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AVYCAZ is supplied as a 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.
Prepare the required dose for intravenous infusion by withdrawing the appropriate volume determined from Table 3 from the constituted vial.
Table 3. Preparation of AVYCAZ Doses
AVYCAZ (ceftazidime and avibactam) Dose
Volume to Withdraw from Constituted Vial for Further Dilution to 50 to 250 mL
2.5 grams (2 grams and 0.5 grams)
12 mL (entire contents)
1.25 grams (1 gram and 0.25 grams)
6 mL
0.94 grams (0.75 grams and 0.19 grams)
4.5 mL
Before infusion, dilute the withdrawn volume of the constituted AVYCAZ solution further with the same diluent used for constitution of the powder (except sterile water for injection), to achieve a total volume between 50 mL (ceftazidime 0.04 grams/mL and avibactam 0.01 grams/mL) to 250 mL (ceftazidime 0.008 grams/mL and avibactam 0.002 grams/mL) in an infusion bag. If sterile water for injection was used for constitution, use any of the other appropriate constitution diluents for dilution.
Mix gently and ensure that the contents are dissolved completely. Visually inspect the diluted AVYCAZ solution (for administration) for particulate matter and discoloration prior to administration (the color of the AVYCAZ infusion solution for administration ranges from clear to light yellow).
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 used within 12 hours of subsequent storage at room temperature.
Stability data:
Stability Refrigerated
Stability Room Temp.
Reconstituted Vial/Powder
Notes
Following dilution of the constituted solutions with the appropriate diluents, AVYCAZ solutions in the infusion bags may also be refrigerated at 2 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.
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.
Upon constitution with appropriate diluent, the constituted AVYCAZ solution may be held for no longer than 30 minutes prior to transfer and dilution in a suitable infusion bag.
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 a 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.
The ceftazidime component of AVYCAZ is a 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 a 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.
AVYCAZ demonstrated in vitro activity against Enterobacteriaceae in the presence of some beta-lactamases and extended-spectrum beta-lactamases (ESBLs) of the following groups: TEM, SHV, CTX-M, Klebsiella pneumoniae carbapenemase (KPCs), AmpC, and certain oxacillinases (OXA). AVYCAZ also demonstrated in vitro activity against P. aeruginosa in the presence of some AmpC beta-lactamases, and certain strains lacking outer membrane porin (OprD). AVYCAZ is not active against bacteria that produce metallo-beta lactamases and may not have activity against gram-negative bacteria that overexpress efflux pumps or have porin mutations.
Resistance No cross-resistance with other classes of antimicrobials has been identified. Some isolates resistant to other cephalosporins (including ceftazidime) and to carbapenems may be susceptible to AVYCAZ.
Interaction with Other Antimicrobials In vitro studies have not demonstrated antagonism between AVYCAZ and colistin, levofloxacin, linezolid, metronidazole, tigecycline, tobramycin, or vancomycin.
Activity against Ceftazidime-Nonsusceptible Bacteria in Animal Infection Models
Avibactam restored activity of ceftazidime in animal models of infection (e.g. thigh infection, pyelonephritis, systemic infection induced by intraperitoneal injection) caused by ceftazidime non-susceptible beta-lactamase- producing (e.g., ESBL, KPC and AmpC) gram-negative bacteria.
Antimicrobial Activity AVYCAZ has been shown to be active against most isolates of the following bacteria, both in vitro and in clinical infections
AVYCAZ is a combination of ceftazidime, a cephalosporin, and avibactam, a beta-lactamase inhibitor, indicated for the treatment of patients 18 years or older with the following infections caused by designated susceptible microorganisms:
Complicated Intra-abdominal Infections (cIAI), used in combination with metronidazole (1.1) Complicated Urinary Tract Infections (cUTI), including Pyelonephritis (1.2)
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 (1.1, 1.2)
To reduce the development of drug-resistant bacteria and maintain the effectiveness of AVYCAZ and other antibacterial drugs, AVYCAZ should be used only to treat infections that are proven or strongly suspected to be caused by susceptible bacteria. (1.3)
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 class
Decreased efficacy in patients with baseline CrCl of 30 to less than or equal to 50 mL/ min. Monitor CrCl at least daily in patients with changing renal function and adjust the dose of AVYCAZ accordingly. (5.1) Hypersensitivity reactions: Includes anaphylaxis and serious skin reactions. Cross-hypersensitivity may occur in patients with a history of penicillin allergy. If an allergic reaction occurs, discontinue AVYCAZ. (5.2) Clostridium difficile-associated diarrhea: Clostridium difficile-associated diarrhea (CDAD) has been reported with nearly all systemic antibacterial agents, including AVYCAZ. Evaluate if diarrhea occurs. (5.3) Central Nervous System Reactions: Seizures and other neurologic events may occur, especially in patients with renal impairment. Adjust dose in patients with renal impairment. (5.4)
The most common adverse reactions in cIAI (>=/ 5%, when used with metronidazole) are diarrhea, nausea and vomiting. In cUTI, the most common adverse reactions (>=10%) are constipation and anxiety. (6.1)
To report SUSPECTED ADVERSE REACTIONS, contact Forest Laboratories, LLC, at 1-800-678-1605 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
See 17 for PATIENT COUNSELING INFORMATION.
Revised: 6/2016
See PACKAGE INSERT for PATIENT COUNSELING INFORMATION and Medication Guide.
The recommended dosage of AVYCAZ is 2.5 grams (ceftazidime 2 grams and avibactam 0.5 grams) administered every 8 hours by intravenous (IV) infusion over 2 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 Table 1.
Table 1. Dosage of AVYCAZ 2.5 grams (ceftazidime 2 grams and avibactam 0.5 grams) by Indication
Infection
Dosage
Frequency
Infusion Time (hours)
Duration of Treatment
Complicated Intra-abdominal Infections [used in combination with metronidazole]
2.5 grams
Every 8 hours
2
5 to 14 days
Complicated Urinary Tract Infections including Pyelonephritis
2.5 grams
Every 8 hours
2
7 to 14 days
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 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)].
Table 2. Dosage of AVYCAZ in Patients with Renal Impairment
Estimated Creatinine Clearance (mL/minute)a
Recommended Dosage Regimen for AVYCAZ (ceftazidime and avibactam)b
31 to 50
AVYCAZ 1.25 grams (ceftazidime 1 gram and avibactam 0.25 grams) intravenously every 8 hours
16 to 30
AVYCAZ 0.94 grams (ceftazidime 0.75 grams and avibactam 0.19 grams) intravenously every 12 hours
6 to 15c
AVYCAZ 0.94 grams (ceftazidime 0.75 grams and avibactam 0.19 grams) intravenously every 24 hours
Less than or equal to 5c
AVYCAZ 0.94 grams (ceftazidime 0.75 grams and avibactam 0.19 grams) intravenously every 48 hours
a As calculated using the Cockcroft-Gault formula.
b All doses of AVYCAZ are administered over 2 hours
c Both ceftazidime and avibactam are hemodialyzable; thus, administer AVYCAZ after hemodialysis on hemodialysis days.
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.
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.
Prepare the required dose for intravenous infusion by withdrawing the appropriate volume determined from Table 3 from the constituted vial.
Table 3. Preparation of AVYCAZ Doses
AVYCAZ (ceftazidime and avibactam) Dose
Volume to Withdraw from Constituted Vial for Further Dilution to 50 to 250 mL
2.5 grams (2 grams and 0.5 grams)
12 mL (entire contents)
1.25 grams (1 gram and 0.25 grams)
6 mL
0.94 grams (0.75 grams and 0.19 grams)
4.5 mL
Before infusion, dilute the withdrawn volume of the constituted AVYCAZ solution further with the same diluent used for constitution of the powder (except sterile water for injection), to achieve a total volume between 50 mL (ceftazidime 0.04 grams/mL and avibactam 0.01 grams/mL) to 250 mL (ceftazidime 0.008 grams/mL and avibactam 0.002 grams/mL) in an infusion bag. If sterile water for injection was used for constitution, use any of the other appropriate constitution diluents for dilution.
Mix gently and ensure that the contents are dissolved completely. Visually inspect the diluted AVYCAZ solution (for administration) for particulate matter and discoloration prior to administration (the color of the AVYCAZ infusion solution for administration ranges from clear to light yellow).
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 used within 12 hours of subsequent storage at room temperature.
2.4 Drug Compatibility
The AVYCAZ solution for administration at the range of diluted concentrations of ceftazidime 0.008 g/mL and avibactam 0.002 g/mL to ceftazidime 0.04 g/mL and avibactam 0.01 g/mL 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
Compatibility of AVYCAZ solution for administration with other drugs has not been established.
2.5 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 a 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 2 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.
DOSAGE FORMS AND STRENGTHS: AVYCAZ 2.5 grams (ceftazidime and avibactam) for injection is supplied in single-dose, clear glass vial containing: ceftazidime 2 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.
