Ceftazidime, Avibactam

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.

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.

8.1 Pregnancy Risk Summary There are no adequate and well-controlled studies of AVYCAZ, ceftazidime, or avibactam in pregnant women. Neither ceftazidime nor avibactam were teratogenic in rats at doses 40 and 9 times the recommended human clinical dose. In the rabbit, at twice the exposure as seen at the human clinical dose, there were no effects on embryofetal development with avibactam. The background risk of major birth defects and miscarriage for the indicated population is unknown. The background risk of major birth defects is 2-4% and of miscarriage is 15-20% of clinically recognized pregnancies within the general population. Because animal reproduction studies are not always predictive of human response, this drug should be used in pregnancy only if clearly needed. Data Animal Data Ceftazidime Reproduction studies have been performed in mice and rats at doses up to 40 times the human dose and showed no evidence of harm to the fetus due to ceftazidime. Avibactam Avibactam was not teratogenic in rats or rabbits. In the rat, intravenous studies with 0, 250, 500 and 1000 mg/kg/day avibactam during gestation days 6-17 showed no embryofetal toxicity at doses up to 1000 mg/kg/day, approximately 9 times the human dose based on exposure (AUC). In a rat pre- and post-natal study at up to 825 mg/kg/day intravenously (11 times the human exposure based on AUC), there were no effects on pup growth and viability. A dose-related increase in the incidence of renal pelvic and ureter dilatation was observed in female weaning pups that was not associated with pathological changes to renal parenchyma or renal function, with renal pelvic dilatation persisting after female weaning pups became adults. Rabbits administered intravenous avibactam on gestation days 6-19 at 0, 100, 300 and 1000 mg/kg/day showed no effects on embryofetal development at a dose of 100 mg/kg, twice the human exposure (AUC). At higher doses, increased post-implantation loss, lower mean fetal weights, delayed ossification of several bones and other anomalies were observed. 8. 2 Lactation Risk Summary Ceftazidime is excreted in human milk in low concentrations. It is not known whether avibactam is excreted into human milk, although avibactam was shown to be excreted in the milk of rats. No information is available on the effects of ceftazidime and avibactam on the breast-fed child or on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for AVYCAZ and any potential adverse effects on the breastfed child from AVYCAZ or from the underlying maternal conditions. Data In a rat pre- and post-natal study at doses up to 825 mg/kg/day intravenously (11 times the human exposure based on AUC), the exposure to avibactam was minimal in the pups in comparison to the dams. Exposure to avibactam was observed in both pups and milk on PND 7.

8.4 Pediatric Use The safety and effectiveness of AVYCAZ in the treatment of cUTI, cIAI, and HABP/VABP have been established in pediatric patients at least 31 weeks gestational age and older. Use of AVYCAZ is supported by evidence from adequate and well-controlled studies of AVYCAZ in adults with cUTI, cIAI, and HABP/VABP and additional pharmacokinetic and safety data from pediatric trials [see Clinical Pharmacology ( 12.3 ), Clinical Studies ( 14.1 and 14.2 )] . The safety profile of AVYCAZ in pediatric patients was similar to adults with cIAI, cUTI, and HABP/VABP treated with AVYCAZ [see Adverse Reactions ( 6.1 ) ] . The safety and effectiveness of AVYCAZ in the treatment of cUTI, cIAI, and HABP/VABP have not been established in pediatric patients less than 31 weeks gestational age.

8.5 Geriatric Use Of the 1809 patients treated with AVYCAZ in the Phase 2 and Phase 3 clinical trials 621 (34.5%) were 65 years of age and older, including 302 (16.7 %) patients 75 years of age and older. In the pooled Phase 2 and Phase 3 cIAI AVYCAZ clinical trials, 20% (126/630) of patients treated with AVYCAZ were 65 years of age and older, including 49 (7.8%) patients 75 years of age and older. The incidence of adverse reactions in both treatment groups was higher in older patients (≥ 65 years of age) and similar in both treatment groups; clinical cure rates for patients 65 years of age or older were 73.0% (73/100) in the AVYCAZ plus metronidazole arm and 78.6% (77/98) in the meropenem arm. In the Phase 3 cUTI trial, 30.7% (157/511) of patients treated with AVYCAZ were 65 years of age or older, including 78 (15.3%) patients 75 years of age or older. The incidence of adverse reactions in both treatment groups was lower in older patients (≥ 65 years of age) and similar between treatment groups. Among patients 65 years of age or older in the Phase 3 cUTI trial, 66.1% (82/124) of patients treated with AVYCAZ had symptomatic resolution at Day 5 compared with 56.6% (77/136) of patients treated with doripenem. The combined response (microbiological cure and symptomatic response) observed at the test-of-cure (TOC) visit for patients 65 years of age or older were 58.1% (72/124) in the AVYCAZ arm and 58.8% (80/136) in the doripenem arm. In the Phase 3 HABP/VABP trial, 54.1% (236/436) of patients treated with AVYCAZ were 65 years of age or older, including 129 (29.6%) patients 75 years of age or older. The incidence of adverse reactions in patients ≥ 65 years of age was similar to patients < 65 years of age. The 28-day all-cause mortality was similar between treatment groups for patients 65 years of age or older (12.7% [29/229] for patients in the AVYCAZ arm and 11.3% [26/230] for patients in the meropenem arm). Ceftazidime and avibactam are known to be substantially excreted by the kidney; therefore, the risk of adverse reactions to ceftazidime and avibactam may be greater in patients with decreased renal function. 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. Healthy elderly subjects had 17% greater exposure relative to healthy young subjects when administered the same single dose of avibactam, which may have been related to decreased renal function in the elderly subjects. Dosage adjustment for elderly patients should be based on renal function [ see Dosage and Administration ( 2.2 ) and Clinical Pharmacology ( 12.3 ) ]. 8. 6 Renal Impairment Dosage adjustment is required in adult patients with moderately or severely impaired renal function (CrCl 50 mL/min or less). For patients with changing renal function, CrCl should be monitored at least daily, particularly early in treatment, and dosage of AVYCAZ adjusted accordingly. Both ceftazidime and avibactam are hemodialyzable; thus, AVYCAZ should be administered after hemodialysis on hemodialysis days [ see Dosage and Administration ( 2.2 ) and Clinical Pharmacology ( 12.3 ) ] . Dosage adjustment is also required in pediatric patients with renal impairment from 2 years to less than 18 years of age with eGFR 50 mL/min/1.73 m 2 or less. There is insufficient information to recommend a dosing regimen for pediatric patients younger than 2 years of age with renal impairment [see Dosage and Administration ( 2.3 ) and Clinical Pharmacology ( 12.3 )] .

12.1 Mechanism of Action AVYCAZ is an antibacterial drug [ see Clinical Pharmacology ( 12.4 ) ].

12.2 Pharmacodynamics As with other beta-lactam antimicrobial drugs, the time that unbound plasma concentrations of ceftazidime exceed the AVYCAZ minimum inhibitory concentration (MIC) against the infecting organism has been shown to best correlate with efficacy in a neutropenic murine thigh infection model with Enterobacteriaceae and Pseudomonas aeruginosa . The time above a threshold concentration has been determined to be the parameter that best predicts the efficacy of avibactam in in vitro and in vivo nonclinical models. Cardiac Electrophysiology In a thorough QT study, a supratherapeutic dose of ceftazidime (3 grams) was investigated for QT effects in combination with a supratherapeutic dose of avibactam (2 grams) given as a 30-minute single infusion. No significant effect on QT c F interval was detected at peak plasma concentration or at any other time. The largest 90% upper bound for the placebo corrected mean change from baseline was 5.9 ms. There were no QT c F intervals greater than 450 ms, nor were there any QT c F interval changes from baseline greater than 30 ms.

12.3 Pharmacokinetics The mean pharmacokinetic parameters for ceftazidime and avibactam in healthy adult male subjects with normal renal function after single and multiple 2-hour intravenous infusions of AVYCAZ 2.5 grams (ceftazidime 2 grams and avibactam 0.5 grams) administered every 8 hours are summarized in Table 14. Pharmacokinetic parameters of ceftazidime and avibactam were similar for single and multiple dose administration of AVYCAZ and were similar to those determined when ceftazidime or avibactam were administered alone. Table 14. Pharmacokinetic Parameters (Geometric Mean [%CV]) of Ceftazidime and Avibactam Following Administration of AVYCAZ 2.5 grams (ceftazidime 2 grams and avibactam 0.5 grams) in Healthy Adult Male Subjects Ceftazidime Avibactam Parameter Single AVYCAZ 2.5 grams a Dose Administered as a 2-hour Infusion (n = 16) Multiple AVYCAZ 2.5 grams a Doses Administered every 8 hours as 2-hour Infusions for 11 Days (n = 16) Single AVYCAZ 2.5 grams a Dose Administered as a 2-hour Infusion (n = 16) Multiple AVYCAZ 2.5 grams a Doses Administered every 8 hours as 2-hour Infusions for 11 Days (n = 16) C max (mg/L) 88.1 (14) 90.4 (16) 15.2 (14) 14.6 (17) AUC (mg-h/L) b 289 (15) c 291 (15) 42.1 (16) d 38.2 (19) T 1/2 (h) 3.27 (33) c 2.76 (7) 2.22 (31) d 2.71 (25) CL (L/h) 6.93 (15) c 6.86 (15) 11.9 (16) d 13.1 (19) V ss (L) 18.1 (20) c 17 (16) 23.2 (23) d 22.2 (18) CL = plasma clearance; C max = maximum observed concentration; T 1/2 = terminal elimination half-life; V ss (L) = volume of distribution at steady state a ceftazidime 2 grams and avibactam 0.5 grams b AUC 0-inf (area under concentration-time curve from time 0 to infinity) reported for single-dose administration; AUC 0 -tau (area under concentration curve over dosing interval) reported for multiple-dose administration c n = 15 d n = 13 The C max and AUC of ceftazidime increase in proportion to dose. Avibactam demonstrated approximately linear pharmacokinetics across the dose range studied (50 mg to 2000 mg) for single intravenous administration. No appreciable accumulation of ceftazidime or avibactam was observed following multiple intravenous infusions of AVYCAZ 2.5 grams (ceftazidime 2 grams and avibactam 0.5 grams) administered every 8 hours for up to 11 days in healthy adults with normal renal function. Distribution Less than 10% of ceftazidime was protein bound. The degree of protein binding was independent of concentration. The binding of avibactam to human plasma proteins was low (5.7% to 8.2%) and was similar across the range of concentrations tested in vitro (0.5 to 50 mg/L). The steady-state volumes of distribution of ceftazidime and avibactam were 17 L and 22.2 L, respectively, in healthy adults following multiple doses of AVYCAZ 2.5 grams (ceftazidime 2 grams and avibactam 0.5 grams) infused every 8 hours over 2 hours for 11 days. Following administration of AVYCAZ 2.5 g (ceftazidime 2 grams and avibactam 0.5 grams) to healthy male subjects every 8 hours as a 2-hour infusion for 3 days, the mean bronchial epithelial lining fluid-to-plasma ratios of avibactam C max and AUC 0-tau were 35%. The mean bronchial epithelial lining fluid-to-plasma ratios of ceftazidime C max and AUC 0-tau were 26% and 31%, respectively. Metabolism Ceftazidime is mostly (80% to 90% of the dose) eliminated as unchanged drug. No metabolism of avibactam was observed in human liver preparations (microsomes and hepatocytes). Unchanged avibactam was the major drug-related component in human plasma and urine after a single intravenous dose of 0.5 grams 14 C-labelled avibactam. Excretion Both ceftazidime and avibactam are excreted mainly by the kidneys. Approximately 80% to 90% of an intravenous dose of ceftazidime is excreted unchanged by the kidneys over a 24-hour period. After the intravenous administration of single 0.5-grams or 1-gram doses, approximately 50% of the dose appeared in the urine in the first 2 hours. An additional 20% was excreted between 2 and 4 hours after dosing, and approximately another 12% of the dose appeared in the urine between 4 and 8 hours later. The elimination of ceftazidime by the kidneys resulted in high therapeutic concentrations in the urine. The mean renal clearance of ceftazidime was approximately 100 mL/min. The calculated plasma clearance of approximately 115 mL/min indicated nearly complete elimination of ceftazidime by the renal route. Following administration of a single 0.5-grams intravenous dose of radiolabeled avibactam, an average of 97% of administered radioactivity was recovered from the urine, with over 95% recovered within 12 hours of dosing. An average of 0.20% of administered total radioactivity was recovered in feces within 96 hours of dosing. An average of 85% of administered avibactam was recovered from the urine as unchanged drug within 96 hours, with over 50% recovered within 2 hours of the start of the infusion. Renal clearance was 158 mL/min, which is greater than the glomerular filtration, suggesting that active tubular secretion contributes to the excretion of avibactam in addition to glomerular filtration. Specific Populations Patients with Renal Impairment Ceftazidime is eliminated almost solely by the kidneys; its serum half-life is significantly prolonged in patients with impaired renal function. The clearance of avibactam was significantly decreased in subjects with mild (CrCl greater than 50 to 80 mL/min, n = 6), moderate (CrCl 30 to less than or equal to 50 mL/min, n = 6), and severe (CrCl 30 mL/min or less, not requiring hemodialysis; n = 6) renal impairment compared to healthy subjects with normal renal function (CrCl greater than 80 mL/min, n = 6) following administration of a single 100-mg intravenous dose of avibactam. The slower clearance resulted in increases in systemic exposure (AUC) of avibactam of 2.6-fold, 3.8-fold, and 7-fold in subjects with mild, moderate, and severe renal impairment, respectively, compared to subjects with normal renal function. A single 100-mg dose of avibactam was administered to subjects with ESRD (n = 6) either 1 hour before or after hemodialysis. The avibactam AUC following the post-hemodialysis infusion was 19.5-fold the AUC of healthy subjects with normal renal function. Avibactam was extensively removed by hemodialysis, with an extraction coefficient of 0.77 and a mean hemodialysis clearance of 9.0 L/h. Approximately 55% of the avibactam dose was removed during a 4-hour hemodialysis session. Dosage adjustment of AVYCAZ is recommended in adult and pediatric patients 2 years and older with moderate and severe renal impairment and end-stage renal disease. Population PK models for ceftazidime and avibactam were used to conduct simulations for patients with impaired renal function. Simulations demonstrated that the recommended dose adjustments [ see Dosage and Administration ( 2.3 ) ] provide comparable exposures of ceftazidime and avibactam in both adult and pediatric patients with moderate and severe renal impairment and end-stage renal disease to those in patients with normal renal function or mild renal impairment. Because the exposure of both ceftazidime and avibactam is highly dependent on renal function, monitor renal function (i.e., CrCl in adult patients and eGFR in pediatric patients) at least daily and adjust the dosage of AVYCAZ accordingly [ see Dosage and Administration ( 2.3 ) ]. There is insufficient information to recommend a dosage regimen for pediatric patients less than 2 years of age with renal impairment. Patients with Hepatic Impairment The presence of hepatic dysfunction had no effect on the pharmacokinetics of ceftazidime in individuals administered 2 grams intravenously every 8 hours for 5 days. The pharmacokinetics of avibactam in patients with hepatic impairment have not been established. Avibactam does not appear to undergo significant hepatic metabolism; therefore, the systemic clearance of avibactam is not expected to be significantly affected by hepatic impairment. Dose adjustments are not currently considered necessary for AVYCAZ in patients with impaired hepatic function. Pediatric Patients Population pharmacokinetic analyses and target attainment simulations were conducted to recommend AVYCAZ dosing in pediatric patients with cIAI, cUTI and HABP/VABP. The recommended pediatric dosing regimens for patients from 2 to less than 18 years of age with eGFR of greater than 50 mL/min/1.73 m 2 and for patients from birth (with gestational age 31 weeks and older) to less than 2 years without renal impairment are predicted to result in systemic exposures similar to that in adult patients given AVYCAZ 2.5 grams. Population PK modeling, including the assumption of proportional effects of renal impairment in adults and pediatric patients, also predicted that the recommended dose adjustments for patients aged 2 years and older with eGFR less than or equal to 50 mL/min/1.73 m 2 result in systemic exposure similar to that in adult patients. There is insufficient information to recommend a dosage adjustment in pediatric patients less than 2 years of age with renal impairment. Geriatric Patients Following single-dose administration of 0.5 grams avibactam as a 30-minute infusion the mean AUC for avibactam was 17% higher in healthy elderly subjects (65 years of age and older, n = 16) than in healthy young adult subjects (18 to 45 years of age, n = 17). There was no statistically significant age effect for avibactam C max . No dose adjustment is recommended based on age. Dosage adjustment for AVYCAZ in elderly patients should be based on renal function [ see Dosage and Administration ( 2.2 ) ]. Gender Following single-dose administration of 0.5 grams avibactam as a 30-minute infusion, healthy male subjects (n = 17) had 18% lower avibactam C max values than healthy female subjects (n = 16). There was no gender effect for avibactam AUC parameters. No dose adjustment is recommended based on gender. Drug Interaction s Avibactam at clinically relevant concentrations does not inhibit the cytochrome P450 isoforms CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1 and CYP3A4/5 in vitro in human liver microsomes. Avibactam showed no potential for in vitro induction of CYP1A2, 2B6, 2C9 and 3A4 isoenzymes in human hepatocytes. Against CYP2E1, avibactam showed a slight induction potential at very high concentrations that exceed any clinically relevant exposure. Ceftazidime was evaluated independently in human hepatocytes and showed no induction potential on the activity or mRNA expression of CYP1A1/2, CYP2B6, and CYP3A4/5. Neither ceftazidime nor avibactam was found to be an inhibitor of the following hepatic and renal transporters in vitro at clinically relevant concentrations: MDR1, BCRP, OAT1, OAT3, OATP1B1, OATP1B3, BSEP, MRP4, OCT1 and OCT2. Avibactam was not a substrate of MDR1, BCRP, MRP4, or OCT2, but was a substrate of human OAT1 and OAT3 kidney transporters based on results generated in human embryonic kidney cells expressing these transporters. Probenecid inhibits 56% to 70% of the uptake of avibactam by OAT1 and OAT3 in vitro . Ceftazidime does not inhibit avibactam transport mediated by OAT1 and OAT3. The clinical impact of potent OAT inhibitors on the pharmacokinetics of avibactam is not known. Co-administration of AVYCAZ with probenecid is not recommended [ see D rug I nteractions ( 7.1 ) ]. Administration of AVYCAZ 2.5 grams (ceftazidime 2 grams and avibactam 0.5 grams) to healthy male subjects (n = 28) as a 2-hour infusion following a 1-hour infusion of metronidazole every 8 hours for 3 days did not affect the C max and AUC values for avibactam or ceftazidime compared to administration of AVYCAZ 2.5 grams (ceftazidime 2 grams and avibactam 0.5 grams) alone. Administration of 0.5 grams metronidazole to healthy male subjects as a 1-hour infusion before a 2-hour infusion of AVYCAZ 2.5 grams (ceftazidime 2 grams and avibactam 0.5 grams) every 8 hours for 3 days did not affect the C max and AUC of metronidazole compared to administration of 0.5 grams metronidazole alone.

12.4 Microbiology Mechanism of Action The ceftazidime component of AVYCAZ is a cephalosporin antibacterial drug with in vitro activity against certain gram-negative and gram-positive bacteria. The bactericidal action of ceftazidime is mediated through binding to essential penicillin-binding proteins (PBPs). The avibactam component of AVYCAZ is a non-beta-lactam beta-lactamase inhibitor that inactivates certain beta-lactamases that degrade ceftazidime. Avibactam does not decrease the activity of ceftazidime against ceftazidime-susceptible organisms. AVYCAZ demonstrated in vitro activity against Enterobacteriaceae in the presence of some beta-lactamases and extended-spectrum beta-lactamases (ESBLs) of the following groups: TEM, SHV, CTX-M, Klebsiella pneumoniae carbapenemase (KPCs), AmpC, and certain oxacillinases (OXA). AVYCAZ also demonstrated in vitro activity against P. aeruginosa in the presence of some AmpC beta-lactamases, and certain strains lacking outer membrane porin (OprD). AVYCAZ is not active against bacteria that produce metallo-beta lactamases and may not have activity against gram-negative bacteria that overexpress efflux pumps or have porin mutations. Resistance No cross-resistance with other classes of antimicrobials has been identified. Some isolates resistant to other cephalosporins (including ceftazidime) and to carbapenems may be susceptible to AVYCAZ. Interaction with Other Antimicrobials In vitro studies have not demonstrated antagonism between AVYCAZ and colistin, levofloxacin, linezolid, metronidazole, tigecycline, tobramycin, or vancomycin. Activity against Ceftazidime - N onsusceptible Bacteria in Animal Infection Models Avibactam restored activity of ceftazidime in animal models of infection (e.g. thigh infection, pyelonephritis, systemic infection induced by intraperitoneal injection) caused by ceftazidime non-susceptible beta-lactamase- producing (e.g., ESBL, KPC and AmpC) gram-negative bacteria. Antimicrobial Activity AVYCAZ has been shown to be active against most isolates of the following bacteria, both in vitro and in clinical infections [ see Indications and Usage ( 1.1 ) , ( 1.2 ) and ( 1.3 ) ] . Complicated Intra-ab dominal Infections (cIAI) Aerobic Bacteria Gram-negative Bacteria Citrobacter freundii complex Enterobacter cloacae Escherichia coli Klebsiella oxytoca Klebsiella pneumoniae Proteus mirabilis Pseudomonas aeruginosa Complicated Urinary Tract Infections (c UTI), including Pyelonephritis Aerobic Bacteria Gram-negative Bacteria Citrobacter freundii complex Enterobacter cloacae Escherichia coli Klebsiella pneumoniae Proteus mirabilis Pseudomonas aeruginosa Hospital-acquired Bacterial Pneumonia and Ventilator-associated Bacterial Pneumonia (HABP/VABP ) Aerobic Bacteria Gram-negative Bacteria Enterobacter cloacae Escherichia coli Haemophilus influenza e Klebsiella pneumoniae Proteus mirabilis Pseudomonas aeruginosa Serratia marcescens The following in vitro data are available, but their clinical significance is unknown. At least 90 percent of the following bacteria exhibit an in vitro minimum inhibitory concentration (MIC) less than or equal to the susceptible breakpoint for AVYCAZ against isolates of similar genus or organism group. However, the efficacy of AVYCAZ in treating clinical infections caused by these bacteria has not been established in adequate and well-controlled clinical trials. Gram-negative Bacteria Citrobacter koseri Enterobacter aerogenes Morganella morganii Pro videncia rettgeri Providencia stuartii Susceptibility Test Methods For specific information regarding susceptibility testing methods, interpretive criteria, and associated test methods and quality control standards recognized by FDA for AVYCAZ, please see: https://www.fda.gov/STIC.

The mean pharmacokinetic parameters for ceftazidime and avibactam in healthy adult male subjects with normal renal function after single and multiple 2-hour intravenous infusions of AVYCAZ 2.5 grams (ceftazidime 2 grams and avibactam 0.5 grams) administered every 8 hours are summarized in Table 14. Pharmacokinetic parameters of ceftazidime and avibactam were similar for single and multiple dose administration of AVYCAZ and were similar to those determined when ceftazidime or avibactam were administered alone. Table 14. Pharmacokinetic Parameters (Geometric Mean [%CV]) of Ceftazidime and Avibactam Following Administration of AVYCAZ 2.5 grams (ceftazidime 2 grams and avibactam 0.5 grams) in Healthy Adult Male Subjects Ceftazidime Avibactam Parameter Single AVYCAZ 2.5 grams a Dose Administered as a 2-hour Infusion (n = 16) Multiple AVYCAZ 2.5 grams a Doses Administered every 8 hours as 2-hour Infusions for 11 Days (n = 16) Single AVYCAZ 2.5 grams a Dose Administered as a 2-hour Infusion (n = 16) Multiple AVYCAZ 2.5 grams a Doses Administered every 8 hours as 2-hour Infusions for 11 Days (n = 16) C max (mg/L) 88.1 (14) 90.4 (16) 15.2 (14) 14.6 (17) AUC (mg-h/L) b 289 (15) c 291 (15) 42.1 (16) d 38.2 (19) T 1/2 (h) 3.27 (33) c 2.76 (7) 2.22 (31) d 2.71 (25) CL (L/h) 6.93 (15) c 6.86 (15) 11.9 (16) d 13.1 (19) V ss (L) 18.1 (20) c 17 (16) 23.2 (23) d 22.2 (18) CL = plasma clearance; C max = maximum observed concentration; T 1/2 = terminal elimination half-life; V ss (L) = volume of distribution at steady state a ceftazidime 2 grams and avibactam 0.5 grams b AUC 0-inf (area under concentration-time curve from time 0 to infinity) reported for single-dose administration; AUC 0 -tau (area under concentration curve over dosing interval) reported for multiple-dose administration c n = 15 d n = 13 The C max and AUC of ceftazidime increase in proportion to dose. Avibactam demonstrated approximately linear pharmacokinetics across the dose range studied (50 mg to 2000 mg) for single intravenous administration. No appreciable accumulation of ceftazidime or avibactam was observed following multiple intravenous infusions of AVYCAZ 2.5 grams (ceftazidime 2 grams and avibactam 0.5 grams) administered every 8 hours for up to 11 days in healthy adults with normal renal function. Distribution Less than 10% of ceftazidime was protein bound. The degree of protein binding was independent of concentration. The binding of avibactam to human plasma proteins was low (5.7% to 8.2%) and was similar across the range of concentrations tested in vitro (0.5 to 50 mg/L). The steady-state volumes of distribution of ceftazidime and avibactam were 17 L and 22.2 L, respectively, in healthy adults following multiple doses of AVYCAZ 2.5 grams (ceftazidime 2 grams and avibactam 0.5 grams) infused every 8 hours over 2 hours for 11 days. Following administration of AVYCAZ 2.5 g (ceftazidime 2 grams and avibactam 0.5 grams) to healthy male subjects every 8 hours as a 2-hour infusion for 3 days, the mean bronchial epithelial lining fluid-to-plasma ratios of avibactam C max and AUC 0-tau were 35%. The mean bronchial epithelial lining fluid-to-plasma ratios of ceftazidime C max and AUC 0-tau were 26% and 31%, respectively. Metabolism Ceftazidime is mostly (80% to 90% of the dose) eliminated as unchanged drug. No metabolism of avibactam was observed in human liver preparations (microsomes and hepatocytes). Unchanged avibactam was the major drug-related component in human plasma and urine after a single intravenous dose of 0.5 grams 14 C-labelled avibactam. Excretion Both ceftazidime and avibactam are excreted mainly by the kidneys. Approximately 80% to 90% of an intravenous dose of ceftazidime is excreted unchanged by the kidneys over a 24-hour period. After the intravenous administration of single 0.5-grams or 1-gram doses, approximately 50% of the dose appeared in the urine in the first 2 hours. An additional 20% was excreted between 2 and 4 hours after dosing, and approximately another 12% of the dose appeared in the urine between 4 and 8 hours later. The elimination of ceftazidime by the kidneys resulted in high therapeutic concentrations in the urine. The mean renal clearance of ceftazidime was approximately 100 mL/min. The calculated plasma clearance of approximately 115 mL/min indicated nearly complete elimination of ceftazidime by the renal route. Following administration of a single 0.5-grams intravenous dose of radiolabeled avibactam, an average of 97% of administered radioactivity was recovered from the urine, with over 95% recovered within 12 hours of dosing. An average of 0.20% of administered total radioactivity was recovered in feces within 96 hours of dosing. An average of 85% of administered avibactam was recovered from the urine as unchanged drug within 96 hours, with over 50% recovered within 2 hours of the start of the infusion. Renal clearance was 158 mL/min, which is greater than the glomerular filtration, suggesting that active tubular secretion contributes to the excretion of avibactam in addition to glomerular filtration. Specific Populations Patients with Renal Impairment Ceftazidime is eliminated almost solely by the kidneys; its serum half-life is significantly prolonged in patients with impaired renal function. The clearance of avibactam was significantly decreased in subjects with mild (CrCl greater than 50 to 80 mL/min, n = 6), moderate (CrCl 30 to less than or equal to 50 mL/min, n = 6), and severe (CrCl 30 mL/min or less, not requiring hemodialysis; n = 6) renal impairment compared to healthy subjects with normal renal function (CrCl greater than 80 mL/min, n = 6) following administration of a single 100-mg intravenous dose of avibactam. The slower clearance resulted in increases in systemic exposure (AUC) of avibactam of 2.6-fold, 3.8-fold, and 7-fold in subjects with mild, moderate, and severe renal impairment, respectively, compared to subjects with normal renal function. A single 100-mg dose of avibactam was administered to subjects with ESRD (n = 6) either 1 hour before or after hemodialysis. The avibactam AUC following the post-hemodialysis infusion was 19.5-fold the AUC of healthy subjects with normal renal function. Avibactam was extensively removed by hemodialysis, with an extraction coefficient of 0.77 and a mean hemodialysis clearance of 9.0 L/h. Approximately 55% of the avibactam dose was removed during a 4-hour hemodialysis session. Dosage adjustment of AVYCAZ is recommended in adult and pediatric patients 2 years and older with moderate and severe renal impairment and end-stage renal disease. Population PK models for ceftazidime and avibactam were used to conduct simulations for patients with impaired renal function. Simulations demonstrated that the recommended dose adjustments [ see Dosage and Administration ( 2.3 ) ] provide comparable exposures of ceftazidime and avibactam in both adult and pediatric patients with moderate and severe renal impairment and end-stage renal disease to those in patients with normal renal function or mild renal impairment. Because the exposure of both ceftazidime and avibactam is highly dependent on renal function, monitor renal function (i.e., CrCl in adult patients and eGFR in pediatric patients) at least daily and adjust the dosage of AVYCAZ accordingly [ see Dosage and Administration ( 2.3 ) ]. There is insufficient information to recommend a dosage regimen for pediatric patients less than 2 years of age with renal impairment. Patients with Hepatic Impairment The presence of hepatic dysfunction had no effect on the pharmacokinetics of ceftazidime in individuals administered 2 grams intravenously every 8 hours for 5 days. The pharmacokinetics of avibactam in patients with hepatic impairment have not been established. Avibactam does not appear to undergo significant hepatic metabolism; therefore, the systemic clearance of avibactam is not expected to be significantly affected by hepatic impairment. Dose adjustments are not currently considered necessary for AVYCAZ in patients with impaired hepatic function. Pediatric Patients Population pharmacokinetic analyses and target attainment simulations were conducted to recommend AVYCAZ dosing in pediatric patients with cIAI, cUTI and HABP/VABP. The recommended pediatric dosing regimens for patients from 2 to less than 18 years of age with eGFR of greater than 50 mL/min/1.73 m 2 and for patients from birth (with gestational age 31 weeks and older) to less than 2 years without renal impairment are predicted to result in systemic exposures similar to that in adult patients given AVYCAZ 2.5 grams. Population PK modeling, including the assumption of proportional effects of renal impairment in adults and pediatric patients, also predicted that the recommended dose adjustments for patients aged 2 years and older with eGFR less than or equal to 50 mL/min/1.73 m 2 result in systemic exposure similar to that in adult patients. There is insufficient information to recommend a dosage adjustment in pediatric patients less than 2 years of age with renal impairment. Geriatric Patients Following single-dose administration of 0.5 grams avibactam as a 30-minute infusion the mean AUC for avibactam was 17% higher in healthy elderly subjects (65 years of age and older, n = 16) than in healthy young adult subjects (18 to 45 years of age, n = 17). There was no statistically significant age effect for avibactam C max . No dose adjustment is recommended based on age. Dosage adjustment for AVYCAZ in elderly patients should be based on renal function [ see Dosage and Administration ( 2.2 ) ]. Gender Following single-dose administration of 0.5 grams avibactam as a 30-minute infusion, healthy male subjects (n = 17) had 18% lower avibactam C max values than healthy female subjects (n = 16). There was no gender effect for avibactam AUC parameters. No dose adjustment is recommended based on gender. Drug Interaction s Avibactam at clinically relevant concentrations does not inhibit the cytochrome P450 isoforms CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1 and CYP3A4/5 in vitro in human liver microsomes. Avibactam showed no potential for in vitro induction of CYP1A2, 2B6, 2C9 and 3A4 isoenzymes in human hepatocytes. Against CYP2E1, avibactam showed a slight induction potential at very high concentrations that exceed any clinically relevant exposure. Ceftazidime was evaluated independently in human hepatocytes and showed no induction potential on the activity or mRNA expression of CYP1A1/2, CYP2B6, and CYP3A4/5. Neither ceftazidime nor avibactam was found to be an inhibitor of the following hepatic and renal transporters in vitro at clinically relevant concentrations: MDR1, BCRP, OAT1, OAT3, OATP1B1, OATP1B3, BSEP, MRP4, OCT1 and OCT2. Avibactam was not a substrate of MDR1, BCRP, MRP4, or OCT2, but was a substrate of human OAT1 and OAT3 kidney transporters based on results generated in human embryonic kidney cells expressing these transporters. Probenecid inhibits 56% to 70% of the uptake of avibactam by OAT1 and OAT3 in vitro . Ceftazidime does not inhibit avibactam transport mediated by OAT1 and OAT3. The clinical impact of potent OAT inhibitors on the pharmacokinetics of avibactam is not known. Co-administration of AVYCAZ with probenecid is not recommended [ see D rug I nteractions ( 7.1 ) ]. Administration of AVYCAZ 2.5 grams (ceftazidime 2 grams and avibactam 0.5 grams) to healthy male subjects (n = 28) as a 2-hour infusion following a 1-hour infusion of metronidazole every 8 hours for 3 days did not affect the C max and AUC values for avibactam or ceftazidime compared to administration of AVYCAZ 2.5 grams (ceftazidime 2 grams and avibactam 0.5 grams) alone. Administration of 0.5 grams metronidazole to healthy male subjects as a 1-hour infusion before a 2-hour infusion of AVYCAZ 2.5 grams (ceftazidime 2 grams and avibactam 0.5 grams) every 8 hours for 3 days did not affect the C max and AUC of metronidazole compared to administration of 0.5 grams metronidazole alone.