warnings and cautions
5 WARNINGS AND PRECAUTIONS Serum Electrolyte Abnormalities : CONTEPO contains 1980 mg sodium in each vial. The high sodium load associated with the use of CONTEPO may result in changes in serum electrolytes, such as increased levels of sodium and decreased levels of potassium, calcium and phosphorus. A low-sodium diet is recommended during CONTEPO treatment. Monitor serum electrolyte levels and fluid status during CONTEPO treatment. Monitor signs and symptoms of edema, particularly in patients with cardiac insufficiency, renal impairment, cirrhosis, hypertension, hyperaldosteronism, hypernatremia or pulmonary edema. ( 5.1 ) QT Prolongation: CONTEPO has been shown to prolong the QT interval in some patients in the clinical trial. Avoid CONTEPO in patients with known prolongation of the QT interval or ventricular arrhythmias, including a history of torsade de pointes. ( 5.2 , 7.1 ) Increased Transaminase Levels : Increase in alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were reported in the clinical trial. Monitor hepatic enzymes during CONTEPO treatment. ( 5.3 ) Hypersensitivity Reactions : Reactions such as rash, urticaria and anaphylaxis were reported with the use of CONTEPO. Before initiating therapy with CONTEPO, it is important to inquire about previous hypersensitivity reactions to oral or parenteral fosfomycin. If an allergic reaction occurs, discontinue CONTEPO immediately. ( 5.4 ) Neutropenia Including Agranulocytosis : Neutropenia, including agranulocytosis, has occurred in patients receiving IV fosfomycin treatment. Monitor complete blood count during CONTEPO therapy. If such reactions occur, discontinue CONTEPO and institute appropriate treatment ( 5.5 ). Clostridioides difficile -Associated Diarrhea (CDAD) : This has been reported with nearly all systemic antibacterial agents, including CONTEPO. Evaluate patients if diarrhea occurs. ( 5.6 ) 5.1 Serum Electrolyte Abnormalities CONTEPO contains 1,980 mg of sodium in each vial. The high sodium load associated with the use of CONTEPO may result in changes in serum electrolytes, such as increased levels of serum sodium and decreased levels of potassium, calcium, and phosphorous. Electrolyte disturbances, such as hypokalemia and hypocalcemia, may potentiate cardiac effects, including QT prolongation [ see Warnings and Precautions ( 5.2 ) and Clinical Pharmacology ( 12.2 ) ] . In Trial 1, a comparator-controlled clinical trial in patients with cUTI, hypokalemia, hypernatremia, hypophosphatemia, and hypocalcemia occurred more frequently in CONTEPO-treated patients compared with piperacillin/tazobactam-treated patients [ see Adverse Reactions ( 6.1 ) ] . Hypokalemia with serum potassium less than 3.0 mEq/L and/or requiring potassium supplementation occurred in 9.9% of patients receiving CONTEPO and 1.7% of patients receiving piperacillin/tazobactam. Hypophosphatemia with serum phosphate concentrations less than 1.0 mg/dL occurred in 2.1% of patients receiving CONTEPO and none of the patients receiving piperacillin/tazobactam. Hypernatremia with serum sodium greater than 150 mEq/L occurred in 3.4% of patients receiving CONTEPO and 0.9% of patients receiving piperacillin/tazobactam. Hypocalcemia with corrected serum calcium less than 8.0 mg/dL occurred in 3.9% of patients receiving CONTEPO and 2.6% of patients receiving piperacillin/tazobactam. A low-sodium diet is recommended during CONTEPO treatment. Minimize administration of drugs containing sodium. Monitor serum electrolyte levels (sodium, potassium, calcium, magnesium, and phosphorus) and fluid status during treatment with CONTEPO. Electrolyte supplementation may be necessary in some cases. Monitor for signs of edema, particularly in patients who should restrict their sodium intake or are prone to fluid overload (e.g., cardiac insufficiency, renal impairment, cirrhosis, hypertension, hyperaldosteronism, hypernatremia or pulmonary edema) [ see Adverse Reactions ( 6.1 ) ] . 5.2 QT Prolongation CONTEPO has been shown to prolong the QT interval in some patients. QT prolongation can lead to development of torsade de pointes-type ventricular tachycardia with the risk increasing as the degree of prolongation increases. In Trial 1, 3.6% of patients treated with CONTEPO had > 60 msec increase in QTcF interval from baseline and 1% of patients had QTcF > 480 msec. Torsade de pointes has been reported during postmarketing experience with fosfomycin [see Adverse Reactions ( 6.2 )] . The risk of QT prolongation may increase in patients with electrolyte abnormalities (such as hypokalemia and hypocalcemia), patients with conditions that have potential to cause electrolyte imbalance (such as renal impairment), or patients taking other drugs affecting electrolyte balance or QT prolongation. Avoid CONTEPO in patients with known QT prolongation or ventricular arrhythmias, including a history of torsade de pointes. Monitor electrolytes during treatment with CONTEPO [see Warnings and Precautions ( 5.1 ), Drug Interactions ( 7.1 ) and Clinical Pharmacology ( 12.2 )] . 5.3 Increased Transaminase Levels In Trial 1, increases in transaminases occurred more frequently in CONTEPO-treated patients compared to piperacillin/tazobactam-treated patients. Transaminases (Alanine Aminotransferase (ALT) or Aspartate Aminotransferase (AST) were elevated ≥ 3x upper limit of normal (ULN) in 10.3% of patients receiving CONTEPO and 4.8% of patients receiving piperacillin/tazobactam. Transaminase elevations were asymptomatic and reversible. No concurrent increases in serum bilirubin or alkaline phosphatase were observed. No patients met Hy's Law criteria, and no patients discontinued CONTEPO therapy because of treatment-related transaminase elevation [see Adverse Reactions ( 6.1 )] . Monitor hepatic enzymes during CONTEPO treatment. 5.4 Hypersensitivity Reactions CONTEPO is contraindicated in patients with known serious hypersensitivity to fosfomycin, or any of the excipients [see Contraindications ( 4 )] . Hypersensitivity reactions, such as rash and urticaria, were reported in patients treated with CONTEPO in Trial 1. Anaphylaxis has been reported postmarketing [see Adverse Reactions ( 6.2 )] . Before initiating therapy with CONTEPO, it is important to inquire about previous hypersensitivity reactions to oral or parenteral fosfomycin. If an allergic reaction to CONTEPO occurs, discontinue the drug immediately. 5.5 Neutropenia Including Agranulocytosis Neutropenia has been reported in patients receiving IV fosfomycin therapy. In Trial 1, 6.4% of patients in the CONTEPO arm developed neutropenia (absolute neutrophil count less than 1500 cells/mm 3 ) as compared to 3.9% in the piperacillin/tazobactam comparator arm. In the post marketing setting, neutropenia cases progressing to agranulocytosis have been reported with IV fosfomycin therapy. Monitor complete blood counts during CONTEPO therapy particularly in patients with pre-existing conditions or patients receiving concomitant drugs that may predispose to bone marrow suppression. Discontinue CONTEPO if neutropenia occurs and consider alternative therapies. 5.6 Clostridioides difficile -Associated Diarrhea Clostridioides difficile -associated diarrhea (CDAD) has been reported with use of nearly all systemic antibacterial agents, including CONTEPO, and may range in severity from mild to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon and may permit overgrowth of C. difficile. C. difficile produces toxins A and B which contribute to the development of CDAD. CDAD must be considered in all patients who present with diarrhea following antibacterial use. Careful medical history is necessary because CDAD has been reported to occur more than 2 months after administration of antibacterial agents. If CDAD is confirmed, discontinue antibacterials not directed against C. difficile, if possible. Manage fluid and electrolyte levels as appropriate, supplement protein intake, monitor antibacterial treatment of C. difficile, and institute surgical evaluation as clinically indicated. 5.7 Development of Drug-resistant Bacteria Prescribing CONTEPO in the absence of a proven or strongly suspected bacterial infection indication is unlikely to provide benefit to the patient and increases the risk of the development of drug resistant bacteria [ see Indications and Usage ( 1.2 ) ] .