pantoprazole 40 MG Enteric Coated Oral Granules for Oral Suspension
Generic Name: PANTOPRAZOLE SODIUM
Brand Name: Protonix Delayed-Release
- Substance Name(s):
- PANTOPRAZOLE SODIUM
DRUG INTERACTIONS
7 Table 4 includes drugs with clinically important drug interactions and interaction with diagnostics when administered concomitantly with PROTONIX and instructions for preventing or managing them.
Consult the labeling of concomitantly used drugs to obtain further information about interactions with PPIs.
Table 4: Clinically Relevant Interactions Affecting Drugs Co-Administered with PROTONIX and Interactions with Diagnostics Antiretrovirals Clinical Impact: The effect of PPIs on antiretroviral drugs is variable.
The clinical importance and the mechanisms behind these interactions are not always known.
• Decreased exposure of some antiretroviral drugs (e.g., rilpivirine atazanavir, and nelfinavir) when used concomitantly with pantoprazole may reduce antiviral effect and promote the development of drug resistance.
• Increased exposure of other antiretroviral drugs (e.g., saquinavir) when used concomitantly with pantoprazole may increase toxicity of the antiretroviral drugs .
• There are other antiretroviral drugs which do not result in clinically relevant interactions with pantoprazole.
Intervention: Rilpivirine-containing products: Concomitant use with PROTONIX is contraindicated [see Contraindications (4) ] .
See prescribing information.
Atazanavir: See prescribing information for atazanavir for dosing information.
Nelfinavir: Avoid concomitant use with PROTONIX.
See prescribing information for nelfinavir.
Saquinavir: See the prescribing information for saquinavir and monitor for potential saquinavir toxicities.
Other antiretrovirals: See prescribing information.
Warfarin Clinical Impact: Increased INR and prothrombin time in patients receiving PPIs, including pantoprazole, and warfarin concomitantly.
Increases in INR and prothrombin time may lead to abnormal bleeding and even death.
Intervention: Monitor INR and prothrombin time.
Dose adjustment of warfarin may be needed to maintain target INR range.
See prescribing information for warfarin.
Clopidogrel Clinical Impact: Concomitant administration of pantoprazole and clopidogrel in healthy subjects had no clinically important effect on exposure to the active metabolite of clopidogrel or clopidogrel-induced platelet inhibition [see Clinical Pharmacology (12.3) ].
Intervention: No dose adjustment of clopidogrel is necessary when administered with an approved dose of PROTONIX.
Methotrexate Clinical Impact: Concomitant use of PPIs with methotrexate (primarily at high dose) may elevate and prolong serum concentrations of methotrexate and/or its metabolite hydroxymethotrexate, possibly leading to methotrexate toxicities.
No formal drug interaction studies of high-dose methotrexate with PPIs have been conducted [see Warnings and Precautions (5.13) ] .
Intervention: A temporary withdrawal of PROTONIX may be considered in some patients receiving high-dose methotrexate.
Drugs Dependent on Gastric pH for Absorption (e.g., iron salts, erlotinib, dasatinib, nilotinib, mycophenolate mofetil, ketoconazole/itraconazole) Clinical Impact: Pantoprazole can reduce the absorption of other drugs due to its effect on reducing intragastric acidity.
Intervention: Mycophenolate mofetil (MMF): Co-administration of pantoprazole sodium in healthy subjects and in transplant patients receiving MMF has been reported to reduce the exposure to the active metabolite, mycophenolic acid (MPA), possibly due to a decrease in MMF solubility at an increased gastric pH [see Clinical Pharmacology (12.3) ] .
The clinical relevance of reduced MPA exposure on organ rejection has not been established in transplant patients receiving PROTONIX and MMF.
Use PROTONIX with caution in transplant patients receiving MMF.
See the prescribing information for other drugs dependent on gastric pH for absorption.
Interactions with Investigations of Neuroendocrine Tumors Clinical Impact: CgA levels increase secondary to PPI-induced decreases in gastric acidity.
The increased CgA level may cause false positive results in diagnostic investigations for neuroendocrine tumors [see Warnings and Precautions (5.11) , Clinical Pharmacology (12.2) ] .
Intervention: Temporarily stop PROTONIX treatment at least 14 days before assessing CgA levels and consider repeating the test if initial CgA levels are high.
If serial tests are performed (e.g., for monitoring), the same commercial laboratory should be used for testing, as reference ranges between tests may vary.
False Positive Urine Tests for THC Clinical Impact: There have been reports of false positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving PPIs [see Warnings and Precautions (5.12) ] .
Intervention: An alternative confirmatory method should be considered to verify positive results.
See full prescribing information for a list of clinically important drug interactions ( 7 )
OVERDOSAGE
10 Experience in patients taking very high doses of PROTONIX (greater than 240 mg) is limited.
Spontaneous post-marketing reports of overdose are generally within the known safety profile of PROTONIX.
Pantoprazole is not removed by hemodialysis.
In case of overdosage, treatment should be symptomatic and supportive.
Single oral doses of pantoprazole at 709 mg/kg, 798 mg/kg, and 887 mg/kg were lethal to mice, rats, and dogs, respectively.
The symptoms of acute toxicity were hypoactivity, ataxia, hunched sitting, limb-splay, lateral position, segregation, absence of ear reflex, and tremor.
If overexposure to PROTONIX occurs, call your Poison Control Center at 1-800-222-1222 for current information on the management of poisoning or overdosage.
DESCRIPTION
11 The active ingredient in PROTONIX (pantoprazole sodium) For Delayed-Release Oral Suspension and PROTONIX (pantoprazole sodium) Delayed-Release Tablets, a PPI, is a substituted benzimidazole, sodium 5-(difluoromethoxy)-2-[[(3,4-dimethoxy-2-pyridinyl)methyl] sulfinyl]-1 H -benzimidazole sesquihydrate, a compound that inhibits gastric acid secretion.
Its empirical formula is C 16 H 14 F 2 N 3 NaO 4 S × 1.5 H 2 O, with a molecular weight of 432.4.
The structural formula is: Pantoprazole sodium sesquihydrate is a white to off-white crystalline powder and is racemic.
Pantoprazole has weakly basic and acidic properties.
Pantoprazole sodium sesquihydrate is freely soluble in water, very slightly soluble in phosphate buffer at pH 7.4, and practically insoluble in n-hexane.
The stability of the compound in aqueous solution is pH-dependent.
The rate of degradation increases with decreasing pH.
At ambient temperature, the degradation half-life is approximately 2.8 hours at pH 5 and approximately 220 hours at pH 7.8.
PROTONIX is supplied as a for delayed-release oral suspension in unit dose packets, available in one strength 40 mg pantoprazole, (equivalent to 45.1 mg of pantoprazole sodium), and as a delayed-release tablet, available in two strengths 20 mg pantoprazole (equivalent to 22.56 mg of pantoprazole sodium) and 40 mg pantoprazole (equivalent to 45.1 mg of pantoprazole sodium).
PROTONIX Delayed-Release Tablets contains the following inactive ingredients: calcium stearate, crospovidone, hypromellose, iron oxide, mannitol, methacrylic acid copolymer, polysorbate 80, povidone, propylene glycol, sodium carbonate, sodium lauryl sulfate, titanium dioxide, and triethyl citrate.
PROTONIX Delayed-Release Tablets (40 mg and 20 mg) complies with USP dissolution test 2.
PROTONIX For Delayed-Release Oral Suspension contains the following inactive ingredients: crospovidone, hypromellose, methacrylic acid copolymer, microcrystalline cellulose, polysorbate 80, povidone, sodium carbonate, sodium lauryl sulfate, talc, titanium dioxide, triethyl citrate, and yellow ferric oxide.
Chemical Structure
CLINICAL STUDIES
14 PROTONIX Delayed-Release Tablets were used in the following clinical trials.
14.1 Erosive Esophagitis (EE) Associated with Gastroesophageal Reflux Disease (GERD) Adult Patients A US multicenter, double-blind, placebo-controlled study of PROTONIX 10 mg, 20 mg, or 40 mg once daily was conducted in 603 patients with reflux symptoms and endoscopically diagnosed EE of grade 2 or above (Hetzel-Dent scale).
In this study, approximately 25% of enrolled patients had severe EE of grade 3, and 10% had grade 4.
The percentages of patients healed (per protocol, n = 541) in this study are shown in Table 8.
Table 8: Erosive Esophagitis Healing Rates (Per Protocol) PROTONIX Placebo Week 10 mg daily (n = 153) 20 mg daily (n = 158) 40 mg daily (n = 162) (n = 68) 4 45.6% (p < 0.001) PROTONIX versus placebo 58.4% (p < 0.05) versus 10 mg PROTONIX 75.0% (p < 0.05) versus 10 mg or 20 mg PROTONIX 14.3% 8 66.0% 83.5% 92.6% 39.7% In this study, all PROTONIX 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 PROTONIX treatment groups.
The 40 mg dose of PROTONIX 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 PROTONIX 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 PROTONIX consumed significantly fewer antacid tablets per day than those taking placebo.
PROTONIX 40 mg and 20 mg once daily were also compared with nizatidine 150 mg twice daily in a US 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 9.
Table 9: Erosive Esophagitis Healing Rates (Per Protocol) PROTONIX Nizatidine Week 20 mg daily (n = 72) 40 mg daily (n = 70) 150 mg twice daily (n = 70) 4 61.4% (p < 0.001) PROTONIX versus nizatidine 64.0% 22.2% 8 79.2% 82.9% 41.4% Once-daily treatment with PROTONIX 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 PROTONIX 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 PROTONIX consumed significantly fewer antacid tablets per day than those taking nizatidine.
Pediatric Patients Ages 5 Years through 16 Years The efficacy of PROTONIX 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 PROTONIX (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 EE to demonstrate efficacy of PROTONIX in long-term maintenance of healing.
The two US studies enrolled 386 and 404 patients, respectively, to receive either 10 mg, 20 mg, or 40 mg of PROTONIX Delayed-Release Tablets once daily or 150 mg of ranitidine twice daily.
As demonstrated in Table 10, PROTONIX 40 mg and 20 mg were significantly superior to ranitidine at every timepoint with respect to the maintenance of healing.
In addition, PROTONIX 40 mg was superior to all other treatments studied.
Table 10: Long-Term Maintenance of Healing of Erosive Gastroesophageal Reflux Disease (GERD Maintenance): Percentage of Patients Who Remained Healed PROTONIX 20 mg daily PROTONIX 40 mg daily Ranitidine 150 mg twice daily Note: PROTONIX 10 mg was superior (p <0.05) to ranitidine in Study 2, but not Study 1.
Study 1 n = 75 n = 74 n = 75 Month 1 91 (p <0.05 vs.
ranitidine) 99 68 Month 3 82 93 (p <0.05 vs.
PROTONIX 20 mg) 54 Month 6 76 90 44 Month 12 70 86 35 Study 2 n = 74 n = 88 n = 84 Month 1 89 92 62 Month 3 78 91 47 Month 6 72 88 39 Month 12 72 83 37 PROTONIX 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.
PROTONIX 20 mg, administered once daily, was also effective in reducing episodes of daytime and nighttime heartburn in one trial, as presented in Table 11.
Table 11: Number of Episodes of Heartburn (mean ± SD) PROTONIX 40 mg daily Ranitidine 150 mg twice daily Month 1 Daytime 5.1 ± 1.6 (p <0.001 vs.
ranitidine, combined data from the two US studies) 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, PROTONIX 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) ] .
PROTONIX was well tolerated at these dose levels for prolonged periods (greater than 2 years in some patients).
HOW SUPPLIED
16 /STORAGE AND HANDLING How Supplied PROTONIX (pantoprazole sodium) Delayed-Release Tablets are supplied as yellow, oval biconvex delayed-release tablets imprinted with PROTONIX (brown ink) on one side containing 40 mg pantoprazole and are available as follows: • NDC 0008-0841-81, bottles of 90 PROTONIX (pantoprazole sodium) Delayed-Release Tablets are supplied as yellow oval biconvex delayed-release tablets imprinted with P20 (brown ink) on one side containing 20 mg pantoprazole and are available as follows: • NDC 0008-0843-81, bottles of 90 PROTONIX (pantoprazole sodium) For Delayed-Release Oral Suspension is supplied as pale yellowish to dark brownish, enteric-coated granules containing 40 mg pantoprazole in a unit-dose packet and are available as follows: • NDC 0008-0844-02, unit-dose carton of 30 Storage Store PROTONIX For Delayed-Release Oral Suspension and PROTONIX Delayed-Release Tablets at 20° to 25°C (68° to 77°F); excursions permitted to 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature] .
RECENT MAJOR CHANGES
Warnings and Precautions, Severe Cutaneous Adverse Reactions ( 5.5 ) 03/2022 Hypomagnesemia and Mineral Metabolism ( 5.8 ) 03/2022
GERIATRIC USE
8.5 Geriatric Use In short-term US clinical trials, EE healing rates in the 107 elderly patients (≥65 years old) treated with PROTONIX 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.
DOSAGE FORMS AND STRENGTHS
3 Delayed-Release Tablets: • 40 mg pantoprazole, yellow oval biconvex tablets imprinted with PROTONIX (brown ink) on one side • 20 mg pantoprazole, yellow oval biconvex tablets imprinted with P20 (brown ink) on one side For Delayed-Release Oral Suspension: • 40 mg pantoprazole, pale yellowish to dark brownish, enteric-coated granules in a unit dose packet • Delayed-Release Tablets: 20 mg and 40 mg pantoprazole ( 3 ) • For Delayed-Release Oral Suspension: 40 mg pantoprazole ( 3 )
MECHANISM OF ACTION
12.1 Mechanism of Action Pantoprazole is a PPI that suppresses the final step in gastric acid production by covalently binding to the (H + , K + )-ATPase enzyme system at the secretory surface of the gastric parietal cell.
This effect leads to inhibition of both basal and stimulated gastric acid secretion, irrespective of the stimulus.
The binding to the (H + , K + )-ATPase results in a duration of antisecretory effect that persists longer than 24 hours for all doses tested (20 mg to 120 mg).
INDICATIONS AND USAGE
1 PROTONIX For Delayed-Release Oral Suspension and PROTONIX Delayed-Release Tablets are indicated for: PROTONIX is a proton pump inhibitor (PPI) indicated for the following: • Short-Term Treatment of Erosive Esophagitis Associated with Gastroesophageal Reflux Disease (GERD) ( 1.1 ) • Maintenance of Healing of Erosive Esophagitis ( 1.2 ) • Pathological Hypersecretory Conditions Including Zollinger-Ellison (ZE) Syndrome ( 1.3 ) 1.1 Short-Term Treatment of Erosive Esophagitis Associated With Gastroesophageal Reflux Disease (GERD) PROTONIX is indicated in adults and pediatric patients five years of age and older for the short-term treatment (up to 8 weeks) in the healing and symptomatic relief of erosive esophagitis (EE).
For those adult patients who have not healed after 8 weeks of treatment, an additional 8-week course of PROTONIX may be considered.
Safety of treatment beyond 8 weeks in pediatric patients has not been established.
1.2 Maintenance of Healing of Erosive Esophagitis PROTONIX is indicated for maintenance of healing of EE 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 PROTONIX is indicated for the long-term treatment of pathological hypersecretory conditions, including Zollinger-Ellison (ZE) Syndrome.
PEDIATRIC USE
8.4 Pediatric Use The safety and effectiveness of PROTONIX 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, PROTONIX is indicated for the short-term treatment of EE associated with GERD for patients 5 years and older.
The safety and effectiveness of PROTONIX for pediatric uses other than EE have not been established.
1 year through 16 years of age Use of PROTONIX 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 PROTONIX 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 PROTONIX 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 PROTONIX (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 PROTONIX 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 PROTONIX for symptomatic GERD in the pediatric population.
The effectiveness of PROTONIX for treating symptomatic GERD in pediatric patients has not been established.
Although the data from the clinical trials support use of PROTONIX 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 PROTONIX 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 PROTONIX daily for four weeks in an open-label phase, then patients were randomized in equal proportion to receive PROTONIX 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 PROTONIX 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 PROTONIX, 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 PROTONIX 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 PROTONIX 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 PROTONIX was not shown to be effective in the randomized, placebo-controlled study in this age group, the use of PROTONIX for treatment of symptomatic GERD in infants less than 1 year of age is not indicated.
Animal Toxicity Data In a pre- and post-natal development study in rats, the pups were administered oral doses of pantoprazole at 5, 15, and 30 mg/kg/day (approximately 1, 2.3, and 3.2 times the exposure (AUC) in children aged 6 to 11 years at a dose of 40 mg) on postnatal day (PND 4) through PND 21, in addition to lactational exposure through milk.
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 children aged 6 to 11 years at the 40 mg dose) and higher doses.
Changes in bone parameters were partially reversible following a recovery period.
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.
PREGNANCY
8.1 Pregnancy 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.
Reproduction studies have been performed in rats at oral doses up to 450 mg/kg/day (about 88 times the recommended human dose) and rabbits at oral doses up to 40 mg/kg/day (about 16 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 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) 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 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.
WARNING AND CAUTIONS
5 WARNINGS AND PRECAUTIONS • Gastric Malignancy: In adults, symptomatic response does not preclude presence of gastric malignancy.
Consider additional follow-up and diagnostic testing.
( 5.1 ) • Acute Tubulointerstitial Nephritis : Discontinue treatment and evaluate patients.
( 5.2 ) • Clostridium difficile- Associated Diarrhea : PPI therapy may be associated with increased risk of Clostridium difficile- associated diarrhea.
( 5.3 ) • Bone Fracture : Long-term and multiple daily dose PPI therapy may be associated with an increased risk for osteoporosis-related fractures of the hip, wrist or spine.
( 5.4 ) • Severe Cutaneous Adverse Reactions : Discontinue at the first signs or symptoms of severe cutaneous adverse reactions or other signs of hypersensitivity and consider further evaluation.
( 5.5 ) • Cutaneous and Systemic Lupus Erythematosus : Mostly cutaneous; new onset or exacerbation of existing disease; discontinue PROTONIX and refer to specialist for evaluation.
( 5.6 ) • Cyanocobalamin (Vitamin B-12) Deficiency : Daily long-term use (e.g., longer than 3 years) may lead to malabsorption or a deficiency of cyanocobalamin.
( 5.7 ) • Hypomagnesemia and Mineral Metabolism : Reported rarely with prolonged treatment with PPIs.
( 5.8 ) • Fundic Gland Polyps: Risk increases with long-term use, especially beyond one year.
Use the shortest duration of therapy.
( 5.10 ) 5.1 Presence of Gastric Malignancy In adults, symptomatic response to therapy with PROTONIX 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 Tubulointerstitial Nephritis Acute tubulointerstitial nephritis (TIN) has been observed in patients taking PPIs and may occur at any point during PPI therapy.
Patients may present with varying signs and symptoms from symptomatic hypersensitivity reactions to non-specific symptoms of decreased renal function (e.g., malaise, nausea, anorexia).
In reported case series, some patients were diagnosed on biopsy and in the absence of extra-renal manifestations (e.g., fever, rash or arthralgia).
Discontinue PROTONIX and evaluate patients with suspected acute TIN [see Contraindications (4) ].
5.3 Clostridium difficile- Associated Diarrhea Published observational studies suggest that PPI therapy like PROTONIX 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 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) , Adverse Reactions (6.2) ].
5.5 Severe Cutaneous Adverse Reactions Severe cutaneous adverse reactions, including erythema multiforme, Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), drug reaction with eosinophilia and systemic symptoms (DRESS), and acute generalized exanthematous pustulosis (AGEP) have been reported in association with the use of PPIs [see Adverse Reactions (6.2) ] .
Discontinue PROTONIX at the first signs or symptoms of severe cutaneous adverse reactions or other signs of hypersensitivity and consider further evaluation.
5.6 Cutaneous and Systemic Lupus Erythematosus Cutaneous lupus erythematosus (CLE) and systemic lupus erythematosus (SLE) have been reported in patients taking PPIs, including pantoprazole sodium.
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 PROTONIX, 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.
5.7 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.
5.8 Hypomagnesemia and Mineral Metabolism Hypomagnesemia, symptomatic and asymptomatic, has been reported rarely in patients treated with PPIs for at least three months, and in most cases after a year of therapy.
Serious adverse events include tetany, arrhythmias, and seizures.
Hypomagnesemia may lead to hypocalcemia and/or hypokalemia and may exacerbate underlying hypocalcemia in at-risk patients.
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) ] .
Consider monitoring magnesium and calcium levels prior to initiation of PROTONIX and periodically while on treatment in patients with a preexisting risk of hypocalcemia (e.g., hypoparathyroidism).
Supplement with magnesium and/or calcium as necessary.
If hypocalcemia is refractory to treatment, consider discontinuing the PPI.
5.9 Tumorigenicity Due to the chronic nature of GERD, there may be a potential for prolonged administration of PROTONIX.
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) ] .
5.10 Fundic Gland Polyps PPI use is associated with an increased risk of fundic gland polyps that increases with long-term use, especially beyond one year.
Most PPI users who developed fundic gland polyps were asymptomatic and fundic gland polyps were identified incidentally on endoscopy.
Use the shortest duration of PPI therapy appropriate to the condition being treated.
5.11 Interference with Investigations for Neuroendocrine Tumors Serum chromogranin A (CgA) levels increase secondary to drug-induced decreases in gastric acidity.
The increased CgA level may cause false positive results in diagnostic investigations for neuroendocrine tumors.
Healthcare providers should temporarily stop PROTONIX treatment at least 14 days before assessing CgA levels and consider repeating the test if initial CgA levels are high.
If serial tests are performed (e.g., for monitoring), the same commercial laboratory should be used for testing, as reference ranges between tests may vary [see Clinical Pharmacology (12.2) ] .
5.12 Interference with Urine Screen for THC There have been reports of false-positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving PPIs, including PROTONIX [see Drug Interactions (7) ] .
5.13 Concomitant Use of PROTONIX 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) ].
INFORMATION FOR PATIENTS
17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Medication Guide and Instructions for Use).
Gastric Malignancy Advise patients to return to their healthcare provider if they have a suboptimal response or an early symptomatic relapse [see Warnings and Precautions (5.1) ] .
Acute Tubulointerstitial Nephritis Advise patients to call their healthcare provider immediately if they experience signs and/or symptoms associated with acute tubulointerstitial nephritis [see Contraindications (4) , Warnings and Precautions (5.2) ] .
Clostridium difficile- Associated Diarrhea Advise patients to immediately call their healthcare provider if they experience diarrhea that does not improve [see Warnings and Precautions (5.3) ] .
Bone Fracture Advise patients to report any fractures, especially of the hip, wrist or spine, to their healthcare provider [see Warnings and Precautions (5.4) ] .
Severe Cutaneous Adverse Reactions Advise patients to discontinue PROTONIX and immediately call their healthcare provider for further evaluation [see Warnings and Precautions (5.5) ] .
Cutaneous and Systemic Lupus Erythematosus Advise patients to immediately call their healthcare provider for any new or worsening of symptoms associated with cutaneous or systemic lupus erythematosus [see Warnings and Precautions (5.6) ] .
Cyanocobalamin (Vitamin B-12) Deficiency Advise patients to report any clinical symptoms that may be associated with cyancobalamin deficiency to their healthcare provider if they have been receiving PROTONIX for longer than 3 years [see Warnings and Precautions (5.7) ] .
Hypomagnesemia and Mineral Metabolism Advise patients to report any clinical symptoms that may be associated with hypomagnesemia, hypocalcemia, and/or hypokalemia, to their healthcare provider, if they have been receiving PROTONIX for at least 3 months [see Warnings and Precautions (5.8) ] .
Drug Interactions Instruct patients to inform their healthcare provider of any other medications they are currently taking, including rilpivirine-containing products [see Contraindications (4) ], digoxin [see Warnings and Precautions (5.8) ] and high dose methotrexate [see Warnings and Precautions (5.13) ] .
Pregnancy Advise a pregnant woman of the potential risk to a fetus.
Advise females of reproductive potential to inform their healthcare provider of a known or suspected pregnancy [see Use in Specific Populations (8.1) ] .
Administration • Do not split, crush, or chew PROTONIX For Delayed-Release Oral Suspension and PROTONIX Delayed-Release Tablets.
• PROTONIX oral suspension packet is a fixed dose and cannot be divided to make a smaller dose.
• Swallow PROTONIX Delayed-Release Tablets whole, with or without food in the stomach.
• Concomitant administration of antacids does not affect the absorption of PROTONIX Delayed-Release Tablets.
• Take PROTONIX For Delayed-Release Oral Suspension approximately 30 minutes before a meal.
• Administer PROTONIX For Delayed-Release Oral Suspension in apple juice or applesauce, as described in the Instructions for Use.
Do not administer in water, other liquids, or foods.
• For patients with a nasogastric (NG) or gastrostomy tube, PROTONIX For Delayed-Release Oral Suspension can be administered with apple juice, as described in the Instructions for Use.
• Take a missed dose as soon as possible.
If it is almost time for the next dose, skip the missed dose and take the next dose at the regular scheduled time.
Do not take 2 doses at the same time.
DOSAGE AND ADMINISTRATION
2 Indication Dose Frequency Short-Term Treatment of Erosive Esophagitis Associated With GERD ( 2.1 ) Adults 40 mg Once Daily for up to 8 wks Children (5 years and older) ≥ 15 kg to < 40 kg 20 mg Once Daily for up to 8 wks ≥ 40 kg 40 mg Maintenance of Healing of Erosive Esophagitis ( 2.1 ) Adults 40 mg Once Daily Controlled studies did not extend beyond 12 months Pathological Hypersecretory Conditions Including Zollinger-Ellison Syndrome ( 2.1 ) Adults 40 mg Twice Daily See full prescribing information for administration instructions 2.1 Recommended Dosing Schedule PROTONIX is supplied as delayed-release granules in packets for preparation of oral suspensions or as delayed-release tablets.
The recommended dosages are outlined in Table 1.
Table 1: Recommended Dosing Schedule for PROTONIX Indication Dose Frequency Short-Term Treatment of Erosive Esophagitis Associated With GERD Adults 40 mg Once daily for up to 8 weeks For adult patients who have not healed after 8 weeks of treatment, an additional 8-week course of PROTONIX may be considered.
Children (5 years and older) ≥ 15 kg to < 40 kg 20 mg Once daily for up to 8 weeks ≥ 40 kg 40 mg Maintenance of Healing of Erosive Esophagitis Adults 40 mg Once daily Controlled studies did not extend beyond 12 months Pathological Hypersecretory Conditions Including Zollinger-Ellison Syndrome Adults 40 mg Twice daily Dosage regimens should be adjusted to individual patient needs and should continue for as long as clinically indicated.
Doses up to 240 mg daily have been administered.
2.2 Administration Instructions Directions for method of administration for each dosage form are presented in Table 2.
Table 2: Administration Instructions Formulation Route Instructions Do not split, chew, or crush PROTONIX Delayed-Release Tablets and PROTONIX For Delayed-Release Oral Suspension.
Delayed-Release Tablets Oral Swallowed whole, with or without food For Delayed-Release Oral Suspension Oral Administered in 1 teaspoonful of applesauce or apple juice approximately 30 minutes prior to a meal For Delayed-Release Oral Suspension Nasogastric tube See instructions below Take a missed dose as soon as possible.
If it is almost time for the next dose, skip the missed dose and take the next dose at the regular scheduled time.
Do not take 2 doses at the same time.
PROTONIX Delayed-Release Tablets Swallow PROTONIX Delayed-Release Tablets whole, with or without food in the stomach.
For patients unable to swallow a 40 mg tablet, two 20 mg tablets may be taken.
Concomitant administration of antacids does not affect the absorption of PROTONIX Delayed-Release Tablets.
PROTONIX For Delayed-Release Oral Suspension Administer PROTONIX For Delayed-Release Oral Suspension approximately 30 minutes prior to a meal via oral administration in apple juice or applesauce or nasogastric tube in apple juice only.
Because proper pH is necessary for stability, do not administer PROTONIX For Delayed-Release Oral Suspension in liquids other than apple juice, or foods other than applesauce.
Do not divide the 40 mg PROTONIX For Delayed-Release Oral Suspension packet to create a 20 mg dosage for pediatric patients who are unable to take the tablet formulation.
PROTONIX For Delayed-Release Oral Suspension – Oral Administration in Applesauce • Open packet.
• Sprinkle granules on one teaspoonful of applesauce.
DO NOT USE OTHER FOODS OR CRUSH OR CHEW THE GRANULES.
• Take within 10 minutes of preparation.
• Take sips of water to make sure granules are washed down into the stomach.
Repeat water sips as necessary.
PROTONIX For Delayed-Release Oral Suspension – Oral Administration in Apple Juice • Open packet.
• Empty granules into a small cup or teaspoon containing one teaspoon of apple juice.
• Stir for 5 seconds (granules will not dissolve) and swallow immediately.
• To make sure that the entire dose is taken, rinse the container once or twice with apple juice to remove any remaining granules.
Swallow immediately.
PROTONIX For Delayed-Release Oral Suspension – Nasogastric (NG) Tube or Gastrostomy Tube Administration For patients who have a nasogastric tube or gastrostomy tube in place, PROTONIX For Delayed-Release Oral Suspension can be given as follows: • Remove the plunger from the barrel of a 2 ounce (60 mL) catheter-tip syringe.
Discard the plunger.
• Connect the catheter tip of the syringe to a 16 French (or larger) tube.
• Hold the syringe attached to the tubing as high as possible while giving PROTONIX For Delayed-Release Oral Suspension to prevent any bending of the tubing.
• Empty the contents of the packet into the barrel of the syringe.
• Add 10 mL (2 teaspoonfuls) of apple juice and gently tap and/or shake the barrel of the syringe to help rinse the syringe and tube.
Repeat at least twice more using the same amount of apple juice (10 mL or 2 teaspoonfuls) each time.
No granules should remain in the syringe.