Label: PANTOPRAZOLE SODIUM - pantoprazole sodium tablet, delayed release

  • Category: HUMAN PRESCRIPTION DRUG LABEL
  • DEA Schedule: None
  • Marketing Status: Abbreviated New Drug Application

Drug Label Information

Updated 02/13

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  • INDICATIONS & USAGE

    Pantoprazole sodium delayed-release tablets, USP are indicated for:

     

    Pantoprazole sodium delayed-release tablets are indicated in adults for the short-term treatment (up to 8 weeks) in the healing and symptomatic relief of erosive esophagitis. For those adult patients who have not healed after 8 weeks of treatment, an additional 8-week course of pantoprazole sodium delayed-release tablets may be considered. Safety of treatment beyond 8 weeks in pediatric patients has not been established.

    Pediatric indication and usage information in pediatric patients ages five years and older with erosive esophagitis associated with GERD is approved for Wyeth Pharmaceuticals Inc.'s pantoprazole sodium delayed-release tablets. However, due to Wyeth Pharmaceuticals Inc.'s marketing exclusivity rights, this drug product is not labeled with that pediatric information.

     

    Pantoprazole sodium delayed-release tablets are indicated for maintenance of healing of erosive esophagitis and reduction in relapse rates of daytime and nighttime heartburn symptoms in adult patients with GERD. Controlled studies did not extend beyond 12 months.

     

    Pantoprazole sodium delayed-release tablets are indicated for the long-term treatment of pathological hypersecretory conditions, including Zollinger-Ellison syndrome.

     

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  • DOSAGE & ADMINISTRATION

     

    Pantoprazole sodium is supplied as delayed-release tablets. The recommended dosages are outlined in Table 1.
    Table 1: Recommended Dosing Schedule for Pantoprazole Sodium Delayed-Release Tablets
    Indication
    Dose
    Frequency
    Short-Term Treatment of Erosive Esophagitis Associated With GERD
      Adults 40 mg Once daily for up to 8 weeks*
    Maintenance of Healing of Erosive Esophagitis
      Adults 40 mg Once daily
    Pathological Hypersecretory Conditions Including Zollinger-Ellison Syndrome
      Adults 40 mg Twice daily**
    Pediatric dosing information in pediatric patients ages five years and older with erosive esophagitis associated with GERD is approved for Wyeth Pharmaceuticals Inc.’s pantoprazole sodium delayed-release tablets. However, due to Wyeth Pharmaceuticals Inc.’s marketing exclusivity rights, this drug product is not labeled with that pediatric information.

     

    Directions for method of administration for each dosage form are presented in Table 2.
    Table 2: Administration Instructions
    Formulation
    Route
    Instructions*
    Delayed-Release Tablets
    Oral Swallowed whole, with or without food
    Pantoprazole Sodium Delayed-Release Tablets, USP
    Pantoprazole sodium delayed-release tablets should be swallowed whole, with or without food in the stomach. If patients are unable to swallow a 40 mg tablet, two 20 mg tablets may be taken. Concomitant administration of antacids does not affect the absorption of pantoprazole sodium delayed-release tablets.

     

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  • DOSAGE FORMS & STRENGTHS

    Delayed-Release Tablets:
    • 40 mg yellow colored, biconvex oval shaped tablets plain on one side and imprinted with “W434” (brown ink) on other side.
    • 20 mg yellow colored, biconvex oval shaped tablets plain on one side and imprinted with “W433” (brown ink) on other side.

     

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  • CONTRAINDICATIONS

    Pantoprazole sodium delayed-release tablets are contraindicated in patients with known hypersensitivity to any component of the formulation [ see Description (11)] or any substituted benzimidazole.

     

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  • WARNINGS AND PRECAUTIONS

     

    Symptomatic response to therapy with pantoprazole sodium delayed-release tablets does not preclude the presence of gastric malignancy.

     

    Atrophic gastritis has been noted occasionally in gastric corpus biopsies from patients treated long-term with pantoprazole sodium delayed-release tablets, particularly in patients who were H. pylori positive.

     

    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.

     

    Several published observational studies suggest that proton pump inhibitor (PPI) therapy may be associated with an increased risk for osteoporosis-related fractures of the hip, wrist, or spine. The risk of fracture was increased in patients who received high-dose, defined as multiple daily doses, and long-term PPI therapy (a year or longer). Patients should use the lowest dose and shortest duration of PPI therapy appropriate to the condition being treated. Patients at risk for osteoporosis-related fractures should be managed according to established treatment guidelines [ see Dosage and Administration (2) and Adverse Reactions (6.2)].

     

    Due to the chronic nature of GERD, there may be a potential for prolonged administration of pantoprazole sodium delayed-release tablets. In long-term rodent studies, pantoprazole was carcinogenic and caused rare types of gastrointestinal tumors. The relevance of these findings to tumor development in humans is unknown [ see Nonclinical Toxicology (13.1)].

     

    See Drug Interactions (7.4).

     

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  • ADVERSE REACTIONS

     

    Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.

    Adults

    Safety in nine randomized comparative US clinical trials in patients with GERD included 1,473 patients on oral pantoprazole sodium delayed-release tablets (20 mg or 40 mg), 299 patients on an H 2-receptor antagonist, 46 patients on another proton pump inhibitor, and 82 patients on placebo. The most frequently occurring adverse reactions are listed in Table 3.
    Table 3: Adverse Reactions Reported in Clinical Trials of Adult Patients with GERD at a Frequency of > 2%
      Pantoprazole sodium delayed-release tablets
    (n=1473)
    %
    Comparators
    (n=345)
    %
    Placebo
    (n=82)
    %
    Headache
    Diarrhea
    Nausea
    Abdominal pain
    Vomiting
    Flatulence
    Dizziness
    Arthralgia
    12.2
    8.8
    7
    6.2
    4.3
    3.9
    3
    2.8
    12.8
    9.6
    5.2
    4.1
    3.5
    2.9
    2.9
    1.4
    8.5
    4.9
    9.8
    6.1
    2.4
    3.7
    1.2
    1.2
    Additional adverse reactions that were reported for pantoprazole sodium delayed-release tablets in clinical trials with a frequency of ≤ 2% are listed below by body system:

    Body as a Whole: allergic reaction, pyrexia, photosensitivity reaction, facial edema

    Gastrointestinal: constipation, dry mouth, hepatitis

    Hematologic: leukopenia, thrombocytopenia

    Metabolic/Nutritional: elevated CK (creatine kinase), generalized edema, elevated triglycerides, liver enzymes elevated

    Musculoskeletal: myalgia

    Nervous: depression, vertigo

    Skin and Appendages: urticaria, rash, pruritus

    Special Senses: blurred vision

    Adverse reaction information in pediatric patients with erosive esophagitis associated with GERD is approved for Wyeth Pharmaceuticals Inc.'s pantoprazole sodium delayed-release tablets. However, due to Wyeth Pharmaceuticals Inc.'s marketing exclusivity rights, this drug product is not labeled with that pediatric information.

    Zollinger-Ellison Syndrome
    In clinical studies of Zollinger-Ellison Syndrome, adverse reactions reported in 35 patients taking pantoprazole sodium delayed-release tablets 80 mg/day to 240 mg/day for up to 2 years were similar to those reported in adult patients with GERD.

     

    The following adverse reactions have been identified during postapproval use of pantoprazole sodium delayed-release tablets. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

    These adverse reactions are listed below by body system:

    Immune System Disorders: anaphylaxis (including anaphylactic shock)

    Skin and Subcutaneous Tissue Disorders: severe dermatologic reactions (some fatal), including erythema multiforme, Stevens-Johnson syndrome, and toxic epidermal necrolysis (TEN, some fatal), and angioedema (Quincke's edema)

    Musculoskeletal and Connective Tissue Disorders: rhabdomyolysis, bone fracture

    Renal and Urinary Disorders: interstitial nephritis

    Hepatobiliary Disorders: hepatocellular damage leading to jaundice and hepatic failure

    Psychiatric Disorders: hallucination, confusion

     

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  • DRUG INTERACTIONS

     

    Concomitant use of atazanavir or nelfinavir with proton pump inhibitors is not recommended. Coadministration of atazanavir or nelfinavir with proton pump inhibitors is expected to substantially decrease atazanavir or nelfinavir plasma concentrations and may result in a loss of therapeutic effect and development of drug resistance.

     

    There have been postmarketing reports of increased INR and prothrombin time in patients receiving proton pump inhibitors, including pantoprazole sodium delayed-release tablets, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Patients treated with proton pump inhibitors and warfarin concomitantly should be monitored for increases in INR and prothrombin time.

     

    Pantoprazole causes long-lasting inhibition of gastric acid secretion. Therefore, pantoprazole may interfere with absorption of drugs where gastric pH is an important determinant of their bioavailability (e.g., ketoconazole, ampicillin esters, and iron salts).

     

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  • USE IN SPECIFIC POPULATIONS


     

    Teratogenic Effects
    Pregnancy CategoryB

    Reproduction studies have been performed in rats at oral doses up to 88 times the recommended human dose and in
    rabbits at oral doses up to 16 times the recommended human dose and have revealed no evidence of impaired fertility
    or harm to the fetus due to pantoprazole. There are, however, no adequate and well-controlled studies in pregnant
    women. Because animal reproduction studies are not always predictive of human response, this drug should be used
    during pregnancy only if clearly needed [ see Nonclinical Toxicology (13.2)].

     

    Pantoprazole and its metabolites are excreted in the milk of rats. Pantoprazole excretion in human milk has been detected in a study of a single nursing mother after a single 40 mg oral dose. The clinical relevance of this finding is not known. Many drugs which are excreted in human milk have a potential for serious adverse reactions in nursing infants. Based on the potential for tumorigenicity shown for pantoprazole in rodent carcinogenicity studies, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the benefit of the drug to the mother.

     

    The effectiveness of pantoprazole sodium delayed-release tablets for treating symptomatic GERD in pediatric patients has not been established.

    Information describing use in pediatric patients with erosive esophagitis associated with GERD is approved for Wyeth Pharmaceuticals Inc.'s pantoprazole sodium delayed-release tablets.  However, due to Wyeth Pharmaceuticals Inc.'s marketing exclusivity rights, this drug product is not labeled with that pediatric information.

     

    In short-term U.S. clinical trials, erosive esophagitis healing rates in the 107 elderly patients (≥ 65 years old) treated with pantoprazole sodium delayed-release tablets were similar to those found in patients under the age of 65. The incidence rates of adverse reactions and laboratory abnormalities in patients aged 65 years and older were similar to those associated with patients younger than 65 years of age.

     

    Erosive esophagitis healing rates in the 221 women treated with pantoprazole sodium delayed-release tablets in U.S. clinical trials were similar to those found in men. In the 122 women treated long-term with pantoprazole sodium delayed-release tablets 40 mg or 20 mg, healing was maintained at a rate similar to that in men. The incidence rates of adverse reactions were also similar for men and women.

     

    Doses higher than 40 mg/day have not been studied in patients with hepatic impairment [see Clinical Pharmacology (12.3)].

     

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  • OVERDOSAGE

    Experience in patients taking very high doses of pantoprazole sodium delayed-release tablets (> 240 mg) is limited. Spontaneous post-marketing reports of overdose are generally within the known safety profile of pantoprazole sodium delayed-release tablets.

    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.

     

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  • DESCRIPTION

    The active ingredient in pantoprazole sodium delayed-release tablets, USP is a substituted benzimidazole, sodium 5-(difluoromethoxy)-2-[[(3,4-dimethoxy-2-pyridinyl)methyl] sulfinyl]1H-benzimidazole sesquihydrate, a compound that inhibits gastric acid secretion. Its empirical formula is C16H14F2N3NaO4S x 1.5 H2O, with a molecular weight of 432.4. The structural formula is:
    MM1
    Pantoprazole sodium sesquihydrate, USP is a white to off-white powder and is racemic. Pantoprazole has weakly basic and acidic properties. Pantoprazole sodium sesquihydrate, USP is freely soluble in water and practically insoluble in 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 sodium is supplied as a delayed-release tablet for oral administration, available in 2 strengths (40 mg and 20 mg).

    Each delayed-release tablet 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: aerosil 200, calcium stearate, colloidal silicon dioxide, mannitol, pregelatinized starch, shellac glaze, sodium carbonate anhydrous, sodium starch glycolate and talc. Each delayed-release tablet contains ammonium hydroxide, eudragit L 100-55, FD and C Blue #2, hypromellose, iron oxide black, iron oxide red, iron oxide yellow, polyethylene glycol 400, polyethylene glycol 4000, polyethylene glycol 6000, propylene glycol, sodium hydroxide, titanium dioxide and triethyl citrate as the coating ingredients.

    Pantoprazole sodium delayed-release tablets USP, 20 mg and 40 mg, meet USP Dissolution Test 3.

     

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  • CLINICAL PHARMACOLOGY

     

    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).

     

    Antisecretory Activity
    Under maximal acid stimulatory conditions using pentagastrin, a dose-dependent decrease in gastric acid output occurs after a single dose of oral (20-80 mg) or a single dose of intravenous (20-120 mg) pantoprazole in healthy volunteers. Pantoprazole given once daily results in increasing inhibition of gastric acid secretion. Following the initial oral dose of 40 mg pantoprazole, a 51% mean inhibition was achieved by 2.5 hours. With once-a-day dosing for 7 days, the mean inhibition was increased to 85%. Pantoprazole suppressed acid secretion in excess of 95% in half of the subjects. Acid secretion had returned to normal within a week after the last dose of pantoprazole; there was no evidence of rebound hypersecretion.

    In a series of dose-response studies, pantoprazole, at oral doses ranging from 20 to 120 mg, caused dose-related increases in median basal gastric pH and in the percent of time gastric pH was > 3 and > 4. Treatment with 40 mg of pantoprazole produced significantly greater increases in gastric pH than the 20 mg dose. Doses higher than 40 mg (60, 80, 120 mg) did not result in further significant increases in median gastric pH. The effects of pantoprazole on median pH from one double-blind crossover study are shown in Table 4.
    Table 4: Effect of Single Daily Doses of Oral Pantoprazole on Intragastric pH
      –––––––—––––––––Median pH on day 7—–––––––––––––
    Time Placebo 20 mg 40 mg 80 mg
    8 a.m. - 8 a.m.
    (24 hours)
    1.3 2.9* 3.8*# 3.9*#
    8 a.m. - 10 p.m.
    (Daytime)
    1.6 3.2* 4.4*# 4.8*#
    10 p.m. - 8 a.m.
    (Nighttime)
    1.2 2.1* 3* 2.6*
    Serum Gastrin Effects
    Fasting serum gastrin levels were assessed in two double-blind studies of the acute healing of erosive esophagitis (EE) in which 682 patients with gastroesophageal reflux disease (GERD) received 10, 20, or 40 mg of pantoprazole sodium delayed-release tablets for up to 8 weeks. At 4 weeks of treatment there was an increase in mean gastrin levels of 7%, 35%, and 72% over pretreatment values in the 10, 20, and 40 mg treatment groups, respectively. A similar increase in serum gastrin levels was noted at the 8-week visit with mean increases of 3%, 26%, and 84% for the three pantoprazole dose groups. Median serum gastrin levels remained within normal limits during maintenance therapy with pantoprazole sodium delayed-release tablets.

    In long-term international studies involving over 800 patients, a 2- to 3-fold mean increase from the pretreatment fasting serum gastrin level was observed in the initial months of treatment with pantoprazole at doses of 40 mg per day during GERD maintenance studies and 40 mg or higher per day in patients with refractory GERD. Fasting serum gastrin levels generally remained at approximately 2 to 3 times baseline for up to 4 years of periodic follow-up in clinical trials.

    Following short-term treatment with pantoprazole sodium delayed-release tablets, elevated gastrin levels return to normal by at least 3 months.

    Enterochromaffin-Like (ECL) Cell Effects
    In 39 patients treated with oral pantoprazole 40 mg to 240 mg daily (majority receiving 40 mg to 80 mg) for up to 5 years, there was a moderate increase in ECL-cell density, starting after the first year of use, which appeared to plateau after 4 years.

    In a nonclinical study in Sprague-Dawley rats, lifetime exposure (24 months) to pantoprazole at doses of 0.5 to 200 mg/kg/day resulted in dose-related increases in gastric ECL cell proliferation and gastric neuroendocrine (NE)-cell tumors. Gastric NE-cell tumors in rats may result from chronic elevation of serum gastrin concentrations. The high density of ECL cells in the rat stomach makes this species highly susceptible to the proliferative effects of elevated gastrin concentrations produced by proton pump inhibitors. However, there were no observed elevations in serum gastrin following the administration of pantoprazole at a dose of 0.5 mg/kg/day. In a separate study, a gastric NE-cell tumor without concomitant ECL-cell proliferative changes was observed in 1 female rat following 12 months of dosing with pantoprazole at 5 mg/kg/day and a 9 month off-dose recovery [ see Nonclinical Toxicology (13.1)].

     

    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 7.6-14 L/h, and its apparent volume of distribution is 11-23.6 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 11-23.6 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
    Pharmacokinetic information in pediatric patients is approved for Wyeth Pharmaceuticals Inc.'s pantoprazole sodium delayed-release tablets. However, due to Wyeth Pharmaceuticals Inc.'s marketing exclusivity rights, this drug product is not labeled with that pediatric information.

    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 7-9 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 primarily by CYP2C19 and to minor extents by CYPs 3A4, 2D6, and 2C9. In in vivo drug-drug interaction studies with CYP2C19 substrates (diazepam [also a CYP3A4 substrate] and phenytoin [also a CYP3A4 inducer]), nifedipine, midazolam, and clarithromycin (CYP3A4 substrates), metoprolol (a CYP2D6 substrate), diclofenac, naproxen and piroxicam (CYP2C9 substrates), and theophylline (a CYP1A2 substrate) in healthy subjects, the pharmacokinetics of pantoprazole were not significantly altered.

    In vivo studies also suggest that pantoprazole does not significantly affect the kinetics of the following drugs (cisapride, theophylline, diazepam [and its active metabolite, desmethyldiazepam], phenytoin, warfarin, metoprolol, nifedipine, carbamazepine, midazolam, clarithromycin, naproxen, piroxicam, and oral contraceptives [levonorgestrel/ethinyl estradiol]). Dosage adjustment of these drugs is not necessary when they are coadministered with pantoprazole. In other in vivo studies, digoxin, ethanol, glyburide, antipyrine, caffeine, metronidazole, and amoxicillin had no clinically relevant interactions with pantoprazole.

    Based on studies evaluating possible interactions of pantoprazole with other drugs, no dosage adjustment is needed with concomitant use of the following: theophylline, cisapride, antipyrine, caffeine, carbamazepine, diazepam (and its active metabolite, desmethyldiazepam), diclofenac, naproxen, piroxicam, digoxin, ethanol, glyburide, an oral contraceptive (levonorgestrel/ethinyl estradiol), metoprolol, nifedipine, phenytoin, warfarin, midazolam, clarithromycin, metronidazole, or amoxicillin.

    There was also no interaction with concomitantly administered antacids.

    There have been postmarketing reports of increased INR and prothrombin time in patients receiving proton pump inhibitors, including pantoprazole sodium delayed-release tablets, and warfarin concomitantly [ see Drug Interactions (7.2)].

    Although no significant drug-drug interactions have been observed in clinical studies, the potential for significant drug-drug interactions with more than once-daily dosing with high doses of pantoprazole has not been studied in poor metabolizers or individuals who are hepatically impaired.

    Other Effects
    In a clinical pharmacology study, pantoprazole sodium delayed-release tablets  40 mg given once daily for 2 weeks had no effect on the levels of the following hormones: cortisol, testosterone, triiodothyronine (T 3), thyroxine (T 4), thyroid-stimulating hormone (TSH), thyronine-binding protein, parathyroid hormone, insulin, glucagon, renin, aldosterone, follicle-stimulating hormone, luteinizing hormone, prolactin, and growth hormone.

    In a 1-year study of GERD patients treated with pantoprazole sodium delayed-release tablets 40 mg or 20 mg, there were no changes from baseline in overall levels of T 3, T 4, and TSH.

     

    CYP2C19 displays a known genetic polymorphism due to its deficiency in some subpopulations (e.g., approximately 3% of Caucasians and African-Americans and 17% to 23% of Asians are poor metabolizers). Although these subpopulations of pantoprazole poor metabolizers have elimination half-life values of 3.5 to 10 hours in adults, they still have minimal accumulation (≤ 23%) with once-daily dosing. For adult patients who are CYP2C19 poor metabolizers, no dosage adjustment is needed.

    Similar to adults, pediatric patients who have the poor metabolizer genotype of CYP2C19 (CYP2C19 *2/*2) exhibited greater than a 6-fold increase in AUC compared to pediatric extensive (CYP2C19 *1/*1) and intermediate (CYP2C19 *1/*x) metabolizers. Poor metabolizers exhibited approximately 10-fold lower apparent oral clearance compared to extensive metabolizers.

    For known pediatric poor metabolizers, a dose reduction should be considered.

     

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  • NONCLINICAL TOXICOLOGY

     

    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).

     

    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.

     

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  • CLINICAL STUDIES

    Pantoprazole sodium delayed-release tablets were used in the following clinical trials.

     

    Adult Patients
    A US multicenter, double-blind, placebo-controlled study of pantoprazole sodium delayed-release tablets 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 5.
    Table 5: Erosive Esophagitis Healing Rates (Per Protocol)
    –––––––––––Pantoprazole Sodium Delayed-Release Tablets––––––––––– Placebo
    Week 10 mg daily
    (n = 153)
    20 mg daily
    (n = 158)
    40 mg daily
    (n = 162)
    (n = 68)
    4 45.6%+ 58.4%+# 75%+* 14.3%
    8 66%+ 83.5 %+# 92.6%+* 39.7%
    In this study, all pantoprazole sodium delayed-release tablets treatment groups had significantly greater healing rates than the placebo group. This was true regardless of H. pylori status for the 40 mg and 20 mg pantoprazole sodium delayed-release tablets treatment groups. The 40 mg dose of pantoprazole sodium delayed-release tablets resulted in healing rates significantly greater than those found with either the 20 mg or 10 mg dose.  

    A significantly greater proportion of patients taking pantoprazole sodium delayed-release tablets 40 mg experienced complete relief of daytime and nighttime heartburn and the absence of regurgitation, starting from the first day of treatment, compared with placebo. Patients taking pantoprazole sodium delayed-release tablets consumed significantly fewer antacid tablets per day than those taking placebo.

    Pantoprazole sodium delayed-release tablets 40 mg and 20 mg once daily were also compared with nizatidine 150 mg twice daily in a 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 6.
    Table 6: Erosive Esophagitis Healing Rates (Per Protocol)

    ––––Pantoprazole Sodium Delayed-Release Tablets–––––
    Nizatidine
    Week 20 mg daily
    (n = 72)
    40 mg daily
    (n = 70)
    150 mg twice daily
    (n = 70)
    4 61.4%+ 64%+ 22.2%
    8 79.2%+ 82.9%+ 41.4%
    Once-daily treatment with pantoprazole sodium delayed-release tablets 40 mg or 20 mg resulted in significantly superior rates of healing at both 4 and 8 weeks compared with twice-daily treatment with 150 mg of nizatidine. For the 40 mg treatment group, significantly greater healing rates compared to nizatidine were achieved regardless of the H. pylori status.

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

    Clinical study information in pediatric patients ages five years through 16 years with erosive esophagitis associated with GERD is approved for Wyeth Pharmaceuticals Inc.'s pantoprazole sodium delayed-release tablets.  However, due to Wyeth Pharmaceuticals Inc.'s marketing exclusivity rights, this drug product is not labeled with that pediatric information.

     

    Two independent, multicenter, randomized, double-blind, comparator-controlled trials of identical design were conducted in adult GERD patients with endoscopically confirmed healed erosive esophagitis to demonstrate efficacy of pantoprazole sodium delayed-release tablets in long-term maintenance of healing. The two 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 7, pantoprazole sodium delayed-release tablets 40 mg and 20 mg were significantly superior to ranitidine at every timepoint with respect to the maintenance of healing. In addition, pantoprazole sodium delayed-release tablet 40 mg was superior to all other treatments studied.
    Table 7: Long-Term Maintenance of Healing of Erosive Gastroesophageal Reflux Disease (GERD Maintenance): Percentage of Patients Who Remained Healed
      Pantoprazole Sodium Delayed-Release Tablets
    20 mg daily
    Pantoprazole Sodium Delayed-Release Tablets
    40 mg daily
    Ranitidine
    150 mg twice daily
    Study 1
    n = 75 n = 74 n = 75
    Month 1
    Month 3
    Month 6
    Month 12
    91*
    82*
    76*
    70*
    99*
    93*#
    90*#
    86*#
    68
    54
    44
    35
    Study 2
    n = 74 n = 88 n = 84
    Month 1
    Month 3
    Month 6
    Month 12
    89*
    78*
    72*
    72*
    92*#
    91*#
    88*#
    83*
    62
    47
    39
    37
    Pantoprazole sodium delayed-release tablet 40 mg was superior to ranitidine in reducing the number of daytime and nighttime heartburn episodes from the first through the twelfth month of treatment. Pantoprazole sodium delayed-release tablet 20 mg, administered once daily was also effective in reducing episodes of daytime and nighttime heartburn in one trial, as presented in Table 8.
    Table 8: Number of Episodes of Heartburn (mean ± SD)
        Pantoprazole Sodium Delayed-Release Tablet
    40 mg daily
    Ranitidine
    150 mg twice daily
    Month 1 Daytime
    Nighttime
    5.1 ± 1.6*
    3.9 ± 1.1*
    18.3 ± 1.6
    11.9 ± 1.1
    Month 12 Daytime
    Nighttime
    2.9 ± 1.5*
    2.5 ± 1.2*
    17.5 ± 1.5
    13.8 ± 1.3

     

    In a multicenter, open-label trial of 35 patients with pathological hypersecretory conditions, such as Zollinger-Ellison syndrome, with or without multiple endocrine neoplasia-type I, pantoprazole sodium delayed-release tablets successfully controlled gastric acid secretion. Doses ranging from 80 mg daily to 240 mg daily maintained gastric acid output below 10 mEq/h in patients without prior acid-reducing surgery and below 5 mEq/h in patients with prior acid-reducing surgery.

    Doses were initially titrated to the individual patient needs, and adjusted in some patients based on the clinical response with time [see Dosage and Administration (2)]. Pantoprazole sodium delayed-release tablet was well tolerated at these dose levels for prolonged periods (greater than 2 years in some patients).

     

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  • HOW SUPPLIED

    How Supplied

    Pantoprazole sodium delayed-release tablets, USP are supplied as 20 mg yellow colored, biconvex oval shaped tablets plain on one side and imprinted with “W433” (brown ink) on other side.

    HDPE bottle of 30 tablets.............................NDC 64679-433-01
    HDPE bottle of 90 tablets.............................NDC 64679-433-04
    HDPE bottle of 1000 tablets.........................NDC 64679-433-02
    Unit dose packages of 100 tablets…..........NDC 64679-433-03
    HDPE bottle of 100 tablets...........................NDC 64679-433-05

    Pantoprazole sodium delayed-release tablets, USP are supplied as 40 mg yellow colored, biconvex oval shaped tablets plain on one side and imprinted with “W434” (brown ink) on other side.

    HDPE bottle of 30 tablets............................NDC 64679-434-01
    HDPE bottle of 90 tablets............................NDC 64679-434-04
    HDPE bottle of 1000 tablets........................NDC 64679-434-02
    Unit dose packages of 100 tablets.............NDC 64679-434-03
    HDPE bottle of 100 tablets..........................NDC 64679-434-05

    Storage
    Store at 20°-25°C (68°-77°F); [See USP Controlled Room Temperature].

     

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  • INFORMATION FOR PATIENTS

    See FDA-Approved Patient Labeling.

    Patient Counseling

     

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  • PACKAGE LABEL.PRINCIPAL DISPLAY PANEL SECTION

    DRUG: PANTOPRAZOLE SODIUM
    GENERIC: PANTOPRAZOLE SODIUM
    DOSAGE: TABLET, DELAYED RELEASE
    ADMINSTRATION: ORAL
    NDC: 49349-984-02
    STRENGTH:20 mg
    COLOR: yellow
    SHAPE: OVAL
    SCORE: No score
    SIZE: 9 mm
    IMPRINT: 30
    QTY: 30

    MM2
    MM3
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  • INGREDIENTS AND APPEARANCE
    PANTOPRAZOLE SODIUM 
    pantoprazole sodium tablet, delayed release
    Product Information
    Product Type HUMAN PRESCRIPTION DRUG LABEL Item Code (Source) NDC:49349-984(NDC:64679-433)
    Route of Administration ORAL DEA Schedule     
    Active Ingredient/Active Moiety
    Ingredient Name Basis of Strength Strength
    PANTOPRAZOLE SODIUM (PANTOPRAZOLE) PANTOPRAZOLE 20 mg
    Inactive Ingredients
    Ingredient Name Strength
    MANNITOL HEXANITRATE  
    STARCH, CORN  
    COLLOIDAL SILICON DIOXIDE  
    CALCIUM STEARATE  
    TALC  
    SODIUM STARCH GLYCOLATE TYPE A POTATO  
    TITANIUM DIOXIDE  
    POLYETHYLENE GLYCOL 4000000  
    FERRIC OXIDE YELLOW  
    FD&C BLUE NO. 2  
    METHACRYLIC ACID - ETHYL ACRYLATE COPOLYMER (1:1) TYPE A  
    SODIUM HYDROXIDE  
    TRIETHYL CITRATE  
    POLYETHYLENE GLYCOL 600000  
    SHELLAC  
    FERROSOFERRIC OXIDE  
    FERRIC OXIDE RED  
    PROPYLENE GLYCOL 1,2-DISTEARATE  
    HYPROMELLOSES  
    Product Characteristics
    Color yellow Score no score
    Shape OVAL (TABLET, DELAYED RELEASE) Size 9mm
    Flavor Imprint Code W433
    Contains     
    Packaging
    # Item Code Package Description Marketing Start Date Marketing End Date
    1 NDC:49349-984-02 30 in 1 BLISTER PACK
    Marketing Information
    Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date
    ANDA ANDA091231 02/08/2013
    Labeler - REMEDYREPACK INC. (829572556)
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