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IV Dilution - AVYCAZ (ceftazidime and avibactam) for injection

IV Dilution - AVYCAZ (ceftazidime and avibactam) for injection

[ Usual Diluents ] [ Standard Dilution ] [ Storage and Stability ]
DESCRIPTION CLINICAL PHARMACOLOGY INDICATIONS AND USAGE
CONTRAINDICATIONS PRECAUTIONS ADVERSE REACTIONS
DOSAGE AND ADMINISTRATION HOW SUPPLIED WARNINGS
PRESCRIBING HIGHLIGHTS:  Please see package insert for additional information and possible updates to ensure safe and effective use of this medication. The authors make no claims of the accuracy of the information contained herein; and these suggested doses are not a substitute for clinical judgment. Neither GlobalRPh Inc. nor any other party involved in the preparation of this program shall be liable for any special, consequential, or exemplary damages resulting in whole or part from any user's use of or reliance upon this material. Please read the disclaimer carefully BEFORE accessing or using this site. BY ACCESSING OR USING THIS SITE, YOU AGREE TO BE BOUND BY THE TERMS AND CONDITIONS SET FORTH IN THE DISCLAIMER.  

Drug UPDATES:   [Drug information  /  PDF]  
PACKAGE INSERT -Dosing:  Click (+) next to Dosage and Administration section (drug info link)
 

Usual Diluents top of page

NS,  D5W

Standard Dilutions   [Amount of drug] [Infusion volume] [Infusion rate] top of page

[2.5 grams]  [50 - 250 ml]  [120 minutes]
(ceftazidime 2 gram and avibactam 0.5 grams)

Renal:
[1.25 grams]  [50 - 250 ml]  [120 minutes]
[0.94 grams]  [50 - 250 ml]  [120 minutes]

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. The final volume is approximately 12 mL. The constituted solution is not for direct injection. The constituted solution must be diluted before intravenous infusion.
  1. 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
  2. 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.
  3. 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).
  4. Use the diluted AVYCAZ solution in the infusion bags within 12 hours when stored at room temperature.
  5. 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 P-Insert
Updated
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.

Revised: 6/2016

WARNINGS  top of page

See warnings and precautions below.


DESCRIPTION  top of page

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.

CLINICAL PHARMACOLOGY: top of page

Mechanism of Action:
 
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

INDICATIONS AND USAGE  top of page

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 top of page

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

PRECAUTIONS top of page

WARNINGS AND PRECAUTIONS:


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)

ADVERSE REACTIONS top of page

ADVERSE REACTIONS:

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.

DOSAGE AND ADMINISTRATION  top of page

2.1 Recommended Dosage

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 15 c AVYCAZ 0.94 grams (ceftazidime 0.75 grams and avibactam 0.19 grams) intravenously every 24 hours
Less than or equal to 5 c 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.

  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. The final volume is approximately 12 mL. The constituted solution is not for direct injection. The constituted solution must be diluted before intravenous infusion.
  1. 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
  2. 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.
  3. 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).
  4. Use the diluted AVYCAZ solution in the infusion bags within 12 hours when stored at room temperature.
  5. 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
  • lactated ringer's injection, USP, and
  • 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

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.



HOW SUPPLIED  top of page

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)

Storage and Stability top of page


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.



Disclaimer
The authors make no claims of the accuracy of the information contained herein; and these suggested doses are not a substitute for clinical judgment. Neither GlobalRPh Inc. nor any other party involved in the preparation of this program shall be liable for any special, consequential, or exemplary damages resulting in whole or part from any user's use of or reliance upon this material.  PLEASE READ THE DISCLAIMER CAREFULLY BEFORE ACCESSING OR USING THIS SITE. BY ACCESSING OR USING THIS SITE, YOU AGREE TO BE BOUND BY THE TERMS AND CONDITIONS SET FORTH IN THE DISCLAIMER.
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