FDA label 2606ce2c-ad3a-4c58-be0d-9a696d366d64

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.

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)

<table width="85%"><caption>Table 2. Selected Adverse Reactions Occurring at a Frequency of &gt;5% in Trial 1</caption><col width="50%" align="left" valign="middle"/><col width="25%" align="center" valign="middle"/><col width="25%" align="center" valign="middle"/><thead><tr><th styleCode="Lrule Rrule" valign="top">Adverse Reaction</th><th styleCode="Rrule" valign="top">XACDURO (N=91) n (%)</th><th styleCode="Rrule" valign="top">Colistin (N=86) n (%)</th></tr></thead><tbody><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Any Adverse Reaction</td><td styleCode="Rrule">80 (88)</td><td styleCode="Rrule">81 (94)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Liver test abnormalities<footnote><content styleCode="italics">Liver test abnormalities</content> includes the following adverse reactions: liver function test abnormal, hepatic function abnormal, increased transaminases, ALT increased, and AST increased; <content styleCode="italics">Acute kidney injury</content> includes the following adverse reactions: renal impairment, blood Cr increased, toxic nephropathy, renal failure and acute kidney injury. </footnote></td><td styleCode="Rrule">17 (19)</td><td styleCode="Rrule">18 (21)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Diarrhea</td><td styleCode="Rrule">15 (17)</td><td styleCode="Rrule">9 (11)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Anemia</td><td styleCode="Rrule">12 (13)</td><td styleCode="Rrule">12 (14)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Hypokalemia</td><td styleCode="Rrule">11 (12)</td><td styleCode="Rrule">9 (11)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Arrhythmia</td><td styleCode="Rrule">8 (9)</td><td styleCode="Rrule">8 (9)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Acute kidney injury</td><td styleCode="Rrule">5 (6)</td><td styleCode="Rrule">31 (36)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Thrombocytopenia</td><td styleCode="Rrule">5 (6)</td><td styleCode="Rrule">3 (4)</td></tr><tr><td styleCode="Lrule Rrule">Constipation</td><td styleCode="Rrule">5 (6)</td><td styleCode="Rrule">5 (6)</td></tr></tbody></table>