PANTIN Gastro-resistant tablet Ref.[116007] Active ingredients: Pantoprazole

Presence of Gastric Malignancy

In adults, symptomatic response to therapy with Pantoprazole Sodium 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.

Hypersensitivity and Severe Skin Reactions

Anaphylaxis and other serious reactions such as erythema multiforme, Stevens-Johnson syndrome, and toxic epidermal necrolysis (TEN) have been reported with use of Pantoprazole Sodium These may require emergency medical treatment.

Injection Site Reactions

Thrombophlebitis was associated with the administration of PROTONIX I.V.

Potential for Exacerbation of Zinc Deficiency

Pantoprazole Sodium 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 who are prone to zinc deficiency. Caution should be used when other EDTA containing products are also co-administered intravenously.

Acute Interstitial Nephritis

Acute interstitial nephritis has been observed in patients taking PPIs including Pantoprazole Sodium Acute interstitial nephritis may occur at any point during PPI therapy and is generally attributed to an idiopathic hypersensitivity reaction. Discontinue Pantoprazole Sodium if acute interstitial nephritis develops.

Clostridium difficile-Associated Diarrhea

Published observational studies suggest that PPI therapy like Pantoprazole Sodium 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.

Patients should use the lowest dose and shortest duration of PPI therapy appropriate to the condition being treated.

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.

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 PPIinduced 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 PROTONIX I.V., 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.

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 is unknown.

Hypomagnesemia

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. 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 medicationssuch as digoxin or drugs that may cause hypomagnesemia (e.g., diuretics), health careprofessionals may consider monitoring magnesium levels prior to initiation of PPItreatment and periodically.

Fundic Gland Polyps

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

Interference with Investigations for Neuroendocrine Tumors

Serum chromogranin A (CgA) levels increase secondary to drug-induced decreases in gastricacidity. The increased CgA level may cause false positive results in diagnostic investigations forneuroendocrine tumors. Healthcare providers should temporarily stop Pantoprazole Sodium treatment at least 14 days before assessing CgA levels and consider repeating the test ifinitial CgA levels are high. If serial tests are performed (e.g. for monitoring), the samecommercial laboratory should be used for testing, as reference ranges between tests may vary.

Interference with Urine Screen for THC

Pantoprazole sodium may produce false-positive urine screen for THC (tetrahydrocannabinol).

Concomitant Use of Pantoprazole Sodium 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.

Pediatric Use

The safety and effectiveness of Pantoprazole Sodium have not been established in pediatric patients.

Animal Toxicity Data

In a pre- and post-natal development toxicity study in rats, the pups were administered oral doses of pantoprazole at 5, 15, and 30 mg/kg/day on postnatal day (PND 4) through PND 21, in addition to lactational exposure through milk. 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 and higher doses. Changes in bone parameters were partially reversible following a recovery period.

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.

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 subjects and younger subjects, and other reported clinical experience with oral pantoprazole sodium has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

Table 2 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 2. Clinically Relevant Interactions Affecting Drugs Co-Administered withPantoprazole Sodium and Interaction with Diagnostics:

Teratogenic Effects

Pregnancy Category C.

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 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.

There are no adequate and well-controlled studies in pregnant women. Advise pregnant women of the potential risk of fetal harm. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Nursing Mothers

Pantoprazole and its metabolites are excreted in the milk of rats. Pantoprazole excretion in human milk has been detected in a study of a single nursing mother after a single 40 mg oral dose of pantoprazole sodium. The clinical relevance of this finding is not known. Many drugs which are excreted in human milk have a potential for serious adverse reactions in nursing infants. Based on the potential for tumorigenicity shown for pantoprazole sodium in rodent carcinogenicity studies, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the benefit of the drug to the mother.

Not applicable.

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

• Hypersensitivity and Severe Skin Reactions
• Injection Site Reactions
• Potential for Exacerbation of Zinc Deficiency
• Acute Interstitial Nephritis
• Clostridium difficile-Associated Diarrhea
• Bone Fracture
• Cutaneous and Systemic Lupus Erythematosus
• Hepatic Effects
• Hypomagnesemia
• Fundic Gland Polyps

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 PROTONIX (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 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 PROTONIX I.V.

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

Additional adverse reactions that were reported for oral PROTONIX 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 doses of 80 mg to 240 mg per day for up to 2 years were similar to those reported in adult patients with GERD.

Postmarketing Experience

The following adverse reactions have been identified during post approval use of PROTONIX and 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:

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, Stevens-Johnson syndrome, toxic epidermal necrolysis (TEN), angioedema (Quincke's edema) and cutaneous lupus erythematosus

Musculoskeletal Disorders: rhabdomyolysis, bone fracture

Renal and Urinary Disorders: interstitial nephritis

Hepatobiliary Disorders: hepatocellular damage leading to jaundice and hepatic failure

Psychiatric Disorder: hallucinations, confusion, insomnia, somnolence

Metabolism and Nutritional Disorders: hyponatremia, hypomagnesemia

Infections and Infestations: Clostridium difficile-associated diarrhea

Hematologic: pancytopenia, agranulocytosis

Nervous: ageusia, dysgeusia

Gastrointestinal Disorders: fundic gland polyps

Not applicable.