PANTOPRAZOLE SODIUM: Package Insert and Label Information (Page 2 of 7)

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 sodium (20 mg or 40 mg), 299 patients on an H ₂ -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 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 Flatulence	4.3 3.9	3.5 2.9	2.4 3.7
Dizziness	3.0	2.9	1.2
Arthralgia	2.8	1.4	1.2

Additional adverse reactions that were reported for pantoprazole sodium 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 sodium 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 sodium 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 sodium 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 sodium 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 sodium. 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 Urinary Disorders: acute tubulointerstitial nephritis 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

7 DRUG INTERACTIONS

Table 4 includes drugs with clinically important drug interactions and interaction with diagnostics when administered concomitantly with pantoprazole sodium 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 Sodium 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 sodium is contraindicated [see Contraindications ( 4)] . See prescribing information. Atazanavir: See prescribing information for atazanavir for dosing information. Nelfinavir: Avoid concomitant use with pantoprazole sodium. 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.
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 sodium 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 and MMF. Use pantoprazole sodium 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 sodium 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.