AVYCAZ

AVYCAZ is an antibacterial combination product consisting of the semisynthetic cephalosporin ceftazidime pentahydrate and the beta-lactamase inhibitor avibactam sodium for intravenous administration. Ceftazidime Ceftazidime is a semisynthetic, beta-lactam antibacterial drug. It is the pentahydrate of (6 R ,7 R , Z )-7-(2-(2-aminothiazol-4-yl)-2-(2-carboxypropan-2-yloxyimino)acetamido)-8-oxo-3-(pyridinium-1-ylmethyl)-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylate. Its molecular weight is 636.6. The empirical formula is C 22 H 32 N 6 O 12 S 2 . Figure 1. Chemical structure of ceftazidime pentahydrate Avibactam Avibactam sodium chemical name is sodium [(2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl] sulfate. Its molecular weight is 287.23. The empirical formula is C 7 H 10 N 3 O 6 SNa. Figure 2. Chemical structure of avibactam sodium AVYCAZ 2.5 grams (ceftazidime and avibactam) for injection is a white to yellow sterile powder for constitution consisting of ceftazidime pentahydrate and avibactam sodium packaged in glass vials. The formulation also contains sodium carbonate. Each AVYCAZ 2.5 grams single-dose vial contains ceftazidime 2 grams (equivalent to 2.601 grams sterile ceftazidime pentahydrate/sodium carbonate) and avibactam 0.5 grams (equivalent to 0.544 grams sterile avibactam sodium). The sodium carbonate content of the mixture is 236.5 mg/vial. The total sodium content of the mixture is approximately 146 mg (6.4 mEq)/vial. Figure 1 Chemical structure of ceftazidime pentahydrate Figure 2 Chemical structure of avibactam sodium

AVYCAZ is a combination of ceftazidime, a cephalosporin, and avibactam, a beta-lactamase inhibitor, indicated for the treatment of the following infections caused by designated susceptible Gram-negative microorganisms in adult and pediatric patients (at least 31 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 ) To reduce the development of drug-resistant bacteria and maintain the effectiveness of AVYCAZ and other antibacterial drugs, AVYCAZ should be used only to treat or prevent infections that are proven or strongly suspected to be caused by susceptible bacteria. ( 1.4 ) 1. 1 Complicated Intra- a bdominal Infections ( cIAI ) AVYCAZ (ceftazidime and avibactam) in combination with metronidazole, is indicated for the treatment of complicated intra-abdominal infections (cIAI) in adult and pediatric patients (at least 31 weeks gestational age) caused by the following susceptible gram-negative microorganisms: Escherichia coli , Klebsiella pneumoniae , Proteus mirabilis, Enterobacter cloacae, Klebsiella oxytoca, Citrobacter freundii complex, and Pseudomonas aeruginosa . 1. 2 Complicated Urinary Tract Infections ( cUTI ), including Pyelonephritis AVYCAZ (ceftazidime and avibactam) is indicated for the treatment of complicated urinary tract infections (cUTI) including pyelonephritis in adult and pediatric patients (at least 31 weeks gestational age) caused by the following susceptible gram-negative microorganisms: Escherichia coli , Klebsiella pneumoniae, Enterobacter cloacae, Citrobacter freundii complex, Proteus mirabilis , and Pseudomonas aeruginosa . 1.3 Hospital-acquired Bacterial Pneumonia and Ventilator-associated Bacterial Pneumonia (HABP/VABP) AVYCAZ (ceftazidime and avibactam) is indicated for the treatment of hospital-acquired bacterial pneumonia and ventilator-associated bacterial pneumonia (HABP/VABP) in adult and pediatric patients (at least 31 weeks gestational age) caused by the following susceptible gram-negative microorganisms: Klebsiella pneumoniae, Enterobacter cloacae, Escherichia coli, Serratia marcescens, Proteus mirabilis, Pseudomonas aeruginosa, and Haemophilus influenzae . 1. 4 Usage To reduce the development of drug-resistant bacteria and maintain the effectiveness of AVYCAZ and other antibacterial drugs, AVYCAZ 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 .

Dosage of AVYCAZ in Adult Patients with Creatinine Clearance ( CrCl ) greater than 50 mL/min ( 2.1 ) Infection Dose Frequency Infusion Time cIAI * , cUTI including Pyelonephritis, and HABP/VABP AVYCAZ 2.5 grams (ceftazidime 2 grams and avibactam 0.5 grams) Every 8 hours 2 hours * Used in conjunction with metronidazole 0.5 g intravenously every 8 hours in adult cIAI patients Dosage of AVYCAZ in Pediatric Patients aged 2 years to less than 18 years with Estimated Glomerular Filtration Rate (eGFR) greater than 50 mL/min/1.73 m 2 and in Pediatric Patients less than 2 years of age without Renal Impairment ( 2.2 ) Infection Age Range Dose Infusion Time/ Frequency cIAI * , cUTI including Pyelonephritis, HABP/VABP 2 years to less than 18 years AVYCAZ 62.5 mg/kg to a maximum of 2.5 grams (ceftazidime 50 mg/kg and avibactam 12.5 mg/kg to a maximum dose of ceftazidime 2 grams and avibactam 0.5 grams) 2 hours/ Every 8 hours 6 months to less than 2 years AVYCAZ 62.5 mg/kg (ceftazidime 50 mg/kg and avibactam 12.5 mg/kg) 3 months to less than 6 months AVYCAZ 50 mg/kg (ceftazidime 40 mg/kg and avibactam 10 mg/kg) Greater than 28 days a to less than 3 months AVYCAZ 37.5 mg/kg (ceftazidime 30 mg/kg and avibactam 7.5 mg/kg) Less than or equal to 28 days b with GA 31 weeks and older AVYCAZ 25 mg/kg (ceftazidime 20 mg/kg and avibactam 5 mg/kg) * Used in conjunction with metronidazole 10 mg/kg intravenously every 8 hours in pediatric cIAI patients a Includes full-term infants with PNA > 28 days and pre-term infants with corrected age > 28 days. Corrected age is calculated by subtracting the number of weeks born before 40 weeks of gestation from the postnatal age. b Includes neonates PNA ≤ 28 days and pre-term infants with corrected age ≤ 28 days. GA = gestational age and PNA = postnatal age. For treatment of cIAI, metronidazole should be given concurrently Recommended duration of treatment in adult and pediatric patients: ( 2.1 , 2.2 ) cIAI: 5 to 14 days cUTI including pyelonephritis: 7 to 14 days HABP/VABP: 7 to 14 days Dosage adjustment is required in adult patients with creatinine clearance (CrCl) less than or equal to 50 mL/min and in pediatric patients aged 2 years and older with renal impairment. There is insufficient information to recommend a dosing regimen for pediatric patients younger than 2 years of age with renal impairment. See Full Prescribing Information for additional information. ( 2.3 ) See Full Prescribing Information for instructions for constituting supplied dry powder and subsequent required dilution. ( 2.4 ) See Full Prescribing Information for drug compatibilities. ( 2.5 ) 2.1 Recommended Dosage in Adult Patients The recommended dosage of AVYCAZ is 2.5 grams (ceftazidime 2 grams and avibactam 0.5 grams) administered every 8 hours by intravenous (IV) infusion over 2 hours in patients 18 years of age and older with CrCl greater than 50 mL/min. For treatment of cIAI, metronidazole should be given concurrently. The guidelines for dosage of AVYCAZ in patients with creatinine clearance (CrCl) greater than 50 mL/min are listed in Table 1 . Table 1. Dosage of AVYCAZ 2.5 grams (ceftazidime 2 grams and avibactam 0.5 grams) by Indication in Adult Patients (18 years of age and older) Infection Dos e Frequency Infusion Time (hours) Duration of Treatment Complicated Intra-abdominal Infections (cIAI) * 2.5 grams Every 8 hours 2 cIAI: 5 to 14 days cUTI: 7 to 14 days HABP/VABP: 7 to 14 days Complicated Urinary Tract Infections including Pyelonephritis (cUTI) Hospital-acquired Bacterial Pneumonia and Ventilator-associated Bacterial Pneumonia (HABP/VABP) * Used in conjunction with metronidazole 0.5 g intravenously every 8 hours in adult cIAI patients [see Clinical Studies ( 14.1 ) ]. 2.2 Recommended Dosage in Pediatric Patients The recommended dosage of AVYCAZ in pediatric patients aged 2 years to less than 18 years and an estimated glomerular filtration rate (eGFR) greater than 50 mL/min/1.73 m 2 and in pediatric patients less than 2 years of age without renal impairment is described in Table 2. AVYCAZ is administered every 8 hours by intravenous infusion over 2 hours. For treatment of cIAI, metronidazole should be given concurrently. Table 2. Dosage of AVYCAZ (ceftazidime and avibactam) in Pediatric Patients Infection Age Range Dose Frequency Infusion Time (hours) Duration of treatment cIAI*, cUTI including Pyelonephritis, and HABP/VABP 2 years to less than 18 years a AVYCAZ 62.5 mg/kg to a maximum of 2.5 grams (ceftazidime 50 mg/kg and avibactam 12.5 mg/kg to a maximum dose of ceftazidime 2 grams and avibactam 0.5 grams) Every 8 hours 2 cIAI: 5 to 14 days cUTI: 7 to 14 days HABP/VABP: 7 to 14 days 6 months to less than 2 years AVYCAZ 62.5 mg/kg (ceftazidime 50 mg/kg and avibactam 12.5 mg/kg) 3 months to less than 6 months AVYCAZ 50 mg/kg (ceftazidime 40 mg/kg and avibactam 10 mg/kg) Greater than 28 days b to less than 3 months AVYCAZ 37.5 mg/kg (ceftazidime 30 mg/kg and avibactam 7.5 mg/kg) Less than or equal to 28 days c with GA 31 weeks and older AVYCAZ 25 mg/kg (ceftazidime 20 mg/kg and avibactam 5 mg/kg) *AVYCAZ was used in conjunction with metronidazole 10 mg/kg intravenously every 8 hours in pediatric cIAI patients [see Clinical Studies ( 14.1 ) ] a For pediatric patients (aged 2 years and older) with eGFR less than or equal to 50 mL/min/1.73m 2 , dosage adjustments are recommended [ s ee Dosage and Administration ( 2.3 )]. b Includes full-term infants with PNA > 28 days and pre-term infants with corrected age > 28 days. Corrected age is calculated by subtracting the number of weeks born before 40 weeks of gestation from the postnatal age. c Includes neonates PNA ≤ 28 days and pre-term infants with corrected age ≤ 28 days. GA = gestational age and PNA = postnatal age. 2.3 Dosage Adjustments in Adult and Pediatric Patients ( Aged 2 Years and Older) with Renal Impairment The recommended AVYCAZ dosage in adult and pediatric patients aged 2 years and older with varying degrees of renal function is presented in Table 3 and Table 4, respectively. For patients with changing renal function, monitor CrCl in adults or eGFR in pediatric patients at least daily and adjust the dosage of AVYCAZ accordingly [ see Warnings and Precautions ( 5.1 ), Use in Specific Populations ( 8.6 ) and Clinical Pharmacology ( 12.3 ) ]. There is insufficient information to recommend a dosing regimen for pediatric patients less than 2 years of age with renal impairment. Adult Patients Table 3 . Dosage of AVYCAZ in Adult Patients with Renal Impairment Estimated Creatinine Clearance (mL/minute) a Dose for AVYCAZ (ceftazidime and avibactam) b Frequency 31 to 50 AVYCAZ 1.25 grams (ceftazidime 1 gram and avibactam 0.25 grams) intravenously Every 8 hours 16 to 30 AVYCAZ 0.94 grams (ceftazidime 0.75 grams and avibactam 0.19 grams) intravenously Every 12 hours 6 to 15 c AVYCAZ 0.94 grams (ceftazidime 0.75 grams and avibactam 0.19 grams) intravenously Every 24 hours Less than or equal to 5 c AVYCAZ 0.94 grams (ceftazidime 0.75 grams and avibactam 0.19 grams) intravenously Every 48 hours a As calculated using the Cockcroft-Gault formula b All doses of AVYCAZ are administered over 2 hours c Both ceftazidime and avibactam are hemodialyzable; thus, administer AVYCAZ after hemodialysis on hemodialysis days Pediatric Patients Table 4 . Dosage of AVYCAZ in Pediatric Patients Aged 2 years and older with Renal Impairment a Estimated eGFR b (mL/min/1.73m 2 ) Dose for AVYCAZ (ceftazidime and avibactam) c Frequency 31 to 50 AVYCAZ 31.25 mg/kg to a maximum of 1.25 grams (ceftazidime 25 mg/kg and avibactam 6.25 mg/kg to a maximum dose of ceftazidime 1 gram and avibactam 0.25 grams) Every 8 hours 16 to 30 AVYCAZ 23.75 mg/kg to a maximum of 0.94 grams (ceftazidime 19 mg/kg and avibactam 4.75 mg/kg to a maximum dose of ceftazidime 0.75 grams and avibactam 0.19 grams) Every 12 hours 6 to 15 AVYCAZ 23.75 mg/kg to a maximum of 0.94 grams (ceftazidime 19 mg/kg and avibactam 4.75 mg/kg to a maximum dose of ceftazidime 0.75 grams and avibactam 0.19 grams) Every 24 hours Less than or equal to 5 d AVYCAZ 23.75 mg/kg to a maximum of 0.94 grams (ceftazidime 19 mg/kg and avibactam 4.75 mg/kg to a maximum dose of ceftazidime 0.75 grams and avibactam 0.19 grams) Every 48 hours a Dosing was derived based on the population PK modeling, which assumed similar proportional effects of renal impairment in adults and pediatric patients aged 2 years and older [see Clinical Pharmacology ( 12.3 )] b As calculated using the Schwartz bedside formula c All doses of AVYCAZ are administered over 2 hours d Both ceftazidime and avibactam are hemodialyzable; thus, administer AVYCAZ after hemodialysis on hemodialysis days 2. 4 Preparation of the AVYCAZ Solution for Administration AVYCAZ is supplied as a dry powder, which must be constituted and subsequently diluted, using aseptic technique prior to intravenous infusion. a) Constitute the powder in the AVYCAZ vial with 10 mL of one of the following solutions: sterile water for injection, USP 0.9% of sodium chloride injection, USP (normal saline) 5% of dextrose injection, USP all combinations of dextrose injection and sodium chloride injection, USP, containing up to 2.5% dextrose, USP, and 0.45% sodium chloride, USP, or lactated Ringer’s injection, USP b) Mix gently and ensure that the contents are dissolved completely. The constituted AVYCAZ solution will have an approximate ceftazidime concentration of 167 mg/mL and an approximate avibactam concentration of 42 mg/mL. The final volume is approximately 12 mL. The constituted solution is not for direct injection. The constituted solution must be diluted before intravenous infusion. c) Prepare the required dose for intravenous infusion by withdrawing the appropriate volume determined from Table 5 from the constituted vial. To prepare doses for pediatric patients weighing less than 40 kg, follow the constitution instruction above to yield a solution with a final AVYCAZ concentration of approximately 209 mg/mL (ceftazidime concentration of 167 mg/mL and an avibactam concentration of 42 mg/mL). Use these concentrations to calculate the volume of AVYCAZ required to prepare the prescribed dose. Table 5 . Preparation of AVYCAZ Doses for Adult and Pediatric Patients (Weighing 40 kg or More) AVYCAZ (ceftazidime and avibactam) Dose Volume to Withdraw from Constituted Vial for Further Dilution to 50 to 250 a mL 2.5 grams (2 grams and 0.5 grams) 12 mL (entire contents) 1.25 grams (1 gram and 0.25 grams) 6 mL 0.94 grams (0.75 grams and 0.19 grams) 4.5 mL a. Dilution to 250 mL should only be used for the 2.5 gram dose d) Before infusion, dilute the withdrawn volume of the constituted AVYCAZ solution further with the same diluent used for constitution of the powder (except sterile water for injection), to achieve a ceftazidime concentration of 8 to 40 mg/mL and an avibactam concentration of 2 to 10 mg/mL in an infusion bag. If sterile water for injection was used for constitution, use any of the other appropriate constitution diluents for dilution. e) Mix gently and ensure that the contents are dissolved completely. Visually inspect the diluted AVYCAZ solution (for administration) for particulate matter and discoloration prior to administration (the color of the AVYCAZ infusion solution for administration ranges from clear to light yellow). f) Use the diluted AVYCAZ solution in the infusion bags within 12 hours when stored at room temperature. g) The diluted AVYCAZ solution in the infusion bags may be stored under refrigeration at 2 to 8°C (36 to 46°F) up to 24 hours following dilution and used within 12 hours of subsequent storage at room temperature. 2. 5 Drug Compatibility The AVYCAZ solution for administration at the range of diluted concentrations of ceftazidime 8 mg/mL and avibactam 2 mg/mL to ceftazidime 40 mg/mL and avibactam 10 mg/mL is compatible with the more commonly used intravenous infusion fluids in infusion bags (including Baxter ® Mini-Bag Plus ™ ) such as: 0.9% sodium chloride injection, USP 5% dextrose injection, USP all combinations of dextrose injection and sodium chloride injection, USP, containing up to 2.5% dextrose, USP, and 0.45% sodium chloride, USP lactated ringer's injection, USP, and Baxter ® Mini-Bag Plus ™ containing 0.9% sodium chloride injection or 5% dextrose injection Intravenous Line Compatibility Simulated Y-site compatibility of AVYCAZ admixed with other drug products in a 1:1 volume ratio at room temperature was evaluated by visual inspection, and measurement of turbidity and particulate matter at 0, 1 and 4 hours after mixing. Ceftazidime and avibactam were tested at concentrations of 20 mg/mL and 5 mg/mL, respectively, which can be obtained by dilution of constituted AVYCAZ solution in a 100 mL intravenous infusion bag. The highest recommended concentration (40 mg/mL of ceftazidime and 10 mg/mL of avibactam) was not tested in this study and should not be used during co-administration of AVYCAZ with other drugs through the same intravenous line. Compatible drugs with the corresponding compatible diluent (i.e., 0.9% Sodium Chloride Injection, 5 % Dextrose Injection or Lactated Ringer’s Injection) are listed in Tables 6, 7, 8 and 9 below. Any drug products not listed in the tables below should not be co-administered with AVYCAZ through the same intravenous line (or cannula). Table 6. Compatible Drugs for use with 0.9% Sodium Chloride, 5% Dextrose or Lactated Ringer’s Injection as Diluents Daptomycin Dexmedetomidine Injection Dopamine Hydrochloride Injection Furosemide Injection Gentamicin Injection Imipenem and Cilastatin for Injection Magnesium Sulfate Injection Norepinephrine Bitartrate Injection Phenylephrine Hydrochloride Injection Vasopressin Injection Vecuronium Bromide Metronidazole Injection Aztreonam Injection or Aztreonam for Injection Colistimethate for Injection Amikacin Sulfate Injection Azithromycin for Injection Ceftaroline fosamil for Injection Levofloxacin Table 7. Compatible Drugs for use with 0.9% Sodium Chloride or 5% Dextrose Injection as Diluents Ertapenem Sodium Potassium Phosphates Injection Table 8. Compatible Drugs for use with 5% Dextrose or Lactated Ringer’s Injection as Diluents Heparin Sodium Injection Linezolid Injection Tobramycin Injection or Tobramycin for Injection Table 9. Compatible Drugs for use with One Compatible Diluent only Meropenem for Injection (0.9% Sodium Chloride Injection diluent only) Sodium Bicarbonate Injection (5% Dextrose Injection diluent only) Tedizolid Phosphate for Injection (5% Dextrose Injection diluent only) Potassium Chloride in Water for Injection (40 mEq/100 mL) (Lactated Ringer’s Injection diluent only) 2. 6 St orage of Constituted Solutions Upon constitution with appropriate diluent, the constituted AVYCAZ solution may be held for no longer than 30 minutes prior to transfer and dilution in a suitable infusion bag. Following dilution of the constituted solutions with the appropriate diluents, AVYCAZ solutions in the infusion bags are stable for 12 hours when stored at room temperature. Following dilution of the constituted solutions with the appropriate diluents, AVYCAZ solutions in the infusion bags may also be refrigerated at 2 to 8°C (36 to 46°F) for up to 24 hours; and then should be used within 12 hours of subsequent storage at room temperature.

AVYCAZ is contraindicated in patients with known serious hypersensitivity to the components of AVYCAZ (ceftazidime and avibactam), avibactam containing products, or other members of the cephalosporin class [see Warnings and Precautions ( 5.2 )] . AVYCAZ is contraindicated in patients with known serious hypersensitivity to the components of AVYCAZ (ceftazidime and avibactam), avibactam-containing products or other members of the cephalosporin class. ( 4 )

The following adverse reactions are discussed in greater detail in the Warnings and Precautions section: Hypersensitivity Reactions [ see Warnings and Precautions ( 5.2 ) ] Clostridi oid e s difficile -Associated Diarrhea [ see Warnings and Precautions ( 5.3 ) ] Central Nervous System Reactions [ see Warnings and Precautions ( 5.4 ) ] Adult Patients : The most common adverse reactions in cIAI (≥ 5%, when used with metronidazole) patients are diarrhea, nausea and vomiting. The most common adverse reactions (3%) in cUTI patients are diarrhea and nausea. The most common adverse reactions (≥ 5%) in HABP/VABP patients were diarrhea and vomiting. ( 6.1 ) Pediatric Patients (aged 3 months to less than 18 years) : The most common adverse reactions (≥ 3%) in pediatric patients aged 3 months and older were vomiting, diarrhea, rash, and infusion site phlebitis. ( 6.1 ) Pediatric Patients (less than 3 months of age) : The most common adverse reactions (>3 %) in pediatric patients less than 3 months of age were vomiting and increased transaminases. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact AbbVie at 1-800-633-9110 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trial s 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 may not reflect the rates observed in practice. Clinical Trials Experience in Adult Patients AVYCAZ was evaluated in six active-controlled clinical trials in patients with cIAI, cUTI, including pyelonephritis, or HABP/VABP. These trials included two Phase 2 trials, one in cIAI and one in cUTI, as well as four Phase 3 trials, one in cIAI, one in cUTI (Trial 1), one in cIAI or cUTI due to ceftazidime non-susceptible pathogens (Trial 2), and one in HABP/VABP. Data from cUTI Trial 1 served as the primary dataset for AVYCAZ safety findings in cUTI as there was a single comparator. cUTI Trial 2 had an open-label design as well as multiple comparator regimens which prevented pooling but provided supportive information. The six clinical trials included a total of 1809 adult patients treated with AVYCAZ and 1809 patients treated with comparators. Complicated Intra- a bdominal Infections The Phase 3 cIAI trial included 529 adult patients treated with AVYCAZ 2.5 grams (ceftazidime 2 grams and avibactam 0.5 grams) administered intravenously over 120 minutes every 8 hours plus 0.5 grams metronidazole administered intravenously over 60 minutes every 8 hours and 529 patients treated with meropenem. The median age of patients treated with AVYCAZ was 50 years (range 18 to 90 years) and 22.5% of patients were 65 years of age or older. Patients were predominantly male (62%) and Caucasian (76.6%). Treatment discontinuation due to an adverse reaction occurred in 2.6% (14/529) of patients receiving AVYCAZ plus metronidazole and 1.3% (7/529) of patients receiving meropenem. Adverse reactions occurring at 5% or greater in patients receiving AVYCAZ plus metronidazole were diarrhea, nausea, and vomiting. Table 11 lists adverse reactions occurring in 1% or more of patients receiving AVYCAZ plus metronidazole and with incidences greater than the comparator in the Phase 3 cIAI clinical trial. Table 11. Incidence of Selected Adverse Reactions Occurring in 1% or more of Adult Patients (18 years of age and older) Receiving AVYCAZ in the Phase 3 cIAI Trial Adverse Reactions AVYCAZ plus metronidazole a (N=529) Meropenem b (N=529) Nervous system disorders Headache 3% 2% Dizziness 2% 1% Gastrointestinal disorders Diarrhea 8% 3% Nausea 7% 5% Vomiting 5% 2% Abdominal Pain 1% 1% a 2.5 grams (ceftazidime 2 grams and avibactam 0.5 grams) IV over 120 minutes every 8 hours (with metronidazole 0.5 grams IV every 8 hours) b 1 gram IV over 30 minutes every 8 hours Increased Mortality In the Phase 3 cIAI trial, death occurred in 2.5% (13/529) of patients who received AVYCAZ plus metronidazole and in 1.5% (8/529) of patients who received meropenem. Among a subgroup of patients with baseline CrCl 30 to less than or equal to 50 mL/min, death occurred in 19.5% (8/41) of patients who received AVYCAZ plus metronidazole and in 7.0% (3/43) of patients who received meropenem. Within this subgroup, patients treated with AVYCAZ received a 33% lower daily dose than is currently recommended for patients with CrCl 30 to less than or equal to 50 mL/min [ see Dosage and Administration ( 2.2 ) and Warnings and Precautions ( 5.1 ) ]. In patients with normal renal function or mild renal impairment (baseline CrCl greater than 50 mL/min), death occurred in 1.0% (5/485) of patients who received AVYCAZ plus metronidazole and in 1.0% (5/484) of patients who received meropenem. The causes of death varied and contributing factors included progression of underlying infection, baseline pathogens isolated that were unlikely to respond to the study drug, and delayed surgical intervention. Complicated Urinary Tract Infections, Including Pyelonephritis The Phase 3 cUTI Trial 1 included 511 adult patients treated with AVYCAZ 2.5 grams (ceftazidime 2 grams and avibactam 0.5 grams) administered intravenously over 120 minutes every 8 hours and 509 patients treated with doripenem; in some patients parenteral therapy was followed by a switch to an oral antimicrobial agent [ s ee Clinical Studies ( 14.2 ) ]. Median age of patients treated with AVYCAZ was 54 years (range 18 to 89 years) and 30.7% of patients were 65 years of age or older. Patients were predominantly female (68.3%) and Caucasian (82.4%). Patients with CrCl less than 30 mL/min were excluded. There were no deaths in Trial 1. Treatment discontinuation due to adverse reactions occurred in 1.4% (7/511) of patients receiving AVYCAZ and 1.2% (6/509) of patients receiving doripenem. The most common adverse reactions occurring in 3% of cUTI patients treated with AVYCAZ were nausea and diarrhea. Table 12 lists adverse reactions occurring in 1% or more of patients receiving AVYCAZ and with incidences greater than the comparator in Trial 1. Table 12. Incidence of Selected Adverse Drug Reactions Occurring in 1% or more of Adult Patients (18 years of age and older) Receiving AVYCAZ in the Phase 3 cUTI Trial 1 Adverse Reactions AVYCAZ a (N= 511 ) Doripenem b (N= 509 ) Gastrointestinal disorders Nausea 3% 2% Diarrhea 3% 1% Constipation 2% 1% Upper abdominal pain 1% < 1% a 2.5 grams (ceftazidime 2 grams and avibactam 0.5 grams) IV over 120 minutes every 8 hours b 0.5 grams IV over 60 minutes every 8 hours Hospital-acquired Bacterial Pneumonia/Ventilator-associated Bacterial Pneumonia The Phase 3 HABP/VABP trial included 436 adult patients treated with AVYCAZ 2.5 grams (ceftazidime 2 grams and avibactam 0.5 grams) administered intravenously over 120 minutes and 434 patients treated with meropenem. The median age of patients treated with AVYCAZ was 66 years (range 18 to 89 years) and 54.1% of patients were 65 years of age or older. Patients were predominantly male (74.5%) and Asian (56.2%). Death occurred in 9.6% (42/ 436) of patients who received AVYCAZ and in 8.3% (36/434) of patients who received meropenem. Treatment discontinuation due to an adverse reaction occurred in 3.7% (16/436) of patients receiving AVYCAZ and 3% (13/434) of patients receiving meropenem. Adverse reactions occurring at 5% or greater in patients receiving AVYCAZ were diarrhea and vomiting. Table 13 lists selected adverse reactions occurring in 1% or more of patients receiving AVYCAZ and with incidences greater than the comparator in the Phase 3 HABP/VABP clinical trial. Table 13. Incidence of Selected Adverse Drug Reactions Occurring in 1% or more of Adult Patients (18 years of age and older) Receiving AVYCAZ in the Phase 3 HABP/VABP Trial Adverse Reactions AVYCAZ a (N= 436) Meropenem b (N= 434 ) Gastrointestinal disorders Nausea 3% 2% Skin and subcutaneous tissue disorders Pruritus 2% 1% a 2.5 grams (ceftazidime 2 grams and avibactam 0.5 grams) IV over 120 minutes every 8 hours b 1 gram IV over 30 minutes every 8 hours Other Adverse Reactions of AVYCAZ and Ceftazidime in Adults Direct Coombs’ Test Seroconversion with AVYCAZ In the Phase 3 trials, seroconversion from a negative to a positive direct Coombs’ test result among patients with an initial negative Coombs’ test and at least one follow up test occurred in 3% (cUTI), 12.9% (cIAI), and 21.4% (HABP/VABP) of patients receiving AVYCAZ and 0.9% (cUTI), 3% (cIAI) and 7% (HABP/VABP) of patients receiving a carbapenem comparator. Less Common Adverse Reactions with AVYCAZ The following selected adverse reactions were reported in AVYCAZ-treated patients at a rate of less than 1% in the Phase 3 trials and are not described elsewhere in the labeling. Blood and lymphatic disorders – Thrombocytopenia, Thrombocytosis, Leukopenia General disorders and administration site conditions – Injection site phlebitis Infections and infestations – Candidiasis Investigations – Increased aspartate aminotransferase, Increased alanine aminotransferase, Increased gamma-glutamyl transferase Metabolism and nutrition disorders – Hypokalemia Nervous system disorders – Dysgeusia Renal and urinary disorders – Acute kidney injury, Renal impairment, Nephrolithiasis Skin and subcutaneous tissue disorders – Rash, Rash maculo-papular, Urticaria Psychiatric disorders – Anxiety Adverse Reactions with Ceftazidime Additionally, adverse reactions reported with ceftazidime alone that were not reported in AVYCAZ-treated patients in the Phase 3 trials are listed below: Blood and lymphatic disorders – Agranulocytosis, Hemolytic anemia, Lymphocytosis, Neutropenia, Eosinophilia General disorders and administration site conditions – Infusion site inflammation, Injection site hematoma, Injection site thrombosis Hepatobiliary disorders – Jaundice Investigations – Increased blood lactate dehydrogenase, Prolonged prothrombin time Nervous system disorders – Paresthesia, seizures, encephalopathy, coma, asterixis, neuromuscular excitability, myoclonia Renal and urinary disorders – Tubulointerstitial nephritis Reproductive and breast disorders – Vaginal inflammation Hypersensitivity Reactions – Anaphylaxis, Angioedema, Erythema multiforme, Stevens-Johnson syndrome, Toxic epidermal necrolysis Clinical Trials Experience in Pediatric Patients Pediatric Patients A ged 3 months to less than 18 years AVYCAZ was evaluated in 128 pediatric patients aged 3 months to < 18 years in two single-blind, randomized, active-controlled clinical trials, one in patients with cUTI and the other in patients with cIAI. Safety data from the two studies were pooled. The AVYCAZ dosing regimen was the same in both of these trials [ see Dosage and Administration ( 2.2 )] with a mean treatment duration of 6 days, and a maximum of 14 days. The regimen was selected to result in pediatric drug exposure comparable to that of adults, and in the cIAI trial, metronidazole was administered concurrently with AVYCAZ. Patients were randomized 3:1 to receive AVYCAZ or comparator, which was meropenem or cefepime in the cIAI and cUTI trials, respectively. The median age of patients treated with AVYCAZ was 8.6 years, and in the comparator group 7.4 years. The majority of patients treated with AVYCAZ were female (57%) and Caucasian (80%). An open-label single-dose pharmacokinetic (PK) and safety trial was conducted in pediatric patients with HABP/VABP and enrolled four patients aged 11.6 months to 9.4 years [see Clinical Pharmacology 12.3 ] . There were no deaths reported in the trials of cUTI, cIAI, and HABP/VABP in pediatric patients aged 3 months and older. Treatment discontinuation due to adverse reactions in the pediatric cUTI and cIAI trials occurred in 2.3% (3/128) of patients receiving AVYCAZ and 0/50 of patients receiving comparator drugs. The most common adverse reactions occurring in greater than 3% of pediatric patients aged 3 months to < 18 years treated with AVYCAZ were vomiting, diarrhea, rash, and infusion site phlebitis. Pediatric Patients less than 3 months of Age AVYCAZ was also evaluated in a trial enrolling 46 pediatric patients less than three months of age as follows: infants > 28 days to < 3 months (N=17), term neonates from birth to 28 days, (N=13), pre-term neonates from birth (gestational age ≥ 31 weeks) to 28 days (N=16). The median age of patients treated with AVYCAZ was 24 days. In this single-arm trial, 25 patients with a suspected or confirmed bacterial infection received a single-dose of AVYCAZ and 21 patients with suspected or confirmed serious gram-negative infections received multiple doses of AVYCAZ [ see Dosage and Administration ( 2.2 )] . The demographics of patients treated with AVYCAZ were female (54%), male (46%); racial groups of White (78%), Asian (11%), Black or African American (9%); ethnicities of Not Hispanic or Latino (91.3%); Hispanic or Latino (4.3%). In patients treated with multiple doses of AVYCAZ [ see Dosage and Administration ( 2.2 )] , the mean treatment duration was 6 days and maximum treatment duration was 12 days. There was one death reported in the trial for pediatric patients less than 3 months of age. There were no treatment discontinuations due to adverse reactions. The most common adverse reactions occurring in greater than 3% of pediatric patients less than 3 months of age were vomiting and increased transaminases. The safety profile of AVYCAZ in pediatric patients was similar to adults with cIAI, cUTI, and HABP/VABP treated with AVYCAZ. 6.2 Postmarketing Experience The following adverse reactions and altered laboratory tests have been identified during post approval use of ceftazidime (a component of AVYCAZ), or other cephalosporin-class antibacterial drugs. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Colitis, toxic nephropathy, hepatic dysfunction including cholestasis, hemorrhage, pancytopenia, aplastic anemia, prolonged prothrombin time, false-positive test for urinary glucose. Acute myocardial ischemia with or without myocardial infarction may occur as part of an allergic reaction.

7.1 Probenecid In vitro , avibactam is a substrate of OAT1 and OAT3 transporters which might contribute to the active uptake from the blood compartment, and thereby its excretion. As a potent OAT inhibitor, probenecid inhibits OAT uptake of avibactam by 56% to 70% in vitro and, therefore, has the potential to decrease the elimination of avibactam when co-administered. Because a clinical interaction study of AVYCAZ or avibactam alone with probenecid has not been conducted, co-administration of AVYCAZ with probenecid is not recommended [ see Clinical Pharmacology ( 12.3 ) ] . 7.2 Drug/Laboratory Test Interactions The administration of ceftazidime may result in a false-positive reaction for glucose in the urine with certain methods. It is recommended that glucose tests based on enzymatic glucose oxidase reactions be used.