Protonix 40 MG Delayed Release Oral Tablet

Generic Name: PANTOPRAZOLE SODIUM
Brand Name: Protonix Delayed-Release
  • Substance Name(s):
  • PANTOPRAZOLE SODIUM

DRUG INTERACTIONS

7 Do not co-administer with atazanavir or nelfinavir (7.1) Concomitant warfarin use may require monitoring (7.2) May interfere with the absorption of drugs where gastric pH is important for bioavailability (e.g.

ketoconazole, ampicillin esters, atazanavir, iron salts, erlotinib and mycophenolate mofetil) (7.4) May produce false-positive urine screen for THC (7.5) Methotrexate: PROTONIX may increase serum level of methotrexate (7.6) 7.1 Interference with Antiretroviral Therapy Concomitant use of atazanavir or nelfinavir with proton pump inhibitors is not recommended.

Co-administration 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.

7.2 Coumarin Anticoagulants There have been postmarketing reports of increased INR and prothrombin time in patients receiving proton pump inhibitors, including PROTONIX, 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.

7.3 Clopidogrel 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)].

No dose adjustment of clopidogrel is necessary when administered with an approved dose of PROTONIX.

7.4 Drugs for Which Gastric pH Can Affect Bioavailability Due to its effects on gastric acid secretion, pantoprazole can reduce the absorption of drugs where gastric pH is an important determinant of their bioavailability.

Like with other drugs that decrease the intragastric acidity, the absorption of drugs such as ketoconazole, ampicillin esters, atazanavir, iron salts, erlotinib, and mycophenolate mofetil (MMF) can decrease.

Co-administration of pantoprazole 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.

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 Clinical Pharmacology (12.3) ].

7.5 False Positive Urine Tests for THC There have been reports of false positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving proton pump inhibitors.

An alternative confirmatory method should be considered to verify positive results.

7.6 Methotrexate Case reports, published population pharmacokinetic studies, and retrospective analyses suggest that concomitant administration of PPIs and methotrexate (primarily at high dose; see methotrexate prescribing information) may elevate and prolong serum levels of methotrexate and/or its metabolite hydroxymethotrexate.

However, no formal drug interaction studies of Methotrexate with PPIs have been conducted [see Warnings and Precautions (5.10)].

OVERDOSAGE

10 Experience in patients taking very high doses of PROTONIX (> 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.

DESCRIPTION

11 The active ingredient in PROTONIX (pantoprazole sodium) For Delayed-Release Oral Suspension and PROTONIX (pantoprazole sodium) Delayed-Release Tablets 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 × 1.5 H2O, 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 (pantoprazole sodium) is supplied as a for delayed-release oral suspension, available in one strength (40 mg), and as a delayed-release tablet, available in two strengths (20 mg and 40 mg).

Each PROTONIX (pantoprazole sodium) Delayed-Release Tablet contains 45.1 mg or 22.56 mg of pantoprazole sodium sesquihydrate (equivalent to 40 mg or 20 mg pantoprazole, respectively) with 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 (pantoprazole sodium) For Delayed-Release Oral Suspension, 40 mg, contains the active ingredient pantoprazole sodium sesquihydrate in the form of enteric-coated granules in unit dose packets.

Each unit dose packet contains enteric-coated granules containing 45.1 mg pantoprazole sodium sesquihydrate (equivalent to 40 mg of pantoprazole) with 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 7.

Table 7: 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 8.

Table 8: 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 erosive esophagitis 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 9, 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 9: 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 10.

Table 10: 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 40 mg yellow, oval biconvex delayed-release tablets imprinted with PROTONIX (brown ink) on one side and are available as follows: NDC 0008-0841-81, bottles of 90 PROTONIX (pantoprazole sodium) Delayed-Release Tablets are supplied as 20 mg yellow oval biconvex delayed-release tablets imprinted with P20 (brown ink) on one side and are available as follows: NDC 0008-0843-81, bottles of 90 PROTONIX (pantoprazole sodium) For Delayed-Release Oral Suspension 40 mg contains pale yellowish to dark brownish, enteric-coated granules in a 40 mg 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, Atrophic Gastritis removed (5.2) 10/2016 Warnings and Precautions, Cutaneous and Systemic Lupus Erythematosus (5.5) 10/2016 Warnings and Precautions, Interference with Laboratory Tests (5.11) 2/2017

GERIATRIC USE

8.5 Geriatric Use In short-term US clinical trials, erosive esophagitis 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, yellow oval biconvex tablets imprinted with PROTONIX (brown ink) on one side 20 mg, yellow oval biconvex tablets imprinted with P20 (brown ink) on one side For Delayed-Release Oral Suspension: 40 mg, pale yellowish to dark brownish, enteric-coated granules in a unit dose packet Delayed-Release Tablets, 20 mg and 40 mg (3) For Delayed-Release Oral Suspension, 40 mg (3)

MECHANISM OF ACTION

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).

INDICATIONS AND USAGE

1 PROTONIX For Delayed-Release Oral Suspension and PROTONIX Delayed-Release Tablets are indicated for: PROTONIX is a proton pump inhibitor 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 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.

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 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.

1.3 Pathological Hypersecretory Conditions Including Zollinger-Ellison Syndrome PROTONIX is indicated for the long-term treatment of pathological hypersecretory conditions, including Zollinger-Ellison syndrome.

PEDIATRIC USE

8.4 Pediatric Use The safety and effectiveness of PROTONIX for short-term treatment (up to eight weeks) of erosive esophagitis (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), and 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.

PREGNANCY

8.1 Pregnancy Teratogenic Effects Pregnancy Category B 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)].

NUSRING MOTHERS

8.3 Nursing Mothers 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.

WARNING AND CAUTIONS

5 WARNINGS AND PRECAUTIONS In adults, symptomatic response does not preclude presence of gastric malignancy.

Consider additional follow-up and diagnostic testing.

(5.1) Acute interstitial nephritis has been observed in patients taking PPIs.

(5.2) 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) Cutaneous and Systemic Lupus Erythematosus: Mostly cutaneous; new onset or exacerbation of existing disease; discontinue PROTONIX and refer to specialist for evaluation.

(5.5) Cyanocobalamin (Vitamin B-12) Deficiency: Daily long-term use (e.g., longer than 3 years) may lead to malabsorption or a deficiency of cyanocobalamin.

(5.6) Hypomagnesemia has been reported rarely with prolonged treatment with PPIs (5.7) 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 Interstitial Nephritis Acute interstitial nephritis has been observed in patients taking PPIs including PROTONIX.

Acute interstitial nephritis may occur at any point during PPI therapy and is generally attributed to an idiopathic hypersensitivity reaction.

Discontinue PROTONIX if acute interstitial nephritis develops [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 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)].

5.5 Cutaneous and Systemic Lupus Erythematosus Cutaneous lupus erythematosus (CLE) and systemic lupus erythematosus (SLE) have been reported in patients taking PPIs, including pantoprazole.

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.

5.6 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.

5.7 Hypomagnesemia Hypomagnesemia, symptomatic and asymptomatic, has been reported rarely in patients treated with PPIs for at least three months, in most cases after a year of therapy.

Serious adverse events include tetany, arrhythmias, and seizures.

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)].

5.8 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)].

5.9 Interference with Urine Screen for THC See Drug Interactions (7.5) .

5.10 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 (7.6)].

5.11 Interference with Laboratory Tests Use of PPIs, including pantoprazole, may increase chromogranin A (CgA) levels which may interfere with investigations for neuroendocrine tumors.

To avoid this interference, PPI treatment should be stopped 14 days before CgA measurements.

INFORMATION FOR PATIENTS

17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Medication Guide).

Adverse Reactions Hypersensitivity Reactions [see Contraindications (4)] Acute Interstitial Nephritis [see Warnings and Precautions (5.2)] Clostridium difficile-Associated Diarrhea [see Warnings and Precautions (5.3)] Bone Fracture [see Warnings and Precautions (5.4)] Cutaneous and Systemic Lupus Erythematosus [see Warnings and Precautions (5.5)] Cyanocobalamin (Vitamin B-12) Deficiency [see Warnings and Precautions (5.6)] Hypomagnesemia [see Warnings and Precautions (5.7)] Drug Interactions Instruct patients to inform their healthcare provider of any other medications they are currently taking, including over-the-counter medications.

Administration Caution patients that PROTONIX For Delayed-Release Oral Suspension and PROTONIX Delayed-Release Tablets should not be split, crushed, or chewed.

PROTONIX oral suspension packet is a fixed dose and cannot be divided to make a smaller dose.

Tell patients that PROTONIX Delayed-Release Tablets 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 PROTONIX Delayed-Release Tablets.

Advise patients to take PROTONIX For Delayed-Release Oral Suspension approximately 30 minutes before a meal.

Advise patients that PROTONIX For Delayed-Release Oral Suspension should only be administered in apple juice or applesauce, not in water, other liquids, or foods.

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 DailyControlled 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 weeksFor 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 dailyControlled studies did not extend beyond 12 months Pathological Hypersecretory Conditions Including Zollinger-Ellison Syndrome Adults 40 mg Twice dailyDosage 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 InstructionsPatients should be cautioned that PROTONIX Delayed-Release Tablets and PROTONIX For Delayed-Release Oral Suspension should not be split, chewed, or crushed.

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 PROTONIX Delayed-Release Tablets PROTONIX 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 PROTONIX Delayed-Release Tablets.

PROTONIX For Delayed-Release Oral Suspension PROTONIX For Delayed-Release Oral Suspension should only be administered 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.