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זרבקסה 1 גרם/0.5 גרם ZERBAXA 1 G/0.5 G (CEFTOLOZANE AS SULFATE, TAZOBACTAM AS SODIUM)
תרופה במרשם
תרופה בסל
נרקוטיקה
ציטוטוקסיקה
צורת מתן:
תוך-ורידי : I.V
צורת מינון:
אבקה להכנת תמיסה מרוכזת לעירוי : POWDER FOR CONCENTRATE FOR SOLUTION FOR INFUSION
עלון לרופא
מינוניםPosology התוויות
Indications תופעות לוואי
Adverse reactions התוויות נגד
Contraindications אינטראקציות
Interactions מינון יתר
Overdose הריון/הנקה
Pregnancy & Lactation אוכלוסיות מיוחדות
Special populations תכונות פרמקולוגיות
Pharmacological properties מידע רוקחי
Pharmaceutical particulars אזהרת שימוש
Special Warning עלון לרופא
Physicians Leaflet
Pharmacological properties : תכונות פרמקולוגיות
Pharmacodynamic Properties
5.1 Pharmacodynamic properties Pharmacotherapeutic group: Antibacterials for systemic use, other cephalosporins and penems, ATC code: J01DI54. Mechanism of action Ceftolozane belongs to the cephalosporin class of antimicrobials. Ceftolozane exerts bactericidal activity through binding to important penicillin-binding proteins (PBPs), resulting in inhibition of bacterial cell-wall synthesis and subsequent cell death. Tazobactam is a beta-lactam structurally related to penicillins. It is an inhibitor of many Molecular Class A beta-lactamases, including CTX-M, SHV, and TEM enzymes. See below. Mechanisms of resistance Mechanisms of bacterial resistance to ceftolozane/tazobactam include: i. Production of beta-lactamases that can hydrolyse ceftolozane and which are not inhibited by tazobactam (see below) ii. Modification of PBPs Tazobactam does not inhibit all Class A enzymes. In addition tazobactam does not inhibit the following types of beta-lactamase: i. AmpC enzymes (produced by Enterobacteriaceae) ii. Serine-based carbapenemases (e.g., Klebsiella pneumoniae carbapenemases [KPCs]) iii. Metallo-beta-lactamases (e.g., New Delhi metallo-beta-lactamase [NDM]) iv. Ambler Class D beta-lactamases (OXA-carbapenemases) Pharmacokinetic/pharmacodynamic relationships For ceftolozane the time that the plasma concentration exceeds the minimum inhibitory concentration of ceftolozane for the infecting organism has been shown to be the best predictor of efficacy in animal models of infection. For tazobactam the PD index associated with efficacy was determined to be the percentage of the dose interval during which the plasma concentration of tazobactam exceeds a threshold value (%T>threshold). The threshold concentration required is dependent on the organism and the amount and type of β-lactamase produced. Susceptibility testing breakpoints Minimum inhibitory concentration breakpoints established by the European Committee on Antimicrobial Susceptibility Testing (EUCAST) are as follows: Minimum Inhibitory Concentrations (mg/L) Pathogen Susceptible Resistant Enterobacteriaceae ≤1 >1 P. aeruginosa ≤4 >4 Clinical efficacy against specific pathogens Efficacy has been demonstrated in clinical studies against the pathogens listed under each indication that were susceptible to Zerbaxa in vitro: 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 Complicated Urinary Tract Infections, including pyelonephritis Gram-negative bacteria Escherichia coli Klebsiella pneumoniae Proteus mirabilis Clinical efficacy has not been established against the following pathogens although in vitro studies suggest that they would be susceptible to Zerbaxa in the absence of acquired mechanisms of resistance: Citrobacter freundii Citrobacter koseri Enterobacter aerogenes Morganella morganii Proteus vulgaris Serratia liquefacians Serratia marcescens In vitro data indicate that the following species are not susceptible to ceftolozane/tazobactam: Staphylococcus aureus Enterococcus faecalis Enterococcus faecium
Pharmacokinetic Properties
5.2 Pharmacokinetic properties The Cmax and AUC of ceftolozane/tazobactam increase approximately in proportion to dose within ceftolozane single-dose range of 250 mg to 3 g and tazobactam single-dose range of 500 mg to 1.5 g. No appreciable accumulation of ceftolozane/tazobactam is observed following multiple 1-hour IV infusions of 1 g / 0.5 g ceftolozane/tazobactam administered every 8 hours for up to 10 days in healthy adults with normal renal function. The elimination half-life (t½) of ceftolozane is independent of dose. Distribution The binding of ceftolozane and tazobactam to human plasma proteins is low (approximately 16% to 21% and 30%, respectively). The mean (coefficient of variation CV%) steady-state volume of distribution of ceftolozane/tazobactam in healthy adult males (n = 51) following a single 1 g / 0.5 g IV dose was 13.5 L (21%) and 18.2 L (25%) for ceftolozane and tazobactam, respectively, similar to extracellular fluid volume. Biotransformation Ceftolozane is eliminated in the urine as unchanged parent substance and thus does not appear to be metabolised to any appreciable extent. The beta-lactam ring of tazobactam is hydrolyzed to form the pharmacologically inactive, tazobactam metabolite M1. Elimination Ceftolozane, tazobactam and the tazobactam metabolite M1 are eliminated by the kidneys. Following administration of a single 1 g / 0.5 g IV dose of ceftolozane/tazobactam to healthy male adults greater than 95% of ceftolozane was excreted in the urine as unchanged parent substance. More than 80% of tazobactam was excreted as the parent compound with the remaining amount excreted as the tazobactam M1 metabolite. After a single dose of ceftolozane/tazobactam, renal clearance of ceftolozane (3.41 - 6.69 L/h) was similar to plasma clearance (4.10 - 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. The mean terminal elimination half-life of ceftolozane and tazobactam in healthy adults with normal renal function is approximately 3 hours and 1 hour, respectively. Linearity/non-linearity The Cmax and AUC of ceftolozane/tazobactam increase in proportion to dose. Plasma levels of ceftolozane/tazobactam do not increase appreciably following multiple IV infusions of up to 2.0 g / 1.0 g administered every 8 hours for up to 10 days in healthy adults with normal renal function. The elimination half-life (t½) of ceftolozane is independent of dose. Special populations Renal impairment Ceftolozane/tazobactam 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 section 4.2). In subjects with end stage renal disease on haemodialysis, approximately two-thirds of the administered ceftolozane/tazobactam dose is removed by haemodialysis. The recommended dose in subjects with end stage renal disease on haemodialysis is a single loading dose of 500 mg / 250 mg ceftolozane/tazobactam followed by a 100 mg / 50 mg maintenance dose of ceftolozane/tazobactam administered every 8 hours for the remainder of the treatment period. With haemodialysis, the dose should be administered immediately following completion of dialysis (see section 4.2). Hepatic impairment As ceftolozane/tazobactam does not undergo hepatic metabolism, the systemic clearance of ceftolozane/tazobactam is not expected to be affected by hepatic impairment. No dose adjustment is recommended for ceftolozane/tazobactam in subjects with hepatic impairment (see section 4.2). Elderly In a population pharmacokinetic analysis of ceftolozane/tazobactam, no clinically relevant trend in exposure was observed with regard to age. No dose adjustment of ceftolozane/tazobactam based on age alone is recommended. Paediatric patients Safety and efficacy in paediatric patients have not been established. Gender In a population pharmacokinetic analysis of ceftolozane/tazobactam, 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. Ethnicity In a population pharmacokinetic analysis of ceftolozane/tazobactam, no clinically relevant differences in ceftolozane/tazobactam AUC were observed in Caucasians (n = 156) compared to all other ethnicities combined (n = 30). No dose adjustment is recommended based on race.
שימוש לפי פנקס קופ''ח כללית 1994
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160 01 34967 00
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