1.1 Complicated Intra-Abdominal Infections (cIAI)

AVYCAZ (ceftazidime-avibactam), in combination with metronidazole, is indicated for the treatment of complicated intra-abdominal infections (cIAI) caused by the following susceptible microorganisms: Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, Providencia stuartii, Enterobacter cloacae, Klebsiella oxytoca, and Pseudomonas aeruginosa in patients 18 years or older.

As only limited clinical safety and efficacy data for AVYCAZ are currently available, reserve AVYCAZ for use in patients who have limited or no alternative treatment options. [see Clinical Studies (14)].

1.2 Complicated Urinary Tract Infections (cUTI), including Pyelonephritis

AVYCAZ (ceftazidime-avibactam) is indicated for the treatment of complicated urinary tract infections (cUTI) including pyelonephritis caused by the following susceptible microorganisms: Escherichia coli, Klebsiella pneumoniae, Citrobacter koseri, Enterobacter aerogenes, Enterobacter cloacae, Citrobacter freundii, Proteus spp., and Pseudomonas aeruginosa in patients 18 years or older.

As only limited clinical safety and efficacy data for AVYCAZ are currently available, reserve AVYCAZ for use in patients who have limited or no alternative treatment options .[see Clinical Studies (14)].

1.3 Usage

To reduce the development of drug-resistant bacteria and maintain the effectiveness of AVYCAZ and other antibacterial drugs, AVYCAZ should be used to treat only indicated infections that are proven or strongly suspected to be caused by susceptible bacteria. When culture and susceptibility information are available, they should be considered in selecting or modifying antibacterial therapy. In the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy [see Dosage and Administration (2.1)].

2.1 Recommended Dosage

The recommended dosage of AVYCAZ is 2.5 grams (2 grams ceftazidime and 0.5 grams avibactam) administered every 8 hours by intravenous (IV) infusion over 2 hours in patients 18 years of age and older. For treatment of cIAI, metronidazole should be given concurrently. The guidelines for dosage of AVYCAZ in patients with normal renal function are listed in Table 1.

2.2 Dosage Adjustments in Patients with Renal Impairment

The recommended AVYCAZ dosage in patients with varying degrees of renal function is presented in Table 2. For patients with changing renal function, monitor creatinine clearance (CrCL) 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)].

2.3 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.

1. 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.
2. Mix gently. The constituted AVYCAZ solution will have an approximate ceftazidime concentration of 0.167 grams/mL and an approximate avibactam concentration of 0.042 grams/mL.
3. With the same diluent used for constitution of the powder (except sterile water for injection), dilute the constituted AVYCAZ solution further to achieve a total volume between 50 mL (40 and 10 mg/mL of ceftazidime and avibactam, respectively) to 250 mL (8 and 2 mg/mL of ceftazidime and avibactam, respectively) before infusion.
4. Mix gently and ensure that the contents are dissolved completely. Visually inspect the diluted AVYCAZ solution (for administration) for particular matter and discoloration prior to administration (the color of the AVYCAZ infusion solution for administration ranges from clear to light yellow).
5. Use the diluted AVYCAZ solution in the infusion bags within 12 hours when stored at room temperature. 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 use within 12 hours of subsequent storage at room temperature.

2.4 Drug Compatibility

The AVYCAZ solution for administration at concentrations between 0.008 g/mL ceftazidime + 0.002 g/mL avibactam and 0.04 g/mL ceftazidime + 0.01 g/mL avibactam 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
• in Baxter® Mini-Bag Plus™ containing 0.9% sodium chloride injection or 5% dextrose injection.

Compatibility of AVYCAZ solution for administration with other drugs has not been established.

2.5 Storage of Constituted Solutions

• Constituted solutions of AVYCAZ in the infusion bags should be used within 12 hours when stored at room temperature.
• Constituted solutions of AVYCAZ in the infusion bags may be refrigerated for up to 24 hours following constitution; and then should be used within 12 hours of subsequent storage at room temperature.

5.1 Decreased Clinical Response in Patients with Baseline Creatinine Clearance of 30 to 50 mL/min

In a Phase 3 cIAI trial, clinical cure rates were lower in a subgroup of patients with baseline CrCL of 30 to 50 mL/min compared to those with CrCL greater than 50 mL/min (Table 3). The reduction in clinical cure rates was more marked in patients treated with AVYCAZ plus metronidazole compared to meropenem-treated patients. 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. Monitor CrCL at least daily in patients with changing renal function and adjust the dosage of AVYCAZ accordingly [see Dosage and Administration (2.2), and Adverse Reactions (6.1)].

5.2 Hypersensitivity Reactions

Serious and occasionally fatal hypersensitivity (anaphylactic) reactions and serious skin reactions have been reported in patients receiving beta-lactam antibacterial drugs. Before therapy with AVYCAZ is instituted, careful inquiry about previous hypersensitivity reactions to other cephalosporins, penicillins, or carbapenems should be made. Exercise caution if this product is to be given to a penicillin or other beta-lactam-allergic patient because cross sensitivity among beta-lactam antibacterial drugs has been established. Discontinue the drug if an allergic reaction to AVYCAZ occurs.

5.3 Clostridium difficile-associated Diarrhea

Clostridium difficile-associated diarrhea (CDAD) has been reported for nearly all systemic antibacterial drugs, including AVYCAZ, and may range in severity from mild diarrhea to fatal colitis. Treatment with antibacterial drugs alters the normal flora of the colon and may permit overgrowth of C. difficile.

C. difficile produces toxins A and B which contribute to the development of CDAD. Hypertoxin producing strains of C. difficile cause increased morbidity and mortality, as these infections can be refractory to antimicrobial therapy and may require colectomy. CDAD must be considered in all patients who present with diarrhea following antibacterial use. Careful medical history is necessary because CDAD has been reported to occur more than 2 months after the administration of antibacterial drugs.

If CDAD is suspected or confirmed, antibacterial drugs not directed against C. difficile may need to be discontinued. Manage fluid and electrolyte levels as appropriate, supplement protein intake, monitor antibacterial treatment of C. difficile, and institute surgical eva luation as clinically indicated.

5.4 Central Nervous System Reactions

Seizures, nonconvulsive status epilepticus, encephalopathy, coma, asterixis, neuromuscular excitability, and myoclonia have been reported in patients treated with ceftazidime, particularly in the setting of renal impairment. Adjust dosing based on creatinine clearance [see Dosage and Administration (2.2)].

5.5 Development of Drug-Resistant Bacteria

Prescribing AVYCAZ in the absence of a proven or strongly suspected bacterial infection is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria [see Indications and Usage (1.3)].

6.1 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 eva luated 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.

7.1 Probenecid

In vitro, avibactam is a substrate of OAT1 and OAT3 transporters which might contribute to the active uptake from the blood compartment, and thereby its excretion. As a potent OAT inhibitor, probenecid inhibits OAT uptake of avibactam by 56% to 70% in vitro and, therefore, has the potential to decrease the elimination of avibactam when co-administered. Because a clinical interaction study of AVYCAZ or avibactam alone with probenecid has not been conducted, co-administration of AVYCAZ with probenecid is not recommended [see Clinical Pharmacology (12.3)].

7.2 Drug/Laboratory Test Interactions

The administration of ceftazidime may result in a false-positive reaction for glucose in the urine with certain methods. It is recommended that glucose tests based on enzymatic glucose oxidase reactions be used.