Pantoprazole Sodium

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Pantoprazole Sodium Prescribing Information

Pantoprazole sodium is supplied as delayed-release granules in packets for preparation of oral suspensions. The recommended dosages are outlined in Table 1.

Table 1: Recommended Dosing Schedule for Pantoprazole Sodium for Delayed-Release Oral Suspension

Indication	Dose	Frequency
Short-Term Treatment of Erosive Esophagitis Associated With GERD
Adults	40 mg	Once daily for up to 8 weeks^*
Children (5 years and older) ≥ 40 kg	40 mg	Once daily for up to 8 weeks
Maintenance of Healing of Erosive Esophagitis
Adults	40 mg	Once daily^***
Pathological Hypersecretory Conditions Including Zollinger-Ellison Syndrome
Adults	40 mg	Twice daily**

* For adult patients who have not healed after 8 weeks of treatment, an additional 8-week course of pantoprazole sodium for delayed-release oral suspension may be considered.

** Dosage regimens should be adjusted to individual patient needs and should continue for as long as clinically indicated. Doses up to 240 mg daily have been administered.

*** Controlled studies did not extend beyond 12 months

Pregnancy

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

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. Reproduction studies have been performed in rats at oral doses up to 450 mg/kg/day (about 88 times the recommended human dose) and rabbits at oral doses up to 40 mg/kg/day (about 16 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)

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 oral pantoprazole doses up to 450 mg/kg/day (about 88 times the recommended human dose based on body surface area) and in rabbits at oral doses up to 40 mg/kg/day (about 16 times the recommended human dose based on body surface area) with administration of pantoprazole sodium during organogenesis in pregnant animals. The studies have revealed no evidence of impaired fertility or harm to the fetus due to pantoprazole.

A pre- and postnatal 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 delayed-release oral suspension is contraindicated in patients with known hypersensitivity to any component of the formulation or any substituted benzimidazole. Hypersensitivity reactions may include anaphylaxis, anaphylactic shock, angioedema, bronchospasm, acute tubulointerstitial nephritis, and urticaria

[

5.2 Acute Tubulointerstitial Nephritis

Acute tubulointerstitial nephritis (TIN) has been observed in patients taking PPIs and may occur at any point during PPI therapy. Patients may present with varying signs and symptoms from symptomatic hypersensitivity reactions to non-specific symptoms of decreased renal function (e.g., malaise, nausea, anorexia). In reported case series, some patients were diagnosed on biopsy and in the absence of extra-renal manifestations (e.g., fever, rash or arthralgia). Discontinue pantoprazole sodium for delayed- release oral suspension and evaluate patients with suspected acute TIN

[see Contraindications (4)].

6 ADVERSE REACTIONS

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

Acute Tubulointerstitial Nephritis
[see Warnings and Precautions (5.2)]
Clostridium difficile-
Associated Diarrhea
[see Warnings and Precautions (5.3)]
Bone Fracture
[see Warnings and Precautions (5.4)]
Severe Cutaneous Adverse Reactions
[see Warnings and Precautions (5.5)]
Cutaneous and Systemic Lupus Erythematosus
[see Warnings and Precautions (5.6)]
Cyanocobalamin (Vitamin B-12) Deficiency
[see Warnings and Precautions (5.7)]
Hypomagnesemia and Mineral Metabolism
[see Warnings and Precautions (5.8)]
Fundic Gland Polyps
[see Warnings and Precautions (5.10)]

Most common adverse reactions are:

For adult use (>2%): headache, diarrhea, nausea, abdominal pain, vomiting, flatulence, dizziness, and arthralgia. ( 6.1 )
For pediatric use (>4%): URI, headache, fever, diarrhea, vomiting, rash, and abdominal pain.

To report SUSPECTED ADVERSE REACTIONS, contact

Edenbridge Pharmaceuticals, LLC at 877-381-3336 or FDA at

1-800-FDA-1088 or

www.fda.gov/medwatch

6.1 Clinical Trials Experience

The adverse reaction profiles for pantoprazole sodium for delayed-release oral suspension and pantoprazole sodium delayed-release tablets are similar.

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.

Adults

Safety in nine randomized comparative US clinical trials in patients with GERD included 1,473 patients on oral pantoprazole (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 3.

Table 3: Adverse Reactions Reported in Clinical Trials of Adult Patients with GERD at a Frequency of >2%

	Pantoprazole (n=1473) %	Comparators (n=345) %	Placebo (n=82) %
Headache	12.2	12.8	8.5
Diarrhea	8.8	9.6	4.9
Nausea	7.0	5.2	9.8
Abdominal pain	6.2	4.1	6.1
Vomiting	4.3	3.5	2.4
Flatulence	3.9	2.9	3.7
Dizziness	3.0	2.9	1.2
Arthralgia	2.8	1.4	1.2

Additional adverse reactions that were reported for pantoprazole in clinical trials with a frequency of ≤2% are listed below by body system:

Body as a Whole:

allergic reaction, pyrexia, photosensitivity reaction, facial edema

Gastrointestinal:

constipation, dry mouth, hepatitis

Hematologic:

leukopenia, thrombocytopenia

Metabolic/Nutritional:

elevated CK (creatine kinase), generalized edema, elevated triglycerides, liver enzymes elevated

Musculoskeletal:

myalgia

Nervous:

depression, vertigo

Skin and Appendages:

urticaria, rash, pruritus

Special Senses:

blurred vision

Pediatric Patients

Safety of pantoprazole in the treatment of EE associated with GERD was evaluated in pediatric patients ages 1 year through 16 years in three clinical trials. Safety trials involved pediatric patients with EE; however, as EE is uncommon in the pediatric population, 249 pediatric patients with endoscopically-proven or symptomatic GERD were also evaluated. All adult adverse reactions to pantoprazole are considered relevant to pediatric patients. In patients ages 1 year through 16 years, the most commonly reported (>4%) adverse reactions include: URI, headache, fever, diarrhea, vomiting, rash, and abdominal pain.

For safety information in patients less than 1 year of age see

Use in Specific Populations (8.4)

Additional adverse reactions that were reported for pantoprazole in pediatric patients in clinical trials with a frequency of ≤4% are listed below by body system:

Body as a Whole:

allergic reaction, facial edema

Gastrointestinal:

constipation, flatulence, nausea

Metabolic/Nutritional:

elevated triglycerides, elevated liver enzymes, elevated CK (creatine kinase)

Musculoskeletal:

arthralgia, myalgia

Nervous:

dizziness, vertigo

Skin and Appendages:

urticaria

The following adverse reactions seen in adults in clinical trials were not reported in pediatric patients in clinical trials, but are considered relevant to pediatric patients: photosensitivity reaction, dry mouth, hepatitis, thrombocytopenia, generalized edema, depression, pruritus, leukopenia, and blurred vision.

Zollinger-Ellison (ZE) Syndrome

In clinical studies of ZE Syndrome, adverse reactions reported in 35 patients taking pantoprazole 80 mg/day to 240 mg/day for up to 2 years were similar to those reported in adult patients with GERD.

6.2 Postmarketing Experience

The following adverse reactions have been identified during postapproval use of pantoprazole. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

These adverse reactions are listed below by body system:

Gastrointestinal Disorders:

fundic gland polyps

General Disorders and Administration Conditions:

asthenia, fatigue, malaise

Hematologic:

pancytopenia, agranulocytosis

Hepatobiliary Disorders:

hepatocellular damage leading to jaundice and hepatic failure

Immune System Disorders:

anaphylaxis (including anaphylactic shock), systemic lupus erythematosus

Infections and Infestations: Clostridium difficile

associated diarrhea

Investigations:

weight changes

Metabolism and Nutritional Disorders:

hypomagnesemia, hypocalcemia, hypokalemia, hyponatremia

Musculoskeletal Disorders:

rhabdomyolysis, bone fracture

Nervous:

ageusia, dysgeusia

Psychiatric Disorders:

hallucination, confusion, insomnia, somnolence

Renal and Genitourinary Disorders:

acute tubulointerstitial nephritis, erectile dysfunction

Skin and Subcutaneous Tissue Disorders:

severe dermatologic reactions (some fatal), including erythema multiforme, SJS/TEN, DRESS, AGEP, angioedema (Quincke’s edema) and cutaneous lupus erythematosus

]

Proton pump inhibitors (PPIs), including pantoprazole sodium for delayed- release oral suspension, are contraindicated in patients receiving rilpivirine-containing products

[

7 DRUG INTERACTIONS

Table 4 includes drugs with clinically important drug interactions and interaction with diagnostics when administered concomitantly with pantoprazole and instructions for preventing or managing them.

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

Table 4: Clinically Relevant Interactions Affecting Drugs Co-Administered with Pantoprazole and Interactions 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 is contraindicated [see Contraindications (4)] . See prescribing information. Atazanavir: See prescribing information for atazanavir for dosing information. Nelfinavir: Avoid concomitant use with pantoprazole. 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.
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 (5.13)] .
Intervention:	A temporary withdrawal of pantoprazole 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 and MMF. Use pantoprazole 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 (5.11), Clinical Pharmacology (12.2)] .
Intervention:	Temporarily stop pantoprazole 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 (5.12)] .
Intervention:	An alternative confirmatory method should be considered to verify positive results.

See full prescribing information for a list of clinically important drug interactions ( 7 )

]

Gastric Malignancy:
In adults, symptomatic response does not preclude presence of gastric malignancy. Consider additional follow-up and diagnostic testing. (
5.1 Presence of Gastric Malignancy
In adults, symptomatic response to therapy with pantoprazole sodium for delayed-release oral suspension 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.
)
Acute Tubulointerstitial Nephritis
: Discontinue treatment and evaluate patients. (
5.2 Acute Tubulointerstitial Nephritis
Acute tubulointerstitial nephritis (TIN) has been observed in patients taking PPIs and may occur at any point during PPI therapy. Patients may present with varying signs and symptoms from symptomatic hypersensitivity reactions to non-specific symptoms of decreased renal function (e.g., malaise, nausea, anorexia). In reported case series, some patients were diagnosed on biopsy and in the absence of extra-renal manifestations (e.g., fever, rash or arthralgia). Discontinue pantoprazole sodium for delayed- release oral suspension and evaluate patients with suspected acute TIN
[see Contraindications (4)].
)
Clostridium difficile-
Associated Diarrhea
: PPI therapy may be associated with increased risk of
Clostridium difficile-
associated diarrhea. (
5.3
Clostridium difficile
-Associated Diarrhea
Published observational studies suggest that PPI therapy like pantoprazole may be associated with an increased risk of
Clostridium difficile
associated diarrhea, especially in hospitalized patients. This diagnosis should be considered for diarrhea that does not improve
[see Adverse Reactions (6.2)]
.
)
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. (
5.4 Bone Fracture
Several published observational studies suggest that PPI therapy may be associated with an increased risk for osteoporosis-related fractures of the hip, wrist, or spine. The risk of fracture was increased in patients who received high-dose, defined as multiple daily doses, and long-term PPI therapy (a year or longer). Patients should use the lowest dose and shortest duration of PPI therapy appropriate to the condition being treated.
Patients at risk for osteoporosis-related fractures should be managed according to established treatment guidelines
[see Dosage and Administration (2), Adverse Reactions (6.2)].
)
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.(
5.5 Severe Cutaneous Adverse Reactions
Severe cutaneous adverse reactions, including erythema multiforme, Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), drug reaction with eosinophilia and systemic symptoms (DRESS), and acute generalized exanthematous pustulosis (AGEP) have been reported in association with the use of PPIs
[see Adverse Reactions (6.2)].
Discontinue pantoprazole sodium for delayed-release oral suspension at the first signs or symptoms of severe cutaneous adverse reactions or other signs of hypersensitivity and consider further evaluation.
)
Cutaneous and Systemic Lupus Erythematosus
: Mostly cutaneous; new onset or exacerbation of existing disease; discontinue pantoprazole and refer to specialist for evaluation.
5.6 Cutaneous and Systemic Lupus Erythematosus
Cutaneous lupus erythematosus (CLE) and systemic lupus erythematosus (SLE) have been reported in patients taking PPIs, including pantoprazole sodium. These events have occurred as both new onset and an exacerbation of existing autoimmune disease. The majority of PPI-induced lupus erythematous cases were CLE.
The most common form of CLE reported in patients treated with PPIs was subacute CLE (SCLE) and occurred within weeks to years after continuous drug therapy in patients ranging from infants to the elderly. Generally, histological findings were observed without organ involvement.
Systemic lupus erythematosus (SLE) is less commonly reported than CLE in patients receiving PPIs. PPI associated SLE is usually milder than non-drug induced SLE. Onset of SLE typically occurred within days to years after initiating treatment primarily in patients ranging from young adults to the elderly. The majority of patients presented with rash; however, arthralgia and cytopenia were also reported.

Avoid administration of PPIs for longer than medically indicated. If signs or symptoms consistent with CLE or SLE are noted in patients receiving pantoprazole sodium for delayed-release oral suspension, 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.
Cyanocobalamin (Vitamin B-12) Deficiency
: Daily long-term use (e.g., longer than 3 years) may lead to malabsorption or a deficiency of cyanocobalamin. (
5.7 Cyanocobalamin (Vitamin B-12) Deficiency
Generally, daily treatment with any acid-suppressing medications over a long period of time (e.g., longer than 3 years) may lead to malabsorption of cyanocobalamin (Vitamin B-12) caused by hypo- or achlorhydria. Rare reports of cyanocobalamin deficiency occurring with acid-suppressing therapy have been reported in the literature. This diagnosis should be considered if clinical symptoms consistent with cyanocobalamin deficiency are observed.
)
Hypomagnesemia and Mineral Metabolism
: Reported rarely with prolonged treatment with PPIs. (
5.8 Hypomagnesemia and Mineral Metabolism
Hypomagnesemia, symptomatic and asymptomatic, has been reported rarely in patients treated with PPIs for at least three months, and in most cases after a year of therapy. Serious adverse events include tetany, arrhythmias, and seizures. Hypomagnesemia may lead to hypocalcemia and/or hypokalemia and may exacerbate underlying hypocalcemia in at-risk patients. In most patients, treatment of hypomagnesemia required magnesium replacement and discontinuation of the PPI.

For patients expected to be on prolonged treatment or who take PPIs with medications such as digoxin or drugs that may cause hypomagnesemia (e.g., diuretics), health care professionals may consider monitoring magnesium levels prior to initiation of PPI treatment and periodically
[see Adverse Reactions (6.2)]
.

Consider monitoring magnesium and calcium levels prior to initiation of pantoprazole sodium for delayed-release oral suspension 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.
)
Fundic Gland Polyps:
Risk increases with long-term use, especially beyond one year. Use the shortest duration of therapy. (
5.10 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.
)

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