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Label Changes for:

Avycaz (ceftazidime and avibactam)

June 2016

Changes have been made to the PRECAUTIONS and ADVERSE REACTIONS sections of the safety label.

Detailed View: Safety Labeling Changes Approved By FDA Center for Drug Evaluation and Research (CDER)

June 2016

ADVERSE REACTIONS

Clinical Trial Experience
  • (addition of new paragraph) AVYCAZ was evaluated in four 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 two Phase 3 trials, one in cIAI and one in cIAI or cUTI due to ceftazidime-resistant pathogens. The four clinical trials included a total of 862 adult patients treated with AVYCAZ and 866 patients treated with comparators.
Complicated Intra-Abdominal Infections (section has been completed updated)
  • 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:  Has extensively changed; please refer to label.
Increased Mortality
  • (updated figures are bolded)
  • 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.
  • 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.
Complicated Urinary Tract Infections, Including Pyelonephritis
  • Adverse reactions occurring 10% or greater in patients receiving AVYCAZ were constipation and anxiety. Table 6 lists adverse reactions occurring in 5% or more of patients receiving AVYCAZ and with incidences greater than the comparator in the Phase 2 cUTI trial.
  • Addition of Table 6:  Incidence of Selected Adverse Drug Reactions Occurring in 5% or more of Patients Receiving AVYCAZ in the Phase 2 cUTI Trial; please see label for information.
Other Adverse Reactions of AVYCAZ and Ceftazidime

The following selected adverse reactions were reported in AVYCAZ-treated subjects at a rate of less than 1% in the Phase 3 cIAI trial or less than 5% in the Phase 2 cUTI trial and are not described elsewhere in the labeling.

  • Blood and lymphatic disorders - Eosinophilia, Thrombocytopenia
  • General disorders and administration site conditions - Injection site phlebitis
  • Infections and infestations - Candidiasis
  • Investigations - Increased aspartate aminotransferase, Increased alanine aminotransferase, Increased gamma-glutamyltransferase, Prolonged prothrombin time
  • Metabolism and nutrition disorders - Hypokalemia
  • Nervous system disorders - Dysgeusia
  • Renal and urinary disorders - Acute renal failure, Renal impairment
  • Skin and subcutaneous tissue disorders - Rash, Rash maculo-papular, Urticaria, Pruritus

Additionally, adverse reactions reported with ceftazidime alone that were not reported in any AVYCAZ-treated subjects in any 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 thrombosis
  • Hepatobiliary disorders – Jaundice
  • Investigations - Increased blood lactate dehydrogenase
  • 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
  • (updated sentence) Seroconversion from a negative to a positive direct Coombs’ test result 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…

USE IN SPECIFIC POPULATIONS

Pregnancy and Lactation

Sections extensively updated to reflect conversion to PLLR; please refer to label.

Geriatric Use
  • (addition) Of the 630 patients in the pooled Phase 2 and Phase 3 cIAI CAZ-AVI clinical trials who were treated with AVYCAZ, 126 (20%) were 65 years of age and older, including 49 (7.8%) 75 years of age and older. In the pooled Phase 2 and Phase 3 cIAI trials, the incidence of adverse reactions in both treatment groups was higher in older patients (= 65 years of age) and similar in both treatment groups. In the Phase 3 cIAI trial, 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.
  • (addition) In the Phase 2 cUTI clinical trial, 11/68 (16.2%) of patients receiving AVYCAZ were 65 years of age or older, including 5/68 (8.8%) 75 years of age or older. Because of limited clinical data in cUTI patients, differences in outcomes or specific risks with AVYCAZ cannot be ruled out for cUTI patients 65 years of age and older.
  • (Updates and additions) 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… Dosage adjustment for elderly patients should be based on renal function.
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