Contepo

1 INDICATIONS AND USAGE CONTEPO is an epoxide antibacterial indicated for the treatment of patients 18 years of age and older with complicated urinary tract infections (cUTI) including acute pyelonephritis caused by susceptible isolates of Escherichia coli and Klebsiella pneumoniae . ( 1.1 ) Usage to Reduce Development of Drug-Resistant Bacteria To reduce the development of drug-resistant bacteria and maintain the effectiveness of CONTEPO and other antibacterial drugs, CONTEPO should be used only to treat infections that are proven or strongly suspected to be caused by bacteria. ( 1.2 ) 1.1 Complicated Urinary Tract Infections (cUTI), including Acute Pyelonephritis CONTEPO is indicated for the treatment of patients 18 years and older with complicated urinary tract infections (cUTI), including acute pyelonephritis, caused by susceptible isolates of Escherichia coli and Klebsiella pneumoniae . 1.2 Usage to Reduce Development of Drug-Resistant Bacteria To reduce the development of drug-resistant bacteria and maintain the effectiveness of CONTEPO and other antibacterial drugs, CONTEPO should be used only to treat infections that are proven or strongly suspected to be caused by susceptible bacteria. When culture and susceptibility information are available, they should be considered in selecting or modifying antibacterial therapy. In the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy.

2 DOSAGE AND ADMINISTRATION Administer CONTEPO, 6 grams every 8 hours by intravenous (IV) infusion over 1 hour for up to 14 days, in patients 18 years of age or older with an estimated creatinine clearance (CLcr) greater than 50 mL/min. ( 2.1 ) The recommended dosage in patients 18 years of age and older with an estimated CLcr of 50 mL/min or less is presented in the table below. ( 2.2 ) a CLcr estimated using Cockcroft-Gault Equation. b All doses of CONTEPO are administered by intravenous infusion over 1 hour. Estimated CLcr (mL/min) a Loading Dose b Maintenance Dosage b Dose Frequency 41-50 6 grams 4 grams Every 8 hours 31-40 6 grams 3 grams Every 8 hours 21-30 6 grams 5 grams Every 24 hours 11-20 6 grams 3 grams Every 24 hours Approximately 60% to 80% of the fosfomycin dose is cleared from the body by hemodialysis. Administer CONTEPO after hemodialysis on hemodialysis days. ( 2.2 ) 2.1 Recommended Dosage The recommended dosage of CONTEPO is 6 grams administered every 8 hours by intravenous (IV) infusion over 1 hour in patients 18 years of age or older with an estimated creatinine clearance (CLcr) greater than 50 mL/min. The duration of therapy is up to 14 days and should be guided by the severity of infection and the patient's clinical status. During treatment, different dosage recommendations may be required based on change in estimated CLcr [ see Dosage and Administration ( 2.2 ) ] . 2.2 Recommended Dosage in Patients (18 Years of Age and Older) with Renal Impairment The recommended dosage of CONTEPO in patients 18 years of age and older with an estimated CLcr of 50 mL/min or less is presented in Table 1 . Monitor estimated CLcr and adjust the dosage of CONTEPO accordingly [ see Warnings and Precautions ( 5.1 ), Use in Specific Populations ( 8.6 ) and Clinical Pharmacology ( 12.3 ) ] . Table 1 Dosage of CONTEPO in Patients (18 Years of Age and Older) with Renal Impairment a CLcr estimated by Cockcroft-Gault Equation. b All doses of CONTEPO are administered by IV infusion over 1 hour. Estimated CLcr (mL/min) a Loading Dose b Maintenance Dosage b Dose Frequency 41-50 6 grams 4 grams Every 8 hours 31-40 6 grams 3 grams Every 8 hours 21-30 6 grams 5 grams Every 24 hours 11-20 6 grams 3 grams Every 24 hours Approximately 60 to 80 % of the fosfomycin dose is cleared from the body by hemodialysis. Administer CONTEPO after hemodialysis on hemodialysis days. 2.3 Preparation of Diluted Solutions of CONTEPO Preparation CONTEPO is supplied as a dry powder in a single-dose vial that must be constituted and further diluted prior to intravenous infusion as described below. CONTEPO does not contain preservatives. Aseptic technique must be used for constitution and dilution prior to IV infusion. Constitute the vial with 30 mL of Sterile Water for Injection, USP and gently mix to completely dissolve contents. A slight degree of warming occurs when the powder is dissolved. The constituted solution should appear clear and colorless. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. The constituted solution is not for direct injection and must be further diluted immediately with Sterile Water for Injection, USP [see Dosage and Administration ( 2.4 )] before intravenous infusion. To prepare the infusion solution, first remove 80 mL from a 250 mL intravenous bag of Sterile Water for Injection, USP for infusion so that it contains approximately 170 mL. Then add the required volume of constituted solution to the infusion bag according to Table 2 . Discard unused portion. The constituted and further diluted solution of CONTEPO has a pH of 7.4 to 7.8. Table 2 Preparation of CONTEPO Doses CONTEPO Dose Volume to Withdraw from Constituted Vial Volume of Final Infusion Bag (Approximate) Final Infusion Concentration of CONTEPO (Approximate) 6 grams 32.6 mL (Entire Contents) 202 mL 30 mg/mL 5 grams 27 mL 197 mL 25 mg/mL 4 grams 21.5 mL 192 mL 20 mg/mL 3 grams 16 mL 186 mL 15 mg/mL 2.4 Stability of CONTEPO Solution in Intravenous Fluids Because CONTEPO contains a high sodium content (1,980 mg per vial) [see Warnings and Precautions ( 5.2 )] , the infusion solution for dilution is Sterile Water for Injection, USP. After dilution, CONTEPO solution for administration is stable for 16 hours at room temperature (20°C to 25°C) at a concentration of 15 mg/mL to 30 mg/mL in Sterile Water for Injection, USP. 2.5 Drug Incompatibility The compatibility of CONTEPO with other drugs and infusion solutions has not been established. CONTEPO should not be mixed or co-administered with solutions containing other drugs.

4 CONTRAINDICATIONS CONTEPO is contraindicated in patients with known serious hypersensitivity to fosfomycin, or any of the excipients [ see Warnings and Precautions ( 5.2 ) ] . CONTEPO is contraindicated in patients with known serious hypersensitivity to fosfomycin, or any of the excipients. ( 4 )

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 ) ] .

7 DRUG INTERACTIONS Avoid co-administration of CONTEPO with drugs known to prolong the QT interval. ( 5.2 , 7.1 ) 7.1 Drugs that prolong QT interval Co-administration of CONTEPO with other drugs known to prolong the QT interval may increase the risk for ventricular arrhythmia. Avoid co-administration of CONTEPO with drugs known to prolong the QT interval, such as class IA or class III antiarrhythmic medications, tricyclic antidepressants, macrolides, and antipsychotics [see Warnings and Precautions ( 5.2 )] .

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

8.1 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.