PANTOPRAZOLE SODIUM- pantoprazole sodium_injection, powder, for solution

Pantoprazole is a PPI that suppresses the final step in gastric acid production by covalently binding to the (H + + + + Antisecretory Activity The magnitude and time course for inhibition of pentagastrin-stimulated acid output (PSAO) by single doses (20 to 120 mg) of pantoprazole sodium for injection were assessed in a single-dose, open-label, placebo-controlled, dose-response study. The results of this study are shown in Table 4 Table 4: Gastric Acid Output (mEq/hr, Mean +/- SD) and Percent Inhibition Compared to individual subject baseline prior to treatment with pantoprazole sodium for injection Inhibition of gastric acid output and the percent inhibition of stimulated acid output in response to pantoprazole sodium for injection may be higher after repeated doses. ------2 hours------ ------4 hours------ ------12 hours------ ------24 hours------ Treatment Dose Acid Output % Inhibition Acid Output % Inhibition Acid Output % Inhibition Acid Output % Inhibition NA = not applicable. 0 mg 39 +/- 21 NA 26 +/- 14 NA 32 +/- 20 NA 38 +/- 24 NA 20 mg 13 +/- 18 47 +/- 27 6 +/- 8 83 +/- 21 20 +/- 20 54 +/- 44 30 +/- 23 45 +/- 43 40 mg 5 +/- 5 82 +/- 11 4 +/- 4 90 +/- 11 11 +/- 10 81 +/- 13 16 +/- 12 52 +/- 36 80 mg 0. 2 96 +/- 6 0. 4 99 +/- 1 2 +/- 2 90 +/- 7 7 +/- 4 63 +/- 18 In one study of gastric pH in healthy subjects, pantoprazole sodium was administered orally (40 mg enteric coated tablets) or pantoprazole sodium for injection (40 mg) once daily for 5 days and pH was measured for 24 hours following the fifth dose. The outcome measure was median percent of time that pH was >=4 and the results were similar for intravenous and oral medications; however, the clinical significance of this parameter is unknown. Serum Gastrin Effects Serum gastrin concentrations were assessed in two placebo-controlled studies. In a 5-day study of oral pantoprazole with 40 and 60 mg doses in healthy subjects, following the last dose on day 5, median 24-hour serum gastrin concentrations were elevated by 3-to 4-fold compared to placebo in both 40 and 60 mg dose groups. However, by 24 hours following the last dose, median serum gastrin concentrations for both groups returned to normal levels. In another placebo-controlled, 7-day study of 40 mg intravenous or oral pantoprazole in patients with GERD and a history of EE, the mean serum gastrin concentration increased approximately 50% from baseline and as compared with placebo, but remained within the normal range. During 6 days of repeated administration of pantoprazole sodium for injection in patients with ZE Syndrome, consistent changes of serum gastrin concentrations from baseline were not observed. Enterochromaffin-Like (ECL) Cell Effects There are no data available on the effects of intravenous pantoprazole sodium on ECL cells. In a nonclinical study in Sprague-Dawley rats, lifetime exposure (24 months) to oral 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 oral 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 oral 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 orally once daily for 2 weeks had no effect on the levels of the following hormones: cortisol, testosterone, triiodothyronine (T 3 4 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 4 Pantoprazole peak serum concentration (C max [see Clinical Pharmacology (12. 5) max 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 (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 (e. , 3% of Whites and African-Americans and 17 to 23% of Asians). Although these sub-populations of slow pantoprazole metabolizers have elimination half-life values from 3. 5 to 10 hours, they still have minimal accumulation (23% or less) with once daily dosing. Excretion After administration of a single intravenous dose of 14 Specific Populations Geriatric Patients After repeated intravenous administration in elderly subjects (65 to 76 years of age), the AUC and elimination half-life values of pantoprazole were similar to those observed in younger subjects. Pediatric Patients The pharmacokinetics of pantoprazole were studied in 40 pediatric patients 1 to less than 16 years of age in three open-label clinical trials in pediatric patients with GERD following intravenous administration and 180 pediatric patients from birth to 16 years of age in four randomized, open-label clinical studies in pediatric patients with GERD following oral administration. Population PK analyses predicted the following dosage regimens would achieve comparable steady-state plasma exposures (AUC0-24) to those observed in adult patients administered 40 mg of pantoprazole sodium for injection once daily: 0. 8 mg/kg once daily for pediatric patients 3 months to less than 1 year, 10 mg once daily for pediatric patients 1 year to 17 years with body weight less than 15 kg, 20 mg once daily for pediatric patients 1 year to 17 years with body weight greater than 15 kg but less than 40 kg, and 40 mg once daily for pediatric patients 1 year to 17 years with body weight of 40 kg and greater. The pharmacokinetics of pantoprazole following intravenous administration in pediatric patients less than 3 months of age have not been characterized. Male and Female Patients After oral administration there was a modest increase in the AUC and C max Patients with Renal Impairment In patients with severe renal impairment, pharmacokinetic parameters for pantoprazole were similar to those of healthy subjects. Patients with Hepatic Impairment In patients with mild to severe hepatic impairment (Child-Pugh Class A to C), maximum pantoprazole concentrations increased only slightly (1. 5-fold) relative to healthy subjects when pantoprazole sodium was administered orally. Although serum half-life values increased to 7 to 9 hours and AUC values increased by 5- to 7-fold in hepatic-impaired patients, these increases were no greater than those observed in CYP2C19 poor metabolizers, where no dosage adjustment is warranted. These pharmacokinetic changes in hepatic-impaired patients result in minimal drug accumulation following once-daily, multiple-dose administration. Oral pantoprazole doses higher than 40 mg per day have not been studied in hepatically impaired patients. Drug Interaction Studies Effect of Other Drugs on Pantoprazole Pantoprazole is metabolized mainly by CYP2C19 and to minor extents by CYPs 3A4, 2D6 and 2C9. In in vivo Effect of Pantoprazole on Other Drugs Clopidogrel Clopidogrel is metabolized to its active metabolite in part by CYP2C19. In a crossover clinical study, 66 healthy subjects were administered clopidogrel (300 mg loading dose followed by 75 mg per day) alone and with oral pantoprazole (80 mg at the same time as clopidogrel) for 5 days. On Day 5, the mean AUC of the active metabolite of clopidogrel was reduced by approximately 14% (geometric mean ratio was 86%, with 90% CI of 79 to 93%) when pantoprazole sodium was coadministered with clopidogrel as compared to clopidogrel administered alone. Pharmacodynamic parameters were also measured and demonstrated that the change in inhibition of platelet aggregation (induced by 5 micromolar ADP) was correlated with the change in the exposure to clopidogrel active metabolite. The clinical significance of this finding is not clear. Mycophenolate Mofetil (MMF) Administration of oral pantoprazole 40 mg twice daily for 4 days and a single 1000 mg dose of MMF approximately one hour after the last dose of pantoprazole to 12 healthy subjects in a cross-over study resulted in a 57% reduction in the C max max [see Drug Interactions (7) Other Drugs In vivo in vivo 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. Antacids There was also no interaction with concomitantly administered antacids. CYP2C19 displays a known genetic polymorphism due to its deficiency in some subpopulations (e. , approximately 3% of Whites 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.

Pantoprazole Sodium is indicated for treatment of: gastroesophageal reflux disease (GERD) and a history of erosive esophagitis (EE) for up to 10 days in adults and up to 7 days in pediatric patients 3 months and older. pathological hypersecretory conditions including Zollinger-Ellison (ZE) Syndrome in adults. Limitations of Use The safety and effectiveness of pantoprazole sodium for the treatment of upper gastrointestinal bleeding have not been established in adult or pediatric patients. Pantoprazole sodium is a proton pump inhibitor (PPI) indicated for treatment of : 1 1 Limitations of Use The safety and effectiveness of pantoprazole sodium for the treatment of upper gastrointestinal bleeding have not been established in adult or pediatric patients.

GERD and a History of EE Adults: 2. 1 Pediatrics 3 Months of Age and Older: 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. 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 2. 1 Pathological Hypersecretion Conditions, Including ZE Syndrome 2. 2 Preparation and Administration Instructions 2. 4 Adult Patients The recommended adult dosage of pantoprazole sodium for injection 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 pantoprazole sodium for injection as soon as the patient is able to tolerate oral treatment. Switch to an appropriate oral medication within 10 days of starting pantoprazole sodium for injection. 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 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 pantoprazole sodium for injection as soon as the patient is able to tolerate oral treatment. Switch to an appropriate oral medication within 7 days of starting pantoprazole sodium for injection. 15-Minute Intravenous Infusion for Pediatric or Adult Patients 1. Reconstitute each vial of pantoprazole sodium for injection with 10 mL of 0. 9% Sodium Chloride Injection, USP. 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. 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. [see Dosage and Administration (2. Storage 2- Minute Intravenous Injection for Adult Patients 1. Storage Fifteen Minute Intravenous Infusion 1. Storage Two Minute Intravenous Injection 1. Storage o o [see Warnings and Precautions (5.

The following serious adverse reactions are described below and elsewhere in labeling: [see Warnings and Precautions (5. 2) ] [see Warnings and Precautions (5. 3) ] [see Warnings and Precautions (5. 4) ] Clostridioides difficile- [see Warnings and Precautions (5. 5) ] [see Warnings and Precautions (5. 6) ] [see Warnings and Precautions (5. 7) ] [see Warnings and Precautions (5. 8) [see Warnings and Precautions (5. 9) [see Warnings and Precautions (5. 10) [see Warnings and Precautions (5. 11) Most common adverse reactions (>2%) are: headache, diarrhea, nausea, abdominal pain, vomiting, flatulence, dizziness, and arthralgia. 1 To report SUSPECTED ADVERSE REACTIONS, contact Fresenius Kabi USA, LLC at 1-800-551-7176 or FDA at 1-800-FDA-1088 or www. gov/medwatch. 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. Gastroesophageal Reflux Disease (GERD) Adults Safety in nine randomized comparative US clinical trials in patients with GERD included 1,473 patients on oral pantoprazole (20 mg or 40 mg), 299 patients on an H 2 Table 2. The number of patients treated in comparative studies with pantoprazole sodium for injection is limited; however, the adverse reactions seen were similar to those seen in the oral studies. Thrombophlebitis was the only new adverse reaction identified with pantoprazole sodium for injection. Table 2: Adverse Reactions Reported in Clinical Trials of Adult Patients with GERD at a Frequency of >2% Oral Pantoprazole Sodium (n=1473) % Comparators (n=345) % Placebo (n=82) % Headache 12. 5 Diarrhea 8. 9 Nausea 7 5. 8 Abdominal pain 6. 1 Vomiting 4. 4 Flatulence 3. 7 Dizziness 3 2. 2 Arthralgia 2. 2 Additional adverse reactions that were reported for oral pantoprazole sodium in US clinical trials with a frequency of <=2% are listed below by body system: Body as a Whole: Gastrointestinal: Hematologic: Metabolic/Nutritional: Musculoskeletal: Nervous: Skin and Appendages: Special Senses: Pediatrics Adverse reactions reported with single and multiple doses of pantoprazole sodium for injection in 18 hospitalized pediatric patients 1 to 16 years of age were generally similar to those reported in adults treated with intravenous or oral pantoprazole sodium and in pediatric patients treated with oral pantoprazole sodium in clinical trials. Additionally, upper respiratory tract infections in pediatric patients less than 16 years of age and otitis media in pediatric patients less than 1 year of age were reported with oral pantoprazole sodium. Zollinger-Ellison (ZE) Syndrome In clinical studies of ZE Syndrome, adverse reactions reported in 35 patients administered pantoprazole sodium for injection doses of 80 mg to 240 mg per day for up to 2 years were similar to those reported in adult patients with GERD. The following adverse reactions have been identified during post approval use of pantoprazole sodium products. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. These adverse reactions are listed below by body system: General disorders and administration conditions: Immune system disorders: Investigations: Skin and subcutaneous tissue disorders: Musculoskeletal disorders: Renal and genitourinary disorders: Hepatobiliary disorders: Psychiatric disorder: Metabolism and nutritional disorders: Infections and infestations: Clostridioides difficile Hematologic: Nervous: Gastrointestinal disorders:.

[see Warnings and Precautions (5. 4) and Adverse Reactions (6) [see Drug Interactions (7) 4 4 7.

Pregnancy: Based on animal data, may cause fetal harm. 1 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 sodium. Reproduction studies have been performed in rats at intravenous doses up to 20 mg/kg/day (4 times the recommended human dose) and rabbits at intravenous doses up to 15 mg/kg/day (6 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 post-natal 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 [see Use in Specific Populations (8. 4) 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. 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. 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. 45] and for spontaneous abortions OR=1. 29 [95% CI 0. Animal Data Reproduction studies have been performed in rats at intravenous pantoprazole doses up to 20 mg/kg/day (4 times the recommended human dose based on body surface area) and rabbits at intravenous doses up to 15 mg/kg/day (6 times the recommended human dose based on body surface area) with administration of pantoprazole sodium during organogenesis in pregnant animals and have revealed no evidence of impaired fertility or harm to the fetus due to pantoprazole. A pre- and post-natal 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. 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. Risk Summary The limited data from a single case report the presence of pantoprazole in human breast milk. There were no effects on the breastfed infant (see Data). The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for pantoprazole sodium for injection and any potential adverse effects on the breastfed child from pantoprazole or from the underlying maternal condition. Data The breast milk of a 42-year-old woman receiving 40 mg of oral pantoprazole, at 10 months postpartum, was studied for 24 hours, to demonstrate low levels of pantoprazole present in the breast milk. Pantoprazole was detectable in milk only 2 and 4 hours after the dose with milk levels of approximately 36 mcg/L and 24 mcg/L, respectively. A milk-to-plasma ratio of 0. 022 was observed at 2 hours after drug administration. Pantoprazole was not detectable (<10 mcg/L) in milk at 6, 8 and 24 hours after the dose. The relative dose to the infant was estimated to be 7. 3 mcg of pantoprazole, which is equivalent to 0. 14% of the weight-adjusted maternal dose. No adverse events in the infant were reported by the mother. The safety and effectiveness of pantoprazole sodium for injection for the treatment of GERD and a history of EE for up to 7 days have been established in pediatric patients 3 months of age and older. Use of pantoprazole sodium for injection for this indication is supported by evidence from adequate and well-controlled studies of intravenous and oral pantoprazole sodium in adults and oral pantoprazole sodium in pediatric patients, with additional pharmacokinetic and safety data of intravenous pantoprazole in pediatric patients 1 year of age and older and oral pantoprazole in pediatric patients 3 months of age and older. Adverse reactions were generally similar to those reported in adults with intravenous or oral pantoprazole sodium [see Adverse Reactions (6. 1) and Clinical Pharmacology (12. 3) ] The safety and effectiveness of pantoprazole sodium for injection have not been established in patients less than 3 months of age for the treatment of GERD and a history of EE. The safety and effectiveness of pantoprazole sodium for injection have not been established in pediatric patients for the treatment of pathological hypersecretory conditions including ZE syndrome. Animal Toxicity Data In neonatal/juvenile animals (rats and dogs) toxicities were similar to those observed in adult animals, including gastric alterations, decreases in red cell mass, increases in lipids, enzyme induction and hepatocellular hypertrophy. An increased incidence of eosinophilic chief cells in adult and neonatal/juvenile rats, and atrophy of chief cells in adult rats and in neonatal/juvenile dogs, was observed in the fundic mucosa of stomachs in repeated-dose studies. Full to partial recovery of these effects were noted in animals of both age groups following a recovery period. Of 286 patients in clinical studies of intravenous pantoprazole sodium in patients with GERD and a history of EE, 86 (43%) were 65 years of age and over. No overall differences in safety or effectiveness were observed between these geriatric and younger adult patients, and other reported clinical experience with oral pantoprazole sodium has not identified differences in responses between the geriatric and younger adult patients, but greater sensitivity of some older individuals cannot be ruled out. No clinically meaningful differences in the pharmacokinetics of pantoprazole were observed in geriatric subjects compared to younger adult subjects [see Clinical Pharmacology (12.

Table 3 Consult the labeling of concomitantly used drugs to obtain further information about interactions with PPIs. Table 3: Clinically Relevant Interactions Affecting Drugs Co-Administered with Pantoprazole Sodium for Injection and Interaction with Diagnostics Antiretrovirals Clinical Impact . Intervention Rilpivirine-containing products: [see Contraindications (4) Atazanavir: Nelfinavir: Saquinavir: Other antiretrovirals: 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 for injection 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. 14) Intervention A temporary withdrawal of pantoprazole sodium for injection may be considered in some patients receiving high-dose methotrexate. Drugs Dependent on Gastric pH for Absorption (e. , 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) 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 diagnostic investigations for neuroendocrine tumors [see Warnings and Precautions (5. 12) and Clinical Pharmacology (12. 2) ] Intervention Temporarily stop pantoprazole sodium for injection treatment at least 14 days before assessing CgA levels and consider repeating the test if initial CgA levels are high. If serial tests are performed (e. for monitoring), the same commercial laboratory should be used for testing, as reference ranges between tests may vary. False Positive Urine Tests for THC Clinical Impact There have been reports of false positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving PPIs [see Warnings and Precautions (5. 13) Intervention An alternative confirmatory method should be considered to verify positive results. See the full prescribing information for a list of clinically important drug interactions.

OVERDOSAGE
Experience in patients taking very high doses of pantoprazole (greater than 240 mg) is limited. Adverse reactions seen in spontaneous reports of overdose generally reflect the known safety profile of pantoprazole. Pantoprazole is not removed by hemodialysis. In case of overdose, treatment should be symptomatic and supportive. Single intravenous doses of pantoprazole at 378, 230, and 266 mg/kg (38, 46, and 177 times the recommended human dose based on body surface area) 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.
NONCLINICAL TOXICOLOGY
In a 24-month carcinogenicity study, Sprague-Dawley rats were treated orally with pantoprazole 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 with 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 with 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 with 50 mg/kg/day and benign polyps and adenocarcinomas of the gastric fundus with 200 mg/kg/day. In the liver, treatment with 0.5 to 200 mg/kg/day produced dose-related increases in the incidences of hepatocellular adenomas and carcinomas. In the thyroid gland, treatment with 200 mg/kg/day produced increased incidences of follicular cell adenomas and carcinomas for both male and female rats. In a 24-month carcinogenicity study, Fischer 344 rats were treated orally with pantoprazole 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 with 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 pantoprazole 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 with 150 mg/kg/day produced increased incidences of hepatocellular adenomas and carcinomas in female mice. Treatment with 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 in vitro in vivo in vitro in vitro in vitro in vitro in vivo There were no effects on fertility or reproductive performance when pantoprazole was given at oral doses up to 500 mg/kg/day in male rats (98 times the recommended human dose based on body surface area) and 450 mg/kg/day in female rats (88 times the recommended human dose based on body surface area).
CLINICAL STUDIES
A multicenter, double-blind, two-period placebo-controlled study was conducted to assess the ability of pantoprazole sodium for injection to maintain gastric acid suppression in patients switched from pantoprazole sodium delayed-release tablets to pantoprazole sodium for injection GERD patients (n=65, 26 to 64 years; 35 female; 9 Black, 11 Hispanic, 44 White, 1 other) with a history of EE were randomized to receive either 20 or 40 mg of oral pantoprazole once per day for 10 days (period 1), and then were switched in period 2 to either daily pantoprazole sodium for injection or placebo for 7 days, matching their respective dose level from period 1. Patients were administered all test medication with a light meal. Maximum acid output (MAO) and basal acid output (BAO) were determined 24 hours following the last day of oral medication (day 10), the first day (day 1) of intravenous administration and the last day of intravenous administration (day 7). MAO was estimated from a 1 hour continuous collection of gastric contents following subcutaneous injection of 6 mcg/kg of pentagastrin. This study demonstrated that, after 10 days of repeated oral administration followed by 7 days of intravenous administration, the oral and intravenous dosage forms of pantoprazole sodium 40 mg are similar in their ability to suppress MAO and BAO in patients with GERD and a history of EE (see Table 5 Table 5 Table 5 Table 5: Antisecretory Effects (mEq/h) of 40 mg Pantoprazole Sodium for Injection and 40 mg Pantoprazole Sodium Delayed-Release Tablets in GERD Patients with a History of EE Parameter Pantoprazole Sodium Delayed-Release Tablets DAY 10 Pantoprazole Sodium for Injection DAY 7 Intravenous Placebo DAY 7 Mean maximum acid output 6. 0001 Significantly different from pantoprazole sodium for injection Mean basal acid output 0. 14 To evaluate the effectiveness of pantoprazole sodium for injection as an initial treatment to suppress gastric acid secretion, two studies were conducted. Study 1 was a multicenter, double-blind, placebo-controlled, study of the pharmacodynamic effects of pantoprazole sodium for injection and pantoprazole sodium delayed-release tablets. Patients with GERD and a history of EE (n=78, 20 to 67 years; 39 females; 7 Black, 19 Hispanic, 52 White) were randomized to receive either 40 mg pantoprazole sodium for injection, 40 mg pantoprazole sodium delayed-release tablets, or placebo once daily for 7 days. Following an overnight fast, test medication was administered and patients were given a light meal within 15 minutes. MAO and BAO were determined 24 hours following the last day of study medication. MAO was estimated from a 1 hour continuous collection of gastric contents following subcutaneous injection of 6 mcg/kg of pentagastrin to stimulate acid secretion. This study demonstrated that, after treatment for 7 days, patients treated with pantoprazole sodium for injection had a significantly lower MAO and BAO than those treated with placebo (p<0. 001), and results were comparable to those of patients treated with pantoprazole sodium delayed-release tablets (see Table 6 Table 6: Antisecretory Effects (mEq/h) of Initial Treatment with 40 mg Pantoprazole Sodium for Injection and 40 mg Pantoprazole Delayed-Release Tablets in GERD Patients with a History of EE Parameter Pantoprazole Sodium for Injection DAY 7 Pantoprazole Sodium Delayed-Release Tablets DAY 7 Placebo DAY 7 Maximum acid output 8. 001 Significantly different from pantoprazole sodium for injection Basal acid output 0. 0 Study 2 was a single-center, double-blind, parallel-group study to compare the clinical effects of pantoprazole sodium for injection and pantoprazole sodium delayed-release tablets. Patients (n=45, median age 56 years, 21 males and 24 females) with acute endoscopically proven reflux esophagitis (Savary/Miller Stage II or III) with at least 1 of 3 symptoms typical for reflux esophagitis (acid eructation, heartburn, or pain on swallowing) were randomized to receive either 40 mg pantoprazole sodium for injection or 40 mg pantoprazole sodium delayed-release tablets once daily for 5 days. After the initial 5 days, all patients were treated with 40 mg oral pantoprazole daily to complete a total of 8 weeks of treatment. Symptom relief was assessed by calculating the daily mean of the sums of the average scores for these 3 symptoms and the daily mean of the average score for each of the symptoms separately. There was no significant difference in symptom relief between pantoprazole sodium for injection and pantoprazole sodium delayed-release tablets within the first 5 days. A repeat endoscopy after 8 weeks of treatment revealed that 20 out of 23 (87%) patients treated with pantoprazole sodium for injection plus pantoprazole sodium delayed-release tablets and 19 out of 22 (86%) of the patients treated with pantoprazole sodium delayed-release tablets had endoscopically proven healing of their esophageal lesions. Data comparing pantoprazole sodium for injection to other PPIs (oral or intravenous) or H 2 Two studies measured the pharmacodynamic effects of 6 day treatment with pantoprazole sodium for injection in patients with ZE Syndrome (with and without multiple endocrine neoplasia type I). In one of these studies, an initial treatment with pantoprazole sodium for injection in 21 patients (29 to 75 years; 8 female; 4 Black, 1 Hispanic, 16 White) reduced acid output to the target level (10 mEq/h or less) and significantly reduced H + In the other study of 14 patients (38 to 67 years; 5 female; 2 Black, 12 White) with ZE Syndrome, treatment was switched from an oral PPI to pantoprazole sodium for injection. Pantoprazole sodium for injection maintained or improved control of gastric acid secretion. In both studies, total doses of 160 or 240 mg per day of pantoprazole sodium for injection, administered in divided doses, maintained basal acid secretion below target levels in all patients. Target levels were 10 mEq/h in patients without prior gastric surgery, and 5 mEq/h in all patients with prior gastric acid-reducing surgery. Once gastric acid secretion was controlled, there was no evidence of tolerance during this 7 day study. Basal acid secretion was maintained below target levels for at least 24 hours in all patients and through the end of treatment in these studies (3 to 7 days) in all but 1 patient who required a dose adjustment guided by acid output measurements until acid control was achieved. In both studies, doses were adjusted to the individual patient need, but gastric acid secretion was controlled in greater than 80% of patients by a starting regimen of 80 mg every 12 hours.

Fresenius Kabi USA, LLC

PANTOPRAZOLE SODIUM- pantoprazole sodium_injection, powder, for solution Product manual source documgent