warnings and cautions
5 WARNINGS AND PRECAUTIONS Gastric Malignancy : In adults, symptomatic response to therapy with PROTONIX I.V. does not preclude the presence of gastric malignancy. Consider additional follow-up and diagnostic testing. ( 5.1 ) Hypersensitivity and Severe Skin Reactions : Anaphylaxis has been reported. ( 5.2 ) Injection Site Reactions : Thrombophlebitis is associated with the administration of intravenous pantoprazole. ( 5.3 ) Potential Exacerbation of Zinc Deficiency : Consider zinc supplementation in patients who are prone to zinc deficiency. Caution should be used when other EDTA containing products are also co-administered intravenously. ( 5.4 ) Acute Interstitial Nephritis : Observed in patients taking PPIs. ( 5.5 ) Clostridium difficile -Associated Diarrhea : PPI therapy may be associated with increased risk. ( 5.6 ) 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. ( 5.7 ) Cutaneous and Systemic Lupus Erythematosus : Mostly cutaneous; new onset or exacerbation of existing disease; discontinue PROTONIX I.V. and refer to specialist for evaluation. ( 5.8 ) Hepatic Effects : Elevations of transaminases observed. ( 5.9 ) Hypomagnesemia : Reported rarely with prolonged treatment with PPIs. ( 5.10 ) Fundic Gland Polyps: Risk increases with long-term use, especially beyond one year. Use the shortest duration of therapy. ( 5.11 ) 5.1 Presence of Gastric Malignancy In adults, symptomatic response to therapy with PROTONIX I.V. 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 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 PROTONIX I.V. These may require emergency medical treatment [see Adverse Reactions (6.2) ] . 5.3 Injection Site Reactions Thrombophlebitis was associated with the administration of PROTONIX I.V. 5.4 Potential for Exacerbation of Zinc Deficiency PROTONIX I.V. 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 PROTONIX I.V. who are prone to zinc deficiency. Caution should be used when other EDTA containing products are also co-administered intravenously [see Dosage and Administration (2.5) ] . 5.5 Acute Interstitial Nephritis Acute interstitial nephritis has been observed in patients taking PPIs including PROTONIX I.V. Acute interstitial nephritis may occur at any point during PPI therapy and is generally attributed to an idiopathic hypersensitivity reaction. Discontinue PROTONIX I.V. if acute interstitial nephritis develops [see Contraindications (4) ] . 5.6 Clostridium difficile- Associated Diarrhea Published observational studies suggest that PPI therapy like PROTONIX I.V. 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. 5.7 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 (2.2 , 2.4) , Adverse Reactions (6) ] . 5.8 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 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. 5.9 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 PROTONIX I.V. is unknown [see Adverse Reactions (6) ]. 5.10 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 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) ]. 5.11 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. 5.12 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 PROTONIX I.V. 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 [see Clinical Pharmacology (12.2) ] . 5.13 Interference with Urine Screen for THC Pantoprazole sodium may produce false-positive urine screen for THC (tetrahydrocannabinol) [see Drug Interactions (7) ] . 5.14 Concomitant Use of PROTONIX I.V. 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) ].