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ZERBAXA(ceftolozane/tazobactam)Injection本年度被批准的第四个的抗菌药：1g/0.5g per vial For Intravenous Infusion
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
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 Add the withdrawn volume to an infusion bag containing 100 mL of 0.9% Sodium Chloride for Injection, USP or 5% Dextrose Injection, USP.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
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. 3 DOSAGE FORMS AND STRENGTHS ZERBAXA (ceftolozane/tazobactam) for Injection is supplied as a white to yellow sterile powder for reconstitution in single-use vials; each vial contains 1 g ceftolozane (equivalent to 1.147 g of ceftolozane sulfate) and 0.5 g tazobactam (equivalent to 0.537 g of tazobactam sodium). 4 CONTRAINDICATIONS ZERBAXA is contraindicated in patients with known serious hypersensitivity to ceftolozane/tazobactam, piperacillin/tazobactam, or other members of the beta-lactam class. 5 WARNINGS AND PRECAUTIONS 5.1 Decreased Efficacy in Patients with Baseline Creatinine Clearance of 30 to ≤50 mL/minIn a subgroup analysis of a Phase 3 cIAI trial, clinical cure rates were lower in patients with baseline creatinine clearance (CrCl) of 30 to ≤50 mL/min compared to those with CrCl ≥50 mL/min (Table 4). 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)]. Table 4: Clinical Cure Rates in a Phase 3 Trial of cIAI by Baseline Renal Function (MITT Population)
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. 5.3 Clostridium difficile-associated Diarrhea Clostridium 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. 5.4 Development of Drug-Resistant Bacteria Prescribing ZERBAXA in the absence of a proven or strongly suspected bacterial infection is unlikely to provide benefit to the patient and risks the development of drug-resistant bacteria. 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)] 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
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: ileus, gastritis, abdominal distension, dyspepsia, flatulence, ileus paralytic General disorders and administration site conditions: infusion site reactions Infections and infestations: candidiasis, oropharyngeal, 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 7 DRUG INTERACTIONS No significant drug-drug interactions are anticipated between ZERBAXA and substrates, inhibitors, and inducers of cytochrome P450 enzymes (CYPs) [see Clinical Pharmacology (12.3)]. 8 USE IN SPECIFIC POPULATIONS 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 (age 65 years and older) in the ceftolozane/tazobactam 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)]. 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. 11 DESCRIPTION ZERBAXA (ceftolozane/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. Figure 1: Chemical structure of ceftolozane sulfate
Distribution The binding of ceftolozane and tazobactam to human plasma proteins is approximately 16% to 21% and 30%, respectively. The mean (CV%) steady-state volume of distribution of ZERBAXA in healthy adult males (n = 51) following a single 1 g/0.5 g (ceftolozane/tazobactam) intravenous dose of ZERBAXA was 13.5 L (21%) and 18.2 L (25%) for ceftolozane and tazobactam, respectively, similar to extracellular fluid volume. Metabolism Ceftolozane is eliminated in the urine as unchanged parent drug and thus does not appear to be metabolized to any appreciable extent. The beta-lactam ring of tazobactam is hydrolyzed to form the pharmacologically inactive tazobactam metabolite M1. Excretion Ceftolozane and the tazobactam metabolite M1 are eliminated by the kidneys. Following administration of a single ceftolozane/tazobactam 1 g/0.5 g intravenous dose to healthy male adults, greater than 95% of ceftolozane was excreted in the urine as unchanged parent drug. More than 80% of tazobactam was excreted as the parent compound with the remainder excreted as the tazobactam M1 metabolite. After a single dose of ZERBAXA, renal clearance of ceftolozane (3.41 – 6.69 L/h) was similar to plasma CL (4.10 to 6.73 L/h) and similar to the glomerular filtration rate for the unbound fraction, suggesting that ceftolozane is eliminated by the kidney via glomerular filtration. Specific Populations Renal Impairment ZERBAXA and the tazobactam metabolite M1 are eliminated by the kidneys. The ceftolozane dose normalized geometric mean AUC increased up to 1.26-fold, 2.5-fold, and 5-fold in subjects with mild, moderate, and severe renal impairment, respectively, compared to healthy subjects with normal renal function. The respective tazobactam dose normalized geometric mean AUC increased approximately up to 1.3-fold, 2-fold, and 4-fold. To maintain similar systemic exposures to those with normal renal function, dosage adjustment is required [see Dosage and Administration (2.2)]. In subjects with ESRD on HD, approximately two-thirds of the administered ZERBAXA dose is removed by HD. The recommended dose in subjects with ESRD on HD is a single loading dose of ZERBAXA (ceftolozane/tazobactam), 500 mg/250 mg, followed by a 100 mg/50 mg maintenance dose of ZERBAXA administered every 8 hours for the remainder of the treatment period. On HD days, administer the dose at the earliest possible time following completion of HD [see Dosage and Administration (2.2)]. Hepatic Impairment As ZERBAXA does not undergo hepatic metabolism, the systemic clearance of ZERBAXA is not expected to be affected by hepatic impairment. No dose adjustment is recommended for ZERBAXA in subjects with hepatic impairment. Geriatric Patients In a population pharmacokinetic analysis of ZERBAXA, no clinically relevant trend in exposure was observed with regard to age. No dose adjustment of ZERBAXA based on age is recommended. Pediatric Patients Safety and effectiveness in pediatric patients have not been established. Gender In a population pharmacokinetic analysis of ZERBAXA, no clinically relevant differences in AUC were observed for ceftolozane (116 males compared to 70 females) and tazobactam (80 males compared to 50 females). No dose adjustment is recommended based on gender. Race In a population pharmacokinetic analysis of ZERBAXA, no clinically relevant differences in ZERBAXA AUC were observed in Caucasians (n = 156) compared to all other races combined (n = 30). No dose adjustment is recommended based on race. Drug Interactions No drug-drug interaction was observed between ceftolozane and tazobactam in a clinical study in 16 healthy subjects. In vitro and in vivo data indicate that ZERBAXA is unlikely to cause clinically relevant drug-drug interactions related to CYPs and transporters at therapeutic concentrations. Drug Metabolizing Enzymes In vivo data indicated that ZERBAXA is not a substrate for CYPs. Thus clinically relevant drug-drug interactions involving inhibition or induction of CYPs by other drugs are unlikely to occur. In vitro studies demonstrated that ceftolozane, tazobactam and the M1 metabolite of tazobactam did not inhibit CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, or CYP3A4 and did not induce CYP1A2, CYP2B6, or CYP3A4 at therapeutic plasma concentrations. In vitro induction studies in primary human hepatocytes demonstrated that ceftolozane, tazobactam, and the tazobactam metabolite M1 decreased CYP1A2 and CYP2B6 enzyme activity and mRNA levels in primary human hepatocytes as well as CYP3A4 mRNA levels at supratherapeutic plasma concentrations. Tazobactam metabolite M1 also decreased CYP3A4 activity at supratherapeutic plasma concentrations. A clinical drug-drug interaction study was conducted and results indicated drug interactions involving CYP1A2 and CYP3A4 inhibition by ZERBAXA are not anticipated. Membrane Transporters Ceftolozane and tazobactam were not substrates for P-gp or BCRP, and tazobactam was not a substrate for OCT2, in vitro at therapeutic concentrations. Tazobactam is a known substrate for OAT1 and OAT3. Co-administration of tazobactam with the OAT1/OAT3 inhibitor probenecid has been shown to prolong the half-life of tazobactam by 71%. Co-administration of ZERBAXA with drugs that inhibit OAT1 and/or OAT3 may increase tazobactam plasma concentrations. In vitro data indicate that ceftolozane did not inhibit P-gp, BCRP, OATP1B1, OATP1B3, OCT1, OCT2, MRP, BSEP, OAT1, OAT3, MATE1, or MATE2-K in vitro at therapeutic plasma concentrations. In vitro data indicate that neither tazobactam nor the tazobactam metabolite M1 inhibit P-gp, BCRP, OATP1B1, OATP1B3, OCT1, OCT2, or BSEP transporters at therapeutic plasma concentrations. In vitro, tazobactam inhibited human OAT1 and OAT3 transporters with IC50 values of 118 and 147 mcg/mL, respectively. A clinical drug-drug interaction study was conducted and results indicated clinically relevant drug interactions involving OAT1/OAT3 inhibition by ZERBAXA are not anticipated. 12.4 Microbiology 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 carbapenamases [K. pneumoniae carbapenemase (KPC)], and metallo-beta lactamases. In ZERBAXA clinical trials, some isolates of E. coli and K. pneumoniae, that produced beta-lactamases, were susceptible to ZERBAXA (minimum inhibitory concentration ≤ 2 mcg/mL). 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 E. coli and K. pneumoniae that were not susceptible to ZERBAXA (minimum inhibitory concentration > 2 mcg/mL). These isolates produced one or more beta-lactamases of the following enzyme groups: CTX-M, OXA, TEM, or SHV. 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). Cross-Resistance 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). List of Microorganisms 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% of the following microorganisms exhibit an in vitro minimum inhibitory concentration (MIC) less than or equal to 2 mcg/mL for ceftolozane/tazobactam. The safety and effectiveness of ZERBAXA in treating clinical infections due to these bacteria have not been established in adequate and well-controlled clinical trials. Gram-negative bacteria Acinetobacter baumannii Burkholderia cepacia Citrobacter freundii Citrobacter koseri Enterobacter aerogenes Enterobacter cloacae Haemophilus influenzae Moraxella catarrhalis Morganella morganii Pantoea agglomerans Proteus vulgaris Providencia rettgeri Providencia stuartii Serratia liquefacians Serratia marcescens Gram-positive bacteria Streptococcus agalactiae Streptococcus intermedius Streptococcus pyogenes Streptococcus pneumoniae Anaerobic bacteria Fusobacterium spp. Prevotella spp. Susceptibility Test Methods When available, the clinical microbiology laboratory should provide the results of in vitro susceptibility test results for antimicrobial drugs used in local hospitals and practice areas to the physician as periodic reports that describe the susceptibility profile of nosocomial and community-acquired pathogens. These reports should aid the physician in selecting an antibacterial drug product for treatment. Dilution Techniques Quantitative methods are used to determine antimicrobial MICs. Ceftolozane/tazobactam susceptibility testing is performed with a fixed 4 mcg/mL concentration of tazobactam. These MICs provide estimates of the susceptibility of bacteria to antibacterial compounds. The MICs should be determined using a standardized test method (broth, and/or agar).1,4 The MIC values should be interpreted according to the criteria in Table 7. Diffusion Techniques Quantitative methods that require measurement of zone diameters can also provide reproducible estimates of the susceptibility of bacteria to antimicrobial compounds. The zone size provides an estimate of the susceptibility of bacteria to antimicrobial compounds. The zone size should be determined using a standardized test method.2,4 This procedure uses paper disks impregnated with 30 mcg of ceftolozane and 10 mcg of tazobactam to test the susceptibility of microorganisms to ceftolozane/tazobactam. The disk diffusion should be interpreted according to the criteria in Table 7. Anaerobic Techniques For anaerobic bacteria, the susceptibility to ceftolozane/tazobactam can be determined by standardized test method.3 The MIC values obtained should be interpreted according to criteria provided in Table 7. Table 7: Susceptibility Interpretive Criteria for Ceftolozane/Tazobactam
Quality Control Standardized susceptibility test procedures require the use of laboratory controls to monitor and ensure the accuracy and precision of supplies and reagents used in the assay, and the techniques of the individuals performing the test.1,2,3,4 Standard ceftolozane/tazobactam powder should provide the following range of MIC values provided in Table 8. For the diffusion technique using the 30 mcg ceftolozane/10 mcg tazobactam disk, the criteria provided in Table 8 should be achieved.4 Table 8: Acceptable Quality Control Ranges for Ceftolozane/Tazobactam
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Long-term carcinogenicity studies in animals have not been conducted with ZERBAXA, ceftolozane, or tazobactam. ZERBAXA was negative for genotoxicity in an in vitro mouse lymphoma assay and an in vivo rat bone-marrow micronucleus assay. In an in vitro chromosomal aberration assay in Chinese hamster ovary cells, ZERBAXA was positive for structural aberrations. Ceftolozane was negative for genotoxicity in an in vitro microbial mutagenicity (Ames) assay, an in vitro chromosomal aberration assay in Chinese hamster lung fibroblast cells, an in vivo mouse micronucleus assay, and an in vivo unscheduled DNA synthesis (UDS) assay. Ceftolozane was positive for mutagenicity in an in vitro mouse lymphoma assay. Tazobactam was negative for genotoxicity in an in vitro microbial mutagenicity (Ames) assay, an in vitro chromosomal aberration assay in Chinese hamster lung fibroblast cells, a mammalian point-mutation (Chinese hamster ovary cell HPRT) assay, an in vivo rat bone-marrow micronucleus assay, and an in vivo UDS assay. In another mammalian (mouse lymphoma cell) gene-mutation assay, tazobactam was positive for genotoxicity. Ceftolozane had no adverse effect on fertility in male or female rats at intravenous doses up to 1000 mg/kg/day. The mean plasma exposure (AUC) value at this dose is approximately 3 times the mean daily human ceftolozane exposure value in healthy adults at the clinical dose of 1 gram thrice daily. In a rat fertility study with intraperitoneal tazobactam twice-daily, male and female fertility parameters were not affected at doses less than or equal to 640 mg/kg/day (approximately 4 times the recommended clinical daily dose based on body surface comparison). 14 CLINICAL STUDIES 14.1 Complicated Intra-abdominal Infections A total of 979 adults hospitalized with cIAI were randomized and received study medications in a multinational, double-blind study comparing ZERBAXA (ceftolozane/tazobactam 1 g/0.5 g intravenously every 8 hours) plus metronidazole (500 mg intravenously every 8 hours) to meropenem (1 g intravenously every 8 hours) for 4 to 14 days of therapy. Complicated intra-abdominal infections included appendicitis, cholecystitis, diverticulitis, gastric/duodenal perforation, perforation of the intestine, and other causes of intra-abdominal abscesses and peritonitis. The majority of patients (75%) were from Eastern Europe; 6.3% were from the United States. The primary efficacy endpoint was clinical response, defined as complete resolution or significant improvement in signs and symptoms of the index infection at the test-of-cure (TOC) visit which occurred 24 to 32 days after the first dose of study drug. The primary efficacy analysis population was the microbiological intent-to-treat (MITT) population, which included all patients who had at least 1 baseline intra-abdominal pathogen regardless of the susceptibility to study drug. The key secondary efficacy endpoint was clinical response at the TOC visit in the microbiologically evaluable (ME) population, which included all protocol-adherent MITT patients. The MITT population consisted of 806 patients; the median age was 52 years and 57.8% were male. The most common diagnosis was appendiceal perforation or peri-appendiceal abscess, occurring in 47% of patients. Diffuse peritonitis at baseline was present in 34.2% of patients. ZERBAXA plus metronidazole was non-inferior to meropenem with regard to clinical cure rates at the TOC visit in the MITT population. Clinical cure rates at the TOC visit are displayed by patient population in Table 9. Clinical cure rates at the TOC visit by pathogen in the MITT population are presented in Table 10. Table 9: Clinical Cure Rates in a Phase 3 Trial of Complicated Intra-Abdominal Infections
14.2 Complicated Urinary Tract Infections, including Pyelonephritis A total of 1068 adults hospitalized with cUTI (including pyelonephritis) were randomized and received study medications in a multinational, double-blind study comparing ZERBAXA (ceftolozane/tazobactam 1 g/0.5 g intravenously every 8 hours) to levofloxacin (750 mg intravenously once daily) for 7 days of therapy. The primary efficacy endpoint was defined as complete resolution or marked improvement of the clinical symptoms and microbiological eradication (all uropathogens found at baseline at ≥105 were reduced to <104 CFU/mL) at the test-of-cure (TOC) visit 7 (± 2) days after the last dose of study drug. The primary efficacy analysis population was the microbiologically modified intent-to-treat (mMITT) population, which included all patients who received study medication and had at least 1 baseline uropathogen. The key secondary efficacy endpoint was the composite microbiological and clinical cure response at the TOC visit in the microbiologically evaluable (ME) population, which included protocol-adherent mMITT patients with a urine culture at the TOC visit. The mMITT population consisted of 800 patients with cUTI, including 656 (82%) with pyelonephritis. The median age was 50.5 years and 74% were female. Concomitant bacteremia was identified in 62 (7.8%) patients at baseline; 608 (76%) patients were enrolled in Eastern Europe and 14 (1.8%) patients were enrolled in the United States. ZERBAXA demonstrated efficacy with regard to the composite endpoint of microbiological and clinical cure at the TOC visit in both the mMITT and ME populations (Table 11). Composite microbiological and clinical cure rates at the TOC visit by pathogen in the mMITT population are presented in Table 12. In the mMITT population, the composite cure rate in ZERBAXA-treated patients with concurrent bacteremia at baseline was 23/29 (79.3%). Although a statistically significant difference was observed in the ZERBAXA arm compared to the levofloxacin arm with respect to the primary endpoint, it was likely attributable to the 212/800 (26.5%) patients with baseline organisms non-susceptible to levofloxacin. Among patients infected with a levofloxacin-susceptible organism at baseline, the response rates were similar (Table 11). Table 11: Composite Microbiological and Clinical Cure Rates in a Phase 3 Trial of Complicated Urinary Tract Infections
15 REFERENCES 1.Clinical and Laboratory Standards Institute (CLSI). Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria that Grow Aerobically; Approved Standard – Ninth Edition. CLSI document M07-A9, Clinical and Laboratory Standards Institute, 950 West Valley Road, Suite 2500, Wayne, Pennsylvania 19087, USA, 2012. 2.Clinical and Laboratory Standards Institute (CLSI). Performance Standards for Antimicrobial Disk Diffusion Susceptibility Tests; Approved Standard – Eleventh Edition. CLSI document M02-A11, Clinical and Laboratory Standards Institute, 950 West Valley Road, Suite 2500, Wayne, Pennsylvania 19087, USA 2012. 3.Clinical and Laboratory Standards Institute (CLSI). Methods for Antimicrobial Susceptibility Testing of Anaerobic Bacteria; Approved Standard – Eighth Edition. CLSI document M11-A8. Clinical and Laboratory Standards Institute, 950 West Valley Road, Suite 2500, Wayne, Pennsylvania 19087, USA, 2012. 4.Clinical and Laboratory Standards Institute (CLSI). Performance Standards for Antimicrobial Susceptibility Testing; Twenty-fourth Informational Supplement. CLSI document M100-S24. Clinical and Laboratory Standards Institute, 950 West Valley Road, Suite 2500, Wayne, Pennsylvania 19087, USA, 2014. 16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied ZERBAXA (ceftolozane/tazobactam) for Injection is supplied in single-use vials containing 1 g ceftolozane (equivalent to 1.147 g of ceftolozane sulfate) and 0.5 g tazobactam (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 HandlingZERBAXA 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).
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ZERBAXA(ceftolozane/tazobactam)Injection简介：
ZERBAXA(ceftolozane/tazobactam)Injection本年度被批准的第四个的抗菌药：1g/0.5g per vial For Intravenous Infusion ZERBAXA（ceftolozane/他唑巴坦）注射为静脉使用批准日期： 2014年12月19日；公司 ... 责任编辑：admin |
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