Pantoprazole Sodium

Pantoprazole sodium sesquihydrate USP is a white to off-white 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.

Pantoprazole is supplied as delayed-release tablets, available in two strengths (20 mg and 40 mg).

Each pantoprazole sodium delayed-release tablet USP contains 45.1 mg or 22.56 mg of pantoprazole sodium sesquihydrate USP (equivalent to 40 mg or 20 mg pantoprazole, respectively) with the following inactive ingredients: calcium stearate USNF, ferric oxide red USNF, ferric oxide black, hypromellose USP, hypromellose phthalate USNF, mannitol USP, methacrylic acid copolymer USNF, polyethylene glycol USNF,  silicon dioxide USNF, sodium carbonate USNF, sucrose USNF, talc USP, titanium dioxide USP, triethyl citrate USNF. In addition to the above, printing ink used to imprint the tablet contains ammonium hydroxide USNF, ferric oxide black, propylene glycol USP, and shellac USNF. Pantoprazole Sodium Delayed-Release Tablets USP (40 mg and 20 mg) comply with USP dissolution test 4.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Pantoprazole is a proton pump inhibitor (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).

12.2 Pharmacodynamics

Antisecretory Activity

Under 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 to120 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

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 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, 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 14.0 L/h, and its apparent volume of distribution is 11.0 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 11.0 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 ¹⁴C-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. A pediatric granule formulation was studied in children through 5 years of age, and Pantoprazole Sodium Delayed-Release Tablets were studied in children older than 5 years.

In a population PK analysis, total clearance increased with increasing bodyweight in a non-linear fashion. The total clearance also increased with increasing age only in children under 3 years of age.

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 Tablets in pediatric patients was about 39% and 10% higher respectively in 6 to 11 and 12 to 16 year-old children, compared to that of adults (Table 5).

Table 5: PK Parameters in Children and Adolescents 6 through 16 years with GERD receiving 40 mg Pantoprazole Sodium Delayed-Release Tablets

^a Geometric mean values 
^b Median values

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 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 5µM ADP) was correlated with the change in the exposure to clopidogrel active metabolite. The clinical significance of this finding is not clear.

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, 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 40 mg given once daily for 2 weeks had no effect on the levels of the following hormones: cortisol, testosterone, triiodothyronine (T₃), thyroxine (T₄), 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 40 mg or 20 mg, there were no changes from baseline in overall levels of T₃, T₄, 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 10.0 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.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

In a 24-month carcinogenicity study, Sprague-Dawley rats were treated orally with doses of 0.5 to 200 mg/kg/day, about 0.1 to 40 times the exposure on a body surface area basis of a 50 kg person dosed at 40 mg/day. In the gastric fundus, treatment at 0.5 to 200 mg/kg/day produced enterochromaffin-like (ECL) cell hyperplasia and benign and malignant neuroendocrine cell tumors in a dose-related manner. In the forestomach, treatment at 50 and 200 mg/kg/day (about 10 and 40 times the recommended human dose on a body surface area basis) produced benign squamous cell papillomas and malignant squamous cell carcinomas. Rare gastrointestinal tumors associated with pantoprazole treatment included an adenocarcinoma of the duodenum at 50 mg/kg/day and benign polyps and adenocarcinomas of the gastric fundus at 200 mg/kg/day. In the liver, treatment at 0.5 to 200 mg/kg/day produced dose-related increases in the incidences of hepatocellular adenomas and carcinomas. In the thyroid gland, treatment at 200 mg/kg/day produced increased incidences of follicular cell adenomas and carcinomas for both male and female rats.

In a 24-month carcinogenicity study, Fischer 344 rats were treated orally with doses of 5 to 50 mg/kg/day, approximately 1 to 10 times the recommended human dose based on body surface area. In the gastric fundus, treatment at 5 to 50 mg/kg/day produced enterochromaffin-like (ECL) cell hyperplasia and benign and malignant neuroendocrine cell tumors. Dose selection for this study may not have been adequate to comprehensively evaluate the carcinogenic potential of pantoprazole.

In a 24-month carcinogenicity study, B6C3F1 mice were treated orally with doses of 5 to 150 mg/kg/day, 0.5 to 15 times the recommended human dose based on body surface area. In the liver, treatment at 150 mg/kg/day produced increased incidences of hepatocellular adenomas and carcinomas in female mice. Treatment at 5 to 150 mg/kg/day also produced gastric-fundic ECL cell hyperplasia.

A 26-week p53 +/- transgenic mouse carcinogenicity study was not positive.

Pantoprazole was positive in the in vitro 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.

14 CLINICAL STUDIES

Pantoprazole Sodium Delayed-Release Tablets were used in the following clinical trials.

14.1 Erosive Esophagitis (EE) Associated with Gastroesophageal Reflux Disease (GERD)

A US multicenter, double-blind, placebo-controlled study of pantoprazole 10 mg, 20 mg, or 40 mg once daily was conducted in 603 patients with reflux symptoms and endoscopically diagnosed EE of grade 2 or above (Hetzel-Dent scale). In this study, approximately 25% of enrolled patients had severe EE of grade 3, and 10% had grade 4. The percentages of patients healed (per protocol, n = 541) in this study are shown in Table 6.

Table 6: Erosive Esophagitis Healing Rates (Per Protocol)

+ (p < 0.001) Pantoprazole versus placebo
* (p < 0.05) versus 10 mg or 20 mg Pantoprazole
# (p < 0.05) versus 10 mg Pantoprazole

In this study, all pantoprazole 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 treatment groups. The 40 mg dose of pantoprazole 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 40 mg experienced complete relief of daytime and nighttime heartburn and the absence of regurgitation, starting from the first day of treatment, compared with placebo. Patients taking pantoprazole consumed significantly fewer antacid tablets per day than those taking placebo.

Pantoprazole 40 mg and 20 mg once daily were also compared with nizatidine 150 mg twice daily in a 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 7.

Table 7: Erosive Esophagitis Healing Rates (Per Protocol)

+ (p < 0.001) Pantoprazole versus nizatidine

Once-daily treatment with pantoprazole 40 mg or 20 mg resulted in significantly superior rates of healing at both 4 and 8 weeks compared with twice-daily treatment with 150 mg of nizatidine. For the 40 mg treatment group, significantly greater healing rates compared to nizatidine were achieved regardless of the H. pylori status.

A significantly greater proportion of the patients in the pantoprazole treatment groups experienced complete relief of nighttime heartburn and regurgitation, starting on the first day and of daytime heartburn on the second day, compared with those taking nizatidine 150 mg twice daily. Patients taking pantoprazole consumed significantly fewer antacid tablets per day than those taking nizatidine.

Pediatric Patients Ages 5 Years through 16 Years
The efficacy of pantoprazole in the treatment of EE associated with GERD in pediatric patients ages 5 years through 16 years is extrapolated from adequate and well-conducted trials in adults, as the pathophysiology is thought to be the same. Four pediatric patients with endoscopically diagnosed EE were studied in multicenter, randomized, double-blind, parallel-treatment trials. Children with endoscopically diagnosed EE (defined as an endoscopic Hetzel-Dent score ≥ 2) were treated once daily for 8 weeks with one of two dose levels of pantoprazole (20 mg or 40 mg). All 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 in long-term maintenance of healing. The two US studies enrolled 386 and 404 patients, respectively, to receive either 10 mg, 20 mg, or 40 mg of Pantoprazole Sodium Delayed-Release Tablets once daily or 150 mg of ranitidine twice daily. As demonstrated in Table 8, pantoprazole 40 mg and 20 mg were significantly superior to ranitidine at every timepoint with respect to the maintenance of healing. In addition, pantoprazole 40 mg was superior to all other treatments studied.

Table 8: Long-Term Maintenance of Healing of Erosive Gastroesophageal Reflux Disease (GERD Maintenance): Percentage of Patients Who Remained Healed

* (p < 0.05 vs. ranitidine)
 # (p < 0.05 vs. pantoprazole 20 mg)
Note: Pantoprazole 10 mg was superior (p < 0.05) to ranitidine in Study 2, but not Study 1.

Pantoprazole 40 mg was superior to ranitidine in reducing the number of daytime and nighttime heartburn episodes from the first through the twelfth month of treatment. Pantoprazole 20 mg, administered once daily, was also effective in reducing episodes of daytime and nighttime heartburn in one trial, as presented in Table 9.

Table 9: Number of Episodes of Heartburn (mean ± SD)

* (p < 0.001 vs. ranitidine, combined data from the two US studies)

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 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 was well tolerated at these dose levels for prolonged periods (greater than 2 years in some patients).

16 HOW SUPPLIED/STORAGE AND HANDLING

How Supplied

Pantoprazole Sodium Delayed-Release Tablets USP 20 mg (pantoprazole) are light  pink to pink colored, biconvex, circular, coated tablets, imprinted with 'C283' on one side and plain on the other side. 

Bottle of 30 - 68788-9660-3

Bottle of 60 - 68788-9660-6

Bottle of 90 - 68788-9660-9

Bottle of 100 - 68788-9660-1

Bottle of 120 - 68788-9660-8

Storage

Store 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].

17 PATIENT COUNSELING INFORMATION

See FDA-Approved Medication Guide.

• •Caution patients that Pantoprazole Sodium Delayed-Release Tablets USP should not be split, crushed, or chewed.
• •Tell patients that Pantoprazole Sodium Delayed-Release Tablets USP should be swallowed whole, with or without food in the stomach.
• •Let patients know that concomitant administration of antacids does not affect the absorption of Pantoprazole Sodium Delayed-Release Tablets USP.
• •Advise patients to immediately report and seek care for any cardiovascular or neurological symptoms including palpitation, dizziness, seizures, and tetany as these may be signs of hypomagnesemia [see Warnings and Precautions (5.6)].
• •Advise patients to immediately report and seek care for diarrhea that does not improve.This may be a sign of Clostridium difficile associated diarrhea [see Warnings and Precautions (5.4)].

Rx Only

Manufactured by:
Jubilant Life Sciences Limited
Roorkee - 247661, India

Marketed by:
Jubilant Cadista Pharmaceuticals Inc.
Salisbury, MD 21801, USA

Revised: February/2014

Repackaged by Preferred Pharmaceuticals, Inc.

MEDICATION GUIDE

PANTOPRAZOLE SODIUM DELAYED-RELEASE TABLETS USP

Read this Medication Guide before you start taking Pantoprazole Sodium Delayed-Release Tablets USP and each time you get a refill. There may be new information. This information does not take the place of talking with your doctor about your medical condition or your treatment.

What is the most important information I should know about Pantoprazole Sodium Delayed-Release Tablets USP?    

Pantoprazole Sodium Delayed-Release Tablets USP may help your acid-related symptoms, but you could still have serious stomach problems. Talk with your doctor.     

Pantoprazole Sodium Delayed-Release Tablets USP can cause serious side effects, including:

•   Diarrhea. Pantoprazole Sodium Delayed-Release Tablets USP may increase your risk of getting severe diarrhea.This diarrhea may be caused by an infection (Clostridium difficile) in your intestines.
•  Call your doctor right away if you have watery stool, stomach pain, and fever that does not go away.
•   Bone fractures.  People who take multiple daily doses of proton pump inhibitor medicines for a long period of time (a year or longer) may have an increased risk of fractures of the hip, wrist or spine.  You should take Pantoprazole Sodium Delayed-Release Tablets USP exactly as prescribed, at the lowest dose possible for your treatment and for the shortest time needed. Talk to your doctor about your risk of bone fracture if you take Pantoprazole Sodium Delayed-Release Tablets USP.

Pantoprazole Sodium Delayed-Release Tablets USP can have other serious side effects.  See “What are the possible side effects of Pantoprazole Sodium Delayed-Release Tablets USP?”

What are Pantoprazole Sodium Delayed-Release Tablets USP?

Pantoprazole Sodium Delayed-Release Tablets USP are a prescription medicine called a proton pump inhibitor (PPI). Pantoprazole Sodium Delayed-Release Tablets USP reduce the amount of acid in your stomach.

Pantoprazole Sodium Delayed-Release Tablets USP are used in adults:

•  for up to 8 weeks to heal acid-related damage to the lining of the esophagus (erosive esophagitis or EE) and to relieve symptoms caused by gastroesophageal reflux disease (GERD).  If needed, your doctor may decide to prescribe another 8 weeks of Pantoprazole Sodium Delayed-Release Tablets USP.
•  to maintain the healing of acid-related damage to the lining of the esophagus and help prevent return of heartburn symptoms caused by GERD. It is not known if Pantoprazole Sodium Delayed-Release Tablets USP are safe and effective if used longer than 12 months (1 year).
•  GERD happens when acid in your stomach backs up into the tube (esophagus) that connects your mouth to your stomach. This may cause a burning feeling in your chest or throat, sour taste, or burping.
•  for the long-term treatment of conditions where your stomach makes too much acid.This includes a rare condition called Zollinger-Ellison syndrome.
  

Pantoprazole Sodium Delayed-Release Tablets USP are used in children 5 years of age and older for up to 8 weeks to heal acid-related damage to the lining of the esophagus (erosive esophagitis or EE) caused by GERD.
It is not known if Pantoprazole Sodium Delayed-Release Tablets USP are safe if used longer than 8 weeks in children. Pantoprazole Sodium Delayed-Release Tablets USP are not for use in children under 5 years of age.

Who should not take Pantoprazole Sodium Delayed-Release Tablets USP?

Do not take Pantoprazole Sodium Delayed-Release Tablets USP if you are:

•  allergic to pantoprazole sodium or any of the other ingredients in Pantoprazole Sodium Delayed-Release Tablets USP. See the end of this Medication Guide for a complete list of ingredients in Pantoprazole Sodium Delayed-Release Tablets USP.
•  allergic to any proton pump inhibitor (PPI) medicine.

What should I tell my doctor before taking Pantoprazole Sodium Delayed-Release Tablets USP?

Before taking Pantoprazole Sodium Delayed-Release Tablets USP, tell your doctor if you:

•  have been told that you have low magnesium levels in your blood
•  have liver problems
•  have any other medical conditions
•  are pregnant or plan to become pregnant. It is not known if Pantoprazole Sodium Delayed-Release Tablets USP will harm your unborn baby.
•  are breastfeeding or plan to breastfeed. Pantoprazole may pass into your milk. You and your doctor should decide if you will take Pantoprazole Sodium Delayed-Release Tablets USP or breastfeed. You should not do both. Talk with your doctor about the best way to feed your baby if you take Pantoprazole Sodium Delayed-Release Tablets USP.

Tell your doctor about all of the medicines you take, including prescription and non‑-prescription drugs, vitamins and herbal supplements. Pantoprazole Sodium Delayed-Release Tablets USP may affect how other medicines work, and other medicines may affect how Pantoprazole Sodium Delayed-Release Tablets USP works.

Especially tell your doctor if you take:

•  atazanavir (Reyataz)
•  nelfinavir (Viracept)
•  warfarin (Coumadin,  Jantoven)
•  ketoconazole (Nizoral)
•  a product that contains iron
•  an antibiotic that contains ampicillin
•  methotrexate

Ask your doctor or pharmacist for a list of these medicines, if you are not sure.

Know the medicines that you take. Keep a list of them to show your doctor and pharmacist when you get a new medicine.

How should I take Pantoprazole Sodium Delayed-Release Tablets USP?

• •Take Pantoprazole Sodium Delayed-Release Tablets USP exactly as prescribed by your doctor.
• •Do not change your dose or stop Pantoprazole Sodium Delayed-Release Tablets USP without talking to your doctor.
• •If you forget to take a dose of Pantoprazole Sodium Delayed-Release Tablets USP, take it as soon as you remember. If it is almost time for your next dose, do not take the missed dose. Take the next dose at your regular time. Do not take two doses to try to make up for a missed dose.
• •If you take too much Pantoprazole Sodium Delayed-Release Tablets USP, call your doctor right away or go to the nearest hospital emergency room.
• •See the Instructions for Use at the end of this Medication Guide for detailed instructions about:
  • •how to take Pantoprazole Sodium Delayed-Release Tablets USP

What are the possible side effects of  Pantoprazole Sodium Delayed-Release Tablets USP?

Pantoprazole Sodium Delayed-Release Tablets USP may cause serious side effects, including:

See “What is the most important information I should know about Pantoprazole Sodium Delayed-Release Tablets USP?”

• • Chronic (lasting a long time) inflammation of the lining of the stomach (Atrophic Gastritis).  Taking Pantoprazole Sodium Delayed-Release Tablets USP for a long period of time may increase the risk of inflammation to your stomach lining. You may or may not have symptoms.  Tell your doctor if you have stomach pain, nausea, vomiting or weight loss.
• • Vitamin B-12 deficiency. Pantoprazole Sodium Delayed-Release Tablets USP reduces the amount of acid in your stomach.Stomach acid is needed to absorb vitamin B-12 properly.  Talk with your doctor about the possibility of vitamin B-12 deficiency if you have been on Pantoprazole Sodium Delayed-Release Tablets USP for a long time (more than 3 years).
• • Low magnesium levels in your body.  This problem can be serious.  Low magnesium can happen in some people who take a proton pump inhibitor medicine for at least 3 months.  If low magnesium levels happen, it is usually after a year of treatment.  You may or may not have symptoms of low magnesium.

Tell your doctor right away if you have any of these symptoms:

•  seizures
•  dizziness
•  abnormal or fast heartbeat
•  jitteriness
•  jerking movements or shaking (tremors)
•  muscle weakness
•  spasms of the hands and feet
•  cramps or muscle aches
•  spasm of the voice box

Your doctor may check the level of magnesium in your body before you start taking Pantoprazole Sodium Delayed-Release Tablets USP or during treatment, if you will be taking Pantoprazole Sodium Delayed-Release Tablets USP for a long period of time.

The most common side effects with Pantoprazole Sodium Delayed-Release Tablets USP in adults include:

The most common side effects with Pantoprazole Sodium Delayed-Release Tablets USP in children include:

Other side effects:

• • Serious allergic reactions. Tell your doctor if you get any of the following symptoms with Pantoprazole Sodium Delayed-Release Tablets USP:
  • •rash
  • •face swelling
  • •throat tightness
  • •difficult breathing

Your doctor may stop Pantoprazole Sodium Delayed-Release Tablets USP if these symptoms happen.

Tell your doctor about any side effects that bother you or that do not go away.

These are not all the possible side effects with Pantoprazole Sodium Delayed-Release Tablets USP. For more information, ask your doctor or pharmacist. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

How should I store Pantoprazole Sodium Delayed-Release Tablets USP?

•  Store 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].

Keep Pantoprazole Sodium Delayed-Release Tablets USP and all medicines out of the reach of children.

General information about Pantoprazole Sodium Delayed-Release Tablets USP

Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use Pantoprazole Sodium Delayed-Release Tablets USP for a condition for which it was not prescribed. Do not give  Pantoprazole Sodium Delayed-Release Tablets USP to other people, even if they have the same symptoms you have. It may harm them.

This Medication Guide summarizes the most important information about Pantoprazole Sodium Delayed-Release Tablets USP. For more information, ask your doctor. You can ask your doctor or pharmacist for information that is written for healthcare professionals.

For more information, call toll-free 1-800-313-4623.

What are the ingredients in Pantoprazole Sodium Delayed-Release Tablets USP?

Active ingredient: pantoprazole sodium sesquihydrate USP
Inactive ingredients : calcium stearate USNF, ferric oxide red USNF, ferric oxide black, hypromellose USP, hypromellose phthalate USNF, mannitol USP, methacrylic acid copolymer USNF, polyethylene glycol USNF, silicon
dioxide USNF, sodium carbonate USNF, sucrose USNF, talc USP, titanium dioxide USP, triethyl citrate USNF. In addition to the above, printing ink used to imprint the delayed-release tablet contains ammonium hydroxide USNF,
ferric oxide black, propylene glycol USP, and shellac USNF. 

Instructions for Use

Pantoprazole Sodium Delayed-Release Tablets USP

• •You can take Pantoprazole Sodium Delayed-Release Tablets USP with food or on an empty stomach.
• •Swallow Pantoprazole Sodium Delayed-Release Tablets USP whole.
• •If you have trouble swallowing a Pantoprazole Sodium Delayed-Release Tablets USP 40 mg, you can take two 20 mg tablets instead.
• •Do not split, chew, or crush Pantoprazole Sodium Delayed-Release Tablets USP.

This Medication Guide has been approved by the U.S. Food and Drug Administration.

All brand names listed are the registered trademarks of their respective owners and are not trademarks of Jubilant Life Sciences Limited.

Rx Only
Manufactured by:
Jubilant Life Sciences Limited
Roorkee - 247661, India

Marketed by:
Jubilant Cadista Pharmaceuticals Inc.
Salisbury, MD 21801, USA

Revised: February/2014

Repackaged by Preferred Pharmaceuticals, Inc.

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL

Pantoprazole Sodium Delayed-Release Tablets, USP 20 mg* 

PHARMACIST: Dispense the accompanying medication guide to each patient. 

Tablets must not be spilt, chewed, or crushed before administration. 

R_x  Only