Ceftolozane-Tazobactam (Zerbaxa™)

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

Usual Diluents

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

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 Add the withdrawn volume to an infusion bag containing 100 mL of 0.9% Sodium Chloride for Injection, USP or 5% Dextrose Injection, USP.

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:

WARNINGS 

DESCRIPTION 

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

CLINICAL PHARMACOLOGY:

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 

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

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

Decreased efficacy in patients with baseline CrCl of 30 to ≤50 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

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 

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):

* 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.

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 

Storage, and Stability

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