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IV Dilution Guidelines -ZERBAXA™ (ceftolozane and tazobactam)

ZERBAXA™ (ceftolozane and tazobactam) for injection, for intravenous use

[ 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.  

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Usual Diluents top of page

NS,  D5W

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

[1.5 grams]  [100 ml]  [60 minutes]
[750 mg]  [100 ml]  [60 minutes]
[prescribed dose]  [100 ml]  [60 minutes]

Preparation of doses:

Constitute the vial with 10 mL of sterile water for injection or 0.9% Sodium Chloride for Injection, USP and gently shake to dissolve. The final volume is approximately 11.4 mL. Caution: The constituted solution is not for direct injection.

To prepare the required dose, withdraw the appropriate volume determined from Table 3 from the reconstituted vial. Add the withdrawn volume to an infusion bag containing 100 mL of 0.9% Sodium Chloride for Injection, USP or 5% Dextrose Injection, USP.

Table 3: Preparation of Doses
ZERBAXA (ceftolozane and tazobactam) Dose Volume to Withdraw from Reconstituted Vial
1.5 g (1 g and 0.5 g) 11.4 mL (entire contents)
750 mg (500 mg and 250 mg) 5.7 mL
375 mg (250 mg and 125 mg) 2.9 mL
150 mg (100 mg and 50 mg) 1.2 mL

ZERBAXA 1.5 gram (g) (ceftolozane 1 g and tazobactam 0.5 g) for injection, every 8 hours by intravenous infusion administered over 1 hour for patients 18 years or older with creatinine clearance (CrCl) greater than 50 mL/min.


Dosage in patients with impaired renal function:

Estimated CrCl (mL/min)* Recommended Dosage Regimen for ZERBAXA (ceftolozane and tazobactam)†
30 to 50 ZERBAXA 750 mg (500 mg and 250 mg) intravenously every 8 hours
15 to 29 ZERBAXA 375 mg (250 mg and 125 mg) intravenously every 8 hours
End-stage renal disease (ESRD) on hemodialysis (HD) A single loading dose of ZERBAXA 750 mg (500 mg and 250 mg) followed by a ZERBAXA 150 mg (100 mg and 50 mg) maintenance dose administered intravenously every 8 hours for the remainder of the treatment period (on hemodialysis days, administer the dose at the earliest possible time following completion of dialysis)



Stability data:

Stability
Refrigerated
Stability
Room Temp.
Reconstituted
Vial/Powder
Notes P-Insert
Updated
Solution:
7 days when stored under refrigeration at 2 to 8°C (36 to 46°F).
Solution:
Following dilution of the solution with 0.9% sodium chloride or 5% dextrose, ZERBAXA is stable for 24 hours when stored at room temperature
Vial:   Upon constitution with sterile water for injection or 0.9% sodium chloride injection, reconstituted ZERBAXA solution may be held for 1 hour prior to transfer and dilution in a suitable infusion bag. Revised: 9/2016

 

WARNINGS  top of page


See warnings and precautions below.


DESCRIPTION  top of page

Description:
These highlights do not include all the information needed to use ZERBAXA safely and effectively. See full prescribing information for ZERBAXA.

ZERBAXA™ (ceftolozane and tazobactam) for injection, for intravenous use
Initial U.S. Approval: 2014

CLINICAL PHARMACOLOGY: top of page

Mechanism of Action:
Ceftolozane belongs to the cephalosporin class of antibacterial drugs. The bactericidal action of ceftolozane results from inhibition of cell wall biosynthesis, and is mediated through binding to penicillin-binding proteins (PBPs). Ceftolozane is an inhibitor of PBPs of P. aeruginosa (e.g., PBP1b, PBP1c, and PBP3) and E. coli (e.g., PBP3).

Tazobactam sodium has little clinically relevant in vitro activity against bacteria due to its reduced affinity to penicillin-binding proteins. It is an irreversible inhibitor of some beta-lactamases (e.g., certain penicillinases and cephalosporinases), and can bind covalently to some chromosomal and plasmid-mediated bacterial beta-lactamases.

 Interaction with Other Antimicrobials
In vitro synergy studies suggest no antagonism between ZERBAXA and other antibacterial drugs (e.g., meropenem, amikacin, aztreonam, levofloxacin, tigecycline, rifampin, linezolid, daptomycin, vancomycin, and metronidazole).

Antimicrobial Activity
ZERBAXA has been shown to be active against the following bacteria, both in vitro and in clinical infections [see Indications and Usage (1)].
Complicated Intra-abdominal Infections
Gram-negative bacteria:
Enterobacter cloacae
Escherichia coli
Klebsiella oxytoca
Klebsiella pneumoniae
Proteus mirabilis
Pseudomonas aeruginosa

Gram-positive bacteria:
Streptococcus anginosus
Streptococcus constellatus
Streptococcus salivarius

Anaerobic bacteria:
Bacteroides fragilis
Complicated Urinary Tract Infections, Including Pyelonephritis

Gram-negative bacteria:
Escherichia coli
Klebsiella pneumoniae
Proteus mirabilis
Pseudomonas aeruginosa

The following in vitro data are available, but their clinical significance is unknown. At least 90 percent of the following bacteria exhibit an in vitro minimum inhibitory concentration (MIC) less than or equal to the susceptible breakpoint for ceftolozane and tazobactam against isolates of similar genus or organism group. However, the efficacy of ZERBAXA in treating clinical infections due to these bacteria has not been established in adequate and well-controlled clinical trials.

Gram-negative bacteria:
Citrobacter koseri
Morganella morganii
Proteus vulgaris
Providencia rettgeri
Providencia stuartii
Serratia liquefaciens
Serratia marcescens
Gram-positive bacteria:
Streptococcus agalactiae
Streptococcus intermedius

INDICATIONS AND USAGE  top of page

INDICATIONS AND USAGE:
ZERBAXA™ (ceftolozane and tazobactam) for injection is indicated for the treatment of patients 18 years or older with the following infections caused by designated susceptible microorganisms.

1.1 Complicated Intra-abdominal Infections

ZERBAXA used in combination with metronidazole is indicated for the treatment of complicated intra-abdominal infections (cIAI) caused by the following Gram-negative and Gram-positive microorganisms: Enterobacter cloacae, Escherichia coli, Klebsiella oxytoca, Klebsiella pneumoniae, Proteus mirabilis, Pseudomonas aeruginosa, Bacteroides fragilis, Streptococcus anginosus, Streptococcus constellatus, and Streptococcus salivarius.

1.2 Complicated Urinary Tract Infections, Including Pyelonephritis

ZERBAXA is indicated for the treatment of complicated urinary tract infections (cUTI), including pyelonephritis, caused by the following Gram-negative microorganisms: Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, and Pseudomonas aeruginosa.

1.3 Usage

To reduce the development of drug-resistant bacteria and maintain the effectiveness of ZERBAXA and other antibacterial drugs, ZERBAXA should be used only to treat 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.

CONTRAINDICATIONS top of page

Contraindications:

ZERBAXA is contraindicated in patients with known serious hypersensitivity to the components of ZERBAXA (ceftolozane and tazobactam), piperacillin/tazobactam, or other members of the beta-lactam class.


PRECAUTIONS top of page

WARNINGS AND PRECAUTIONS

Decreased efficacy in patients with baseline CrCl of 30 to leq50 mL/min. Monitor CrCl at least daily in patients with changing renal function and adjust the dose of ZERBAXA accordingly. (5.1)
Serious hypersensitivity (anaphylactic) reactions have been reported with beta-lactam antibacterial drugs. Exercise caution in patients with known hypersensitivity to beta-lactam antibacterial drugs. (5.2)
Clostridium difficile-associated diarrhea (CDAD) has been reported with nearly all systemic antibacterial agents, including ZERBAXA. Evaluate if diarrhea occurs. (5.3)

ADVERSE REACTIONS top of page

ADVERSE REACTIONS

The most common adverse reactions (>/=5% in either indication) are nausea, diarrhea, headache and pyrexia. (6.1)

To report SUSPECTED ADVERSE REACTIONS, contact Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., at 1-877-888-4231 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
USE IN SPECIFIC POPULATIONS

Dosage adjustment is required in patients with moderately or severely impaired renal function and in patients with end-stage renal disease on hemodialysis (HD). (2.2, 8.5, 8.6, 12.3)
Higher incidence of adverse reactions was observed in patients aged 65 years and older. In complicated intra-abdominal infections, cure rates were lower in patients aged 65 years and older. (8.5)
ZERBAXA has not been studied in pediatric patients. (8.4)

DOSAGE AND ADMINISTRATION  top of page

DOSAGE AND ADMINISTRATION:

ZERBAXA 1.5 gram (g) (ceftolozane 1 g and tazobactam 0.5 g) for injection, every 8 hours by intravenous infusion administered over 1 hour for patients 18 years or older with creatinine clearance (CrCl) greater than 50 mL/min. (2.1)


Dosage in patients with impaired renal function (2.2):

Estimated CrCl (mL/min)* Recommended Dosage Regimen for ZERBAXA (ceftolozane and tazobactam)†
30 to 50 ZERBAXA 750 mg (500 mg and 250 mg) intravenously every 8 hours
15 to 29 ZERBAXA 375 mg (250 mg and 125 mg) intravenously every 8 hours
End-stage renal disease (ESRD) on hemodialysis (HD) A single loading dose of ZERBAXA 750 mg (500 mg and 250 mg) followed by a ZERBAXA 150 mg (100 mg and 50 mg) maintenance dose administered intravenously every 8 hours for the remainder of the treatment period (on hemodialysis days, administer the dose at the earliest possible time following completion of dialysis)

* CrCl estimated using Cockcroft-Gault formula
† All doses of ZERBAXA are administered over 1 hour

2.3 Preparation of Solutions

ZERBAXA does not contain a bacteriostatic preservative. Aseptic technique must be followed in preparing the infusion solution.

Preparation of doses:

Constitute the vial with 10 mL of sterile water for injection or 0.9% Sodium Chloride for Injection, USP and gently shake to dissolve. The final volume is approximately 11.4 mL. Caution: The constituted solution is not for direct injection.

To prepare the required dose, withdraw the appropriate volume determined from Table 3 from the reconstituted vial. Add the withdrawn volume to an infusion bag containing 100 mL of 0.9% Sodium Chloride for Injection, USP or 5% Dextrose Injection, USP.

Table 3: Preparation of Doses
ZERBAXA (ceftolozane and tazobactam) Dose Volume to Withdraw from Reconstituted Vial
1.5 g (1 g and 0.5 g) 11.4 mL (entire contents)
750 mg (500 mg and 250 mg) 5.7 mL
375 mg (250 mg and 125 mg) 2.9 mL
150 mg (100 mg and 50 mg) 1.2 mL

Inspect drug products visually for particulate matter and discoloration prior to use. ZERBAXA infusions range from clear, colorless solutions to solutions that are clear and slightly yellow. Variations in color within this range do not affect the potency of the product.

2.4 Compatibility

Compatibility of ZERBAXA with other drugs has not been established. ZERBAXA should not be mixed with other drugs or physically added to solutions containing other drugs.

2.5 Storage of Constituted Solutions

Upon constitution with sterile water for injection or 0.9% sodium chloride injection, reconstituted ZERBAXA solution may be held for 1 hour prior to transfer and dilution in a suitable infusion bag.

Following dilution of the solution with 0.9% sodium chloride or 5% dextrose, ZERBAXA is stable for 24 hours when stored at room temperature or 7 days when stored under refrigeration at 2 to 8°C (36 to 46°F).

Constituted ZERBAXA solution or diluted ZERBAXA infusion should not be frozen.


HOW SUPPLIED  top of page

DOSAGE FORMS AND STRENGTHS:
ZERBAXA 1.5 g (ceftolozane and tazobactam) for injection supplied as a sterile powder for reconstitution in single-dose vials containing ceftolozane 1 g (equivalent to 1.147 g ceftolozane sulfate) and tazobactam 0.5 g (equivalent to 0.537 g tazobactam sodium)

Storage, and Stability top of page

Storage and Handling
ZERBAXA vials should be stored refrigerated at 2 to 8°C (36 to 46°F) and protected from light.
The reconstituted solution, once diluted, may be stored for 24 hours at room temperature or for 7 days under refrigeration at 2 to 8° C (36 to 46°F)

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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