Pantoprazole Sodium (Page 5 of 11)
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]).
Reproduction studies have been performed in rats at oral pantoprazole doses up to 450 mg/kg/day (about 88 times the recommended human dose based on body surface area) and in rabbits at oral doses up to 40 mg/kg/day (about 16 times the recommended human dose based on body surface area) with administration of pantoprazole sodium during organogenesis in pregnant animals. The studies have revealed no evidence of impaired fertility or harm to the fetus due to pantoprazole.
A pre- and postnatal 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.
Pantoprazole has been detected in breast milk of a nursing mother after a single 40 mg oral dose of pantoprazole. 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 delayed-release tablets and any potential adverse effects on the breastfed child from pantoprazole or from the underlying maternal condition.
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.
8.4 Pediatric Use
The safety and effectiveness of pantoprazole for short-term treatment (up to eight weeks) of 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 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), 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 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 (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 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 for symptomatic GERD in the pediatric population. The effectiveness of pantoprazole for treating symptomatic GERD in pediatric patients has not been established.
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 2.4 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 μg•hr/mL.
Neonates to Less Than One Year of Age
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 two weeks. Patients received pantoprazole daily for four weeks in an open-label phase, then patients were randomized in equal proportion to receive pantoprazole 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 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, 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 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.
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