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Ceftolozane And Tazobactam

FDA Drug Information • Also known as: Zerbaxa

Brand Names
Zerbaxa
Route
INTRAVENOUS
Dosage Form
INJECTION, POWDER, LYOPHILIZED, FOR SOLUTION
Product Type
HUMAN PRESCRIPTION DRUG

Description

11 DESCRIPTION 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 1 H -Pyrazolium, 5-amino-4-[[[(2-aminoethyl)amino]carbonyl]amino]-2-[[(6 R ,7 R )-7-[[(2 Z )-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 C 23 H 31 N 12 O 8 S 2 + ∙HSO 4 - and the molecular weight is 764.77. Figure 1: Chemical structure of ceftolozane sulfate 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 C 10 H 11 N 4 NaO 5 S and the molecular weight is 322.3. Figure 2: Chemical structure of tazobactam sodium 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. Figure 1 Figure 2

What Is Ceftolozane And Tazobactam Used For?

1 INDICATIONS AND USAGE ZERBAXA (ceftolozane and tazobactam) is a combination of ceftolozane, a cephalosporin antibacterial, and tazobactam, a beta-lactamase inhibitor, indicated for the treatment of the following infections caused by designated susceptible microorganisms: Complicated Intra-abdominal Infections (cIAI), used in combination with metronidazole, in adult and pediatric patients (birth to less than 18 years old). ( 1.1 ) Complicated Urinary Tract Infections (cUTI), Including Pyelonephritis, in adult and pediatric patients (birth to less than 18 years old). ( 1.2 ) Hospital-acquired Bacterial Pneumonia and Ventilator-associated Bacterial Pneumonia (HABP/VABP), in adult patients 18 years and older. ( 1.3 ) 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 bacteria. ( 1.4 ) 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 . 1.4 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...

Dosage and Administration

2 DOSAGE AND ADMINISTRATION Administer all doses of ZERBAXA every 8 hours by intravenous infusion over 1 hour in adult and pediatric patients. ( 2.1 , 2.2 ) See Full Prescribing Information for instructions on the preparation of solutions. ( 2.3 ) 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 in the Full Prescribing Information), and add to the same infusion bag. ( 2.3 ) Recommended Dosage of ZERBAXA by Infection in Adult Patients (18 years or older) with Creatinine Clearance (CrCl) Greater than 50 mL/min ( 2.1 ) Infection Dose Duration of Treatment Complicated Intra-abdominal Infections (cIAI) Used in conjunction with metronidazole 500 mg intravenously every 8 hours 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 Recommended Dosage of ZERBAXA by infection in Pediatric Patients (birth to less than 18 years of age) with Estimated Glomerular Filtration Rate (eGFR) Estimated GFR using an age-appropriate equation for use in the pediatric population Greater than 50 mL/min/1.73 m 2 ( 2.2 ) Infection Dose Duration of Treatment Complicated Intra-abdominal Infections Used in conjunction with metronidazole. 30 mg/kg up to a maximum dose of 1.5 g Pediatric patients weighing greater than 50 kg should not exceed a maximum dose of 1.5g 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 Recommended Dosage of ZERBAXA in Adult Patients (18 years or older) with CrCl 50 mL/min or less ( 2.2 ) Estimated CrCl (mL/min) CrCl estimated using Cockcroft-Gault formula 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) 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...

Side Effects (Adverse Reactions)

6 ADVERSE REACTIONS The following serious reactions are described in greater detail in the Warnings and Precautions section: Hypersensitivity reactions [see Warnings and Precautions (5.2) ] Clostridioides difficile -associated diarrhea [see Warnings and Precautions (5.3) ] Adult cIAI, cUTI and HAB/VABP Patients : The most common adverse reactions in adult patients (≥5% in either the cIAI or cUTI indication) are nausea, diarrhea, headache, and pyrexia. ( 6.1 ). The most common adverse reactions (≥5% in the HABP/VABP indication) are increase in hepatic transaminases, renal impairment/renal failure, and diarrhea. ( 6.1 ) Pediatric cIAI and cUTI Patients: The most common adverse reactions in pediatric patients (≥7% in either the cIAI or cUTI indication) are thrombocytosis, diarrhea, pyrexia, leukopenia, abdominal pain, vomiting, increased aspartate aminotransferase, and anemia. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Merck Sharp & Dohme LLC at 1-877-888-4231 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and also may not reflect rates observed in practice. Adult Patients Complicated Intra-abdominal Infections and Complicated Urinary Tract Infections, Including Pyelonephritis ZERBAXA was evaluated in Phase 3 comparator-controlled clinical trials of cIAI and cUTI, which included a total of 1015 patients treated with ZERBAXA (1.5 g every 8 hours, adjusted based on renal function where appropriate) and 1032 patients treated with comparator (levofloxacin 750 mg daily in cUTI or meropenem 1 g every 8 hours in cIAI) for up to 14 days. The mean age of treated patients was 48 to 50 years (range 18 to 92 years), across treatment arms and indications. In both indications, about 25% of the subjects were 65 years of age or older. Most patients (75%) enrolled in the cUTI trial were female, and most patients (58%) enrolled in the cIAI trial were male. Most patients (>70%) in both trials were enrolled in Eastern Europe and were White. The most common adverse reactions (5% or greater in either indication) occurring in patients receiving ZERBAXA were nausea, diarrhea, headache, and pyrexia. Table 6 lists adverse reactions occurring in 1% or greater of patients receiving ZERBAXA in Phase 3 cIAI and cUTI clinical trials. Table 6: Adverse Reactions Occurring in 1% or Greater of Adult Patients (18 years and older) Receiving ZERBAXA in Phase 3 cIAI and cUTI Clinical Trials Adverse Reaction Complicated Intra-abdominal Infections Complicated Urinary Tract Infections, Including Pyelonephritis ZERBAXA The ZERBAXA for injection dose was 1.5 g intravenously every 8 hours, adjusted to match renal function where appropriate. In the cIAI trials, ZERBAXA was given in conjunction with metronidazole. (N=482) n (%) Meropenem (N=497) n (%) ZERBAXA (N=533) n (%) Levofloxacin (N=535) n (%) Nausea 38 (7.9) 29 (5.8) 15 (2.8) 9 (1.7) Headache 12 (2.5) 9 (1.8) 31 (5.8) 26 (4.9) Diarrhea 30 (6.2) 25 (5) 10 (1.9) 23 (4.3) Pyrexia 27 (5.6) 20 (4) 9 (1.7) 5 (0.9) Constipation 9 (1.9) 6 (1.2) 21 (3.9) 17 (3.2) Insomnia 17 (3.5) 11 (2.2) 7 (1.3) 14 (2.6) Vomiting 16 (3.3) 20 (4) 6 (1.1) 6 (1.1) Hypokalemia 16 (3.3) 10 (2) 4 (0.8) 2 (0.4) ALT increased 7 (1.5) 5 (1) 9 (1.7) 5 (0.9) AST increased 5 (1) 3 (0.6) 9 (1.7) 5 (0.9) Anemia 7 (1.5) 5 (1) 2 (0.4) 5 (0.9) Thrombocytosis 9 (1.9) 5 (1) 2 (0.4) 2 (0.4) Abdominal pain 6 (1.2) 2 (0.4) 4 (0.8) 2 (0.4) Anxiety 9 (1.9) 7 (1.4) 1 (0.2) 4 (0.7) Dizziness 4 (0.8) 5 (1) 6 (1.1) 1 (0.2) Hypotension 8 (1.7) 4 (0.8) 2 (0.4) 1 (0.2) Atrial fibrillation 6 (1.2) 3 (0.6) 1 (0.2) 0 Rash 8 (1.7) 7 (1.4) 5 (0.9) 2 (0.4) Treatment discontinuation due to adverse events occurred in 2.0% (20/1015) of patients receiving ZERBAXA and 1.9% (20/1032) of patients receiving comparator drugs. Renal...

Contraindications

4 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. 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. ( 4 )

Pregnancy and Breastfeeding

8.1 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...

Overdosage

10 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.

How Supplied

16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied ZERBAXA 1.5 g (ceftolozane and tazobactam) for injection is supplied in single-dose vials containing 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. Vials are supplied in cartons containing 10 vials. (NDC 67919-030-01) 16.2 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). Discard unused portion.

About This Information

This drug information is sourced from FDA-approved labeling via the openFDA database. It is intended for educational and reference purposes only. This is not medical advice. Always consult your healthcare provider before making decisions about medication. Drug information may be updated by the FDA; check with your pharmacist for the most current information.

What are side effects?

Side effects are unwanted reactions that can occur when taking a medication. They range from mild (headache, nausea) to severe (allergic reactions, organ damage). Not everyone experiences side effects, and severity varies. Report any concerning side effects to your doctor.

What are drug interactions?

Drug interactions occur when a medication is affected by another drug, food, or supplement. Interactions can make medications less effective or cause dangerous side effects. Always tell your doctor about all medications and supplements you take.