Protonix Delayed-Release

1 INDICATIONS AND USAGE PROTONIX For Delayed-Release Oral Suspension and PROTONIX Delayed-Release Tablets are indicated for: PROTONIX is a proton pump inhibitor (PPI) indicated for the following: • Short-Term Treatment of Erosive Esophagitis Associated with Gastroesophageal Reflux Disease (GERD) ( 1.1 ) • Maintenance of Healing of Erosive Esophagitis ( 1.2 ) • Pathological Hypersecretory Conditions Including Zollinger-Ellison (ZE) Syndrome ( 1.3 ) 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 (EE). 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 EE and reduction in relapse rates of daytime and nighttime heartburn symptoms in adult patients with GERD. Controlled studies did not extend beyond 12 months. 1.3 Pathological Hypersecretory Conditions Including Zollinger-Ellison Syndrome PROTONIX is indicated for the long-term treatment of pathological hypersecretory conditions, including Zollinger-Ellison (ZE) Syndrome.

2 DOSAGE AND ADMINISTRATION Indication Dose 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 Controlled studies did not extend beyond 12 months Pathological Hypersecretory Conditions Including Zollinger-Ellison Syndrome ( 2.1 ) Adults 40 mg Twice Daily See full prescribing information for administration instructions 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 Dose Frequency Short-Term Treatment of Erosive Esophagitis Associated With GERD Adults 40 mg Once daily for up to 8 weeks For adult patients who have not healed after 8 weeks of treatment, an additional 8-week course of PROTONIX may be considered. 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 Controlled studies did not extend beyond 12 months Pathological Hypersecretory Conditions Including Zollinger-Ellison Syndrome Adults 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. 2.2 Administration Instructions Directions for method of administration for each dosage form are presented in Table 2. Table 2: Administration Instructions Formulation Route Instructions Do not split, chew, or crush PROTONIX Delayed-Release Tablets and PROTONIX For Delayed-Release Oral Suspension. Delayed-Release 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 Take a missed dose as soon as possible. If it is almost time for the next dose, skip the missed dose and take the next dose at the regular scheduled time. Do not take 2 doses at the same time. PROTONIX Delayed-Release Tablets Swallow PROTONIX Delayed-Release Tablets whole, with or without food in the stomach. For patients unable to swallow a 40 mg tablet, two 20 mg tablets may be taken. Concomitant administration of antacids does not affect the absorption of PROTONIX Delayed-Release Tablets. PROTONIX For Delayed-Release Oral Suspension Administer PROTONIX For Delayed-Release Oral Suspension 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-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. PRO…

5 WARNINGS AND PRECAUTIONS • Gastric Malignancy: In adults, symptomatic response does not preclude presence of gastric malignancy. Consider additional follow-up and diagnostic testing. ( 5.1 ) • Acute Tubulointerstitial Nephritis : Discontinue treatment and evaluate patients. ( 5.2 ) • Clostridium difficile- Associated Diarrhea : PPI therapy may be associated with increased risk of Clostridium difficile- associated diarrhea. ( 5.3 ) • Bone Fracture : Long-term and multiple daily dose PPI therapy may be associated with an increased risk for osteoporosis-related fractures of the hip, wrist or spine. ( 5.4 ) • Severe Cutaneous Adverse Reactions : Discontinue at the first signs or symptoms of severe cutaneous adverse reactions or other signs of hypersensitivity and consider further evaluation. ( 5.5 ) • Cutaneous and Systemic Lupus Erythematosus : Mostly cutaneous; new onset or exacerbation of existing disease; discontinue PROTONIX and refer to specialist for evaluation. ( 5.6 ) • Cyanocobalamin (Vitamin B-12) Deficiency : Daily long-term use (e.g., longer than 3 years) may lead to malabsorption or a deficiency of cyanocobalamin. ( 5.7 ) • Hypomagnesemia and Mineral Metabolism : Reported rarely with prolonged treatment with PPIs. ( 5.8 ) • Fundic Gland Polyps: Risk increases with long-term use, especially beyond one year. Use the shortest duration of therapy. ( 5.10 ) 5.1 Presence of Gastric Malignancy In adults, symptomatic response to therapy with PROTONIX does not preclude the presence of gastric malignancy. Consider additional follow-up and diagnostic testing in adult patients who have a suboptimal response or an early symptomatic relapse after completing treatment with a PPI. In older patients, also consider an endoscopy. 5.2 Acute Tubulointerstitial Nephritis Acute tubulointerstitial nephritis (TIN) has been observed in patients taking PPIs and may occur at any point during PPI therapy. Patients may present with varying signs and symptoms from symptomatic hypersensitivity reactions to non-specific symptoms of decreased renal function (e.g., malaise, nausea, anorexia). In reported case series, some patients were diagnosed on biopsy and in the absence of extra-renal manifestations (e.g., fever, rash or arthralgia). Discontinue PROTONIX and evaluate patients with suspected acute TIN [see Contraindications (4) ]. 5.3 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. 5.4 Bone Fracture Several published observational studies suggest that PPI therapy may be associated with an increased risk for osteoporosis-related fractures of the hip, wrist, or spine. The risk of fracture was increased in patients who received high-dose, defined as multiple daily doses, and long-term PPI therapy (a year or longer). Patients should use the lowest dose and shortest duration of PPI therapy appropriate to the condition being treated. Patients at risk for osteoporosis-related fractures should be managed according to established treatment guidelines [see Dosage and Administration (2) , Adverse Reactions (6.2) ]. 5.5 Severe Cutaneous Adverse Reactions Severe cutaneous adverse reactions, including erythema multiforme, Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), drug reaction with eosinophilia and systemic symptoms (DRESS), and acute generalized exanthematous pustulosis (AGEP) have been reported in association with the use of PPIs [see Adverse Reactions (6.2) ] . Discontinue PROTONIX at the first signs or symptoms of severe cutaneous adverse reactions or other signs of hypersensitivity and consider further evaluation. 5.6 Cutaneous …

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 tubulointerstitial nephritis, and urticaria [see Warnings and Precautions (5.2) , Adverse Reactions (6) ] . • Proton pump inhibitors (PPIs), including PROTONIX, are contraindicated in patients receiving rilpivirine-containing products [see Drug Interactions (7) ] . • Patients with known hypersensitivity to any component of the formulation or to substituted benzimidazoles ( 4 ) • Patients receiving rilpivirine-containing products ( 4 , 7 )

7 DRUG INTERACTIONS Table 4 includes drugs with clinically important drug interactions and interaction with diagnostics when administered concomitantly with PROTONIX and instructions for preventing or managing them. Consult the labeling of concomitantly used drugs to obtain further information about interactions with PPIs. Table 4: Clinically Relevant Interactions Affecting Drugs Co-Administered with PROTONIX and Interactions with Diagnostics Antiretrovirals Clinical Impact: The effect of PPIs on antiretroviral drugs is variable. The clinical importance and the mechanisms behind these interactions are not always known. • Decreased exposure of some antiretroviral drugs (e.g., rilpivirine atazanavir, and nelfinavir) when used concomitantly with pantoprazole may reduce antiviral effect and promote the development of drug resistance. • Increased exposure of other antiretroviral drugs (e.g., saquinavir) when used concomitantly with pantoprazole may increase toxicity of the antiretroviral drugs . • There are other antiretroviral drugs which do not result in clinically relevant interactions with pantoprazole. Intervention: Rilpivirine-containing products: Concomitant use with PROTONIX is contraindicated [see Contraindications (4) ] . See prescribing information. Atazanavir: See prescribing information for atazanavir for dosing information. Nelfinavir: Avoid concomitant use with PROTONIX. See prescribing information for nelfinavir. Saquinavir: See the prescribing information for saquinavir and monitor for potential saquinavir toxicities. Other antiretrovirals: See prescribing information. Warfarin Clinical Impact: Increased INR and prothrombin time in patients receiving PPIs, including pantoprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Intervention: Monitor INR and prothrombin time. Dose adjustment of warfarin may be needed to maintain target INR range. See prescribing information for warfarin. Clopidogrel Clinical Impact: Concomitant administration of pantoprazole and clopidogrel in healthy subjects had no clinically important effect on exposure to the active metabolite of clopidogrel or clopidogrel-induced platelet inhibition [see Clinical Pharmacology (12.3) ]. Intervention: No dose adjustment of clopidogrel is necessary when administered with an approved dose of PROTONIX. Methotrexate Clinical Impact: Concomitant use of PPIs with methotrexate (primarily at high dose) may elevate and prolong serum concentrations of methotrexate and/or its metabolite hydroxymethotrexate, possibly leading to methotrexate toxicities. No formal drug interaction studies of high-dose methotrexate with PPIs have been conducted [see Warnings and Precautions (5.13) ] . Intervention: A temporary withdrawal of PROTONIX may be considered in some patients receiving high-dose methotrexate. Drugs Dependent on Gastric pH for Absorption (e.g., iron salts, erlotinib, dasatinib, nilotinib, mycophenolate mofetil, ketoconazole/itraconazole) Clinical Impact: Pantoprazole can reduce the absorption of other drugs due to its effect on reducing intragastric acidity. Intervention: Mycophenolate mofetil (MMF): Co-administration of pantoprazole sodium in healthy subjects and in transplant patients receiving MMF has been reported to reduce the exposure to the active metabolite, mycophenolic acid (MPA), possibly due to a decrease in MMF solubility at an increased gastric pH [see Clinical Pharmacology (12.3) ] . The clinical relevance of reduced MPA exposure on organ rejection has not been established in transplant patients receiving PROTONIX and MMF. Use PROTONIX with caution in transplant patients receiving MMF. See the prescribing information for other drugs dependent on gastric pH for absorption. Interactions with Investigations of Neuroendocrine Tumors Clinical Impact: CgA levels increase secondary to PPI-induced decreases in gastric acidity. The increased CgA level may cause false positive results in…

8.1 Pregnancy Risk Summary Available data from published observational studies did not demonstrate an association of major malformations or other adverse pregnancy outcomes with pantoprazole. In animal reproduction studies, no evidence of adverse development outcomes was observed with pantoprazole. Reproduction studies have been performed in rats at oral doses up to 450 mg/kg/day (about 88 times the recommended human dose) and rabbits at oral doses up to 40 mg/kg/day (about 16 times the recommended human dose) with administration of pantoprazole during organogenesis in pregnant animals and have revealed no evidence of harm to the fetus due to pantoprazole in this study (see Data ) . A pre-and postnatal development toxicity study in rats with additional endpoints to evaluate the effect on bone development was performed with pantoprazole sodium. Oral pantoprazole doses of 5, 15, and 30 mg/kg/day (approximately 1, 3, and 6 times the human dose of 40 mg/day) were administered to pregnant females from gestation day (GD) 6 through lactation day (LD) 21. Changes in bone morphology were observed in pups exposed to pantoprazole in utero and through milk during the period of lactation as well as by oral dosing from postnatal day (PND) 4 through PND 21 [see Use in Specific Populations (8.4) ] . There were no drug-related findings in maternal animals . Advise pregnant women of the potential risk of fetal harm. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in the clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. Data Human Data Available data from published observational studies failed to demonstrate an association of adverse pregnancy-related outcomes and pantoprazole use. Methodological limitations of these observational studies cannot definitely establish or exclude any drug-associated risk during pregnancy. In a prospective study by the European Network of Teratology Information Services, outcomes from a group of 53 pregnant women administered median daily doses of 40 mg pantoprazole were compared to a control group of 868 pregnant women who did not take any proton pump inhibitors (PPIs). There was no difference in the rate of major malformations between women exposed to PPIs and the control group, corresponding to a Relative Risk (RR)=0.55, [95% Confidence Interval (CI) 0.08–3.95]. In a population-based retrospective cohort study covering all live births in Denmark from 1996 to 2008, there was no significant increase in major birth defects during analysis of first trimester exposure to pantoprazole in 549 live births. A meta-analysis that compared 1,530 pregnant women exposed to PPIs in at least the first trimester with 133,410 unexposed pregnant women showed no significant increases in risk for congenital malformations or spontaneous abortion with exposure to PPIs (for major malformations OR=1.12 ([95% CI 0.86–1.45] and for spontaneous abortions OR=1.29 [95% CI 0.84–1.97]). Animal Data Reproduction studies have been performed in rats at oral pantoprazole doses up to 450 mg/kg/day (about 88 times the recommended human dose based on body surface area) and in rabbits at oral doses up to 40 mg/kg/day (about 16 times the recommended human dose based on body surface area) with administration of pantoprazole sodium during organogenesis in pregnant animals. The studies have revealed no evidence of impaired fertility or harm to the fetus due to pantoprazole. A pre- and postnatal development toxicity study in rats with additional endpoints to evaluate the effect on bone development was performed with pantoprazole sodium. Oral pantoprazole doses of 5, 15, and 30 mg/kg/day (approximately 1, 3, and 6 times the human dose of 40 mg/day on a body surface area basis) were admini…

12.5 Pharmacogenomics CYP2C19 displays a known genetic polymorphism due to its deficiency in some subpopulations (e.g., approximately 3% of Caucasians and African-Americans and 17% to 23% of Asians are poor metabolizers). Although these subpopulations of pantoprazole poor metabolizers have elimination half-life values of 3.5 to 10 hours in adults, they still have minimal accumulation (23% or less) with once-daily dosing. For adult patients who are CYP2C19 poor metabolizers, no dosage adjustment is needed. Similar to adults, pediatric patients who have the poor metabolizer genotype of CYP2C19 (CYP2C19 *2/*2) exhibited greater than a 6-fold increase in AUC compared to pediatric extensive (CYP2C19 *1/*1) and intermediate (CYP2C19 *1/*x) metabolizers. Poor metabolizers exhibited approximately 10-fold lower apparent oral clearance compared to extensive metabolizers. For known pediatric poor metabolizers, a dose reduction should be considered.

6 ADVERSE REACTIONS The following serious adverse reactions are described below and elsewhere in labeling: • Acute Tubulointerstitial Nephritis [see Warnings and Precautions (5.2) ] • Clostridium difficile- Associated Diarrhea [see Warnings and Precautions (5.3) ] • Bone Fracture [see Warnings and Precautions (5.4) ] • Severe Cutaneous Adverse Reactions [see Warnings and Precautions (5.5) ] • Cutaneous and Systemic Lupus Erythematosus [see Warnings and Precautions (5.6) ] • Cyanocobalamin (Vitamin B-12) Deficiency [see Warnings and Precautions (5.7) ] • Hypomagnesemia and Mineral Metabolism [see Warnings and Precautions (5.8) ] • Fundic Gland Polyps [see Warnings and Precautions (5.10) ] Most common adverse reactions are: • For adult use (>2%): headache, diarrhea, nausea, abdominal pain, vomiting, flatulence, dizziness, and arthralgia. ( 6.1 ) • For pediatric use (>4%): URI, headache, fever, diarrhea, vomiting, rash, and abdominal pain. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Pfizer Inc at 1-800-438-1985 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Trials Experience The adverse reaction profiles for PROTONIX (pantoprazole sodium) For Delayed-Release Oral Suspension and PROTONIX (pantoprazole sodium) Delayed-Release Tablets are similar. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. Adults Safety in nine randomized comparative US clinical trials in patients with GERD included 1,473 patients on oral PROTONIX (20 mg or 40 mg), 299 patients on an H 2 -receptor antagonist, 46 patients on another PPI, and 82 patients on placebo. The most frequently occurring adverse reactions are listed in Table 3. Table 3: Adverse Reactions Reported in Clinical Trials of Adult Patients with GERD at a Frequency of >2% PROTONIX (n=1473) % Comparators (n=345) % Placebo (n=82) % Headache 12.2 12.8 8.5 Diarrhea 8.8 9.6 4.9 Nausea 7.0 5.2 9.8 Abdominal pain 6.2 4.1 6.1 Vomiting 4.3 3.5 2.4 Flatulence 3.9 2.9 3.7 Dizziness 3.0 2.9 1.2 Arthralgia 2.8 1.4 1.2 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 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 rea…