PANTOPRAZOLE: 78,692 Adverse Event Reports & Safety Profile

The active ingredient in PROTONIX (pantoprazole sodium)

For

Delayed-Release Oral Suspension and PROTONIX (pantoprazole sodium) Delayed-Release Tablets, a PPI, is a substituted benzimidazole, sodium 5-(difluoromethoxy)-2-[[(3,4-dimethoxy-2-pyridinyl)methyl] sulfinyl]-1 H -benzimidazole sesquihydrate, a compound that inhibits gastric acid secretion. Its empirical formula is C 16 H 14 F 2 N 3 NaO 4 S × 1.5 H 2 O, with a molecular weight of 432.4. The structural formula is: Pantoprazole sodium sesquihydrate is a white to off-white crystalline powder and is racemic. Pantoprazole has weakly basic and acidic properties. Pantoprazole sodium sesquihydrate is freely soluble in water, very slightly soluble in phosphate buffer at pH 7.4, and practically insoluble in n-hexane. The stability of the compound in aqueous solution is pH-dependent. The rate of degradation increases with decreasing pH. At ambient temperature, the degradation half-life is approximately 2.8 hours at pH 5 and approximately 220 hours at pH 7.8. PROTONIX is supplied as a for delayed-release oral suspension in unit dose packets, available in one strength 40 mg pantoprazole, (equivalent to 45.1 mg of pantoprazole sodium), and as a delayed-release tablet, available in two strengths 20 mg pantoprazole (equivalent to 22.56 mg of pantoprazole sodium) and 40 mg pantoprazole (equivalent to 45.1 mg of pantoprazole sodium).

Protonix

Delayed-Release Tablets contains the following inactive ingredients: calcium stearate, crospovidone, hypromellose, iron oxide, mannitol, methacrylic acid copolymer, polysorbate 80, povidone, propylene glycol, sodium carbonate, sodium lauryl sulfate, titanium dioxide, and triethyl citrate.

Protonix

Delayed-Release Tablets (40 mg and 20 mg) complies with USP dissolution test 2.

Protonix

For Delayed-Release Oral Suspension contains the following inactive ingredients: crospovidone, hypromellose, methacrylic acid copolymer, microcrystalline cellulose, polysorbate 80, povidone, sodium carbonate, sodium lauryl sulfate, talc, titanium dioxide, triethyl citrate, and yellow ferric oxide.

Chemical

Structure

AND USAGE Pantoprazole sodium for delayed-release oral suspension is indicated for: Pantoprazole sodium for delayed-release oral suspension is a proton pump inhibitor (PPI) indicated for the following: Short-Term Treatment of Erosive Esophagitis Associated with Gastroesophageal Reflux Disease (GERD) ( 1.1 ) Maintenance of Healing of Erosive Esophagitis ( 1.2 )

Pathological Hypersecretory Conditions Including

Zollinger-Ellison (ZE) Syndrome ( 1.3 )

1.1 Short-Term Treatment of Erosive Esophagitis Associated With Gastroesophageal Reflux Disease (GERD) Pantoprazole sodium for delayed-release oral suspension is indicated in adults and pediatric patients five years of age and older for the short-term treatment (up to 8 weeks) in the healing and symptomatic relief of erosive esophagitis (EE). For those adult patients who have not healed after 8 weeks of treatment, an additional 8-week course of pantoprazole sodium for delayed-release oral suspension may be considered. Safety of treatment beyond 8 weeks in pediatric patients has not been established.

1.2 Maintenance of Healing of Erosive Esophagitis Pantoprazole sodium for delayed-release oral suspension is indicated for maintenance of healing of EE and reduction in relapse rates of daytime and nighttime heartburn symptoms in adult patients with GERD. Controlled studies did not extend beyond 12 months.

1.3 Pathological Hypersecretory Conditions Including Zollinger-Ellison Syndrome Pantoprazole sodium for delayed-release oral suspension is indicated for the long-term treatment of pathological hypersecretory conditions, including Zollinger-Ellison (ZE) Syndrome.

AND ADMINISTRATION GERD and a History of EE Adults:

• The recommended dosage is 40 mg once daily by intravenous injection (over at least 2 minutes) or intravenous infusion (for 15 minutes) for up to 10 days. ( 2.1 )
• Discontinue as soon as the patient is able to receive oral treatment. Switch to an appropriate oral medication within 10 days of starting PROTONIX I.V. ( 2.1 )

Pediatrics

3 Months of Age and Older:

• The recommended dosage for pediatric patients 3 months of age and older is based on age and actual body weight as shown in the table. ( 2.1 )
• Administer as an intravenous infusion over 15 minutes once daily. ( 2.1 ) Age and Body Weight Recommended Dosage Regimen (up to 7 days) 3 months to less than 1 year of age Less than 12.5 kg 0.8 mg/kg once daily 12.5 kg and above 10 mg once daily 1 year to 17 years of age Up to 15 kg 10 mg once daily Greater than 15 kg up to 40 kg 20 mg once daily Greater than 40 kg 40 mg once daily
• Discontinue PROTONIX I.V. as soon as the patient is able to tolerate oral treatment. Switch to an appropriate oral medication within 7 days of starting PROTONIX I.V. ( 2.1 )

Pathological Hypersecretion

Conditions, Including ZE Syndrome:

• The recommended adult dosage is 80 mg every 12 hours by intravenous injection (over at least 2 minutes) or intravenous infusion (for 15 minutes). ( 2.2 )
• For information on how to adjust dosing for individual patient needs, see the full prescribing information. ( 2.2 )
• When switching between intravenous to oral formulations of gastric acid inhibitors, consider the pharmacodynamic action of the drugs to ensure continuity of acid suppression. ( 2.2 ) Preparation and Administration Instructions
• See full prescribing information for preparation and administration instructions by indication. ( 2.3 , 2.4 )

2.1 Recommended Dosage for GERD Associated with a History of EE Adult Patients The recommended adult dosage of PROTONIX I.V. is 40 mg once daily by intravenous injection (over at least 2 minutes) or intravenous infusion (for 15 minutes) for up to 10 days. Discontinue PROTONIX I.V. as soon as the patient is able to tolerate oral treatment. Switch to an appropriate oral medication within 10 days of starting PROTONIX I.V.

Pediatric

Patients

• The recommended dosage for pediatric patients 3 months of age and older is based on age and actual body weight as shown in Table 1 below.
• Administer as an intravenous infusion over 15 minutes once daily.

Table

1: Recommended Pediatric Dosage Regimen for GERD and a History of EE Age and Body Weight Recommended Dosage Regimen (up to 7 days) 3 months to less than 1 year of age Less than 12.5 kg 0.8 mg/kg once daily 12.5 kg and above 10 mg once daily 1 year to 17 years of age Up to 15 kg 10 mg once daily Greater than 15 kg up to 40 kg 20 mg once daily Greater than 40 kg 40 mg once daily

• Discontinue PROTONIX I.V. as soon as the patient is able to tolerate oral treatment. Switch to an appropriate oral medication within 7 days of starting PROTONIX I.V.

2.2 Recommended Dosage for Pathological Hypersecretion Including Zollinger-Ellison Syndrome

• The recommended adult dosage of PROTONIX I.V. is 80 mg every 12 hours by intravenous injection (over at least 2 minutes) or intravenous infusion (for 15 minutes).
• Adjust the frequency of dosing to individual patient needs based on acid output measurements. In those patients who need a higher dosage, 80 mg intravenously every 8 hours is expected to maintain acid output below 10 mEq/h.
• When switching between intravenous to oral formulations of gastric acid inhibitors, consider the pharmacodynamic action of the drugs to ensure continuity of acid suppression.

2.3 Preparation and Administration Instructions for GERD Associated with a History of EE 15-Minute Intravenous Infusion for Pediatric or Adult Patients 1. Reconstitute each vial of PROTONIX I.V. with 10 mL of 0.9% Sodium Chloride Injection. 2. Dilute the resulting solution to a final concentration as described below:

• Pediatric patients 3 months to less than 1 year of age : Dilute with 21 mL 0.9% Sodium Chloride Injection to a final concentration of approximately 1.3 mg/mL.
• Pediatric patients 1 year to 17 years old and adult patients : Further dilute with 100 mL 5% Dextrose Injection or 0.9% Sodium Chloride Injection to a final concentration of approximately 0.4 mg/mL. 3. Inspect the diluted PROTONIX I.V. solution visually for particulate matter and discoloration prior to and during administration. 4. Withdraw the desired dose of the diluted PROTONIX I.V. solution for a pediatric or adult dose. 5. Discard any unused portion of the remaining PROTONIX I.V. solution. 6. Infuse intravenously over a period of approximately 15 minutes through a dedicated line or through a Y-site [see Dosage and Administration (2.5) ] . 7. Flush the intravenous line before and after administration of PROTONIX I.V. with either 5% Dextrose Injection or 0.9% Sodium Chloride Injection. Storage
• Store the reconstituted solution may be up to 6 hours at room temperature up to 30°C (86°F) prior to further dilution.
• Store the diluted solution at room temperature up to 30°C (86°F) and must be used within 24 hours from the time of initial reconstitution.
• Do not freeze the reconstituted or diluted solution. 2-Minute Intravenous Injection for Adult Patients 1. Reconstitute each vial of PROTONIX I.V. with 10 mL of 0.9% Sodium Chloride Injection, to a final concentration of approximately 4 mg/mL. 2. Withdraw the dose of 40 mg of reconstituted PROTONIX I.V. solution. 3. Inspect the diluted PROTONIX I.V. solution visually for particulate matter and discoloration prior to and during administration. 4. Administer intravenously over a period of at least 2 minutes. 5. Flush the intravenous line before and after administration of PROTONIX I.V. with either 5% Dextrose Injection or 0.9% Sodium Chloride Injection. Storage
• Store the reconstituted solution may be stored for up to 24 hours at room temperature up to 30°C (86°F) prior to intravenous infusion.
• Do not freeze the reconstituted solution.

2.4 Preparation and Administration Instructions for Pathological Hypersecretion Including Zollinger-Ellison Syndrome 15-Minute Intravenous Infusion 1. Reconstitute each vial of PROTONIX I.V. with 10 mL of 0.9% Sodium Chloride Injection. 2. Combine the contents of the two vials and dilute with 80 mL of 5% Dextrose Injection or Sodium Chloride Injection to a total volume of 100 mL with a final concentration of approximately 0.8 mg/mL. 3. Inspect the diluted PROTONIX I.V. solution visually for particulate matter and discoloration prior to and during administration. 4. Administer intravenously over a period of approximately 15 minutes at a rate of approximately 7 mL/min. 5. Flush the intravenous line before and after administration of PROTONIX I.V. with either 5% Dextrose Injection or 0.9% Sodium Chloride Injection. Storage

• The reconstituted solution can be stored at room temperature up to 30°C (86°F) for up to 6 hours prior to further dilution.
• Once further diluted, the diluted solution can be stored at room temperature up to 30°C (86°F) for up to 24 hours from the time of initial reconstitution.
• Do not freeze the reconstituted or diluted solution. 2-Minute Intravenous Injection 1. Reconstitute each vial of PROTONIX I.V. with 10 mL of 0.9% Sodium Chloride Injection per vial to a final concentration of approximately 4 mg/mL. 2. Inspect the diluted PROTONIX I.V. solution visually for particulate matter and discoloration prior to and during administration. 3. Administer the total volume from both vials intravenously over a period of at least 2 minutes. 4. Flush the intravenous line before and after administration of PROTONIX I.V. with either 5% Dextrose Injection or 0.9% Sodium Chloride Injection. Storage
• The reconstituted solution may be stored for up to 24 hours at room temperature.
• Do not freeze the reconstituted solution.

2.5 Compatibility Information

• Administer PROTONIX I.V. intravenously through a dedicated line or through a Y-site.
• When administering through a Y-site, PROTONIX I.V. is compatible with the following solutions: o 5% Dextrose Injection o 0.9% Sodium Chloride Injection
• Midazolam hydrochloride is incompatible with Y-site administration of PROTONIX I.V.
• PROTONIX I.V. may not be compatible with products containing zinc [see Warnings and Precautions ( 5.3 )] .
• Stop administering PROTONIX I.V. immediately through a Y-site if precipitation or discoloration occurs.

4 CONTRAINDICATIONS

• Pantoprazole sodium in 0.9% sodium chloride injection is contraindicated in patients with known hypersensitivity reactions including anaphylaxis to the formulation or any substituted benzimidazole. Hypersensitivity reactions may include anaphylaxis, anaphylactic shock, angioedema, bronchospasm, acute tubulointerstitial nephritis, and urticaria [see Warnings and Precautions (5.2 , 5.4 ), Adverse Reactions (6) ] .
• Proton pump inhibitors (PPIs), including pantoprazole sodium in 0.9% sodium chloride injection, are contraindicated in patients receiving rilpivirine-containing products [see Drug Interactions (7) ] .
• Patients with a known hypersensitivity to any component of the formulation or to substituted benzimidazoles. (4)
• Patients receiving rilpivirine-containing products. ( 4 , 7 )

REACTIONS The following serious adverse reactions are described below and elsewhere in labeling: Acute Tubulointerstitial 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) ]

Severe Cutaneous Adverse

Reactions [see Warnings and Precautions (5.5) ] Cutaneous and Systemic Lupus Erythematosus [see Warnings and Precautions (5.6) ] Cyanocobalamin (Vitamin B-12) Deficiency [see Warnings and Precautions (5.7) ] Hypomagnesemia and Mineral Metabolism [see Warnings and Precautions (5.8) ]

Fundic Gland

Polyps [see Warnings and Precautions (5.10) ] Most common adverse reactions are: For adult use (>2%): headache, diarrhea, nausea, abdominal pain, vomiting, flatulence, dizziness, and arthralgia. ( 6.1 ) For pediatric use (>4%): URI, headache, fever, diarrhea, vomiting, rash, and abdominal pain. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Aurobindo Pharma USA, Inc. at 1-866-850-2876 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1 Clinical Trials Experience The adverse reaction profiles for Pantoprazole Sodium For Delayed-Release Oral Suspension and PROTONIX Delayed-Release Tablets are similar. 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 (20 mg or 40 mg), 299 patients on an H 2 -receptor antagonist, 46 patients on another PPI, 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 for delayed-release oral suspension (n=1473) % Comparators (n=345) % Placebo (n=82) % Headache 12.2 12.8

8.5 Diarrhea 8.8 9.6

4.9 Nausea 7.0 5.2

9.8 Abdominal pain 6.2 4.1

6.1 Vomiting 4.3 3.5

2.4 Flatulence 3.9 2.9

3.7 Dizziness 3.0 2.9

1.2 Arthralgia 2.8 1.4

1.2 Additional adverse reactions that were reported for pantoprazole sodium for delayed-release oral suspension 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 Pediatric Patients Safety of pantoprazole sodium for delayed-release oral suspension in the treatment of EE associated with GERD was evaluated in pediatric patients ages 1 year through 16 years in three clinical trials. Safety trials involved pediatric patients with EE; however, as EE is uncommon in the pediatric population, 249 pediatric patients with endoscopically-proven or symptomatic GERD were also evaluated. All adult adverse reactions to pantoprazole sodium for delayed-release oral suspension are considered relevant to pediatric patients. In patients ages 1 year through 16 years, the most commonly reported (>4%) adverse reactions include: URI, headache, fever, diarrhea, vomiting, rash, and abdominal pain. For safety information in patients less than 1 year of age see Use in Specific Populations (8.4) . Additional adverse reactions that were reported for pantoprazole sodium for delayed-release oral suspension in pediatric patients in clinical trials with a frequency of ≤4% are listed below by body system: Body as a Whole: allergic reaction, facial edema Gastrointestinal: constipation, flatulence, nausea Metabolic/Nutritional: elevated triglycerides, elevated liver enzymes, elevated CK (creatine kinase) Musculoskeletal: arthralgia, myalgia Nervous: dizziness, vertigo Skin and Appendages: urticaria The following adverse reactions seen in adults in clinical trials were not reported in pediatric patients in clinical trials, but are considered relevant to pediatric patients: photosensitivity reaction, dry mouth, hepatitis, thrombocytopenia, generalized edema, depression, pruritus, leukopenia, and blurred vision. Zollinger-Ellison (ZE) Syndrome In clinical studies of ZE Syndrome, adverse reactions reported in 35 patients taking pantoprazole sodium for delayed-release oral suspension 80 mg/day to 240 mg/day for up to 2 years were similar to those reported in adult patients with GERD.

6.2 Postmarketing Experience The following adverse reactions have been identified during postapproval use of pantoprazole sodium for delayed-release oral suspension. 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: Gastrointestinal Disorders: fundic gland polyps General Disorders and Administration Conditions: asthenia, fatigue, malaise Hematologic: pancytopenia, agranulocytosis Hepatobiliary Disorders: hepatocellular damage leading to jaundice and hepatic failure Immune System Disorders: anaphylaxis (including anaphylactic shock), systemic lupus erythematosus Infections and Infestations: Clostridium difficile associated diarrhea Investigations: weight changes Metabolism and Nutritional Disorders: hypomagnesemia, hypocalcemia, hypokalemia, hyponatremia Musculoskeletal Disorders: rhabdomyolysis, bone fracture Nervous: ageusia, dysgeusia Psychiatric Disorders: hallucination, confusion, insomnia, somnolence Renal and Genitourinary Disorders: acute tubulointerstitial nephritis, erectile dysfunction Skin and Subcutaneous Tissue Disorders: severe dermatologic reactions (some fatal), including erythema multiforme, SJS/TEN, DRESS, AGEP, angioedema (Quincke’s edema) and cutaneous lupus erythematosus

AND PRECAUTIONS

• Gastric Malignancy : In adults, symptomatic response to therapy with pantoprazole sodium in 0.9% sodium chloride injection does not preclude the presence of gastric malignancy. Consider additional follow-up and diagnostic testing. ( 5.1 )
• Injection Site Reactions : Thrombophlebitis is associated with the administration of intravenous pantoprazole. ( 5.2 )
• Potential Exacerbation of Zinc Deficiency : Consider zinc supplementation in patients who are prone to zinc deficiency. Caution should be used when other EDTA containing products are also co-administered intravenously. ( 5.3 )
• Acute Tubulointerstitial Nephritis : Discontinue treatment and evaluate patients. ( 5.4 )
• Clostridium difficile- Associated Diarrhea : PPI therapy may be associated with increased risk. ( 5.5 )
• 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. ( 5.6 )
• Severe Cutaneous Adverse Reactions : Discontinue at the first signs or symptoms of severe cutaneous adverse reactions or other signs of hypersensitivity and consider further evaluation. ( 5.7 )
• Cutaneous and Systemic Lupus Erythematosus : Mostly cutaneous; new onset or exacerbation of existing disease; discontinue pantoprazole sodium in 0.9% sodium chloride injection and refer to specialist for evaluation. ( 5.8 )
• Hepatic Effects : Elevations of transaminases observed. ( 5.9 )
• Hypomagnesemia and Mineral Metabolism : Reported rarely with prolonged treatment with PPIs. ( 5.10 )
• Fundic Gland Polyps : Risk increases with long-term use, especially beyond one year. Use the shortest duration of therapy. ( 5.11 )

5.1 Presence of Gastric Malignancy In adults, symptomatic response to therapy with pantoprazole sodium in 0.9% sodium chloride injection 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 Injection Site Reactions Thrombophlebitis was associated with the administration of pantoprazole sodium injection.

5.3 Potential for Exacerbation of Zinc Deficiency Pantoprazole sodium in 0.9% sodium chloride injection contains edetate disodium (the salt form of EDTA), a chelator of metal ions including zinc. Therefore, zinc supplementation should be considered in patients treated with pantoprazole sodium in 0.9% sodium chloride injection who are prone to zinc deficiency. Caution should be used when other EDTA containing products are also co-administered intravenously <span class="opacity-50 text-xs">[see Dosage and Administration (2.4) ]</span> .

5.4 Acute Tubulointerstitial Nephritis Acute tubulointerstitial nephritis (TIN) has been observed in patients taking PPIs and may occur at any point during PPI therapy. Patients may present with varying signs and symptoms from symptomatic hypersensitivity reactions to non-specific symptoms of decreased renal function (e.g., malaise, nausea, anorexia). In reported case series, some patients were diagnosed on biopsy and in the absence of extra-renal manifestations (e.g., fever, rash or arthralgia). Discontinue pantoprazole sodium in 0.9% sodium chloride injection and evaluate patients with suspected acute TIN <span class="opacity-50 text-xs">[see Contraindications (4) ]</span> .

5.5 Clostridium difficile- Associated Diarrhea Published observational studies suggest that PPI therapy like pantoprazole sodium in 0.9% sodium chloride injection 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 <span class="opacity-50 text-xs">[see Adverse Reactions (6.2) ]</span>. Patients should use the lowest dose and shortest duration of PPI therapy appropriate to the condition being treated.

5.6 Bone Fracture Several published observational studies suggest that PPI therapy may be associated with an increased risk for osteoporosis-related fractures of the hip, wrist, or spine. The risk of fracture was increased in patients who received high-dose, defined as multiple daily doses, and long-term PPI therapy (a year or longer). Patients should use the lowest dose and shortest duration of PPI therapy appropriate to the condition being treated. Patients at risk for osteoporosis-related fractures should be managed according to established treatment guidelines <span class="opacity-50 text-xs">[see Dosage and Administration (2.1 , 2.2) , Adverse Reactions (6) ]</span> .

5.7 Severe Cutaneous Adverse Reactions Severe cutaneous adverse reactions, including erythema multiforme, Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), drug reaction with eosinophilia and systemic symptoms (DRESS), and acute generalized exanthematous pustulosis (AGEP) have been reported in association with the use of PPIs <span class="opacity-50 text-xs">[see Adverse Reactions (6.2) ]</span>. Discontinue pantoprazole sodium in 0.9% sodium chloride injection at the first signs or symptoms of severe cutaneous adverse reactions or other signs of hypersensitivity and consider further evaluation.

5.8 Cutaneous and Systemic Lupus Erythematosus Cutaneous lupus erythematosus (CLE) and systemic lupus erythematosus (SLE) have been reported in patients taking PPIs, including pantoprazole sodium. These events have occurred as both new onset and an exacerbation of existing autoimmune disease. The majority of PPI-induced lupus erythematous cases were CLE. The most common form of CLE reported in patients treated with PPIs was subacute CLE (SCLE) and occurred within weeks to years after continuous drug therapy in patients ranging from infants to the elderly. Generally, histological findings were observed without organ involvement. Systemic lupus erythematosus (SLE) is less commonly reported than CLE in patients receiving PPIs. PPI associated SLE is usually milder than non-drug induced SLE. Onset of SLE typically occurred within days to years after initiating treatment primarily in patients ranging from young adults to the elderly. The majority of patients presented with rash; however, arthralgia and cytopenia were also reported. Avoid administration of PPIs for longer than medically indicated. If signs or symptoms consistent with CLE or SLE are noted in patients receiving pantoprazole sodium in 0.9% sodium chloride injection, 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.

5.9 Hepatic Effects Mild, transient transaminase elevations have been observed in clinical studies. The clinical significance of this finding in a large population of subjects administered pantoprazole sodium injection is unknown <span class="opacity-50 text-xs">[see Adverse Reactions (6) ]</span>.

5.10 Hypomagnesemia and Mineral Metabolism Hypomagnesemia, symptomatic and asymptomatic, has been reported rarely in patients treated with PPIs for at least three months, and in most cases after a year of therapy. Serious adverse events include tetany, arrhythmias, and seizures. Hypomagnesemia may lead to hypocalcemia and/or hypokalemia and may exacerbate underlying hypocalcemia in at-risk patients. In most patients, treatment of hypomagnesemia required magnesium replacement and discontinuation of the PPI. For patients expected to be on prolonged treatment or who take PPIs with medications such as digoxin or drugs that may cause hypomagnesemia (e.g., diuretics), health care professionals may consider monitoring magnesium levels prior to initiation of PPI treatment and periodically <span class="opacity-50 text-xs">[see Adverse Reactions (6.2) ]</span> . Consider monitoring magnesium and calcium levels prior to initiation of pantoprazole sodium in 0.9% sodium chloride injection and periodically while on treatment in patients with a preexisting risk of hypocalcemia (e.g., hypoparathyroidism). Supplement with magnesium and/or calcium as necessary. If hypocalcemia is refractory to treatment, consider discontinuing the PPI.

5.11 Fundic Gland Polyps PPI use is associated with an increased risk of fundic gland polyps that increases with long-term use, especially beyond one year. Most PPI users who developed fundic gland polyps were asymptomatic and fundic gland polyps were identified incidentally on endoscopy. Use the shortest duration of PPI therapy appropriate to the condition being treated.

5.12 Interference with Investigations for Neuroendocrine Tumors Serum chromogranin A (CgA) levels increase secondary to drug-induced decreases in gastric acidity. The increased CgA level may cause false positive results in diagnostic investigations for neuroendocrine tumors. Healthcare providers should temporarily stop pantoprazole sodium injection treatment at least 14 days before assessing CgA levels and consider repeating the test if initial CgA levels are high. If serial tests are performed (e.g., for monitoring), the same commercial laboratory should be used for testing, as reference ranges between tests may vary <span class="opacity-50 text-xs">[see Clinical Pharmacology (12.2) ]</span> .

5.13 Interference with Urine Screen for THC Pantoprazole sodium may produce false-positive urine screen for THC (tetrahydrocannabinol) <span class="opacity-50 text-xs">[see Drug Interactions (7) ]</span>.

5.14 Concomitant Use of Pantoprazole in 0.9% Sodium Injection 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 <span class="opacity-50 text-xs">[see Drug Interactions (7) ]</span>.

INTERACTIONS Table 2 includes drugs with clinically important drug interactions and interaction with diagnostics when administered concomitantly with pantoprazole sodium for injection and instructions for preventing or managing them. Consult the labeling of concomitantly used drugs to obtain further information about interactions with PPIs.

Table

2: Clinically Relevant Interactions Affecting Drugs Co-Administered with Pantoprazole Sodium for Injection and Interaction with Diagnostics Antiretrovirals Clinical Impact: The effect of PPIs on antiretroviral drugs is variable. The clinical importance and the mechanisms behind these interactions are not always known. Decreased exposure of some antiretroviral drugs (e.g., rilpivirine atazanavir, and nelfinavir) when used concomitantly with pantoprazole may reduce antiviral effect and promote the development of drug resistance. Increased exposure of other antiretroviral drugs (e.g., saquinavir) when used concomitantly with pantoprazole may increase toxicity of the antiretroviral drugs . There are other antiretroviral drugs which do not result in clinically relevant interactions with pantoprazole. Intervention: Rilpivirine-containing products: Concomitant use with pantoprazole sodium for injection is contraindicated [see Contraindications (4) ] . See prescribing information. Atazanavir: See prescribing information for atazanavir for dosing information. Nelfinavir: Avoid concomitant use with pantoprazole sodium for injection See prescribing information for nelfinavir. Saquinavir: See the prescribing information for saquinavir and monitor for potential saquinavir toxicities. Other antiretrovirals: See prescribing information.

Warfarin Clinical

Impact: Increased INR and prothrombin time in patients receiving PPIs, including pantoprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Intervention: Monitor INR and prothrombin time. Dose adjustment of warfarin may be needed to maintain target INR range. See prescribing information for warfarin.

Clopidogrel Clinical

Impact: Concomitant administration of pantoprazole and clopidogrel in healthy subjects had no clinically important effect on exposure to the active metabolite of clopidogrel or clopidogrel-induced platelet inhibition [see Clinical Pharmacology (12.3) ]. Intervention: No dose adjustment of clopidogrel is necessary when administered with an approved dose of pantoprazole sodium for injection..

Methotrexate Clinical

Impact: Concomitant use of PPIs with methotrexate (primarily at high dose) may elevate and prolong serum concentrations of methotrexate and/or its metabolite hydroxymethotrexate, possibly leading to methotrexate toxicities. No formal drug interaction studies of high-dose methotrexate with PPIs have been conducted [see Warnings and Precautions (5.14) ] . Intervention: A temporary withdrawal of pantoprazole sodium for injection may be considered in some patients receiving high-dose methotrexate.

Drugs

Dependent on Gastric pH for Absorption (e.g., Iron salts, erlotinib, dasatinib, nilotinib, mycophenolate mofetil, ketoconazole/itraconazole)

Clinical

Impact: Pantoprazole can reduce the absorption of other drugs due to its effect on reducing intragastric acidity. Intervention: Mycophenolate mofetil (MMF): Co-administration of pantoprazole sodium in healthy subjects and in transplant patients receiving MMF has been reported to reduce the exposure to the active metabolite, mycophenolic acid (MPA), possibly due to a decrease in MMF solubility at an increased gastric pH [see Clinical Pharmacology (12.3) ] . The clinical relevance of reduced MPA exposure on organ rejection has not been established in transplant patients receiving pantoprazole sodium for injection and MMF. Use pantoprazole sodium for injection with caution in transplant patients receiving MMF. See the prescribing information for other drugs dependent on gastric pH for absorption. Interactions with Investigations of Neuroendocrine Tumors Clinical Impact: CgA levels increase secondary to PPI-induced decreases in gastric acidity. The increased CgA level may cause false positive results in diagnostic investigations for neuroendocrine tumors [see Warnings and Precautions (5.12 and Clinical Pharmacology (12.2) ] . Intervention: Temporarily stop pantoprazole sodium for injection treatment at least 14 days before assessing CgA levels and consider repeating the test if initial CgA levels are high. If serial tests are performed (e.g. for monitoring), the same commercial laboratory should be used for testing, as reference ranges between tests may vary.

False Positive Urine

Tests for THC Clinical Impact: There have been reports of false positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving PPIs [see Warnings and Precautions (5.13) ] . Intervention: An alternative confirmatory method should be considered to verify positive results. See the full prescribing information for a list of clinically important drug interactions ( 7 ) 8 USE IN SPECIFIC POPULATIONS . Pregnancy : Based on animal data, may cause fetal harm. ( 8.1 )

See

17 for PATIENT COUNSELING INFORMATION. Pediatric use information is approved for Pfizer Inc.’s PROTONIX ® I.V. (pantoprazole sodium) for Injection. However, due to Pfizer Inc.›s marketing exclusivity rights, this drug product is not labeled with that information. Revised: 05/2025

8.1 Pregnancy Risk Summary Available data from published observational studies did not demonstrate an association of major malformations or other adverse pregnancy outcomes with pantoprazole. In animal reproduction studies, no evidence of adverse development outcomes was observed with pantoprazole sodium. Reproduction studies have been performed in rats at intravenous doses up to 20 mg/kg/day (4 times the recommended human dose) and rabbits at intravenous doses up to 15 mg/kg/day (6 times the recommended human dose) with administration of pantoprazole during organogenesis in pregnant animals and have revealed no evidence of harm to the fetus due to pantoprazole in this study (see Data ). A pre- and post-natal development toxicity study in rats with additional endpoints to evaluate the effect on bone development was performed with pantoprazole sodium. Oral pantoprazole doses of 5, 15, and 30 mg/kg/day (approximately 1, 3, and 6 times the human dose of 40 mg/day) were administered to pregnant females from gestation day (GD) 6 through lactation day (LD) 21. Changes in bone morphology were observed in pups exposed to pantoprazole in utero and through milk during the period of lactation as well as by oral dosing from postnatal day (PND) 4 through PND 21 [ see Use in Specific Populations (8.4) ]. There were no drug-related findings in maternal animals. Advise pregnant women of the potential risk of fetal harm. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in the clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.

Data Human Data

Available data from published observational studies failed to demonstrate an association of adverse pregnancy-related outcomes and pantoprazole use. Methodological limitations of these observational studies cannot definitely establish or exclude any drug associated risk during pregnancy. In a prospective study by the European Network of Teratology Information Services, outcomes from a group of 53 pregnant women administered median daily doses of 40 mg pantoprazole were compared to a control group of 868 pregnant women who did not take any proton pump inhibitors (PPIs). There was no difference in the rate of major malformations between women exposed to PPIs and the control group, corresponding to a Relative Risk (RR)=0.55, [95% Confidence Interval (CI) 0.08-3.95]. In a population-based retrospective cohort study covering all live births in Denmark from 1996 to 2008, there was no significant increase in major birth defects during analysis of first trimester exposure to pantoprazole in 549 live births. A meta-analysis that compared 1,530 pregnant women exposed to PPIs in at least the first trimester with 133,410 unexposed pregnant women showed no significant increases in risk for congenital malformations or spontaneous abortion with exposure to PPIs (for major malformations OR=1.12 ([95% CI 0.86-1.45] and for spontaneous abortions OR=1.29 [95% CI 0.84-1.97]).

Animal Data

Reproduction studies have been performed in rats at intravenous pantoprazole doses up to 20 mg/kg/day (4 times the recommended human dose based on body surface area) and rabbits at intravenous doses up to 15 mg/kg/day (6 times the recommended human dose based on body surface area) with administration of pantoprazole sodium during organogenesis in pregnant animals and have revealed no evidence of impaired fertility or harm to the fetus due to pantoprazole. A pre- and post-natal development toxicity study in rats with additional endpoints to evaluate the effect on bone development was performed with pantoprazole sodium. Oral pantoprazole doses of 5, 15, and 30 mg/kg/day (approximately 1, 3, and 6 times the human dose of 40 mg/day on a body surface area basis) were administered to pregnant females from gestation day (GD) 6 through lactation day (LD) 21. On postnatal day (PND 4) through PND 21, the pups were administered oral doses at 5, 15, and 30 mg/kg/day (approximately 1, 2.3, and 3.2 times the exposure (AUC) in humans at a dose of 40 mg). There were no drug-related findings in maternal animals. During the preweaning dosing phase (PND 4 to 21) of the pups, there were increased mortality and/or moribundity and decreased body weight and body weight gain at 5 mg/kg/day (approximately equal exposures (AUC) in humans receiving the 40 mg dose) and higher doses. On PND 21, decreased mean femur length and weight and changes in femur bone mass and geometry were observed in the offspring at 5 mg/kg/day (approximately equal exposures (AUC) in humans at the 40 mg dose) and higher doses. The femur findings included lower total area, bone mineral content and density, periosteal and endosteal circumference, and cross-sectional moment of inertia. There were no microscopic changes in the distal femur, proximal tibia, or stifle joints. Changes in bone parameters were partially reversible following a recovery period, with findings on PND 70 limited to lower femur metaphysis cortical/subcortical bone mineral density in female pups at 5 mg/kg/day (approximately equal exposures (AUC) in humans at the 40 mg dose) and higher doses.

8.2 Lactation .

Risk Summary

The limited data from a single case report the presence of pantoprazole in human breast milk. There were no effects on the breastfed infant (see Data ) . There are no data on pantoprazole effects on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for pantoprazole sodium for injection and any potential adverse effects on the breastfed child from pantoprazole or from the underlying maternal condition.

Data

The breast milk of a 42-year-old woman receiving 40 mg of oral pantoprazole, at 10 months postpartum, was studied for 24 hours, to demonstrate low levels of pantoprazole present in the breast milk. Pantoprazole was detectable in milk only 2 and 4 hours after the dose with milk levels of approximately 36 mcg/L and 24 mcg/L, respectively. A milk-to-plasma ratio of 0.022 was observed at 2 hours after drug administration. Pantoprazole was not detectable (<10 mcg/L) in milk at 6, 8 and 24 hours after the dose. The relative dose to the infant was estimated to be 7.3 mcg of pantoprazole, which is equivalent to 0.14% of the weight-adjusted maternal dose. No adverse events in the infant were reported by the mother.

8.4 Pediatric Use The safety and effectiveness of pantoprazole sodium for injection have not been established in patients less than 3 months of age for the treatment of GERD and a history of EE. The safety and effectiveness of pantoprazole sodium for injection have not been established in pediatric patients for the treatment of pathological hypersecretory conditions including ZE syndrome.

Animal Toxicity

Data In neonatal/juvenile animals (rats and dogs) toxicities were similar to those observed in adult animals, including gastric alterations, decreases in red cell mass, increases in lipids, enzyme induction and hepatocellular hypertrophy. An increased incidence of eosinophilic chief cells in adult and neonatal/juvenile rats, and atrophy of chief cells in adult rats and in neonatal/juvenile dogs, was observed in the fundic mucosa of stomachs in repeated-dose studies. Full to partial recovery of these effects were noted in animals of both age groups following a recovery period. Pediatric use information is approved for Pfizer Inc.’s PROTONIX ® I.V. (pantoprazole sodium) for Injection. However, due to Pfizer Inc.’s marketing exclusivity rights, this drug product is not labeled with that information.

8.5 Geriatric Use Of 286 patients in clinical studies of intravenous pantoprazole sodium in patients with GERD and a history of EE, 86 (43%) were 65 years of age and over. No overall differences in safety or effectiveness were observed between these geriatric and younger adult patients, and other reported clinical experience with oral pantoprazole sodium has not identified differences in responses between geriatric and younger adult patients, but greater sensitivity of some older individuals cannot be ruled out. No clinically meaningful differences in the pharmacokinetics of pantoprazole were observed in geriatric subjects compared to younger adult subjects <span class="opacity-50 text-xs">[see Clinical Pharmacology ( 12.3 )]</span>.