warnings and cautions
5 WARNINGS AND PRECAUTIONS Gastric Malignancy: In adults, symptomatic response does not preclude presence of gastric malignancy. Consider additional follow-up and diagnostic testing. ( 5.1 ) Acute Interstitial Nephritis: Observed in patients taking PPIs. ( 5.2 ) Clostridium difficile- Associated Diarrhea: PPI therapy may be associated with increased risk of Clostridium difficile -associated diarrhea. ( 5.3 ) 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 ) Cutaneous and Systemic Lupus Erythematosus: Mostly cutaneous; new onset or exacerbation of existing disease; discontinue Pantoprazole and refer to specialist for evaluation. ( 5.5 ) Cyanocobalamin (Vitamin B-12) Deficiency: Daily long-term use (e.g., longer than 3 years) may lead to malabsorption or a deficiency of cyanocobalamin. ( 5.6 ) Hypomagnesemia: Reported rarely with prolonged treatment with PPIs. ( 5.7 ) Fundic Gland Polyps: Risk increases with long-term use, especially beyond one year. Use the shortest duration of therapy. ( 5.9 ) 5.1 Presence of Gastric Malignancy In adults, symptomatic response to therapy with Pantoprazole 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 Acute Interstitial Nephritis Acute interstitial nephritis has been observed in patients taking PPIs including Pantoprazole. Acute interstitial nephritis may occur at any point during PPI therapy and is generally attributed to an idiopathic hypersensitivity reaction. Discontinue Pantoprazole if acute interstitial nephritis develops [see Contraindications ( 4 )]. 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 )]. Patients should use the lowest dose and shortest duration of PPI therapy appropriate to the condition being treated. 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 )]. 5.5 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, 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. 5.6 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. 5.7 Hypomagnesemia Hypomagnesemia, symptomatic and asymptomatic, has been reported rarely in patients treated with PPIs for at least three months, 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 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 )]. 5.8 Tumorigenicity Due to the chronic nature of GERD, there may be a potential for prolonged administration of Pantoprazole. In long-term rodent studies, pantoprazole was carcinogenic and caused rare types of gastrointestinal tumors. The relevance of these findings to tumor development in humans is unknown [see Nonclinical Toxicology ( 13.1 )]. 5.9 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. 5.10 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 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 very [see Clinical Pharmacology ( 12.2 )]. 5.11 Interference with Urine Screen for THC There have been reports of false-positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving PPIs, including Pantoprazole [see Drug Interactions ( 7 )]. 5.12 Concomitant Use of Pantoprazole 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 )].