Ceftazidime-avibactam for Injection

The following adverse reactions are discussed in greater detail in the Warnings and Precautions section:

• Hypersensitivity Reactions [see WARNINGS AND PRECAUTIONS]
• Clostridium difficile-Associated Diarrhea [see WARNINGS AND PRECAUTIONS]
• Central Nervous System Reactions [see WARNINGS AND PRECAUTIONS]

Clinical Trial 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.

AVYCAZ was evaluated in five active-controlled clinical trials in patients with cIAI or cUTI, including pyelonephritis. These trials included two Phase 2 trials, one in cIAI and one in cUTI, as well as three Phase 3 trials, one in cIAI, one in cUTI (Trial 1), and one in cIAI or cUTI due to ceftazidime non-susceptible pathogens (Trial 2). Data from Trial 1 served as the primary dataset for AVYCAZ safety findings in cUTI as there was a single comparator. Trial 2 had an open-label design as well as multiple comparator regimens which prevented pooling, but provided supportive information. The five clinical trials included a total of 1373 adult patients treated with AVYCAZ and 1375 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. There was no specific adverse reaction leading to discontinuation.

Adverse reactions occurring at 5% or greater in patients receiving AVYCAZ plus metronidazole were diarrhea, nausea and vomiting.

Table 5 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 5: Incidence of Selected Adverse Reactions Occurring in 1 % or more of Patients Receiving AVYCAZ in the Phase 3 cIAI Trial

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 and WARNINGS AND PRECAUTIONS]. 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

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]. Median age of patients treated with AVYCAZ was 54 years (range 18 to 89 years). 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. There was no specific adverse reaction leading to discontinuation.

The most common adverse reactions occurring in 3% of cUTI patients treated with AVYCAZ were nausea and diarrhea.

Table 6 lists adverse reactions occurring in 1% or more of patients receiving AVYCAZ and with incidences greater than the comparator in Trial 1.

Table 6: Incidence of Selected Adverse Drug Reactions Occurring in 1% or more of Patients Receiving AVYCAZ in Trial 1

Other Adverse Reactions Of AVYCAZ And Ceftazidime

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

General disorders and administration site conditions -Injection site phlebitis

Infections and infestations -Candidiasis

Investigations -Increased aspartate aminotransferase, Increased alanine aminotransferase, Increased gamma-glutamyltransferase

Metabolism and nutrition disorders -Hypokalemia

Nervous system disorders -Dysgeusia

Renal and urinary disorders -Acute renal failure, Renal impairment, Nephrolithiasis

Skin and subcutaneous tissue disorders -Rash, Rash maculo-papular, Urticaria, Pruritus

Psychiatric disorders -Anxiety

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, Leukopenia, Lymphocytosis, Neutropenia, Thrombocytosis, 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

Renal and urinary disorders -Tubulointerstitial nephritis

Reproductive and breast disorders -Vaginal inflammation

Skin and subcutaneous tissue disorders -Angioedema, Erythema multiforme, Stevens-Johnson syndrome, Toxic epidermal necrolysis

Laboratory Changes

Seroconversion from a negative to a positive direct Coombs' test result at any time up to the last visit occurred in 31/240 (12.9%) of patients receiving AVYCAZ plus metronidazole with initial negative Coombs' test and at least one follow up test and in 7/235 (3.0%) of patients receiving meropenem in the Phase 3 cIAI trial.

Seroconversion from a negative to a positive direct Coombs' test result at any time up to the last visit occurred in 7/216 (3.2%) of patients receiving AVYCAZ with initial negative Coombs' test and at least one follow up test and 2/214 (0.9%) of patients receiving doripenem in the Phase 3 cUTI trial. No adverse reactions representing hemolytic anemia were reported in any treatment group.