Pantoprazole Sodium: Package Insert and Label Information

PANTOPRAZOLE SODIUM — pantoprazole sodium injection, powder, for solution
Novadoz Pharmaceuticals LLC

1 INDICATIONS AND USAGE

1.1 Gastroesophageal Reflux Disease Associated with a History of Erosive Esophagitis

Pantoprazole sodium for injection is indicated for short-term treatment (7 to 10 days) of adult patients with gastroesophageal reflux disease (GERD) and a history of erosive esophagitis (EE).

Safety and efficacy of pantoprazole sodium for injection as a treatment of patients with GERD and a history of EE for more than 10 days have not been demonstrated.

1.2 Pathological Hypersecretion Including Zollinger-Ellison Syndrome

Pantoprazole sodium for injection is indicated for the treatment of pathological hypersecretory conditions including Zollinger-Ellison (ZE) Syndrome in adults.

2 DOSAGE AND ADMINISTRATION

2.1 Dosage for Gastroesophageal Reflux Disease Associated With a History of Erosive Esophagitis

The recommended adult dosage of pantoprazole sodium for injection is 40 mg given once daily by intravenous infusion for 7 to 10 days.

Discontinue treatment with pantoprazole sodium for injection as soon as the patient is able to receive treatment with pantoprazole sodium delayed-release tablets or oral suspension.

Data on the safe and effective dosing for conditions other than those described [see Indications and Usage (1)] such as life-threatening upper gastrointestinal bleeds, are not available. Pantoprazole sodium for injection 40 mg once daily does not raise gastric pH to levels sufficient to contribute to the treatment of such life-threatening conditions.

2.2 Preparation and Administration Instructions for Gastroesophageal Reflux Disease Associated with a History of Erosive Esophagitis

Only for intravenous infusion; other parenteral routes of administration are not recommended.

Fifteen Minute Infusion

1. Reconstitute pantoprazole sodium for injection with 10 mL of 0.9% Sodium Chloride Injection, USP.

2. Further dilute with 100 mL of 5% Dextrose Injection, USP, 0.9% Sodium Chloride Injection, USP, or Lactated Ringer’s Injection, USP, to a final concentration of approximately 0.4 mg/mL.

3. Inspect the diluted pantoprazole sodium for injection solution visually for particular 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.

Storage

The reconstituted solution may be stored for up to 6 hours at room temperature prior to further dilution. The admixed solution may be stored at room temperature and must be used within 24 hours from the time of initial reconstitution. Both the reconstituted solution and the admixed solution do not need to be protected from light.

Do not freeze the reconstituted solution. Discard unused portion.

Two Minute Infusion

1. Reconstitute pantoprazole sodium for injection with 10 mL of 0.9% Sodium Chloride Injection, USP, to a final concentration of approximately 4 mg/mL.
2. Inspect the diluted pantoprazole sodium for injection solution visually for particular matter and discoloration prior to and during administration.
3. Administer intravenously over a period of at least 2 minutes.
Storage

The reconstituted solution may be stored for up to 24 hours at room temperature prior to intravenous infusion and does not need to be protected from light.

Do not freeze the reconstituted solution. Discard unused portion.

2.3 Dosage for Pathological Hypersecretion Including Zollinger-Ellison Syndrome

The recommended adult dosage of pantoprazole sodium for injection is 80 mg intravenously every 12 hours. The frequency of dosing can be adjusted 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. Daily doses higher than 240 mg or administered for more than 6 days have not been studied [see Clinical Studies (14)]. Transition from oral to intravenous and from intravenous to oral formulations of gastric acid inhibitors should be performed in such a manner to ensure continuity of effect of suppression of acid secretion. Patients with ZE Syndrome may be vulnerable to serious clinical complications of increased acid production even after a short period of loss of effective inhibition.

2.4 Preparation and Administration Instructions for Pathological Hypersecretion Including Zollinger-Ellison Syndrome

Only for intravenous infusion; other parenteral routes of administration are not recommended.

Fifteen Minute Infusion

1. Reconstitute each vial of pantoprazole sodium for injection with 10 mL of 0.9% Sodium Chloride Injection, USP.

2. Combine the contents of the two vials and further dilute with 80 mL of 5% Dextrose Injection, USP, 0.9% Sodium Chloride Injection, USP, or Lactated Ringer’s Injection, USP, to a total volume of 100 mL with a final concentration of approximately 0.8 mg/mL.

3. Inspect the diluted pantoprazole sodium for injection solution visually for particular 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.

Storage

The reconstituted solution may be stored for up to 6 hours at room temperature prior to further dilution. The admixed solution may be stored at room temperature and must be used within 24 hours from the time of initial reconstitution. Both the reconstituted solution and the admixed solution do not need to be protected from light.

Do not freeze the reconstituted solution. Discard unused portion.

Two Minute Infusion

1. Reconstitute pantoprazole sodium for injection with 10 mL of 0.9% Sodium Chloride Injection, USP, per vial to a final concentration of approximately 4 mg/mL.
2. Inspect the diluted pantoprazole sodium for injection solution visually for particular 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.
Storage

The reconstituted solution may be stored for up to 24 hours at room temperature prior to intravenous infusion and does not need to be protected from light.

Do not freeze the reconstituted solution. Discard unused portion.

2.5 Compatibility Information

• Administer pantoprazole sodium for injection intravenously through a dedicated line or through a Y-site.
• Flush the intravenous line before and after administration of pantoprazole sodium for injection with either 5% Dextrose Injection, USP, 0.9% Sodium Chloride Injection, USP, or Lactated Ringer’s Injection, USP.
• When administered through a Y-site, pantoprazole sodium for injection is compatible with the following solutions: 5% Dextrose Injection, USP, 0.9% Sodium Chloride Injection, USP, or Lactated Ringer’s Injection, USP.
• Midazolam HCl has been shown to be incompatible with Y-site administration of pantoprazole sodium for injection.
• Pantoprazole sodium for injection may not be compatible with products containing zinc [see Warnings and Precautions (5.3)].
• When pantoprazole sodium for injection is administered through a Y-site, immediately stop use if precipitation or discoloration occurs.

3 DOSAGE FORMS AND STRENGTHS

For Injection: 40 mg of pantoprazole white to off-white lyophilized cake or powder in a single-dose vial for reconstitution.

4 CONTRAINDICATIONS

• Pantoprazole sodium for 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 for injection, are contraindicated in patients receiving rilpivirine-containing products [see Drug Interactions (7)].

5 WARNINGS AND PRECAUTIONS

5.1 Presence of Gastric Malignancy

In adults, symptomatic response to therapy with pantoprazole sodium for 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 for injection.

5.3 Potential for Exacerbation of Zinc Deficiency

Pantoprazole sodium for 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 for injection who are prone to zinc deficiency. Caution should be used when other EDTA containing products are also co-administered intravenously [see Dosage and Administration (2.5)].

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 for injection and evaluate patients with suspected acute TIN [see Contraindications (4)].

5.5 Clostridium difficile -Associated Diarrhea

Published observational studies suggest that PPI therapy like pantoprazole sodium for 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 [see Adverse Reactions (6.2)].

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 [see Dosage and Administration (2.2, 2.4),Adverse Reactions (6)].

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 [see Adverse Reactions (6.2)]. Discontinue pantoprazole sodium for 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 for 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 for injection is unknown [see Adverse Reactions (6)].

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 [see Adverse Reactions (6.2)].

​ Consider monitoring magnesium and calcium levels prior to initiation of pantoprazole sodium for 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 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 [see Clinical Pharmacology (12.2)].

5.13 Interference with Urine Screen for THC

Pantoprazole sodium may produce false-positive urine screen for THC (tetrahydrocannabinol) [see Drug Interactions (7)].

5.14 Concomitant Use of pantoprazole sodium for 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 [see Drug Interactions (7)].

6 ADVERSE REACTIONS

The following serious adverse reactions are described below and elsewhere in labeling:

• Injection Site Reactions [see Warnings and Precautions (5.2)]
• Potential for Exacerbation of Zinc Deficiency [see Warnings and Precautions (5.3)]
• Acute Tubulointerstitial Nephritis [see Warnings and Precautions (5.4)]
• Clostridium difficile-Associated Diarrhea [see Warnings and Precautions (5.5)]
• Bone Fracture [see Warnings and Precautions (5.6)]

• Severe Cutaneous Adverse Reactions [see Warnings and Precautions (5.7)]
• Cutaneous and Systemic Lupus Erythematosus [see Warnings and Precautions (5.8)]
• Hepatic Effects [see Warnings and Precautions (5.9)]
• Hypomagnesemia and Mineral Metabolism [see Warnings and Precautions (5.10)] • Fundic Gland Polyps [see Warnings and Precautions (5.11)]