Xacduro

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 prepared XACDURO solution should appear as a clear, light yellow to orange solution, free of particulates. If the XACDURO solution is cloudy or contains particulates, do not administer. 2.5 Compatibility XACDURO is compatible with 0.9% Sodium Chloride Injection, USP. The compatibility of XACDURO for administration with solutions containing other drugs or other diluents has not been established. XACDURO should not be mixed with other drugs or physically added to solutions containing other drugs. 2.6 Storage of Prepared Solution in Infusion Bag Store the prepared bag in the refrigerator at 2°C to 8°C (36°F to 46°F) until administration. The time between starting the reconstitution of the powders and the conclusion of the infusion should not exceed 24 hours. Do not freeze.

4 CONTRAINDICATIONS XACDURO is contraindicated in patients with a history of known severe hypersensitivity to the components of XACDURO (sulbactam and durlobactam), or other beta-lactam antibacterial drugs [see Warnings and Precautions (5.1) ] . Known history of severe hypersensitivity to the components of XACDURO (sulbactam and durlobactam), or other beta-lactam antibacterial drugs. ( 4 )

5 WARNINGS AND PRECAUTIONS Hypersensitivity Reactions : Serious and occasionally fatal hypersensitivity (anaphylactic) reactions have been reported with beta-lactam antibacterial drugs. Hypersensitivity was observed in patients treated with XACDURO. If an allergic reaction occurs, discontinue XACDURO. ( 5.1 ) Clostridioides difficile -Associated Diarrhea (CDAD): CDAD has been reported with nearly all systemic antibacterial agents, including XACDURO. Evaluate if diarrhea occurs. ( 5.2 ) 5.1 Hypersensitivity Reactions Serious and occasionally fatal hypersensitivity (anaphylactic) reactions and serious skin reactions have been reported in patients receiving beta-lactam antibacterial drugs. These reactions are more likely to occur in individuals with a history of beta-lactam hypersensitivity and/or a history of sensitivity to multiple allergens. Hypersensitivity was observed in patients treated with XACDURO in clinical trials [see Adverse Reactions (6.1) ] . Before initiating therapy with XACDURO, careful inquiry should be made concerning previous hypersensitivity reactions to carbapenems, penicillins, cephalosporins, other beta lactams, and other allergens. Discontinue XACDURO if an allergic reaction occurs. 5.2 Clostridioides difficile -Associated Diarrhea (CDAD) Clostridioides difficile -associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including XACDURO, and may range in severity from mild diarrhea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon leading to overgrowth of C. difficile . C. difficile produces toxins A and B which contribute to the development of CDAD. Hypertoxin producing strains of C. difficile cause increased morbidity and mortality, as these infections can be refractory to antimicrobial therapy and may require colectomy. CDAD must be considered in all patients who present with diarrhea following antibacterial drug use. Careful medical history is necessary since CDAD has been reported to occur over two months after the administration of antibacterial agents. If CDAD is suspected or confirmed, the risk/benefit of continuing treatment with XACDURO should be assessed. Appropriate fluid and electrolyte management, protein supplementation, antibacterial drug treatment of C. difficile , and surgical evaluation should be instituted as clinically indicated. 5.3 Development of Drug-Resistant Bacteria Prescribing XACDURO in the absence of a proven or strongly suspected bacterial infection or a prophylactic indication is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria.

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) ] .

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)

8.1 Pregnancy Risk Summary XACDURO There are no available data on the use of XACDURO in pregnancy to evaluate for a drug-associated risk of major birth defects, miscarriage, or other adverse maternal or fetal outcomes. Individual Components of XACDURO Sulbactam: Available published data from case reports and case series with sulbactam use in combination with ampicillin during pregnancy over many decades have not identified a drug-associated risk of major birth defects, miscarriage or other adverse maternal or fetal outcomes. The published literature reports that sulbactam crosses the human placenta. Reproduction studies have been performed in mice, rats, and rabbits at doses up to ten (10) times the human dose and have revealed no evidence of harm to the fetus due to sulbactam (see Data ). Durlobactam: There are no available data on the use of durlobactam in pregnancy to evaluate for a drug-associated risk of major birth defects, miscarriage, or other adverse maternal or fetal outcomes. Durlobactam administered to pregnant mice and rats during organogenesis, showed no drug-induced fetal malformations but an increased incidence of skeletal variations was observed in mice at 2- and 4-times the Maximum Recommended Human Dose (MRHD) (see Data ) . 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 defects and miscarriages in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Data Animal Data Sulbactam: Reproduction studies have been performed in mice, rats, and rabbits at doses up to ten (10) times the human dose and have revealed no evidence of harm to the fetus due to sulbactam sodium/ampicillin sodium. Durlobactam: Daily administration of durlobactam at 400, 800, or 1600 mg/kg/day (administered as four doses per day) via subcutaneous injection to pregnant mice from gestation day (GD) 6 through 15 resulted in durlobactam-related, increased incidence of skeletal variations (unossified calcaneum) of the hindlimb and asymmetrical ossification of the sternebrae and supernumerary ribs at 800 and/or 1600 mg/kg, equivalent to 2- and 4-times the maximum recommended human dose based on area under the curve (AUC) comparisons. No adverse effects on mean body weight, reproductive performance, or cesarean section parameters were observed in any pregnant mice. IV infusion (2 hours/day) of durlobactam to pregnant female Sprague Dawley rats from GD 6 to weaning on Lactation Day 20 at a dose level of 300 or 1000 mg/kg/day was well tolerated with no adverse maternal effects in either group. Similarly, there was no adverse effect of maternal treatment in either group on embryo-fetal, perinatal or postnatal development up to 1000 mg/kg/day (approximately 4 times the MRHD based on AUC).