Zerbaxa

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:

• Complicated Intra-abdominal Infections (cIAI), used in combination with metronidazole, in adult and pediatric patients (birth to less than 18 years old). (
  1.1 Complicated Intra-abdominal Infections

  ZERBAXA used in combination with metronidazole is indicated for the treatment of adult and pediatric patients (birth to less than 18 years old) 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

  .
  )
• Complicated Urinary Tract Infections (cUTI), Including Pyelonephritis, in adult and pediatric patients (birth to less than 18 years old). (
  1.2 Complicated Urinary Tract Infections, Including Pyelonephritis

  ZERBAXA is indicated for the treatment of adult and pediatric patients (birth to less than 18 years old) 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

  .
  )
• Hospital-acquired Bacterial Pneumonia and Ventilator-associated Bacterial Pneumonia (HABP/VABP), in adult patients 18 years and older. (
  1.3 Hospital-acquired Bacterial Pneumonia and Ventilator-associated Bacterial Pneumonia (HABP/VABP)

  ZERBAXA is indicated for the treatment of adult patients (18 years and older) 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

  .
  )

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. (

• Administer all doses of ZERBAXA every 8 hours by intravenous infusion over 1 hour in adult and pediatric patients. (
  2.1 Recommended Dosage in Adult Patients

  The recommended dosage of ZERBAXA in adult patients 18 years and older with creatinine clearance (CrCl) greater than 50 mL/min 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 The duration of therapy should be guided by the severity and site of infection and the patient’s clinical and bacteriological progress as shown in Table 1.

  Table 1: Dosage of ZERBAXA by Infection in Adult Patients (18 years and older) with CrClCrCl estimated using Cockcroft-Gault formulaGreater than 50 mL/min

  Infection	Dose	Frequency	Infusion Time	Duration of Treatment
  Complicated Intra-abdominal InfectionsUsed in conjunction with metronidazole 500 mg intravenously every 8 hours	1.5 g	Every 8 Hours	1 hour	4 to 14 days
  Complicated Urinary Tract Infections, Including Pyelonephritis	1.5 g	Every 8 Hours	1 hour	7 days
  Hospital-acquired Bacterial Pneumonia and Ventilator-associated Bacterial Pneumonia (HABP/VABP)	3 g	Every 8 Hours	1 hour	8 to 14 days
  ,
  2.2 Recommended Dosage in Pediatric Patients with cIAI or cUTI (birth to less than 18 years of age)

  The recommended dosage regimen of ZERBAXA in pediatric patients from birth to less than 18 years of age with cIAI and cUTI with an estimated glomerular filtration rate (eGFR) greater than 50 mL/min/1.73 m²is described in Table 2. ZERBAXA is administered every 8 hours by intravenous infusion over 1 hour. The duration of treatment should be guided by the severity and site of infection and the patient’s clinical and bacteriological progress as shown in Table 2. For the treatment of cIAI, metronidazole should be given concurrently.

  ZERBAXA is not recommended in pediatric patients who have an eGFR 50 mL/min/1.73m²or less

  [see Use in Specific Populations (8.4)].

  There is insufficient information to recommend a dosage regimen for pediatric patients with HABP/VABP

  [see Use in Specific Populations (8.4)]

  .

  Table 2: Dosage of ZERBAXA by infection in Pediatric Patients (birth to less 18 years of age) with eGFREstimated GFR using an age-appropriate equation for use in the pediatric populationgreater than 50 mL/min/1.73 m²

  Infection	Dose	Frequency	Infusion time	Duration of treatment
  Complicated Intra-abdominal InfectionsUsed in conjunction with metronidazole [see Clinical Studies (14.1)] .	30 mg/kg up to a maximum dose of 1.5 gPediatric patients weighing greater than 50 kg should not exceed a maximum dose of 1.5 g	Every 8 hours	1 hour	5 to 14 days
  Complicated Urinary Tract Infections including Pyelonephritis	30 mg/kg up to a maximum dose of 1.5 g	Every 8 hours	1 hour	7 to 14 days
  )
• See Full Prescribing Information for instructions on the preparation of solutions. (
  2.3 Dosage Adjustments in Adult Patients with Renal Impairment

  Dose adjustment is required for adult patients (18 years and older) with CrCl 50 mL/min or less (Table 3). All doses of ZERBAXA are administered over 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: Dosage of ZERBAXA in Adult Patients (18 years and older) with CrCl 50 mL/min or less

  Estimated CrCl (mL/min)CrCl estimated using Cockcroft-Gault formula	Complicated Intra-abdominal Infections and Complicated Urinary Tract Infections, Including Pyelonephritis	Hospital-acquired Bacterial Pneumonia and Ventilator-associated Bacterial Pneumonia (HABP/VABP)
  30 to 50	750 mg (500 mg and 250 mg) intravenously every 8 hours	1.5 g (1 g and 0.5 g) intravenously every 8 hours
  15 to 29	375 mg (250 mg and 125 mg) intravenously every 8 hours	750 mg (500 mg and 250 mg) intravenously every 8 hours
  End-stage renal disease (ESRD) on hemodialysis (HD)	A single loading dose of 750 mg (500 mg and 250 mg) followed by a 150 mg (100 mg and 50 mg) maintenance dose administered intravenously 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 2.25 g (1.5 g and 0.75 g) followed by a 450 mg (300 mg and 150 mg) maintenance dose administered intravenously 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)
  )
• 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 Dosage Adjustments in Adult Patients with Renal Impairment

  Dose adjustment is required for adult patients (18 years and older) with CrCl 50 mL/min or less (Table 3). All doses of ZERBAXA are administered over 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: Dosage of ZERBAXA in Adult Patients (18 years and older) with CrCl 50 mL/min or less

  Estimated CrCl (mL/min)CrCl estimated using Cockcroft-Gault formula	Complicated Intra-abdominal Infections and Complicated Urinary Tract Infections, Including Pyelonephritis	Hospital-acquired Bacterial Pneumonia and Ventilator-associated Bacterial Pneumonia (HABP/VABP)
  30 to 50	750 mg (500 mg and 250 mg) intravenously every 8 hours	1.5 g (1 g and 0.5 g) intravenously every 8 hours
  15 to 29	375 mg (250 mg and 125 mg) intravenously every 8 hours	750 mg (500 mg and 250 mg) intravenously every 8 hours
  End-stage renal disease (ESRD) on hemodialysis (HD)	A single loading dose of 750 mg (500 mg and 250 mg) followed by a 150 mg (100 mg and 50 mg) maintenance dose administered intravenously 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 2.25 g (1.5 g and 0.75 g) followed by a 450 mg (300 mg and 150 mg) maintenance dose administered intravenously 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)
  )

ZERBAXA 1.5 g (ceftolozane and tazobactam) for injection is supplied as a white to yellow sterile powder for reconstitution in single-dose vials; each vial contains ceftolozane 1 g (equivalent to 1.147 g of ceftolozane sulfate) and tazobactam 0.5 g (equivalent to 0.537 g of tazobactam sodium).

• Pediatrics:
  Safety and effectiveness in pediatric patients with HABP/VABP have not been established. (
  8.4 Pediatric Use

  Complicated Intra-abdominal Infections (cIAI) and Complicated Urinary Tract Infections (cUTI), including Pyelonephritis

  The safety and effectiveness of ZERBAXA for the treatment of cIAI and cUTI have been established in pediatric patients aged birth to less than 18 years old. Use of ZERBAXA in these age groups is supported by evidence from adequate and well-controlled studies of ZERBAXA in adults with cUTI and cIAI and additional pharmacokinetic and safety data from pediatric trials

  [see Clinical Pharmacology (12.3)and Clinical Studies (14.1and 14.2)]

  .

  The safety profile of ZERBAXA in pediatric patients was similar to adults with cIAI and cUTI, treated with ZERBAXA

  [see Adverse Reactions (6.1)]

  .

  There is insufficient information to recommend dosage adjustment for pediatric patients younger than 18 years of age with cIAI and cUTI with eGFR 50 mL/min/1.73m²or less

  [see Dosage and Administration (2.4)and Clinical Pharmacology (12.3)].

  ZERBAXA is not recommended in pediatric patients who have an eGFR 50 mL/min/1.73m²or less. Pediatric patients born at term or pre-term may not have an eGFR of 50 mL/min/1.73m²or greater at birth or within the first few months of life.

  Hospital-acquired Bacterial Pneumonia and Ventilator-associated Bacterial Pneumonia (HABP/VABP)

  The safety and effectiveness of ZERBAXA in pediatric patients have not been established for the treatment of HABP and VABP.
  )
• Geriatrics:
  Higher incidence of adverse reactions was observed in patients aged 65 years and older. In a Phase 3 cIAI trial, cure rates were lower in patients 65 years and older. (
  8.5 Geriatric Use

  Of the 1015 patients treated with ZERBAXA in the Phase 3 cIAI and cUTI clinical trials, 250 (24.6%) were 65 years or older, including 113 (11.1%) 75 years or older. The incidence of adverse events in both treatment groups was higher in older subjects (65 years or older) in the trials for both indications. In the cIAI trial, cure rates in the elderly (aged 65 years and older) in the ZERBAXA plus metronidazole arm were 69/100 (69%) and in the comparator arm were 70/85 (82.4%). This finding in the elderly population was not observed in the cUTI trial.

  Of the 361 patients treated with ZERBAXA in the Phase 3 HABP/VABP clinical trial, 160 (44.3%) were 65 years or older, including 83 (23%) 75 years or older. The incidence of adverse events in both treatment groups was higher in older subjects (65 years or older). In the trial, Day 28 all-cause mortality rates in the elderly (aged 65 years and older) were comparable between treatment arms:50/160 (31.3%) in the ZERBAXA arm and 54/160 (33.8%) in the comparator arm.

  ZERBAXA is substantially excreted by the kidney and the risk of adverse reactions to ZERBAXA may be greater in patients with renal impairment. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function. Adjust dosage for elderly patients based on renal function

  [see Dosage and Administration (2.2)and Clinical Pharmacology (12.3)]

  .
  )