Pantoprazole Sodium: Package Insert and Label Information (Page 2 of 4)

5.14 Concomitant Use of Pantoprazole Sodium for Injection with Methotrexate

Literature suggests that concomitant use of PPIs with methotrexate (primarily at high dose; see methotrexate prescribing information) may elevate and prolong serum levels of methotrexate and/or its metabolite, possibly leading to methotrexate toxicities. In high-dose methotrexate administration, a temporary withdrawal of the PPI may be considered in some patients [see Drug Interactions (7)].

6 ADVERSE REACTIONS

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

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Injection Site Reactions [see Warnings and Precautions (5.2)]

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Potential for Exacerbation of Zinc Deficiency [see Warnings and Precautions (5.3)]

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Acute Tubulointerstitial Nephritis [see Warnings and Precautions (5.4)]

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Clostridium difficile- Associated Diarrhea [see Warnings and Precautions (5.5)]

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Bone Fracture [see Warnings and Precautions (5.6)]

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Severe Cutaneous Adverse Reactions [see Warnings and Precautions (5.7)]

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Cutaneous and Systemic Lupus Erythematosus [see Warnings and Precautions (5.8)]

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Hepatic Effects [see Warnings and Precautions (5.9)]

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Hypomagnesemia and Mineral Metabolism [see Warnings and Precautions (5.10)]

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Fundic Gland Polyps [see Warnings and Precautions (5.11)]

6.1 Clinical Trials Experience

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.

Gastroesophageal Reflux Disease (GERD)

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 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.

Table 1: Adverse Reactions Reported in Clinical Trials of Adult Patients with GERD at a Frequency of >2%

	Oral 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	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	2.9	1.2
Arthralgia	2.8	1.4	1.2

Additional adverse reactions that were reported for oral pantoprazole 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

Zollinger-Ellison (ZE) Syndrome

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.

6.2 Postmarketing Experience

The following adverse reactions have been identified during postapproval use of pantoprazole 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:

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 Urinary Disorders: acute tubulointerstitial nephritis

Hepatobiliary Disorders: hepatocellular damage leading to jaundice and hepatic failure

Psychiatric Disorder: hallucinations, confusion, insomnia, somnolence

Metabolism and Nutritional Disorders: hyponatremia, hypomagnesemia, hypocalcemia, hypokalemia, hyponatremia

Infections and Infestations: Clostridium difficile associated diarrhea

Hematologic: pancytopenia, agranulocytosis

Nervous: ageusia, dysgeusia

Gastrointestinal Disorders: fundic gland polyps

7 DRUG 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), 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.

8 USE IN SPECIFIC POPULATIONS

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 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.