Gastroesophageal Reflux Disease (GERD)
Adults
Safety in nine randomized comparative US clinical trials in patients with GERD included 1,473 patients on oral pantoprazole (20 mg or 40 mg), 299 patients on an H2-receptor antagonist, 46 patients on another PPI, and 82 patients on placebo. The most frequently occurring adverse reactions are listed in Table 2.
The number of patients treated in comparative studies with pantoprazole sodium for injection is limited; however, the adverse reactions seen were similar to those seen in the oral studies. Thrombophlebitis was the only new adverse reaction identified with pantoprazole sodium for injection.
Table 2: Adverse Reactions Reported in Clinical Trials of Adult Patients with GERD at a Frequency of > 2% | Oral Pantoprazole Sodium
(n=1473)
% | Comparators
(n=345)
% | Placebo
(n=82)
% |
|---|
Headache | 12.2 | 12.8 | 8.5 |
Diarrhea | 8.8 | 9.6 | 4.9 |
Nausea | 7.0 | 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 | 3.0 | 2.9 | 1.2 |
Arthralgia | 2.8 | 1.4 | 1.2 |
Additional adverse reactions that were reported for oral pantoprazole sodium in US clinical trials with a frequency of ≤2% are listed below by body system:
Body as a Whole: allergic reaction, fever, photosensitivity reaction, facial edema, thrombophlebitis (intravenous only)
Gastrointestinal: constipation, dry mouth, hepatitis
Hematologic: leukopenia (reported in ex-US clinical trials only), thrombocytopenia
Metabolic/Nutritional: elevated CPK (creatine phosphokinase), generalized edema, elevated triglycerides, liver function tests abnormal
Musculoskeletal: myalgia
Nervous: depression, vertigo
Skin and Appendages: urticaria, rash, pruritus
Special Senses: blurred vision
Zollinger-Ellison (ZE) Syndrome
In clinical studies of ZE Syndrome, adverse reactions reported in 35 patients administered pantoprazole sodium for injection doses of 80 mg to 240 mg per day for up to 2 years were similar to those reported in adult patients with GERD.
Pediatric use information is approved for Pfizer Inc.'s PROTONIX® I.V. (pantoprazole sodium) for Injection. However, due to Pfizer Inc.'s marketing exclusivity rights, this drug product is not labeled with that information.
Risk Summary
Available data from published observational studies did not demonstrate an association of major malformations or other adverse pregnancy outcomes with pantoprazole.
In animal reproduction studies, no evidence of adverse development outcomes was observed with pantoprazole sodium. Reproduction studies have been performed in rats at intravenous doses up to 20 mg/kg/day (4 times the recommended human dose) and rabbits at intravenous doses up to 15 mg/kg/day (6 times the recommended human dose) with administration of pantoprazole during organogenesis in pregnant animals and have revealed no evidence of harm to the fetus due to pantoprazole in this study (see Data).
A pre-and post-natal development toxicity study in rats with additional endpoints to evaluate the effect on bone development was performed with pantoprazole sodium. Oral pantoprazole doses of 5, 15, and 30 mg/kg/day (approximately 1, 3, and 6 times the human dose of 40 mg/day) were administered to pregnant females from gestation day (GD) 6 through lactation day (LD) 21. Changes in bone morphology were observed in pups exposed to pantoprazole in utero and through milk during the period of lactation as well as by oral dosing from postnatal day (PND) 4 through PND 21 [see Use in Specific Populations (8.4)]. There were no drug-related findings in maternal animals. Advise pregnant women of the potential risk of fetal harm.
The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in the clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.
Data
Human Data
Available data from published observational studies failed to demonstrate an association of adverse pregnancy-related outcomes and pantoprazole use. Methodological limitations of these observational studies cannot definitely establish or exclude any drug-associated risk during pregnancy. In a prospective study by the European Network of Teratology Information Services, outcomes from a group of 53 pregnant women administered median daily doses of 40 mg pantoprazole were compared to a control group of 868 pregnant women who did not take any proton pump inhibitors (PPIs). There was no difference in the rate of major malformations between women exposed to PPIs and the control group, corresponding to a Relative Risk (RR)=0.55, [95% Confidence Interval (CI) 0.08–3.95]. In a population-based retrospective cohort study covering all live births in Denmark from 1996 to 2008, there was no significant increase in major birth defects during analysis of first trimester exposure to pantoprazole in 549 live births. A meta-analysis that compared 1,530 pregnant women exposed to PPIs in at least the first trimester with 133,410 unexposed pregnant women showed no significant increases in risk for congenital malformations or spontaneous abortion with exposure to PPIs (for major malformations OR=1.12 ([95% CI 0.86–1.45] and for spontaneous abortions OR=1.29 [95% CI 0.84–1.97]).
Animal Data
Reproduction studies have been performed in rats at intravenous pantoprazole doses up to 20 mg/kg/day (4 times the recommended human dose based on body surface area) and rabbits at intravenous doses up to 15 mg/kg/day (6 times the recommended human dose based on body surface area) with administration of pantoprazole sodium during organogenesis in pregnant animals and have revealed no evidence of impaired fertility or harm to the fetus due to pantoprazole.
A pre- and post-natal development toxicity study in rats with additional endpoints to evaluate the effect on bone development was performed with pantoprazole sodium. Oral pantoprazole doses of 5, 15, and 30 mg/kg/day (approximately 1, 3, and 6 times the human dose of 40 mg/day on a body surface area basis) were administered to pregnant females from gestation day (GD) 6 through lactation day (LD) 21. On postnatal day (PND 4) through PND 21, the pups were administered oral doses at 5, 15, and 30 mg/kg/day (approximately 1, 2.3, and 3.2 times the exposure (AUC) in humans at a dose of 40 mg). There were no drug-related findings in maternal animals. During the preweaning dosing phase (PND 4 to 21) of the pups, there were increased mortality and/or moribundity and decreased body weight and body weight gain at 5 mg/kg/day (approximately equal exposures (AUC) in humans receiving the 40 mg dose) and higher doses. On PND 21, decreased mean femur length and weight and changes in femur bone mass and geometry were observed in the offspring at 5 mg/kg/day (approximately equal exposures (AUC) in humans at the 40 mg dose) and higher doses. The femur findings included lower total area, bone mineral content and density, periosteal and endosteal circumference, and cross-sectional moment of inertia. There were no microscopic changes in the distal femur, proximal tibia, or stifle joints. Changes in bone parameters were partially reversible following a recovery period, with findings on PND 70 limited to lower femur metaphysis cortical/subcortical bone mineral density in female pups at 5 mg/kg/day (approximately equal exposures (AUC) in humans at the 40 mg dose) and higher doses.
Risk Summary
The limited data from a single case report the presence of pantoprazole in human breast milk. There were no effects on the breastfed infant (see Data). There are no data on pantoprazole effects on milk production.
The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for pantoprazole sodium for injection and any potential adverse effects on the breastfed child from pantoprazole or from the underlying maternal condition.
Data
The breast milk of a 42-year-old woman receiving 40 mg of oral pantoprazole, at 10 months postpartum, was studied for 24 hours, to demonstrate low levels of pantoprazole present in the breast milk. Pantoprazole was detectable in milk only 2 and 4 hours after the dose with milk levels of approximately 36 mcg/L and 24 mcg/L, respectively. A milk-to-plasma ratio of 0.022 was observed at 2 hours after drug administration. Pantoprazole was not detectable (<10 mcg/L) in milk at 6, 8 and 24 hours after the dose. The relative dose to the infant was estimated to be 7.3 mcg of pantoprazole, which is equivalent to 0.14% of the weight-adjusted maternal dose. No adverse events in the infant were reported by the mother.
Animal Toxicity Data
In neonatal/juvenile animals (rats and dogs) toxicities were similar to those observed in adult animals, including gastric alterations, decreases in red cell mass, increases in lipids, enzyme induction and hepatocellular hypertrophy. An increased incidence of eosinophilic chief cells in adult and neonatal/juvenile rats, and atrophy of chief cells in adult rats and in neonatal/juvenile dogs, was observed in the fundic mucosa of stomachs in repeated-dose studies. Full to partial recovery of these effects were noted in animals of both age groups following a recovery period.
Pediatric use information is approved for Pfizer Inc.'s PROTONIX® I.V. (pantoprazole sodium) for Injection. However, due to Pfizer Inc.'s marketing exclusivity rights, this drug product is not labeled with that information.
Antisecretory Activity
The magnitude and time course for inhibition of pentagastrin-stimulated acid output (PSAO) by single doses (20 to 120 mg) of pantoprazole sodium for injection were assessed in a single-dose, open-label, placebo-controlled, dose-response study. The results of this study are shown in Table 4. Healthy subjects received a continuous infusion for 25 hours of pentagastrin (PG) at 1 mcg/kg/h, a dose known to produce submaximal gastric acid secretion. The placebo group showed a sustained, continuous acid output for 25 hours, validating the reliability of the testing model. Pantoprazole sodium for injection had an onset of antisecretory activity within 15 to 30 minutes of administration. Doses of 20 to 80 mg of pantoprazole sodium for injection substantially reduced the 24-hour cumulative PSAO in a dose-dependent manner, despite a short plasma elimination half-life. Complete suppression of PSAO was achieved with 80 mg within approximately 2 hours and no further significant suppression was seen with 120 mg. The duration of action of pantoprazole sodium for injection was 24 hours.
Table 4: Gastric Acid Output (mEq/hr, Mean ± SD) and Percent InhibitionCompared to individual subject baseline prior to treatment with pantoprazole sodium for injection.
(Mean ± SD) of Pentagastrin Stimulated Acid Output Over 24 Hours Following a Single Dose of Pantoprazole Sodium for InjectionInhibition of gastric acid output and the percent inhibition of stimulated acid output in response to pantoprazole sodium for injection may be higher after repeated doses.
in Healthy Subjects| NA = not applicable. |
| ------2 hours------ | ------4 hours------ | ------12 hours------ | ------24 hours------ |
Treatment Dose | Acid Output | % Inhibition | Acid Output | % Inhibition | Acid Output | % Inhibition | Acid Output | % Inhibition |
0 mg (Placebo, n=4) | 39 ± 21 | NA | 26 ± 14 | NA | 32 ± 20 | NA | 38 ± 24 | NA |
20 mg (n=4–6) | 13 ± 18 | 47 ± 27 | 6 ± 8 | 83 ± 21 | 20 ± 20 | 54 ± 44 | 30 ± 23 | 45 ± 43 |
40 mg (n=8) | 5 ± 5 | 82 ± 11 | 4 ± 4 | 90 ± 11 | 11 ± 10 | 81 ± 13 | 16 ± 12 | 52 ± 36 |
80 mg (n=8) | 0.1 ± 0.2 | 96 ± 6 | 0.3 ± 0.4 | 99 ± 1 | 2 ± 2 | 90 ± 7 | 7 ± 4 | 63 ± 18 |
In one study of gastric pH in healthy subjects, pantoprazole was administered orally (40 mg enteric coated tablets) or pantoprazole sodium for injection (40 mg) once daily for 5 days and pH was measured for 24 hours following the fifth dose. The outcome measure was median percent of time that pH was ≥4 and the results were similar for intravenous and oral medications; however, the clinical significance of this parameter is unknown.
Serum Gastrin Effects
Serum gastrin concentrations were assessed in two placebo-controlled studies.
In a 5-day study of oral pantoprazole with 40 and 60 mg doses in healthy subjects, following the last dose on day 5, median 24-hour serum gastrin concentrations were elevated by 3- to 4-fold compared to placebo in both 40 and 60 mg dose groups. However, by 24 hours following the last dose, median serum gastrin concentrations for both groups returned to normal levels.
In another placebo-controlled, 7-day study of 40 mg intravenous or oral pantoprazole in patients with GERD and a history of EE, the mean serum gastrin concentration increased approximately 50% from baseline and as compared with placebo, but remained within the normal range.
During 6 days of repeated administration of pantoprazole sodium for injection in patients with ZE Syndrome, consistent changes of serum gastrin concentrations from baseline were not observed.
Enterochromaffin-Like (ECL) Cell Effects
There are no data available on the effects of intravenous pantoprazole sodium on ECL cells.
In a nonclinical study in Sprague-Dawley rats, lifetime exposure (24 months) to oral pantoprazole at doses of 0.5 to 200 mg/kg/day resulted in dose-related increases in gastric ECL-cell proliferation and gastric neuroendocrine (NE)-cell tumors. Gastric NE-cell tumors in rats may result from chronic elevation of serum gastrin concentrations. The high density of ECL cells in the rat stomach makes this species highly susceptible to the proliferative effects of elevated gastrin concentrations produced by PPIs. However, there were no observed elevations in serum gastrin following the administration of oral pantoprazole at a dose of 0.5 mg/kg/day. In a separate study, a gastric NE-cell tumor without concomitant ECL-cell proliferative changes was observed in 1 female rat following 12 months of dosing with oral pantoprazole at 5 mg/kg/day and a 9 month off-dose recovery [see Nonclinical Toxicology (13.1)].
Endocrine Effects
In a clinical pharmacology study, pantoprazole 40 mg given orally once daily for 2 weeks had no effect on the levels of the following hormones: cortisol, testosterone, triiodothyronine (T3), thyroxine (T4), thyroid-stimulating hormone, thyronine-binding protein, parathyroid hormone, insulin, glucagon, renin, aldosterone, follicle-stimulating hormone, luteinizing hormone, prolactin and growth hormone.
In a 1-year study of GERD patients treated with pantoprazole 40 mg or 20 mg, there were no changes from baseline in overall levels of T3, T4, and TSH.
Distribution
The apparent volume of distribution of pantoprazole is approximately 11 to 23.6 L, distributing mainly in extracellular fluid. The serum protein binding of pantoprazole is about 98%, primarily to albumin.
Elimination
Metabolism
Pantoprazole is extensively metabolized in the liver through the cytochrome P450 (CYP) system. Pantoprazole metabolism is independent of the route of administration (intravenous or oral). The main metabolic pathway is demethylation, by CYP2C19, with subsequent sulfation; other metabolic pathways include oxidation by CYP3A4. There is no evidence that any of the pantoprazole metabolites have significant pharmacologic activity. CYP2C19 displays a known genetic polymorphism due to its deficiency in some sub-populations (e.g., 3% of Whites and African-Americans and 17 to 23% of Asians). Although these sub-populations of slow pantoprazole metabolizers have elimination half-life values from 3.5 to 10 hours, they still have minimal accumulation (23% or less) with once daily dosing.
Excretion
After administration of a single intravenous dose of 14C-labeled pantoprazole sodium to healthy, extensive CYP2C19 metabolizers, approximately 71% of the dose was excreted in the urine with 18% excreted in the feces through biliary excretion. There was no renal excretion of unchanged pantoprazole.
Specific Populations
Geriatric Patients
After repeated intravenous administration in elderly subjects (65 to 76 years of age), the AUC and elimination half-life values of pantoprazole were similar to those observed in younger subjects.
Male and Female Patients
After oral administration there was a modest increase in the AUC and Cmax of pantoprazole in women compared to men. However, weight-normalized clearance values are similar in women and men.
Patients with Renal Impairment
In patients with severe renal impairment, pharmacokinetic parameters for pantoprazole were similar to those of healthy subjects.
Patients with Hepatic Impairment
In patients with mild to severe hepatic impairment (Child-Pugh Class A to C), maximum pantoprazole concentrations increased only slightly (1.5-fold) relative to healthy subjects when pantoprazole sodium was administered orally. Although serum half-life values increased to 7 to 9 hours and AUC values increased by 5- to 7-fold in hepatic-impaired patients, these increases were no greater than those observed in CYP2C19 poor metabolizers, where no dosage adjustment is warranted. These pharmacokinetic changes in hepatic-impaired patients result in minimal drug accumulation following once daily, multiple-dose administration. Oral pantoprazole doses higher than 40 mg per day have not been studied in hepatically impaired patients.
Drug Interaction Studies
Effect of Other Drugs on Pantoprazole
Pantoprazole is metabolized mainly by CYP2C19 and to minor extents by CYPs 3A4, 2D6 and 2C9.
In in vivo drug-drug interaction studies with CYP2C19 substrates (diazepam [also a CYP3A4 substrate] and phenytoin [also a CYP3A4 inducer]), 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.
Effect of Pantoprazole on Other Drugs
Clopidogrel
Clopidogrel is metabolized to its active metabolite in part by CYP2C19. In a crossover clinical study, 66 healthy subjects were administered clopidogrel (300 mg loading dose followed by 75 mg per day) alone and with oral pantoprazole (80 mg at the same time as clopidogrel) for 5 days. On Day 5, the mean AUC of the active metabolite of clopidogrel was reduced by approximately 14% (geometric mean ratio was 86%, with 90% CI of 79 to 93%) when pantoprazole sodium was coadministered with clopidogrel as compared to clopidogrel administered alone. Pharmacodynamic parameters were also measured and demonstrated that the change in inhibition of platelet aggregation (induced by 5 micromolar ADP) was correlated with the change in the exposure to clopidogrel active metabolite. The clinical significance of this finding is not clear.
Mycophenolate Mofetil (MMF)
Administration of oral pantoprazole 40 mg twice daily for 4 days and a single 1000 mg dose of MMF approximately one hour after the last dose of pantoprazole to 12 healthy subjects in a cross-over study resulted in a 57% reduction in the Cmax 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 oral pantoprazole 40 mg per day (n=21). There was a 78% reduction in the Cmax and a 45% reduction in the AUC of MPA in patients receiving both pantoprazole and MMF [see Drug Interactions (7)].
Other Drugs
In vivo studies also suggest that pantoprazole does not significantly affect the kinetics of other drugs (theophylline, diazepam [and its active metabolite, desmethyldiazepam], phenytoin, metoprolol, nifedipine, carbamazepine, midazolam, clarithromycin, diclofenac, naproxen, piroxicam and oral contraceptives [levonorgestrel/ethinyl estradiol]). In other in vivo studies, digoxin, ethanol, glyburide, antipyrine, caffeine, metronidazole, and amoxicillin had no clinically relevant interactions with pantoprazole.
Although no significant drug-drug interactions have been observed in clinical studies, the potential for significant drug-drug interactions with more than once daily dosing with high doses of pantoprazole has not been studied in poor metabolizers or individuals who are hepatically impaired.
Antacids
There was also no interaction with concomitantly administered antacids.
Pediatric use information is approved for Pfizer Inc.'s PROTONIX® I.V. (pantoprazole sodium) for Injection. However, due to Pfizer Inc.'s marketing exclusivity rights, this drug product is not labeled with that information.
Adverse Reactions
Advise patients to report to their healthcare provider if they experience any signs or symptoms consistent with:
