The active ingredient in PROTONIX® (pantoprazole sodium) Delayed-Release Tablets and PROTONIX® (pantoprazole sodium) For Delayed-Release Oral Suspension 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 C₁₆H₁₄F₂N₃NaO₄S x 1.5 H₂O, 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 5.0 and approximately 220 hours at pH 7.8.

PROTONIX (pantoprazole sodium) is supplied as a delayed-release tablet for oral administration, available in 2 strengths (40 mg and 20 mg); and as delayed-release granules for oral administration, available in the 40 mg strength.

Each PROTONIX (pantoprazole sodium) Delayed-Release tablet contains 45.1 mg or 22.6 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 (pantoprazole sodium) For Delayed-Release Oral Suspension 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 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.

PROTONIX® Delayed-Release Tablets and PROTONIX® For Delayed-Release Oral Suspension are indicated for:

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

PROTONIX® is indicated for the short-term treatment (up to 8 weeks) in the healing and symptomatic relief of erosive esophagitis. For those patients who have not healed after 8 weeks of treatment, an additional 8-week course of PROTONIX may be considered.

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 patients with gastroesophageal reflux disease (GERD). Controlled studies did not extend beyond 12 months.

Pathological Hypersecretory Conditions Including Zollinger-Ellison Syndrome

PROTONIX is indicated for the long-term treatment of pathological hypersecretory conditions, including Zollinger-Ellison syndrome.

Treatment of Erosive Esophagitis

The recommended adult oral dose is 40 mg given once daily for up to 8 weeks. For those patients who have not healed after 8 weeks of treatment, an additional 8-week course of PROTONIX may be considered (see INDICATIONS AND USAGE).

Maintenance of Healing of Erosive Esophagitis

The recommended adult oral dose is PROTONIX 40 mg, taken daily (see CLINICAL PHARMACOLOGY, Clinical Studies).

Pathological Hypersecretory Conditions Including Zollinger-Ellison Syndrome

The dosage of PROTONIX in patients with pathological hypersecretory conditions varies with the individual patient. The recommended adult starting dose is 40 mg twice daily. 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. Some patients have been treated continuously with PROTONIX for more than 2 years.

No dosage adjustment is necessary in patients with renal impairment, hepatic impairment, or for elderly patients. Doses higher than 40 mg/day have not been studied in hepatically-impaired patients. No dosage adjustment is necessary in patients undergoing hemodialysis.

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 should be administered in applesauce or apple juice approximately 30 minutes prior to a meal. See Administration Options subsection below. Patients should be cautioned that PROTONIX Delayed-Release Tablets and PROTONIX For Delayed-Release Oral Suspension should not be split, chewed or crushed.
• PROTONIX For Delayed-Release Oral Suspension should only be administered in apple juice or applesauce, not in water or other liquids, or foods.

Administration Options

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

• Open packet.
• Sprinkle intact granules on one teaspoonful of applesauce.
• Swallow within 10 minutes of preparation.

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

• Open packet.
• Empty intact granules into a small cup containing 5 mL of apple juice (approximately one teaspoonful).
• Stir for 5 seconds and swallow immediately.
• To ensure complete delivery of the dose, rinse the container once or twice with apple juice to remove any remaining granules and swallow immediately.

PROTONIX For Delayed-Release Oral Suspension - Nasogastric Tube Administration

• For patients who have a nasogastric tube in place, PROTONIX For Delayed-Release Oral Suspension can be administered as follows:
• Separate the plunger from the barrel of a 2 ounce (60 mL) catheter tip syringe.
• Connect the catheter tip of the syringe to a 16 French (or larger) nasogastric tube.
• Hold the syringe attached to the tubing as high as possible during application steps to prevent any bending of the tubing in order to provide smooth flow of contents under gravity.
• Empty the contents of the packet into the barrel of the syringe.
• Add 10 mL of apple juice and gently tap and/or shake the barrel of the syringe to help empty the syringe.
• Add an additional 10 mL of apple juice and gently tap and/or shake the barrel of the syringe to help rinse the syringe and the nasogastric tube. Repeat with at least 2 additional 10 mL aliquots of apple juice. No granules should remain in the syringe.
• Make sure the nasogastric tube is not clogged to ensure that patients receive the full dose.

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.

They are available as follows:

NDC 0008-0841-10 bottles of 100
NDC 0008-0841-81 bottles of 90
NDC 0008-0841-99 carton of 10 Redipak® blister strips of 10 tablets each

PROTONIX® (pantoprazole sodium) Delayed-Release Tablets are supplied as 20 mg yellow oval biconvex delayed-release tablets imprinted with P20 (brown ink) on one side.

They are available as follows:

NDC 0008-0843-81 bottles of 90

PROTONIX® (pantoprazole sodium) For Delayed-Release Oral Suspension contain pale yellowish to dark brownish pantoprazole sodium enteric coated granules in a 40 mg unit dose packet.

They are available as follows:

NDC 0008-0844-02 unit dose carton of 30

Storage

Store PROTONIX® Delayed-Release Tablets and PROTONIX® For Delayed-Release Oral Suspension at 20°-25°C (68 -77°F); excursions permitted to 15°-30°C (59°-86°F). [See USP Controlled Room Temperature.]

This product's label may have been updated. For current package insert and further product information, please visit www.wyeth.com or call our medical communications department toll-free at 1-800-934-5556. Packaged by: Wyeth Pharmaceuticals, Inc.,Philadelphia, PA 19101., under license from Nycomed GmbH, D78467 Konstanz, Germany, FDA revision date: 11/14/2007

Worldwide, more than 11,100 patients have been treated with pantoprazole in clinical trials involving various dosages and duration of treatment. In general, pantoprazole has been well tolerated in both short-term and long-term trials.

The adverse reaction profile for PROTONIX® (pantoprazole sodium) For Delayed-Release Oral Suspension is similar to the established safety profile of PROTONIX® (pantoprazole sodium) Delayed-Release Tablets.

In two U.S. controlled clinical trials involving PROTONIX 10-, 20-, or 40-mg doses for up to 8 weeks, there were no dose-related effects on the incidence of adverse events. The following adverse events considered by investigators to be possibly, probably, or definitely related to drug occurred in 1% or more in the individual studies of GERD patients on therapy with PROTONIX.

Most Frequent Adverse Events Reported as Drug Related in Short-term Domestic Trials

Note: Only adverse events with an incidence greater than or equal to the comparators are shown.

In international short-term, double-blind or open-label clinical trials involving 20 mg to 80 mg per day, the following adverse events were reported to occur in 1% or more of 2805 GERD patients receiving pantoprazole for up to 8 weeks.

Adverse Events in GERD Patients in Short-term International Trials

In two U.S. controlled clinical trials involving PROTONIX 10-, 20-, or 40-mg doses for up to 12 months, the following adverse events considered by investigators to be possibly, probably, or definitely related to drug occurred in 1% or more of GERD patients on long-term therapy.

Most Frequent Adverse Events Reported as Drug Related in Long-term Domestic Trials

Note: Only adverse events with an incidence greater than or equal to the comparators are shown.

In addition, in these short- and long-term domestic and international trials, the following treatment-emergent events, regardless of causality, occurred at a rate of ≥ 1% in pantoprazole-treated patients: anxiety, arthralgia, asthenia, back pain, bronchitis, chest pain, constipation, cough increased, dizziness, dyspepsia, dyspnea, flu syndrome, gastroenteritis, gastrointestinal disorder, hyperlipemia, hypertonia, infection, liver function tests abnormal, migraine, nausea, neck pain, pain, pharyngitis, rectal disorder, rhinitis, SGPT increased, sinusitis, upper respiratory tract infection, urinary frequency, urinary tract infection, and vomiting.

Additional treatment-emergent adverse experiences occurring in < 1% of pantoprazole-treated patients from these trials are listed below by body system. In most instances the relationship to pantoprazole was unclear.

BODY AS A WHOLE: abscess, allergic reaction, chills, cyst, face edema, fever, generalized edema, heat stroke, hernia, laboratory test abnormal, malaise, moniliasis, neoplasm, non-specified drug reaction, photosensitivity reaction.

CARDIOVASCULAR SYSTEM: abnormal electrocardiogram, angina pectoris, arrhythmia, atrial fibrillation/flutter, cardiovascular disorder, chest pain substernal, congestive heart failure, hemorrhage, hypertension, hypotension, myocardial infarction, myocardial ischemia, palpitation, retinal vascular disorder, syncope, tachycardia, thrombophlebitis, thrombosis, vasodilatation.

DIGESTIVE SYSTEM: anorexia, aphthous stomatitis, cardiospasm, colitis, dry mouth, duodenitis, dysphagia, enteritis, esophageal hemorrhage, esophagitis, gastrointestinal carcinoma, gastrointestinal hemorrhage, gastrointestinal moniliasis, gingivitis, glossitis, halitosis, hematemesis, increased appetite, melena, mouth ulceration, oral moniliasis, periodontal abscess, periodontitis, rectal hemorrhage, stomach ulcer, stomatitis, stools abnormal, tongue discoloration, ulcerative colitis.

ENDOCRINE SYSTEM: diabetes mellitus, glycosuria, goiter.

HEPATO-BILIARY SYSTEM: biliary pain, hyperbilirubinemia, cholecystitis, cholelithiasis, cholestatic jaundice, hepatitis, alkaline phosphatase increased, gamma glutamyl transpeptidase increased, SGOT increased.

HEMIC AND LYMPHATIC SYSTEM: anemia, ecchymosis, eosinophilia, hypochromic anemia, iron deficiency anemia, leukocytosis, leukopenia, thrombocytopenia.

METABOLIC AND NUTRITIONAL: dehydration, edema, gout, peripheral edema, thirst, weight gain, weight loss.

MUSCULOSKELETAL SYSTEM: arthritis, arthrosis, bone disorder, bone pain, bursitis, joint disorder, leg cramps, neck rigidity, myalgia, tenosynovitis.

NERVOUS SYSTEM: abnormal dreams, confusion, convulsion, depression, dry mouth, dysarthria, emotional lability, hallucinations, hyperkinesia, hypesthesia, libido decreased, nervousness, neuralgia, neuritis, neuropathy, paresthesia, reflexes decreased, sleep disorder, somnolence, thinking abnormal, tremor, vertigo.

RESPIRATORY SYSTEM: asthma, epistaxis, hiccup, laryngitis, lung disorder, pneumonia, voice alteration.

SKIN AND APPENDAGES: acne, alopecia, contact dermatitis, dry skin, eczema, fungal dermatitis, hemorrhage, herpes simplex, herpes zoster, lichenoid dermatitis, maculopapular rash, pruritus, skin disorder, skin ulcer, sweating, urticaria.

SPECIAL SENSES: abnormal vision, amblyopia, cataract specified, deafness, diplopia, ear pain, extraocular palsy, glaucoma, otitis externa, taste perversion, tinnitus.

UROGENITAL SYSTEM: albuminuria, balanitis, breast pain, cystitis, dysmenorrhea, dysuria, epididymitis, hematuria, impotence, kidney calculus, kidney pain, nocturia, prostatic disorder, pyelonephritis, scrotal edema, urethral pain, urethritis, urinary tract disorder, urination impaired, vaginitis.

In an open-label US clinical trial conducted in 35 patients with pathological hypersecretory conditions treated with PROTONIX for up to 27 months, the adverse events reported were consistent with the safety profile of the drug in other populations.

Postmarketing Reports

There have been spontaneous reports of adverse events with the postmarketing use of pantoprazole. These reports include the following:

BODY AS A WHOLE: anaphylaxis (including anaphylactic shock), angioedema (Quincke's edema).

DIGESTIVE SYSTEM: increased salivation, nausea, pancreatitis.

HEMIC AND LYMPHATIC SYSTEM: pancytopenia.

HEPATO-BILIARY SYSTEM: hepatocellular damage leading to jaundice and hepatic failure. MUSCULOSKELETAL SYSTEM: elevated CPK (creatine phosphokinase), rhabdomyolysis. NERVOUS SYSTEM: confusion, hypokinesia, speech disorder, vertigo.

SKIN AND APPENDAGES: severe dermatologic reactions, including erythema multiforme, Stevens-Johnson syndrome, and toxic epidermal necrolysis (TEN, some fatal).

SPECIAL SENSES: anterior ischemic optic neuropathy, blurred vision, tinnitus.

UROGENITAL SYSTEM: interstitial nephritis.

Laboratory Values

In two U.S. controlled, short-term trials in patients with erosive esophagitis associated with GERD, 0.4% of the patients on PROTONIX 40 mg experienced SGPT elevations of greater than three times the upper limit of normal at the final treatment visit. In two U.S. contr €led, long-term trial €in patients with erosive esophagitis associated with GERD, none of 178 patients (0%) on PROTONIX 40 mg and two of €1 patients (1.1%) on PROTONIX 20 mg experienced significant transaminase elevations at 12 months (or earlier if a patient discontinued prematurely). Significant elevations of SGOT or SGPT were defined as values at least three times the upper limit of normal that were non-sporadic and had no clear alternative explanation. The following changes in laboratory parameters were reported as adverse events: creatinine increased, hypercholesterolemia, and hyperuricemia.

Pantoprazole is metabolized through the cytochrome P450 system, primarily the CYP2C19 and to a minor extent the CYP3A4 isozymes, and subsequently undergoes Phase II conjugation (see CLINICAL PHARMACOLOGY, Drug-Drug Interactions).

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 (see below), midazolam, clarithromycin, metronidazole, or amoxicillin. Clinically relevant interactions of pantoprazole with other drugs with the same metabolic pathways are not expected. Therefore, when coadministered with pantoprazole, adjustment of the dosage of pantoprazole or of such drugs may not be necessary. There was also no interaction with concomitantly administered antacids. There have been postmarketing reports of increased INR and prothrombin time in patients receiving proton pump inhibitors, including pantoprazole, 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.

Concomitant use of atazanavir and proton pump inhibitors is not recommended. Coadministration of atazanavir with proton pump inhibitors is expected to substantially decrease atazanavir plasma concentrations and thereby reduce its therapeutic effect.

Because of profound and long lasting inhibition of gastric acid secretion, pantoprazole may interfere with absorption of drugs where gastric pH is an important determinant of their bioavailability (eg, ketoconazole, ampicillin esters, and iron salts).

No information provided.

General

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

Owing to the chronic nature of erosive esophagitis, there may be a potential for prolonged administration of pantoprazole. 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.

Generally, daily treatment with any acid-suppressing medications over a long period of time (eg, 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 possibility should be considered if clinical symptoms consistent with cyanocobalamin deficiency are observed.

Atrophic gastritis has been noted occasionally in gastric corpus biopsies from patients treated long-term with pantoprazole, particularly in patients who were H. pylori positive.

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.

Sporadic occurrences of hepatocellular adenomas and a hepatocellular carcinoma were observed in Sprague-Dawley rats exposed to pantoprazole in 6-month and 12-month toxicity studies.

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.

Pantoprazole 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) was found to have no effect on fertility and reproductive performance.

Pregnancy

Teratogenic Effects

Pregnancy Category B

Teratology 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. 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.

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.

Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

Use in Women

Erosive esophagitis healing rates in the 221 women treated with PROTONIX Delayed-Release Tablets in U.S. 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 events were also similar for men and women.

Use in Elderly

In short-term U.S. 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 events and laboratory abnormalities in patients aged 65 years and older were similar to those associated with patients younger than 65 years of age.

Laboratory Tests

There have been reports of false-positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving most proton pump inhibitors, including pantoprazole. An alternative confirmatory method should be considered to verify positive results.

Experience in patients taking very high doses of pantoprazole is limited. There have been spontaneous reports of overdosage with pantoprazole, including a suicide in which pantoprazole 560 mg and undetermined amounts of chloroquine and zopiclone were also ingested. There have also been spontaneous reports of patients taking similar amounts of pantoprazole (400 mg and 600 mg) with no adverse effects.

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.

PROTONIX is contraindicated in patients with known hypersensitivity to any component of the formulation.

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 (Cmax) 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 (see CLINICAL PHARMACOLOGY, Pharmacokinetics, Metabolism) with normal liver function receiving an oral dose of the enteric-coated 40 mg pantoprazole tablet, the peak concentration (Cmax) is 2.5μg/mL, the time to reach the peak concentration (tmax) is 2.5 h and the total area under the plasma concentration versus time curve (AUC) is 4.8μg·hr/mL. When pantoprazole is given with food, its tmax is highly variable and may increase significantly. 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.

PROTONIX® (pantoprazole sodium) For Delayed-Release Oral Suspension has been shown to be comparable to PROTONIX® (pantoprazole sodium) Delayed-Release Tablets in suppressing pentagastrin-stimulated maximum acid output (MAO) in patients with gastroesophageal reflux disease (GERD) and a history of erosive esophagitis (EE) (see CLINICAL PHARMACOLOGY, Pharmacodynamics).

PROTONIX For Delayed-Release Oral Suspension is bioequivalent when administered orally in applesauce or apple juice, or mixed in apple juice and administered through a nasogastric tube. The plasma pharmacokinetic parameters from a crossover study in healthy subjects are summarized in the table below. In this study, a single oral 40 mg dose of Protonix For Delayed-Release Oral Suspension was administered to healthy subjects (N = 22) as granules sprinkled over a teaspoonful of applesauce, as granules mixed with apple juice and, mixed with apple juice followed by administration through a nasogastric tube.

Pharmacokinetics parameters (mean ± SD) of Pantoprazole with Administration of Protonix For Delayed-Release Oral Suspension Sprinkled on Applesauce, Mixed with Apple Juice, Mixed with Apple Juice and Administered through a Nasogastric Tube

Absorption

The absorption of pantoprazole is rapid, with a Cmax of 2.5 g/mL that occurs approximately 2.5 hours after administration of single or multiple 40 mg doses of PROTONIX® (pantoprazole sodium) Delayed-Release Tablets. Pantoprazole is well absorbed; it 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® (pantoprazole sodium) Delayed-Release Tablets with food may delay its absorption up to 2 hours or longer; however, the Cmax and the extent of pantoprazole absorption (AUC) are not altered. Thus, PROTONIX® (pantoprazole sodium) Delayed-Release Tablets may be taken without regard to timing of meals.

PROTONIX® (pantoprazole sodium) For Delayed-Release Oral Suspension should be taken approximately 30 minutes before a meal.

Distribution

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.

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. CYP2C19 displays a known genetic polymorphism due to its deficiency in some sub-populations (eg, 3% of Caucasians and African-Americans and 17%-23% of Asians). Although these sub-populations of slow pantoprazole metabolizers have elimination half-life values of 3.5 to 10.0 hours, they still have minimal accumulation ( ≤ 23%) with once daily dosing.

Elimination

After a single oral or intravenous dose of ¹⁴C-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.

Special Populations

Geriatric

Only slight to moderate increases in pantoprazole AUC (43%) and Cmax (26%) were found in elderly volunteers (64 to 76 years of age) after repeated oral administration, compared with younger subjects. No dosage adjustment is recommended based on age.

Pediatric

The pharmacokinetics of pantoprazole have not been investigated in patients < 18 years of age.

Gender

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. No dosage adjustment is needed based on gender (see PRECAUTIONS, Use in Women).

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, 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 slow CYP2C19 metabolizers, where no dosage frequency adjustment is warranted. These pharmacokinetic changes in hepatic-impaired patients result in minimal drug accumulation following once daily multiple-dose administration. No dosage adjustment is needed in patients with mild to severe hepatic impairment. Doses higher than 40 mg/day have not been studied in hepatically-impaired patients.

Drug-Drug Interactions

Pantoprazole 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]), 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. It is, therefore, expected that other drugs metabolized by CYPs 2C19, 3A4, 2D6, 2C9, and 1A2 would not significantly affect the pharmacokinetics of pantoprazole. In vivo studies also suggest that pantoprazole does not significantly affect the kinetics of other drugs (cisapride, theophylline, diazepam [and its active metabolite, desmethyldiazepam], phenytoin, warfarin, metoprolol, nifedipine, carbamazepine, midazolam, clarithromycin, naproxen, piroxicam, and oral contraceptives [levonorgestrel/ethinyl estradiol]) metabolized by CYPs 2C19, 3A4, 2C9, 2D6, and 1A2. Therefore, it is expected that pantoprazole would not significantly affect the pharmacokinetics of other drugs metabolized by these isozymes. Dosage adjustment of such 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. 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.

Pharmacodynamics

PROTONIX® (pantoprazole sodium) For Delayed-Release Oral Suspension 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 then assessed from hour 23 to 24 at steady state.

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.

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 optimal increases in gastric pH which were significantly greater 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 below.

Effect of Single Daily Doses of Oral Pantoprazole on Intragastric pH

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 healing of gastric or duodenal ulcers with pantoprazole treatment, 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 PRECAUTIONS, Carcinogenesis, Mutagenesis, Impairment of Fertility).

Other Effects

No clinically relevant effects of pantoprazole on cardiovascular, respiratory, ophthalmic, or central nervous system function have been detected. In a clinical pharmacology study, pantoprazole 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 40 mg or 20 mg, there were no changes from baseline in overall levels of T3, T4, and TSH.

Clinical Studies

PROTONIX Delayed-Release Tablets were used in the following clinical trials:

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

A U.S. 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 were as follows:

Erosive Esophagitis Healing Rates (per protocol)

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- 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 U.S. 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) were as follows:

Erosive Esophagitis Healing Rates (per protocol)

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.

Long-Term Maintenance of Healing of Erosive Esophagitis

Two independent, multicenter, randomized, double-blind, comparator-controlled trials of identical design were conducted in GERD patients with endoscopically-confirmed healed erosive esophagitis to demonstrate efficacy of PROTONIX in long-term maintenance of healing. The two U.S. 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 the table below, PROTONIX 40 mg and 20 mg were significantly superior to ranitidine at every time point with respect to the maintenance of healing. In addition, PROTONIX 40 mg was superior to all other treatments studied.

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

Note: PROTONIX 10 mg was superior (p < 0.05) to ranitidine in study 2 but not study 1.

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.

Number of Episodes of Heartburn (mean SD)

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). PROTONIX was well tolerated at these dose levels for prolonged periods (greater than 2 years in some patients).

Patients should be cautioned that PROTONIX® Delayed-Release Tablets SHOULD NOT BE SPLIT, CRUSHED, OR CHEWED. PROTONIX Delayed-Release Tablets should be swallowed whole, with or without food in the stomach. Concomitant administration of antacids does not affect the absorption of PROTONIX® Delayed-Release Tablets.

• Patients should be cautioned that PROTONIX® For Delayed-Release Oral Suspension SHOULD NOT BE CRUSHED OR CHEWED. PROTONIX For Delayed-Release Oral Suspension should be taken approximately 30 minutes before a meal.
• PROTONIX For Delayed-Release Oral Suspension should only be administered in apple juice or applesauce, not in water or other liquids, or foods.

(See the DOSAGE AND ADMINISTRATION Section, Administration Options subsection)

IMPORTANT NOTE: This is a summary and does not contain all possible information about this product. For complete information about this product or your specific health needs, ask your health care professional. Always seek the advice of your health care professional if you have any questions about this product or your medical condition. This information is not intended as individual medical advice and does not substitute for the knowledge and judgment of your health care professional. This information does not contain any assurances that this product is safe, effective, or appropriate for you.

PANTOPRAZOLE DELAYED-RELEASE - ORAL

(pan-TOE-pruh-zole)

COMMON BRAND NAME(S): Protonix

USES: Pantoprazole works by blocking acid production in the stomach. This medication is known as a proton pump inhibitor (PPI). It is used to treat acid-related stomach and throat (esophagus) problems such as acid reflux (GERD), erosive esophagitis, and Zollinger-Ellison syndrome. Decreasing extra stomach acid can help relieve symptoms such as heartburn, difficulty swallowing, persistent cough, and trouble sleeping. It can also prevent serious acid damage to your digestive system (e.g., ulcers, cancer of the esophagus).

OTHER USES: This section contains uses of this drug that are not listed in the approved professional labeling for the drug but that may be prescribed by your health care professional. Use this drug for a condition that is listed in this section only if it has been so prescribed by your health care professional.

This medication may also be used to treat stomach or intestinal ulcers. In addition, it may be used with antibiotics to treat certain types of ulcers caused by bacteria.

HOW TO USE: Take this medication by mouth, usually once daily or as directed by your doctor. Swallow the medication whole. Do not split, crush, or chew the medication. Doing so may destroy the drug and prevent it from treating your condition. If you are using the tablets, you may take them with or without food. If you are using the granules, take them 30 minutes before a meal.

Mix the granules into apple juice or applesauce. Do not use other liquids or foods to mix this medication. Sprinkle the granules on 1 teaspoon of applesauce and swallow all of the mixture immediately (within 10 minutes). Or mix the granules into 1 teaspoon of apple juice, stir for 5 seconds, and swallow all of the mixture immediately. Rinse the container once or twice with apple juice to remove any remaining granules, and swallow the rinsing juice immediately. Do not crush or chew the granules in either mixture. Do not prepare a supply in advance.

The granules may also be given through a tube into the stomach (nasogastric or gastric tube). If you are giving this medication through a tube, consult your health care professional for detailed instructions on how to properly mix and give it.

You may take an antacid with this medication, if needed.

The dosage and length of treatment is based on your medical condition and response to treatment.

Use this medication regularly to get the most benefit from it. Remember to use it at the same time each day. Continue to take this medication for the whole time prescribed by your doctor, even if you are feeling better.

Tell your doctor if your condition persists or worsens.

SIDE EFFECTS: Headache, diarrhea, nausea, vomiting, or stomach/abdominal pain may occur. If any of these effects persist or worsen, tell your doctor or pharmacist promptly.

Remember that your doctor has prescribed this medication because he or she has judged that the benefit to you is greater than the risk of side effects. Many people using this medication do not have serious side effects.

Tell your doctor immediately if any of these unlikely but serious side effects occur: signs of increased blood sugar levels (e.g., increased thirst, increased urination, confusion).

If you have been taking this drug for a long time (more than 3 years), tell your doctor immediately if any of these rare but very serious side effects occur: signs of low levels of vitamin B12 (e.g., unusual weakness, sore tongue, numbness or tingling of the hands/feet).

A serious allergic reaction to this drug is rare. However, seek immediate medical attention you have any of the following symptoms of a serious allergic reaction: rash, itching/swelling (especially of the face/tongue/throat), dizziness, trouble breathing.

This is not a complete list of possible side effects. If you notice other effects not listed above, contact your doctor or pharmacist.

Contact your doctor for medical advice about side effects. The following numbers do not provide medical advice, but in the US you may report side effects to the Food and Drug Administration (FDA) at 1-800-FDA-1088. In Canada, you may call Health Canada at 1-866-234-2345.

PRECAUTIONS: Before taking pantoprazole, tell your doctor or pharmacist if you are allergic to it; or to similar drugs (e.g., lansoprazole, omeprazole); or if you have any other allergies.

Before using this medication, tell your doctor or pharmacist your medical history, especially of: severe liver disease, poorly controlled diabetes, other stomach problems (e.g., tumors).

Some symptoms may actually be signs of a more serious condition. Tell your doctor immediately if you have: heartburn combined with lightheadedness/sweating/dizziness, chest pain or shoulder/jaw pain (especially with trouble breathing), pain spreading to arms/neck/shoulders, unexplained weight loss.

This medication should be used only when clearly needed during pregnancy. Discuss the risks and benefits with your doctor.

Pantoprazole passes into breast milk and may harm a nursing infant. Therefore, breast-feeding is not recommended. Consult your doctor before breast-feeding.

DRUG INTERACTIONS: Your doctor or pharmacist may already be aware of any possible drug interactions and may be monitoring you for them. Do not start, stop, or change the dosage of any medicine before checking with your doctor or pharmacist first.

This drug should not be used with the following medications because a very serious interaction may occur: atazanavir, nelfinavir.

If you are currently using either of these medications, tell your doctor or pharmacist before starting pantoprazole.

Before using this medication, tell your doctor or pharmacist of all prescription and nonprescription/herbal products you may use, especially of: warfarin.

Some products need stomach acid so that the body can absorb them properly (such as ampicillin, iron supplements, calcium supplements, dasatinib, azole antifungals including ketoconazole). Pantoprazole decreases stomach acid, so it may change how well these other products work. Before using pantoprazole, consult your doctor or pharmacist about the other medications you take and for advice on how to reduce or avoid these types of interactions.

This medication may affect the results of certain lab tests (e.g., urine test for tetrahydrocannabinol-THC). Make sure laboratory personnel and your doctors know you use this drug.

This document does not contain all possible interactions. Therefore, before using this product, tell your doctor or pharmacist of all the products you use. Keep a list of all your medications with you, and share the list with your doctor and pharmacist.

OVERDOSE: If overdose is suspected, contact your local poison control center or emergency room immediately. US residents can call the US National Poison Hotline at 1-800-222-1222. Canada residents can call a provincial poison control center.

NOTES: Do not share this medication with others.

Laboratory and/or medical tests may be performed periodically to monitor your progress or check for side effects.

MISSED DOSE: If you miss a dose, use it as soon as you remember. If it is near the time of the next dose, skip the missed dose and resume your usual dosing schedule. Do not double the dose to catch up.

STORAGE: Store the US product at room temperature between 68-77 degrees F (20-25 degrees C) away from light and moisture. Brief storage between 59-86 degrees F (15-30 degrees C) is permitted.

Store the Canadian product between 59-86 degrees F (15-30 degrees C) in the recommended packaging.

Do not store in the bathroom. Keep all medicines away from children and pets.

Do not flush medications down the toilet or pour them into a drain unless instructed to do so. Properly discard this product when it is expired or no longer needed. Consult your pharmacist or local waste disposal company for more details about how to safely discard your product.

Information last revised July 2008 Copyright(c) 2008 First DataBank, Inc.