Durlobactam

12.1 Mechanism of Action XACDURO is an antibacterial drug [see Microbiology (12.4) ].

1 INDICATIONS AND USAGE XACDURO is a co-packaged product containing sulbactam, a beta-lactam antibacterial and beta lactamase inhibitor, and durlobactam, a beta lactamase inhibitor, indicated in patients 18 years of age and older for the treatment of hospital-acquired bacterial pneumonia and ventilator-associated bacterial pneumonia (HABP/VABP), caused by susceptible isolates of Acinetobacter baumannii-calcoaceticus complex. ( 1.1 ) Limitations of Use : XACDURO is not indicated for the treatment of HABP/VABP caused by pathogens other than susceptible isolates of Acinetobacter baumannii-calcoaceticus complex. ( 1.1 , 14 ) To reduce the development of drug-resistant bacteria and maintain the effectiveness of XACDURO and other antibacterial drugs, XACDURO should be used only to treat or prevent infections that are proven or strongly suspected to be caused by bacteria. ( 1.2 ) 1.1 Hospital-acquired Bacterial Pneumonia and Ventilator-associated Bacterial Pneumonia (HABP/VABP) XACDURO is indicated in patients 18 years of age and older for the treatment of hospital-acquired bacterial pneumonia and ventilator-associated bacterial pneumonia (HABP/VABP), caused by susceptible isolates of Acinetobacter baumannii-calcoaceticus complex. Limitations of Use XACDURO is not indicated for the treatment of HABP/VABP caused by pathogens other than susceptible isolates of Acinetobacter baumannii-calcoaceticus complex [see Clinical Studies (14) ] . 1.2 Usage To reduce the development of drug-resistant bacteria and maintain the effectiveness of XACDURO and other antibacterial drugs, XACDURO should be used only to treat or prevent 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 XACDURO (1 g of sulbactam, 1 g of durlobactam) every 6 hours by intravenous (IV) infusion over 3 hours in patients with creatinine clearance (CLcr) of 45 to 129 mL/min. ( 2.1 ) Dosing regimen adjustments are recommended for CLcr less than 45 mL/min and CLcr greater than or equal to 130 mL/min. ( 2.2 ) Administer all doses of XACDURO by IV infusion over 3 hours. ( 2.3 ) See full prescribing information for instructions on the preparation of the intravenous solution. ( 2.4 ) 2.1 Recommended Dosage XACDURO is a co-packaged product containing sulbactam for injection and durlobactam for injection. The recommended dosage of XACDURO is 1 gram (g) of sulbactam and 1 g of durlobactam every 6 hours administered by intravenous (IV) infusion over 3 hours in adults with a creatinine clearance (CLcr) of 45 to 129 mL/min. Adjustments to the dosing regimen for XACDURO are recommended for patients with CLcr less than 45 mL/min and for patients with CLcr greater than or equal to 130 mL/min [see Dosage and Administration (2.2) ] . The recommended duration of treatment with XACDURO is 7 to 14 days. The duration of therapy should be guided by the patient's clinical status. 2.2 Dosage in Patients (18 Years of Age and Older) Based on Renal Function See Table 1 for the recommended dosage of XACDURO in patients (18 years of age and older) based on renal function [see Use in Specific Populations (8.6) and Clinical Pharmacology (12.3) ] . Adjustments to the dosing regimen are recommended for patients with creatinine clearance (CLcr) less than 45 mL/min and patients with augmented renal clearance (CLcr greater than or equal to 130 mL/min). For patients undergoing intermittent hemodialysis (HD), start the dosing of XACDURO immediately after the completion of HD. For patients with fluctuating renal function, monitor CLcr and adjust dosage accordingly [see Use in Specific Populations (8.6) ] . Table 1: Dosage of XACDURO (Sulbactam and Durlobactam) in Patients (18 Years of Age and Older) Based on Renal Function Dose of Sulbactam and Durlobactam (g) Estimated CLcr (mL/min) CLcr = creatinine clearance estimated by Cockcroft-Gault equation Frequency sulbactam 1 g and durlobactam 1 g Greater than or equal to 130 Every 4 hours 45 to 129 Every 6 hours 30 to 44 Every 8 hours 15 to 29 Every 12 hours less than 15 For patients on hemodialysis, the dose should be administered after the dialysis session has ended For patients initiating XACDURO: Every 12 hours for the first 3 doses (0, 12, and 24 hours), followed by every 24 hours after the third dose For patients currently receiving XACDURO whose CLcr declines to less than 15 mL/min: Every 24 hours 2.3 Administration The prepared XACDURO solution [see Dosage and Administration (2.4) ] should be brought to ambient room temperature (over 15 to 30 min) prior to infusion to the patient. Administer all doses of XACDURO by intravenous (IV) infusion over 3 hours. 2.4 Preparation of XACDURO for Intravenous Administration XACDURO is a co-packaged kit containing 1 clear single-dose vial of sulbactam 1g and 2 amber single-dose vials of durlobactam 0.5g as sterile powders that must be reconstituted and further diluted using aseptic technique prior to intravenous infusion. XACDURO does not contain a bacteriostatic preservative and the prepared solution must be used within 24 hours when stored refrigerated at 2°C to 8°C (36°F to 46°F). Discard unused portion. Items required to prepare XACDURO: XACDURO kit (includes one sulbactam 1 g single-dose vial and two durlobactam 0.5 g single-dose vials) 100 mL infusion bag containing 0.9% Sodium Chloride Injection, USP 10 mL Sterile Water for Injection, USP 10 mL sterile syringe and alcohol wipes Preparation of XACDURO: Reconstitute the sulbactam 1 g single-dose vial with 5 mL of Sterile Water for Injection and gently shake to dissolve. Each reconstituted vial contains 1 g of sulbactam per 5 mL of clear, colorless to slightly yellow solution. The reconstituted solution is not for direct injection and must be diluted before intravenous infusion. Dilution must occur within 1 hour of reconstitution. Reconstitute each durlobactam 0.5 g single-dose vial with 2.5 mL of Sterile Water for Injection and gently shake to dissolve. Each reconstituted vial contains 0.5 g of durlobactam per 2.5 mL of clear, light yellow to orange solution. The reconstituted solution is not for direct injection and must be diluted before intravenous infusion. Dilution must occur within 1 hour of reconstitution. To prepare the required XACDURO dose, withdraw 5 mL of reconstituted sulbactam and 5 mL (2.5 mL from each vial) of reconstituted durlobactam. Add the withdrawn volume of both sulbactam and durlobactam to a 100 mL infusion bag of 0.9% Sodium Chloride for Injection, USP. Discard unused portion. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. The prepa

6 ADVERSE REACTIONS The following serious adverse reactions are described in greater detail in the Warnings and Precautions section: Hypersensitivity Reactions [see Warnings and Precautions (5.1) ] Clostridioides difficile -Associated Diarrhea (CDAD) [see Warnings and Precautions (5.2) ] The most common adverse reactions (incidence > 10%) were liver test abnormalities, diarrhea, anemia, and hypokalemia. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Entasis Therapeutics Inc. at 1-800-651-3861 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Clinical trials are conducted under widely varying conditions, therefore 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. The safety of durlobactam with or without sulbactam was evaluated in 380 adult subjects across six phase 1 trials, one phase 2 trial in patients with complicated urinary tract infections (cUTIs) including acute pyelonephritis, and one phase 3 trial (also referred to as Trial 1) in adult patients with infections caused by Acinetobacter baumannii-calcoaceticus complex including hospital-acquired bacterial pneumonia (HABP), ventilator-associated bacterial pneumonia (VABP), and ventilated pneumonia (VP) [see Clinical Studies (14) ]. In the randomized, active-controlled portion of the phase 3 trial, 91 patients received XACDURO (1 g sulbactam and 1 g durlobactam, or renally adjusted dose) intravenously over 3 hours every 6 hours and 86 patients were treated with colistin 2.5 mg/kg (or renally adjusted dose) intravenously over 30 minutes every 12 hours after an initial loading dose of colistin 2.5 to 5 mg/kg. Both treatment arms also received 1 g imipenem/1 g cilastatin (or renally adjusted dose) intravenously every 6 hours as background therapy for potential HABP/VABP pathogens other than Acinetobacter baumannii-calcoaceticus complex. The mean duration of XACDURO therapy was 9 days versus 8 days for colistin. Serious Adverse Reactions and Discontinuation of Treatment Thirty-six patients (40%) in the XACDURO treatment group and 42 patients (49%) in the colistin treatment group experienced serious adverse reactions. Discontinuation of treatment due to any adverse reaction occurred in 10/91 (11%) patients treated with XACDURO and in 14/86 (16%) patients treated with colistin. One patient treated with XACDURO developed anaphylactic shock which led to discontinuation of treatment. Common Adverse Reactions Adverse reactions were reported in 88% (80/91) of patients in the XACDURO treatment group and 94% (81/86) of patients in the colistin treatment group. The most common adverse reactions reported in >10% of patients treated with XACDURO were liver test abnormalities, diarrhea, anemia, and hypokalemia. Table 2 lists selected adverse reactions occurring at a frequency of >5% in Trial 1. Table 2. Selected Adverse Reactions Occurring at a Frequency of >5% in Trial 1 Adverse Reaction XACDURO (N=91) n (%) Colistin (N=86) n (%) Any Adverse Reaction 80 (88) 81 (94) Liver test abnormalities Liver test abnormalities includes the following adverse reactions: liver function test abnormal, hepatic function abnormal, increased transaminases, ALT increased, and AST increased; Acute kidney injury includes the following adverse reactions: renal impairment, blood Cr increased, toxic nephropathy, renal failure and acute kidney injury. 17 (19) 18 (21) Diarrhea 15 (17) 9 (11) Anemia 12 (13) 12 (14) Hypokalemia 11 (12) 9 (11) Arrhythmia 8 (9) 8 (9) Acute kidney injury 5 (6) 31 (36) Thrombocytopenia 5 (6) 3 (4) Constipation 5 (6) 5 (6)

7 DRUG INTERACTIONS Organic Anion Transporter 1 (OAT1) Inhibitors : Concomitant administration with OAT1 inhibitors may increase plasma concentrations of XACDURO. Concomitant administration is not recommended. ( 7.1 ) 7.1 Organic Anion Transporter 1 (OAT1) Inhibitors Concomitant administration with OAT1 inhibitors may increase plasma concentrations of sulbactam. Concomitant administration of OAT1 inhibitors (e.g., probenecid) with XACDURO is not recommended. [see Clinical Pharmacology (12.3) ] .