ZERBAXA® (ceftolozane and tazobactam) for injection

ZERBAXA® (ceftolozane and tazobactam) for injection

ZERBAXA® (ceftolozane and tazobactam) for injection

ZERBAXA (ceftolozane and tazobactam) is an antibacterial combination product consisting of the cephalosporin antibacterial drug ceftolozane sulfate and the beta-lactamase inhibitor tazobactam sodium for intravenous administration.

Ceftolozane sulfate is a semi-synthetic antibacterial drug of the beta-lactam class for parenteral administration. The chemical name of ceftolozane sulfate is 1H-Pyrazolium, 5-amino-4-[[[(2-aminoethyl)amino]carbonyl]amino]-2-[[(6R,7R)-7-[[(2Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-[(1-carboxy-1-methylethoxy)imino]acetyl]amino]-2-carboxy-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-en-3-yl]methyl]-1- methyl-,sulfate (1:1). The molecular formula is C23H31N12O8S2+•HSO4- and the molecular weight is 764.77.

Tazobactam sodium, a derivative of the penicillin nucleus, is a penicillanic acid sulfone. Its chemical name is sodium (2S,3S,5R)-3-methyl-7-oxo-3-(1H-1,2,3-triazol-1-ylmethyl)-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylate-4,4-dioxide. The chemical formula is C10H11N4NaO5S and the molecular weight is 322.3.

ZERBAXA 1.5 g (ceftolozane and tazobactam) for injection is a white to yellow sterile powder for reconstitution consisting of ceftolozane 1 g (equivalent to 1.147 g of ceftolozane sulfate) and tazobactam 0.5 g (equivalent to 0.537 g of tazobactam sodium) per vial, packaged in single-dose glass vials. The product contains sodium chloride (487 mg/vial) as a stabilizing agent, citric acid (21 mg/vial), and L-arginine (approximately 600 mg/vial) as excipients.

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.

Resistance

Mechanisms of beta-lactam resistance may include the production of beta-lactamases, modification of PBPs by gene acquisition or target alteration, up-regulation of efflux pumps, and loss of outer membrane porin.

Clinical isolates may produce multiple beta-lactamases, express varying levels of beta-lactamases, or have amino acid sequence variations, and other resistance mechanisms that have not been identified.

Culture and susceptibility information and local epidemiology should be considered in selecting or modifying antibacterial therapy.

ZERBAXA demonstrated in vitro activity against Enterobacteriaceae in the presence of some extended-spectrum beta-lactamases (ESBLs) and other beta-lactamases of the following groups: TEM, SHV, CTX-M, and OXA. ZERBAXA is not active against bacteria that produce serine carbapenemases [K. pneumoniae carbapenemase (KPC)], and metallo-beta-lactamases.

In ZERBAXA clinical trials, some isolates of Enterobacteriaceae with minimum inhibitory concentration to ZERBAXA of ≤2 mcg/mL produced beta-lactamases. These isolates produced one or more beta-lactamases of the following enzyme groups: CTX-M, OXA, TEM, or SHV.

Some of these beta-lactamases were also produced by isolates of Enterobacteriaceae with minimum inhibitory concentration to ZERBAXA >2 mcg/mL.

ZERBAXA demonstrated in vitro activity against P. aeruginosa isolates tested that had chromosomal AmpC, loss of outer membrane porin (OprD), or up regulation of efflux pumps (MexXY, MexAB).

Isolates resistant to other cephalosporins may be susceptible to ZERBAXA, although cross-resistance may occur.

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).

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INDICATIONS AND USAGE

Complicated Intra-abdominal Infections: ZERBAXA used in combination with metronidazole is indicated for the treatment of adult and pediatric patients (birth to less than 18 years old) with complicated intra-abdominal infections (cIAI) caused by the following susceptible 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.

Complicated Urinary Tract Infections, Including Pyelonephritis: ZERBAXA is indicated for the treatment of adult and pediatric patients (birth to less than 18 yearsold) with complicated urinary tract infections (cUTI), including pyelonephritis, caused by the following susceptible Gram-negative microorganisms: Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, and Pseudomonas aeruginosa.

Hospital-acquired Bacterial Pneumonia and Ventilator-associated Bacterial Pneumonia (HABP/VABP): ZERBAXA is indicated for the treatment of adult patients (18 years and older) with hospital-acquiredbacterial pneumonia and ventilator-associated bacterial pneumonia (HABP/VABP), caused by the followingsusceptible Gram-negative microorganisms: Enterobacter cloacae, Escherichia coli, Haemophilusinfluenzae, Klebsiella oxytoca, Klebsiella pneumoniae, Proteus mirabilis, Pseudomonas aeruginosa, andSerratia marcescens.

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 or prevent 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.

DOSAGE AND ADMINISTRATION

Recommended Dosage in Adult Patients:

The recommended dosage of ZERBAXA in adult patients 18 years and older with creatinine clearance (CrCl) greater than 50 mL/min is 1.5 gram (g) (ceftolozane 1 g and tazobactam 0.5 g for Ciai and cUTI and 3 g (ceftolozane 2 g and tazobactam 1 g) for HABP/VABP administered every 8 hours by intravenous infusion over 1 hour The duration of therapy should be guided by the severity and site of infection and the patient’s clinical and bacteriological progress as shown in Table 1.

Table 1: Dosage of ZERBAXA by Infection in Adult Patients (18 years and older) with CrCl* Greater than 50 mL/min

InfectionDoseFrequencyInfusion timeDuration of Treatment
Complicated Intra-abdominal Infections**1.5gEvery 8 hours1 hour4 to 14 days
Complicated Urinary Tract Infections, Including Pyelonephritis1.5gEvery 8 hours1 hour7 days
Hospital-acquired Bacterial Pneumonia and Ventilatorassociated Bacterial Pneumonia (HABP/VABP)3gEvery 8 hours1 hour8 to 14 days

* CrCl estimated using Cockcroft-Gault formula

** Used in conjunction with metronidazole 500 mg intravenously every 8 hours

Recommended Dosage in Pediatric Patients with cIAI or cUTI (birth to less than 18 years of age):

The recommended dosage regimen of ZERBAXA in pediatric patients from birth to less than 18 years of age with cIAI and cUTI with an estimated glomerular filtration rate (eGFR) greater than 50 mL/min/1.73m2 is described in Table 2. ZERBAXA is administered every 8 hours by intravenous infusion over 1 hour.

The duration of treatment should be guided by the severity and site of infection and the patient’s clinical and bacteriological progress as shown in Table 2. For the treatment of cIAI, metronidazole should be given concurrently.

Table 2: Dosage of ZERBAXA by infection in Pediatric Patients (birth to less 18 years of age) with eGFR+ greater than 50 mL/min/1.73 m2

InfectionDoseFrequencyInfusion timeDuration of Treatment
Complicated Intra-abdominal Infections30 mg/kg up to a maximum dose of 1.5 g**Every 8 hours1 hour5 to 14 days
Complicated Urinary Tract Infections, Including Pyelonephritis30 mg/kg up to a maximum dose of 1.5 g**Every 8 hours1 hour7 to 14 days

+ Estimated GFR using an age-appropriate equation for use in the pediatric population

* Used in conjunction with metronidazole.

** Pediatric patients weighing greater than 50 kg should not exceed a maximum dose of 1.5 g

Dosage Adjustments in Adult Patients with Renal Impairment:

Dose adjustment is required for adult patients (18 years and older) with CrCl 50 mL/min or less (Table 3). All doses of ZERBAXA are administered over 1 hour. For patients with changing renal function, monitor CrCl at least daily and adjust the dosage of ZERBAXA accordingly

Table 3: Dosage of ZERBAXA in Adult Patients (18 years and older) with CrCl 50 mL/min or Less

Estimated CrCl (mL/min)*Complicated Intra-abdominal Infections and Complicated Urinary Tract Infections, Including PyelonephritisHospital-acquired Bacterial Pneumonia and Ventilatorassociated Bacterial Pneumonia (HABP/VABP)
30 to 50  750 mg (500 mg and 250 mg) intravenously every 8 hours1.5 g (1 g and 0.5 g) intravenously every 8 hours
15 to 29  375 mg (250 mg and 125 mg) intravenously every 8 hours750 mg (500 mg and 250 mg) intravenously every 8 hours
End-stage renal disease (ESRD) on hemodialysis (HD)A single loading dose of 750 mg (500 mg and 250 mg) followed by a 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)A single loading dose of 2.25 g (1.5 g and 0.75 g) followed by a 450 mg (300 mg and 150 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

Preparation of Solutions

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

Preparation of doses:

Constitute each vial of ZERBAXA 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 per vial.

Caution: The constituted solution is not for direct injection.

To prepare the required dose, withdraw the appropriate volume determined from Table 4 from the reconstituted vial(s). Add the withdrawn volume to an infusion bag containing 100 mL of 0.9% Sodium Chloride for Injection, USP or 5% Dextrose Injection, USP. For doses above 1.5 g, reconstitute a second vial in the same manner as the first one, withdraw an appropriate volume (per Table 3), and add to the same infusion bag. Discard unused portion.

Table 4: Preparation of Doses

ZERBAXA (ceftolozane and tazobactam) DoseVolume to Withdraw from Reconstituted Vial(s)
3 g (2 g and 1 g)Two vials of 11.4 mL each (entire contents from two vials)
2.25 g (1.5 g and 0.75 g)11.4 mL from one vial (entire contents) and 5.7 mL from a second vial
1.5 g (1 g and 0.5 g)11.4 mL (entire contents from one vial)
750 mg (500 mg and 250 mg)5.7 mL
450 mg (300 mg and 150 mg)3.5 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.

 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.

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). Discard unused portion.

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

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.

WARNINGS AND PRECAUTIONS

Decreased Efficacy in Patients with Baseline Creatinine Clearance of 30 to 50 mL/min:

In a subgroup analysis of a Phase 3 cIAI trial of adult patients, clinical cure rates were lower in patients with baseline CrCl of 30 to 50 mL/min compared to those with CrCl greater than 50 mL/min. The reduction in clinical cure rates was more marked in the ZERBAXA plus metronidazole arm compared to the meropenem arm. A similar trend was also seen in the cUTI trial. Monitor CrCl at least daily in patients with changing renal function and adjust the dosage of ZERBAXA accordingly

Hypersensitivity Reactions:

Serious and occasionally fatal hypersensitivity (anaphylactic) reactions have been reported in patients receiving beta-lactam antibacterial drugs.

Before initiating therapy with ZERBAXA, make careful inquiry about previous hypersensitivity reactions to other cephalosporins, penicillins, or other beta-lactams. If this product is to be given to a patient with a cephalosporin, penicillin, or other beta-lactam allergy, exercise caution because cross sensitivity has been established. If an anaphylactic reaction to ZERBAXA occurs, discontinue the drug and institute appropriate therapy.

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Clostridioides difficile-associated Diarrhea:

Clostridioides difficile-associated diarrhea (CDAD) has been reported for nearly all systemic antibacterial agents, including ZERBAXA, and may range in severity from mild diarrhea to fatal colitis.

Treatment with antibacterial agents alters the normal flora of the colon and may permit overgrowth of C. difficile. C. difficile produces toxins A and B which contribute to the development of CDAD. CDAD must be considered in all patients who present with diarrhea following antibacterial use. Careful medical history is necessary because CDAD has been reported to occur more than 2 months after the administration of antibacterial agents.

If CDAD is confirmed, discontinue antibacterials not directed against C. difficile, if possible. Manage fluid and electrolyte levels as appropriate, supplement protein intake, monitor antibacterial treatment of C. difficile, and institute surgical evaluation as clinically indicated.

Development of Drug-resistant Bacteria:

Prescribing ZERBAXA in the absence of a proven or strongly suspected bacterial infection or a prophylactic indication is unlikely to provide benefit to the patient and risks the development of drug-resistant bacteria.

ADVERSE REACTIONS

Pregnancy: There are no data available on ZERBAXA, ceftolozane or tazobactam use in pregnant women toallow assessment of a drug-associated risk of major birth defects, miscarriage or adverse maternal or fetaloutcomes.

Lactation: There are no data on the presence of ceftolozane or tazobactam in human milk. There are no dataon the effects of tazobactam or ceftolozane on the breastfed infant, or the effects on milk production.

The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for ZERBAXA and any potential adverse effects on the breastfed child from ZERBAXA or from the underlying maternal conditions.

Pediatric Use: The safety and effectiveness of ZERBAXA for the treatment of cIAI and cUTI have been established in pediatric patients aged birth to less than 18 years old. Use of ZERBAXA in these age groups is supported by evidence from adequate and well-controlled studies of ZERBAXA in adults with cUTI and cIAI and additional pharmacokinetic and safety data from pediatric trials.

Patients with Renal Impairment:

Dosage adjustment is required in adult patients with CrCl 50 mL/min or less, including adult patients with ESRD on HD.

No dose adjustment has been established in pediatric patients aged birth to less than 18 years of age with eGFR 50 mL/min/1.73 m2 or less.

OVERDOSAGE

In the event of overdose, discontinue ZERBAXA and provide general supportive treatment.

ZERBAXA can be removed by hemodialysis. Approximately 66% of ceftolozane, 56% of tazobactam, and 51% of the tazobactam metabolite M1 were removed by dialysis. No information is available on the use of hemodialysis to treat overdosage.

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