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The following are discussed in greater detail in the WARNINGS AND PRECAUTIONS section:

  • Decreased Clinical Response in Patients with Baseline CrCL of 30 to 50 mL/min [see WARNINGS AND PRECAUTIONS]
  • Hypersensitivity Reactions [see WARNINGS AND PRECAUTIONS]
  • Clostridium difficile-Associated Diarrhea [see WARNINGS AND PRECAUTIONS]
  • Central Nervous System Reactions [see WARNINGS AND PRECAUTIONS]
  • Development of Drug-Resistant Bacteria [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 two active-controlled Phase 2 clinical trials, one each in cIAI and cUTI, including pyelonephritis. The Phase 2 trials included a total of 169 adult patients treated with AVYCAZ and 169 patients treated with comparators.

Complicated Intra-Abdominal Infections

The Phase 2 cIAI trial included 101 adult patients treated with AVYCAZ (2 grams ceftazidime and 0.5 grams avibactam) administered intravenously over 30 minutes every 8 hours plus 500 mg metronidazole administered intravenously over 60 minutes every 8 hours and 102 patients treated with meropenem. The median age of patients treated with AVYCAZ was 41 years (range 18 to 79 years). Patients were predominantly male (69.3%) and Caucasian (55.4%). Patients with an estimated baseline CrCL 50 mL/min or less were excluded.

Serious adverse reactions occurred in 9/101 (8.9%) of patients receiving AVYCAZ (with metronidazole) and 11/102 (10.8%) of patients receiving meropenem. The most common adverse reactions leading to discontinuation in patients receiving AVYCAZ were skin and subcutaneous tissue disorders (3%).

Adverse reactions occurring in 10% or more of patients receiving AVYCAZ were vomiting and nausea.

Increased Mortality

In a Phase 3 cIAI trial, death occurred in 2.5% (13/529) of patients who received AVYCAZ/ metronidazole and in 1.5% (8/529) of patients who received meropenem. Among a subgroup of patients with baseline CrCL 30 to 50 mL/min, death occurred in 25.8% (8/31) of patients who received AVYCAZ/metronidazole and in 8.6% (3/35) 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 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% (5/498) of patients who received AVYCAZ/metronidazole and in 1.0% (5/494) 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 2 cUTI trial included 68 adult patients treated with AVYCAZ (0.5 grams ceftazidime + 0.125 grams avibactam) administered intravenously over 30 minutes every 8 hours and 67 patients treated with imipenem-cilastatin (0.5 grams intravenously every 6 hours). The dose of AVYCAZ in this trial was lower than the recommended dose [see DOSAGE AND ADMINISTRATION]. Median age of patients treated with AVYCAZ was 47.5 years (range 18 to 85 years). Patients were predominantly female (75%) and Caucasian (58.8%). Patients with CrCL less than 70 mL/min were excluded.

Serious adverse reactions occurred in 6/68 (8.8%) of patients receiving AVYCAZ and 2/67 (3.0%) of patients receiving imipenem-cilastatin. Two patients prematurely discontinued treatment with AVYCAZ: one due to an accidental overdose and one due to atrial fibrillation.

Adverse reactions occurring in 10% or more of patients receiving AVYCAZ were constipation and anxiety.

Table 4 lists adverse reactions occurring in 5% or more of patients receiving AVYCAZ in the Phase 2 cIAI trial or the Phase 2 cUTI trial.

Table 4: Incidence of Selected Adverse Drug Reactions Occurring in 5% or more of Patients Receiving AVYCAZ in the Phase 2 cIAI Trial or the Phase 2 cUTI Trial

  Phase 2 cIAI Trial Phase 2 cUTI Trial
AVYCAZ plus Metronidazole a
(N = 101)
Meropenem b
(N = 102)
AVYCAZc
(N = 68)
Imipenem- Cilastatin d
(N = 67)
Gastrointestinal disorders
  Vomiting 14% 5% 0% 0%
  Nausea 10% 6% 2% 5%
  Constipation 4% 1% 10% 3%
  Abdominal pain 8% 3% 7% 5%
  Upper abdominal pain 1% 0% 7% 2%
Investigations
  Increased blood alkaline phosphatase  9% 7% 3% 2%
  Increased alanine aminotransferase 8% 13% 3% 6%
Nervous system disorders
  Dizziness 0% 2% 6% 0%
Psychiatric disorders
  Anxiety 5% 1% 10% 8%
a 2.5 grams (2 grams/0.5 grams) intravenously over 30 minutes every 8 hours (with metronidazole 500 mg intravenously every 8 hours)
b 1 gram intravenously over 30 minutes every 8 hours
c 0.625 grams (0.5 grams/0.125 grams) intravenously over 30 minutes every 8 hours
d 0.5 grams intravenously over 30 minutes every 6 hours

Other Adverse Reactions of AVYCAZ and Ceftazidime

The following selected adverse reactions were reported in AVYCAZ-treated subjects at a rate of less than 5% in the Phase 2 trials and are not described elsewhere in the labeling.

Blood and lymphatic disorders -Eosinophilia, Thrombocytopenia

Investigations -Increased gamma-glutamyltransferase, Prolonged prothrombin time

Metabolism and nutrition disorders -Hypokalemia

Renal and urinary disorders -Acute renal failure, Renal impairment

Skin and subcutaneous tissue disorders -Rash

Additionally, adverse reactions reported with ceftazidime alone that were not reported in AVYCAZ clinical trials are listed below:

Blood and lymphatic disorders -Agranulocytosis, Hemolytic anemia, Leukopenia, Lymphocytosis, Neutropenia, Thrombocytosis

General disorders and administration site conditions -Infusion site inflammation, Injection site hematoma, Injection site phlebitis, Injection site thrombosis

Hepatobiliary disorders – Jaundice

Infections and infestations -Candidiasis

Investigations -Increased blood lactate dehydrogenase

Nervous system disorders -Dysgeusia, Paresthesia

Renal and urinary disorders -Tubulointerstitial nephritis

Reproductive and breast disorders -Vaginal inflammation

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

Laboratory Changes

Seroconversion from a negative to a positive direct Coombs' test result occurred in 6/82 (7.3%) of patients receiving AVYCAZ plus metronidazole and 2/84 (2.4%) of patients receiving meropenem in the cIAI trial. Seroconversion from a negative to a positive direct Coombs' test result occurred in 1/52 (1.9%) of patients receiving AVYCAZ and 5/60 (8.3%) of patients receiving imipenem cilastatin in the cUTI trial. No adverse reactions representing hemolytic anemia were reported in any treatment group.