头孢托罗注射剂 ceftobiprole(商标名:Zeftera)获欧盟批准上市的第一个广谱抗生素,用于治疗包括糖尿病 脚感染在内的复杂性皮肤和皮肤软组织感染。
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via Yellow Card Scheme, web site: www.mhra.gov.uk/yellowcard. 4.9 Overdose Information on overdosage with Zevtera in humans is not available. The highest total daily dose administered in Phase 1 trials was 3 g (1 g every 8 hours). If overdosage should occur, it should be treated symptomatically. Ceftobiprole plasma concentrations can be reduced by haemodialysis. 5. Pharmacological properties 5.1 Pharmacodynamic properties Pharmacotherapeutic group: Other cephalosporins, ATC code: J01DI01 Mechanism of Action Ceftobiprole exerts bactericidal activity through binding to important penicillin-binding proteins (PBPs) in susceptible species. In Gram-positive bacteria, including methicillin-resistant Staphylococcus aureus (MRSA), Ceftobiprole binds to PBP2a. Ceftobiprole has demonstrated in vitro activity against strains with divergent mecA homolog (mecC or mecALGA251). Ceftobiprole also binds to PBP2b in Streptococcus pneumoniae (penicillin-intermediate), PBP2x in S. pneumoniae (penicillin resistant), and to PBP5 in Enterococcus faecalis. Mechanisms of Resistance Ceftobiprole is inactive against strains of Enterobacteriaceae that express Ambler class A β-lactamases, especially TEM, SHV and CTX-M type extended-spectrum β-lactamases (ESBL) and the KPC-type carbapenemases, Ambler class B β-lactamases and Ambler class D β-lactamases, especially ESBL variants and carbapenemases (OXA-48). Ceftobiprole is also inactive against strains that have high levels of expression of Ambler class C β-lactamases. Ceftobiprole is inactive against strains of P. aeruginosa that express enzymes belonging to Ambler class A (e.g., PSE-1), Ambler class B (e.g., IMP-1, VIM-1, VIM-2) and Ambler class D (e.g., OXA-10). It is also inactive against isolates that have acquired mutations in regulatory genes leading to de-repressed levels of expression of the chromosomal Ambler class C β-lactamase, or over-expression of the Mex XY efflux pump. Ceftobiprole is inactive against strains of Acinetobacter spp. that express enzymes belonging to Ambler class A (e.g., VEB-1), Ambler class B (e.g., IMP-1, IMP-4) Ambler class D (e.g., OXA-25, OXA-26), or that have de-repressed levels of expression of the chromosomal Ambler class C β-lactamase. Susceptibility testing breakpoints Minimum inhibitory concentration (MIC) breakpoints established by the European Committee on Antimicrobial Susceptibility Testing (EUCAST) are as follows:
As with other beta-lactam antimicrobial agents, the per cent time above the minimum inhibitory concentration (MIC) of the infecting organism over the dosing interval (%T > MIC) has been shown to be the parameter that best correlates with the efficacy of ceftobiprole. Clinical efficacy against specific pathogens Efficacy has been demonstrated in clinical studies against the following pathogens in patients with HAP (not including VAP) and CAP that were susceptible to ceftobiprole in vitro: Staphylococcus aureus (including MRSA) Streptococcus pneumoniae (including MDRSP) Escherichia coli Klebsiella pneumoniae Antibacterial activity against other relevant pathogens Clinical efficacy has not been established against the following pathogens, although in vitro studies suggest that they would often be susceptible to ceftobiprole in the absence of an acquired mechanism of resistance: Acinetobacter spp. Citrobacter spp. Enterobacter spp. Haemophilus influenzae Klebsiella oxytoca Moraxella catarrhalis Morganella morganii Proteus mirabilis Providencia spp. Pseudomonas spp. Serratia spp. In vitro data indicate that the following species are not susceptible to ceftobiprole: Chlamydophila (Chlamydia) pneumoniae Burkholderia cepacia complex Mycoplasma pneumoniae Mycobacteria Norcardia spp. Stenotrophomonas maltophilia Data from clinical studies Nosocomial pneumonia Zevtera demonstrated efficacy in a well-controlled randomised Phase 3 study in patients with HAP. Non- inferiority between Zevtera and the comparator group could not be demonstrated in patients with VAP (i.e., patients who develop pneumonia > 48 hours after onset of ventilation). In VAP, clinical cure rates in Zevtera treated patients were 37.7% in the Zevtera group (20 out of 53 patients) compared to 55.9% in the ceftazidime plus linezolid group (33 out of 59 patients), see also sections 4.1 and 4.4. Paediatric population The European Medicines Agency has deferred the obligation to submit the results of studies with Zevtera in one or more subsets of the paediatric population in the treatment of pneumonia (see section 4.2 for information on paediatric use). 5.2 Pharmacokinetic properties Plasma concentrations The mean pharmacokinetic parameters of Zevtera in adults for a single 500 mg dose administered as a 2-hour infusion and multiple 500 mg doses administered every 8 hours as 2-hour infusions are summarised in Table 1. Pharmacokinetic characteristics were similar with single and multiple dose administration. Mean (standard deviation) pharmacokinetic parameters of Zevtera in adults
Ceftobiprole binds minimally (16%) to plasma proteins and binding is independent of concentration. Ceftobiprole steady-state volume of distribution (18 litres) approximates extracellular fluid volume in humans. Metabolism The active substance of Zevtera is ceftobiprole medocaril sodium, which is the pro-drug of the active moiety ceftobiprole. Conversion from the prodrug ceftobiprole medocaril sodium, to the active moiety ceftobiprole, occurs rapidly and is mediated by non-specific plasma esterases. Prodrug concentrations are negligible and are measurable in plasma and urine only during infusion. The metabolite resulting from the cleavage of the prodrug is diacetyl which is an endogenous human compound. Ceftobiprole undergoes minimal metabolism to the open-ring metabolite, which is microbiologically inactive. Systemic exposure of the open-ring metabolite was considerably lower than for ceftobiprole, accounting for approximately 4% of the parent exposure in subject with a normal renal function. In vitro studies demonstrated that ceftobiprole is an inhibitor of the hepatocyte uptake transporters OATP1B1 and OATP1B3, but is not an inhibitor of PgP, BCRP, MDR1, MRP2, OAT1, OAT3, OCT1 or OCT2. Ceftobiprole is potentially a weak substrate of the renal tubule cells uptake transporters OAT1 and OCT2. Ceftobiprole protein binding is low (16%) and is not a PgP inhibitor or substrate. The potential for other drugs to interact with ceftobiprole is minimal, since only a small fraction of ceftobiprole is metabolised. Therefore, no relevant drug-drug interactions are anticipated (see section 4.5). Since ceftobiprole does not undergo tubular secretion and only a fraction is reabsorbed, renal drug-drug interactions are not expected. Elimination Ceftobiprole is eliminated primarily unchanged by renal excretion, with a half-life of approximately 3 hours. The predominant mechanism responsible for elimination is glomerular filtration, with some active reabsorption. Following single dose administration in human, approximately 89% of the administered dose is recovered in the urine as active ceftobiprole (83%), the open-ring metabolite (5%) and ceftobiprole medocaril (<1%). Linearity/non-linearity Ceftobiprole exhibits linear and time-independent pharmacokinetics. The Cmax and AUC of Zevtera increase in proportion to dose over a range of 125 mg to 1 g. Steady-state active substance concentrations are attained on the first day of dosing; no appreciable accumulation occurs with every-8-hour dosing in subjects with normal renal function. Pharmacokinetic/Pharmacodynamic Relationship Similar to other beta-lactam antimicrobial agents, the time that the plasma concentration of Zevtera exceeds the minimum inhibitory concentration of the infecting organism (%T>MIC) has been shown to best correlate with efficacy in clinical and pre-clinical pharmacokinetic/pharmacodynamic studies. Special Populations Renal impairment The estimation of creatinine clearance should be based on the Cockcroft-Gault formula using actual body weight. During treatment with ceftobiprole it is recommended that an enzymatic method of measuring serum creatinine be used (see section 4.4). The pharmacokinetics of ceftobiprole are similar in healthy volunteers and subjects with mild renal impairment (CLCR 50 to 80 mL/min). Ceftobiprole AUC was 2.5- and 3.3-fold higher in subjects with moderate (CLCR 30 to < 50 mL/min) and severe (CLCR < 30 mL/min) renal impairment, respectively, than in healthy subjects with normal renal function. Dosage adjustment is recommended in patients with moderate to severe renal impairment (see section 4.2). End-stage renal disease requiring dialysis AUCs of ceftobiprole and of the microbiologically inactive ring-opened metabolite are substantially increased in patients with end stage renal disease who require haemodialysis compared with healthy subjects. In a study where six subjects with end stage renal disease on haemodialysis received a single dose of 250 mg Zevtera by intravenous infusion, ceftobiprole was demonstrated haemodialysable with an extraction ratio of 0.7 (see section 4.2). Patients with creatinine clearance > 150mL/min Ceftobiprole systemic clearance (CLSS) was 40% greater in subjects with a CLCR > 150 mL/min compared to subjects with a normal renal function (CLCR = 80-150 mL/min). Volume of distribution was 30% larger. In this population, based on pharmacokinetic/pharmacodynamic considerations, prolongation of duration of infusion is recommended (see section 4.2). Hepatic impairment The pharmacokinetics of ceftobiprole in patients with hepatic impairment have not been established. As ceftobiprole undergoes minimal hepatic metabolism and is predominantly excreted unchanged in the urine, the clearance of Zevtera is not expected to be affected by hepatic impairment (see section 4.2). Elderly Population pharmacokinetic data showed that age as an independent parameter has no effect on the pharmacokinetics of ceftobiprole. Dosage adjustment is not considered necessary in elderly patients with normal renal function (see section 4.2). Gender Systemic exposure to ceftobiprole was higher in females than males (21% for Cmax and 15% for AUC), however the %T>MIC was similar in both males and females. Therefore, dosage adjustments based on gender are not considered necessary. Race Population pharmacokinetic analyses (including Caucasians, Black and Other groups) and a dedicated pharmacokinetic study in healthy Japanese subjects showed no effect of race on the pharmacokinetics of ceftobiprole. Therefore, dosage adjustments based on race are not considered necessary. Body weight A study was performed in morbidly obese subjects. No dose adjustments based on body weight are required. 5.3 Preclinical safety data Reversible renal toxicity in the distal tubules due to precipitation of drug-like material was observed at high doses only in small animals such as rats and marmosets and after bolus administration. Absence of kidney toxicity was observed in animals at urinary concentrations up to 12 times higher than those observed in humans at the therapeutic dose. Convulsions were observed after both single and multiple doses at exposures of six times the human exposure and higher, based on Cmax. Infusion-site irritation leading to thrombus formation was observed in small animals (rats and marmosets) but not in dogs. In a pre- and post-natal development study in rats, litter size and survival up to 4 days postpartum were decreased at maternally toxic doses. The relevance of all these findings for humans is unknown. 6. Pharmaceutical particulars 6.1 List of excipients Citric acid monohydrate Sodium hydroxide 6.2 Incompatibilities This medicinal product must not be mixed with other medicinal products except those mentioned in section 6.6. This medicinal product must not be mixed or administered simultaneously with calcium-containing solutions (except Lactated Ringer's solution for injection). See sections 4.2, 4.4, 6.6. This medicinal product should not be simultaneously administered via a Y site with: Acyclovir sodium, Amikacin sulphate, Amiodarone hydrochloride, Amphotericin B (colloidal), Calcium gluconate, Caspofungin acetate, Ciprofloxacin, Cisatracurium besylate, Diazepam, Diltiazem hydrochloride, Diphenhydramine hydrochloride, Dobutamine hydrochloride, Dopamine hydrochloride, Esomeprazole sodium, Famotidine, Filgrastim, Gentamicin sulphate, Haloperidol lactate, Hydromorphone hydrochloride, Hydroxyzine hydrochloride, Insulin human regular, Insulin lispro, Labetalol hydrochloride, Levofloxacin, Lidocaine hydrochloride, Magnesium sulphate, Meperidine hydrochloride, Metoclopramide hydrochloride, Midazolam hydrochloride, Milrinone lactate, Morphine sulphate, Moxifloxacin hydrochloride, Ondansetron hydrochloride, Pantoprazole sodium, Potassium phosphates, Promethazine hydrochloride, Remifentanil hydrochloride, Sodium phosphates, Tobramycin sulphate. 6.3 Shelf life Powder vial 3 years After reconstitution Chemical, and physical in-use stability of the reconstituted solution (50 mg/mL) has been demonstrated for 1 hour at 25°C and up to 24 hours at 2°C–8°C. After dilution Chemical, and physical in-use stability data support the total times for reconstitution and infusion (2.67 mg/mL) described in the table below: Total time by which reconstitution and infusion (including a 2-hour period of infusion, see Section 4.2) must be completed
The reconstituted and infusion solutions should not be frozen or exposed to direct sunlight. If the infusion solution is stored in the refrigerator, it should be equilibrated to room temperature prior to administration. The infusion solution does not need to be protected from light during administration. The infusion solution should be prepared and used as defined in section 6.6. 6.4 Special precautions for storage Store in a refrigerator (2°C–8°C). Keep the vial in the outer carton in order to protect from light. For storage conditions of the reconstituted and/or diluted medicinal product, see section 6.3. 6.5 Nature and contents of container 20 mL clear type I glass vials fitted with a grey bromobutyl elastomeric closure and an aluminium seal with a blue plastic flip-off cap. Pack size: 10 vials. 6.6 Special precautions for disposal and other handling Each vial is for single use only. Zevtera must be reconstituted and then further diluted prior to infusion. Step 1. Reconstitution 10 mL of sterile water for injections or dextrose 50 mg/mL (5%) solution for injection should be added to the vial and the vial should be shaken vigorously until complete dissolution, which in some cases may take up to 10 minutes. The volume of the resulting concentrate is approximately 10.6 mL. Any foam should be allowed to dissipate and the reconstituted solution should be inspected visually to ensure the product is in solution and particulate matter is absent. The reconstituted concentrate contains 50 mg/mL of ceftobiprole and must be further diluted prior to administration. It is recommended that the reconstituted solution be further diluted immediately. However, if this is not possible the reconstituted solution can be stored at room temperature for up to one hour, or in a refrigerator for up to 24 hours. Step 2. Dilution Preparation of 500 mg dose of Zevtera solution for infusion 10 mL of the reconstituted solution should be withdrawn from the vial and injected into a suitable container (e.g. PVC or PE infusion bags, glass bottles) containing 250 mL of sodium chloride 9 mg/mL (0.9%) solution for injection, dextrose 50 mg/mL (5%) solution for injection, or Lactated Ringer's solution for injection. The infusion solution should be gently inverted 5-10 times to form a homogenous solution. Vigorous agitation should be avoided to prevent foaming. The entire contents of the infusion bag should be infused to administer a 500 mg dose of Zevtera. Preparation of 250 mg dose of Zevtera solution for infusion for patients with severe renal impairment 5 mL of the reconstituted solution should be withdrawn from the vial and injected into a suitable container (e.g. PVC or PE infusion bags, glass bottles) containing 125 mL of sodium chloride 9 mg/mL (0.9%) solution for injection, dextrose 50 mg/mL (5%) solution for injection, or Lactated Ringer's solution for injection. The infusion solution should be gently inverted 5-10 times to form a homogenous solution. Vigorous agitation should be avoided to prevent foaming. The entire contents of the infusion bag should be infused to administer a 250 mg dose of Zevtera. The solution for infusion should be clear to slightly opalescent and yellowish in colour. The solution for infusion should be inspected visually for particulate matter prior to administration, and discarded if particulate matter is visible. Detailed information on the time by which reconstitution, dilution and infusion must complete is provided in section 6.3. Disposal Any unused medicinal product or waste material should be disposed of in accordance with local requirements. 7. Marketing authorisation holder Basilea Medical Ltd. (c/o Cox Costello & Horne Limited) Langwood House 63-81 High Street Rickmansworth Hertfordshire WD3 1EQ United Kingdom Phone number: +44 (0)203 281 7645 Email: medical.information@basilea.com 8. Marketing authorisation number(s) PL 32205/0003 9. Date of first authorisation/renewal of the authorisation 20/11/2013 10. Date of revision of the text 26/11/2014 |
Zevtera 500mg powder infusion(ceftobiprole 头孢托罗冻干粉注射剂)简介:
Zeftera(头孢medocaril注射)用于成人复杂性皮肤和软组织感染新的治疗选择新型抗广谱抗生素,ZEVTERA是第一个批准的广谱抗MRSA头孢类抗生素属于该类。头孢作为单一静脉内剂已经证明广谱活性CONTRE的宽 ... 责任编辑:admin
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