ZERBAXA

1 INDICATIONS AND USAGE ZERBAXA (ceftolozane and tazobactam) is a combination of ceftolozane, a cephalosporin antibacterial, and tazobactam, a beta-lactamase inhibitor, indicated for the treatment of the following infections caused by designated susceptible microorganisms in adult and pediatric patients (at least 32 weeks gestational age): Complicated Intra-abdominal Infections (cIAI), used in combination with metronidazole. ( 1.1 ) Complicated Urinary Tract Infections (cUTI), Including Pyelonephritis. ( 1.2 ) Hospital-acquired Bacterial Pneumonia and Ventilator-associated Bacterial Pneumonia (HABP/VABP). ( 1.3 ) Usage to Reduce Development of Drug-Resistant Bacteria To reduce the development of drug-resistant bacteria and maintain the effectiveness of ZERBAXA and other antibacterial drugs, ZERBAXA should be used only to treat or prevent infections that are proven or strongly suspected to be caused by bacteria. ( 1.4 ) 1.1 Complicated Intra-abdominal Infections ZERBAXA used in combination with metronidazole is indicated for the treatment of adult and pediatric patients (at least 32 weeks gestational age) with complicated intra-abdominal infections (cIAI) caused by the following susceptible Gram-negative and Gram-positive microorganisms: Enterobacter cloacae, Escherichia coli, Klebsiella oxytoca, Klebsiella pneumoniae, Proteus mirabilis, Pseudomonas aeruginosa, Bacteroides fragilis, Streptococcus anginosus, Streptococcus constellatus, and Streptococcus salivarius . 1.2 Complicated Urinary Tract Infections, Including Pyelonephritis ZERBAXA is indicated for the treatment of adult and pediatric patients (at least 32 weeks gestational age) with complicated urinary tract infections (cUTI), including pyelonephritis, caused by the following susceptible Gram-negative microorganisms: Escherichia coli , Klebsiella pneumoniae , Proteus mirabilis , and Pseudomonas aeruginosa . 1.3 Hospital-acquired Bacterial Pneumonia and Ventilator-associated Bacterial Pneumonia ZERBAXA is indicated for the treatment of adult and pediatric patients (at least 32 weeks gestational age) with hospital-acquired bacterial pneumonia and ventilator-associated bacterial pneumonia (HABP/VABP), caused by the following susceptible Gram-negative microorganisms: Enterobacter cloacae , Escherichia coli , Haemophilus influenzae , Klebsiella oxytoca , Klebsiella pneumoniae , Proteus mirabilis , Pseudomonas aeruginosa , and Serratia marcescens . 1.4 Usage to Reduce Development of Drug-Resistant Bacteria To reduce the development of drug-resistant bacteria and maintain the effectiveness of ZERBAXA and other antibacterial drugs, ZERBAXA 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 all doses of ZERBAXA every 8 hours by intravenous infusion over 1 hour in adult patients. ( 2.1 ) Administer all doses of ZERBAXA every 8 hours by intravenous infusion over 1 hour in pediatric patients (at least 32 weeks gestational age) with cIAI or cUTI. ( 2.2 ) Administer all doses of ZERBAXA every 8 hours by intravenous infusion over 2 hours in pediatric patients (at least 32 weeks gestational age) with HABP/VABP. ( 2.2 ) Recommended Dosage of ZERBAXA by Infection in Adult Patients ( 2.1 ) Infection Dose Duration of Treatment cIAI Used in conjunction with metronidazole 500 mg intravenously every 8 hours ZERBAXA 1.5 g Administer all doses of ZERBAXA intravenously every 8 hours over 1 hour Provides 1 g ceftolozane and 0.5 g tazobactam 4 to 14 days cUTI, Including Pyelonephritis ZERBAXA 1.5 g 7 days HABP/VABP ZERBAXA 3 g Provides 2 g ceftolozane and 1 g tazobactam 8 to 14 days Recommended Dosage of ZERBAXA by infection in Pediatric Patients (at least 32 weeks gestational age) ( 2.2 ) Infection Dose Duration of Treatment cIAI Used in conjunction with metronidazole. ZERBAXA 30 mg/kg Provides 20 mg/kg ceftolozane and 10 mg/kg tazobactam. Pediatric patients with cIAI or cUTI weighing greater than 50 kg should not exceed a maximum dose of 1.5 g. up to a maximum dose of 1.5 g Administer all doses of ZERBAXA intravenously every 8 hours over 1 hour in pediatric patients with cIAI or cUTI. Provides 1 g ceftolozane and 0.5 g tazobactam. 5 to 14 days cUTI, Including Pyelonephritis ZERBAXA 30 mg/kg up to a maximum dose of 1.5 g 7 to 14 days HABP/VABP (at least 32 weeks gestational age to less than 2 years) ZERBAXA 60 mg/kg Provides 40 mg/kg ceftolozane and 20 mg/kg tazobactam. up to a maximum dose of 3 g Administer all doses of ZERBAXA intravenously every 8 hours over 2 hours in pediatric patients with HABP/VABP. Provides 2 g ceftolozane and 1 g tazobactam. Pediatric patients with HABP/VABP weighing greater than 40 kg should not exceed a maximum dose of 3 g. 8 to 14 days HABP/VABP (from 2 years and older) ZERBAXA 75 mg/kg Provides 50 mg/kg ceftolozane and 25 mg/kg tazobactam. up to a maximum dose of 3 g 8 to 14 days Dosage adjustment is recommended in adult patients and in pediatric patients aged 2 years of age and older with renal impairment. There is insufficient information to recommend a dosage for pediatric patients younger than 2 years of age with renal impairment. ( 2.3 , 2.4 ) See Full Prescribing Information for instructions on the preparation of solutions. ( 2.3 ) For doses above 1.5 g, reconstitute a second vial in the same manner as the first one, withdraw an appropriate volume (per Table 4 in the Full Prescribing Information), and add to the same infusion bag. ( 2.3 ) 2.1 Recommended Dosage in Adult Patients The recommended dosage of ZERBAXA in adult patients is 1.5 gram (g) (ceftolozane 1 g and tazobactam 0.5 g) for cIAI and cUTI and 3 g (ceftolozane 2 g and tazobactam 1 g) for HABP/VABP administered every 8 hours by intravenous infusion over 1 hour. As shown in Table 1, guide the duration of therapy by the severity and site of infection and the patient’s clinical and bacteriological progress. For the treatment of cIAI, administer metronidazole concurrently. See Table 3 for the recommended dosage in adult patients with renal impairment, [see Dosage and Administration (2.3) ] Table 1: Recommended Dosage of ZERBAXA by Infection in Adult Patients Infection Dose Frequency Infusion Time Duration of Treatment Complicated Intra-abdominal Infections Used in conjunction with metronidazole 500 mg intravenously every 8 hours ZERBAXA 1.5 g Provides 1 g ceftolozane and 0.5 g tazobactam Every 8 Hours 1 hour 4 to 14 days Complicated Urinary Tract Infections, Including Pyelonephritis ZERBAXA 1.5 g Every 8 Hours 1 hour 7 days Hospital-acquired Bacterial Pneumonia and Ventilator-associated Bacterial Pneumonia ZERBAXA 3 g Provides 2 g ceftolozane and 1 g tazobactam Every 8 Hours 1 hour 8 to 14 days 2.2 Recommended Dosage in Pediatric Patients (at least 32 weeks gestational age) The recommended dosage regimen for ZERBAXA in pediatric patients (at least 32 weeks gestational age) is described in Table 2. As shown in Table 2, guide the duration of therapy by the severity and site of infection and the patient’s clinical and bacteriological progress. For the treatment of cIAI, administer metronidazole concurrently. See Table 4 for the recommended dosage in pediatric patients with renal impairment [see Dosage and Administration (2.4) ] . Table 2: Recommended Dosage of ZERBAXA by Infection in Pediatric Patients (at least 32 weeks gestational age) Infection Age Range Dose Frequency Infusion time Duration of treatment Complicated Intra-abdominal Infections Used in conjunction with metronidazole. All pediatric patients (at least 32 weeks gestational age) ZERBAXA 30 mg/kg Provides 20 mg/kg ceftolozane and 10 mg/kg tazobactam. up to a maximum dose of 1.5 g For pediatric patients with cUTI or cIAI weighing greater than 50 kg, do not exceed a maximum dose of 1.5 g. Provides 1 g ceftolozane and 0.5 g tazobactam Every 8 hours 1 hour 5 to 14 days Complicated Urinary Tract Infections, Including Pyelonephritis ZERBAXA 30 mg/kg up to a maximum dose of 1.5 g 1 hour 7 to 14 days Hospital-acquired Bacterial Pneumonia and Ventilator-associated Bacterial Pneumonia Pediatric patients from at least 32 weeks of gestational age to less than 2 years ZERBAXA 60 mg/kg Provides 40 mg/kg ceftolozane and 20 mg/kg tazobactam. up to a maximum dose of 3 g For pediatric patients with HABP/VABP weighing greater than 40 kg, do not exceed a maximum dose of 3 g. Provides 2 g ceftolozane and 1 g tazobactam. 2 hours 8 to 14 days Pediatric patients from 2 years and older ZERBAXA 75 mg/kg Provides 50 mg/kg ceftolozane and 25 mg/kg tazobactam. up to a maximum dose of 3 g 2.3 Recommended Dosage in Adult Patients with Renal Impairment The recommended dosage of ZERBAXA in adult patients with renal impairment is based on CrCl as described in Table 3. Administer all doses of ZERBAXA for 1 hour. For patients with changing renal function, monitor CrCl at least daily and adjust the dosage of ZERBAXA accordingly [see Use in Specific Populations (8.6) and Clinical Pharmacology (12.3) ] . Table 3: Recommended Dosage of ZERBAXA in Adult Patients with Renal Impairment Estimated CrCl (mL/min) Estimated CrCl using the Cockcroft-Gault formula Complicated Intra-abdominal Infections and Complicated Urinary Tract Infections, Including Pyelonephritis Hospital-acquired Bacterial Pneumonia and Ventilator-associated Bacterial Pneumonia Dosage Infusion time Dosage Infusion time 51 to less than 90 ZERBAXA 1.5 g Provides 1 g ceftolozane and 0.5 g tazobactam. intravenously every 8 hours 1 hour ZERBAXA 3 g Provides 2 g ceftolozane and 1 g tazobactam. intravenously every 8 hours 1 hour 30 to 50 ZERBAXA 750 mg Provides 500 mg ceftolozane and 250 mg tazobactam. intravenously every 8 hours ZERBAXA 1.5 g intravenously every 8 hours 15 to 29 ZERBAXA 375 mg Provides 250 mg ceftolozane and 125 mg tazobactam. intravenously every 8 hours ZERBAXA 750 mg intravenously every 8 hours Less than 15 (not receiving intermittent hemodialysis) ZERBAXA dosage not established ZERBAXA dosage not established Receiving Intermittent Hemodialysis A single loading dose of ZERBAXA 750 mg followed by a ZERBAXA 150 mg Provides 100 mg ceftolozane and 50 mg tazobactam. maintenance dose administered intravenously every 8 hours for the remainder of the treatment period (on intermittent hemodialysis days, administer the dose at the earliest possible time following completion of dialysis) A single loading dose of ZERBAXA 2.25 g Provides 1.5 g ceftolozane and 0.75 g tazobactam. followed by a ZERBAXA 450 mg Provides 300 mg ceftolozane and 150 mg tazobactam. maintenance dose administered intravenously every 8 hours for the remainder of the treatment period (on intermittent hemodialysis days, administer the dose at the earliest possible time following completion of dialysis) 2.4 Recommended Dosage in Pediatric Patients with Renal Impairment The recommended dosage of ZERBAXA in pediatric patients 2 years of age and older with renal impairment based on an estimated GFR is described in Table 4. For pediatric patients with cUTI, including pyelonephritis, or cIAI, administer all ZERBAXA doses for 1 hour. For pediatric patients with HABP/VABP, administer all ZERBAXA doses over 2 hours. For patients with changing renal function, monitor eGFR at least daily and adjust the dosage of ZERBAXA accordingly [see Use in Special Populations (8.4 and 8.6) and Clinical Pharmacology (12.3) ] . ZERBAXA is not recommended in pediatric patients less than 2 years of age with renal impairment [see Use in Specific Populations (8.4) ]. Table 4: Recommended Dosage Regimens for ZERBAXA in Pediatric Patients 2 years of age and older with Renal Impairment For pediatric patients with cUTI or cIAI and renal impairment weighing greater than 50 kg, do not exceed the recommended dose for adults with renal impairment (see Table 3 ). For pediatric patients with HABP/VABP and renal impairment weighing greater than 40 kg, do not exceed the recommended dose for adults with renal impairment (See Table 3 ). Estimated GFR Estimate eGFR using an equation validated in pediatric patients in the approved age range. (mL/min/1.73 m 2 ) Complicated Intra-abdominal Infections and Complicated Urinary Tract Infections, including Pyelonephritis Hospital-acquired Bacterial Pneumonia and Ventilator-associated Bacterial Pneumonia Dosage Infusion time Dosage Infusion time 51 to less than 90 ZERBAXA 30 mg/kg Provides 20 mg/kg ceftolozane and 10 mg/kg tazobactam. intravenously every 8 hours 1 hour ZERBAXA 75 mg/kg Provides 50 mg/kg ceftolozane and 25 mg/kg tazobactam. intravenously every 8 hours 2 hours 30 to 50 ZERBAXA 15 mg/kg Provides 10 mg/kg ceftolozane and 5 mg/kg tazobactam. intravenously every 8 hours ZERBAXA 37.5 mg/kg Provides 25 mg/kg ceftolozane and 12.5 mg/kg tazobactam. intravenously every 8 hours 15 to 29 ZERBAXA 7.5 mg/kg Provides 5 mg/kg ceftolozane and 2.5 mg/kg tazobactam intravenously every 8 hours ZERBAXA 18.75 mg/kg Provides 12.5 mg/kg ceftolozane and 6.25 mg/kg tazobactam. intravenously every 8 hours Less than 15 (not receiving intermittent hemodialysis) ZERBAXA dosage not established ZERBAXA dosage not established Receiving Intermittent Hemodialysis A single loading dose of ZERBAXA 15 mg/kg followed by a ZERBAXA 3 mg/kg Provides 2 mg/kg ceftolozane and 1 mg/kg tazobactam. maintenance dose administered every 8 hours for the remainder of the treatment period (on hemodialysis days, administer the dose at the earliest possible time following completion of dialysis) A single loading dose of ZERBAXA 45 mg/kg Provides 30 mg/kg ceftolozane and 15 mg/kg tazobactam followed by a ZERBAXA 9 mg/kg Provides 6 mg/kg ceftolozane and 3 mg/kg tazobactam maintenance dose administered every 8 hours for the remainder of the treatment period (on hemodialysis days, administer the dose at the earliest possible time following completion of dialysis) 2.5 Preparation of Solutions ZERBAXA does not contain a bacteriostatic preservative. Aseptic technique must be followed in preparing the infusion solution. Preparation of doses: Constitute each vial of ZERBAXA with 10 mL of sterile water for injection or 0.9% Sodium Chloride for Injection, USP and gently shake to dissolve. The final volume is approximately 11.4 mL per vial. Caution: The constituted solution is not for direct injection. To prepare the required dose, withdraw the appropriate volume determined from Table 4 from the reconstituted vial(s). Add the withdrawn volume to an infusion bag containing 100 mL of 0.9% Sodium Chloride for Injection, USP or 5% Dextrose Injection, USP. For doses above 1.5 g, reconstitute a second vial in the same manner as the first one, withdraw an appropriate volume (per Table 5), and add to the same infusion bag. Discard unused portion. Table 5: Preparation of Doses ZERBAXA (ceftolozane and tazobactam) Dose Volume to Withdraw from Reconstituted Vial(s) ZERBAXA 3 g (2 g and 1 g) Two vials of 11.4 mL each (entire contents from two vials) ZERBAXA 2.25 g (1.5 g and 0.75 g) 11.4 mL from one vial (entire contents) and 5.7 mL from a second vial ZERBAXA 1.5 g (1 g and 0.5 g) 11.4 mL (entire contents from one vial) ZERBAXA 750 mg (500 mg and 250 mg) 5.7 mL ZERBAXA 450 mg (300 mg and 150 mg) 3.5 mL ZERBAXA 375 mg (250 mg and 125 mg) 2.9 mL ZERBAXA 150 mg (100 mg and 50 mg) 1.2 mL Inspect drug products visually for particulate matter and discoloration prior to use. ZERBAXA infusions range from clear, colorless solutions to solutions that are clear and slightly yellow. Variations in color within this range do not affect the potency of the product. 2.6 Compatibility Compatibility of ZERBAXA with other drugs has not been established. ZERBAXA should not be mixed with other drugs or physically added to solutions containing other drugs. 2.7 Storage of Constituted Solutions Upon constitution with sterile water for injection or 0.9% sodium chloride injection, reconstituted ZERBAXA solution may be held for 1 hour prior to transfer and dilution in a suitable infusion bag. Following dilution of the solution with 0.9% sodium chloride or 5% dextrose, ZERBAXA is stable for 24 hours when stored at room temperature or 7 days when stored under refrigeration at 2 C to 8°C (36 F to 46°F). Discard unused portion. Constituted ZERBAXA solution or diluted ZERBAXA infusion should not be frozen.

4 CONTRAINDICATIONS ZERBAXA is contraindicated in patients with known serious hypersensitivity to the components of ZERBAXA (ceftolozane and tazobactam), piperacillin/tazobactam, or other members of the beta-lactam class. ZERBAXA is contraindicated in patients with known serious hypersensitivity to the components of ZERBAXA (ceftolozane and tazobactam), piperacillin/tazobactam, or other members of the beta-lactam class. ( 4 )

5 WARNINGS AND PRECAUTIONS Decreased efficacy was observed in a Phase 3 cIAI trial in a subgroup of patients with baseline CrCl of 30 to 50 mL/min. Monitor CrCl at least daily in patients with changing renal function and adjust the dose of ZERBAXA accordingly. ( 5.1 ) Serious hypersensitivity (anaphylactic) reactions have been reported with beta-lactam antibacterial drugs. Exercise caution in patients with known hypersensitivity to beta-lactam antibacterial drugs. If an anaphylactic reaction to ZERBAXA occurs, discontinue the drug and institute appropriate therapy. ( 5.2 ) Clostridioides difficile -Associated Diarrhea (has been reported with nearly all systemic antibacterial agents, including ZERBAXA. Evaluate if diarrhea occurs. ( 5.3 ) 5.1 Decreased Efficacy in Patients with Baseline Creatinine Clearance of 30 to 50 mL/min In a subgroup analysis of a Phase 3 cIAI trial of adult patients, clinical cure rates were lower in patients with baseline CrCl of 30 to 50 mL/min compared to those with CrCl greater than 50 mL/min (Table 6). The reduction in clinical cure rates was more marked in the ZERBAXA plus metronidazole arm compared to the meropenem arm. A similar trend was also seen in the cUTI trial. Monitor CrCl at least daily in patients with changing renal function and adjust the dosage of ZERBAXA accordingly [see Dosage and Administration (2.2) ] . Table 6: Clinical Cure Rates in a Phase 3 Trial of Adult cIAI Patients by Baseline Renal Function (MITT Population) Baseline Renal Function ZERBAXA plus Metronidazole n/N (%) Meropenem n/N (%) CrCl greater than 50 mL/min 312/366 (85.2) 355/404 (87.9) CrCl 30 to 50 mL/min 11/23 (47.8) 9/13 (69.2) 5.2 Hypersensitivity Reactions Serious and occasionally fatal hypersensitivity (anaphylactic) reactions have been reported in patients receiving beta-lactam antibacterial drugs. Before initiating therapy with ZERBAXA, make careful inquiry about previous hypersensitivity reactions to other cephalosporins, penicillins, or other beta-lactams. If this product is to be given to a patient with a cephalosporin, penicillin, or other beta-lactam allergy, exercise caution because cross sensitivity has been established. If an anaphylactic reaction to ZERBAXA occurs, discontinue the drug and institute appropriate therapy. 5.3 Clostridioides difficile -Associated Diarrhea Clostridioides difficile -associated diarrhea (CDAD) has been reported for nearly all systemic antibacterial agents, including ZERBAXA, and may range in severity from mild diarrhea 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 the 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. 5.4 Development of Drug-resistant Bacteria Prescribing ZERBAXA in the absence of a proven or strongly suspected bacterial infection or a prophylactic indication is unlikely to provide benefit to the patient and risks the development of drug-resistant bacteria.

6 ADVERSE REACTIONS The following serious reactions are described in greater detail in the Warnings and Precautions section: Hypersensitivity reactions [see Warnings and Precautions (5.2) ] Clostridioides difficile -associated diarrhea [see Warnings and Precautions (5.3) ] Adult cIAI, cUTI and HABP/VABP Patients : The most common adverse reactions in adult patients (≥5% in either the cIAI or cUTI indication) are nausea, diarrhea, headache, and pyrexia. ( 6.1 ) The most common adverse reactions (≥5% in the HABP/VABP indication) are increase in hepatic transaminases, renal impairment/renal failure, and diarrhea. ( 6.1 ) Pediatric cIAI, cUTI and HABP/VABP Patients: The most common adverse reactions in pediatric patients (≥7% in cIAI, cUTI, or HABP/VABP) are thrombocytosis, diarrhea, pyrexia, leukopenia, abdominal pain, vomiting, increased aspartate aminotransferase, increased alanine aminotransferase, and anemia. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Merck Sharp & Dohme LLC at 1-877-888-4231 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 also may not reflect rates observed in practice. Adult Patients Complicated Intra-abdominal Infections and Complicated Urinary Tract Infections, Including Pyelonephritis ZERBAXA was evaluated in Phase 3 comparator-controlled clinical trials of cIAI (Trial 1) and cUTI (Trial 2), which included a total of 1015 patients treated with ZERBAXA (1.5 g every 8 hours, adjusted based on renal function where appropriate) and 1032 patients treated with comparator (levofloxacin 750 mg daily in cUTI or meropenem 1 g every 8 hours in cIAI) for up to 14 days. The mean age of treated patients was 48 to 50 years (range 18 to 92 years), across treatment arms and indications. In both indications, about 25% of the subjects were 65 years of age or older. Most patients (75%) enrolled in the cUTI trial were female, and most patients (58%) enrolled in the cIAI trial were male. Most patients (>70%) in both trials were enrolled in Eastern Europe and were White. The most common adverse reactions (5% or greater in either indication) occurring in patients receiving ZERBAXA were nausea, diarrhea, headache, and pyrexia. Table 7 lists adverse reactions occurring in 1% or greater of patients receiving ZERBAXA in Phase 3 cIAI and cUTI clinical trials. Table 7: Adverse Reactions Occurring in 1% or Greater of Adult Patients Receiving ZERBAXA in Phase 3 cIAI and cUTI Clinical Trials (Trial 1 and Trial 2) Adverse Reaction Complicated Intra-abdominal Infections Complicated Urinary Tract Infections, Including Pyelonephritis ZERBAXA The ZERBAXA for injection dose was 1.5 g intravenously every 8 hours, adjusted to match renal function where appropriate. In the cIAI trials, ZERBAXA was given in conjunction with metronidazole. (N=482) n (%) Meropenem (N=497) n (%) ZERBAXA (N=533) n (%) Levofloxacin (N=535) n (%) Nausea 38 (7.9) 29 (5.8) 15 (2.8) 9 (1.7) Headache 12 (2.5) 9 (1.8) 31 (5.8) 26 (4.9) Diarrhea 30 (6.2) 25 (5) 10 (1.9) 23 (4.3) Pyrexia 27 (5.6) 20 (4) 9 (1.7) 5 (0.9) Constipation 9 (1.9) 6 (1.2) 21 (3.9) 17 (3.2) Insomnia 17 (3.5) 11 (2.2) 7 (1.3) 14 (2.6) Vomiting 16 (3.3) 20 (4) 6 (1.1) 6 (1.1) Hypokalemia 16 (3.3) 10 (2) 4 (0.8) 2 (0.4) ALT increased 7 (1.5) 5 (1) 9 (1.7) 5 (0.9) AST increased 5 (1) 3 (0.6) 9 (1.7) 5 (0.9) Anemia 7 (1.5) 5 (1) 2 (0.4) 5 (0.9) Thrombocytosis 9 (1.9) 5 (1) 2 (0.4) 2 (0.4) Abdominal pain 6 (1.2) 2 (0.4) 4 (0.8) 2 (0.4) Anxiety 9 (1.9) 7 (1.4) 1 (0.2) 4 (0.7) Dizziness 4 (0.8) 5 (1) 6 (1.1) 1 (0.2) Hypotension 8 (1.7) 4 (0.8) 2 (0.4) 1 (0.2) Atrial fibrillation 6 (1.2) 3 (0.6) 1 (0.2) 0 Rash 8 (1.7) 7 (1.4) 5 (0.9) 2 (0.4) Treatment discontinuation due to adverse events occurred in 2.0% (20/1015) of patients receiving ZERBAXA and 1.9% (20/1032) of patients receiving comparator drugs. Renal impairment (including the terms renal impairment, renal failure, and renal failure acute) led to discontinuation of treatment in 5/1015 (0.5%) subjects receiving ZERBAXA and none in the comparator arms. Increased Mortality In the cIAI trials (Phase 2 and 3), death occurred in 2.5% (14/564) of patients receiving ZERBAXA and in 1.5% (8/536) of patients receiving meropenem. The causes of death varied and included worsening and/or complications of infection, surgery, and underlying conditions. Less Common Adverse Reactions in Phase 3 cIAI and cUTI Clinical Trials The following selected adverse reactions were reported in ZERBAXA-treated subjects at a rate of less than 1%: Cardiac disorders: tachycardia, angina pectoris Gastrointestinal disorders: gastritis, abdominal distension, dyspepsia, flatulence, ileus paralytic General disorders and administration site conditions: infusion site reactions Infections and infestations: candidiasis including oropharyngeal and vulvovaginal, fungal urinary tract infection Investigations: increased serum gamma-glutamyl transpeptidase (GGT), increased serum alkaline phosphatase, positive Coombs’ test Metabolism and nutrition disorders: hyperglycemia, hypomagnesemia, hypophosphatemia Nervous system disorders: ischemic stroke Renal and urinary system: renal impairment, renal failure Respiratory, thoracic, and mediastinal disorders: dyspnea Skin and subcutaneous tissue disorders: urticaria Vascular disorders: venous thrombosis Hospital-acquired Bacterial Pneumonia and Ventilator-associated Bacterial Pneumonia ZERBAXA was evaluated in a Phase 3 comparator-controlled clinical trial for HABP/VABP (Trial 3), which included a total of 361 patients treated with ZERBAXA (3 g every 8 hours, adjusted based on renal function where appropriate) and 359 patients treated with comparator (meropenem 1 g every 8 hours) for up to 14 days. The mean age of treated patients was 60 years (range 18 to 98 years), across treatment arms. About 44% of the subjects were 65 years of age or older. Most patients (71%) enrolled in the trial were male. All subjects were mechanically ventilated at randomization and 92% were in an intensive care unit (ICU) at randomization. The median APACHE II score was 17, and 33% of subjects had a baseline APACHE II score of ≥20, indicating a high severity of illness for many patients enrolled in this trial. Table 8 lists adverse reactions occurring in 2% or greater of patients receiving ZERBAXA in a Phase 3 HABP/VABP clinical trial. Table 8: Adverse Reactions Occurring in 2% or Greater of Adult Patients Receiving ZERBAXA in a Phase 3 HABP/VABP Clinical Trial (Trial 3) Adverse Reactions ZERBAXA The ZERBAXA for injection dose was 3 g intravenously every 8 hours, adjusted to match renal function where appropriate. N=361 n (%) Meropenem N=359 n (%) Hepatic transaminase increased Includes alanine aminotransferase (ALT) increased, aspartate aminotransferase (AST) increased, hepatic enzyme increased, hypertransaminasemia, liver function test abnormal. 43 (11.9) 26 (7.2) Renal impairment/renal failure Includes acute renal failure, anuria, azotemia, oliguria, prerenal failure, renal failure, renal impairment. 32 (8.9) 22 (6.1) Diarrhea 23 (6.4) 25 (7.0) Intracranial hemorrhage Includes cerebellar hemorrhage, cerebral hematoma, cerebral hemorrhage, hemorrhage intracranial, hemorrhagic stroke, hemorrhagic transformation stroke, intraventricular hemorrhage, subarachnoid hemorrhage, subdural hematoma. 16 (4.4) 5 (1.4) Vomiting 12 (3.3) 10 (2.8) Clostridioides difficile colitis Includes Clostridioides difficile colitis , Clostridioides difficile infection, Clostridioides test positive . 10 (2.8) 2 (0.6) Treatment discontinuation due to adverse reactions occurred in 1.1% (4/361) of patients receiving ZERBAXA and 1.4% (5/359) of patients receiving meropenem. Less Common Adverse Reactions in a Phase 3 HABP/VABP Clinical Trial The following selected adverse reactions were reported in ZERBAXA-treated subjects at a rate of less than 2%: Investigations: blood alkaline phosphatase increased, gamma-glutamyltransferase increased, Coombs direct test positive Pediatric Patients Complicated Intra-abdominal Infections and Complicated Urinary Tract Infections, Including Pyelonephritis ZERBAXA was evaluated in two blinded, randomized, active-controlled clinical studies in pediatric patients from birth to less than 18 years of age, one in cIAI (Trial 4) and the other in cUTI (Trial 5), which included a total of 170 pediatric patients treated with ZERBAXA and 54 pediatric patients treated with the comparator. The ZERBAXA dosing regimen was the same in each trial [see Dosage and Administration (2.2) ] . Patients were randomized 3:1 to receive ZERBAXA plus metronidazole or meropenem plus placebo in the cIAI study and ZERBAXA or meropenem in the cUTI study [see Clinical Studies (14.1 , 14.2) ] . In these pediatric patients, the type of adverse reactions were generally comparable to those observed in adults. Table 9 lists adverse reactions occurring in 4% or greater of pediatric patients receiving ZERBAXA in either the pediatric cIAI or cUTI clinical trial. Table 9: Adverse Reactions Occurring in 4% or Greater of Pediatric Patients (birth to less than 18 years of age) Receiving ZERBAXA in either the cIAI or cUTI Clinical Trials (Trial 4 and Trial 5) Adverse Reaction Complicated Intra-abdominal Infections Complicated Urinary Tract Infections, Including Pyelonephritis ZERBAXA In the cIAI trials, ZERBAXA was given in conjunction with metronidazole. (N=70) n (%) Meropenem (N=21) n (%) ZERBAXA (N=100) n (%) Meropenem (N=33) n (%) Thrombocytosis Includes platelet count increased. 11 (16) 3 (14) 9 (9) 3 (9) Diarrhea 12 (17) 5 (24) 7 (7) 3 (9) Pyrexia Includes hyperthermia. 9 (13) 3 (14) 7 (7) 1 (3) Leukopenia Includes neutropenia and neutrophil count decreased. 3 (4) 0 (0) 8 (8) 0 (0) Abdominal pain Includes upper abdominal pain. 8 (11) 0 (0) 2 (2) 1 (3) AST increased 5 (7) 1 (5) 4 (4) 2 (6) Vomiting 7 (10) 1 (5) 1 (1) 1 (3) ALT increased 4 (6) 1 (5) 4 (4) 2 (6) Anemia 5 (7) 0 (0) 2 (2) 0 (0) Phlebitis Includes superficial phlebitis. 4 (6) 0 (0) 1 (1) 1 (3) Hypertension 3(4) 0 (0) 0 (0) 1 (3) Gastritis 3 (4) 0 (0) 0 (0) 0 (0) Hypokalemia Includes blood potassium decreased. 3 (4) 0 (0) 0 (0) 0 (0) Bradypnea Includes respiratory rate decreased. , 3 (4) 0 (0) 0 (0) 0 (0) Hospital-acquired Bacterial Pneumonia and Ventilator-associated Bacterial Pneumonia The safety of ZERBAXA was evaluated in an open-label, non-comparative, multicenter clinical study in pediatric patients from 33 weeks post-menstrual age to less than 18 years of age diagnosed with HABP/VABP (NCT04223752; Trial 6). A total of 40 pediatric patients ranging from 10 days of age up to 16 years and 7 months of age were enrolled in the study and received ZERBAXA 60 mg/kg (ceftolozane 40 mg/kg and tazobactam 20 mg/kg) every 8 hours, up to a maximum dose of 3 g, intravenously over 1 hour for a duration of 8 to 14 days [see Dosage and Administration (2.2) ]. The safety profile of ZERBAXA in pediatric patients with HABP/VABP was similar to that in pediatric patients with cIAI and cUTI and adult patients with HABP/VABP. The most common adverse reactions that occurred in greater than 7% of pediatric patients included thrombocytosis, pyrexia, increased AST and ALT, anemia, diarrhea, and leukopenia. Laboratory Values The development of a positive direct Coombs test may occur during treatment with ZERBAXA. The incidence of seroconversion to a positive direct Coombs test was 0.2% in patients receiving ZERBAXA and 0% in patients receiving the comparator in the adult cUTI and cIAI clinical trials. The incidence of seroconversion to a positive direct Coombs test was 31.2% in patients receiving ZERBAXA and 3.6% in patients receiving meropenem in the adult HABP/VABP clinical trial. The incidence of seroconversion to a positive direct Coombs test was 45.3% in patients receiving ZERBAXA and 33.3% in patients receiving meropenem in the pediatric cIAI clinical trial. The incidence of seroconversion to a positive direct Coombs test was 29.7% in patients receiving ZERBAXA and 8.7% in patients receiving meropenem in the pediatric cUTI clinical trial. In clinical trials, there was no evidence of hemolysis in patients who developed a positive direct Coombs test in any treatment group.

8.1 Pregnancy Risk Summary There are no data available on ZERBAXA, ceftolozane or tazobactam use in pregnant women to allow assessment of a drug-associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes. Available data from published prospective cohort studies, case series, and case reports over several decades have not identified an association of cephalosporin use during pregnancy with major birth defects, miscarriage, or other adverse maternal or fetal outcomes (see Data ). Neither ceftolozane nor tazobactam produced embryo-fetal toxicity when administered to rodents during the period of organogenesis at ceftolozane doses approximately 3.5 times higher in mice and 2 times higher in rats than the maximum recommended human dose (MRHD) of 2 grams every 8 hours based on plasma AUC comparison or at tazobactam doses approximately 10 times higher in rats than the MRHD of 1 gram every 8 hours based on body surface area comparison. In pre-postnatal studies, where pregnant rats were administered intravenous ceftolozane or intraperitoneal tazobactam in gestation and through the lactation period, ceftolozane was associated with a decrease in auditory startle response in first generation offspring at a dose lower than the MRHD based on AUC comparison, and tazobactam was associated with reduced maternal body weight gain and increased stillbirths at a dose equivalent to approximately 4 times the MRHD and reduced fetal body weights in first generation offspring at a dose approximately equivalent to the MRHD based on body surface area comparison (see Data ). The estimated 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 miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. Data Human Data While available studies with multiple cephalosporins cannot definitively establish the absence of risk, published data from prospective cohort studies, case series, and case reports over several decades have not identified an association of cephalosporin use during pregnancy with major birth defects, miscarriage, or other adverse maternal or fetal outcomes. Available studies have methodologic limitations, including small sample size, retrospective data collection, and inconsistent comparator groups. Animal Data Ceftolozane Embryo-fetal development studies were performed in mice administered intravenous ceftolozane at doses of 300, 1000, and 2000 mg/kg/day during the period of organogenesis (Gestation Day 6 through 15) and in rats administered intravenous ceftolozane in doses of 100, 300, and 1000 mg/kg/day during the period of organogenesis (Gestation Day 6 through 17). In mice, ceftolozane was not associated with maternal or embryo-fetal toxicity with doses up to the highest dose of 2000 mg/kg/ day (approximately 3.5 times the MRHD of 2 grams every 8 hours based on plasma AUC comparison). In rats, no embryo-fetal toxicity was observed, but maternal body weight gain was reduced at a ceftolozane dose of 1000 mg/kg/day. No adverse maternal effects in rats were observed at a dose of 300 mg/kg/day and no adverse embryo-fetal effects were observed at a dose of 1000 mg/kg/day (respectively equivalent to approximately 0.7- and 2-times the MRHD based on plasma AUC comparison). In a pre-postnatal study in rats, intravenous ceftolozane administered during pregnancy and lactation (Gestation Day 6 through Lactation Day 20) was associated with a decrease in auditory startle response in postnatal Day 60 male pups at maternal doses greater than or equal to 300 mg/kg/day. No adverse effects were observed in rats at a dose of 100 mg/kg/day, a dose lower than the MRHD of 2 grams every 8 hours based on plasma AUC comparison. Tazobactam In an embryo-fetal study in rats, tazobactam was administered intravenously during the period of organogenesis (Gestation Day 7 through 17) at doses of 125, 500, and 3000 mg/kg/day. The high dose of 3000 mg/kg/day produced maternal toxicity (decreased food consumption and body weight gain) but was not associated with fetal toxicity. No adverse maternal effects were observed at a dose of 500 mg/kg/day and no adverse fetal effects were observed at a dose of 3000 mg/kg/day (respectively equivalent to approximately 2- and 10-times the MRHD of 1 gram every 8 hours based on body surface area comparison). In rats, tazobactam was shown to cross the placenta. Concentrations in the fetus were less than or equal to 10% of those found in maternal plasma. In a pre-postnatal study in rats, tazobactam administered intraperitoneally in doses of 40, 320, and 1280 mg/kg/day at the end of gestation and during lactation (Gestation Day 17 through Lactation Day 21) was associated with decreased maternal food consumption and body weight gain at the end of gestation and significantly more stillbirths at the high dose of 1280 mg/kg/day. No effects on the physical development, neurological function, or fertility and reproductive ability of first generation (F1) pups were noted, but postnatal body weights for F1 pups delivered to dams receiving 320 and 1280 mg/kg/day tazobactam were significantly reduced 21 days after delivery. The second generation (F2) fetuses were normal for all doses of tazobactam. No adverse effects on maternal reproduction were observed at doses up to 320 mg/kg/day and F1 body weights were not reduced at a dose of 40 mg/kg/day (respectively equivalent to approximately 1.0 and 0.1 times the MRHD of 1 gram every 8 hours based on body surface area comparison).