Fosfomycin

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 ) ] .

6 ADVERSE REACTIONS The following adverse reactions are discussed in greater detail in the Warnings and Precautions section: Serum Electrolyte Abnormalities [see Warnings and Precautions ( 5.1 )] QT Prolongation [see Warnings and Precautions ( 5.2 )] Increased Transaminase Levels [see Warnings and Precautions ( 5.3 )] Hypersensitivity Reactions [see Warnings and Precautions ( 5.4 )] Neutropenia Including Agranulocytosis [see Warnings and Precautions ( 5.5 )] Clostridioides difficile -Associated Diarrhea [see Warnings and Precautions ( 5.6 )] Development of Drug-Resistant Bacteria [see Warnings and Precautions ( 5.7 )] Most common adverse reactions (incidence ≥2%) are transaminase elevations, hypokalemia, neutropenia, nausea, vomiting, diarrhea, hypocalcemia, hypernatremia, headache, and hypophosphatemia. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Meitheal Pharmaceuticals Inc. at 1-844-824-8426 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 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 practice. CONTEPO was evaluated in a comparator-controlled clinical trial (Trial 1) in patients with cUTI, including acute pyelonephritis, which included 233 patients treated with CONTEPO and 231 treated with comparator (piperacillin/tazobactam 4.5 g every 8 hours) for 7 days, allowing bacteremic patients to receive up to 14 days. No switch to oral antibacterial drugs was allowed. The median age of treated patients was 54 years (range 18-89 years) and 64% were female. All patients were white (100%). Patients (99%) were predominantly enrolled in Eastern Europe. Concomitant bacteremia was identified in 9% of patients at baseline. Serious Adverse Reactions and Adverse Reactions Leading to Discontinuation Serious adverse reactions occurred in 2.1% (5/233) CONTEPO and 2.6% (6/231) piperacillin/tazobactam-treated patients, respectively. Treatment was discontinued due to adverse reactions in 3% (7/233) of patients receiving CONTEPO and in 2.6% (7/231) of patients receiving piperacillin/tazobactam. The most common adverse reactions resulting in discontinuation of CONTEPO were gastrointestinal disorders (nausea, vomiting, and abdominal pain) in 1.3% (3/233) of patients. No deaths occurred in the clinical trial. Common Adverse Reactions Table 3 lists adverse reactions occurring in 2% or greater of patients receiving CONTEPO in Trial 1. These adverse reactions were reversible upon completion of therapy. Table 3 Adverse Reactions Occurring in 2% or Greater of Patients with cUTI Receiving CONTEPO in Trial 1 a Transaminase elevations include increased ALT and AST ≥3x ULN. b Neutropenia includes absolute neutrophil count <1500 cells/mm 3 Adverse Reaction CONTEPO N=233 % Piperacillin/Tazobactam N=231 % Gastrointestinal Disorders Nausea 4.3 1.3 Diarrhea 3.9 4.8 Vomiting 3.9 0.4 Laboratory Investigations Transaminase elevations a 10.3 4.8 Hypokalemia 9.9 1.7 Hypophosphatemia 2.1 0.0 Hypocalcemia 3.9 2.6 Hypernatremia 3.4 0.9 Blood and Lymphatic System Disorders Neutropenia b 6.4 3.9 Nervous System Disorders Headache 2.6 2.2 Adverse Reactions Occurring in < 2% of Patients Receiving CONTEPO in Trial 1: Blood and lymphatic system disorders : anemia, thrombocytopenia Cardiac disorders : atrial fibrillation, palpitations, tachycardia, heart failure Ear and labyrinth disorders : hearing loss Gastrointestinal disorders : constipation General disorders and administration site conditions : asthenia, infusion site reactions, peripheral edema Hepatobiliary disorders : hepatic steatosis, hepatomegaly Infections and infestations : vaginal infection, vaginitis Investigations : increase creatinine kinase Metabolism and nutritional disorders : hyperglycemia Nervous system disorders : dysgeusia, syncope Respiratory, thoracic, and mediastinal disorders : dyspnea Skin and subcutaneous disorders : urticaria, rash, pruritis 6.2 Postmarketing Experience The following additional adverse reactions were not reported with CONTEPO-treated patients in Trial 1 but have been identified with the use of oral fosfomycin tromethamine or during use of intravenous fosfomycin sodium outside of the United States for various indications and dosing regimens. 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: Blood and lymphatic system disorders : aplastic anemia, eosinophilia, agranulocytosis, leukopenia, pancytopenia Cardiac disorders: torsade de pointes Ear and labyrinth disorders : vertigo Eye disorders : visual impairment Gastrointestinal disorders : dyspepsia, C. difficile -associated diarrhea and colitis, toxic megacolon Hepatobiliary disorders : alkaline phosphatase increased, cholestatic hepatitis, icterus, hepatic necrosis Immune system disorders : anaphylaxis Metabolism and nutrition disorders : decreased appetite Nervous system disorders : cerebral edema, dizziness, optic neuritis Psychiatric disorders : confusion Respiratory, thoracic, and mediastinal disorders : asthma attack, pulmonary edema Skin and subcutaneous tissue disorders : angioedema, facial edema Vascular disorders : hypertension

8 USE IN SPECIFIC POPULATIONS Lactation: Breastfeeding not recommended during treatment and 24 hours after the last dose (8.2). 8.1 Pregnancy Risk Summary Available data from observational studies and pharmacovigilance reports with fosfomycin use in pregnant women are insufficient to identify a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. Fosfomycin crosses the placental barrier. There are no animal data that meet current standards for nonclinical developmental toxicity studies. However, some reproductive toxicity data are available from published literature. Intravenous or intraperitoneal fosfomycin-sodium did not cause malformations in rabbits or rats, respectively, but showed evidence of fetotoxicity (see Data ). The clinical relevance of these animal data is uncertain. The background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defect and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Data Animal Data Fosfomycin crosses the placenta in rats and rabbits. In rats administered intraperitoneal fosfomycin sodium on Days 7 to 17 of gestation (during organogenesis), there were increased numbers of dead or resorbed fetuses at 1500 mg/kg (approximately 0.8 times the recommended human dose of 18 g/day, based on body surface area comparisons), a dose associated with maternal toxicity . Rabbits were administered intravenous fosfomycin sodium on Days 6 to 18 of gestation (during organogenesis) at doses 800 mg/kg (approximately 0.9 times the recommended human dose). No malformations were observed in rabbits or rats after intravenous or intraperitoneal fosfomycin sodium, respectively. In a pre- and post-natal developmental study in rats (dosed intraperitoneally with fosfomycin tromethamine between gestational day 6 and postnatal Day 21), no effects were observed in first-generation offspring at doses up to 1000 mg/kg, about 0.5 times the clinical dose, based on body surface area comparisons. Survival and postnatal body growth also were normal in the second-generation offspring at all doses. 8.2 Lactation Risk Summary Fosfomycin is present in human milk. There are no data on the effects of fosfomycin on the breastfed child or on milk production. Because of the potential for adverse reactions in a breastfed infant, advise patients not to breastfeed during treatment with CONTEPO and for 24 hours after the last dose. 8.4 Pediatric Use Safety and effectiveness of CONTEPO in patients less than 18 years of age has not been established. 8.5 Geriatric Use Of the 233 patients treated with CONTEPO in Trial 1, 32% (74/233) were 65 years of age and older, including 11.2% (26/233) who were 75 years of age and older. For patients included in the microbiological modified intent-to-treat (mMITT) population, lower overall success rates were observed for CONTEPO-treated and piperacillin/tazobactam-treated patients ≥ 65 years of age (53.6% and 43.9%, respectively) as compared to patients < 65 years (68.4% and 61.6%, respectively). For patients ≥ 65 years of age, the incidence rate of adverse reactions was 39.2% (29/74) in CONTEPO-treated patients and 28.6% (22/77) in the piperacillin/tazobactam-treated patients. For patients <65 years of age, the incidence rate of adverse reactions was 43.4% (69/159) in CONTEPO-treated patients and 33.8% (52/154) in the piperacillin/tazobactam-treated patients. Because elderly patients are more likely to have decreased cardiac and renal function, care should be taken in dose selection, and electrolytes, fluid status, and renal function should be monitored. Dosage adjustment in elderly patients should take into account renal function [ see Dosage and Administration ( 2.2 , 2.3 , 2.4 ) and Clinical Pharmacology ( 12.3 ) ] . 8.6 Renal Impairment Dosage adjustment is required for patients with estimated CLcr 50 mL/min or less. Monitor estimated CLcr and adjust the dosage of CONTEPO accordingly [ see Dosage and Administration ( 2.2 ) ] . In patients requiring hemodialysis, CONTEPO should be administered after hemodialysis on hemodialysis days [see Dosage and Administration ( 2.2 ), Clinical Pharmacology ( 12.3 )] . 8.7 Hepatic Impairment Monitor patients with severe hepatic impairment closely for fluid overload and electrolyte abnormalities [see Warnings and Precautions ( 5.1 ), Clinical Pharmacology ( 12.3 )] .

8.1 Pregnancy Risk Summary Available data from observational studies and pharmacovigilance reports with fosfomycin use in pregnant women are insufficient to identify a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. Fosfomycin crosses the placental barrier. There are no animal data that meet current standards for nonclinical developmental toxicity studies. However, some reproductive toxicity data are available from published literature. Intravenous or intraperitoneal fosfomycin-sodium did not cause malformations in rabbits or rats, respectively, but showed evidence of fetotoxicity (see Data ). The clinical relevance of these animal data is uncertain. The background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defect and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Data Animal Data Fosfomycin crosses the placenta in rats and rabbits. In rats administered intraperitoneal fosfomycin sodium on Days 7 to 17 of gestation (during organogenesis), there were increased numbers of dead or resorbed fetuses at 1500 mg/kg (approximately 0.8 times the recommended human dose of 18 g/day, based on body surface area comparisons), a dose associated with maternal toxicity . Rabbits were administered intravenous fosfomycin sodium on Days 6 to 18 of gestation (during organogenesis) at doses 800 mg/kg (approximately 0.9 times the recommended human dose). No malformations were observed in rabbits or rats after intravenous or intraperitoneal fosfomycin sodium, respectively. In a pre- and post-natal developmental study in rats (dosed intraperitoneally with fosfomycin tromethamine between gestational day 6 and postnatal Day 21), no effects were observed in first-generation offspring at doses up to 1000 mg/kg, about 0.5 times the clinical dose, based on body surface area comparisons. Survival and postnatal body growth also were normal in the second-generation offspring at all doses.