PANTOPRAZOLE SODIUM- pantoprazole sodium_tablet, delayed release

Pantoprazole is a proton pump inhibitor (PPI) that suppresses the final step in gastric acid production by covalently binding to the (H + + + + Pantoprazole sodium for delayed-release oral suspension, 40 mg has been shown to be comparable to pantoprazole sodium delayed-release tablets in suppressing pentagastrin-stimulated MAO in patients (n = 49) with GERD and a history of EE. In this multicenter, pharmacodynamic crossover study, a 40 mg oral dose of pantoprazole sodium for delayed-release oral suspension administered in a teaspoonful of applesauce was compared with a 40 mg oral dose of pantoprazole sodium delayed-release tablets after administration of each formulation once daily for 7 days. Both medications were administered 30 minutes before breakfast. Pentagastrin-stimulated (MAO) was assessed from hour 23 to 24 at steady-state. Under maximal acid stimulatory conditions using pentagastrin, a dose dependent decrease in gastric acid output occurs after a single dose of oral (20 mg to 80 mg) or a single dose of intravenous (20 mg to 120 mg) pantoprazole in healthy volunteers. Pantoprazole given once daily results in increasing inhibition of gastric acid secretion. Following the initial oral dose of 40 mg pantoprazole, a 51% mean inhibition was achieved by 2. 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 mg 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 mg, 80 mg, 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 4. Table 4: 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. 9 Significantly different from placebo 3. 8 Significantly different from 20 mg 3. 6 Fasting serum gastrin levels were assessed in two double-blind studies of the acute healing of erosive esophagitis (EE) in which 682 patients with gastroesophageal reflux disease (GERD) received 10 mg, 20 mg, 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 mg, 20 mg, 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. In 39 patients treated with oral pantoprazole 40 mg to 240 mg daily (majority receiving 40 mg to 80 mg) for up to 5 years, there was a moderate increase in ECL-cell density, starting after the first year of use, which appeared to plateau after 4 years. In a nonclinical study in Sprague-Dawley rats, lifetime exposure (24 months) to pantoprazole at doses of 0. 5 to 200 mg/kg/day resulted in dose-related increases in gastric ECL cell proliferation and gastric neuroendocrine (NE)-cell tumors. Gastric NE-cell tumors in rats may result from chronic elevation of serum gastrin concentrations. The high density of ECL cells in the rat stomach makes this species highly susceptible to the proliferative effects of elevated gastrin concentrations produced by proton pump inhibitors. However, there were no observed elevations in serum gastrin following the administration of pantoprazole at a dose of 0. 5 mg/kg/day. In a separate study, a gastric NE-cell tumor without concomitant ECL-cell proliferative changes was observed in one 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) 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 In extensive metabolizers with normal liver function receiving an oral dose of the enteric-coated 40 mg pantoprazole tablet, the peak concentration (C max max 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 Administration of pantoprazole sodium delayed-release tablets with food may delay its absorption up to 2 hours or longer; however, the C max The apparent volume of distribution of pantoprazole is approximately 11 L to 23. 6 L, distributing mainly in extracellular fluid. The serum protein binding of pantoprazole is about 98%, primarily to albumin. 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. After a single oral or intravenous dose of 14 Only slight to moderate increases in pantoprazole AUC (43%) and C max The pharmacokinetics of pantoprazole were studied in children less than 16 years of age in four randomized, open-label clinical trials in pediatric patients with presumed/proven GERD. A pediatric granule formulation was studied in children through 5 years of age, and pantoprazole sodium delayed-release tablets were studied in children older than 5 years. In a population PK analysis, total clearance increased with increasing bodyweight in a non-linear fashion. The total clearance also increased with increasing age only in children under 3 years of age. See Use in Specific Populations (8. 4) The pharmacokinetics of pantoprazole sodium delayed-release tablets were evaluated in children ages 6 through 16 years with a clinical diagnosis of GERD. The PK parameters following a single oral dose of 20 mg or 40 mg of pantoprazole sodium delayed-release tablets in children ages 6 through 16 years were highly variable (%CV ranges 40% to 80%). The geometric mean AUC estimated from population PK analysis after a 40 mg pantoprazole sodium delayed-release tablet in pediatric patients was about 39% and 10% higher respectively in 6 to 11 and 12 to 16 year-old children, compared to that of adults (Table 5). Table 5: PK Parameters in Children and Adolescents 6 Through 16 Years with GERD Receiving 40 mg Pantoprazole Sodium Delayed-release Tablets 6 to 11 Years (n = 12) 12 to 16 Years (n = 11) C max Geometric mean values 1. 8 t max Median values 2 2 AUC (mugh/mL) 6. 5 CL/F (L/h) 6. 8 There is a modest increase in pantoprazole AUC and C max In patients with severe renal impairment, pharmacokinetic parameters for pantoprazole were similar to those of healthy subjects. No dosage adjustment is necessary in patients with renal impairment or in patients undergoing hemodialysis. In patients with mild to severe hepatic impairment (Child-Pugh A to C cirrhosis), maximum pantoprazole concentrations increased only slightly (1. 5-fold) relative to healthy subjects. 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. No dosage adjustment is needed in patients with mild to severe hepatic impairment. Doses higher than 40 mg/day have not been studied in hepatically impaired patients. Pantoprazole is metabolized mainly by CYP2C19 and to minor extents by CYPs 3A4, 2D6, and 2C9. In in vivo 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 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 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 muM ADP) was correlated with the change in the exposure to clopidogrel active metabolite. The clinical significance of this finding is not clear. Administration of 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 crossover study resulted in a 57% reduction in the C max max In vivo in vivo Based on studies evaluating possible interactions of pantoprazole with other drugs, no dosage adjustment is needed with concomitant use of the following: theophylline, cisapride, antipyrine, caffeine, carbamazepine, diazepam (and its active metabolite, desmethyldiazepam), diclofenac, naproxen, piroxicam, digoxin, ethanol, glyburide, an oral contraceptive (levonorgestrel/ethinyl estradiol), metoprolol, nifedipine, phenytoin, warfarin, midazolam, clarithromycin, metronidazole, or amoxicillin. There was also no interaction with concomitantly administered antacids. There have been post-marketing reports of increased INR and prothrombin time in patients receiving proton pump inhibitors, including pantoprazole, and warfarin concomitantly [see Drug Interactions (7. 2) 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. 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 4 In a one-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, CYP2C19 displays a known genetic polymorphism due to its deficiency in some subpopulations (e. , 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%) 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.

Pantoprazole sodium delayed-release tablets, USP are indicated for: Pantoprazole sodium delayed-release tablets, USP are a proton pump inhibitor indicated for the following: 1. 3 Pantoprazole sodium delayed-release tablets 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 may be considered. Safety of treatment beyond 8 weeks in pediatric patients has not been established. Pantoprazole sodium delayed-release tablets 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. Pantoprazole sodium delayed-release tablets are indicated for the long-term treatment of pathological hypersecretory conditions, including Zollinger-Ellison syndrome.

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. Pantoprazole sodium is 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 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. 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. Directions for method of administration for the delayed-release tablet dosage form are presented in Table 2. Table 2: Administration Instructions Formulation Route Instructions Patients should be cautioned that pantoprazole sodium delayed-release tablets should not be split, chewed, or crushed. Delayed-release Tablets Oral Swallowed whole, with or without food Pantoprazole sodium delayed-release tablets should be swallowed whole, with or without food in the stomach. If patients are unable to swallow a 40 mg tablet, two 20 mg tablets may be taken. Concomitant administration of antacids does not affect the absorption of pantoprazole sodium delayed-release tablets.

The most frequently occurring adverse reactions are as follows: 6 6 To report SUSPECTED ADVERSE REACTIONS, contact Mylan Pharmaceuticals Inc. at 1-877-446-3679 (1-877-4-INFO-RX) 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. Safety in nine randomized comparative U. 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 3: Adverse Reactions Reported in Clinical Trials of Adult Patients with GERD at a Frequency of > 2% Pantoprazole (n = 1,473) % 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 pantoprazole in 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: Safety of pantoprazole in the treatment of Erosive Esophagitis (EE) associated with GERD was evaluated in pediatric patients ages one 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 are considered relevant to pediatric patients. In patients ages one 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 one year of age see Use in Specific Populations (8. 4) Additional adverse reactions that were reported for pantoprazole in pediatric patients in clinical trials with a frequency of <= 4% are listed below by body system: Body as a Whole: Gastrointestinal: Metabolic/Nutritional: Musculoskeletal: Nervous: Skin and Appendages: The following adverse reactions seen in adults in clinical trials were not reported in pediatric patients in clinical trials, but are considered relevant to pediatric patients: photosensitivity reaction, dry mouth, hepatitis, thrombocytopenia, generalized edema, depression, pruritus, leukopenia, and blurred vision. In clinical studies of Zollinger-Ellison Syndrome, adverse reactions reported in 35 patients taking pantoprazole 80 mg/day to 240 mg/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. 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: Hematologic: Hepatobiliary Disorders: Immune System Disorders: Infections and Infestations: Investigations: Metabolism and Nutritional Disorders: Musculoskeletal Disorders: Nervous: Psychiatric Disorders: Renal and Urinary Disorders: Skin and Subcutaneous Tissue Disorders:.

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 interstitial nephritis, and urticaria [see Adverse Reactions (6) Known hypersensitivity to any component of the formulation or to substituted benzimidazoles.

Reproduction studies have been performed in rats at oral doses up to 88 times the recommended human dose and in rabbits at oral doses up to 16 times the recommended human dose and have revealed no evidence of impaired fertility or harm to the fetus due to pantoprazole. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed [see Nonclinical Toxicology (13. 2) Pantoprazole and its metabolites are excreted in the milk of rats. Pantoprazole excretion in human milk has been detected in a study of a single nursing mother after a single 40 mg oral dose. The clinical relevance of this finding is not known. Many drugs which are excreted in human milk have a potential for serious adverse reactions in nursing infants. Based on the potential for tumorigenicity shown for pantoprazole in rodent carcinogenicity studies, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the benefit of the drug to the mother. The safety and effectiveness of pantoprazole for short-term treatment (up to 8 weeks) of erosive esophagitis (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 one 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 is indicated for the short-term treatment of EE associated with GERD for patients 5 years and older. The safety and effectiveness of pantoprazole for pediatric uses other than EE have not been established. Use of pantoprazole in pediatric patients 1 year through 16 years of age for short-term treatment (up to 8 weeks) of EE associated with GERD is supported by: a) extrapolation of results from adequate and well-controlled studies that supported the approval of pantoprazole for treatment of EE associated with GERD in adults, and b) safety, effectiveness, and pharmacokinetic studies performed in pediatric patients [see Clinical Studies (14. 1) Clinical Pharmacology (12. 3) Safety of pantoprazole in the treatment of EE associated with GERD in pediatric patients 1 through 16 years of age was evaluated in three multicenter, randomized, double-blind, parallel-treatment studies, involving 249 pediatric patients, including eight with EE (four patients ages 1 year to 5 years and four patients 5 years to 11 years). The children ages 1 year to 5 years with endoscopically diagnosed EE (defined as an endoscopic Hetzel-Dent score >= 2) were treated once daily for 8 weeks with one of two dose levels of pantoprazole (approximating 0. 6 mg/kg or 1. All four of these patients with EE were healed (Hetzel-Dent score of 0 or 1) at 8 weeks. Because EE is uncommon in the pediatric population, predominantly pediatric patients with endoscopically-proven or symptomatic GERD were also included in these studies. Patients were treated with a range of doses of pantoprazole once daily for 8 weeks. For safety findings see Adverse Reactions (6. 1) Although the data from the clinical trials support use of pantoprazole for the short-term treatment of EE associated with GERD in pediatric patients 1 year through 5 years, there is no commercially available dosage formulation appropriate for patients less than 5 years of age [see Dosage and Administration (2) In a population pharmacokinetic analysis, clearance values in the children 1 to 5 years old with endoscopically proven GERD had a median value of 2. Following a 1. 2 mg/kg equivalent dose (15 mg for <= 12. 5 kg and 20 mg for > 12. 5 to < 25 kg), the plasma concentrations of pantoprazole were highly variable and the median time to peak plasma concentration was 3 to 6 hours. The estimated AUC for patients 1 to 5 years old was 37% higher than for adults receiving a single 40 mg tablet, with a geometric mean AUC value of 6. 8 mughr/mL. Pantoprazole was not found to be effective in a multicenter, randomized, double-blind, placebo-controlled, treatment-withdrawal study of 129 pediatric patients 1 through 11 months of age. Patients were enrolled if they had symptomatic GERD based on medical history and had not responded to non-pharmacologic interventions for GERD for 2 weeks. Patients received pantoprazole daily for 4 weeks in an open-label phase, then patients were randomized in equal proportion to receive pantoprazole treatment or placebo for the subsequent 4 weeks in a double-blind manner. Efficacy was assessed by observing the time from randomization to study discontinuation due to symptom worsening during the 4-week treatment-withdrawal phase. There was no statistically significant difference between pantoprazole and placebo in the rate of discontinuation. In this trial, the adverse reactions that were reported more commonly (difference of >= 4%) in the treated population compared to the placebo population were elevated CK, otitis media, rhinitis, and laryngitis. In a population pharmacokinetic analysis, the systemic exposure was higher in patients less than one year of age with GERD compared to adults who received a single 40 mg dose (geometric mean AUC was 103% higher in preterm infants and neonates receiving single dose of 2. 5 mg of pantoprazole, and 23% higher in infants 1 through 11 months of age receiving a single dose of approximately 1. In these patients, the apparent clearance (CL/F) increased with age (median clearance: 0. 6 L/hr, range: 0. These doses resulted in pharmacodynamic effects on gastric but not esophageal pH. Following once daily dosing of 2. 5 mg of pantoprazole in preterm infants and neonates, there was an increase in the mean gastric pH (from 4. 3 at baseline to 5. 2 at steady-state) and in the mean % time that gastric pH was > 4 (from 60% at baseline to 80% at steady-state). Following once daily dosing of approximately 1. 2 mg/kg of pantoprazole in infants 1 through 11 months of age, there was an increase in the mean gastric pH (from 3. 1 at baseline to 4. 2 at steady-state) and in the mean % time that gastric pH was > 4 (from 32% at baseline to 60% at steady-state). However, no significant changes were observed in mean intraesophageal pH or % time that esophageal pH was < 4 in either age group. Because pantoprazole was not shown to be effective in the randomized, placebo-controlled study in this age group, the use of pantoprazole for treatment of symptomatic GERD in infants less than 1 year of age is not indicated. In short-term U. clinical trials, erosive esophagitis healing rates in the 107 elderly patients (>= 65 years old) treated with pantoprazole were similar to those found in patients under the age of 65. The incidence rates of adverse reactions and laboratory abnormalities in patients aged 65 years and older were similar to those associated with patients younger than 65 years of age. Erosive esophagitis healing rates in the 221 women treated with pantoprazole sodium delayed-release tablets in U. clinical trials were similar to those found in men. In the 122 women treated long-term with pantoprazole 40 mg or 20 mg, healing was maintained at a rate similar to that in men. The incidence rates of adverse reactions were also similar for men and women. Doses higher than 40 mg/day have not been studied in patients with hepatic impairment [see Clinical Pharmacology (12.

DRUG INTERACTIONS
6 Concomitant use of atazanavir or nelfinavir with proton pump inhibitors is not recommended. Coadministration of atazanavir or nelfinavir with proton pump inhibitors is expected to substantially decrease atazanavir or nelfinavir plasma concentrations and may result in a loss of therapeutic effect and development of drug resistance. There have been post-marketing reports of increased INR and prothrombin time in patients receiving proton pump inhibitors, including pantoprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Patients treated with proton pump inhibitors and warfarin concomitantly should be monitored for increases in INR and prothrombin time. Concomitant 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) Due to its effects on gastric acid secretion, pantoprazole can reduce the absorption of drugs where gastric pH is an important determinant of their bioavailability. Like with other drugs that decrease the intragastric acidity, the absorption of drugs such as ketoconazole, ampicillin esters, atazanavir, iron salts, erlotinib, and mycophenolate mofetil (MMF) can decrease. Coadministration of pantoprazole 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. The clinical relevance of reduced MPA exposure on organ rejection has not been established in transplant patients receiving pantoprazole and MMF. Use pantoprazole with caution in transplant patients receiving MMF [see Clinical Pharmacology (12. 3) There have been reports of false positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving proton pump inhibitors. An alternative confirmatory method should be considered to verify positive results. Case reports, published population pharmacokinetic studies, and retrospective analyses suggest that concomitant administration of PPIs and methotrexate (primarily at high dose; see methotrexate prescribing information) may elevate and prolong serum levels of methotrexate and/or its metabolite hydroxymethotrexate. However, no formal drug interaction studies of methotrexate with PPIs have been conducted [see Warnings and Precautions (5.
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 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 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 muM 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 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 crossover study resulted in a 57% reduction in the C max max In vivo in vivo Based on studies evaluating possible interactions of pantoprazole with other drugs, no dosage adjustment is needed with concomitant use of the following: theophylline, cisapride, antipyrine, caffeine, carbamazepine, diazepam (and its active metabolite, desmethyldiazepam), diclofenac, naproxen, piroxicam, digoxin, ethanol, glyburide, an oral contraceptive (levonorgestrel/ethinyl estradiol), metoprolol, nifedipine, phenytoin, warfarin, midazolam, clarithromycin, metronidazole, or amoxicillin. There was also no interaction with concomitantly administered antacids. There have been post-marketing reports of increased INR and prothrombin time in patients receiving proton pump inhibitors, including pantoprazole, and warfarin concomitantly [see Drug Interactions (7.2) 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.

OVERDOSAGE
Experience in patients taking very high doses of pantoprazole (> 240 mg) is limited. Spontaneous post-marketing reports of overdose are generally within the known safety profile of pantoprazole. 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.
NONCLINICAL TOXICOLOGY
In a 24-month carcinogenicity study, Sprague-Dawley rats were treated orally with doses of 0. 5 to 200 mg/kg/day, about 0. 1 to 40 times the exposure on a body surface area basis of a 50 kg person dosed at 40 mg/day. In the gastric fundus, treatment at 0. 5 to 200 mg/kg/day produced enterochromaffin-like (ECL) cell hyperplasia and benign and malignant neuroendocrine cell tumors in a dose-related manner. In the forestomach, treatment at 50 and 200 mg/kg/day (about 10 and 40 times the recommended human dose on a body surface area basis) produced benign squamous cell papillomas and malignant squamous cell carcinomas. Rare gastrointestinal tumors associated with pantoprazole treatment included an adenocarcinoma of the duodenum at 50 mg/kg/day and benign polyps and adenocarcinomas of the gastric fundus at 200 mg/kg/day. In the liver, treatment at 0. 5 to 200 mg/kg/day produced dose-related increases in the incidences of hepatocellular adenomas and carcinomas. In the thyroid gland, treatment at 200 mg/kg/day produced increased incidences of follicular cell adenomas and carcinomas for both male and female rats. In a 24-month carcinogenicity study, Fischer 344 rats were treated orally with doses of 5 to 50 mg/kg/day, approximately 1 to 10 times the recommended human dose based on body surface area. In the gastric fundus, treatment at 5 to 50 mg/kg/day produced enterochromaffin-like (ECL) cell hyperplasia and benign and malignant neuroendocrine cell tumors. Dose selection for this study may not have been adequate to comprehensively evaluate the carcinogenic potential of pantoprazole. In a 24-month carcinogenicity study, B6C3F1 mice were treated orally with doses of 5 to 150 mg/kg/day, 0. 5 to 15 times the recommended human dose based on body surface area. In the liver, treatment at 150 mg/kg/day produced increased incidences of hepatocellular adenomas and carcinomas in female mice. Treatment at 5 to 150 mg/kg/day also produced gastric-fundic ECL cell hyperplasia. A 26-week p53 +/- transgenic mouse carcinogenicity study was not positive. Pantoprazole was positive in the in vitro 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). Studies in neonatal/juvenile and adult rats and dogs were performed. The data from these studies revealed that animals in both age groups respond to pantoprazole in a similar manner. Gastric alterations, including increased stomach weights, 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, were observed in the fundic mucosa of stomachs in repeated-dose studies. Decreases in red cell mass parameters, increases in cholesterol and triglycerides, increased liver weight, enzyme induction, and hepatocellular hypertrophy were also seen in repeated-dose studies in rats and/or dogs. Full to partial recovery of these effects were noted in animals of both age groups following a recovery period. Reproduction studies have been performed in rats at oral doses up to 450 mg/kg/day (88 times the recommended human dose based on body surface area) and rabbits at oral doses up to 40 mg/kg/day (16 times the recommended human dose based on body surface area) and have revealed no evidence of impaired fertility or harm to the fetus due to pantoprazole.
CLINICAL STUDIES
Pantoprazole sodium delayed-release tablets were used in the following clinical trials. multicenter, double-blind, placebo-controlled study of pantoprazole 10 mg, 20 mg, or 40 mg once daily was conducted in 603 patients with reflux symptoms and endoscopically diagnosed EE of grade 2 or above (Hetzel-Dent scale). In this study, approximately 25% of enrolled patients had severe EE of grade 3, and 10% had grade 4. The percentages of patients healed (per protocol, n = 541) in this study are shown in Table 6. Table 6: Erosive Esophagitis Healing Rates (Per Protocol) Pantoprazole Placebo Week 10 mg daily (n = 153) 20 mg daily (n = 158) 40 mg daily (n = 162) (n = 68) 4 45. 001) pantoprazole vs. 10 mg or 20 mg pantoprazole 75% (p < 0. 10 mg pantoprazole 14. 3% 8 66% 83. 7% In this study, all pantoprazole treatment groups had significantly greater healing rates than the placebo group. This was true regardless of H. pylori A significantly greater proportion of patients taking pantoprazole 40 mg experienced complete relief of daytime and nighttime heartburn and the absence of regurgitation, starting from the first day of treatment, compared with placebo. Patients taking pantoprazole consumed significantly fewer antacid tablets per day than those taking placebo. Pantoprazole 40 mg and 20 mg once daily were also compared with nizatidine 150 mg twice daily in a U. multicenter, double-blind study of 243 patients with reflux symptoms and endoscopically diagnosed EE of grade 2 or above. The percentages of patients healed (per protocol, n = 212) are shown in Table 7. Table 7: Erosive Esophagitis Healing Rates (Per Protocol) Pantoprazole Nizatidine Week 20 mg daily (n = 72) 40 mg daily (n = 70) 150 mg twice daily (n = 70) 4 61. nizatidine 64% 22. 4% Once daily treatment with pantoprazole 40 mg or 20 mg resulted in significantly superior rates of healing at both 4 and 8 weeks compared with twice daily treatment with 150 mg of nizatidine. For the 40 mg treatment group, significantly greater healing rates compared to nizatidine were achieved regardless of the H. pylori A significantly greater proportion of the patients in the pantoprazole treatment groups experienced complete relief of nighttime heartburn and regurgitation, starting on the first day and of daytime heartburn on the second day, compared with those taking nizatidine 150 mg twice daily. Patients taking pantoprazole consumed significantly fewer antacid tablets per day than those taking nizatidine. The efficacy of pantoprazole in the treatment of EE associated with GERD in pediatric patients ages 5 years through 16 years is extrapolated from adequate and well-conducted trials in adults, as the pathophysiology is thought to be the same. Four pediatric patients with endoscopically diagnosed EE were studied in multicenter, randomized, double-blind, parallel-treatment trials. Children with endoscopically diagnosed EE (defined as an endoscopic Hetzel-Dent score >= 2) were treated once daily for 8 weeks with one of two dose levels of pantoprazole (20 mg or 40 mg). All four patients with EE were healed (Hetzel-Dent score of 0 or 1) at 8 weeks. Two independent, multicenter, randomized, double-blind, comparator-controlled trials of identical design were conducted in adult GERD patients with endoscopically confirmed healed erosive esophagitis to demonstrate efficacy of pantoprazole in long-term maintenance of healing. The two US studies enrolled 386 and 404 patients, respectively, to receive either 10 mg, 20 mg, or 40 mg of pantoprazole sodium delayed-release tablets once daily or 150 mg of ranitidine twice daily. As demonstrated in Table 8, pantoprazole 40 mg and 20 mg were significantly superior to ranitidine at every timepoint with respect to the maintenance of healing. In addition, pantoprazole 40 mg was superior to all other treatments studied. Table 8: Long-term Maintenance of Healing of Erosive Gastroesophageal Reflux Disease (GERD Maintenance): Percentage of Patients Who Remained Healed Pantoprazole 20 mg daily Pantoprazole 40 mg daily Ranitidine 150 mg twice daily Study 1 n = 75 n = 74 n = 75 Month 1 91 (p < 0. ranitidine) 99 68 Month 3 82 93 (p < 0. pantoprazole 20 mg) 54 Month 6 76 90 44 Month 12 70 86 35 Study 2 n = 74 n = 88 n = 84 Month 1 89 92 62 Month 3 78 91 47 Month 6 72 88 39 Month 12 72 83 37 Pantoprazole 40 mg was superior to ranitidine in reducing the number of daytime and nighttime heartburn episodes from the first through the twelfth month of treatment. Pantoprazole 20 mg, administered once daily, was also effective in reducing episodes of daytime and nighttime heartburn in one trial, as presented in Table 9. Table 9: Number of Episodes of Heartburn (Mean +/- SD) Pantoprazole 40 mg daily Ranitidine 150 mg twice daily Month 1 Daytime 5. ranitidine, combined data from the two U. studies) 18. 6 Nighttime 3. 1 Month 12 Daytime 2. 5 Nighttime 2. 3 In a multicenter, open-label trial of 35 patients with pathological hypersecretory conditions, such as Zollinger-Ellison syndrome, with or without multiple endocrine neoplasia-type I, pantoprazole successfully controlled gastric acid secretion. Doses ranging from 80 mg daily to 240 mg daily maintained gastric acid output below 10 mEq/h in patients without prior acid-reducing surgery and below 5 mEq/h in patients with prior acid-reducing surgery. Doses were initially titrated to the individual patient needs, and adjusted in some patients based on the clinical response with time [see Dosage and Administration (2).

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