sulfate, talc, titanium dioxide, triethyl citrate, and yellow

ferric oxide.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Pantoprazole is a proton pump inhibitor (PPI) that suppresses the final step in gastric acid production by

covalently binding to the (H , K )-ATPase enzyme system at the secretory surface of the gastric

parietal cell. This effect leads to inhibition of both basal and stimulated gastric acid secretion,

irrespective of the stimulus. The binding to the (H , K )-ATPase results in a duration of antisecretory

effect that persists longer than 24 hours for all doses tested (20 mg to 120 mg).

12.2 Pharmacodynamics

PROTONIX (pantoprazole sodium) For Delayed-Release Oral Suspension, 40 mg has been shown to be

comparable to PROTONIX (pantoprazole sodium) Delayed-Release Tablets in suppressing

pentagastrin-stimulated MAO in patients (n = 49) with GERD and a history of EE. In this multicenter,

pharmacodynamic crossover study, a 40 mg oral dose of PROTONIX For Delayed-Release Oral

Suspension administered in a teaspoonful of applesauce was compared with a 40 mg oral dose of

PROTONIX Delayed-Release Tablets after administration of each formulation once daily for 7 days.

Both medications were administered thirty minutes before breakfast. Pentagastrin-stimulated (MAO) was

assessed from hour 23 to 24 at steady state.

Antisecretory Activity

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

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

pantoprazole in healthy volunteers. 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 4.

Table 4: 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)

8 a.m. – 10 p.m.

*†

*†

*†

*†

(Daytime)

10 p.m. – 8 a.m.

(Nighttime)

Serum Gastrin Effects

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

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

or 40 mg of PROTONIX 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 PROTONIX Delayed-Release Tablets.

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

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

pantoprazole 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 PROTONIX, 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 proton

pump inhibitors. 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)].

12.3 Pharmacokinetics

PROTONIX 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 μg/mL; the time to reach the peak concentration

) is 2.5 h, and the mean total area under the plasma concentration versus time curve (AUC) is 4.8

μg·h/mL (range 1.4 to 13.3 μg·h/mL). Following intravenous administration of pantoprazole to extensive

metabolizers, its total clearance is 7.6–14.0 L/h, and its apparent volume of distribution is 11.0–23.6 L.

Significantly different from placebo

Significantly different from 20 mg

*†

*†

A single oral dose of PROTONIX For Delayed-Release Oral Suspension, 40 mg, was shown to be

bioequivalent when administered to healthy subjects (N = 22) as granules sprinkled over a teaspoonful

of applesauce, as granules mixed with apple juice, or mixed with apple juice followed by administration

through a nasogastric tube. The plasma pharmacokinetic parameters from a crossover study in healthy

subjects are summarized in Table 5.

Table 5: Pharmacokinetics Parameters (mean ± SD) of PROTONIX For

Delayed-Release Oral Suspension at 40 mg

Pharmacokinetic

Parameters

Granules in

Apples auce

Granules in

Apple Juice

Granules in

Nas ogas tric

Tube

AUC (µg·hr/mL)

4.0 ± 1.5

4.0 ± 1.5

4.1 ± 1.7

(µg/mL)

2.0 ± 0.7

1.9 ± 0.5

2.2 ± 0.7

(hr)

Abs orption

After administration of a single or multiple oral 40 mg doses of PROTONIX Delayed-Release Tablets,

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

2.5 μg/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 PROTONIX 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, PROTONIX Delayed-Release Tablets may be taken without regard to timing of meals.

Administration of pantoprazole granules, 40 mg, with a high-fat meal delayed median time to peak

plasma concentration by 2 hours. With a concomitant high-fat meal, the C

and AUC of pantoprazole

granules, 40 mg, sprinkled on applesauce decreased by 51% and 29%, respectively. Thus, PROTONIX

For Delayed-Release Oral Suspension should be taken approximately 30 minutes before a meal.

Dis tribution

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

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

Metabolis m

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.

Elimination

After a single oral or intravenous dose of

C-labeled pantoprazole to healthy, normal metabolizer

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

through biliary excretion. There was no renal excretion of unchanged pantoprazole.

Geriatric

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

(26%) were found in elderly

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

No dosage adjustment is recommended based on age.

Median values are reported for T

Pediatric

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. A pediatric

granule formulation was studied in children through 5 years of age, and PROTONIX Delayed-Release

Tablets were studied in children older than 5 years.

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

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

Neonate through 5 years of age

See Use in Specific Populations (8.4).

Children and Adolescents 6 through 16 Years of Age

The pharmacokinetics of PROTONIX 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 PROTONIX 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 PROTONIX 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 6).

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

with GERD receiving 40 mg PROTONIX Tablets

6–11 years (n=12)

12–16 years (n=11)

(µg/mL)

AUC (µg·h/mL)

CL/F (L/h)

Gender

There is a modest increase in pantoprazole AUC and C

in women compared to men. However,

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

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

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

analysis.

Renal Impairment

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

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

patients undergoing hemodialysis.

Hepatic Impairment

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

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

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

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

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

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

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

hepatically impaired patients.

Geometric mean values

Median values

Drug-Drug Interactions

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.

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.

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,

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

oral contraceptives [levonorgestrel/ethinyl estradiol]). Dosage adjustment of these drugs is not

necessary when they are coadministered with pantoprazole. In other in vivo studies, digoxin, ethanol,

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

with pantoprazole.

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

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

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

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

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

There was also no interaction with concomitantly administered antacids.

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

proton pump inhibitors, including PROTONIX, and warfarin concomitantly [see Drug Interactions (7.2)].

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

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

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

Other Effects

In a clinical pharmacology study, PROTONIX 40 mg given once daily for 2 weeks had no effect on the

levels of the following hormones: cortisol, testosterone, triiodothyronine (T ), thyroxine (T ), thyroid-

stimulating hormone (TSH), thyronine-binding protein, parathyroid hormone, insulin, glucagon, renin,

aldosterone, follicle-stimulating hormone, luteinizing hormone, prolactin, and growth hormone.

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

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

12.4 Pharmacogenomics

CYP2C19 displays a known genetic polymorphism due to its deficiency in some subpopulations (e.g.,

approximately 3% of Caucasians and African-Americans and 17% to 23% of Asians are poor

metabolizers). Although these subpopulations of pantoprazole poor metabolizers have elimination half-

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

dosing. For adult patients who are CYP2C19 poor metabolizers, no dosage adjustment is needed.

Similar to adults, pediatric patients who have the poor metabolizer genotype of CYP2C19 (CYP2C19

*2/*2) exhibited greater than a 6-fold increase in AUC compared to pediatric extensive (CYP2C19

*1/*1) and intermediate (CYP2C19 *1/*x) metabolizers. Poor metabolizers exhibited approximately 10-

fold lower apparent oral clearance compared to extensive metabolizers.

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

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

In a 24-month carcinogenicity study, Sprague-Dawley rats were treated orally with doses of 0.5 to 200

mg/kg/day, about 0.1 to 40 times the exposure on a body surface area basis of a 50 kg person dosed at

40 mg/day. In the gastric fundus, treatment at 0.5 to 200 mg/kg/day produced enterochromaffin-like

(ECL) cell hyperplasia and benign and malignant neuroendocrine cell tumors in a dose-related manner. In

the forestomach, treatment at 50 and 200 mg/kg/day (about 10 and 40 times the recommended human dose

on a body surface area basis) produced benign squamous cell papillomas and malignant squamous cell

carcinomas. Rare gastrointestinal tumors associated with pantoprazole treatment included an

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

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

in the incidences of hepatocellular adenomas and carcinomas. In the thyroid gland, treatment at 200

mg/kg/day produced increased incidences of follicular cell adenomas and carcinomas for both male and

female rats.

In a 24-month carcinogenicity study, Fischer 344 rats were treated orally with doses of 5 to 50

mg/kg/day, approximately 1 to 10 times the recommended human dose based on body surface area. In the

gastric fundus, treatment at 5 to 50 mg/kg/day produced enterochromaffin-like (ECL) cell hyperplasia

and benign and malignant neuroendocrine cell tumors. Dose selection for this study may not have been

adequate to comprehensively evaluate the carcinogenic potential of pantoprazole.

In a 24-month carcinogenicity study, B6C3F1 mice were treated orally with doses of 5 to 150

mg/kg/day, 0.5 to 15 times the recommended human dose based on body surface area. In the liver,

treatment at 150 mg/kg/day produced increased incidences of hepatocellular adenomas and carcinomas

in female mice. Treatment at 5 to 150 mg/kg/day also produced gastric-fundic ECL cell hyperplasia.

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

Pantoprazole 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).

13.2 Animal Toxicology and/or Pharmacology

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

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

including increased stomach weights, increased incidence of eosinophilic chief cells in adult and

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

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

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

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

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

Reproductive Toxicology Studies

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

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

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

impaired fertility or harm to the fetus due to pantoprazole.

14 CLINICAL STUDIES

PROTONIX 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 PROTONIX 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 7.

Table 7: Erosive Esophagitis Healing Rates (Per Protocol)

PROTONIX

Placebo

Week

10 mg daily

(n = 153)

20 mg daily

(n = 158)

40 mg daily

(n = 162)

(n = 68)

45.6%

58.4%

75.0%

14.3%

66.0%

83.5%

92.6%

39.7%

In this study, all PROTONIX 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 PROTONIX treatment

groups. The 40 mg dose of PROTONIX 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 PROTONIX 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 PROTONIX consumed significantly fewer antacid tablets per

day than those taking placebo.

PROTONIX 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

(p < 0.001) PROTONIX versus placebo

(p < 0.05) versus 10 mg PROTONIX

(p < 0.05) versus 10 mg or 20 mg PROTONIX

*†

*‡

*†

*‡

Table 8: Erosive Esophagitis Healing Rates (Per Protocol)

PROTONIX

Nizatidine

Week

20 mg daily

(n = 72)

40 mg daily

(n = 70)

150 mg twice

daily

(n = 70)

61.4%

64.0%

22.2%

79.2%

82.9%

41.4%

Once-daily treatment with PROTONIX 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 PROTONIX 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

PROTONIX consumed significantly fewer antacid tablets per day than those taking nizatidine.

Pediatric Patients Ages 5 Years through 16 Years

The efficacy of PROTONIX 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 PROTONIX (20 mg or 40 mg). All 4 patients with EE were

healed (Hetzel-Dent score of 0 or 1) at 8 weeks.

14.2 Long-Term Maintenance of Healing of Erosive Esophagitis

Two independent, multicenter, randomized, double-blind, comparator-controlled trials of identical

design were conducted in adult GERD patients with endoscopically confirmed healed erosive

esophagitis to demonstrate efficacy of PROTONIX 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

PROTONIX Delayed-Release Tablets once daily or 150 mg of ranitidine twice daily. As demonstrated

in Table 9, PROTONIX 40 mg and 20 mg were significantly superior to ranitidine at every timepoint

with respect to the maintenance of healing. In addition, PROTONIX 40 mg was superior to all other

treatments studied.

Table 9: Long-Term Maintenance of Healing of Erosive

Gastroesophageal Reflux Disease (GERD Maintenance): Percentage of

Patients Who Remained Healed

PROTONIX

20 mg daily

PROTONIX

40 mg daily

Ranitidine

150 mg twice

daily

Study 1

n = 75

n = 74

n = 75

Month 1

Month 3

Month 6

(p < 0.001) PROTONIX versus nizatidine

*†

*†

*†

Note: PROTONIX 10 mg was superior (p < 0.05) to ranitidine in Study 2, but

not Study 1.

Month 12

Study 2

n = 74

n = 88

n = 84

Month 1

Month 3

Month 6

Month 12

PROTONIX 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. PROTONIX 20 mg, administered once

daily, was also effective in reducing episodes of daytime and nighttime heartburn in one trial, as

presented in Table 10.

Table 10: Number of Episodes of Heartburn (mean ± SD)

PROTONIX

40 mg daily

Ranitidine

150 mg twice daily

Month 1

Daytime

5.1 ± 1.6

18.3 ± 1.6

Nighttime

3.9 ± 1.1

11.9 ± 1.1

Month 12

Daytime

2.9 ± 1.5

17.5 ± 1.5

Nighttime

2.5 ± 1.2

13.8 ± 1.3

14.3 Pathological Hypersecretory Conditions Including Zollinger-Ellison Syndrome

In a multicenter, open-label trial of 35 patients with pathological hypersecretory conditions, such as

Zollinger-Ellison syndrome, with or without multiple endocrine neoplasia-type I, PROTONIX

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)]. PROTONIX 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

PROTONIX (pantoprazole sodium) Delayed-Release Tablets are supplied as 40 mg yellow, oval

biconvex delayed-release tablets imprinted with PROTONIX (brown ink) on one side and are available

as follows:

NDC 0008-0841-81, bottles of 90

NDC 0008-0841-99, carton of 10 Redipak blister strips of 10 tablets each

69189-0841-1 single dose pack with 1 tablet as

repackaged by Avera McKennan

Hospital

Storage

Store PROTONIX For Delayed-Release Oral Suspension and PROTONIX Delayed-Release Tablets at

(p < 0.05 vs. ranitidine)

(p < 0.05 vs. PROTONIX 20 mg)

*†

*†

*†

*†

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

20° to 25°C (68° to 77°F); excursions permitted to 15° to 30°C (59° to 86°F) [see USP Controlled Room

Temperature].

17 PATIENT COUNSELING INFORMATION

See FDA-Approved Medication Guide

Caution patients that PROTONIX For Delayed-Release Oral Suspension and PROTONIX Delayed-

Release Tablets should not be split, crushed, or chewed.

PROTONIX oral suspension packet is a fixed dose and cannot be divided to make a smaller dose.

Tell patients that PROTONIX Delayed-Release Tablets should be swallowed whole, with or

without food in the stomach.

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

PROTONIX Delayed-Release Tablets.

Advise patients to take PROTONIX For Delayed-Release Oral Suspension approximately 30

minutes before a meal.

Advise patients that PROTONIX For Delayed-Release Oral Suspension should only be

administered in apple juice or applesauce, not in water, other liquids, or foods.

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

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

hypomagnesemia [see Warnings and Precautions (5.7)].

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

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

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

www.pfizer.com.

under license from

Takeda GmbH

D78467 Konstanz, Germany

LAB-0459-9.0

MEDICATION GUIDE

PROTONIX (pro-TAH-nix)

(pantoprazole sodium)

Delayed-Release Tablets

and

For Delayed-Release Oral Suspension

Read this Medication Guide before you start taking PROTONIX and each time you get a refill. There

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

medical condition or your treatment.

What is the most important information I should know about PROTONIX?

PROTONIX may help your acid-related symptoms, but you could still have serious stomach

problems. Talk with your doctor.

PROTONIX can cause serious side effects, including:

Diarrhea. PROTONIX may increase your risk of getting severe diarrhea. This diarrhea may be

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

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

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

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

spine. You should take PROTONIX exactly as prescribed, at the lowest dose possible for your

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

you take PROTONIX.

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

PROTONIX?"

What is PROTONIX?

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

PROTONIX reduces the amount of acid in your stomach.

PROTONIX is used in adults:

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

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

doctor may decide to prescribe another 8 weeks of PROTONIX.

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

of heartburn symptoms caused by GERD. It is not known if PROTONIX is safe and effective if used

longer than 12 months (1 year).

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

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

burping.

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

rare condition called Zollinger-Ellison syndrome.

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

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

It is not known if PROTONIX is safe if used longer than 8 weeks in children. PROTONIX is not for

use in children under 5 years of age.

Who should not take PROTONIX?

Do not take PROTONIX if you are:

allergic to pantoprazole sodium or any of the other ingredients in PROTONIX. See the end of this

Medication Guide for a complete list of ingredients in PROTONIX.

allergic to any proton pump inhibitor (PPI) medicine.

What should I tell my doctor before taking PROTONIX?

Before taking PROTONIX, tell your doctor if you:

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

have liver problems

have any other medical conditions

are pregnant or plan to become pregnant. It is not known if PROTONIX will harm your unborn baby.

are breastfeeding or plan to breastfeed. PROTONIX may pass into your milk. You and your doctor

should decide if you will take PROTONIX or breastfeed. You should not do both. Talk with your

doctor about the best way to feed your baby if you take PROTONIX.

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

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

medicines may affect how PROTONIX works.

Especially tell your doctor if you take:

atazanavir (Reyataz)

nelfinavir (Viracept)

warfarin (Coumadin, Jantoven)

ketoconazole (Nizoral)

a product that contains iron

an antibiotic that contains ampicillin

methotrexate

mycophenolate mofetil (Cellcept)

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

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

a new medicine.

How should I take PROTONIX?

Take PROTONIX exactly as prescribed by your doctor.

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

If you forget to take a dose of PROTONIX, take it as soon as you remember. If it is almost time for

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

doses to try to make up for a missed dose.

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

emergency room.

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

how to take PROTONIX Tablets

how to take PROTONIX Delayed-Release Oral Suspension

how to mix and give PROTONIX For Delayed-Release Oral Suspension through a nasogastric

tube or gastric tube.

What are the possible side effects of PROTONIX?

PROTONIX may cause serious side effects, including:

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

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

Taking PROTONIX for a long period of time may increase the risk of inflammation to your stomach

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

vomiting or weight loss.

Vitamin B-12 deficiency. PROTONIX reduces the amount of acid in your stomach. Stomach acid is

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

deficiency if you have been on PROTONIX for a long time (more than 3 years).

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

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

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

magnesium.

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

seizures

dizziness

abnormal or fast heartbeat

jitteriness

jerking movements or shaking (tremors)

muscle weakness

spasms of the hands and feet

cramps or muscle aches

spasm of the voice box

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

during treatment, if you will be taking PROTONIX for a long period of time.

The most common side effects with PROTONIX in adults include:

Headache

Diarrhea

Nausea

Stomach pain

Vomiting

Dizziness

Pain in your joints

The most common side effects with PROTONIX in children include:

Upper respiratory infection

Headache

Fever

Diarrhea

Vomiting

Rash

Stomach pain

Other side effects:

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

PROTONIX:

rash

face swelling

throat tightness

difficult breathing

Your doctor may stop PROTONIX if these symptoms happen.

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

These are not all the possible side effects with PROTONIX. For more information, ask your doctor or

pharmacist.

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 PROTONIX?

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

Keep PROTONIX and all medicines out of the reach of children.

General information about PROTONIX

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

use PROTONIX for a condition for which it was not prescribed. Do not give PROTONIX to other

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

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

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

healthcare professionals.

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

What are the ingredients in PROTONIX?

Active ingredient: pantoprazole sodium sesquihydrate

Inactive ingredients in PROTONIX Delayed-Release Tablets: calcium stearate, crospovidone,

hypromellose, iron oxide, mannitol, methacrylic acid copolymer, polysorbate 80, povidone, propylene

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

Inactive ingredients in PROTONIX For Delayed-Release Oral Suspension: crospovidone,

hypromellose, methacrylic acid copolymer, microcrystalline cellulose, polysorbate 80, povidone,

sodium carbonate, sodium lauryl sulfate, talc, titanium dioxide, triethyl citrate, and yellow ferric oxide.

Instructions for Use

PROTONIX Delayed-Release Tablets:

You can take PROTONIX tablets with food or on an empty stomach.

Swallow PROTONIX tablets whole.

If you have trouble swallowing a PROTONIX 40 mg tablet, you can take two 20 mg tablets instead.

Do not split, chew, or crush PROTONIX tablets.

PROTONIX Delayed-Release For Oral Suspension:

PROTONIX Oral Suspension should be taken 30 minutes before a meal

PROTONIX Oral Suspension should only be taken with applesauce or apple juice 30 minutes before

a meal.

PROTONIX Oral Suspension should not be taken in or with water or other liquids, or with other

foods. See "Directions for use" below.

PROTONIX Oral Suspension should not be chewed or crushed.

PROTONIX Oral Suspension packet should not be divided to make a smaller dose.

Directions for use with applesauce:

Open packet.

Sprinkle granules on one teaspoonful of applesauce. Do not use any other foods. Do not crush

or chew the granules.

Take within 10 minutes of putting the granules into the teaspoon of applesauce.

Take sips of water to make sure the granules are washed down into the stomach. Repeat water

sips as necessary.

Directions for use with apple juice:

Open packet.

Empty granules into a small cup or teaspoon with one teaspoonful of apple juice.

Stir the mix for 5 seconds (granules will not break up) and swallow it right away.

To make sure that the entire dose is taken, rinse the container once or twice with apple juice to

get out any leftover granules. Swallow the apple juice right away.

Giving PROTONIX Oral Suspension through a Nasogastric Tube or Gastrostomy Tube:

For people who have a nasogastric (NG) tube or gastrostomy tube in place, PROTONIX Oral

Suspension can be given as follows:

Remove the plunger from the barrel of a 2 ounce (60 mL) catheter-tip syringe. Throw away the

plunger.

Connect the catheter tip of the syringe to a 16 French (or larger) tube.

Hold the syringe attached to the tubing as high as possible while giving PROTONIX Oral

Suspension to prevent any bending of the tubing.

Empty the contents of the packet into the barrel of the syringe.

Add 10 mL (2 teaspoonfuls) of apple juice and gently tap or shake the barrel of the syringe to help

empty the syringe.

Do this again at least two more times using the same amount of apple juice (10 mL or 2 teaspoonfuls)

each time. No granules should be left in the syringe.

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

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

www.pfizer.com.

under license from

Takeda GmbH

D78467 Konstanz, Germany

LAB-0574-7.0

December 2014

PRINCIPAL DISPLAY PANEL - 20 mg Tablet Bottle Label

PROTONIX DELAYED-RELEASE

pantoprazole sodium tablet, delayed release

Product Information

Product T ype

HUMAN PRESCRIPTION

DRUG

Ite m Code (Source )

NDC:6 9 18 9 -0 8 41(NDC:0 0 0 8 -0 8 41)

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

40 mg

Inactive Ingredients

Ingredient Name

Stre ng th

CALCIUM STEARATE (UNII: 776 XM70 47L)

CRO SPO VIDO NE (UNII: 6 8 40 19 6 0 MK)

MANNITO L (UNII: 3OWL53L36 A)

FERRIC O XIDE YELLO W (UNII: EX438 O2MRT)

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

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

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

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

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

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

SO DIUM LAURYL SULFATE (UNII: 36 8 GB5141J)

TITANIUM DIO XIDE (UNII: 15FIX9 V2JP)

TRIETHYL CITRATE (UNII: 8 Z9 6 QXD6 UM)

HYPRO MELLO SE 2 9 10 ( 6 MPA.S) (UNII: 0 WZ8 WG20 P6 )

Product Characteristics

Color

YELLOW (YELLOW)

S core

no sco re

S hap e

OVAL (BICONVEX)

S iz e

12mm

Flavor

Imprint Code

PROTONIX

Contains

Packag ing

#

Item Code

Package Description

Marketing Start Date

Marketing End Date

1

NDC:6 9 18 9 -0 8 41-1

1 in 1 DOSE PACK; Type 0 : No t a Co mbinatio n Pro duct

Marketing Information

Marke ting Cate gory

Application Numbe r or Monograph Citation

Marke ting Start Date

Marke ting End Date

NDA0 20 9 8 7

0 9 /21/20 15

Labeler -

Avera McKennan Hospital (068647668)

Establishment

Name

Ad d re s s

ID/FEI

Busine ss Ope rations

Avera McKennan Hospital

Avera McKennan Ho spital

0 6 8 6 476 6 8

relabel(6 9 18 9 -0 8 41) , repack(6 9 18 9 -0 8 41)

Revised: 11/2015

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