Zerbaxa
(ceftolozane / tazobactam)Dosage & Administration
| Infection | Dose | Duration of Treatment |
|---|---|---|
| Complicated Intra-abdominal Infections (cIAI) * | 1.5 g | 4 to 14 days |
| Complicated Urinary Tract Infections (cUTI), Including Pyelonephritis | 1.5 g | 7 days |
| Hospital-acquired Bacterial Pneumonia and Ventilator-associated Bacterial Pneumonia (HABP/VABP) | 3 g | 8 to 14 days |
| Infection | Dose | Duration of Treatment |
|---|---|---|
| Complicated Intra-abdominal Infections † | 30 mg/kg up to a maximum dose of 1.5 g ‡ | 5 to 14 days |
| Complicated Urinary Tract Infections, including Pyelonephritis | 30 mg/kg up to a maximum dose of 1.5 g ‡ | 7 to 14 days |
| Estimated CrCl (mL/min) * | cIAI and cUTI, including pyelonephritis | HABP/VABP |
|---|---|---|
| 30 to 50 | ZERBAXA 750 mg (500 mg and 250 mg) intravenously every 8 hours | ZERBAXA 1.5 g (1 g and 0.5 g) intravenously every 8 hours |
| 15 to 29 | ZERBAXA 375 mg (250 mg and 125 mg) intravenously every 8 hours | ZERBAXA 750 mg (500 mg and 250 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) | A single loading dose of ZERBAXA 2.25 g (1.5 g and 0.75 g) followed by a ZERBAXA 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) |
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Zerbaxa Prescribing Information
1.1 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.
1.2 Complicated Urinary Tract Infections, Including Pyelonephritis
ZERBAXA is indicated for the treatment of adult and pediatric patients (birth to less than 18 years old) 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.
1.3 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-acquired bacterial pneumonia and ventilator-associated bacterial pneumonia (HABP/VABP), caused by the following susceptible Gram-negative microorganisms: Enterobacter cloacae, Escherichia coli, Haemophilus influenzae, Klebsiella oxytoca, Klebsiella pneumoniae, Proteus mirabilis, Pseudomonas aeruginosa, and Serratia 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.
2.1 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.
| Infection | Dose | Frequency | Infusion Time | Duration of Treatment |
|---|---|---|---|---|
| ||||
| Complicated Intra-abdominal Infections † | 1.5 g | Every 8 Hours | 1 hour | 4 to 14 days |
| Complicated Urinary Tract Infections, Including Pyelonephritis | 1.5 g | Every 8 Hours | 1 hour | 7 days |
| Hospital-acquired Bacterial Pneumonia and Ventilator-associated Bacterial Pneumonia (HABP/VABP) | 3 g | Every 8 Hours | 1 hour | 8 to 14 days |
2.2 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/1.73 m2 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.
ZERBAXA is not recommended in pediatric patients who have an eGFR 50 mL/min/1.73m2 or less [see Use in Specific Populations (8.4)].
There is insufficient information to recommend a dosage regimen for pediatric patients with HABP/VABP [see Use in Specific Populations (8.4)].
| Infection | Dose | Frequency | Infusion time | Duration of treatment |
|---|---|---|---|---|
| ||||
| Complicated Intra-abdominal Infections † | 30 mg/kg up to a maximum dose of 1.5 g ‡ | Every 8 hours | 1 hour | 5 to 14 days |
| Complicated Urinary Tract Infections including Pyelonephritis | 30 mg/kg up to a maximum dose of 1.5 g ‡ | Every 8 hours | 1 hour | 7 to 14 days |
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 [see Use in Specific Populations (8.6) and Clinical Pharmacology (12.3)].
| Estimated CrCl (mL/min) * | Complicated Intra-abdominal Infections and Complicated Urinary Tract Infections, Including Pyelonephritis | Hospital-acquired Bacterial Pneumonia and Ventilator-associated Bacterial Pneumonia (HABP/VABP) |
|---|---|---|
| ||
| 30 to 50 | 750 mg (500 mg and 250 mg) intravenously every 8 hours | 1.5 g (1 g and 0.5 g) intravenously every 8 hours |
| 15 to 29 | 375 mg (250 mg and 125 mg) intravenously every 8 hours | 750 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) |
Dosage Adjustments in Pediatric Patients with Renal Impairment
Dosage adjustment of ZERBAXA in pediatric patients (birth to less than 18 years of age) with eGFR 50 mL/min/1.73 m2 or less has not been determined.
ZERBAXA is not recommended in pediatric patients who have an eGFR 50 mL/min/1.73m2 or less [see Use in Specific Populations (8.4)].
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 4), and add to the same infusion bag. Discard unused portion.
| ZERBAXA (ceftolozane and tazobactam) Dose | Volume 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.
ZERBAXA 1.5 g (ceftolozane and tazobactam) for injection is supplied as a white to yellow sterile powder for reconstitution in single-dose vials; each vial contains ceftolozane 1 g (equivalent to 1.147 g of ceftolozane sulfate) and tazobactam 0.5 g (equivalent to 0.537 g of tazobactam sodium).
Pregnancy
Risk Summary
There are no data available on ZERBAXA, ceftolozane or tazobactam use in pregnant women to allow assessment of a drug-associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes. Available data from published prospective cohort studies, case series, and case reports over several decades have not identified an association of cephalosporin use during pregnancy with major birth defects, miscarriage, or other adverse maternal or fetal outcomes (see Data). Neither ceftolozane nor tazobactam produced embryo-fetal toxicity when administered to rodents during the period of organogenesis at ceftolozane doses approximately 3.5 times higher in mice and 2 times higher in rats than the maximum recommended human dose (MRHD) of 2 grams every 8 hours based on plasma AUC comparison or at tazobactam doses approximately 10 times higher in rats than the MRHD of 1 gram every 8 hours based on body surface area comparison. In pre-postnatal studies, where pregnant rats were administered intravenous ceftolozane or intraperitoneal tazobactam in gestation and through the lactation period, ceftolozane was associated with a decrease in auditory startle response in first generation offspring at a dose lower than the MRHD based on AUC comparison, and tazobactam was associated with reduced maternal body weight gain and increased stillbirths at a dose equivalent to approximately 4 times the MRHD and reduced fetal body weights in first generation offspring at a dose approximately equivalent to the MRHD based on body surface area comparison (see Data).
The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.
Data
Human Data
While available studies with multiple cephalosporins cannot definitively establish the absence of risk, published data from prospective cohort studies, case series, and case reports over several decades have not identified an association of cephalosporin use during pregnancy with major birth defects, miscarriage, or other adverse maternal or fetal outcomes. Available studies have methodologic limitations, including small sample size, retrospective data collection, and inconsistent comparator groups.
Animal Data
Ceftolozane
Embryo-fetal development studies were performed in mice administered intravenous ceftolozane at doses of 300, 1000, and 2000 mg/kg/day during the period of organogenesis (Gestation Day 6 through 15) and in rats administered intravenous ceftolozane in doses of 100, 300, and 1000 mg/kg/day during the period of organogenesis (Gestation Day 6 through 17). In mice, ceftolozane was not associated with maternal or embryo-fetal toxicity with doses up to the highest dose of 2000 mg/kg/ day (approximately 3.5 times the MRHD of 2 grams every 8 hours based on plasma AUC comparison). In rats, no embryo-fetal toxicity was observed, but maternal body weight gain was reduced at a ceftolozane dose of 1000 mg/kg/day. No adverse maternal effects in rats were observed at a dose of 300 mg/kg/day and no adverse embryo-fetal effects were observed at a dose of 1000 mg/kg/day (respectively equivalent to approximately 0.7- and 2-times the MRHD based on plasma AUC comparison).
In a pre-postnatal study in rats, intravenous ceftolozane administered during pregnancy and lactation (Gestation Day 6 through Lactation Day 20) was associated with a decrease in auditory startle response in postnatal Day 60 male pups at maternal doses greater than or equal to 300 mg/kg/day. No adverse effects were observed in rats at a dose of 100 mg/kg/day, a dose lower than the MRHD of 2 grams every 8 hours based on plasma AUC comparison.
Tazobactam
In an embryo-fetal study in rats, tazobactam was administered intravenously during the period of organogenesis (Gestation Day 7 through 17) at doses of 125, 500, and 3000 mg/kg/day. The high dose of 3000 mg/kg/day produced maternal toxicity (decreased food consumption and body weight gain) but was not associated with fetal toxicity. No adverse maternal effects were observed at a dose of 500 mg/kg/day and no adverse fetal effects were observed at a dose of 3000 mg/kg/day (respectively equivalent to approximately 2- and 10-times the MRHD of 1 gram every 8 hours based on body surface area comparison). In rats, tazobactam was shown to cross the placenta. Concentrations in the fetus were less than or equal to 10% of those found in maternal plasma.
In a pre-postnatal study in rats, tazobactam administered intraperitoneally in doses of 40, 320, and 1280 mg/kg/day at the end of gestation and during lactation (Gestation Day 17 through Lactation Day 21) was associated with decreased maternal food consumption and body weight gain at the end of gestation and significantly more stillbirths at the high dose of 1280 mg/kg/day. No effects on the physical development, neurological function, or fertility and reproductive ability of first generation (F1) pups were noted, but postnatal body weights for F1 pups delivered to dams receiving 320 and 1280 mg/kg/day tazobactam were significantly reduced 21 days after delivery. The second generation (F2) fetuses were normal for all doses of tazobactam. No adverse effects on maternal reproduction were observed at doses up to 320 mg/kg/day and F1 body weights were not reduced at a dose of 40 mg/kg/day (respectively equivalent to approximately 1.0 and 0.1 times the MRHD of 1 gram every 8 hours based on body surface area comparison).
Lactation
Risk Summary
There are no data on the presence of ceftolozane or tazobactam in human milk. There are no data on 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
Complicated Intra-abdominal Infections (cIAI) and Complicated Urinary Tract Infections (cUTI), including Pyelonephritis
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 [see Clinical Pharmacology (12.3) and Clinical Studies (14.1 and 14.2)].
The safety profile of ZERBAXA in pediatric patients was similar to adults with cIAI and cUTI, treated with ZERBAXA [see Adverse Reactions (6.1)].
There is insufficient information to recommend dosage adjustment for pediatric patients younger than 18 years of age with cIAI and cUTI with eGFR 50 mL/min/1.73m2 or less [see Dosage and Administration (2.4) and Clinical Pharmacology (12.3)].
ZERBAXA is not recommended in pediatric patients who have an eGFR 50 mL/min/1.73m2 or less. Pediatric patients born at term or pre-term may not have an eGFR of 50 mL/min/1.73m2 or greater at birth or within the first few months of life.
Hospital-acquired Bacterial Pneumonia and Ventilator-associated Bacterial Pneumonia (HABP/VABP)
The safety and effectiveness of ZERBAXA in pediatric patients have not been established for the treatment of HABP and VABP.
Geriatric Use
Of the 1015 patients treated with ZERBAXA in the Phase 3 cIAI and cUTI clinical trials, 250 (24.6%) were 65 years or older, including 113 (11.1%) 75 years or older. The incidence of adverse events in both treatment groups was higher in older subjects (65 years or older) in the trials for both indications. In the cIAI trial, cure rates in the elderly (aged 65 years and older) in the ZERBAXA plus metronidazole arm were 69/100 (69%) and in the comparator arm were 70/85 (82.4%). This finding in the elderly population was not observed in the cUTI trial.
Of the 361 patients treated with ZERBAXA in the Phase 3 HABP/VABP clinical trial, 160 (44.3%) were 65 years or older, including 83 (23%) 75 years or older. The incidence of adverse events in both treatment groups was higher in older subjects (65 years or older). In the trial, Day 28 all-cause mortality rates in the elderly (aged 65 years and older) were comparable between treatment arms:50/160 (31.3%) in the ZERBAXA arm and 54/160 (33.8%) in the comparator arm.
ZERBAXA is substantially excreted by the kidney and the risk of adverse reactions to ZERBAXA may be greater in patients with renal impairment. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function. Adjust dosage for elderly patients based on renal function [see Dosage and Administration (2.2) and Clinical Pharmacology (12.3)].
Patients with Renal Impairment
Adult Patients
Dosage adjustment is required in adult patients with CrCl 50 mL/min or less, including adult patients with ESRD on HD [see Dosage and Administration (2.2), Warnings and Precautions (5.1) and Clinical Pharmacology (12.3)].
Pediatric Patients
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 [see Clinical Pharmacology (12.3)].
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.
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 (Table 5). 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 [see Dosage and Administration (2.2)].
| Baseline Renal Function | ZERBAXA plus Metronidazole n/N (%) | Meropenem n/N (%) |
|---|---|---|
| CrCl greater than 50 mL/min | 312/366 (85.2) | 355/404 (87.9) |
| CrCl 30 to 50 mL/min | 11/23 (47.8) | 9/13 (69.2) |
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.
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.