receiving proton pump inhibitors, including pantoprazole sodium delayed-release tablets, 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. 7.3 clopidogrel 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) ] . no dose adjustment of clopidogrel is necessary when administered with an approved dose of pantoprazole sodium delayed-release tablets. 7.4 drugs for which gastric ph can affect bioavailability 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. co-administration 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 sodium delayed-release tablets and mmf. use pantoprazole sodium delayed-release tablets with caution in transplant patients receiving mmf [see clinical pharmacology (12.3) ]. 7.5 false positive urine tests for thc 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. 7.6 methotrexate 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 (5.10) ].

blished. 1.2 maintenance of healing of erosive esophagitis 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. 1.3 pathological hypersecretory conditions including zollinger-ellison syndrome pantoprazole sodium delayed-release tablets are indicated for the long-term treatment of pathological hypersecretory conditions, including zollinger-ellison syndrome.

gastric malignancy in adults, symptomatic response to therapy with pantoprazole sodium delayed-release tablets does not preclude the presence of gastric malignancy. consider additional follow-up and diagnostic testing in adult patients who have a suboptimal response or an early symptomatic relapse after completing treatment with a ppi. in older patients, also consider an endoscopy. 5.2 acute interstitial nephritis acute interstitial nephritis has been observed in patients taking ppis including pantoprazole sodium delayed-release tablets. acute interstitial nephritis may occur at any point during ppi therapy and is generally attributed to an idiopathic hypersensitivity reaction. discontinue pantoprazole sodium delayed-release tablets if acute interstitial nephritis develops [see contraindications (4) ]. 5.3 clostridium difficile -associated diarrhea published observational studies suggest that ppi therapy like pantoprazole sodium delayed-release tablets may be associated with an increased risk of clostridium difficile associated diarrhea, especially in hospitalized patients. this diagnosis should be considered for diarrhea that does not improve [see adverse reactions (6.2) ] . patients should use the lowest dose and shortest duration of ppi therapy appropriate to the condition being treated. 5.4 bone fracture several published observational studies suggest that proton pump inhibitor (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) and adverse reactions (6.2) ] . 5.5 cutaneous and systemic lupus erythematosus cutaneous lupus erythematosus (cle) and systemic lupus erythematosus (sle) have been reported in patients taking ppis, including pantoprazole. 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 delayed-release tablets, 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. 5.6 cyanocobalamin (vitamin b-12) deficiency generally, daily treatment with any acid-suppressing medications over a long period of time (e.g., longer than 3 years) may lead to malabsorption of cyanocobalamin (vitamin b-12) caused by hypo- or achlorhydria. rare reports of cyanocobalamin deficiency occurring with acid-suppressing therapy have been reported in the literature. this diagnosis should be considered if clinical symptoms consistent with cyanocobalamin deficiency are observed. 5.7 hypomagnesemia hypomagnesemia, symptomatic and asymptomatic, has been reported rarely in patients treated with ppis for at least three months, in most cases after a year of therapy. serious adverse events include tetany, arrhythmias, and seizures. 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)] . 5.8 tumorigenicity due to the chronic nature of gerd, there may be a potential for prolonged administration of pantoprazole sodium delayed-release tablets. in long-term rodent studies, pantoprazole was carcinogenic and caused rare types of gastrointestinal tumors. the relevance of these findings to tumor development in humans is unknown [see nonclinical toxicology (13.1) ] . 5.9 interference with urine screen for thc see drug interactions (7.5) . 5.10 concomitant use of pantoprazole sodium delayed-release tablets with methotrexate literature suggests that concomitant use of ppis with methotrexate (primarily at high dose; see methotrexate prescribing information) may elevate and prolong serum levels of methotrexate and/or its metabolite, possibly leading to methotrexate toxicities. in high-dose methotrexate administration, a temporary withdrawal of the ppi may be considered in some patients [see drug interactions (7.6) ] .

sted to individual patient needs and should continue for as long as clinically indicated. doses up to 240 mg daily have been administered. *** controlled studies did not extend beyond 12 months indication dose frequency short-term treatment of erosive esophagitis associated with gerd adults 40 mg once daily for up to 8 weeks* children (5 years and older) ≥ 15 kg to < 40 kg 20 mg once daily for up to 8 weeks ≥ 40 kg 40 mg maintenance of healing of erosive esophagitis adults 40 mg once daily*** pathological hypersecretory conditions including zollinger-ellison syndrome adults 40 mg twice daily** 2.2 administration instructions directions for method of administration of pantoprazole sodium delayed-release tablets are presented in table 2. table 2: administration instructions * patients should be cautioned that pantoprazole sodium delayed-release tablets should not be split, chewed, or crushed. formulation route instructions* 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.

for pantoprazole sodium for delayed-release oral suspension and pantoprazole sodium delayed-release tablets are similar. because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. adults safety in nine randomized comparative u.s. clinical trials in patients with gerd included 1,473 patients on oral pantoprazole sodium delayed-release tablets (20 mg or 40 mg), 299 patients on an h 2 -receptor antagonist, 46 patients on another proton pump inhibitor, and 82 patients on placebo. the most frequently occurring adverse reactions are listed in table 3. table 3: adverse reactions reported in clinical trials of adult patients with gerd at a frequency of > 2% pantoprazole sodium delayed-release tablets (n=1473) % comparators (n=345) % placebo (n=82) % headache 12.2 12.8 8.5 diarrhea 8.8 9.6 4.9 nausea 7 5.2 9.8 abdominal pain 6.2 4.1 6.1 vomiting 4.3 3.5 2.4 flatulence 3.9 2.9 3.7 dizziness 3 2.9 1.2 arthralgia 2.8 1.4 1.2 additional adverse reactions that were reported for pantoprazole sodium delayed-release tablets in clinical trials with a frequency of ≤ 2% are listed below by body system: body as a whole: allergic reaction, pyrexia, photosensitivity reaction, facial edema gastrointestinal: constipation, dry mouth, hepatitis hematologic: leukopenia, thrombocytopenia metabolic/nutritional: elevated ck (creatine kinase), generalized edema, elevated triglycerides, liver enzymes elevated musculoskeletal: myalgia nervous: depression, vertigo skin and appendages: urticaria, rash, pruritus special senses: blurred vision pediatric patients safety of pantoprazole sodium delayed-release tablets in the treatment of erosive esophagitis (ee) associated with gerd was evaluated in pediatric patients ages 1 year through 16 years in three clinical trials. safety trials involved pediatric patients with ee; however, as ee is uncommon in the pediatric population, 249 pediatric patients with endoscopically-proven or symptomatic gerd were also evaluated. all adult adverse reactions to pantoprazole sodium delayed-release tablets are considered relevant to pediatric patients. in patients ages 1 year through 16 years, the most commonly reported (> 4%) adverse reactions include: uri, headache, fever, diarrhea, vomiting, rash, and abdominal pain. for safety information in patients less than 1 year of age see use in specific populations (8.4) . additional adverse reactions that were reported for pantoprazole sodium delayed-release tablets in pediatric patients in clinical trials with a frequency of ≤ 4% are listed below by body system: body as a whole: allergic reaction, facial edema gastrointestinal: constipation, flatulence, nausea metabolic/nutritional: elevated triglycerides, elevated liver enzymes, elevated ck (creatine kinase) musculoskeletal: arthralgia, myalgia nervous: dizziness, vertigo skin and appendages: urticaria 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. zollinger-ellison syndrome in clinical studies of zollinger-ellison syndrome, adverse reactions reported in 35 patients taking pantoprazole sodium delayed-release tablets 80 mg/day to 240 mg/day for up to 2 years were similar to those reported in adult patients with gerd. 6.2 postmarketing experience the following adverse reactions have been identified during postapproval use of pantoprazole sodium delayed-release tablets. 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: asthenia, fatigue, malaise hematologic: pancytopenia, agranulocytosis hepatobiliary disorders: hepatocellular damage leading to jaundice and hepatic failure immune system disorders: anaphylaxis (including anaphylactic shock), systemic lupus erythematosus infections and infestations : clostridium difficile associated diarrhea investigations: weight changes metabolism and nutritional disorders: hyponatremia, hypomagnesemia musculoskeletal disorders: rhabdomyolysis, bone fracture nervous: ageusia, dysgeusia psychiatric disorders: hallucination, confusion, insomnia, somnolence renal and urinary disorders: interstitial nephritis skin and subcutaneous tissue disorders: severe dermatologic reactions (some fatal), including erythema multiforme, stevens-johnson syndrome, toxic epidermal necrolysis (ten, some fatal), angioedema (quincke’s edema) and cutaneous lupus erythematosus

receiving proton pump inhibitors, including pantoprazole sodium delayed-release tablets, 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. 7.3 clopidogrel 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) ] . no dose adjustment of clopidogrel is necessary when administered with an approved dose of pantoprazole sodium delayed-release tablets. 7.4 drugs for which gastric ph can affect bioavailability 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. co-administration 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 sodium delayed-release tablets and mmf. use pantoprazole sodium delayed-release tablets with caution in transplant patients receiving mmf [see clinical pharmacology (12.3) ]. 7.5 false positive urine tests for thc 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. 7.6 methotrexate 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 (5.10) ].

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. 8.4 pediatric use the safety and effectiveness of pantoprazole sodium delayed-release tablets for short-term treatment (up to eight 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 1 year of age. in addition, for patients less than 5 years of age, there is no appropriate dosage strength in an age-appropriate formulation available. therefore, pantoprazole sodium delayed-release tablets are indicated for the short-term treatment of ee associated with gerd for patients 5 years and older. the safety and effectiveness of pantoprazole sodium delayed-release tablets for pediatric uses other than ee have not been established. 1 year through 16 years of age use of pantoprazole sodium delayed-release tablets in pediatric patients 1 year through 16 years of age for short-term treatment (up to eight 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 sodium delayed-release tablets 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) , and clinical pharmacology (12.3) ]. safety of pantoprazole sodium delayed-release tablets 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 8 with ee (4 patients ages 1 year to 5 years and 4 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 sodium delayed-release tablets (approximating 0.6 mg/kg or 1.2 mg/kg). all 4 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 sodium delayed-release tablets once daily for 8 weeks. for safety findings see adverse reactions (6.1) . because these pediatric trials had no placebo, active comparator, or evidence of a dose response, the trials were inconclusive regarding the clinical benefit of pantoprazole sodium delayed-release tablets for symptomatic gerd in the pediatric population. the effectiveness of pantoprazole sodium delayed-release tablets for treating symptomatic gerd in pediatric patients has not been established. although the data from the clinical trials support use of pantoprazole sodium delayed-release tablets 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 2.4 l/h. 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 mcg•hr/ml. neonates to less than one year of age pantoprazole sodium delayed-release tablets were 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 two weeks. patients received pantoprazole sodium delayed-release tablets daily for four weeks in an open-label phase, then patients were randomized in equal proportion to receive pantoprazole sodium delayed-release tablets treatment or placebo for the subsequent four weeks in a double-blind manner. efficacy was assessed by observing the time from randomization to study discontinuation due to symptom worsening during the four-week treatment-withdrawal phase. there was no statistically significant difference between pantoprazole sodium delayed-release tablets 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 1 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 sodium delayed-release tablets, and 23% higher in infants 1 through 11 months of age receiving a single dose of approximately 1.2 mg/kg). in these patients, the apparent clearance (cl/f) increased with age (median clearance: 0.6 l/hr, range: 0.03 to 3.2 l/hr). these doses resulted in pharmacodynamic effects on gastric but not esophageal ph. following once daily dosing of 2.5 mg of pantoprazole sodium delayed-release tablets 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 sodium delayed-release tablets 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 sodium delayed-release tablets were not shown to be effective in the randomized, placebo-controlled study in this age group, the use of pantoprazole sodium delayed-release tablets for treatment of symptomatic gerd in infants less than 1 year of age is not indicated. 8.5 geriatric use in short-term u.s. clinical trials, erosive esophagitis healing rates in the 107 elderly patients (≥ 65 years old) treated with pantoprazole sodium delayed-release tablets 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. 8.6 gender erosive esophagitis healing rates in the 221 women treated with pantoprazole sodium delayed-release tablets in u.s. clinical trials were similar to those found in men. in the 122 women treated long-term with pantoprazole sodium delayed-release tablets 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. 8.7 patients with hepatic impairment doses higher than 40 mg/day have not been studied in patients with hepatic impairment [see clinical pharmacology (12.3) ] .

: a) extrapolation of results from adequate and well-controlled studies that supported the approval of pantoprazole sodium delayed-release tablets 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) , and clinical pharmacology (12.3) ]. safety of pantoprazole sodium delayed-release tablets 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 8 with ee (4 patients ages 1 year to 5 years and 4 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 sodium delayed-release tablets (approximating 0.6 mg/kg or 1.2 mg/kg). all 4 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 sodium delayed-release tablets once daily for 8 weeks. for safety findings see adverse reactions (6.1) . because these pediatric trials had no placebo, active comparator, or evidence of a dose response, the trials were inconclusive regarding the clinical benefit of pantoprazole sodium delayed-release tablets for symptomatic gerd in the pediatric population. the effectiveness of pantoprazole sodium delayed-release tablets for treating symptomatic gerd in pediatric patients has not been established. although the data from the clinical trials support use of pantoprazole sodium delayed-release tablets 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 2.4 l/h. 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 mcg•hr/ml. neonates to less than one year of age pantoprazole sodium delayed-release tablets were 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 two weeks. patients received pantoprazole sodium delayed-release tablets daily for four weeks in an open-label phase, then patients were randomized in equal proportion to receive pantoprazole sodium delayed-release tablets treatment or placebo for the subsequent four weeks in a double-blind manner. efficacy was assessed by observing the time from randomization to study discontinuation due to symptom worsening during the four-week treatment-withdrawal phase. there was no statistically significant difference between pantoprazole sodium delayed-release tablets 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 1 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 sodium delayed-release tablets, and 23% higher in infants 1 through 11 months of age receiving a single dose of approximately 1.2 mg/kg). in these patients, the apparent clearance (cl/f) increased with age (median clearance: 0.6 l/hr, range: 0.03 to 3.2 l/hr). these doses resulted in pharmacodynamic effects on gastric but not esophageal ph. following once daily dosing of 2.5 mg of pantoprazole sodium delayed-release tablets 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 sodium delayed-release tablets 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 sodium delayed-release tablets were not shown to be effective in the randomized, placebo-controlled study in this age group, the use of pantoprazole sodium delayed-release tablets for treatment of symptomatic gerd in infants less than 1 year of age is not indicated.

der maximal acid stimulatory conditions using pentagastrin, a dose-dependent decrease in gastric acid output occurs after a single dose of oral (20 to 80 mg) or a single dose of intravenous (20 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 2.5 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 4. table 4: effect of single daily doses of oral pantoprazole on intragastric ph * significantly different from placebo # significantly different from 20 mg time median ph on day 7 placebo 20 mg 40 mg 80 mg 8 a.m. to 8 a.m. (24 hours) 1.3 2.9* 3.8*# 3.9*# 8 a.m. to 10 p.m. (daytime) 1.6 3.2* 4.4*# 4.8*# 10 p.m. to 8 a.m. (nighttime) 1.2 2.1* 3* 2.6* serum gastrin effects 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, 20, or 40 mg of pantoprazole sodium 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 sodium delayed-release tablets, 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 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 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) ] . 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 and intravenous doses from 10 mg to 80 mg. pantoprazole does not accumulate, and its pharmacokinetics are unaltered with multiple daily dosing. following oral or intravenous 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). following intravenous administration of pantoprazole to extensive metabolizers, its total clearance is 7.6 to 14 l/h, and its apparent volume of distribution is 11 to 23.6 l. 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. 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. elimination after a single oral or intravenous dose of 14 c-labeled pantoprazole to healthy, normal metabolizer volunteers, 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. geriatric only slight to moderate increases in pantoprazole auc (43%) and c max (26%) were found in elderly volunteers (64 to 76 years of age) after repeated oral administration, compared with younger subjects. no dosage adjustment is recommended based on age. pediatric 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. 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. neonate through 5 years of age see use in specific populations (8.4) . children and adolescents 6 through 16 years of age 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 6). table 6: pk parameters in children and adolescents 6 through 16 years with gerd receiving 40 mg pantoprazole sodium delayed-release tablets a geometric mean values b median values 6 to 11 years (n=12) 12 to 16 years (n=11) c max (mcg/ml) a 1.8 1.8 t max (h) b 2 2 auc (mcg•h/ml) a 6.9 5.5 cl/f (l/h) b 6.6 6.8 gender there is a modest increase in pantoprazole auc and c max in women compared to men. however, weight-normalized clearance values are similar in women and men. no dosage adjustment is recommended based on gender. in pediatric patients ages 1 through 16 years there were no clinically relevant effects of gender on clearance of pantoprazole, as shown by population pharmacokinetic analysis. renal impairment 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. hepatic impairment 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. drug-drug interactions pantoprazole is metabolized mainly by cyp2c19 and to minor extents by cyps 3a4, 2d6, and 2c9. in in vivo drug-drug interaction studies with cyp2c19 substrates (diazepam [also a cyp3a4 substrate] and phenytoin [also a cyp3a4 inducer] and clopidogrel), nifedipine, midazolam, and clarithromycin (cyp3a4 substrates), metoprolol (a cyp2d6 substrate), diclofenac, naproxen and piroxicam (cyp2c9 substrates), and theophylline (a cyp1a2 substrate) in healthy subjects, the pharmacokinetics of pantoprazole were not significantly altered. 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 μm 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 cross-over study resulted in a 57% reduction in the c max and 27% reduction in the auc of mpa. transplant patients receiving approximately 2000 mg per day of mmf (n=12) were compared to transplant patients receiving approximately the same dose of mmf and pantoprazole 40 mg per day (n=21). there was a 78% reduction in the c max and a 45% reduction in the auc of mpa in patients receiving both pantoprazole and mmf. in vivo studies also suggest that pantoprazole does not significantly affect the kinetics of the following drugs (cisapride, theophylline, diazepam [and its active metabolite, desmethyldiazepam], phenytoin, warfarin, metoprolol, nifedipine, carbamazepine, midazolam, clarithromycin, naproxen, piroxicam, and oral contraceptives [levonorgestrel/ ethinyl estradiol]). dosage adjustment of these drugs is not necessary when they are coadministered with pantoprazole. in other in vivo studies, digoxin, ethanol, glyburide, antipyrine, caffeine, metronidazole, and amoxicillin had no clinically relevant interactions with pantoprazole. 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 postmarketing reports of increased inr and prothrombin time in patients receiving proton pump inhibitors, including pantoprazole sodium delayed-release tablets, 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. other effects in a clinical pharmacology study, pantoprazole sodium delayed-release tablets 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 sodium delayed-release tablets 40 mg or 20 mg, there were no changes from baseline in overall levels of t 3 , t 4 , and tsh. 12.4 pharmacogenomics cyp2c19 displays a known genetic polymorphism due to its deficiency in some subpopulations (e.g., approximately 3% of caucasians and african-americans and 17% to 23% of asians are poor metabolizers). although these subpopulations of pantoprazole poor metabolizers have elimination half-life values of 3.5 to 10 hours in adults, they still have minimal accumulation (≤ 23%) 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.

¢h/ml). following intravenous administration of pantoprazole to extensive metabolizers, its total clearance is 7.6 to 14 l/h, and its apparent volume of distribution is 11 to 23.6 l. 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. 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. elimination after a single oral or intravenous dose of 14 c-labeled pantoprazole to healthy, normal metabolizer volunteers, 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. geriatric only slight to moderate increases in pantoprazole auc (43%) and c max (26%) were found in elderly volunteers (64 to 76 years of age) after repeated oral administration, compared with younger subjects. no dosage adjustment is recommended based on age. pediatric 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. 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. neonate through 5 years of age see use in specific populations (8.4) . children and adolescents 6 through 16 years of age 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 6). table 6: pk parameters in children and adolescents 6 through 16 years with gerd receiving 40 mg pantoprazole sodium delayed-release tablets a geometric mean values b median values 6 to 11 years (n=12) 12 to 16 years (n=11) c max (mcg/ml) a 1.8 1.8 t max (h) b 2 2 auc (mcg•h/ml) a 6.9 5.5 cl/f (l/h) b 6.6 6.8 gender there is a modest increase in pantoprazole auc and c max in women compared to men. however, weight-normalized clearance values are similar in women and men. no dosage adjustment is recommended based on gender. in pediatric patients ages 1 through 16 years there were no clinically relevant effects of gender on clearance of pantoprazole, as shown by population pharmacokinetic analysis. renal impairment 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. hepatic impairment 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. drug-drug interactions pantoprazole is metabolized mainly by cyp2c19 and to minor extents by cyps 3a4, 2d6, and 2c9. in in vivo drug-drug interaction studies with cyp2c19 substrates (diazepam [also a cyp3a4 substrate] and phenytoin [also a cyp3a4 inducer] and clopidogrel), nifedipine, midazolam, and clarithromycin (cyp3a4 substrates), metoprolol (a cyp2d6 substrate), diclofenac, naproxen and piroxicam (cyp2c9 substrates), and theophylline (a cyp1a2 substrate) in healthy subjects, the pharmacokinetics of pantoprazole were not significantly altered. 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 μm 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 cross-over study resulted in a 57% reduction in the c max and 27% reduction in the auc of mpa. transplant patients receiving approximately 2000 mg per day of mmf (n=12) were compared to transplant patients receiving approximately the same dose of mmf and pantoprazole 40 mg per day (n=21). there was a 78% reduction in the c max and a 45% reduction in the auc of mpa in patients receiving both pantoprazole and mmf. in vivo studies also suggest that pantoprazole does not significantly affect the kinetics of the following drugs (cisapride, theophylline, diazepam [and its active metabolite, desmethyldiazepam], phenytoin, warfarin, metoprolol, nifedipine, carbamazepine, midazolam, clarithromycin, naproxen, piroxicam, and oral contraceptives [levonorgestrel/ ethinyl estradiol]). dosage adjustment of these drugs is not necessary when they are coadministered with pantoprazole. in other in vivo studies, digoxin, ethanol, glyburide, antipyrine, caffeine, metronidazole, and amoxicillin had no clinically relevant interactions with pantoprazole. 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 postmarketing reports of increased inr and prothrombin time in patients receiving proton pump inhibitors, including pantoprazole sodium delayed-release tablets, 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. other effects in a clinical pharmacology study, pantoprazole sodium delayed-release tablets 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 sodium delayed-release tablets 40 mg or 20 mg, there were no changes from baseline in overall levels of t 3 , t 4 , and tsh.

ences 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 human lymphocyte chromosomal aberration assays, in one of two mouse micronucleus tests for clastogenic effects, and in the in vitro chinese hamster ovarian cell/hgprt forward mutation assay for mutagenic effects. equivocal results were observed in the in vivo rat liver dna covalent binding assay. pantoprazole was negative in the in vitro ames mutation assay, the in vitro unscheduled dna synthesis (uds) assay with rat hepatocytes, the in vitro as52/gpt mammalian cell-forward gene mutation assay, the in vitro thymidine kinase mutation test with mouse lymphoma l5178y cells, and the in vivo rat bone marrow cell chromosomal aberration assay. 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). 13.2 animal toxicology and/or pharmacology 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. reproductive toxicology studies 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.

enomas 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 human lymphocyte chromosomal aberration assays, in one of two mouse micronucleus tests for clastogenic effects, and in the in vitro chinese hamster ovarian cell/hgprt forward mutation assay for mutagenic effects. equivocal results were observed in the in vivo rat liver dna covalent binding assay. pantoprazole was negative in the in vitro ames mutation assay, the in vitro unscheduled dna synthesis (uds) assay with rat hepatocytes, the in vitro as52/gpt mammalian cell-forward gene mutation assay, the in vitro thymidine kinase mutation test with mouse lymphoma l5178y cells, and the in vivo rat bone marrow cell chromosomal aberration assay. 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).

cebo (n = 68) 10 mg daily (n = 153) 20 mg daily (n = 158) 40 mg daily (n = 162) 4 45.6% + 58.4% + # 75% + * 14.3% 8 66% + 83.5% + # 92.6% + * 39.7% in this study, all pantoprazole sodium delayed-release tablets treatment groups had significantly greater healing rates than the placebo group. this was true regardless of h. pylori status for the 40 mg and 20 mg pantoprazole sodium delayed-release tablets treatment groups. the 40 mg dose of pantoprazole sodium delayed-release tablets resulted in healing rates significantly greater than those found with either the 20 mg or 10 mg dose. a significantly greater proportion of patients taking pantoprazole sodium delayed-release tablets 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 sodium delayed-release tablets consumed significantly fewer antacid tablets per day than those taking placebo. pantoprazole sodium delayed-release tablets 40 mg and 20 mg once daily were also compared with nizatidine 150 mg twice daily in a u.s. 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 8. table 8: erosive esophagitis healing rates (per protocol) + (p < 0.001) pantoprazole sodium delayed-release tablets versus nizatidine week pantoprazole sodium delayed-release tablets nizatidine 150 mg twice daily (n = 70) 20 mg daily (n = 72) 40 mg daily (n = 70) 4 61.4% + 64% + 22.2% 8 79.2% + 82.9% + 41.4% once-daily treatment with pantoprazole sodium delayed-release tablets 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 status. a significantly greater proportion of the patients in the pantoprazole sodium delayed-release tablets 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 sodium delayed-release tablets consumed significantly fewer antacid tablets per day than those taking nizatidine. pediatric patients ages 5 years through 16 years the efficacy of pantoprazole sodium delayed-release tablets 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 sodium delayed-release tablets (20 mg or 40 mg). all 4 patients with ee were healed (hetzel-dent score of 0 or 1) at 8 weeks. 14.2 long-term maintenance of healing of erosive esophagitis 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 sodium delayed-release tablets in long-term maintenance of healing. the two u.s. 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 9, pantoprazole sodium delayed-release tablets 40 mg and 20 mg were significantly superior to ranitidine at every timepoint with respect to the maintenance of healing. in addition, pantoprazole sodium delayed-release tablets 40 mg was superior to all other treatments studied. table 9: long-term maintenance of healing of erosive gastroesophageal reflux disease (gerd maintenance): percentage of patients who remained healed * (p < 0.05 vs. ranitidine) # (p < 0.05 vs. pantoprazole sodium delayed-release tablets 20 mg) pantoprazole sodium delayed- release tablets 20 mg daily pantoprazole sodium delayed- release tablets 40 mg daily ranitidine 150 mg twice daily study 1 n = 75 n = 74 n = 75 month 1 91* 99* 68 month 3 82* 93*# 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 note: pantoprazole sodium delayed-release tablets 10 mg was superior (p < 0.05) to ranitidine in study 2, but not study 1. pantoprazole sodium delayed-release tablets 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 sodium delayed-release tablets 20 mg, administered once daily, were also effective in reducing episodes of daytime and nighttime heartburn in one trial, as presented in table 10. table 10: number of episodes of heartburn (mean ± sd) *(p < 0.001 vs. ranitidine, combined data from the two u.s. studies) pantoprazole sodium delayed- release tablets 40 mg daily ranitidine 150 mg twice daily month 1 daytime 5.1 ± 1.6* 18.3 ± 1.6 nighttime 3.9 ± 1.1* 11.9 ± 1.1 month 12 daytime 2.9 ± 1.5* 17.5 ± 1.5 nighttime 2.5 ± 1.2* 13.8 ± 1.3 14.3 pathological hypersecretory conditions including zollinger-ellison syndrome 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 sodium delayed-release tablets 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) ] . pantoprazole sodium delayed-release tablets were well tolerated at these dose levels for prolonged periods (greater than 2 years in some patients).

n the stomach. let patients know that concomitant administration of antacids does not affect the absorption of pantoprazole sodium delayed-release tablets. dispense with medication guide available at: www.prasco.com manufactured for: prasco laboratories mason, oh 45040 usa manufactured by: aurobindo pharma limited unit-vii (sez) mahaboob nagar (dt)-509302 india revised: 11/2016 logo