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-abdominal 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.

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 [see 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.

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.

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.

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 Aged 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.