pantoprazole 40 MG Delayed Release Oral Tablet [Protonix]

INDICATIONS AND USAGE Pantoprazole sodium for delayed-release oral suspension is indicated for: Pantoprazole sodium for delayed-release oral suspension 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) Pantoprazole sodium for delayed-release oral suspension is indicated in adults and pediatric patients five years of age and older for the short-term treatment (up to 8 weeks) in the healing and symptomatic relief of erosive esophagitis (EE). For those adult patients who have not healed after 8 weeks of treatment, an additional 8-week course of pantoprazole sodium for delayed-release oral suspension 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 for delayed-release oral suspension 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 Pantoprazole sodium for delayed-release oral suspension is indicated for the long-term treatment of pathological hypersecretory conditions, including Zollinger-Ellison (ZE) Syndrome.

DOSAGE AND ADMINISTRATION GERD and a History of EE Adults: • The recommended dosage is 40 mg once daily by intravenous injection (over at least 2 minutes) or intravenous infusion (for 15 minutes) for up to 10 days. ( 2.1 ) • Discontinue as soon as the patient is able to receive oral treatment. Switch to an appropriate oral medication within 10 days of starting PROTONIX I.V. ( 2.1 ) Pediatrics 3 Months of Age and Older: • The recommended dosage for pediatric patients 3 months of age and older is based on age and actual body weight as shown in the table. ( 2.1 ) • Administer as an intravenous infusion over 15 minutes once daily. ( 2.1 ) Age and Body Weight Recommended Dosage Regimen (up to 7 days) 3 months to less than 1 year of age Less than 12.5 kg 0.8 mg/kg once daily 12.5 kg and above 10 mg once daily 1 year to 17 years of age Up to 15 kg 10 mg once daily Greater than 15 kg up to 40 kg 20 mg once daily Greater than 40 kg 40 mg once daily • Discontinue PROTONIX I.V. as soon as the patient is able to tolerate oral treatment. Switch to an appropriate oral medication within 7 days of starting PROTONIX I.V. ( 2.1 ) Pathological Hypersecretion Conditions, Including ZE Syndrome • The recommended adult dosage is 80 mg every 12 hours by intravenous injection (over at least 2 minutes) or intravenous infusion (for 15 minutes). ( 2.2 ) • For information on how to adjust dosing for individual patient needs, see the full prescribing information. ( 2.2 ) • When switching between intravenous to oral formulations of gastric acid inhibitors, consider the pharmacodynamic action of the drugs to ensure continuity of acid suppression. ( 2.2 ) Preparation and Administration Instructions • See full prescribing information for preparation and administration instructions by indication. ( 2.3 , 2.4 ) 2.1 Recommended Dosage for GERD Associated with a History of EE Adult Patients The recommended adult dosage of PROTONIX I.V. is 40 mg once daily by intravenous injection (over at least 2 minutes) or intravenous infusion (for 15 minutes) for up to 10 days. Discontinue PROTONIX I.V. as soon as the patient is able to tolerate oral treatment. Switch to an appropriate oral medication within 10 days of starting PROTONIX I.V. Pediatric Patients • The recommended dosage for pediatric patients 3 months of age and older is based on age and actual body weight as shown in Table 1 below. • Administer as an intravenous infusion over 15 minutes once daily. Table 1: Recommended Pediatric Dosage Regimen for GERD and a History of EE Age and Body Weight Recommended Dosage Regimen (up to 7 days) 3 months to less than 1 year of age Less than 12.5 kg 0.8 mg/kg once daily 12.5 kg and above 10 mg once daily 1 year to 17 years of age Up to 15 kg 10 mg once daily Greater than 15 kg up to 40 kg 20 mg once daily Greater than 40 kg 40 mg once daily • Discontinue PROTONIX I.V. as soon as the patient is able to tolerate oral treatment. Switch to an appropriate oral medication within 7 days of starting PROTONIX I.V. 2.2 Recommended Dosage for Pathological Hypersecretion Including Zollinger-Ellison Syndrome • The recommended adult dosage of PROTONIX I.V. is 80 mg every 12 hours by intravenous injection (over at least 2 minutes) or intravenous infusion (for 15 minutes). • Adjust the frequency of dosing to individual patient needs based on acid output measurements. In those patients who need a higher dosage, 80 mg intravenously every 8 hours is expected to maintain acid output below 10 mEq/h. • When switching between intravenous to oral formulations of gastric acid inhibitors, consider the pharmacodynamic action of the drugs to ensure continuity of acid suppression. 2.3 Preparation and Administration Instructions for GERD Associated with a History of EE 15-Minute Intravenous Infusion for Pediatric or Adult Patients 1. Reconstitute each vial of PROTONIX I.V. with 10 mL of 0.9% Sodium Chloride Injection. 2. Dilute the resulting solution to a final concentration as described below: • Pediatric patients 3 months to less than 1 year of age: Dilute with 21 mL 0.9% Sodium Chloride Injection to a final concentration of approximately 1.3 mg/mL. • Pediatric patients 1 year to 17 years old and adult patients : Further dilute with 100 mL 5% Dextrose Injection or 0.9% Sodium Chloride Injection to a final concentration of approximately 0.4 mg/mL. 3. Inspect the diluted PROTONIX I.V. solution visually for particulate matter and discoloration prior to and during administration. 4. Withdraw the desired dose of the diluted PROTONIX I.V. solution for a pediatric or adult dose. 5. Discard any unused portion of the remaining PROTONIX I.V. solution. 6. Infuse intravenously over a period of approximately 15 minutes through a dedicated line or through a Y-site [see Dosage and Administration (2.5) ] . 7. Flush the intravenous line before and after administration of PROTONIX I.V. with either 5% Dextrose Injection or 0.9% Sodium Chloride Injection. Storage • Store the reconstituted solution may be stored for up to 24 hours at room temperature up to 30°C (86°F) prior to intravenous infusion. • Do not freeze the reconstituted solution. 2-Minute Intravenous Injection for Adult Patients 1. Reconstitute each vial of PROTONIX I.V. with 10 mL of 0.9% Sodium Chloride Injection, to a final concentration of approximately 4 mg/mL. 2. Withdraw the dose of 40 mg of reconstituted PROTONIX I.V. solution. 3. Inspect the diluted PROTONIX I.V. solution visually for particulate matter and discoloration prior to and during administration. 4. Administer intravenously over a period of at least 2 minutes. 5. Flush the intravenous line before and after administration of PROTONIX I.V. with either 5% Dextrose Injection or 0.9% Sodium Chloride Injection. Storage • Store the reconstituted solution may be up to 6 hours at room temperature up to 30°C (86°F) prior to further dilution. • Store the diluted solution at room temperature up to 30°C (86°F) and must be used within 24 hours from the time of initial reconstitution. • Do not freeze the reconstituted or diluted solution. 2.4 Preparation and Administration Instructions for Pathological Hypersecretion Including Zollinger-Ellison Syndrome 15-Minute Intravenous Infusion 1. Reconstitute each vial of PROTONIX I.V. with 10 mL of 0.9% Sodium Chloride Injection. 2. Combine the contents of the two vials and dilute with 80 mL of 5% Dextrose Injection or Sodium Chloride Injection to a total volume of 100 mL with a final concentration of approximately 0.8 mg/mL. 3. Inspect the diluted PROTONIX I.V. solution visually for particulate matter and discoloration prior to and during administration. 4. Administer intravenously over a period of approximately 15 minutes at a rate of approximately 7 mL/min. 5. Flush the intravenous line before and after administration of PROTONIX I.V. with either 5% Dextrose Injection or 0.9% Sodium Chloride Injection. Storage • The reconstituted solution can be stored at room temperature up to 30°C (86°F) for up to 6 hours prior to further dilution. • Once further diluted, the diluted solution can be stored at room temperature up to 30°C (86°F) for up to 24 hours from the time of initial reconstitution. • Do not freeze the reconstituted or diluted solution. 2-Minute Intravenous Injection 1. Reconstitute each vial of PROTONIX I.V. with 10 mL of 0.9% Sodium Chloride Injection, per vial to a final concentration of approximately 4 mg/mL. 2. Inspect the diluted PROTONIX I.V. solution visually for particulate matter and discoloration prior to and during administration. 3. Administer the total volume from both vials intravenously over a period of at least 2 minutes. 4. Flush the intravenous line before and after administration of PROTONIX I.V. with either 5% Dextrose Injection or 0.9% Sodium Chloride Injection. Storage • The reconstituted solution may be stored for up to 24 hours at room temperature. • Do not freeze the reconstituted solution. 2.5 Compatibility Information • Administer PROTONIX I.V. intraven

WARNINGS AND PRECAUTIONS Gastric Malignancy : In adults, symptomatic response to therapy with pantoprazole sodium does not preclude the presence of gastric malignancy. Consider additional follow-up and diagnostic testing. ( 5.1 ) Injection Site Reactions : Thrombophlebitis is associated with the administration of intravenous pantoprazole sodium. Assess the patient and remove the catheter if clinically indicated. ( 5.2 ) Potential Exacerbation of Zinc Deficiency : Consider zinc supplementation in patients who are prone to zinc deficiency. Caution should be used when other EDTA containing products are also co-administered intravenously. ( 5.3 ) Acute Tubulointerstitial Nephritis : Discontinue treatment and evaluate patients. ( 5.4 ) Clostridioides difficile -Associated Diarrhea : PPI therapy may be associated with increased risk. ( 5.5 ) Bone Fracture : Long-term and multiple daily dose PPI therapy may be associated with an increased risk for osteoporosis-related fractures of the hip, wrist, or spine. ( 5.6 ) 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. ( 5.7 ) Cutaneous and Systemic Lupus Erythematosus : Mostly cutaneous; new onset or exacerbation of existing disease; discontinue treatment and refer to specialist for evaluation. ( 5.8 ) Hepatic Effects : Elevations of transaminases observed. ( 5.9 ) Hypomagnesemia and Mineral Metabolism : Reported rarely with prolonged treatment with PPIs. ( 5.10 ) Fundic Gland Polyp s : Risk increases with long-term use, especially beyond one year. Use the shortest duration of therapy. ( 5.11 ) 5.1 Presence of Gastric Malignancy In adults, symptomatic response to therapy with pantoprazole sodium does not preclude the presence of gastric malignancy. Consider additional follow-up and diagnostic testing in adult patients who have a suboptimal response or an early symptomatic relapse after completing treatment with a PPI. In older patients, also consider an endoscopy. 5.2 Injection Site Reactions Thrombophlebitis was associated with the administration of pantoprazole sodium. Assess the patient and remove the catheter if clinically indicated. 5.3 Potential for Exacerbation of Zinc Deficiency Pantoprazole sodium for injection contains edetate disodium (the salt form of EDTA), a chelator of metal ions including zinc. Therefore, zinc supplementation should be considered in patients treated with pantoprazole sodium for injection who are prone to zinc deficiency. Caution should be used when other EDTA containing products are also co-administered intravenously [see Dosage and Administration (2.5) ] . 5.4 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 pantoprazole sodium and evaluate patients with suspected acute TIN [see Contraindications (4) ] . 5.5 Clostridioides difficile -Associated Diarrhea Published observational studies suggest that PPI therapy like pantoprazole sodium may be associated with an increased risk of Clostridioides difficile associated diarrhea, especially in hospitalized patients. This diagnosis should be considered for diarrhea that does not improve [see Adverse Reactions (6.2) ]. Patients should use the lowest dose and shortest duration of PPI therapy appropriate to the condition being treated. 5.6 Bone Fracture Several published observational studies suggest that 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 (2.2 , 2.4 ) and Adverse Reactions (6) ] . 5.7 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 pantoprazole sodium at the first signs or symptoms of severe cutaneous adverse reactions or other signs of hypersensitivity and consider further evaluation. 5.8 Cutaneous and Systemic Lupus Erythematosus Cutaneous lupus erythematosus (CLE) and systemic lupus erythematosus (SLE) have been reported in patients taking PPIs, including pantoprazole sodium. These events have occurred as both new onset and an exacerbation of existing autoimmune disease. The majority of PPI-induced lupus erythematous cases were CLE. The most common form of CLE reported in patients treated with PPIs was subacute CLE (SCLE) and occurred within weeks to years after continuous drug therapy in patients ranging from infants to the elderly. Generally, histological findings were observed without organ involvement. Systemic lupus erythematosus (SLE) is less commonly reported than CLE in patients receiving PPIs. PPI associated SLE is usually milder than non-drug induced SLE. Onset of SLE typically occurred within days to years after initiating treatment primarily in patients ranging from young adults to the elderly. The majority of patients presented with rash; however, arthralgia and cytopenia were also reported. Avoid administration of PPIs for longer than medically indicated. If signs or symptoms consistent with CLE or SLE are noted in patients receiving pantoprazole sodium, discontinue the drug and refer the patient to the appropriate specialist for evaluation. Most patients improve with discontinuation of the PPI alone in 4 to 12 weeks. Serological testing (e.g., ANA) may be positive and elevated serological test results may take longer to resolve than clinical manifestations. 5.9 Hepatic Effects Mild, transient transaminase elevations have been observed in clinical studies. The clinical significance of this finding in a large population of subjects administered pantoprazole sodium is unknown [see Adverse Reactions (6) ]. 5.10 Hypomagnesemia and Mineral Metabolism Hypomagnesemia, symptomatic and asymptomatic, has been reported rarely in patients treated with PPIs for at least three months, and in most cases after a year of therapy. Serious adverse events include tetany, arrhythmias, and seizures. Hypomagnesemia may lead to hypocalcemia and/or hypokalemia and may exacerbate underlying hypocalcemia in at-risk patients. In most patients, treatment of hypomagnesemia required magnesium replacement and discontinuation of the PPI. For patients expected to be on prolonged treatment or who take PPIs with medications such as digoxin or drugs that may cause hypomagnesemia (e.g., diuretics), health care professionals may consider monitoring magnesium levels prior to initiation of PPI treatment and periodically [see Adverse Reactions (6.2) ]. Consider monitoring magnesium and calcium levels prior to initiation of pantoprazole sodium and periodically while on treatment in patients with a preexisting risk of hypocalcemia (e.g., hypoparathyroidism). Supplement with magnesium and/or calcium as necessary. If hypocalcemia is refractory to treatment, consider discontinuing the PPI. 5.11 Fundic Gland Polyps PPI use is associated with an increased risk of fun

CONTRAINDICATIONS Pantoprazole sodium for delayed-release oral suspension 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 pantoprazole sodium for delayed-release oral suspension, 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 )

CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Pantoprazole is a PPI that suppresses the final step in gastric acid production by covalently binding to the (H+, K+)-ATPase enzyme system at the secretory surface of the gastric parietal cell. This effect leads to inhibition of both basal and stimulated gastric acid secretion, irrespective of the stimulus. The binding to the (H+, K+)-ATPase results in a duration of antisecretory effect that persists longer than 24 hours for all doses tested (20 mg to 120 mg). 12.2 Pharmacodynamics Antisecretory Activity Under maximal acid stimulatory conditions using pentagastrin, a dose-dependent decrease in gastric acid output occurs after a single dose of oral (20-80 mg) pantoprazole in healthy subjects. Pantoprazole given once daily results in increasing inhibition of gastric acid secretion. Following the initial oral dose of 40 mg pantoprazole, a 51% mean inhibition was achieved by 2.5 hours. With once-a-day dosing for 7 days, the mean inhibition was increased to 85%. Pantoprazole suppressed acid secretion in excess of 95% in half of the subjects. Acid secretion had returned to normal within a week after the last dose of pantoprazole; there was no evidence of rebound hypersecretion. In a series of dose-response studies, pantoprazole, at oral doses ranging from 20 to 120 mg, caused dose-related increases in median basal gastric pH and in the percent of time gastric pH was > 3 and > 4. Treatment with 40 mg of pantoprazole produced significantly greater increases in gastric pH than the 20 mg dose. Doses higher than 40 mg (60, 80, 120 mg) did not result in further significant increases in median gastric pH. The effects of pantoprazole on median pH from one double-blind crossover study are shown in Table 5. Table 5: Effect of Single Daily Doses of Oral Pantoprazole on Intragastric pH Median pH on day 7 Time Placebo 20 mg 40 mg 80 mg 8 a.m. - 8 a.m. (24 hours) 1.3 2.9 Significantly different from placebo 3.8 * Significantly different from 20 mg 3.9 *† 8 a.m. - 10 p.m. (Daytime) 1.6 3.2 * 4.4 *† 4.8 *† 10 p.m. - 8 a.m. (Nighttime) 1.2 2.1 * 3.0 * 2.6 * Serum Gastrin Effects Fasting serum gastrin levels were assessed in two double-blind studies of the acute healing of EE in which 682 patients with gastroesophageal reflux disease (GERD) received 10, 20, or 40 mg of Pantoprazole for up to 8 weeks. At 4 weeks of treatment there was an increase in mean gastrin levels of 7%, 35%, and 72% over pretreatment values in the 10, 20, and 40 mg treatment groups, respectively. A similar increase in serum gastrin levels was noted at the 8-week visit with mean increases of 3%, 26%, and 84% for the three pantoprazole dose groups. Median serum gastrin levels remained within normal limits during maintenance therapy with Pantoprazole Sodium Delayed-Release Tablets. In long-term international studies involving over 800 patients, a 2- to 3-fold mean increase from the pretreatment fasting serum gastrin level was observed in the initial months of treatment with pantoprazole at doses of 40 mg per day during GERD maintenance studies and 40 mg or higher per day in patients with refractory GERD. Fasting serum gastrin levels generally remained at approximately 2 to 3 times baseline for up to 4 years of periodic follow-up in clinical trials. Following short-term treatment with Pantoprazole, elevated gastrin levels return to normal by at least 3 months. Enterochromaffin-Like (ECL) Cell Effects In 39 patients treated with oral pantoprazole 40 mg to 240 mg daily (majority receiving 40 mg to 80 mg) for up to 5 years, there was a moderate increase in ECL-cell density, starting after the first year of use, which appeared to plateau after 4 years. In a nonclinical study in Sprague-Dawley rats, lifetime exposure (24 months) to pantoprazole at doses of 0.5 to 200 mg/kg/day resulted in dose-related increases in gastric ECL-cell proliferation and gastric neuroendocrine (NE)-cell tumors. Gastric NE-cell tumors in rats may result from chronic elevation of serum gastrin concentrations. The high density of ECL cells in the rat stomach makes this species highly susceptible to the proliferative effects of elevated gastrin concentrations produced by PPIs. However, there were no observed elevations in serum gastrin following the administration of pantoprazole at a dose of 0.5 mg/kg/day. In a separate study, a gastric NE-cell tumor without concomitant ECL-cell proliferative changes was observed in 1 female rat following 12 months of dosing with pantoprazole at 5 mg/kg/day and a 9 month off-dose recovery [see Nonclinical Toxicology ( 13.1 )] . Endocrine Effects In a clinical pharmacology study, Pantoprazole 40 mg given once daily for 2 weeks had no effect on the levels of the following hormones: cortisol, testosterone, triiodothyronine (T 3 ), thyroxine (T 4 ), 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 T 3 , T 4 , and TSH. 12.3 Pharmacokinetics Pantoprazole Sodium Delayed-Release Tablets are prepared as enteric-coated tablets so that absorption of pantoprazole begins only after the tablet leaves the stomach. Peak serum concentration (C max ) and area under the serum concentration time curve (AUC) increase in a manner proportional to oral doses from 10 mg to 80 mg. Pantoprazole does not accumulate, and its pharmacokinetics are unaltered with multiple daily dosing. Following oral administration, the serum concentration of pantoprazole declines biexponentially, with a terminal elimination half-life of approximately one hour. In extensive metabolizers with normal liver function receiving an oral dose of the enteric-coated 40 mg pantoprazole tablet, the peak concentration (C max ) is 2.5 mcg/mL; the time to reach the peak concentration (t max ) is 2.5 h, and the mean total area under the plasma concentration versus time curve (AUC) is 4.8 mcg∙h/mL (range 1.4 to 13.3 mcg∙h/mL). Absorption After administration of a single or multiple oral 40 mg doses of Pantoprazole Sodium Delayed-Release Tablets, the peak plasma concentration of pantoprazole was achieved in approximately 2.5 hours, and C max was 2.5 mcg/mL. Pantoprazole undergoes little first-pass metabolism, resulting in an absolute bioavailability of approximately 77%. Pantoprazole absorption is not affected by concomitant administration of antacids. Administration of Pantoprazole Sodium Delayed-Release Tablets with food may delay its absorption up to 2 hours or longer; however, the C max and the extent of pantoprazole absorption (AUC) are not altered. Thus, Pantoprazole Sodium Delayed-Release Tablets may be taken without regard to timing of meals. Distribution The apparent volume of distribution of pantoprazole is approximately 11 to 23.6 L, distributing mainly in extracellular fluid. The serum protein binding of pantoprazole is about 98%, primarily to albumin. Elimination Metabolism Pantoprazole is extensively metabolized in the liver through the cytochrome P450 (CYP) system. Pantoprazole metabolism is independent of the route of administration (oral). The main metabolic pathway is demethylation, by CYP2C19, with subsequent sulfation; other metabolic pathways include oxidation by CYP3A4. There is no evidence that any of the pantoprazole metabolites have significant pharmacologic activity. Excretion After a single oral dose of 14 C-labeled pantoprazole to healthy, normal metabolizer subjects, approximately 71% of the dose was excreted in the urine, with 18% excreted in the feces through biliary excretion. There was no renal excretion of unchanged pantoprazole. Specific Populations Geriatric Patients Only slight to moderate increases in the AUC (43%) and C max (26%) of pantoprazole were found in elderly subjects (64 to 76 years of age