For: Intraabdominal Infection, Urinary Tract Infection, Pneumonia
Avycaz (avibactam and ceftazidime) is a next generation, non-β lactam β-lactamase inhibitor and third-generation, antipseudomonal cephalosporin antibiotic combination for the treatment of complicated intra-abdominal infections, complicated urinary tract infections, hospital-acquired bacterial pneumonia, and ventilator-associated bacterial pneumonia. DESCRIPTION
AVYCAZ is an antibacterial combination product consisting of the semisynthetic cephalosporin ceftazidime pentahydrate and the beta-lactamase inhibitor avibactam sodium for intravenous administration.
Ceftazidime
Ceftazidime is semisynthetic, beta-lactam antibacterial drug. It is the pentahydrate of (6R ,7R ,Z)-7-(2-(2-aminothiazol-4-yl)-2-(2-carboxypropan-2-yloxyimino)acetamido)-8-oxo-3-(pyridinium-1-ylmethyl)-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylate. Its molecular weight is 636.6. The empirical formula is C22 H32 N6 O12 S2
Avibactam
Avibactam sodium chemical name is sodium [(2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl] sulfate. Its molecular weight is 287.23. The empirical formula is C7 H10 N3 O6 SNa.
AVYCAZ 2.5 grams (ceftazidime and avibactam) for injection is white to yellow sterile powder for constitution consisting of ceftazidime pentahydrate and avibactam sodium packaged in glass vials. The formulation also contains sodium carbonate.
Each AVYCAZ 2.5 grams single-dose vial contains ceftazidime grams (equivalent to 2.635 grams sterile ceftazidime pentahydrate/sodium carbonate) and avibactam 0.5 grams (equivalent to 0.551 grams sterile avibactam sodium). The sodium carbonate content of the mixture is 239.6 mg/vial. The total sodium content of the mixture is approximately 146 mg (6.4 mEq)/vial.
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
AVYCAZ is an antibacterial drug [
12.2 Pharmacodynamics
As with other beta-lactam antimicrobial drugs, the time that unbound plasma concentrations of ceftazidime exceeds the AVYCAZ minimum inhibitory concentration (MIC) against the infecting organism has been shown to best correlate with efficacy in neutropenic murine thigh infection model with Enterobacteriaceae and Pseudomonas aeruginosa. The time above threshold concentration has been determined to be the parameter that best predicts the efficacy of avibactam in in vitro and in vivo nonclinical models.
Microbiology
Mechanism of Action
The ceftazidime component of AVYCAZ is cephalosporin antibacterial drug with in vitro activity against certain gram-negative and gram-positive bacteria. The bactericidal action of ceftazidime is mediated through binding to essential penicillin-binding proteins (PBPs). The avibactam component of AVYCAZ is non-beta-lactam beta-lactamase inhibitor that inactivates some beta-lactamases and protects ceftazidime from degradation by certain beta-lactamases. Avibactam does not decrease the activity of ceftazidime against ceftazidime-susceptible organisms.
INDICATIONS AND USAGE
1.1 Complicated Intra-Abdominal Infections (cIAI)
AVYCAZ (ceftazidime and avibactam) in combination with metronidazole, is indicated for the treatment of complicated intra-abdominal infections (cIAI) caused by the following susceptible gram-negative microorganisms: Escherichia coli Klebsiella pneumoniae Proteus mirabilis Enterobacter cloacae Klebsiella oxytoca Citrobacter freundii complex, and Pseudomonas aeruginosa in patients 18 years or older.
1.2 Complicated Urinary Tract Infections (cUTI), including Pyelonephritis
AVYCAZ (ceftazidime and 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.
In the treatment of cUTI, as only limited clinical safety and efficacy data for AVYCAZ are currently available, reserve AVYCAZ for use in patients with cUTI who have limited or no alternative treatment options
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 info. 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.
2 DOSAGE AND ADMINISTRATION
2.1 Recommended Dosage
The recommended dosage of AVYCAZ is 2.5 grams (ceftazidime grams and avibactam 0.5 grams) administered every hours by intravenous (IV) infusion over hours in patients 18 years of age and older in patients with normal renal function. For treatment of cIAI, metronidazole should be given concurrently. The guidelines for dosage of AVYCAZ in patients with creatinine clearance [CrCl] greater than 50 mL/min are listed in
Preparation of the AVYCAZ Solution for Administration
AVYCAZ is supplied as dry powder, which must be constituted and subsequently diluted, using aseptic technique prior to intravenous infusion.
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
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. The final volume is approximately 12 mL. The constituted solution is not for direct injection. The constituted solution must be diluted before intravenous infusion.
Storage of Constituted Solutions
Upon constitution with appropriate diluent, the constituted AVYCAZ solution may be held for no longer than 30 minutes prior to transfer and dilution in suitable infusion bag.
Following dilution of the constituted solutions with the appropriate diluents, AVYCAZ solutions in the infusion bags are stable for 12 hours when stored at room temperature.
Following dilution of the constituted solutions with the appropriate diluents, AVYCAZ solutions in the infusion bags may also be refrigerated at to 8?C (36 to 46?F) for up to 24 hours; and then should be used within 12 hours of subsequent storage at room temperature.
3 DOSAGE FORMS AND STRENGTHS
AVYCAZ 2.5 grams (ceftazidime and avibactam) for injection is supplied as white to yellow sterile powder for constitution in single-dose, sterile, clear glass vial containing ceftazidime grams (equivalent to 2.635 grams of ceftazidime pentahydrate/sodium carbonate powder) and avibactam 0.5 grams (equivalent to 0.551 grams of avibactam sodium).
4 CONTRAINDICATIONS
AVYCAZ is contraindicated in patients with known serious hypersensitivity to the components of AVYCAZ (ceftazidime and avibactam), avibactam-containing products, or other members of the cephalosporin
ADVERSE REACTIONS
The following adverse reactions are discussed in greater detail in the Warnings and Precautions section:
Hypersensitivity Reactions
Clostridium difficile -Associated Diarrhea
Central Nervous System Reactions
AVYCAZ 2.5 grams (ceftazidime and avibactam) for injection is supplied in single-dose, clear glass vial containing: ceftazidime grams (equivalent to 2.635 grams of ceftazidime pentahydrate/sodium carbonate) and avibactam 0.5 grams (equivalent to 0.551 grams of avibactam sodium). Vials are supplied as individual vial (NDC# 0456-2700-01) and in cartons containing 10 vials (NDC# 0456-2700-10)
AVYCAZ vials should be stored at 25?C (77?F); excursions permitted between 15?C and 30?C (59?F and 86?F) [See USP Controlled Room Temperature]. Protect from light. Store in carton until time of use
