Pantoprazole Sodium - Pantoprazole Sodium injection, Powder, For Solution
(Pantoprazole Sodium)Pantoprazole Sodium - Pantoprazole Sodium injection, Powder, For Solution Prescribing Information
Warnings and Precautions,
Severe Cutaneous Adverse Reactions (
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
Hypomagnesemia and Mineral Metabolism (
Pantoprazole sodium is a proton pump inhibitor (PPI) indicated in adults for the following:
• Short-term treatment (7 to 10 days) of gastroesophageal reflux disease (GERD) associated with a history of Erosive Esophagitis (EE).
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.
• Pathological hypersecretion conditions including Zollinger-Ellison (ZE) Syndrome.
Pantoprazole sodium for injection is indicated for the treatment of pathological hypersecretory conditions including Zollinger-Ellison (ZE) Syndrome in adults.
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
• The recommended adult dosage is 40 mg given once daily by intravenous infusion for 7 to 10 days.
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
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
• The recommended adult dosage is 80 mg administered every 12 hours by intravenous infusion. For information on how to adjust dosing for individual patient needs, see the full prescribing information.
Only for intravenous infusion; other parenteral routes of administration are not recommended.
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.
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.
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.
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.
Only for intravenous infusion; other parenteral routes of administration are not recommended.
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.
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.
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.
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.
• Only for intravenous infusion.
• The intravenous infusion can be administered over 2 minutes or 15 minutes.
• For information on how to prepare and administer for each indication, see the full prescribing information.
For Injection: 40 mg of pantoprazole white to off-white lyophilized cake or powder in a single-dose vial for reconstitution.
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. 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
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
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
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]).
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.
• 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
Thrombophlebitis was associated with the administration of pantoprazole sodium for injection.
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
The following serious adverse reactions are described below and elsewhere in labeling:
• Injection Site Reactions
• Potential for Exacerbation of Zinc Deficiency
• Acute Tubulointerstitial Nephritis
• Clostridium difficile-Associated Diarrhea
• Bone Fracture
• Cutaneous and Systemic Lupus Erythematosus
• Hepatic Effects
• Hypomagnesemia and Mineral Metabolism
• Fundic Gland Polyps
Most common adverse reactions (>2%) are: headache, diarrhea, nausea, abdominal pain, vomiting, flatulence, dizziness, and arthralgia. (6.1)
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.
Worldwide, approximately 80,500 patients have been treated with pantoprazole in clinical trials involving various dosages and duration of treatment.
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 H2-receptor antagonist, 46 patients on another PPI, and 82 patients on placebo. The most frequently occurring adverse reactions are listed in Table 1.
The number of patients treated in comparative studies with pantoprazole sodium for injection is limited; however, the adverse reactions seen were similar to those seen in the oral studies. Thrombophlebitis was the only new adverse reaction identified with pantoprazole sodium for injection.
| Oral Pantoprazole Sodium (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 oral pantoprazole sodium in US clinical trials with a frequency of ≤2% are listed below by body system:
Body as a Whole: allergic reaction, fever, photosensitivity reaction, facial edema, thrombophlebitis (I.V. only)
Gastrointestinal: constipation, dry mouth, hepatitis
Hematologic: leukopenia (reported in ex-US clinical trials only), thrombocytopenia
Metabolic/Nutritional: elevated CPK (creatine phosphokinase), generalized edema, elevated triglycerides, liver function tests abnormal
Musculoskeletal: myalgia
Nervous: depression, vertigo
Skin and Appendages: urticaria, rash, pruritus
Special Senses: blurred vision
In clinical studies of ZE Syndrome, adverse reactions reported in 35 patients administered pantoprazole sodium for injection doses of 80 mg to 240 mg per day for up to 2 years were similar to those reported in adult patients with GERD.
The following adverse reactions have been identified during postapproval use of pantoprazole sodium and pantoprazole sodium for injection. 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:
• Proton pump inhibitors (PPIs), including pantoprazole sodium for injection, are contraindicated in patients receiving rilpivirine-containing products
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.
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.
|
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), 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)