Pantoprazole Sodium

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

1 INDICATIONS AND USAGE Pantoprazole sodium delayed-release tablets, USP are indicated for: Pantoprazole sodium delayed-release tablets, USP are 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) 1.1 Short-Term Treatment of Erosive Esophagitis Associated With Gastroesophageal Reflux Disease (GERD) Pantoprazole sodium delayed-release tablets, USP are indicated in adults and pediatric patients five years of age and older for the short-term treatment (up to 8 weeks) in the healing and symptomatic relief of erosive esophagitis. For those adult patients who have not healed after 8 weeks of treatment, an additional 8-week course of pantoprazole sodium delayed-release tablets, USP may be considered. Safety of treatment beyond 8 weeks in pediatric patients has not been established. 1.2 Maintenance of Healing of Erosive Esophagitis Pantoprazole sodium delayed-release tablets, USP are indicated for maintenance of healing of erosive esophagitis and reduction in relapse rates of daytime and nighttime heartburn symptoms in adult patients with GERD. Controlled studies did not extend beyond 12 months. 1.3 Pathological Hypersecretory Conditions Including Zollinger-Ellison Syndrome Pantoprazole sodium delayed-release tablets, USP are indicated for the long-term treatment of pathological hypersecretory conditions, including Zollinger-Ellison 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 * Pathological Hypersecretory Conditions Including Zollinger-Ellison Syndrome ( 2.1 ) Adults 40 mg Twice Daily * Controlled studies did not extend beyond 12 months See full prescribing information for administration instructions 2.1 Recommended Dosing Schedule Pantoprazole sodium delayed-release tablets are supplied as delayed-release tablets. The recommended dosages are outlined in Table 1. Table 1: Recommended Dosing Schedule for Pantoprazole Sodium Delayed-Release Tablets Indication Dose Frequency 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 ** * For adult patients who have not healed after 8 weeks of treatment, an additional 8-week course of pantoprazole sodium delayed-release tablets may be considered. ** Dosage regimens should be adjusted to individual patient needs and should continue for as long as clinically indicated. Doses up to 240 mg daily have been administered. *** Controlled studies did not extend beyond 12 months. 2.2 Administration Instructions Directions for method of administration is presented in Table 2. Table 2: Administration Instructions Formulation Route Instructions * Delayed-Release Tablets Oral Swallowed whole, with or without food * Do not split, chew, or crush pantoprazole sodium delayed-release tablets. Take a missed dose as soon as possible. If it is almost time for the next dose, skip the missed dose and take the next dose at the regular scheduled time. Do not take 2 doses at the same time. Pantoprazole Sodium Delayed-Release Tablets Swallow pantoprazole sodium delayed-release tablets whole, with or without food in the stomach. For patients unable to swallow a 40 mg tablet, two 20 mg tablets may be taken. Concomitant administration of antacids does not affect the absorption of pantoprazole sodium delayed-release tablets.

3 DOSAGE FORMS AND STRENGTHS Pantoprazole Sodium Delayed-Release Tablets, USP are available containing 22.55 mg or 45.10 mg of pantoprazole sodium, USP equivalent to 20 mg or 40 mg of pantoprazole, respectively. • The 20 mg tablets are dark yellow, film-coated, oval, unscored tablets imprinted with M P8 in black ink on one side of the tablet and blank on the other side. • The 40 mg tablets are dark yellow, film-coated, oval, unscored tablets imprinted with M P9 in black ink on one side of the tablet and blank on the other side. • Delayed-Release Tablets: 20 mg and 40 mg pantoprazole ( 3 )

4 CONTRAINDICATIONS • Pantoprazole sodium delayed-release tablets are contraindicated in patients with known hypersensitivity to any component of the formulation or any substituted benzimidazole. Hypersensitivity reactions may include anaphylaxis, anaphylactic shock, angioedema, bronchospasm, acute tubulointerstitial nephritis, and urticaria [see Warnings and Precautions ( 5.2 ), Adverse Reactions ( 6 )]. • Proton pump inhibitors (PPIs), including pantoprazole sodium delayed-release tablets, 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 )

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 Aurobindo Pharma USA, Inc. at 1-866-850-2876 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience The adverse reaction profiles for pantoprazole sodium for delayed-release oral suspension and pantoprazole sodium delayed-release tablets are similar. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. Adults Safety in nine randomized comparative U.S. clinical trials in patients with GERD included 1,473 patients on oral pantoprazole sodium delayed-release tablets (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% Pantoprazole Sodium Delayed-Release Tablets (n=1473) % Comparators (n=345) % Placebo (n=82) % Headache 12.2 12.8 8.5 Diarrhea 8.8 9.6 4.9 Nausea 7 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 2.9 1.2 Arthralgia 2.8 1.4 1.2 Additional adverse reactions that were reported for pantoprazole sodium delayed-release tablets in clinical trials with a frequency of ≤2% are listed below by body system: Body as a Whole : allergic reaction, pyrexia, photosensitivity reaction, facial edema Gastrointestinal: constipation, dry mouth, hepatitis Hematologic: leukopenia, thrombocytopenia Metabolic/Nutritional: elevated CK (creatine kinase), generalized edema, elevated triglycerides, liver enzymes elevated Musculoskeletal: myalgia Nervous: depression, vertigo Skin and Appendages : urticaria, rash, pruritus Special Senses: blurred vision Pediatric Patients Safety of pantoprazole sodium delayed-release tablets in the treatment of EE associated with GERD was evaluated in pediatric patients ages 1 year through 16 years in three clinical trials. Safety trials involved pediatric patients with EE; however, as EE is uncommon in the pediatric population, 249 pediatric patients with endoscopically-proven or symptomatic GERD were also evaluated. All adult adverse reactions to pantoprazole sodium delayed-release tablets are considered relevant to pediatric patients. In patients ages 1 year through 16 years, the most commonly reported (>4%) adverse reactions include: URI, headache, fever, diarrhea, vomiting, rash, and abdominal pain. For safety information in patients less than 1 year of age see Use in Specific Populations (8.4) . Additional adverse reactions that were reported for pantoprazole sodium delayed-release tablets 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 triglyc …

7 DRUG INTERACTIONS Table 4 includes drugs with clinically important drug interactions and interaction with diagnostics when administered concomitantly with pantoprazole sodium delayed-release tablets and instructions for preventing or managing them. Consult the labeling of concomitantly used drugs to obtain further information about interactions with PPIs. Table 4: Clinically Relevant Interactions Affecting Drugs Co-Administered with Pantoprazole Sodium Delayed-Release Tablets 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 pantoprazole sodium delayed-release tablets is contraindicated [see Contraindications (4) ] . See prescribing information. Atazanavir: See prescribing information for atazanavir for dosing information. Nelfinavir: Avoid concomitant use with pantoprazole sodium delayed-release tablets. 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 pantoprazole sodium delayed-release tablets. 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 pantoprazole sodium delayed-release tablets 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 pantoprazole sodium delayed-release tablets and MMF. Use pantoprazole sodium delayed-release tablets with caution in transplant patients receiving MMF. See the prescrib …

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Teratogenic Effects Pregnancy Category C Reproduction studies have been performed in rats at oral pantoprazole doses up to 450 mg/kg/day (about 88 times the recommended human dose based on body surface area) and in rabbits at oral doses up to 40 mg/kg/day (about 16 times the recommended human dose based on body surface area) with administration of pantoprazole sodium during organogenesis in pregnant animals. The studies have revealed no evidence of impaired fertility or harm to the fetus due to pantoprazole. A pre- and postnatal development toxicity study in rats with additional endpoints to evaluate the effect on bone development was performed with pantoprazole sodium. Oral pantoprazole doses of 5, 15, and 30 mg/kg/day (approximately 1, 3, and 6 times the human dose of 40 mg/day on a body surface area basis) were administered to pregnant females from gestation day (GD) 6 through lactation day (LD) 21. On postnatal day (PND 4) through PND 21, the pups were administered oral doses at 5, 15, and 30 mg/kg/day (approximately 1, 2.3, and 3.2 times the exposure (AUC) in humans at a dose of 40 mg). There were no drug-related findings in maternal animals. During the preweaning dosing phase (PND 4 to 21) of the pups, there were increased mortality and/or moribundity and decreased body weight and body weight gain at 5 mg/kg/day (approximately equal exposures (AUC) in humans receiving the 40 mg dose) and higher doses. On PND 21, decreased mean femur length and weight and changes in femur bone mass and geometry were observed in the offspring at 5 mg/kg/day (approximately equal exposures (AUC) in humans at the 40 mg dose) and higher doses. The femur findings included lower total area, bone mineral content and density, periosteal and endosteal circumference, and cross-sectional moment of inertia. There were no microscopic changes in the distal femur, proximal tibia, or stifle joints. Changes in bone parameters were partially reversible following a recovery period, with findings on PND 70 limited to lower femur metaphysis cortical/subcortical bone mineral density in female pups at 5 mg/kg/day (approximately equal exposures (AUC) in humans at the 40 mg dose) and higher doses. There are no adequate and well-controlled studies in pregnant women. Advise pregnant women of the potential risk of fetal harm. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. 8.3 Nursing Mothers Pantoprazole and its metabolites are excreted in the milk of rats. Pantoprazole excretion in human milk has been detected in a study of a single nursing mother after a single 40 mg oral dose of pantoprazole sodium. The clinical relevance of this finding is not known. Many drugs which are excreted in human milk have a potential for serious adverse reactions in nursing infants. Based on the potential for tumorigenicity shown for pantoprazole sodium in rodent carcinogenicity studies, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the benefit of the drug to the mother. 8.4 Pediatric Use The safety and effectiveness of pantoprazole sodium delayed-release tablets for short-term treatment (up to eight weeks) of EE associated with GERD have been established in pediatric patients 1 year through 16 years of age. Effectiveness for EE has not been demonstrated in patients less than 1 year of age. In addition, for patients less than 5 years of age, there is no appropriate dosage strength in an age-appropriate formulation available. Therefore, pantoprazole sodium delayed-release tablets are indicated for the short-term treatment of EE associated with GERD for patients 5 years and older. The safety and effectiveness of pantoprazole sodium delayed-release tablets for pediatric uses other than EE have not been established. 1 year through 16 years of …

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).

11 DESCRIPTION The active ingredient in pantoprazole sodium delayed-release tablets USP, a PPI, is a substituted benzimidazole, sodium 5-(difluoromethoxy)-2-[[(3,4-dimethoxy-2-pyridinyl)methyl] sulfinyl]-1 H -benzimidazole sesquihydrate, a compound that inhibits gastric acid secretion. Its empirical formula is C 16 H 14 F 2 N 3 NaO 4 S x 1.5 H 2 O, with a molecular weight of 432.4. The structural formula is: Pantoprazole sodium, USP sesquihydrate is a white to off-white crystalline powder and is racemic. Pantoprazole has weakly basic and acidic properties. Pantoprazole sodium, USP sesquihydrate is freely soluble in water, very slightly soluble in phosphate buffer at pH 7.4, and practically insoluble in n-hexane. The stability of the compound in aqueous solution is pH-dependent. The rate of degradation increases with decreasing pH. At ambient temperature, the degradation half-life is approximately 2.8 hours at pH 5 and approximately 220 hours at pH 7.8. Pantoprazole sodium, USP is supplied as a delayed-release tablet, available in two strengths (20 mg and 40 mg). Each pantoprazole sodium delayed-release tablet, USP contains 45.1 mg or 22.56 mg of pantoprazole sodium, USP sesquihydrate (equivalent to 40 mg or 20 mg pantoprazole, respectively). Pantoprazole sodium delayed-release tablets, USP contains the following inactive ingredients: ammonium hydroxide, crospovidone, hydroxyl propyl cellulose, hypromellose, iron oxide black, iron oxide yellow, mannitol, methacrylic acid copolymer dispersion, polyethylene glycol, polyvinyl alcohol, povidone, propylene glycol, shellac, sodium carbonate, sodium hydroxide, sodium stearyl fumarate, talc, titanium dioxide and triethyl citrate. Pantoprazole sodium delayed-release tablets, USP (40 mg and 20 mg) complies with USP dissolution test 2. 1

10. Overdosage Experience in patients taking very high doses of pantoprazole sodium delayed-release tablets (greater than 240 mg) is limited. Spontaneous post-marketing reports of overdose are generally within the known safety profile of pantoprazole sodium delayed-release tablets. Pantoprazole is not removed by hemodialysis. In case of overdosage, treatment should be symptomatic and supportive. Single oral doses of pantoprazole at 709 mg/kg, 798 mg/kg, and 887 mg/kg were lethal to mice, rats, and dogs, respectively. The symptoms of acute toxicity were hypoactivity, ataxia, hunched sitting, limb-splay, lateral position, segregation, absence of ear reflex, and tremor. If overexposure to pantoprazole sodium delayed-release tablets occurs, call your Poison Control Center at 1-800-222-1222 for current information on the management of poisoning or overdosage.

16 HOW SUPPLIED/STORAGE AND HANDLING How Supplied Pantoprazole Sodium Delayed-Release Tablets, USP are supplied as 20 mg yellow to pale yellow, oval, biconvex, delayed-release tablets imprinted “H125” on one side with black ink and plain on the other side. They are supplied as follows: Bottles of 7 tablets NDC 85766-224-07 (repackaged from NDC 31722-712-XX) Bottles of 10 tablets NDC 85766-224-10 (repackaged from NDC 31722-712-XX) Bottles of 14 tablets NDC 85766-224-14 (repackaged from NDC 31722-712-XX) Bottles of 20 tablets NDC 85766-224-20 (repackaged from NDC 31722-712-XX) Bottles of 30 tablets NDC 85766-224-30 (repackaged from NDC 31722-712-XX) Bottles of 60 tablets NDC 85766-224-60 (repackaged from NDC 31722-712-XX) Bottles of 90 tablets NDC 85766-224-90 (relabeledfrom NDC 31722-712-90) Bottles of 100 tablets NDC 85766-224-01 (repackaged from NDC 31722-712-XX) Pantoprazole Sodium Delayed-Release Tablets, USP are supplied as 40 mg yellow to pale yellow, oval, biconvex, delayed-release tablets imprinted “H126” on one side with black ink and plain on the other side. They are supplied as follows: Bottles of 7 tablets NDC 85766-225-07 (repackaged from NDC 31722-713-XX) Bottles of 10 tablets NDC 85766-225-10 (repackaged from NDC 31722-713-XX) Bottles of 14 tablets NDC 85766-225-14 (repackaged from NDC 31722-713-XX) Bottles of 20 tablets NDC 85766-225-20 (repackaged from NDC 31722-713-XX) Bottles of 30 tablets NDC 85766-225-30 (repackaged from NDC 31722-713-XX) Bottles of 60 tablets NDC 85766-225-60 (repackaged from NDC 31722-713-XX) Bottles of 90 tablets NDC 85766-225-90 (relabeledfrom NDC 31722-713-90) Bottles of 100 tablets NDC 85766-225-01 (repackaged from NDC 31722-713-XX) Storage Store pantoprazole sodium delayed-release tablets, USP at 20° to 25°C (68° to 77°F) [see USP Controlled Room Temperature].