PANTOPRAZOLE Drug Interactions: What You Need to Know

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

Table

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

Warfarin Clinical

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

Clopidogrel Clinical

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

Methotrexate Clinical

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

Drugs

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

Clinical

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

False Positive Urine

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

See

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

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

Data Human Data

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

Animal Data

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

8.2 Lactation .

Risk Summary

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

Data

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

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

Animal Toxicity

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

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

4 CONTRAINDICATIONS

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

AND PRECAUTIONS

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

5.1 Presence of Gastric Malignancy In adults, symptomatic response to therapy with pantoprazole sodium in 0.9% sodium chloride injection does not preclude the presence of gastric malignancy. Consider additional follow-up and diagnostic testing in adult patients who have a suboptimal response or an early symptomatic relapse after completing treatment with a PPI. In older patients, also consider an endoscopy.

5.2 Injection Site Reactions Thrombophlebitis was associated with the administration of pantoprazole sodium injection.

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

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

5.5 Clostridium difficile- Associated Diarrhea Published observational studies suggest that PPI therapy like pantoprazole sodium in 0.9% sodium chloride injection may be associated with an increased risk of Clostridium difficile associated diarrhea, especially in hospitalized patients. This diagnosis should be considered for diarrhea that does not improve <span class="opacity-50 text-xs">[see Adverse Reactions (6.2) ]</span>. Patients should use the lowest dose and shortest duration of PPI therapy appropriate to the condition being treated.

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

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

5.8 Cutaneous and Systemic Lupus Erythematosus Cutaneous lupus erythematosus (CLE) and systemic lupus erythematosus (SLE) have been reported in patients taking PPIs, including pantoprazole sodium. These events have occurred as both new onset and an exacerbation of existing autoimmune disease. The majority of PPI-induced lupus erythematous cases were CLE. The most common form of CLE reported in patients treated with PPIs was subacute CLE (SCLE) and occurred within weeks to years after continuous drug therapy in patients ranging from infants to the elderly. Generally, histological findings were observed without organ involvement. Systemic lupus erythematosus (SLE) is less commonly reported than CLE in patients receiving PPIs. PPI associated SLE is usually milder than non-drug induced SLE. Onset of SLE typically occurred within days to years after initiating treatment primarily in patients ranging from young adults to the elderly. The majority of patients presented with rash; however, arthralgia and cytopenia were also reported. Avoid administration of PPIs for longer than medically indicated. If signs or symptoms consistent with CLE or SLE are noted in patients receiving pantoprazole sodium in 0.9% sodium chloride injection, discontinue the drug and refer the patient to the appropriate specialist for evaluation. Most patients improve with discontinuation of the PPI alone in 4 to 12 weeks. Serological testing (e.g., ANA) may be positive and elevated serological test results may take longer to resolve than clinical manifestations.

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

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

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

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

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

5.14 Concomitant Use of Pantoprazole in 0.9% Sodium Injection with Methotrexate Literature suggests that concomitant use of PPIs with methotrexate (primarily at high dose; see methotrexate prescribing information) may elevate and prolong serum levels of methotrexate and/or its metabolite, possibly leading to methotrexate toxicities. In high-dose methotrexate administration, a temporary withdrawal of the PPI may be considered in some patients <span class="opacity-50 text-xs">[see Drug Interactions (7) ]</span>.