These Highlights Do Not Include All The Information Needed To Use Protonix I.v. Safely And Effectively. See Full Prescribing Information For Protonix I.v.

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 and Handling

Store PROTONIX I.V. 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].

Protect from light.

• •
  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.

Experience in patients taking very high doses of pantoprazole (greater than 240 mg) is limited. Adverse reactions seen in spontaneous reports of overdose generally reflect the known safety profile of pantoprazole.

Pantoprazole is not removed by hemodialysis. In case of overdose, treatment should be symptomatic and supportive.

Single intravenous doses of pantoprazole at 378, 230, and 266 mg/kg (38, 46, and 177 times the recommended human dose based on body surface area) 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.

The active ingredient in PROTONIX^® I.V. (pantoprazole sodium), a PPI, is a substituted benzimidazole, sodium 5-(difluoromethoxy)-2-[[(3,4-dimethoxy-2-pyridinyl)methyl] sulfinyl]-1H-benzimidazole, a compound that inhibits gastric acid secretion. Its empirical formula is C₁₆H₁₄F₂N₃NaO₄S, with a molecular weight of 405.4. The structural formula is:

Pantoprazole sodium is a white to off-white crystalline powder and is racemic. Pantoprazole has weakly basic and acidic properties. Pantoprazole sodium is freely soluble in water, very slightly soluble in phosphate buffer at pH 7.4, and practically insoluble in n-hexane. The reconstituted solution of PROTONIX I.V. is in the pH range of 9.0 to 10.5.

PROTONIX I.V. is supplied for intravenous administration as a sterile, freeze-dried powder in a single-dose clear glass vial fitted with a rubber stopper and crimp seal. Each vial contains 40 mg pantoprazole (equivalent to 45.1 mg of pantoprazole sodium), edetate disodium (1 mg), and sodium hydroxide to adjust pH.

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) and Adverse Reactions (6)].

The safety and effectiveness of PROTONIX I.V. for the treatment of GERD and a history of EE for up to 7 days have been established in pediatric patients 3 months of age and older. Use of PROTONIX I.V. for this indication is supported by evidence from adequate and well-controlled studies of intravenous and oral pantoprazole sodium in adults and oral pantoprazole sodium in pediatric patients, with additional pharmacokinetic and safety data of intravenous pantoprazole in pediatric patients 1 year of age and older and oral pantoprazole in pediatric patients 3 months of age and older. Adverse reactions were generally similar to those reported in adults with intravenous or oral pantoprazole sodium [see Adverse Reactions (6.1) and Clinical Pharmacology (12.3)].

The safety and effectiveness of PROTONIX I.V. 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 PROTONIX I.V. have not been established in pediatric patients for the treatment of pathological hypersecretory conditions including ZE syndrome.

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 [see Clinical Pharmacology (12.3)].

The pharmacokinetics of pantoprazole were studied in 40 pediatric patients 1 to less than 16 years of age in three open-label clinical trials in pediatric patients with GERD following intravenous administration and 180 pediatric patients from birth to 16 years of age in four randomized, open-label clinical studies in pediatric patients with GERD following oral administration.

Population PK analyses predicted the following dosage regimens would achieve comparable steady-state plasma exposures (AUC_0-24) to those observed in adult patients administered 40 mg of PROTONIX I.V. once daily: 0.8 mg/kg once daily for pediatric patients 3 months to less than 1 year, 10 mg once daily for pediatric patients 1 year to 17 years with body weight less than 15 kg, 20 mg once daily for pediatric patients 1 year to 17 years with body weight greater than 15 kg but less than 40 kg, and 40 mg once daily for pediatric patients 1 year to 17 years with body weight of 40 kg and greater. The pharmacokinetics of pantoprazole following intravenous administration in pediatric patients less than 3 months of age have not been characterized.

• •
  PROTONIX I.V. 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) and Adverse Reactions (6)].
• •
  Proton pump inhibitors (PPIs), including PROTONIX I.V., are contraindicated in patients receiving rilpivirine-containing products [see Drug Interactions (7)].

Mild, transient transaminase elevations have been observed in clinical studies. The clinical significance of this finding in a large population of subjects administered PROTONIX I.V. is unknown [see Adverse Reactions (6)].

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)]
• •
  Clostridioides 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)]

Table 3 includes drugs with clinically important drug interactions and interaction with diagnostics when administered concomitantly with PROTONIX I.V. and instructions for preventing or managing them.

Consult the labeling of concomitantly used drugs to obtain further information about interactions with PPIs.

Pantoprazole peak serum concentration (C_max) and area under the serum concentration-time curve (AUC) increase in a manner proportional to intravenous doses from 10 mg to 80 mg. Pantoprazole does not accumulate and its pharmacokinetics are unaltered with multiple daily dosing. Following the administration of PROTONIX I.V., the serum concentration of pantoprazole declines biexponentially with a terminal elimination half-life of approximately one hour. In CYP2C19 extensive metabolizers [see Clinical Pharmacology (12.5)] with normal liver function receiving a 40 mg dose of PROTONIX I.V. by constant rate over 15 minutes, the peak concentration (C_max) is 5.52 ±1.42 mcg/mL and the total area under the plasma concentration versus time curve (AUC) is 5.4 ±1.5 mcg• hr/mL. The total clearance is 7.6 to 14 L/h.

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

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

PROTONIX I.V. is indicated for treatment of:

• •
  gastroesophageal reflux disease (GERD) and a history of erosive esophagitis (EE) for up to 10 days in adults and up to 7 days in pediatric patients 3 months and older.
• •
  pathological hypersecretory conditions including Zollinger-Ellison (ZE) Syndrome in adults.

Limitations of Use

The safety and effectiveness of PROTONIX I.V. for the treatment of upper gastrointestinal bleeding have not been established in adult or pediatric patients.

Pantoprazole is a 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).

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.

• •
  Gastric Malignancy: In adults, symptomatic response to therapy with PROTONIX I.V. 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 PROTONIX I.V. Assess the patient and remove the catheter if clinically indicated. (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)
• •
  Clostridioides 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 treatment 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)

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)

• •
  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)

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

Thrombophlebitis was associated with the administration of PROTONIX I.V. Assess the patient and remove the catheter if clinically indicated.

The following adverse reactions have been identified during post approval use of pantoprazole sodium products. 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:

General disorders and administration conditions: asthenia, fatigue, malaise

Immune system disorders: anaphylaxis (including anaphylactic shock), systemic lupus erythematosus

Investigations: weight changes

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

Musculoskeletal disorders: rhabdomyolysis, bone fracture

Renal and genitourinary disorders: acute tubulointerstitial nephritis, erectile dysfunction

Hepatobiliary disorders: hepatocellular damage leading to jaundice and hepatic failure

Psychiatric disorder: hallucinations, confusion, insomnia, somnolence

Metabolism and nutritional disorders: hyponatremia, hypomagnesemia, hypocalcemia, hypokalemia

Infections and infestations: Clostridioides difficile-associated diarrhea

Hematologic: pancytopenia, agranulocytosis

Nervous: ageusia, dysgeusia

Gastrointestinal disorders: fundic gland polyps

• •
  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.

Published observational studies suggest that PPI therapy like PROTONIX I.V. may be associated with an increased risk of Clostridioides 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.

Pregnancy: Based on animal data, may cause fetal harm. (8.1)

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.

In adults, symptomatic response to therapy with PROTONIX I.V. 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.

PROTONIX^® I.V. (pantoprazole sodium) is supplied in a single-dose vial as a white to off-white freeze-dried powder for reconstitution and dilution containing 40 mg of pantoprazole.

PROTONIX I.V. is available as follows:

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 PROTONIX I.V. and evaluate patients with suspected acute TIN [see Contraindications (4)].

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 PROTONIX I.V. at the first signs or symptoms of severe cutaneous adverse reactions or other signs of hypersensitivity and consider further evaluation.

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 PROTONIX I.V. 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.

NDC 0008-4001-01

PROTONIX^® I.V.

(pantoprazole sodium)

for Injection

40 mg/vial

Sterile

For Intravenous Use

Single-dose vial

Rx only

PREMIERProRx^®

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

NDC 0008-4001-01

Rx only

PROTONIX^® I.V.

(pantoprazole sodium)

for Injection

40 mg/vial

Sterile

For Intravenous Use

Single-dose vial

Contains 1 mg edetate disodium

No filter required

PREMIERProRx^®

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 PROTONIX I.V., 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.

NDC 0008-4001-25

Contains 25 of NDC 0008-4001-01

Rx only

25 x 40 mg Vials

PROTONIX^® I.V.

(pantoprazole sodium)

for Injection

40 mg/vial

Sterile

For Intravenous Use

Single-dose vial

PREMIERProRx^®

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.

PROTONIX I.V. 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 PROTONIX I.V. 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)].

Each vial contains:

Pantoprazole

40 mg

(equivalent to 45.1 mg of pantoprazole

sodium)

Contains 1 mg edetate disodium

Store at 20°-25°C (68°-77°F);

excursions permitted to 15°-30°C

(59°-86°F). [See USP Controlled Room

Temperature].

Protect vials from light; use of vial

carton is recommended.

Dist. by Wyeth Pharmaceuticals LLC

A subsidiary of Pfizer Inc

Philadelphia, PA 19101

Under license from Takeda GmbH

D78467 Konstanz, Germany

PREMIERProRx^® is a registered trademark

of Premier Healthcare Alliance, L.P.,

used under license.

MADE IN FRANCE

R04/0924/6171043

1 Bundle of 10 unit cartons

NDC 0008-4001-10

PROTONIX^® I.V.

(pantoprazole sodium) for Injection

40 mg/vial

Sterile

For Intravenous Use

Single-dose vial

PREMIERProRx^®

Rx only

LOT

EXP

SN

GTIN: 00300084001109

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)].

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

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

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

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

Pantoprazole was positive in the in vitro human lymphocyte chromosomal aberration assays, in one of two mouse micronucleus tests for clastogenic effects, and in the in vitro Chinese hamster ovarian cell/HGPRT forward mutation assay for mutagenic effects. Equivocal results were observed in the in vivo rat liver DNA covalent binding assay. Pantoprazole was negative in the in vitro Ames mutation assay, the in vitro unscheduled DNA synthesis (UDS) assay with rat hepatocytes, the in vitro AS52/GPT mammalian cell-forward gene mutation assay, the in vitro thymidine kinase mutation test with mouse lymphoma L5178Y cells, and the in vivo rat bone marrow cell chromosomal aberration assay.

There were no effects on fertility or reproductive performance when pantoprazole was given at oral doses up to 500 mg/kg/day in male rats (98 times the recommended human dose based on body surface area) and 450 mg/kg/day in female rats (88 times the recommended human dose based on body surface area).

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.

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.

• •
  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.

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 PROTONIX I.V. 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)].

Two studies measured the pharmacodynamic effects of 6 day treatment with PROTONIX I.V. in patients with ZE Syndrome (with and without multiple endocrine neoplasia type I). In one of these studies, an initial treatment with PROTONIX I.V. in 21 patients (29 to 75 years; 8 female; 4 Black, 1 Hispanic, 16 White) reduced acid output to the target level (10 mEq/h or less) and significantly reduced H⁺ concentration and the volume of gastric secretions; target levels were achieved within 45 minutes of drug administration.

In the other study of 14 patients (38 to 67 years; 5 female; 2 Black, 12 White) with ZE Syndrome, treatment was switched from an oral PPI to PROTONIX I.V. PROTONIX I.V. maintained or improved control of gastric acid secretion.

In both studies, total doses of 160 or 240 mg per day of PROTONIX I.V., administered in divided doses, maintained basal acid secretion below target levels in all patients. Target levels were 10 mEq/h in patients without prior gastric surgery, and 5 mEq/h in all patients with prior gastric acid-reducing surgery. Once gastric acid secretion was controlled, there was no evidence of tolerance during this 7 day study. Basal acid secretion was maintained below target levels for at least 24 hours in all patients and through the end of treatment in these studies (3 to 7 days) in all but 1 patient who required a dose adjustment guided by acid output measurements until acid control was achieved. In both studies, doses were adjusted to the individual patient need, but gastric acid secretion was controlled in greater than 80% of patients by a starting regimen of 80 mg every 12 hours.

• •
  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.

A multicenter, double-blind, two-period placebo-controlled study was conducted to assess the ability of PROTONIX^® I.V. to maintain gastric acid suppression in patients switched from pantoprazole sodium delayed-release tablets to PROTONIX I.V. GERD patients (n=65, 26 to 64 years; 35 female; 9 Black, 11 Hispanic, 44 White, 1 other) with a history of EE were randomized to receive either 20 or 40 mg of oral pantoprazole once per day for 10 days (period 1), and then were switched in period 2 to either daily PROTONIX I.V. or placebo for 7 days, matching their respective dose level from period 1. Patients were administered all test medication with a light meal. Maximum acid output (MAO) and basal acid output (BAO) were determined 24 hours following the last day of oral medication (day 10), the first day (day 1) of intravenous administration and the last day of intravenous administration (day 7). MAO was estimated from a 1 hour continuous collection of gastric contents following subcutaneous injection of 6.0 mcg/kg of pentagastrin.

This study demonstrated that, after 10 days of repeated oral administration followed by 7 days of intravenous administration, the oral and intravenous dosage forms of pantoprazole 40 mg are similar in their ability to suppress MAO and BAO in patients with GERD and a history of EE (see Table 5). Also, patients on oral PROTONIX who were switched to intravenous placebo experienced a significant increase in acid output within 48 hours of their last oral dose (see Table 5). However, at 48 hours after their last oral dose, patients treated with PROTONIX I.V. had a significantly lower mean basal acid output (see Table 5) than those treated with placebo.

To evaluate the effectiveness of PROTONIX I.V. as an initial treatment to suppress gastric acid secretion, two studies were conducted.

Study 1 was a multicenter, double-blind, placebo-controlled, study of the pharmacodynamic effects of PROTONIX I.V. and pantoprazole sodium delayed-release tablets. Patients with GERD and a history of EE (n=78, 20 to 67 years; 39 females; 7 Black, 19 Hispanic, 52 White) were randomized to receive either 40 mg PROTONIX I.V., 40 mg pantoprazole sodium delayed-release tablets, or placebo once daily for 7 days. Following an overnight fast, test medication was administered and patients were given a light meal within 15 minutes. MAO and BAO were determined 24 hours following the last day of study medication. MAO was estimated from a 1 hour continuous collection of gastric contents following subcutaneous injection of 6.0 mcg/kg of pentagastrin to stimulate acid secretion. This study demonstrated that, after treatment for 7 days, patients treated with PROTONIX I.V. had a significantly lower MAO and BAO than those treated with placebo (p<0.001), and results were comparable to those of patients treated with pantoprazole sodium delayed-release tablets (see Table 6).

Study 2 was a single-center, double-blind, parallel-group study to compare the clinical effects of PROTONIX I.V. and pantoprazole sodium delayed-release tablets. Patients (n=45, median age 56 years, 21 males and 24 females) with acute endoscopically proven reflux esophagitis (Savary/Miller Stage II or III) with at least 1 of 3 symptoms typical for reflux esophagitis (acid eructation, heartburn, or pain on swallowing) were randomized to receive either 40 mg PROTONIX I.V. or 40 mg pantoprazole sodium delayed-release tablets once daily for 5 days. After the initial 5 days, all patients were treated with 40 mg oral pantoprazole daily to complete a total of 8 weeks of treatment. Symptom relief was assessed by calculating the daily mean of the sums of the average scores for these 3 symptoms and the daily mean of the average score for each of the symptoms separately. There was no significant difference in symptom relief between PROTONIX I.V. and pantoprazole sodium delayed-release tablets within the first 5 days. A repeat endoscopy after 8 weeks of treatment revealed that 20 out of 23 (87%) patients treated with PROTONIX I.V. plus pantoprazole sodium delayed-release tablets and 19 out of 22 (86%) of the patients treated with pantoprazole sodium delayed-release tablets had endoscopically proven healing of their esophageal lesions.

Data comparing PROTONIX I.V. to other PPIs (oral or intravenous) or H₂-receptor antagonists (oral or intravenous) are limited, and therefore, are inadequate to support any conclusions regarding comparative efficacy.

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 and Handling

Store PROTONIX I.V. 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].

Protect from light.

• •
  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.

Experience in patients taking very high doses of pantoprazole (greater than 240 mg) is limited. Adverse reactions seen in spontaneous reports of overdose generally reflect the known safety profile of pantoprazole.

Pantoprazole is not removed by hemodialysis. In case of overdose, treatment should be symptomatic and supportive.

Single intravenous doses of pantoprazole at 378, 230, and 266 mg/kg (38, 46, and 177 times the recommended human dose based on body surface area) 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.

The active ingredient in PROTONIX^® I.V. (pantoprazole sodium), a PPI, is a substituted benzimidazole, sodium 5-(difluoromethoxy)-2-[[(3,4-dimethoxy-2-pyridinyl)methyl] sulfinyl]-1H-benzimidazole, a compound that inhibits gastric acid secretion. Its empirical formula is C₁₆H₁₄F₂N₃NaO₄S, with a molecular weight of 405.4. The structural formula is:

Pantoprazole sodium is a white to off-white crystalline powder and is racemic. Pantoprazole has weakly basic and acidic properties. Pantoprazole sodium is freely soluble in water, very slightly soluble in phosphate buffer at pH 7.4, and practically insoluble in n-hexane. The reconstituted solution of PROTONIX I.V. is in the pH range of 9.0 to 10.5.

PROTONIX I.V. is supplied for intravenous administration as a sterile, freeze-dried powder in a single-dose clear glass vial fitted with a rubber stopper and crimp seal. Each vial contains 40 mg pantoprazole (equivalent to 45.1 mg of pantoprazole sodium), edetate disodium (1 mg), and sodium hydroxide to adjust pH.

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) and Adverse Reactions (6)].

The safety and effectiveness of PROTONIX I.V. for the treatment of GERD and a history of EE for up to 7 days have been established in pediatric patients 3 months of age and older. Use of PROTONIX I.V. for this indication is supported by evidence from adequate and well-controlled studies of intravenous and oral pantoprazole sodium in adults and oral pantoprazole sodium in pediatric patients, with additional pharmacokinetic and safety data of intravenous pantoprazole in pediatric patients 1 year of age and older and oral pantoprazole in pediatric patients 3 months of age and older. Adverse reactions were generally similar to those reported in adults with intravenous or oral pantoprazole sodium [see Adverse Reactions (6.1) and Clinical Pharmacology (12.3)].

The safety and effectiveness of PROTONIX I.V. 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 PROTONIX I.V. have not been established in pediatric patients for the treatment of pathological hypersecretory conditions including ZE syndrome.

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 [see Clinical Pharmacology (12.3)].

The pharmacokinetics of pantoprazole were studied in 40 pediatric patients 1 to less than 16 years of age in three open-label clinical trials in pediatric patients with GERD following intravenous administration and 180 pediatric patients from birth to 16 years of age in four randomized, open-label clinical studies in pediatric patients with GERD following oral administration.

Population PK analyses predicted the following dosage regimens would achieve comparable steady-state plasma exposures (AUC_0-24) to those observed in adult patients administered 40 mg of PROTONIX I.V. once daily: 0.8 mg/kg once daily for pediatric patients 3 months to less than 1 year, 10 mg once daily for pediatric patients 1 year to 17 years with body weight less than 15 kg, 20 mg once daily for pediatric patients 1 year to 17 years with body weight greater than 15 kg but less than 40 kg, and 40 mg once daily for pediatric patients 1 year to 17 years with body weight of 40 kg and greater. The pharmacokinetics of pantoprazole following intravenous administration in pediatric patients less than 3 months of age have not been characterized.

• •
  PROTONIX I.V. 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) and Adverse Reactions (6)].
• •
  Proton pump inhibitors (PPIs), including PROTONIX I.V., are contraindicated in patients receiving rilpivirine-containing products [see Drug Interactions (7)].

Mild, transient transaminase elevations have been observed in clinical studies. The clinical significance of this finding in a large population of subjects administered PROTONIX I.V. is unknown [see Adverse Reactions (6)].

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)]
• •
  Clostridioides 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)]

Table 3 includes drugs with clinically important drug interactions and interaction with diagnostics when administered concomitantly with PROTONIX I.V. and instructions for preventing or managing them.

Consult the labeling of concomitantly used drugs to obtain further information about interactions with PPIs.

Pantoprazole peak serum concentration (C_max) and area under the serum concentration-time curve (AUC) increase in a manner proportional to intravenous doses from 10 mg to 80 mg. Pantoprazole does not accumulate and its pharmacokinetics are unaltered with multiple daily dosing. Following the administration of PROTONIX I.V., the serum concentration of pantoprazole declines biexponentially with a terminal elimination half-life of approximately one hour. In CYP2C19 extensive metabolizers [see Clinical Pharmacology (12.5)] with normal liver function receiving a 40 mg dose of PROTONIX I.V. by constant rate over 15 minutes, the peak concentration (C_max) is 5.52 ±1.42 mcg/mL and the total area under the plasma concentration versus time curve (AUC) is 5.4 ±1.5 mcg• hr/mL. The total clearance is 7.6 to 14 L/h.

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

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

PROTONIX I.V. is indicated for treatment of:

• •
  gastroesophageal reflux disease (GERD) and a history of erosive esophagitis (EE) for up to 10 days in adults and up to 7 days in pediatric patients 3 months and older.
• •
  pathological hypersecretory conditions including Zollinger-Ellison (ZE) Syndrome in adults.

Limitations of Use

The safety and effectiveness of PROTONIX I.V. for the treatment of upper gastrointestinal bleeding have not been established in adult or pediatric patients.

Pantoprazole is a 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).

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.

• •
  Gastric Malignancy: In adults, symptomatic response to therapy with PROTONIX I.V. 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 PROTONIX I.V. Assess the patient and remove the catheter if clinically indicated. (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)
• •
  Clostridioides 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 treatment 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)

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)

• •
  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)

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

Thrombophlebitis was associated with the administration of PROTONIX I.V. Assess the patient and remove the catheter if clinically indicated.

The following adverse reactions have been identified during post approval use of pantoprazole sodium products. 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:

General disorders and administration conditions: asthenia, fatigue, malaise

Immune system disorders: anaphylaxis (including anaphylactic shock), systemic lupus erythematosus

Investigations: weight changes

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

Musculoskeletal disorders: rhabdomyolysis, bone fracture

Renal and genitourinary disorders: acute tubulointerstitial nephritis, erectile dysfunction

Hepatobiliary disorders: hepatocellular damage leading to jaundice and hepatic failure

Psychiatric disorder: hallucinations, confusion, insomnia, somnolence

Metabolism and nutritional disorders: hyponatremia, hypomagnesemia, hypocalcemia, hypokalemia

Infections and infestations: Clostridioides difficile-associated diarrhea

Hematologic: pancytopenia, agranulocytosis

Nervous: ageusia, dysgeusia

Gastrointestinal disorders: fundic gland polyps

• •
  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.

Published observational studies suggest that PPI therapy like PROTONIX I.V. may be associated with an increased risk of Clostridioides 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.

Pregnancy: Based on animal data, may cause fetal harm. (8.1)

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.

In adults, symptomatic response to therapy with PROTONIX I.V. 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.

PROTONIX^® I.V. (pantoprazole sodium) is supplied in a single-dose vial as a white to off-white freeze-dried powder for reconstitution and dilution containing 40 mg of pantoprazole.

PROTONIX I.V. is available as follows:

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 PROTONIX I.V. and evaluate patients with suspected acute TIN [see Contraindications (4)].

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 PROTONIX I.V. at the first signs or symptoms of severe cutaneous adverse reactions or other signs of hypersensitivity and consider further evaluation.

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 PROTONIX I.V. 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.

NDC 0008-4001-01

PROTONIX^® I.V.

(pantoprazole sodium)

for Injection

40 mg/vial

Sterile

For Intravenous Use

Single-dose vial

Rx only

PREMIERProRx^®

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

NDC 0008-4001-01

Rx only

PROTONIX^® I.V.

(pantoprazole sodium)

for Injection

40 mg/vial

Sterile

For Intravenous Use

Single-dose vial

Contains 1 mg edetate disodium

No filter required

PREMIERProRx^®

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 PROTONIX I.V., 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.

NDC 0008-4001-25

Contains 25 of NDC 0008-4001-01

Rx only

25 x 40 mg Vials

PROTONIX^® I.V.

(pantoprazole sodium)

for Injection

40 mg/vial

Sterile

For Intravenous Use

Single-dose vial

PREMIERProRx^®

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.

PROTONIX I.V. 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 PROTONIX I.V. 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)].

Each vial contains:

Pantoprazole

40 mg

(equivalent to 45.1 mg of pantoprazole

sodium)

Contains 1 mg edetate disodium

Store at 20°-25°C (68°-77°F);

excursions permitted to 15°-30°C

(59°-86°F). [See USP Controlled Room

Temperature].

Protect vials from light; use of vial

carton is recommended.

Dist. by Wyeth Pharmaceuticals LLC

A subsidiary of Pfizer Inc

Philadelphia, PA 19101

Under license from Takeda GmbH

D78467 Konstanz, Germany

PREMIERProRx^® is a registered trademark

of Premier Healthcare Alliance, L.P.,

used under license.

MADE IN FRANCE

R04/0924/6171043

1 Bundle of 10 unit cartons

NDC 0008-4001-10

PROTONIX^® I.V.

(pantoprazole sodium) for Injection

40 mg/vial

Sterile

For Intravenous Use

Single-dose vial

PREMIERProRx^®

Rx only

LOT

EXP

SN

GTIN: 00300084001109

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)].

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

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

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

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

Pantoprazole was positive in the in vitro human lymphocyte chromosomal aberration assays, in one of two mouse micronucleus tests for clastogenic effects, and in the in vitro Chinese hamster ovarian cell/HGPRT forward mutation assay for mutagenic effects. Equivocal results were observed in the in vivo rat liver DNA covalent binding assay. Pantoprazole was negative in the in vitro Ames mutation assay, the in vitro unscheduled DNA synthesis (UDS) assay with rat hepatocytes, the in vitro AS52/GPT mammalian cell-forward gene mutation assay, the in vitro thymidine kinase mutation test with mouse lymphoma L5178Y cells, and the in vivo rat bone marrow cell chromosomal aberration assay.

There were no effects on fertility or reproductive performance when pantoprazole was given at oral doses up to 500 mg/kg/day in male rats (98 times the recommended human dose based on body surface area) and 450 mg/kg/day in female rats (88 times the recommended human dose based on body surface area).

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.

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.

• •
  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.

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 PROTONIX I.V. 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)].

Two studies measured the pharmacodynamic effects of 6 day treatment with PROTONIX I.V. in patients with ZE Syndrome (with and without multiple endocrine neoplasia type I). In one of these studies, an initial treatment with PROTONIX I.V. in 21 patients (29 to 75 years; 8 female; 4 Black, 1 Hispanic, 16 White) reduced acid output to the target level (10 mEq/h or less) and significantly reduced H⁺ concentration and the volume of gastric secretions; target levels were achieved within 45 minutes of drug administration.

In the other study of 14 patients (38 to 67 years; 5 female; 2 Black, 12 White) with ZE Syndrome, treatment was switched from an oral PPI to PROTONIX I.V. PROTONIX I.V. maintained or improved control of gastric acid secretion.

In both studies, total doses of 160 or 240 mg per day of PROTONIX I.V., administered in divided doses, maintained basal acid secretion below target levels in all patients. Target levels were 10 mEq/h in patients without prior gastric surgery, and 5 mEq/h in all patients with prior gastric acid-reducing surgery. Once gastric acid secretion was controlled, there was no evidence of tolerance during this 7 day study. Basal acid secretion was maintained below target levels for at least 24 hours in all patients and through the end of treatment in these studies (3 to 7 days) in all but 1 patient who required a dose adjustment guided by acid output measurements until acid control was achieved. In both studies, doses were adjusted to the individual patient need, but gastric acid secretion was controlled in greater than 80% of patients by a starting regimen of 80 mg every 12 hours.

• •
  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.

A multicenter, double-blind, two-period placebo-controlled study was conducted to assess the ability of PROTONIX^® I.V. to maintain gastric acid suppression in patients switched from pantoprazole sodium delayed-release tablets to PROTONIX I.V. GERD patients (n=65, 26 to 64 years; 35 female; 9 Black, 11 Hispanic, 44 White, 1 other) with a history of EE were randomized to receive either 20 or 40 mg of oral pantoprazole once per day for 10 days (period 1), and then were switched in period 2 to either daily PROTONIX I.V. or placebo for 7 days, matching their respective dose level from period 1. Patients were administered all test medication with a light meal. Maximum acid output (MAO) and basal acid output (BAO) were determined 24 hours following the last day of oral medication (day 10), the first day (day 1) of intravenous administration and the last day of intravenous administration (day 7). MAO was estimated from a 1 hour continuous collection of gastric contents following subcutaneous injection of 6.0 mcg/kg of pentagastrin.

This study demonstrated that, after 10 days of repeated oral administration followed by 7 days of intravenous administration, the oral and intravenous dosage forms of pantoprazole 40 mg are similar in their ability to suppress MAO and BAO in patients with GERD and a history of EE (see Table 5). Also, patients on oral PROTONIX who were switched to intravenous placebo experienced a significant increase in acid output within 48 hours of their last oral dose (see Table 5). However, at 48 hours after their last oral dose, patients treated with PROTONIX I.V. had a significantly lower mean basal acid output (see Table 5) than those treated with placebo.

To evaluate the effectiveness of PROTONIX I.V. as an initial treatment to suppress gastric acid secretion, two studies were conducted.

Study 1 was a multicenter, double-blind, placebo-controlled, study of the pharmacodynamic effects of PROTONIX I.V. and pantoprazole sodium delayed-release tablets. Patients with GERD and a history of EE (n=78, 20 to 67 years; 39 females; 7 Black, 19 Hispanic, 52 White) were randomized to receive either 40 mg PROTONIX I.V., 40 mg pantoprazole sodium delayed-release tablets, or placebo once daily for 7 days. Following an overnight fast, test medication was administered and patients were given a light meal within 15 minutes. MAO and BAO were determined 24 hours following the last day of study medication. MAO was estimated from a 1 hour continuous collection of gastric contents following subcutaneous injection of 6.0 mcg/kg of pentagastrin to stimulate acid secretion. This study demonstrated that, after treatment for 7 days, patients treated with PROTONIX I.V. had a significantly lower MAO and BAO than those treated with placebo (p<0.001), and results were comparable to those of patients treated with pantoprazole sodium delayed-release tablets (see Table 6).

Study 2 was a single-center, double-blind, parallel-group study to compare the clinical effects of PROTONIX I.V. and pantoprazole sodium delayed-release tablets. Patients (n=45, median age 56 years, 21 males and 24 females) with acute endoscopically proven reflux esophagitis (Savary/Miller Stage II or III) with at least 1 of 3 symptoms typical for reflux esophagitis (acid eructation, heartburn, or pain on swallowing) were randomized to receive either 40 mg PROTONIX I.V. or 40 mg pantoprazole sodium delayed-release tablets once daily for 5 days. After the initial 5 days, all patients were treated with 40 mg oral pantoprazole daily to complete a total of 8 weeks of treatment. Symptom relief was assessed by calculating the daily mean of the sums of the average scores for these 3 symptoms and the daily mean of the average score for each of the symptoms separately. There was no significant difference in symptom relief between PROTONIX I.V. and pantoprazole sodium delayed-release tablets within the first 5 days. A repeat endoscopy after 8 weeks of treatment revealed that 20 out of 23 (87%) patients treated with PROTONIX I.V. plus pantoprazole sodium delayed-release tablets and 19 out of 22 (86%) of the patients treated with pantoprazole sodium delayed-release tablets had endoscopically proven healing of their esophageal lesions.

Data comparing PROTONIX I.V. to other PPIs (oral or intravenous) or H₂-receptor antagonists (oral or intravenous) are limited, and therefore, are inadequate to support any conclusions regarding comparative efficacy.