CONTEPO

CONTEPO (fosfomycin) for injection, for intravenous use, contains fosfomycin disodium, an epoxide antibacterial drug. Fosfomycin disodium is a powder with the chemical name of disodium [(2R,3S)-3-methyloxiran-2-yl]-dioxido-oxophosphorane, an empirical formula of C 3 H 5 Na 2 O 4 P and molecular weight of 182. Figure 1 Chemical Structure of Fosfomycin Disodium Each CONTEPO for Injection single-dose vial contains white to almost white sterile powder with 6 grams of fosfomycin (equivalent to 7.9 grams fosfomycin disodium) and the inactive ingredient succinic acid (150 mg) for pH adjustment. It is intended for constitution and further dilution prior to intravenous infusion . Each gram of fosfomycin disodium contains 330 mg of sodium (i.e., each vial contains 1,980 mg of sodium). Figure 1

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.

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.

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 )

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

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 )] .