Data from FDA - Curated by EPG Health - Last updated 13 June 2018

Indication(s)

1 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. ZERBAXA (ceftolozane and tazobactam) is a combination product consisting of a cephalosporin-class antibacterial drug and a beta-lactamase inhibitor indicated for the treatment of the following infections caused by designated susceptible microorganisms: Complicated Intra-abdominal Infections, used in combination with metronidazole (1.1) Complicated Urinary Tract Infections, including Pyelonephritis (1.2) 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. (1.3) 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.

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Advisory information

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)
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)] Clostridium difficile-associated diarrhea [see Warnings and Precautions (5.3)] 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. 6.1 Clinical Trial 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. ZERBAXA was evaluated in Phase 3 comparator-controlled clinical trials of cIAI and cUTI, which included a total of 1015 patients treated with ZERBAXA 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 5 lists adverse reactions occurring in 1% or greater of patients receiving ZERBAXA in Phase 3 clinical trials. Table 5: Adverse Reactions Occurring in 1% or Greater of Patients Receiving ZERBAXA in Phase 3 Clinical Trials Preferred Term Complicated Intra-abdominal Infections Complicated Urinary Tract Infections, Including Pyelonephritis ZERBAXAThe 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 impairment (including the terms renal impairment, renal failure, and renal failure acute) led to discontinuation of treatment in 5/1015 (0.5%) subjects receiving ZERBAXA and none in the comparator arms. Increased Mortality In the cIAI trials (Phase 2 and 3), death occurred in 2.5% (14/564) of patients receiving ZERBAXA and in 1.5% (8/536) of patients receiving meropenem. The causes of death varied and included worsening and/or complications of infection, surgery and underlying conditions. Less Common Adverse Reactions The following selected adverse reactions were reported in ZERBAXA-treated subjects at a rate of less than 1%: Cardiac disorders: tachycardia, angina pectoris Gastrointestinal disorders: gastritis, abdominal distension, dyspepsia, flatulence, ileus paralytic General disorders and administration site conditions: infusion site reactions Infections and infestations: candidiasis including oropharyngeal and vulvovaginal, fungal urinary tract infection Investigations: increased serum gamma-glutamyl transpeptidase (GGT), increased serum alkaline phosphatase, positive Coombs test Metabolism and nutrition disorders: hyperglycemia, hypomagnesemia, hypophosphatemia Nervous system disorders: ischemic stroke Renal and urinary system: renal impairment, renal failure Respiratory, thoracic and mediastinal disorders: dyspnea Skin and subcutaneous tissue disorders: urticaria Vascular disorders: venous thrombosis

Usage information

Dosing and administration
2 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)CrCl estimated using Cockcroft-Gault formula Recommended Dosage Regimen for ZERBAXA (ceftolozane and tazobactam)All doses of ZERBAXA are administered over 1 hour. 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) 2.1 Recommended Dosage The recommended dosage regimen is ZERBAXA 1.5 gram (g) (ceftolozane 1 g and tazobactam 0.5 g) for injection administered every 8 hours by intravenous infusion over 1 hour in patients 18 years or older and with normal renal function or mild renal impairment. The duration of therapy should be guided by the severity and site of infection and the patient's clinical and bacteriological progress (Table 1). Table 1: Dosage of ZERBAXA 1.5 g (ceftolozane 1 g and tazobactam 0.5 g) by Infection in Patients with Creatinine Clearance (CrCl) Greater than 50 mL/min Infection Dose Frequency Infusion Time (hours) Duration of Treatment Complicated Intra-abdominal InfectionsUsed in conjunction with metronidazole 500 mg intravenously every 8 hours 1.5 g Every 8 Hours 1 4-14 days Complicated Urinary Tract Infections, including Pyelonephritis 1.5 g Every 8 Hours 1 7 days 2.2 Patients with Renal Impairment Dose adjustment is required for patients whose creatinine clearance is 50 mL/min or less. Renal dose adjustments are listed in Table 2. 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)]. Table 2: Dosage of ZERBAXA in Patients with Renal Impairment Estimated CrCl (mL/min)CrCl estimated using Cockcroft-Gault formula Recommended Dosage Regimen for ZERBAXA 1.5 g (ceftolozane 1 g and tazobactam 0.5 g)All doses of ZERBAXA are administered over 1 hour. 30 to 50 750 mg (500 mg and 250 mg) intravenously every 8 hours 15 to 29 375 mg (250 mg and 125 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 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) 2.3 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.
Use in special populations
8 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) 8.1 Pregnancy Pregnancy Category B. There are no adequate and well-controlled trials in pregnant women with either ceftolozane or tazobactam. Because animal reproduction studies are not always predictive of human response, ZERBAXA should be used during pregnancy only if the potential benefit outweighs the possible risk. Embryo-fetal development studies performed with intravenous ceftolozane in mice and rats with doses up to 2000 and 1000 mg/kg/day, respectively, revealed no evidence of harm to the fetus. The mean plasma exposure (AUC) values associated with these doses are approximately 7 (mice) and 4 (rats) times the mean daily human ceftolozane exposure in healthy adults at the clinical dose of 1 gram thrice-daily. It is not known if ceftolozane crosses the placenta in animals. 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 of greater than or equal to 300 mg/kg/day. The plasma exposure (AUC) associated with the NOAEL dose of 100 mg/kg/day in rats is approximately 0.4 fold of the mean daily human ceftolozane exposure in healthy adults at the clinical dose of 1 gram thrice-daily. In an embryo-fetal study in rats, tazobactam administered intravenously at doses up to 3000 mg/kg/day (approximately 19 times the recommended human dose based on body surface area comparison) produced maternal toxicity (decreased food consumption and body weight gain) but was not associated with fetal toxicity. 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 twice daily at the end of gestation and during lactation (Gestation Day 17 through Lactation Day 21) produced decreased maternal food consumption and body weight gain at the end of gestation and significantly more stillbirths with a tazobactam dose of 1280 mg/kg/day (approximately 8 times the recommended human dose based on body surface area comparison). No effects on the development, function, learning or fertility of 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. F2-generation fetuses were normal for all doses of tazobactam. The NOAEL for reduced F1 body weights was considered to be 40 mg/kg/day (approximately 0.3 times the recommended human dose based on body surface area comparison). 8.3 Nursing Mothers It is not known whether ceftolozane or tazobactam is excreted in human milk. Because many drugs are excreted in human milk, exercise caution when administering ZERBAXA to a nursing woman. 8.4 Pediatric Use Safety and effectiveness in pediatric patients have not been established. 8.5 Geriatric Use Of the 1015 patients treated with ZERBAXA in the Phase 3 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. ZERBAXA is substantially excreted by the kidney and the risk of adverse reactions to ZERBAXA may be greater in patients with impaired renal function. 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)]. 8.6 Patients with Renal Impairment Dosage adjustment is required in patients with moderate (CrCl 30 to 50 mL/min) or severe (CrCl 15 to 29 mL/min) renal impairment and in patients with ESRD on HD [see Dosage and Administration (2.2), Warnings and Precautions (5.1) and Clinical Pharmacology (12.3)].
Pregnancy and lactation
8.3 Nursing Mothers It is not known whether ceftolozane or tazobactam is excreted in human milk. Because many drugs are excreted in human milk, exercise caution when administering ZERBAXA to a nursing woman.

More information

Category Value
Authorisation number NDA206829
Orphan designation No
Product NDC 67919-030
Date Last Revised 26-10-2016
Type HUMAN PRESCRIPTION DRUG
Storage and handling 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).
Marketing authorisation holder Merck Sharp & Dohme Corp.